A Multicenter, Open-Label Extension Study to Evaluate the Long-Term Safety and Tolerability of Faricimab in Patients With Neovascular Age-Related Macular Degeneration (AVONELLE-X)
Phase: PHASE3
Conditions: Neovascular Age-related Macular Degeneration
Sponsor: Hoffmann-La Roche

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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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 GR42691, Version 3 
PROTOCOL 
TITLE: 
A MULTICENTER, OPEN-LABEL EXTENSION 
STUDY TO EVALUATE THE LONG-TERM SAFETY 
AND TOLERABILITY OF FARICIMAB IN PATIENTS 
WITH NEOVASCULAR AGE-RELATED MACULAR 
DEGENERATION (AVONELLE-X) 
PROTOCOL NUMBER: GR42691 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2020-004523-16 
IND NUMBER: 
119225 
NCT NUMBER: 
NCT04777201 
TEST PRODUCT: 
Faricimab (RO6867461) 
MEDICAL MONITOR: 
, M.D., Ph.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
APPROVAL: 
See electronic signature and date stamp on the final 
page of this document. 

 
Faricimab—F. Hoffmann-La Roche Ltd 
2/Protocol GR42691, Version 3 
PROTOCOL HISTORY 
Protocol 
Version 
Date Final 
3 
See electronic date stamp on the 
final page of this document. 
2 
4 February 2021 
1 
20 October 2020 
 

 
Faricimab—F. Hoffmann-La Roche Ltd 
3/Protocol GR42691, Version 3 
PROTOCOL AMENDMENT, VERSION 3: 
RATIONALE 
Protocol GR42691 has been amended to add the option of a dosing interval of every 
4 weeks (Q4W) to the personalized treatment interval (PTI).  Changes to the protocol, 
along with a rationale for each change, are summarized below: 
 
The Medical Monitors have been updated (protocol cover page, Protocol 
Amendment Acceptance Form, and Section 5.4.1). 
 
The study status of the Phase III studies in diabetic macular edema (DME), 
neovascular age-related macular degeneration (nAMD), and retinal vein occlusion 
have been updated (Sections 1.2 and 1.2.1).  
 
The rationale for faricimab schedule has been revised to add the rationale for Q4W 
dosing interval and to condense the rationale for dosing intervals of every 8 weeks 
(Q8W), every 12 weeks (Q12W), and every 16 weeks (Q16W) (Sections 1.3 and 
3.3.1.2). 
 
The analysis populations have been updated to replace the modified intent-to-treat 
population with the efficacy-evaluable population, which comprises all eligible 
patients enrolled into this study (Sections 2.1, 2.2, 6.2.1, 6.2.2, 6.3, 6.4, and 6.6). 
 
The exploratory efficacy endpoint "The proportion of patients on a Q8W, Q12W, and 
Q16W treatment interval during the study" has been simplified to "The proportion of 
patients on each treatment interval during the study" (Sections 2.2 and 6.6.1).  
 
The PTI algorithm has been amended to include Q4W dosing as an option in 
recognition that some patients may require more frequent dosing than Q8W 
(Sections 3.1.2.1, 3.1.2.2, 3.1.3.2, and 3.3.1.2).   
 
Instructions have been added that it is not possible for a site to manually modify the 
PTI algorithm to adjust the faricimab treatment interval (new Section 3.1.3.6 has 
been added). 
 
Wording has been added to clarify that after the site has submitted the patient's 
optical coherence tomography images to the reading center and added the central 
subfield thickness value to the interactive voice or web-based response system 
(IxRS), IxRS will issue a confirmation email to the site if the patient has completed 
their final treatment visit.  Patients who completed their final treatment visit are 
expected to attend a safety follow-up visit 2834 days after the date of the Year 2 
visit or the date of their final study treatment, whichever is later (Section 3.2). 
 
The time frame for the exclusion of patients who are pregnant or breastfeeding, or 
intending to become pregnant has been extended from within 28 days to within 
3 months after the final dose of faricimab (Section 4.1.2).  
 
To align with the responsibility of the Principal Investigator (PI) for the overall safety 
of the patients, it has been clarified that the treatment administrator must be an 
ophthalmologist, and, ideally, a retina specialist, and it is the PI’s responsibility to 
ensure that the treatment administrator is suitably qualified (Section 4.2.1.2).  

 
Faricimab—F. Hoffmann-La Roche Ltd 
4/Protocol GR42691, Version 3 
 
Language has been added to indicate that sites can confirm that appropriate 
temperature conditions have been maintained during investigational medicinal 
product transit either by time monitoring (shipment arrival date and time) or 
temperature monitoring (Section 4.3.3) 
 
As faricimab is made commercially available globally, the requirements for ongoing 
reimbursements of other anti-VEGF therapies licensed for ocular use in the fellow 
eye has been revised and must be approved by the Sponsor unless the patient is 
enrolled in the corneal endothelial cells substudy.  Reimbursements will cease if the 
patient is discontinued from the faricimab study treatment or once the patient has 
completed the trial (Section 4.4.1.1) 
 
Chronic usage of topical ophthalmic corticosteroids has been defined as continuous 
usage for 100 days or more (Section 4.4.2). 
 
Therapies that claim to have an effect on macular pathology (e.g., kallidinogenase) 
have been added as a prohibited therapy (Section 4.4.2). 
 
The types of ocular assessments have been clarified, with ultra-wide photography of 
color fundus photograph (CFP) and fundus fluorescein angiography imaging 
permitted only when no other alternative is available and after discussion with the 
central reading center (Section 4.5.4). 
 
The guidance for collecting missed mandatory plasma pharmacokinetic or anti-drug 
antibody samples has been revised and may be obtained at the next visit the patient 
attends, with the exception of Week 8 because the next scheduled visit (Week 12) is 
also a sampling visit (Section 4.5.6 and Appendix 1). 
 
The requirement for optional collection of aqueous humor and associated plasma 
samples that are missed per the specified timepoints have been revised; missed 
samples are not required to be made up at a later visit.  However, unscheduled 
sampling may be performed at the discretion of the investigator after obtaining the 
patient's agreement (Section 4.5.6.1 and Appendix 1). 
 
The email address for withdrawal from the Research Biosample Repository after site 
closure has been corrected (Section 4.5.8.6) 
 
The early termination visit has been updated to early treatment/study termination for 
clarity.  The window for this visit has been updated to a minimum of 28 days after 
receiving the final dose of study drug (Sections 4.6.1, 4.6.2, and Appendix 1). 
 
The description of the safety plan has been updated to reflect that faricimab has 
been approved in various countries for the treatment of nAMD and DME 
(Section 5.1). 
 
The risks associated with faricimab has been updated to align with the Faricimab 
Investigator’s Brochure version 11 (Section 5.1.1). 
 
The responsibilities of the investigator and the role of the Medical Monitor in 
restarting study treatment after a dose interruption have been clarified 
(Section 5.1.2.1 [Table 2]).  

 
Faricimab—F. Hoffmann-La Roche Ltd 
5/Protocol GR42691, Version 3 
 
The timing of reporting adverse events, serious adverse events, and adverse events 
of special interest has been revised to begin after enrollment in this study, not after 
initiation of study drug (Sections 5.3.1 and 5.4.2.1) 
 
The reporting of adverse events associated with a special situation that also qualify 
as adverse events of special interest has been revised and should be reported to 
the Sponsor within 24 hours (Section 5.3.5.11) 
 
Language has been added to indicate that the Informed Consent Form will instruct 
female patients to inform the investigator if they become pregnant (Section 5.4.3.1). 
 
The definition for baseline has been revised to Day 1 of this study for patients 
randomized to faricimab in the parent study and as the first day of faricimab 
treatment for patients randomized to aflibercept in the parent study (Sections 6.2.1, 
6.2.3, and 6.6.1). 
 
The definition for safety-evaluable population has been revised to comprise all 
patients enrolled in this study regardless of whether they received faricimab 
treatment during this study (Section 6.2.3). 
 
The statistical analysis of all efficacy endpoints has been revised and will be 
assessed over time (Section 6.6.1). 
 
The definitions for the Year 1 and Year 2 visits (annual visits) have been removed 
from Section 6.6.1 as the definitions are duplicative with those given in Appendix 1.  
Instructions have been added that in the case of multiple visits within the annual visit 
windows, if the earliest scheduled visit is missed, then the next visit will be 
considered as the annual visit (Appendix 1). 
 
CFP has been added as an assessment that may be performed during an 
unscheduled safety assessment visit as this imaging modality may be helpful in 
evaluating adverse events (Appendix 2). 
 
The purpose of unscheduled safety visits has been revised, specifying that they 
should only be used for the assessment of adverse events and are not intended for 
standard-of-care procedures (Appendix 2). 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 

 
Faricimab—F. Hoffmann-La Roche Ltd 
6/Protocol GR42691, Version 3 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 13 
PROTOCOL SYNOPSIS .................................................................................... 14 
1. 
BACKGROUND ............................................................................ 21 
1.1 
Background on Neovascular Age-Related 
Macular Degeneration ............................................................. 21 
1.2 
Background on Faricimab ........................................................ 21 
1.2.1 
Phase III Faricimab Studies:  GR40306 (TENAYA) and 
GR40844 (LUCERNE) ............................................................. 23 
1.3 
Study Rationale and BenefitRisk Assessment ....................... 24 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 25 
2.1 
Primary Objective .................................................................... 25 
2.2 
Exploratory Efficacy Objective ................................................. 25 
2.3 
Pharmacokinetic Objective ...................................................... 26 
2.4 
Immunogenicity Objective ........................................................ 26 
2.5 
Exploratory Biomarker Objectives ............................................ 26 
2.6 
Exploratory Substudy ............................................................... 27 
3. 
STUDY DESIGN ........................................................................... 27 
3.1 
Description of the Study ........................................................... 27 
3.1.1 
Overview of Study Design........................................................ 27 
3.1.1.1 
LTE Visit Schedule during the Masked Period ......................... 30 
3.1.1.2 
LTE Visit Schedule following Masked Period ........................... 30 
3.1.2 
Faricimab Dosing Schedule ..................................................... 30 
3.1.2.1 
Faricimab Personalized Treatment Interval ............................. 30 
3.1.2.2 
Faricimab Dosing Intervals:  Phase III to LTE .......................... 31 
3.1.3 
Additional Considerations for PTI IxRS Study DrugDosing 
Interval Decision ...................................................................... 32 
3.1.3.1 
Missed Faricimab Dosing Visits ............................................... 32 
3.1.3.2 
Treatment Interruption ............................................................. 32 
3.1.3.3 
Missing CST Value at LTE Study Visit ..................................... 33 
3.1.3.4 
Missing BCVA Value at LTE Study Visit .................................. 33 

 
Faricimab—F. Hoffmann-La Roche Ltd 
7/Protocol GR42691, Version 3 
3.1.3.5 
Timely Reporting of BCVA and OCT Data to electronic 
Case Report Form, Central Reading Center, and IxRS ........... 33 
3.1.3.6 
Modifications to the PTI Algorithm ........................................ 33 
3.2 
End of Study and Length of Study ........................................... 34 
3.3 
Rationale for Study Design ...................................................... 34 
3.3.1 
Rationale for Faricimab Dose and Schedule............................ 34 
3.3.1.1 
Dose ........................................................................................ 34 
3.3.1.2 
Schedule .................................................................................. 35 
3.3.2 
Rationale for Patient Population .............................................. 36 
3.3.3 
Rationale for Optional Biomarker Assessments ....................... 36 
4. 
MATERIALS AND METHODS ...................................................... 37 
4.1 
Patients .................................................................................... 37 
4.1.1 
Inclusion Criteria ...................................................................... 37 
4.1.2 
Exclusion Criteria ..................................................................... 38 
4.2 
Method of Treatment Assignment and Masking....................... 38 
4.2.1 
Masking Requirements during the Masked Period of LTE 
Study ....................................................................................... 39 
4.2.1.1 
Masked Roles during the Masked Period of the LTE Study ..... 39 
4.2.1.2 
Unmasked Roles ..................................................................... 40 
4.2.1.3 
Delegation Log ......................................................................... 41 
4.2.1.4 
Role Switching ......................................................................... 41 
4.2.1.5 
Study Backup Staff .................................................................. 41 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 41 
4.3.1 
Study Treatment Formulation and Packaging .......................... 41 
4.3.1.1 
Faricimab ................................................................................. 41 
4.3.1.2 
Sham ....................................................................................... 41 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 41 
4.3.2.1 
Faricimab Administration ......................................................... 42 
4.3.2.2 
Sham Administration ................................................................ 42 
4.3.3 
Investigational Medicinal Product Handling and 
Accountability ........................................................................... 43 
4.3.4 
Continued Access to Faricimab ............................................... 43 
4.4 
Concomitant Therapy .............................................................. 44 

 
Faricimab—F. Hoffmann-La Roche Ltd 
8/Protocol GR42691, Version 3 
4.4.1 
Permitted Therapy ................................................................... 44 
4.4.1.1 
Fellow (Non-Study) Eye Treatment with Anti-
VEGF Therapy ......................................................................... 45 
4.4.2 
Prohibited Therapy .................................................................. 46 
4.5 
Study Assessments ................................................................. 46 
4.5.1 
Informed Consent Forms ......................................................... 46 
4.5.2 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ......................................... 46 
4.5.3 
Vital Signs ................................................................................ 47 
4.5.4 
Ocular Assessments ................................................................ 47 
4.5.5 
Concurrent Ocular Procedures ................................................ 48 
4.5.6 
Laboratory and Other Biological Samples ............................... 48 
4.5.6.1 
Optional Aqueous Humor and Associated Optional Plasma 
Samples ................................................................................... 49 
4.5.6.2 
Optional Unscheduled Vitreous Humor and Associated 
Optional Plasma Samples ....................................................... 51 
4.5.7 
Patient-Reported Outcomes .................................................... 52 
4.5.7.1 
Data Collection Methods for Patient-Reported Outcome 
Assessments ........................................................................... 52 
4.5.7.2 
Description of Patient-Reported Outcomes Instrument ............ 52 
4.5.8 
Optional Samples for Research Biosample Repository ........... 53 
4.5.8.1 
Overview of the Research Biosample Repository .................... 53 
4.5.8.2 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................... 53 
4.5.8.3 
Sample Collection .................................................................... 54 
4.5.8.4 
Confidentiality .......................................................................... 54 
4.5.8.5 
Consent to Participate in the Research Biosample 
Repository................................................................................ 55 
4.5.8.6 
Withdrawal from the Research Biosample Repository ............. 55 
4.5.8.7 
Monitoring and Oversight ......................................................... 56 
4.6 
Treatment, Patient, Study, and Site Discontinuation ................ 56 
4.6.1 
Study Treatment Discontinuation ............................................. 56 
4.6.2 
Patient Discontinuation from the Study .................................... 56 
4.6.3 
Study Discontinuation .............................................................. 57 
4.6.4 
Site Discontinuation ................................................................. 57 

 
Faricimab—F. Hoffmann-La Roche Ltd 
9/Protocol GR42691, Version 3 
5. 
ASSESSMENT OF SAFETY ......................................................... 57 
5.1 
Safety Plan .............................................................................. 57 
5.1.1 
Risks Associated with Faricimab ............................................. 58 
5.1.2 
Management of Patients Who Experience Adverse Events ..... 58 
5.1.2.1 
Treatment Interruption ............................................................. 58 
5.2 
Safety Parameters and Definitions .......................................... 59 
5.2.1 
Adverse Events ........................................................................ 59 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................. 60 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 61 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 61 
5.3.1 
Adverse Event Reporting Period .............................................. 62 
5.3.2 
Eliciting Adverse Event Information ......................................... 62 
5.3.3 
Assessment of Severity of Adverse Events ............................. 62 
5.3.4 
Assessment of Causality of Adverse Events............................ 63 
5.3.5 
Procedures for Recording Adverse Events .............................. 63 
5.3.5.1 
Diagnosis versus Signs and Symptoms ................................... 64 
5.3.5.2 
Adverse Events That Are Secondary to Other Events ............. 64 
5.3.5.3 
Persistent or Recurrent Adverse Events .................................. 65 
5.3.5.4 
Abnormal Laboratory Values ................................................... 65 
5.3.5.5 
Abnormal Vital Sign Values ..................................................... 66 
5.3.5.6 
Abnormal Liver Function Tests ................................................ 66 
5.3.5.7 
Deaths ..................................................................................... 67 
5.3.5.8 
Preexisting Medical Conditions ................................................ 67 
5.3.5.9 
Lack of Efficacy or Worsening of nAMD in the Study Eye ....... 67 
5.3.5.10 
Hospitalization or Prolonged Hospitalization ............................ 68 
5.3.5.11 
Cases of Accidental Overdose or Medication Error ................. 68 
5.3.5.12 
Patient-Reported Outcome Data .............................................. 70 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 70 
5.4.1 
Medical Monitors and Emergency Medical Contacts ............... 71 

 
Faricimab—F. Hoffmann-La Roche Ltd 
10/Protocol GR42691, Version 3 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 71 
5.4.2.1 
Events That Occur after Enrollment ........................................ 71 
5.4.3 
Reporting Requirements for Pregnancies ................................ 72 
5.4.3.1 
Pregnancies in Female Patients .............................................. 72 
5.4.3.2 
Abortions.................................................................................. 72 
5.4.3.3 
Congenital Anomalies/Birth Defects ........................................ 72 
5.5 
Follow-Up of Patients after Adverse Events............................. 73 
5.5.1 
Investigator Follow-Up ............................................................. 73 
5.5.2 
Sponsor Follow-Up .................................................................. 73 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period ...................................................................... 73 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............... 73 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 74 
6.1 
Determination of Sample Size ................................................. 74 
6.2 
Analysis Populations ................................................................ 74 
6.2.1 
Efficacy-Evaluable Population ................................................. 74 
6.2.2 
Per-Protocol Population ........................................................... 74 
6.2.3 
Safety-Evaluable Population .................................................... 74 
6.2.4 
Pharmacokinetic Population .................................................... 75 
6.2.5 
Immunogenicity Population ...................................................... 75 
6.3 
Summaries of Conduct of Study .............................................. 75 
6.4 
Summaries of Demographic and Baseline Characteristics ...... 75 
6.5 
Safety Analyses ....................................................................... 76 
6.6 
Exploratory Efficacy Analyses .................................................. 76 
6.6.1 
Endpoints (Variables) .............................................................. 76 
6.7 
Pharmacokinetic Analyses ....................................................... 77 
6.8 
Immunogenicity Analyses ........................................................ 77 
6.9 
Biomarker Analyses ................................................................. 78 
6.10 
Interim Analysis ....................................................................... 78 
7. 
DATA COLLECTION AND MANAGEMENT ................................. 78 
7.1 
Data Quality Assurance ........................................................... 78 

 
Faricimab—F. Hoffmann-La Roche Ltd 
11/Protocol GR42691, Version 3 
7.2 
Electronic Case Report Forms ................................................. 79 
7.3 
Source Data Documentation .................................................... 79 
7.4 
Use of Computerized Systems ................................................ 80 
7.5 
Retention of Records ............................................................... 80 
8. 
ETHICAL CONSIDERATIONS ...................................................... 80 
8.1 
Compliance with Laws and Regulations .................................. 80 
8.2 
Informed Consent .................................................................... 81 
8.3 
Institutional Review Board or Ethics Committee ...................... 82 
8.4 
Confidentiality .......................................................................... 82 
8.5 
Financial Disclosure ................................................................. 83 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ....................................................................... 83 
9.1 
Study Documentation .............................................................. 83 
9.2 
Protocol Deviations .................................................................. 83 
9.3 
Management of Study Quality .................................................. 84 
9.4 
Site Inspections ....................................................................... 84 
9.5 
Administrative Structure ........................................................... 84 
9.6 
Dissemination of Data and Protection of Trade Secrets .......... 84 
9.7 
Protocol Amendments ............................................................. 85 
10. 
REFERENCES.............................................................................. 86 
 
 
LIST OF TABLES 
Table 1 
Personalized Treatment Interval Algorithm ................................. 31 
Table 2 
Dose Interruption and Treatment Discontinuation Criteria .......... 58 
Table 3 
Adverse Event Severity Grading Scale ....................................... 62 
Table 4 
Causal Attribution Guidance ....................................................... 63 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 29 
 

 
Faricimab—F. Hoffmann-La Roche Ltd 
12/Protocol GR42691, Version 3 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities .................................................................. 90 
Appendix 2 
Unscheduled Safety Assessment Visit ........................................ 96 
Appendix 3 
Grading Scale for Assessment of Anterior Chamber Flare or 
Cells and Vitreous Cells .............................................................. 97 
Appendix 4 
Best-Corrected Visual Acuity Testing .......................................... 98 
Appendix 5 
Low-Luminance Best-Corrected Visual Acuity Testing ............... 99 
Appendix 6 
Color Fundus Photography ....................................................... 100 
Appendix 7 
Fundus Fluorescein Angiography and Optional Indocyanine 
Green Angiography ................................................................... 101 
Appendix 8 
Spectral-Domain Optical Coherence Tomography .................... 102 
Appendix 9 
Biological Sample Collection and Shipping Instructions ............ 103 
Appendix 10 
National Eye Institute 25-Item Visual Function Questionnaire .. 105 
 
 

 
Faricimab—F. Hoffmann-La Roche Ltd 
13/Protocol GR42691, Version 3 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A MULTICENTER, OPEN-LABEL EXTENSION 
STUDY TO EVALUATE THE LONG-TERM SAFETY 
AND TOLERABILITY OF FARICIMAB IN PATIENTS 
WITH NEOVASCULAR AGE-RELATED MACULAR 
DEGENERATION (AVONELLE-X) 
PROTOCOL NUMBER: GR42691 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2020-004523-16 
IND NUMBER: 
119225 
NCT NUMBER: 
NCT04777201 
TEST PRODUCT: 
Faricimab (RO6867461) 
MEDICAL MONITOR: 
, M.D., Ph.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 
14/Protocol GR42691, Version 3 
PROTOCOL SYNOPSIS 
TITLE: 
A MULTICENTER, OPEN-LABEL EXTENSION STUDY TO 
EVALUATE THE LONG-TERM SAFETY AND TOLERABILITY OF 
FARICIMAB IN PATIENTS WITH NEOVASCULAR AGE-RELATED 
MACULAR DEGENERATION (AVONELLE-X) 
PROTOCOL NUMBER: 
GR42691 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2020-004523-16 
IND NUMBER: 
119225 
NCT NUMBER: 
NCT04777201 
TEST PRODUCT: 
Faricimab (RO6867461) 
PHASE: 
III (Long-term extension) 
INDICATION: 
Neovascular age-related macular degeneration 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the long-term safety and tolerability of intravitreal (IVT) faricimab in 
patients with neovascular age-related macular degeneration (nAMD)  who have completed 
either of the Phase III (GR40306 or GR40844) studies.  Additional assessments relating to 
efficacy, pharmacokinetics, immunogenicity, and biomarkers will be performed.  Specific 
objectives and corresponding endpoints for the study are outlined below. 
In this protocol, study drug refers to faricimab and study treatment refers to faricimab or the 
sham procedure. 
PRIMARY OBJECTIVE 
The primary objective is to evaluate the long-term ocular and systemic safety and tolerability of 
faricimab in all patients who have enrolled in the long-term extension (LTE) study, regardless of 
adherence to treatment or to the protocol, on the basis of the following endpoints: 
 
Incidence and severity of ocular adverse events 
 
Incidence and severity of non-ocular adverse events. 
 
EXPLORATORY OBJECTIVE 
The exploratory efficacy objective of this study is to assess the long-term efficacy of IVT 
faricimab for the management of nAMD in all patients who have enrolled in the LTE study on 
the basis of the following endpoints:  
 
Change in best-corrected visual acuity (BCVA) as measured using the Early Treatment 
Diabetic Retinopathy Study chart at a starting distance of 4 meters 
 
Proportion of patients avoiding loss of  15,  10 or  5 letters in BCVA 
 
Proportion of patients gaining  15,  10  5, or  0 letters in BCVA 
 
Change in central subfield thickness (CST) as measured by optical coherence 
tomography (OCT) 
 
As determined by OCT, proportion of patients with absence of central retina:  
- 
Intraretinal fluid 

 
Faricimab—F. Hoffmann-La Roche Ltd 
15/Protocol GR42691, Version 3 
- 
Subretinal fluid 
- 
Both intraretinal and subretinal fluid 
- 
Intraretinal cysts 
- 
Pigment epithelial detachment 
 
Change in total area of choroidal neovascularization lesion as assessed by fundus 
fluorescein angiography (FFA) 
 
Change in total area of leakage as assessed by FFA 
 
Number of faricimab injections received during the LTE study 
 
The proportion of patients on each treatment interval during the study 
 
Change in patient-reported vision-related functioning and quality of life as assessed using 
the National Eye Institute Visual Functioning Questionnaire 25-item Version composite 
score, the near activity subscale score, the distance activities subscale score, and driving 
subscale score 
Note: Additional exploratory efficacy endpoints may be evaluated using color fundus 
photograph, OCT, FFA, optional OCT-angiography, and optional indocyanine green 
angiography (ICGA) and will be detailed in the Statistical Analysis Plan. 
 
PHARMACOKINETIC OBJECTIVE 
The exploratory pharmacokinetic objective for this study is to assess the pharmacokinetics of 
faricimab, including in patients who have switched from the Phase III active comparator, as well 
as explore concentration-effect relationships on the basis of the following endpoints: 
 
Plasma concentration of faricimab over time from the start of the LTE study 
 
The correlation between concentration of aqueous humor faricimab and the change in 
BCVA and other endpoints (e.g., anatomical markers) over time from the start of the 
LTE study 
 
IMMUNOGENICITY OBJECTIVE 
The immunogenicity objective for this study is to evaluate the immune response to faricimab on 
the basis of the following endpoint: 
 
Presence of anti-drug antibodies (ADAs) at baseline (Day 1 of the parent study and Day 1 
of the LTE) and incidence of ADAs during the study from the start of the LTE study 
 
EXPLORATORY BIOMARKER OBJECTIVES 
The exploratory biomarker objectives for this study are to identify and/or evaluate biomarkers 
that are predictive of response to faricimab (i.e., predictive biomarkers), are associated with 
progression to a more severe disease state (i.e., prognostic biomarkers), are associated with 
susceptibility to developing adverse events or can lead to improved adverse event monitoring or 
investigation (i.e., safety biomarkers), can provide evidence of faricimab activity 
(i.e., pharmacodynamic [PD] biomarkers), or can increase the knowledge and understanding of 
disease biology, on the basis of the following endpoints: 
 
Relationship between anatomic measures at baseline of the LTE study or during the course 
of the study and the change in VA or other endpoints (e.g., the frequency of study drug 
administration) over time from the start of the LTE study 
 
Relationship between low-luminance deficit and/or low-luminance BCVA and BCVA or other 
endpoints (e.g., anatomical markers) at baseline of the LTE study and over time 
 
EXPLORATORY SUBSTUDY 
At selected sites, the Sponsor may propose exploratory substudies associated with the 
Study GR42691 protocol.  Each substudy will be documented in a separate substudy protocol 
and will have a separate associated Informed Consent Form. 

 
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STUDY DESIGN 
DESCRIPTION OF STUDY 
This is a multicenter LTE study designed to evaluate the long-term safety and tolerability of 
faricimab 6 mg administered by IVT injection at a personalized treatment interval (PTI) to 
patients who enrolled in and completed one of the Phase III studies (GR40306 or GR40844), 
also referred to as the parent studies.  Patients in the parent studies who discontinued from the 
study or study treatment prior to completion of the 108-week treatment period are not eligible for 
enrollment in this extension study. 
Eligible patients who consent to participate in this study will be enrolled upon completion of the 
end-of-study visit in the parent study (i.e., Week 112 visit in studies GR40306 and GR40844).  
All assessments from the parent study end-of-study visit must be completed prior to the LTE 
study enrollment visit assessments.  Assessments that are required for the Week 112 study visit 
of the parent study do not need to be repeated as part of Day 1 of the LTE if the visits are done 
on the same day.  If the end-of-study visit of the parent study and enrollment visit for this 
extension study cannot be completed on the same day, or within 2 business days, the 
investigator must contact the Sponsor for further discussion prior to scheduling the extension 
study enrollment visit. 
Approximately 1280 patients are expected to participate in this extension study after completion 
of the parent studies, and will follow a single faricimab 6 mg PTI regimen.  In this extension 
study, the study eye will be the same as that randomized in the parent studies, GR40306 and 
GR40844.   
Eligible patients who choose to enroll into the LTE study will have monthly, masked, study visits 
for the first 3 months of the study (Day 1 through to Week 12).  During the masked period, 
patients and physicians will only be masked to the faricimab treatment interval (if faricimab or 
sham is administered).  Note:  The BCVA examiner will remain masked for the duration of the 
LTE study. 
Following the masked period, the study will follow an open-label design in which patients will 
only be required to attend study visits at which faricimab is to be administered, at intervals 
determined according to the PTI algorithm.  However, the treatment arm to which patients were 
assigned in the parent Phase III study will not be disclosed until the final Phase III analysis 
(Year 2) is reported.  
An interactive web-based response system will be used to calculate a patient’s PTI interval, 
using the patient’s BCVA and optical coherence tomography CST values obtained at dosing 
visits. 
Patients will also attend a final safety follow-up visit 28 days and 35 days after the actual date 
of the Year 2 visit or the actual date of the last study treatment, whichever is later. 
NUMBER OF PATIENTS 
Approximately 1280 patients are expected to participate in this LTE study after completion of 
the parent studies. 
TARGET POPULATION 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Previous enrollment in and completion of Study GR40306 (TENAYA) or Study GR40844 
(LUCERNE), without study or study drug discontinuation 
 
Signed Informed Consent Form 
 
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 contraception, and agreement to refrain from donating 
eggs, as defined below: 
Women must remain abstinent or use contraceptive methods with a failure rate of  1% 
per year during the treatment period and for 3 months after the final dose of faricimab.  
Women must refrain from donating eggs during this same period. 

 
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A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state ( 12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis).  The definition of 
childbearing potential may be adapted for alignment with local guidelines or 
regulations. 
Examples of contraceptive methods with a failure rate of  1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not adequate methods of contraception.  If required per local guidelines or 
regulations, locally recognized adequate methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Pregnant or breastfeeding, or intending to become pregnant during the study or within 
3 months after the final dose of faricimab 
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. 
 
Presence of other ocular diseases that give reasonable suspicion of a disease or condition 
that contraindicates the use of faricimab, that might affect interpretation of the results of the 
study or that renders the patient at high risk for treatment complications 
 
Presence of other diseases, metabolic dysfunction, or clinical laboratory finding giving 
reasonable suspicion of a disease or condition that contraindicates the use of faricimab and 
that might affect interpretation of the results of the study or that renders the patient at high 
risk of treatment complications 
 
History of a severe allergic reaction or anaphylactic reaction to a biologic agent or known 
hypersensitivity to any component of the faricimab injections, study-related procedure 
preparations (including fluorescein), dilating drops, or any of the anesthetic and 
antimicrobial preparations used by a patient during the study 
 
Requirement for continuous use of any medications or treatments indicated as prohibited 
therapy 
 
END OF STUDY 
The end of this study is defined as the date when the last patient, last visit occurs.   
LENGTH OF STUDY 
The end of study is expected to occur approximately 108 weeks after the last patient is enrolled. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
FARICIMAB 
The investigational medicinal product for this study is faricimab.  Faricimab 6 mg will be 
administered intravitreally to patients at a PTI for the duration of the LTE study. 
SHAM 
To preserve the masking of the Phase III treatment arm assignment, patients enrolling in the 
LTE study will attend Q4W visits for the first 3 months of the study and will have the sham 
procedure performed at these visits when they are not treated with faricimab. 
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. 

 
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STATISTICAL METHODS 
PRIMARY ANALYSIS 
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., intraocular pressure [IOP]). 
Verbatim descriptions of treatment emergent adverse events will be mapped to MedDRA 
thesaurus terms, and the incidence and severity will be summarized.  A treatment emergent 
adverse event is defined as any new adverse event reported or any worsening of an existing 
condition on or after the first day (Day 1) of this LTE study.  Only adverse events captured in 
this LTE study will be included for summaries. 
Adverse events will be tabulated by System Organ Class and preferred term and presented 
overall, and by parent study treatment group.  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 timepoint and by eye 
(study vs. fellow) using descriptive summaries.  In addition, changes, from parent study Day 1 
and from LTE study Day 1 for patients randomized to faricimab in the parent study and from 
the first day of faricimab treatment for patients randomized to aflibercept in th e parent study, 
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.  Additional analyses may be conducted from Day 1 of the parent study. 
DETERMINATION OF SAMPLE SIZE   
No formal sample size calculations will be performed for this LTE study.  This study is open to 
all patients who complete study treatment and the Week 112 visit in one of the parent studies 
GR40306 (TENAYA) or GR40844 (LUCERNE). 
INTERIM ANALYSES 
No formal interim analysis is planned.  An interim analysis may be performed for publication 
purposes. 
 
 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
anti-drug antibody 
AMD 
age-related macular degeneration 
Ang-1 
angiopoietin-1 (protein) 
Ang-2 
angiopoietin-2 (protein)  
anti-VEGF 
anti-vascular endothelial growth factor 
AST 
aspartate transaminase 
BCVA 
best-corrected visual acuity 
CATT 
Comparison of Age-Related Macular Degeneration Treatment 
Trials (Research Group) 
CFP 
color fundus photograph 
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 
HIPAA 
Health Insurance Portability and Accountability Act 
ICGA 
indocyanine green angiography 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IOP 
intraocular pressure 
IRB 
Institutional Review Board 
IVT 
intravitreal 
IxRS 
interactive voice or web-based response system 
LLD 
low-luminance deficit 
LPLV 
last patient, last visit 
LTE 
long-term extension 
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 

 
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Abbreviation 
Definition 
OLE 
open-label extension 
PD 
pharmacodynamic 
PI 
Principal Investigator 
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 
SAP 
Statistical Analysis Plan 
SD-OCT 
spectral-domain optical coherence tomography 
SS-OCT 
swept-source optical coherence tomography 
Tie2 
TEK receptor tyrosine kinase 
ULN 
upper limit of normal 
UWP 
ultra-wide photography 
VA 
visual acuity 
VEGF (-A) 
vascular endothelial growth factor (-A) 
WES 
whole exome sequencing 
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 (Flaxel et al. 2020).  
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). 
1.2 
BACKGROUND ON FARICIMAB 
Faricimab is a humanized bispecific IgG1 monoclonal antibody that selectively binds to 
angiopoietin-2 (Ang-2) and VEGF-A.  The Ang-2 binding component binds to Ang-2 with 
high affinity, and the VEGF-A binding component binds to all isoforms of VEGF-A with 
high affinity. 

 
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Angiopoietin-1 (Ang-1) and Ang-2 are of key importance in the homeostasis of the 
vascular compartment, functioning as ligands of TEK receptor tyrosine kinase (Tie2) 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 (Yancopoulos 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). 
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-A reduces leakage from vessels, allowing for 
some normalization of structure and restoration of function. 
Nonclinical studies have shown that Ang-2 and VEGF-A act in concert to regulate the 
vasculature and to increase retinal endothelial cell permeability in vitro.  Simultaneous 
inhibition of Ang-2 and VEGF-A 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Ang-2 or 
antiVEGF-A (ranibizumab) alone.  Earlier experiments using a mouse model of 
spontaneous CNV showed that dual inhibition of Ang-2 and VEGF-A 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).  

 
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In addition, aqueous and vitreous concentrations of both Ang-2 and VEGF-A 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, Ang-2 and VEGF-A, 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).  The global phase of two Phase III studies in 
DME are completed (GR40349 [YOSEMITE] and GR40398 [RHINE]) and the China 
extension phase of RHINE is ongoing.  The global phase of two Phase III studies in 
nAMD are completed (GR40306 [TENAYA] and GR40844 [LUCERNE]) 
(see Section 1.2.1) and the extension phase is ongoing in Japan and China in TENAYA 
and LUCERNE respectively.  An open-label extension (OLE) study in DME for subjects 
who completed GR40349 or GR40398 is ongoing (GR41987 [RHONE-X]).  Two Phase 
III studies in retinal vein occlusion (GR41984 [BALATON] for macular edema secondary 
to branch retinal vein occlusion and GR41986 [COMINO] for macular edema secondary 
to central retinal or hemiretinal vein occlusion) are ongoing.  
Refer to the Faricimab (RO6867461) Investigator’s Brochure for details on nonclinical 
and clinical studies. 
1.2.1 
Phase III Faricimab Studies:  GR40306 (TENAYA) and GR40844 
(LUCERNE) 
The Sponsor is currently investigating the efficacy and safety of faricimab 6 mg in 
nAMD in two identical, global, Phase III, randomized, double-masked, active comparator 
controlled trials.  The global phase of the studies is completed with 1335 patients 
randomized in a 1:1 ratio to one of two treatment arms.  The extension phase of the 
studies is ongoing in Japan and China with an additional 166 patients randomized.   
The Phase III study treatment arms are as follows: 
 
Arm A (faricimab up to every 16 weeks [Q16W]):  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, 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 
an every 8 weeks (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 

 
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every 12 weeks (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 an every 16 weeks (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):  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. 
 
The aim of the Phase III program is to 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 nAMD.  The effect on 
visual function will be assessed by measuring the change from baseline in 
best-corrected visual acuity (BCVA).  The effect on retinal anatomy will be evaluated by 
retinal imaging (spectral-domain or swept-source optical coherence tomography 
[SD-OCT or SS-OCT], fundus fluorescein angiography [FFA], and other imaging 
modalities) to assess nAMD outcomes.  In addition, safety, patient-reported outcomes 
(PROs), and the pharmacokinetics of faricimab will be assessed. 
1.3 
STUDY RATIONALE AND BENEFITRISK ASSESSMENT 
Positive trial results from the completed Phase II and Phase III nAMD clinical 
development program support the positive benefitrisk profile for the use of 6-mg IVT 
injections of faricimab for patients with nAMD (Khanani et al. 2020; Heier et al. 2022) at 
the proposed dosing regimen of up to Q16W.  The AVENUE data and exposure
safety 
analysis supports a positive benefitrisk balance for nAMD patients who may need to 
be dosed as frequently as Q4W in this long term extension (LTE) Study GR42691 
(Section 3.3.1.2). 
The purpose of this extension study is to assess the long-term safety and tolerability of 
6 mg faricimab administered intravitreally in patients who complete the Phase III studies 
and choose to participate in this extension study.  This will also provide opportunity for 
eligible patients from the aflibercept control treatment arm to receive faricimab.  This 
extension study will add to the evidence base for the benefit-risk profile of long-term 
faricimab IVT injection treatment in patients with nAMD. 
An assessment was conducted to determine whether there is any impact of the 
COVID-19 pandemic on the benefitrisk assessment of this study protocol including but 
not limited to the patient population under study and study treatment being evaluated.  
Based on that assessment, no impact is anticipated and the existing safety monitoring 

 
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and management guidelines, and risk mitigation measures provided in the study protocol 
are considered adequate. 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the long-term safety and tolerability of IVT faricimab in patients 
with nAMD who have completed either of the Phase III (GR40306 or GR40844) studies.  
Additional assessments relating to efficacy, pharmacokinetics, immunogenicity, and 
biomarkers will be performed.  Specific objectives and corresponding endpoints for the 
study are outlined below.  An overview of the proposed statistical analyses is described 
in Section 6. 
In this protocol, study drug refers to faricimab and study treatment refers to faricimab or 
the sham procedure (see Section 4.3 for further details). 
2.1 
PRIMARY OBJECTIVE 
The primary objective is to evaluate the long-term ocular and systemic safety and 
tolerability of faricimab in all patients who have enrolled in the LTE study, regardless of 
adherence to treatment or to the protocol, on the basis of the following endpoints: 
 
Incidence and severity of ocular adverse events 
 
Incidence and severity of non-ocular adverse events. 
 
2.2 
EXPLORATORY EFFICACY OBJECTIVE 
The exploratory efficacy objective of this study is to assess the long-term efficacy of IVT 
faricimab for the management of nAMD in all patients who have enrolled in the LTE 
study on the basis of the following endpoints:  
 
Change in BCVA as measured using the Early Treatment Diabetic Retinopathy 
Study (ETDRS) chart at a starting distance of 4 meters 
 
Proportion of patients avoiding loss of  15,  10 or  5 letters in BCVA 
 
Proportion of patients gaining  15,  10  5, or  0 letters in BCVA 
 
Change in central subfield thickness (CST) as measured by optical coherence 
tomography (OCT) 
 
As determined by OCT, proportion of patients with absence in the central retina of:  
– 
Intraretinal fluid 
– 
Subretinal fluid 
– 
Both intraretinal and subretinal fluid 
– 
Intraretinal cysts 
– 
Pigment epithelial detachment 
 
Change in total area of CNV lesion as assessed by FFA 
 
Change in total area of leakage as assessed by FFA 

 
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 
Number of faricimab injections received during the LTE study 
 
The proportion of patients on each treatment interval during the study 
 
Change in patient-reported vision-related functioning and quality of life as assessed 
using the National Eye Institute Visual Functioning Questionnaire 25-item Version 
(NEI VFQ-25) composite score, the near activity subscale score, the distance 
activities subscale score, and driving subscale score 
 
Note: Additional exploratory efficacy endpoints may be evaluated using color fundus 
photograph (CFP), OCT, FFA, optional OCT-angiography (OCT-A), and optional 
indocyanine green angiography (ICGA) and will be detailed in the Statistical Analysis 
Plan (SAP). 
2.3 
PHARMACOKINETIC OBJECTIVE 
The exploratory pharmacokinetic (PK) objective for this study is to assess the 
pharmacokinetics of faricimab, including in patients who have switched from the 
Phase III active comparator, as well as explore concentration-effect relationships on the 
basis of the following endpoints: 
 
Plasma concentration of faricimab over time from the start of the LTE study 
 
The correlation between concentration of aqueous humor faricimab and the change 
in BCVA and other endpoints (e.g., anatomical markers) over time from the start of 
the LTE study 
 
2.4 
IMMUNOGENICITY OBJECTIVE 
The immunogenicity objective for this study is to evaluate the immune response to 
faricimab on the basis of the following endpoint: 
 
Presence of anti-drug antibodies (ADAs) at baseline (Day 1 of the parent study and 
Day 1 of the LTE) and incidence of ADAs during the study from the start of the LTE 
study 
 
2.5 
EXPLORATORY BIOMARKER OBJECTIVES 
The exploratory biomarker objectives for this study are to identify and/or evaluate 
biomarkers that are predictive of response to faricimab (i.e., predictive biomarkers), are 
associated with progression to a more severe disease state (i.e., prognostic biomarkers), 
are associated with susceptibility to developing adverse events or can lead to improved 
adverse event monitoring or investigation (i.e., safety biomarkers), can provide evidence 
of faricimab activity (i.e., pharmacodynamic [PD] biomarkers), or can increase the 
knowledge and understanding of disease biology, on the basis of the following 
endpoints: 
 
Relationship between anatomic measures at baseline of the LTE study or during the 
course of the study and the change in VA or other endpoints (e.g., the frequency of 
study drug administration) over time from the start of the LTE study 

 
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 
Relationship between LLD and/or low-luminance BCVA and BCVA or other 
endpoints (e.g., anatomical markers) at baseline of the LTE study and over time 
 
2.6 
EXPLORATORY SUBSTUDY 
At selected sites, the Sponsor may propose exploratory substudies associated with the 
Study GR42691 protocol.  Each substudy will be documented in a separate substudy 
protocol and will have a separate associated Informed Consent Form. 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY  
This is a multicenter LTE study designed to evaluate the long-term safety and tolerability 
of faricimab 6 mg administered by IVT injection at a PTI to patients who enrolled in and 
completed one of the Phase III studies (GR40306 or GR40844), also referred to as the 
parent studies.  Patients in the parent studies who discontinued from the study or study 
treatment prior to completion of the 108-week treatment period are not eligible for 
enrollment in this extension study. 
Eligible patients who consent to participate in this study will be enrolled upon completion 
of the end-of-study visit in the parent study (i.e., Week 112 visit in Studies GR40306 and 
GR40844).  Patients will be enrolled into the extension study using the same interactive 
web-based response system (IxRS) as was used in the parent study. 
The end-of-study visit (Week 112) of the parent study and the enrollment visit for this 
extension study will occur on the same day.  All assessments from the parent study 
end-of-study visit must be completed prior to the LTE study enrollment visit assessments 
(refer to the schedule of activities in Appendix 1).  Assessments that are required for the 
Week 112 study visit of the parent study do not need to be repeated as part of Day 1 of 
the LTE if the visits are done on the same day.  If the end-of-study visit of the parent 
study and enrollment visit for this extension study cannot be completed on the same 
day, or within 2 business days, the investigator must contact the Sponsor for further 
discussion prior to scheduling the extension study enrollment visit. 
3.1.1 
Overview of Study Design  
Approximately 1280 patients are expected to participate in this extension study after 
completion of the parent studies, and will follow a single faricimab 6 mg PTI regimen.  In 
this extension study, the study eye will be the same as that randomized in the parent 
studies, GR40306 and GR40844.  
Patients will be required to attend monthly study assessment visits between Day 1 and 
Week 12 (the masked period of the study) in order to preserve masking of a patient’s 
treatment assignment in the parent study.  From Week 16 until approximately Week 104, 
patients will attend study visits at intervals as scheduled by the IxRS system based on 

 
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the PTI algorithm.  A final safety follow-up visit will take place at least 28 days after the 
final faricimab treatment visit (see Figure 1). 
Figure 1 outlines the study design, and the schedule of activities is provided in 
Appendix 1. 
 

 
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Figure 1 Study Schema 
 
LTE  long-term extension; PTI  personalized treatment interval; Q8W  every 8 weeks; SFU  safety follow-up. 
Note:  In the LTE study, all patients will move from the Phase III parent study arm to a faricimab PTI arm.  Refer to Section 3.1.1.1 and 
Section 3.1.1.2 for study design details.   

 
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Informed consent must be administered and signed by a patient before any 
study-specific procedures are performed for this LTE study.  Each consented patient 
must satisfy the eligibility criteria at the Day 1 visit (see Section 4.1.1 and Section 4.1.2). 
3.1.1.1 
LTE Visit Schedule during the Masked Period  
Eligible patients who choose to enroll into the LTE study will have monthly, masked, 
study visits for the first 3 months of the study (Day 1 through to Week 12; see Figure 1).  
During the masked period, patients and physicians will only be masked to the faricimab 
treatment interval (if faricimab or sham is administered).  Note:  The BCVA examiner will 
remain masked for the duration of the LTE study (refer to Section 4.2.1.1 for further 
details). 
Refer to Section 4.2.1 for further masking details. 
3.1.1.2 
LTE Visit Schedule following Masked Period  
Following the masked period, the study will follow an open-label design in which patients 
will only be required to attend study visits at which faricimab is to be administered, at 
intervals determined according to the PTI algorithm.  However, the treatment arm to 
which patients were assigned in the parent Phase III study will not be disclosed until the 
final Phase III analysis (Year 2) is reported. 
An IxRS system will be used to calculate a patient’s PTI interval, using the patient’s 
BCVA and OCT CST values obtained at dosing visits.  
Patients will also attend a final safety follow-up visit 28 days and 35 days after the 
actual date of the Year 2 visit or the actual date of the last study treatment, whichever is 
later (see Appendix 1). 
3.1.2 
Faricimab Dosing Schedule 
Faricimab dosing visits are visits when a patient is assigned to receive faricimab.  The 
dosing interval decisions in the LTE study are automatically calculated by IxRS based on 
the algorithm described in this section (Section 3.1.2). 
3.1.2.1 
Faricimab Personalized Treatment Interval 
The PTI algorithm used in this study is based on the algorithm used in the Phase III 
studies and has been expanded to include Q4W as a possible dosing interval.  The PTI 
uses data obtained at dosing visits during both the parent study and the LTE to 
determine the next interval for faricimab dosing.  Faricimab dosing intervals can be 
extended in 4-week increments to a maximum of Q16W, maintained, or reduced by 
either 4- or 8-week increments to a minimum of Q4W.  Faricimab dosing interval 
decisions are automatically calculated by the IxRS based on the algorithm described in 
Table 1. 

 
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Note:  The Q4W dosing interval will become available once the IxRS programming is 
implemented. 
Table 1 
Personalized Treatment Interval Algorithm 
Dosing Interval 
Criteria 
Interval extended by 4 weeks 
(to a maximum of Q16W) 
 Stable CST a 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 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 
Q4W) 
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 by 
8 weeks. 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; Q4W  every 4 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. 
  
3.1.2.2 
Faricimab Dosing Intervals:  Phase III to LTE 
As described in Section 1.2.1, the parent Phase III studies (GR40306 or GR40844) 
include patients randomized in a 1:1 fashion to one of two regimens:  faricimab 
administered up to Q16W (Arm A: faricimab up to Q16W), and a fixed interval 
comparator arm (Arm B: aflibercept Q8W).  In contrast, the LTE will have only one 
treatment regimen, faricimab PTI. 
Upon enrolling in the LTE study: 
 
Patients previously randomized to Arm A (faricimab up to Q16W) will remain on their 
previously calculated faricimab interval at entry to the LTE study. 
Patients previously randomized to Arm B (aflibercept Q8W) who have had their last dose 
of aflibercept at Week 104 of the parent study (see Figure 1) will have a dose of 

 
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faricimab at Day 1 of the LTE study, and will then be eligible to have their subsequent 
faricimab dosing interval extended by 4 weeks, reduced by 4 weeks, or maintained based 
on the PTI algorithm. 
Patients in this arm who (e.g., because of treatment interruption/missed visits in 
the parent study) received their last aflibercept dose at Week 108 of the parent 
study will have a faricimab dose on Week 4 of the LTE study.  These patients will 
then be eligible to have their subsequent dosing interval extended by 4 weeks, 
reduced by 4 weeks, or maintained based on the PTI algorithm. 
 
Note:  During the masked period of the LTE study (from Day 1 through to Week 12; 
see Section 3.1.1.1), as patients roll in from the parent studies, patients will receive 
sham injections at study visits at which they are not scheduled to receive faricimab.  
See Section 4.2 for further details regarding the masked period. 
3.1.3 
Additional Considerations for PTI IxRS Study DrugDosing 
Interval Decision 
Sites will report missed visits and treatment interruption visits to the IxRS. 
3.1.3.1 
Missed Faricimab Dosing Visits 
In view of the potentially extended treatment intervals during the open-label period in the 
LTE study, sites must follow up on any missed study visits and reschedule patients to 
attend the clinic as soon as possible—ideally no later than 2 weeks from the 
scheduled visit date.  
If a dosing visit is missed during the open-label period, the IxRS will assign the patient to 
receive faricimab at the next visit the patient can attend, and the subsequent PTI will be 
based on the interval the patient was on prior to the missed visit, using CST, BCVA, and 
clinical assessments captured at the attended dosing visit. 
3.1.3.2 
Treatment Interruption 
If a patient's dosing has to be interrupted (e.g., because of an adverse event), the IxRS 
will assign the patient to receive faricimab at the earliest visit when the patient is 
permitted to resume faricimab dosing, which should be no sooner than 28 days of the 
treatment interruption date.  Refer to Section 5.1.2.1 for details regarding the criteria for 
treatment interruption and resuming of treatment.  
For treatment interruption periods lasting longer than 28 days, the patient should be 
monitored at appropriate intervals as judged by the investigator.  The case may also be 
discussed with the Medical Monitor, as appropriate. 
Once treatment is resumed, the IxRS will determine the next dosing interval based on a 
Q8W interval, unless the patient was treated with a Q4W dosing interval, in which case 
it will be based on a Q4W interval. 

 
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3.1.3.3 
Missing CST Value at LTE Study Visit 
If a patient attends an LTE study visit when faricimab is scheduled to be administered, 
but the CST value is not available for any reason (e.g., OCT machine is not available or 
is broken), the IxRS will maintain the study drug dosing interval, unless the BCVA or 
clinical criteria for dose reduction are met, in which case the IxRS will reduce the study 
drug dosing interval accordingly.   
3.1.3.4 
Missing BCVA Value at LTE Study Visit 
If a patient attends an LTE study visit when faricimab is scheduled to be administered, 
but the BCVA value is not available for any reason, the IxRS will maintain the study drug 
dosing interval unless the CST or clinical criteria for dose reduction are met, in which 
case the IxRS will reduce the study drug dosing interval accordingly. 
3.1.3.5 
Timely Reporting of BCVA and OCT Data to electronic Case 
Report Form, Central Reading Center, and IxRS 
For the duration of the LTE study, a central reading center (CRC) will be used to read 
the OCT images obtained from patients participating in the study.  The CRC will inform 
the IxRS of the patients’ CST value, which is used to determine the patients’ next 
faricimab treatment interval. 
As such, from the start of the LTE study, the following procedures must be followed: 
 
OCT images obtained at each LTE study visit must be forwarded to the CRC as 
soon as possible (ideally within 24 hours) to allow for evaluation and transfer of 
CST data to IxRS for a timely calculation of the patient’s next LTE study visit 
schedule. 
 
The CRC should be notified as soon as possible (ideally within 24 hours) if there 
are no OCT images available at a scheduled LTE study visit, to allow the CRC to 
inform IxRS accordingly.  
 
Note:  Failure to follow these procedures for OCT reporting will result in a delay to 
patient notification of subsequent dosing visit timeframe. 
In addition, sites must enter the following information in the electronic Case Report Form 
(eCRF) and/or IxRS, as appropriate: 
 
The BCVA total score obtained at the current LTE visit 
Note:  BCVA data obtained at each study visit should be entered in the eCRF as 
soon as possible (ideally within 24 hours) to allow data to be reconciled against 
that entered in IxRS. 
 
Study treatment interruption information (if applicable) 
 
Missed LTE study visits (if applicable) 
 
3.1.3.6 
Modifications to the PTI Algorithm 
The IxRS PTI algorithm cannot be modified by the investigator, and faricimab will be 
administered according to the PTI dispensing schedule.  If a patient is deemed to have 

 
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nAMD that requires immediate treatment, the patient will need to be withdrawn from 
the faricimab study treatment and treated with standard of care. 
If a patient discontinues from the faricimab study treatment, he or she should be 
encouraged to continue their study participation as outlined in Section 4.6.1.  Note:  
The Sponsor will not provide reimbursements for the standard of care treatment in the 
study eye and fellow eye reimbursement (if applicable) will cease once a patient has 
been discontinued from the faricimab study treatment. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last patient, last visit (LPLV) 
occurs.  The end of study is expected to occur approximately 108 weeks after the last 
patient is enrolled. 
In view of the PTI study design, the Year 2 visit will occur at the earliest scheduled 
study visit between Week 96 and Week 104.  The IxRS next study visit notification 
email will indicate if the visit is within the Year 2 study visit window. 
Depending on the PTI schedule, it is possible that patients who complete the Year 2 
visit may also continue to receive faricimab up to and including Week 104.  Once the 
site has submitted OCT images to the reading center, and the CST value has been added 
to IxRS, the IxRS will issue a confirmation email if that was the final treatment visit.  
Upon confirmation of the final study treatment from the IxRS, patients are expected to 
attend a safety follow-up visit 2834 days after the actual date of the Year 2 visit or the 
actual date of their final study treatment, whichever is later. 
The Sponsor may decide to terminate the study at any time. 
3.3 
RATIONALE FOR STUDY DESIGN 
A single arm, open-label trial design is appropriate to meet the objectives of this LTE 
study assessing the long-term safety and tolerability of faricimab for eligible patients who 
originally participated in and completed a Phase III, multicenter, randomized, 
comparator-controlled, double-masked study of faricimab in patients with nAMD. 
3.3.1 
Rationale for Faricimab Dose and Schedule 
The 6 mg dose of faricimab at a PTI schedule will be administered to patients eligible to 
participate in the extension study as outlined in Section 3.1.1. 
3.3.1.1 
Dose 
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 

 
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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 (AVENUE) and CR39521 
(STAIRWAY) 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 Ang-2 and VEGF-A 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 was 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. 
3.3.1.2 
Schedule 
The dosing schedule in the LTE study will follow a PTI regimen and uses data obtained 
at dosing visits to determine the next interval for faricimab dosing.  At study start, the 
PTI algorithm was the same as that used in the parent Phase III studies.  The PTI 
algorithm was subsequently updated during the conduct of the study and after all 
patients had enrolled.  The updated PTI algorithm is based on the algorithm used in the 
parent Phase III studies and has been expanded to include Q4W as a possible dosing 
interval. 
In addition to the heterogeneity of nAMD disease activity, the results of the PK and PD 
aqueous humor assessments and the differences in treatment response across patients 
observed in the Phase II studies (CR39521 [STAIRWAY] and BP29647 [AVENUE]) and 
Phase III studies (GR40306 [TENAYA] and GR40844 [LUCERNE]) support a flexible 
dosing regimen with intervals ranging from Q4W to Q16W.  This flexible dosing regimen 
provides patients with the opportunity to either extend, maintain, or reduce treatment 
frequency according to their need, thus minimizing the administration of unnecessary 
IVT injections while maintaining gains in VA achieved during the parent study. 
Q12W and Q16W dosing intervals are supported by findings from Study CR39521 
(STAIRWAY) (Khanani et al, 2020), GR40306 (TENAYA), and GR40844 (LUCERNE) 
(Heier et al 2022).  The option for Q8W dosing (which was shown to be effective in 
Study BP29647 [AVENUE]) was included in the Phase III study design to help ensure 
that individual treatment needs were met by allowing dosing according to the most 

 
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appropriate frequency.  However, it is recognized that some nAMD patients with more 
active disease may benefit from receiving more frequent dosing (Ho et al. 2014; 
Arnold et al 2015; Richard et al. 2015).  In Study BP29647 (AVENUE), the safety and 
efficacy of faricimab 6 mg Q4W was comparable to the faricimab 6 mg Q8W regimen 
and the comparator ranibizumab Q4W.  Therefore, based on the possible need for more 
frequent dosing, as well as the positive safety profile of Q4W dosing demonstrated in 
Phase II Study BP29647 (AVENUE), the GR42691 PTI has now been expanded to 
include a Q4W dosing option.   
Real-world evidence suggests that the improvements in VA achieved in the clinical trial 
setting with anti-VEGF monotherapy are not always replicated in clinical practice, 
potentially due to the reduced frequency of injections administered in clinical practice 
(Chong 2016; Gillies et al. 2014; Kim et al. 2016; Writing Committee for the UK 
Age-Related Macular Degeneration EMR Users Group 2014).  The PTI regimen aims to 
maximize efficacy while reducing the IVT injection treatment burden in patients with 
nAMD by treating according to individual visual and anatomic needs, which in turn may 
increase patient compliance and reduce the burden to patients, their caregivers, and the 
healthcare system. 
Adopting a personalized treatment approach in the LTE study will provide long-term 
evidence regarding whether the efficacy outcomes in the pivotal Phase III trials can be 
maintained over a longer follow-up period. 
3.3.2 
Rationale for Patient Population 
This LTE study will enroll patients with nAMD who have completed the parent Phase III 
study (GR40306 or GR40844) and who have not discontinued study treatment. 
The rationale for not including patients who were discontinued from treatment is to avoid 
enrolling patients who may have experienced adverse events or who may not benefit 
from continued dosing with faricimab, and for whom the risks of treating with further IVT 
injections outweigh any benefits that may be gained from continued dosing.  In addition, 
as the objective of the LTE study is to evaluate the long-term safety and tolerability of 
faricimab in patients who have received treatment for 2 years according to protocol, 
patients who discontinued study treatment may comprise a different population. 
3.3.3 
Rationale for Optional Biomarker Assessments 
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. 2017).  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 

 
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ocular pharmacokinetics and pharmacodynamics of faricimab.  Aqueous humor and 
vitreous humor samples will be measured for free Ang-2 and free VEGF-A, and data 
from these analyses may 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. 
Moreover, other biochemical entities involved in inflammation (e.g., intracellular 
adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin among others) 
and angiogenic growth factors such as angiopoietin 1 may be analyzed in these 
specimens in an exploratory analysis.  These analyses are intended to investigate the 
role of biochemical and biological processes, such as angiogenesis, inflammation, and 
oxidative stress in the pathogenesis of nAMD and in the response to faricimab 
treatment.  Given that these biomarkers may also have prognostic value, their potential 
association with disease progression will also be explored. 
The concentration of free Ang-2 and free VEGF-A will be measured in plasma to assess 
the systemic target suppression following IVT faricimab injection. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 1280 patients are expected to participate in this LTE study after 
completion of the parent studies, and will be enrolled into a single 6-mg faricimab dose 
PTI arm.  In this extension study, the study eye will be the same as that randomized in 
the parent Studies, GR40306 and GR40844. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Previous enrollment in and completion of Study GR40306 (TENAYA) or 
Study GR40844 (LUCERNE), without study or study drug discontinuation 
 
Signed Informed Consent Form 
 
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 contraception, and agreement to refrain from 
donating eggs, as defined below: 
Women must remain abstinent or use contraceptive methods with a failure rate 
of  1% per year during the treatment period and for 3 months after the final 
dose of faricimab.  Women must refrain from donating eggs during this same 
period. 
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 

 
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and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations. 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of contraception.  
If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 3 months after the final dose of faricimab 
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. 
 
Presence of other ocular diseases that give reasonable suspicion of a disease or 
condition that contraindicates the use of faricimab, that might affect interpretation of 
the results of the study or that renders the patient at high risk for treatment 
complications 
 
Presence of other diseases, metabolic dysfunction, or clinical laboratory finding 
giving reasonable suspicion of a disease or condition that contraindicates the use of 
faricimab and that might affect interpretation of the results of the study or that 
renders the patient at high risk of treatment complications 
 
History of a severe allergic reaction or anaphylactic reaction to a biologic agent or 
known hypersensitivity to any component of the faricimab injections, study-related 
procedure preparations (including fluorescein), dilating drops, or any of the 
anesthetic and antimicrobial preparations used by a patient during the study 
 
Requirement for continuous use of any medications or treatments indicated as 
prohibited therapy (see Section 4.4.2) 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND MASKING  
This is a non-randomized study.  After initial written informed consent has been 
obtained, all procedures and assessments have been completed, and eligibility has been 
established for a patient, the study site will obtain the patient's study number and 
treatment assignment from the IxRS. 

 
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As outlined in Section 3.1, there will be a masked period in the early phase of the LTE 
study (Day 1 to Week 12).  Masked site staff and patients will be informed that the 
patient will receive faricimab 6 mg IVT injections, and that they will be masked to the 
faricimab treatment interval only.  During this masked period, patients will be advised 
that at masked study visits they will either receive faricimab or sham injection.  After the 
Week 12 treatment procedure, the study will follow an open-label design and patients 
will only be required to attend study visits at which they are scheduled to receive 
faricimab, and a final safety follow-up visit. 
4.2.1 
Masking Requirements during the Masked Period of LTE Study 
To fulfill the masking requirements, LTE study assessments will be performed by an 
investigator masked to the patients’ faricimab treatment interval, while treatment 
administration will be undertaken by an unmasked treatment administrator.  The sham 
procedure is designed to mimic the injection procedure to ensure that patients also 
remain masked to their treatment interval during the masked period of the LTE study. 
4.2.1.1 
Masked Roles during the Masked Period of the LTE Study 
Principal Investigator 
The Principal Investigator (PI) for the LTE study may be the same individual as in the 
parent Phase III study and will be a retina specialist (or the equivalent in ex-U.S. 
countries).  For the masked period of the LTE study, the PI must be masked to the 
treatment interval of the patient.  During the masked period of the LTE study, the PI can 
assume any other masked role as described in this section (Section 4.2.1.1), with the 
exception of being a BCVA examiner. 
Assessor Physician 
Sites are permitted to have at least one additional investigator designated as a masked 
assessor physician, who will be a retina specialist (or the equivalent in ex-U.S. 
countries).  The masked assessor physician must also be masked to treatment interval 
of the patient and will evaluate all pre-treatment assessments.  The masked 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 
with the exception of being a BCVA examiner. 
Photographer(s) and OCT Technician(s) 
If qualified, the photographer(s) and OCT technician(s) can share any other masked role 
tasks except tasks performed by the BCVA examiner. 
Study Coordinator(s) 
If qualified, the study coordinator(s) can share any other masked role tasks except tasks 
performed by the BCVA examiner. 

 
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BCVA Examiner  
For the duration of the LTE study, to minimize bias, the BCVA examiner will be 
masked to the study eye (right vs. left) and must not have access to the medical charts 
of patients or the BCVA scores from a patient’s previous visits.  The BCVA examiner 
may have access to a patient’s refraction data from previous visits.  The BCVA examiner 
is not allowed to perform any other task involving direct or indirect patient care. 
Phlebotomist 
Any qualified masked or unmasked individual, with the exception of those in the 
BCVA examiner role, can perform the tasks of the phlebotomist.  
4.2.1.2 
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 must be 
an ophthalmologist, and, ideally, a retina specialist (or the equivalent in ex-U.S. 
countries).  It is the PI’s responsibility to ensure that the treatment administrator 
ophthalmologist is suitably qualified to safely perform the IVT injection procedure and 
other tasks as outlined below.  
Following treatment administration, the treatment administrator must also perform the 
post-treatment administration vision testing (finger-counting/hand movement/light 
perception tests), perform post-treatment intraocular pressure (IOP) testing, and treat 
adverse events that occur during or shortly after the study treatment administration.  
During the masked period of the LTE study, the person in this role should not evaluate 
the causality of adverse events; this is the responsibility of the masked assessor 
physician.  The treatment administrator will also undertake optional aqueous humor 
sample collection. 
During the masked period of the LTE study, the treatment administrator must not be 
involved in any other aspect of the study and must not divulge treatment assignment 
to anyone. 
Unmasked Assistant and Pharmacist 
If desired, sites may have designated qualified unmasked assistant(s) who can assist 
with tasks such as assembly of study treatment supplies, preparation of sterile field, 
preparation of the patient’s study eye for treatment, disposal of all injection materials 
(i.e., syringes and needles) immediately following study treatment, and placing the used 
vial in the kit box.  The qualified unmasked assistant(s) may measure post-dose IOP.  
If the site uses a pharmacy, then the unmasked role is also assigned to the pharmacist 
who can take on investigational medicinal product (IMP)-related tasks as applicable per 
delegation of authority log. 

 
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Any other study assisting personnel not listed above must be in the masked roles during 
the masked period of the LTE study. 
4.2.1.3 
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 PI. 
4.2.1.4 
Role Switching 
During the masked period of the LTE study, once personnel assigned to a designated 
unmasked role start performing that role, the personnel cannot switch to a masked role.  
However, personnel switching from a masked role to an unmasked role may be possible 
and must be documented in the Delegation Log.  
4.2.1.5 
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. 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The IMP for this study is faricimab. 
4.3.1 
Study Treatment Formulation and Packaging 
4.3.1.1 
Faricimab 
Faricimab will be supplied by the Sponsor as a sterile liquid for IVT injection in 
single-use glass vials.  For information on the faricimab formulation, see the pharmacy 
manual. 
4.3.1.2 
Sham 
The sham vial will be supplied by the Sponsor and 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. 
See Section 3.1.1 for further details regarding the masked period in the LTE study. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1.1. 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 

 
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Details on treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration eCRF.  Cases of accidental overdose or medication error, 
along with any associated adverse events, should be reported as described in 
Section 5.3.5.11. 
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1. 
4.3.2.1 
Faricimab Administration 
Faricimab 6 mg will be administered intravitreally to patients at a PTI for the duration of 
the LTE study (see Figure 1). 
Refer to the pharmacy manual for the pre-treatment procedures, the administration of 
faricimab, or sham (when appropriate; refer to Section 3.1.1), and the post-treatment 
procedures for all LTE patients. 
The pharmacist responsible for dispensing the study treatment, or designated unmasked 
site personnel, will prepare the correct study treatment (faricimab or sham, when 
appropriate) as assigned through the IxRS. 
The Sponsor has specified the mandatory materials required and detailed stepwise 
instructions for the preparation of study treatment administration (or sham, when 
appropriate) in the pharmacy manual. 
A specified filter needle must be used for each dose preparation of faricimab according 
to the instructions provided in the pharmacy manual.  All materials to prepare and 
administer study treatments will be provided or reimbursed by the Sponsor, and no other 
material than specified should be used. 
Vials of faricimab drug product are for single use only (one injection preparation per 
patient per eye).  Vials used for one patient must not be used for any other patient.  
Partially used vials, remaining faricimab drug product and administration material must 
not be reused. 
4.3.2.2 
Sham Administration 
As discussed in Section 3.1.1, to preserve the masking of the Phase III treatment arm 
assignment, patients enrolling in the LTE study will attend Q4W visits for the first 
3 months of the study and will have the sham procedure performed at these visits when 
they are not treated with faricimab. 

 
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4.3.3 
Investigational Medicinal Product Handling and Accountability 
The IMP required for completion of this study will be provided by the Sponsor.  The 
study site (i.e., investigator or other authorized personnel [e.g., pharmacist]) is 
responsible for maintaining records of IMP delivery to the site, IMP inventory at the site, 
IMP use by each patient, and disposition or return of unused IMP, thus enabling 
reconciliation of all IMP received, and for ensuring that patients are provided with doses 
specified by the protocol. 
The study site should follow all instructions included with each shipment of IMP.  The 
study site will acknowledge receipt of IMPs supplied by the Sponsor, using the IxRS, to 
confirm the shipment condition and content.  Any damaged shipments will be replaced.  
The investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit, either by time monitoring (shipment arrival date and 
time) or temperature monitoring, for all IMPs received and that any discrepancies have 
been reported and resolved before use of the IMPs.  All IMPs must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions, with access limited to the investigator 
and authorized staff. 
Only patients enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs. 
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 
documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the drug accountability log. 
Refer to the pharmacy manual and/or the Faricimab (RO6867461) Investigator's 
Brochure for information on IMP handling, including preparation and storage, and 
accountability.  
4.3.4 
Continued Access to Faricimab 
The Sponsor will offer continued access to Roche IMP (faricimab) free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 

 
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A patient will be eligible to receive Roche IMP (faricimab) after completing the study if all 
of the following conditions are met: 
 
The patient has a sight-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being 
 
There are no appropriate alternative treatments available to the patient 
 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 
A patient will not be eligible to receive Roche IMP (faricimab) after completing the study 
if any of the following conditions are met: 
 
The Roche IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient) 
 
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 medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment for the 
duration of the LTE study.  All such medications should be reported to the investigator 
and recorded on the Concomitant Medications eCRF, except as specified in 
Section 4.4.1.1 and Section 4.5.5. 
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 4.4.2. 
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. 

 
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 
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 5.1.2.1, Table 2) may apply with cataract surgery. 
 
Short-term use of topical corticosteroids after cataract surgery, yttrium-aluminum 
garnet laser capsulotomy, peripheral iridotomy, argon/selective laser 
trabeculoplasty, or for ocular allergic conditions. 
 
Patients who require anti-VEGF treatment for their fellow eye should continue or 
initiate treatment according to instructions in Section 4.4.1.1. 
 
4.4.1.1 
Fellow (Non-Study) Eye Treatment with Anti-VEGF Therapy 
At the discretion of the PI, patients enrolled in the LTE study may have their fellow 
(non-study) eye treated with anti-VEGF therapy.  Consult the region-specific anti-VEGF 
prescribing information for the recommended dose and frequency of treatment.  The 
Sponsor will cover the cost of approved anti-VEGF therapy licensed for ocular use, in 
accordance with local regulations, until faricimab is made available in that region, after 
which the Sponsor will only support fellow eye treatment with faricimab, which will be 
provided while the participant remains on study treatment, unless prohibited by local 
regulator.  Ongoing reimbursements of other anti-VEGF therapies must be approved by 
the Sponsor unless the patient is enrolled in the corneal endothelial cells substudy.  
Patients participating in the substudy will continue to have anti-VEGF therapy other 
than faricimab reimbursed.  Avastin use is not prohibited in the fellow eye; however, 
the Sponsor cannot cover the cost of anti-VEGF therapies not licensed for ocular use. 
Fellow eye treatment reimbursement will cease if the patient is discontinued from 
faricimab study treatment.  Fellow eye treatment reimbursement will cease once the 
patient has completed the study. 
If treatment with anti-VEGF is to be given to the fellow (non-study) eye at the same visit 
as the study eye treatment, 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 during the masked period of the LTE study). 
Individual trays and sterile preparation must be separately prepared for each 
eye treatment.  
Note:  If anti-VEGF treatment of the fellow eye is required outside of the study visit 
schedule, then any qualified physician can administer this treatment. 
Anti-VEGF therapy in the fellow eye should be recorded on a separate Fellow Eye 
anti-VEGF Administration eCRF.   

 
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4.4.2 
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 during a patient’s study treatment 
participation.  If necessary, patients may be discontinued from faricimab treatment 
and/or the study to receive these therapies: 
 
Systemic anti-VEGF therapy  
 
Systemic drugs known to cause macular edema (fingolimod, tamoxifen, etc.) 
 
IVT anti-VEGF agents (other than faricimab) in study eye  
 
IVT, periocular (subtenon), steroid implants (i.e., Ozurdex®, Iluvien®), or chronic 
topical ocular corticosteroids (defined as continuous usage for 100 days or longer) 
in 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) and 
therapies that claim to have an effect on macular pathology (e.g., kallidinogenase) 
 
Patients who discontinue faricimab due to receipt of prohibited therapy should be 
encouraged to continue their study participation and attend LTE annual visits (Year 1 
and Year 2), as outlined in the schedule of activities (see Appendix 1). 
4.5 
STUDY ASSESSMENTS  
The schedule of activities to be performed during the study is provided in Appendix 1 
(see Appendix 2 for the schedule of activities for unscheduled-visits).  All activities 
should be performed and documented for each patient. 
All assessments for a scheduled visit are to be performed on the same day.   
4.5.1 
Informed Consent Forms 
Written informed consent for participation in the study must be obtained before 
performing any LTE study-related procedures (i.e., treatment administration and related 
procedures).  Informed Consent Forms for enrolled patients and for patients who are not 
subsequently enrolled will be maintained at the study site. 
All evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before enrollment. 
4.5.2 
Medical History, Baseline Conditions, Concomitant Medication, 
and Demographic Data 
Medical history and demographic data were collected in the parent studies and will not 
be obtained again during this extension study. 

 
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Concomitant medication information will be obtained at each visit. 
4.5.3 
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 at specified timepoints according to the 
schedule of activities in Appendix 1. 
4.5.4 
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 
 
Ocular imaging (see below for further details) 
 
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 (during the masked phase 
of the study). 
 
At each visit, post-treatment IOP measurement in the study eye by qualified 
personnel assigned to the unmasked role (unmasked and masked roles are only 
relevant up until the open-label period of the study; see Section 3.1.1 for details).  
If there are no safety concerns following the 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:  The same device must be used to assess the patient’s pre-treatment IOP and 
their post-treatment IOP and must remain consistent throughout the study. 
Ocular Imaging 
The protocol for image acquisition for the LTE study will be the same as that used in the 
parent Phase III studies.  The CRC has previously provided sites with CRC manuals and 
training materials on image acquisition requirements for specified study ocular images.  
LTE study images will be obtained by site personnel and imaging systems (including 

 
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software) that have been certified by the CRC.  The method for obtaining CRC 
certification is detailed in the CRC manual.  Photographers and study imaging 
technicians are to obtain CRC certification prior to acquiring any LTE study images. 
All ocular images obtained by trained and CRC certified site personnel are to be 
forwarded to the CRC as soon as possible (see Section 3.1.3.5 and Appendix 1, 
Appendix 6 [CFP], Appendix 7 [FFA and ICGA], and Appendix 8 [SD-OCT]). 
If a patient misses a study visit when CFP, FFA, OCT-A (if applicable), or ICGA (if 
applicable) images are scheduled (see Appendix 1) or the images are not taken at the 
scheduled visit (e.g., due to broken equipment), the images are to be obtained at the 
next visit the patient attends. 
Ocular images include the following: 
 
CFP of both eyes (please note that ultra-wide photography [UWP)] is only permitted 
when no other alternative is available and must be discussed with the CRC) 
 
FFA of both eyes (performed after laboratory samples are obtained; please note that 
UWP is only permitted when no other alternative is available and must be 
discussed with the CRC) 
 
SD-OCT or SS-OCT images of both eyes 
Certain SS-OCT machines may be acceptable; consult the CRC.   
 
Optional OCT-A of both eyes at sites with agreed OCT-A capabilities 
 
Optional ICGA of both eyes at selected sites with agreed ICGA capabilities.   
This imaging is to be 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 CRC 
manual. 
 
All imaging is to be undertaken using the same device as that used in the parent study. 
Additional details on obtaining these images are included in the CRC manual. 
4.5.5 
Concurrent Ocular Procedures 
Any ocular procedures performed on either eye during the study will be recorded on the 
Concurrent Ocular Procedures Log on the eCRF. 
4.5.6 
Laboratory and Other Biological Samples 
At scheduled visits (see Appendix 1), all samples must be obtained prior to study 
treatment, and blood samples must be obtained prior to FFA assessments (as 
applicable).  Fasting is not required prior to specimen collection. 
The specimens will be forwarded to the central laboratory (with the exception of the urine 
pregnancy test, which will be analyzed locally).  The central laboratory will either perform 

 
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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. 
The following assessments will be performed: 
 
Urine pregnancy test 
All women of childbearing potential (including those who have had tubal ligation) will 
have a urine pregnancy test prior to each study treatment, performed at site.  
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 faricimab immunogenicity analysis 
 
Plasma samples for faricimab PK analysis 
 
If a patient misses a study visit when mandatory plasma PK or ADA samples are 
scheduled (see Appendix 1) or the samples are not taken at the scheduled visit, the 
samples may be obtained at the next visit the patient attends.  This does not apply to 
missed Week 8 samples because Week 12 is also a sampling visit. 
Drug concentration, 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 samples to be stored for 
optional exploratory research (see Section 4.5.8), plasma samples collected for PK or 
immunogenicity analysis will be destroyed no later than 5 years after the final Clinical 
Study Report has been completed.  Pregnancy test samples will be destroyed after their 
analysis during the study. 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4. 
4.5.6.1 
Optional Aqueous Humor and Associated Optional Plasma 
Samples 
Collection and submission of optional aqueous humor and optional plasma samples is 
contingent upon review and approval by the site, each site's Institutional Review Board 
(IRB) or Ethics Committee (EC) and, if applicable, an appropriate regulatory body.  If a 
site has not been granted approval for sampling, this section of the protocol 
(Section 4.5.6.1) will not be applicable at that site.  

 
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For patients who consent to provide study eye aqueous humor sampling, the aqueous 
humor sample should be collected just prior to study treatment (it is acceptable to collect 
the sample after FFA assessment) by a qualified unmasked treatment administrator, 
using an aseptic procedure and sterile field and according to local guidelines (see 
Appendix 9 and the central laboratory manual for aqueous samples collection, storage, 
and transfer). 
All efforts should be made to obtain a baseline aqueous humor sample on Day 1 
(pre-treatment).  The schedule of activities (Appendix 1) provides guidance on 
recommended visits at which aqueous humor samples should be obtained.  Any missed 
optional samples are not required to be made up at a later visit.  Patients who are 
prematurely discontinued from study treatment but who agree to continue to participate 
in the study should discontinue collection of optional aqueous humor samples and any 
associated optional plasma samples.  However, (unscheduled) sampling may be 
performed at other or additional planned visits at the discretion of the investigator and 
in agreement with the participating patient. 
Aqueous humor samples will be analyzed for faricimab, free Ang-2, and free VEGF-A 
concentrations.  Data from these analyses will be used to develop better predictive 
models for determining optimal patient treatment interval(s) and to support selection of a 
dosing regimen for future clinical trials.  Remaining samples will be analyzed for 
additional biomarkers, including those involved in angiogenesis (which may include, but 
are not limited to, Ang-1 and platelet-derived growth factor) and inflammation (which 
may include, but are not limited to, intracellular adhesion molecule 1 and E-selectin), to 
identify new therapeutic targets, better understand variability in patient responses to 
faricimab, and to support patient selection and/or stratification in future clinical trials. 
Sites will collect optional plasma PK samples for measurement of faricimab 
concentration using validated immunoassay methods.  Optional plasma PD samples will 
be collected and analyzed for systemic free Ang-2 and free VEGF-A.  Remaining plasma 
samples may be analyzed for additional biomarkers.  See Appendix 1 and the Covance 
manual for details on sample 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 4.5.8), optional aqueous humor and 
associated plasma PK and PD samples will be destroyed no later than 5 years after the 
final Clinical Study Report has been completed. 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 

 
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Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 
4.5.6.2 
Optional Unscheduled Vitreous Humor and Associated 
Optional Plasma Samples 
Collection and submission of optional vitreous humor and optional plasma samples is 
contingent upon review and approval by the site, each site's IRB or EC and, if applicable, 
an appropriate regulatory body.  If a site has not been granted approval for sampling, 
this section (Section 4.5.6.2) of the protocol will not be applicable at that site. 
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 concentration.  See the Covance manual for vitreous and PK sample 
collection, storage, and transfer. 
Vitreous humor samples will be analyzed primarily for faricimab concentrations.  The 
remaining samples may be analyzed for free Ang-2 free and VEGF-A concentrations, as 
well as additional biomarkers, including those involved in angiogenesis (which may 
include, but are not limited to, Ang-1 and platelet-derived growth factor) and 
inflammation (which may include, but are not limited to, intracellular adhesion molecule 1 
and E-selectin), to identify new therapeutic targets, better understand variability in 
patient responses to faricimab, and to support patient selection and/or stratification in 
future clinical trials. 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.8), optional vitreous humor and 
associated plasma PK samples will be destroyed no later than 5 years after the final 
Clinical Study Report has been completed. 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4. 

 
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Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 
4.5.7 
Patient-Reported Outcomes 
The NEI VFQ-25 will be completed to assess the treatment benefit of faricimab (see 
Appendix 10). 
4.5.7.1 
Data Collection Methods for Patient-Reported Outcome 
Assessments 
The NEI VFQ-25 will be interviewer-administered by masked site staff (when 
appropriate; see Section 3.1.1), excluding the BCVA examiner, at the clinic at specified 
timepoints during the study (see schedule of activities in Appendix 1).  At the clinic, the 
instrument will be administered before the patient receives any information on disease 
status and prior to the administration of study treatment, unless otherwise specified.  In 
the event that the patient is unable to come to the clinic for a scheduled visit, the 
NEI VFQ-25 may be administered over the phone. 
The NEI VFQ-25 translated into the local language as appropriate, will be provided by 
the Sponsor to enable the instrument to be administered at each specified timepoint. 
During clinic visits, the NEI VFQ-25 should be administered by masked site staff as 
outlined below: 
 
Patients' health status should not be discussed prior to administration of the 
instrument. 
 
Sites must administer the official version of the instrument, as provided by the 
Sponsor.  The instrument must not be copied from the protocol. 
 
Sites should allow sufficient time for patients to complete the instrument, estimated 
to be 1015 minutes at each specified visit. 
 
Sites should administer the instrument in a quiet area with minimal distractions and 
disruptions. 
 
Patients should be instructed to answer questions to the best of their ability; there 
are no right or wrong answers. 
 
Site staff should read questions verbatim and not attempt to interpret or explain 
questions. 
 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instrument. 
 
4.5.7.2 
Description of Patient-Reported Outcomes Instrument 
PROs will be assessed using the NEI VFQ-25 (Mangione et al. 2001) (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 

 
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11 vision-related subscales and one item on general health.  In this study, an additional 
six appendix items will be included for the Near Activities and Distance Activities 
subscales.  The composite score and subscale scores range from 0 to 100, with higher 
scores indicating better vision-related functioning.  Subscale scores include General 
Vision, Ocular Pain, Near Activities, Distance Activities, Social Functioning, Mental 
Health, Role Difficulties, Dependency, Driving, Color Vision, and Peripheral Vision. 
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.   
4.5.8 
Optional Samples for Research Biosample Repository 
4.5.8.1 
Overview of the Research Biosample Repository 
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future. 
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives: 
 
To study the association of biomarkers with efficacy or disease progression 
 
To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation 
 
To increase knowledge and understanding of disease biology and drug safety 
 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.8.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 4.5.8) will 
not be applicable at that site. 

 
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4.5.8.3 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to faricimab, diseases, or 
drug safety: 
 
Blood sample collected at Day 1 visit 
 
Leftover aqueous humor, plasma, and vitreous humor samples and any derivatives 
thereof (e.g., DNA, RNA, proteins, peptides) 
 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via whole genome sequencing (WGS), whole exome sequencing 
(WES), or other genomic analysis methods.  Genomics is increasingly informing 
researcher's understanding of disease pathobiology.  WGS and WES provide a 
comprehensive characterization of the genome and exome, respectively, and, along with 
clinical data collected in this study, may increase the opportunity for developing new 
therapeutic approaches or new methods for monitoring efficacy and safety or predicting 
which patients are more likely to respond to a drug or develop adverse events. 
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.8.4 
Confidentiality 
RBR samples and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 

 
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Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.8.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research. 
4.5.8.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed.  However, if RBR samples have been tested prior to withdrawal of 
consent, results from those tests will remain as part of the overall research data.  If a 
patient wishes to withdraw consent to the testing of his or her RBR samples during the 
study, the investigator must inform the Medical Monitor in writing of the patient's wishes 
through use of the appropriate RBR Subject Withdrawal Form and must enter the date of 
withdrawal on the RBR Research Sample Withdrawal of Informed Consent eCRF.  If a 
patient wishes to withdraw consent to the testing of his or her RBR samples after closure 
of the site, the investigator must inform the Sponsor by emailing the study number and 
patient number to the following email address: 
global.rcr-withdrawal@roche.com 
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study. 

 
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4.5.8.7 
Monitoring and Oversight 
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples. 
4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment if they experience any of the 
following: 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
 
Pregnancy 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. 
Patients who discontinue study treatment should be encouraged to continue their study 
participation and attend LTE annual visits (Year 1 and Year 2), as outlined in the 
schedule of activities (see Appendix 1).  In addition to this, patients will return to the 
clinic for an early treatment/study termination visit a minimum of 28 days after 
receiving the final dose of study drug (see Appendix 1 for additional details). 
4.6.2 
Patient Discontinuation from the Study 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time. 
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following: 
 
Patient withdrawal of consent 
 
Study termination or site closure 
 
Adverse event 
 
Loss to follow-up 
 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 

 
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Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator. 
Patients who discontinue from the study early but have not withdrawn consent should 
return for an early treatment/study 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 
 
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: 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
As of July 2022, faricimab has been approved in various counties for the treatment of 
nAMD and DME and has licensing applications under health authority review in other 
countries.  Clinical development is ongoing.  The safety plan for patients in this study is 
based on clinical experience with faricimab in completed and ongoing studies.  The 
anticipated important safety risks for faricimab are outlined below.  Please refer to the 
Faricimab (RO6867461) Investigator's Brochure for a complete summary of safety 
information.  
Several measures will be taken to ensure the safety of patients participating in this 
study.  Patients will undergo safety monitoring during the study, including assessment of 
the nature, frequency, and severity of adverse events.  In addition, guidelines for 
managing adverse events, including criteria for treatment interruption or discontinuation, 
are provided below. 

 
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5.1.1 
Risks Associated with Faricimab 
The known side effects associated with faricimab, as well as potential side effects based 
on human and laboratory studies, are listed below.  These risks are either from the drug 
itself or the injection procedure. 
Anticipated risks of faricimab include intraocular inflammation, IVT injection-related risks 
of infectious endophthalmitis, retinal detachment or tear, and transient increased IOP.  
Potential risks associated with faricimab include iatrogenic traumatic cataract, 
immunogenicity, and the non-ocular risk of arterial thromboembolic events.  An 
independent clinical events coding committee will adjudicate thromboembolic events 
(myocardial infarcts, strokes, and deaths) reported during the study. 
Refer to the Faricimab (RO6867461) Investigator's Brochure for more details on the risks 
of faricimab. 
5.1.2 
Management of Patients Who Experience Adverse Events 
5.1.2.1 
Treatment Interruption 
Study treatment interruption/patient discontinuation from study treatment for adverse 
events will be determined using the criteria listed in Table 2.  If any of these criteria are 
met, treatment will be interrupted (or discontinued, if appropriate) and will not be 
resumed earlier than 28 days of the treatment interruption date.  The reason for study 
treatment interruption/discontinuation should be recorded on the appropriate eCRF and, 
if applicable, on the Adverse Event eCRF. 
Table 2 
Dose Interruption and Treatment Discontinuation Criteria 
Event  
Criteria 
Intraocular 
inflammation 
 
Interrupt faricimab treatment if intraocular inflammation (iritis, 
iridocyclitis or vitritis) is  2 in the study eye. 
 
Faricimab treatment may be resumed subsequently as determined 
by the investigator.  The investigator may contact the Medical 
Monitor to discuss any concerns regarding individual cases, as 
appropriate. 
Cataract surgery in the 
study eye 
 
Interrupt faricimab treatment after cataract surgery in study eye. 
 
Faricimab 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, faricimab treatment may be permitted as 
determined by the investigator.  The investigator may contact the 
Medical Monitor to discuss any concerns regarding individual 
cases, as appropriate. 
BCVA  best-corrected visual acuity; IOP  intraocular pressure. 

 
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Table 2 
Dose Interruption and Treatment Discontinuation Criteria (cont.) 
Event  
Criteria 
BCVA decrease 
 
Interrupt faricimab treatment if there is a study treatment-related 
decrease in BCVA of  30 letters in the study eye compared with 
the last assessment of BCVA prior to the most recent treatment. 
 
Faricimab treatment may be permitted subsequently, as 
determined by the investigator. 
Elevated IOP 
 
Interrupt faricimab 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 by treatment, as determined 
by the investigator. 
Rhegmatogenous 
retinal break 
 
Interrupt faricimab treatment if a retinal break is present in the 
study eye. 
 
Faricimab treatment may be resumed no earlier than 28 days after 
successful laser retinopexy, as determined by the investigator. 
Rhegmatogenous 
retinal detachment or 
macular hole 
 
Interrupt faricimab treatment if rhegmatogenous retinal detachment 
or Stage 3 or 4 macular hole occurs in the study eye. 
 
Faricimab treatment may be subsequently permitted as determined 
by the investigator.  The investigator may contact the Medical 
Monitor to discuss any concerns regarding individual cases, as 
appropriate. 
Active or suspected 
infection  
 
Interrupt faricimab treatment if active or suspected ocular or 
periocular infections are present (e.g., infectious conjunctivitis, 
infectious keratitis, infectious scleritis, or endophthalmitis) in either 
eye or if the patient requires treatment for an active systemic 
infection.  Study treatment may be interrupted for other medically 
significant systemic infections as determined by the investigator.  
The investigator may contact the Medical Monitor to discuss any 
concerns regarding individual cases, as appropriate.  
On-study prohibited 
medications 
 
Refer to Section 4.4.2 for additional reasons for potential faricimab 
treatment discontinuation. 
BCVA  best-corrected visual acuity; IOP  intraocular pressure. 
  
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, measuring 
protocol-specified vital signs, and conducting other protocol-specified tests that are 
deemed critical to the safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 

 
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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 Section 5.3.5.8 and 
Section 5.3.5.9 for more information) 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
enrollment 
 
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) 
 
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 
Events Grading Scale; see Section 5.3.3); the event itself may be of relatively minor 
medical significance (such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 

 
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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: 
– 
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 5.3.5 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. 

 
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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 during the masked 
period of the study, 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 enrollment in this study, all adverse events will be reported until the final 
safety follow-up visit.  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 but continue to participate in the study, adverse 
events will be reported until their last or final study visit. 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
Table 3 provides guidance for assessing adverse event severity. 
Table 3 
Adverse Event Severity Grading Scale 
Severity 
Description 
Mild 
Discomfort noticed, but no disruption of normal daily activity 
Moderate 
Discomfort sufficient to reduce or affect normal daily activity 
Severe 
Incapacitating with inability to work or to perform normal daily activity 
Note:  Regardless of severity, some events may also meet seriousness criteria.  
Refer to definition of a serious adverse event (see Section 5.2.2). 
  

 
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5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 4)  
 
Temporal relationship of event onset to the initiation of study drug 
 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
 
Known association of the event with the study drug or with similar treatments 
 
Known association of the event with the disease under study 
 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
Table 4 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
  
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. 

 
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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. 
Note:  Trace, benign, pigmented cells in the anterior chamber visible on slitlamp 
examination caused by dilation, and are not red blood cells or white blood cells or the 
result of any ocular disorder, should not be recorded as an adverse event. 
5.3.5.1 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.2 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 

 
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 
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. 
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. 

 
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If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5  ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events). 
5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment  
 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  ULN) in combination with either an elevated 
total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 

 
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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 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2). 
5.3.5.7 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2). 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the Day 1 visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF or as an ongoing event on the Adverse Events eCRF from the parent 
Phase III study. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.9 
Lack of Efficacy or Worsening of nAMD in the Study Eye 
Medical occurrences or symptoms of deterioration that are anticipated as part of nAMD 
should be recorded as an adverse event if judged by the investigator to have 

 
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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"). 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
– 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
– 
The patient has not experienced an adverse event 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
  
5.3.5.11 
Cases of Accidental Overdose or Medication Error 
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
 
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, 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).   

 
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During the Masked Period (Day 1 to Week 12) 
For masked study treatment, adverse events associated with special situations should 
be recorded in a masked manner as described below: 
 
Enter the adverse event caused by the medication error as the primary adverse 
event term.  Check the "Medication error" box. 
 
In addition, all special situations associated with 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. 
 
For intercepted medication error enter “Intercepted Medication Error” on the 
Adverse Event eCRF as the primary event term and 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" boxes would need to be checked for both 
entries. 
During the Open-Label Period (Week 16 to Week 104) 
For faricimab, adverse events associated with special situations should be recorded as 
described below for each situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
In addition, all special situations associated with faricimab, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF as described 
below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 

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

 
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5.4.1 
Medical Monitors and Emergency Medical Contacts 
Contact Information for Western Hemisphere 
Medical Monitor/Emergency Medical Contact: 
, M.D., Ph.D. (Primary) 
Mobile Telephone No.: 
 
Medical Monitor/Emergency Medical Contact: 
, M.D. 
(Secondary) 
Mobile Telephone No.: 
 
Contact Information for Eastern Hemisphere 
Medical Monitor/Emergency Medical Contact: 
, M.D. 
Mobile Telephone No.: 
Contact Information for Asia-Pacific 
Medical Monitor/Emergency Medical Contact: 
, M.D., Ph.D. 
Mobile Telephone No.: 
 
To ensure the safety of study patients, an Emergency Medical Call Center will be 
available 24 hours per day, 7 days per week, in case the above-listed contacts cannot 
be reached.  The Emergency Medical Call Center will connect the investigator with an 
Emergency Medical Contact, provide medical translation service if necessary, and track 
all calls.  Contact information, including toll-free numbers for the Emergency Medical Call 
Center, will be distributed to investigators.  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur after Enrollment  
After enrollment in this study, serious adverse events and adverse events of special 
interest will be reported until the final safety follow-up visit.  For patients who terminate 
from the study treatment and the study early, all adverse events will be reported up to 
the early termination visit. 
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 
via the electronic data capture (EDC) system.  A report will be generated and sent to 
Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.   

 
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Instructions for reporting post-study adverse events are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed 
Consent Form to immediately inform the investigator if they become pregnant during the 
study or within 3 months after the final dose of study drug.  A paper Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
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 (see 
definition in Section 5.3.1), if the event is believed to be related to prior study drug 
treatment.  These events should be reported through use of the Adverse Event eCRF.  
However, if the EDC system is not available, the investigator should report these events 
directly to the Sponsor or its designee, either by faxing or by scanning and emailing the 
paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest Reporting 
Form using the fax number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 

 
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To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the document listed below: 
Drug 
Document 
Faricimab 
Faricimab Investigator's Brochure  
  
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
6.1 
DETERMINATION OF SAMPLE SIZE 
No formal sample size calculations will be performed for this LTE study.  This study is 
open to all patients who complete study treatment and the Week 112 visit in one of the 
parent studies GR40306 (TENAYA) or GR40844 (LUCERNE) (see Section 4.1.1, and 
Section 4.1.2). 
6.2 
ANALYSIS POPULATIONS 
6.2.1 
Efficacy-Evaluable Population 
The efficacy-evaluable population will comprise all eligible patients enrolled into this LTE 
study.  Baseline will be calculated as Day 1 of this LTE study for patients randomized 
to faricimab in the parent study and as the first day of faricimab treatment for patients 
randomized to aflibercept in the parent study.  For analyses using the parent study 
treatment group, patients will be grouped according to the treatment assigned at 
randomization in the parent study 
6.2.2 
Per-Protocol Population 
The per-protocol population is defined as all efficacy-evaluable patients who do not have 
a major protocol violation that impact the efficacy evaluation or the treatment interval 
determination.  For analyses using the parent study treatment group, patients will be 
grouped according to the treatment assigned at randomization in the parent study. 
6.2.3 
Safety-Evaluable Population 
The safety-evaluable population will comprise all eligible patients enrolled into this LTE 
study.  Baseline will be calculated as Day 1 of this LTE study for patients randomized 
to faricimab in the parent study and from the first day of faricimab treatment for 
patients randomized to aflibercept in the parent study. For analyses based on the 
parent study treatment groups, patients will be grouped according to the actual treatment 
received in the parent study up to the Week 108.  If during the parent study by error, a 

 
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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.  If during the 
parent study 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 Population 
The PK population will include safety-evaluable patients who have at least one plasma 
sample, and if sufficient dosing information (dose and dosing time) is available.  The 
parent study treatment group will be defined similar to the safety-evaluable population 
(see Section 6.2.3). 
6.2.5 
Immunogenicity Population 
The immunogenicity population will consist of all patients with at least one plasma 
sample for ADA assessment.  For analyses using the parent study treatment group, 
patients will be grouped according to treatment received in the parent study. 
6.3 
SUMMARIES OF CONDUCT OF STUDY 
Summaries of conduct of study will be based on the efficacy-evaluable population and 
presented overall, and by parent study treatment group.  The number and percentage of 
patients who enroll (including from which parent study) will be summarized by country 
and site. The number and percentage of patients who enroll (including from which parent 
study), discontinue or complete the LTE study will be summarized overall.  Reasons for 
premature study withdrawal will be listed and summarized.  Eligibility criteria exceptions 
and other major protocol deviations will be listed and evaluated for their potential effects 
on the interpretation of the study results. 
6.4 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics will be summarized using the 
efficacy-evaluable population presented overall, and by parent study treatment group.  
Demographic data (e.g., age, sex, and race/ethnicity) will originate from the parent 
study.  Baseline disease characteristics (e.g., baseline BCVA, ocular assessments) will 
be summarized for both the parent study and the LTE study.  Descriptive statistics for 
continuous data will include number of observations, arithmetic mean, SD, median, 
minimum, and maximum.  Descriptive statistics for categorical data will include 
frequency and/or percent. 
Exposure to study drug (number of treatments and duration of treatment) will be 
summarized cumulatively from Day 1 of the parent study and throughout the LTE study 
as well as separately for the parent study only and the LTE study only. Exposure will be 
presented overall, and by parent treatment group for the safety-evaluable population. 

 
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6.5 
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). 
Verbatim descriptions of treatment emergent adverse events will be mapped to Medical 
Dictionary for Regulatory Activities thesaurus terms, and the incidence and severity will 
be summarized.  A treatment emergent adverse event is defined as any new adverse 
event reported or any worsening of an existing condition on or after the first day (Day 1) 
of this LTE study.  Only adverse events captured in this LTE study will be included for 
summaries. 
Adverse events will be tabulated by System Organ Class and Preferred Term and 
presented overall, and by parent study treatment group.  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 timepoint and by eye (study 
vs. fellow) using descriptive summaries.  In addition, changes, from parent study Day 1 
and from LTE study Day 1 for patients randomized to faricimab in the parent study and 
from the first day of faricimab treatment for patients randomized to aflibercept in the 
parent study, 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 SAP.  
Additional analyses may be conducted from Day 1 of the parent study. 
6.6 
EXPLORATORY EFFICACY ANALYSES 
Unless otherwise noted, the exploratory efficacy analyses will be based on the 
efficacy-evaluable population and will be presented overall for the whole LTE study 
cohort for both binary and continuous endpoints.  The exploratory efficacy analyses will 
be based on all available observations.  
Additional analyses based on the per-protocol population will also be conducted for the 
BCVA score and CST analyses at 1 and 2 year timepoints. 
6.6.1 
Endpoints (Variables) 
All efficacy endpoints will be assessed over time, at 1 and 2 year timepoints in the LTE 
study.  Change from baseline will be calculated from Day 1 of this LTE study for patients 
randomized to faricimab in the parent study and from the first day of faricimab 
treatment for patients randomized to aflibercept in the parent study.  Additional 
analyses may be conducted from Day 1 of the parent study.   

 
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The following endpoints will be included in the exploratory efficacy analyses: 
 
Change in BCVA as measured using the ETDRS chart at a starting distance of 
4 meters 
 
Proportion of patients avoiding loss of  15,  10 or  5, letters in BCVA 
 
Proportion of patients gaining  15,  10  5, or  0 letters in BCVA 
 
Change in CST as measured by OCT 
 
As determined by OCT, proportion of patients with absence of central retina:  
– 
Intraretinal fluid 
– 
Subretinal fluid 
– 
Both intraretinal and subretinal fluid 
– 
Intraretinal cysts 
– 
Pigment epithelial detachment 
 
Change in total area of CNV lesion as assessed by FFA 
 
Change in total area of leakage as assessed by FFA 
 
Number of faricimab injections received during the LTE study 
 
The proportion of patients on each treatment interval during the study 
 
Change in patient-reported vision-related functioning and quality of life as assessed 
using the NEI VFQ-25 composite score, the near activity subscale score, the 
distance activities subscale score, and driving subscale score 
 
Efficacy endpoints will be assessed descriptively wherein continuous endpoints will be 
summarized using the number of observations, arithmetic mean, SD, median, minimum, 
and maximum.  Categorical endpoints will be summarized using frequency and/or 
percent. Details regarding additional exploratory efficacy endpoints will also be provided 
in the SAP. 
6.7 
PHARMACOKINETIC ANALYSES 
PK analyses will be performed using the PK population (Section 6.2.4).  The analyses 
will be summarized overall and by parent study treatment group.  Plasma concentrations 
of faricimab will be summarized descriptively. 
Concentrations of faricimab from the optional collection of aqueous humor may be 
reported and/or summarized as appropriate.  Additional PK/PD and exposure response 
analyses may be conducted as appropriate.  Population PK modeling may be performed 
to characterize interindividual variability, which may be reported separately from the 
Clinical Study Report. 
6.8 
IMMUNOGENICITY ANALYSES 
Immunogenicity analyses will be based on the immunogenicity analysis population. 

 
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The number and proportion of ADA-positive patients and ADA-negative patients at 
baseline Day 1 in the parent study (baseline prevalence 1), LTE baseline Day 1 
(baseline prevalence 2), and after LTE enrollment (post-baseline 1 and 2 incidence) will 
be summarized overall and by parent study treatment group.  When determining the 
post-baseline incidences, patients are considered to be ADA positive if they are ADA 
negative or have missing data at baseline but who develop an ADA response following 
study drug exposure, or if they are ADA positive at baseline and the titer of one or more 
post-dose samples is greater than the titer of the baseline sample by a scientifically 
reasonable margin (details to be provided in the SAP).  Patients are considered to be 
ADA negative if they are ADA negative or have missing data at baseline and all 
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. 
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported using descriptive statistics. 
6.9 
BIOMARKER ANALYSES 
Biomarker analyses will be based on the safety-evaluable population.  Results will be 
summarized descriptively. 
Analyses will be performed 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. 
6.10 
INTERIM ANALYSIS 
No formal interim analysis is planned.  An interim analysis may be performed for 
publication purposes.  
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 reading 
center images will be sent directly to the Sponsor, using the Sponsor's standard 
procedures to handle and process the electronic transfer of these data. 

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

 
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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 15 years after completion or discontinuation of the study or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 

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

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

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

 
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9.3 
MANAGEMENT OF STUDY QUALITY 
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  The 
Sponsor will identify potential risks associated with critical trial processes and data and 
will implement plans for evaluating and controlling these risks.  Risk evaluation and 
control will include the selection of risk-based parameters (e.g., adverse event rate, 
protocol deviation rate) and the establishment of quality tolerance limits for these 
parameters.  Detection of deviations from quality tolerance limits will trigger an 
evaluation to determine if action is needed.  Details on the establishment and monitoring 
of quality tolerance limits will be provided in a Quality Tolerance Limit Management Plan. 
9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.. 
9.5 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring. 
Approximately 400 sites globally participated in the parent studies, and these same sites 
will enroll approximately 1280 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. 
9.6 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/  
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 

 
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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. 
9.7 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 

 
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10. 
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Appendix 1  
Schedule of Activities 
 
Day 1a Week 4 Week 8 Week 12 PTI interval Year 1 b Year 2 b 
Safety Follow-Up c 
Early 
Treatment/Study 
Termination d 
Visit Window (days) 
 
(7) 
(7) 
(7) 
(7) 
 
 
 28 days and  35 
days after Year 2 or 
final study treatment, 
whichever is later 
 28 days after 
final study 
treatment 
Main informed consent e 
x  
 
 
 
 
 
 
 
 
Informed consent for optional 
collection of aqueous humor, blood, 
and vitreous humor samples e 
x 
 
 
 
 
 
 
 
 
Informed consent for optional 
collection and/or storage of samples 
for the RBR e 
x 
 
 
 
 
 
 
 
 
Review of inclusion and exclusion 
criteria 
x 
 
 
 
 
 
 
 
 
Vital signs f 
(x) g 
 
 
 
 
 
x 
x 
x 
NEI VFQ-25 h 
(x) i 
 
 
 
 
x 
x 
 
x 
BCVA j 
(x) g 
x 
x 
x 
x 
x 
x 
x 
x 
Low-luminance BCVA 
(x) g 
 
 
 
 
x 
x 
 
 
Pre-treatment IOP k 
(x) l 
x 
x 
x 
x 
x 
x 
x 
x 
Urine pregnancy test m 
(x) l 
x 
x 
x 
x 
x 
x 
x 
x 
Mandatory plasma PK sample n 
(x) i 
 
x 
x 
 
x 
x 
 
x 
Mandatory plasma ADA sample n 
(x) i 
 
x 
x 
 
x 
x 
 
x 
Optional aqueous humor sample o 
x 
x 
x 
x 
 
 
 
 
 

Appendix 1: Schedule of Activities 
 
Faricimab—F. Hoffmann-La Roche Ltd 
91/Protocol GR42691, Version 3 
 
Day 1a Week 4 Week 8 Week 12 PTI interval Year 1 b Year 2 b 
Safety Follow-Up c 
Early 
Treatment/Study 
Termination d 
Visit Window (days) 
 
(7) 
(7) 
(7) 
(7) 
 
 
 28 days and  35 
days after Year 2 or 
final study treatment, 
whichever is later 
 28 days after 
final study 
treatment 
Optional PK plasma sample (only 
if optional aqueous humor sample is 
collected) o 
 
x 
 
 
 
 
 
 
 
Optional PD plasma sample (only if 
aqueous humor sample is collected) 
o 
(x) i 
x 
x 
x 
 
 
 
 
 
Optional RBR whole blood sample 
for DNA p 
x 
 
 
 
 
 
 
 
 
Optional vitreous humor sample q 
Can be collected if vitrectomy is necessary 
Optional PK plasma sample (only if 
optional vitreous humor sample is 
collected) q 
Collect if vitreous humor sample is collected 
Slitlamp examination 
(x) l 
x 
x 
x 
x 
x 
x 
x 
x 
Indirect ophthalmoscopy 
(x) l 
x 
x 
x 
x 
x 
x 
x 
x 
OCT r 
(x) g 
x 
x 
x 
x 
x 
x 
x 
x 
Optional OCT-A s 
(x) g 
x 
x 
x 
 
x 
x 
 
x 
FFA t 
(x) i 
 
 
 
 
x 
x 
 
x 
CFP t 
(x) i 
 
 
x 
 
x 
x 
 
x 
Optional ICGA u 
(x) i 
 
 
 
 
x 
x 
 
x 
Administration of study treatment v 
x 
x 
x 
x 
x 
x  
(x) w 
 
 

Appendix 1: Schedule of Activities 
 
Faricimab—F. Hoffmann-La Roche Ltd 
92/Protocol GR42691, Version 3 
 
Day 1a Week 4 Week 8 Week 12 PTI interval Year 1 b Year 2 b 
Safety Follow-Up c 
Early 
Treatment/Study 
Termination d 
Visit Window (days) 
 
(7) 
(7) 
(7) 
(7) 
 
 
 28 days and  35 
days after Year 2 or 
final study treatment, 
whichever is later 
 28 days after 
final study 
treatment 
Finger-counting test x 
x 
x 
x 
x 
x 
x 
(x) w 
 
 
Post-treatment IOP y 
x 
x 
x 
x 
x 
x  
(x) w 
 
 
Adverse events z 
x 
x 
x 
x 
x 
x  
x  
x 
x 
Concomitant medications aa 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concurrent ocular procedures bb 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
ADA  anti-drug antibody; BCVA  best-corrected visual acuity; CFP  color fundus photograph; CRC  central reading center; EC  Ethics 
Committee; eCRF  electronic Case Report Form; FFA  fundus fluorescein angiography; ICGA  indocyanine green angiography; 
IOP  intraocular pressure; IRB  Institutional Review Board; IxRS  interactive voice or web-based response system; LTE  long-term extension; 
NEI VFQ-25  National Eye Institute Visual Functioning Questionnaire25; OCT  optical coherence tomography; OCT-A  optical coherence 
tomographyangiography; PD  pharmacodynamic; PK  pharmacokinetic; PTI  personalized treatment interval; RBR  Research Biosample 
Repository.  
Notes:  All ocular assessments are to be performed for both eyes unless noted otherwise.  All assessments must be performed on the 
same day (except safety follow-up and early treatment/study termination). 
a The LTE study Day 1 visit and the parent Phase III study Week 112 visit should be on the same day.  If this is not possible, the Day 1 LTE visit 
should be performed within 2 business days of the Phase III Week 112 visit. 
b Annual visits are defined as the scheduled PTI visit that is closest to 52 weeks (occurring between Week 48 and 64 for Year 1) and 104 weeks 
(occurring between Week 96 and 104 for Year 2) from Day 1.  IxRS will advise the site whether the next scheduled visit should be considered 
the Year 1 or Year 2 visit.  If more than one visit meets the criteria of the annual visits, then the earliest eligible visit will be considered Year 1 or 
Year 2.  If the patient is not scheduled to return for a PTI visit between Week 96 and 104, then the patient should return to the site at Week 104 
to perform the Year 2 visit.  If the earliest scheduled visit is missed, then the next visit within the period should be considered the annual 
visit. 

Appendix 1: Schedule of Activities 
 
Faricimab—F. Hoffmann-La Roche Ltd 
93/Protocol GR42691, Version 3 
c The safety follow-up visit must occur 28 days and 35 days after the actual date of the Year 2 visit or the actual date of last study treatment, 
whichever is later. 
d Patients who discontinue the study or study treatment (but will remain in the study) prior to the final study visit who have not withdrawn 
consent should return for an early treatment/study termination visit after a minimum of 28 days have elapsed since the last study treatment.  
The early treatment/study termination visit should only be completed once in the event a patient discontinues study treatment and later 
discontinues the study.  
e Informed consent must be administered and documented before any study assessment or procedure is performed and may be obtained more 
than 28 days before the Day 1 visit.  The Optional Collection of Aqueous Humor, Blood, and Vitreous Humor Samples Informed Consent Form 
as well as the Optional Collection and/or Storage of Samples for the Research Biosample Repository Informed Consent Form can be signed 
either at the parent study Week 108 visit or the LTE study Day 1 visit prior to sample collection.  
f Vital signs include measurement of temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressure and should be recorded 
before study treatment (if applicable).  Vital signs will be measured with the patient in a seated position after resting for 5 minutes. 
g Assessment will be collected as part of the parent Phase III Week 112 visit, and will not be obtained again for LTE Day 1 if the LTE Day 1 visit is 
completed on the same day or within 2 business days of the parent Week 112 visit; see Section 3.1. 
h To be administered by masked site staff (except for the BCVA examiner) prior to any other visit assessments being performed on that day.  
Refer to Section 4.5.7.1 for further details on questionnaire administration. 
i Assessment must be collected as part of parent Phase III Week 112 visit prior to enrollment in the LTE and will not be collected again as part of 
LTE Day 1 visit; see Section 3.1. 
j To be performed on both eyes prior to other ocular assessments and prior to dilating the eyes.  BCVA data for both eyes to be entered in 
appropriate eCRF log at each visit.  Study eye BCVA data must be entered in IxRS at each visit as soon as possible—ideally within 24 hours of 
the study visit.  These data will be required by the IxRS to calculate the next treatment interval, and failure to follow this procedure will result in a 
delay to the patient receiving notification of the timeframe for their subsequent dosing visit. 
k Pre-treatment IOP should be measured before pupillary dilation at each study visit.  IOP should be measured at the safety follow-up and early 
treatment/study termination visit, if applicable, although study treatment will not be administered. 
l Assessment will be collected as part of parent Phase III Week 112 visit if Week 112 and LTE Day 1 are performed on the same day.  
Assessment will also be performed as part of the LTE Day 1 visit if Week 112 and Day 1 visits are conducted on different days; see Section 3.1.  
m Urine pregnancy test should be performed on women of childbearing potential, including those who have had tubal ligation, at each study 
treatment visit as well as the safety follow-up and early treatment/study termination visits.  If positive, study treatment should be withheld and 
a serum pregnancy sample collected and forwarded to the central laboratory for testing.  If the serum pregnancy test is positive, study treatment 
should be withheld. 

Appendix 1: Schedule of Activities 
 
Faricimab—F. Hoffmann-La Roche Ltd 
94/Protocol GR42691, Version 3 
n Samples should be collected prior to study treatment administration, and, if scheduled, FFA.  If a patient misses a study visit where mandatory 
sample collection is scheduled, or the sample collection is missed, mandatory samples may be obtained at the next scheduled visit.  This does 
not apply to missed Week 8 samples because Week 12 is also a sampling visit. 
o Only applicable to sites for whom IRB/EC approval has been granted and in patients who have consented to optional sampling.  Samples to be 
collected from the study eye prior to study treatment administration.  If applicable, samples may be collected after FFA.  Please collect 
associated optional plasma PK and PD samples at the indicated timepoints if aqueous humor sample is collected.  Missed optional aqueous 
humor samples and associated plasma samples are not required to be made up at the next visit. 
p Optional whole blood sample collection only in patients for whom optional sample was not collected in the parent study.  If the 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, ADA). This sample collection is not applicable for a site that has not been granted approval by the country 
regulators or site’s Institutional Review Board or Ethics Committee. The samples will be collected from patients who give specific consent to 
participate in this optional research.  
q If vitrectomy is medically necessary and the patient consents, a vitreous sample can be obtained from the study eye.  An associated PK blood 
sample should also be collected at this time.  Samples to be shipped to the central laboratory as per manual instructions. 
r Parent study CRC certified equipment to be used.  OCT images must be sent to the CRC as soon as possible (ideally within 24 hours), as these 
need to be read by the CRC who will update IxRS to calculate the next treatment interval.  Failure to follow this procedure will result in a 
delay to the patient receiving notification of the timeframe for their subsequent dosing visit. 
s Parent study CRC certified equipment to be used.  Only at sites with OCT-A capabilities.  If a patient misses a study visit when OCT-A is 
scheduled, or scheduled images missed (e.g., due to faulty equipment), images must be obtained at the next scheduled visit. 
t Parent study CRC certified equipment to be used.  FFA should be performed after laboratory samples have been collected.  If a patient misses 
a study visit when FFA or CFP is scheduled, or scheduled images missed (e.g., due to faulty equipment), images must be obtained at the next 
scheduled visit. 
u Parent study CRC certified equipment to be used.  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.  If a patient misses a study visit when ICGA is scheduled, or 
scheduled images missed (e.g., due to faulty equipment), images must be obtained at the next scheduled visit. 
v During the masked period of the LTE study, patients will receive either faricimab or sham injection.  Refer to Section 3.1, Section 4.2, and 
Section 4.3 for further details. 
w Study treatment administration and post-dose safety assessments only to be conducted if the Year 2 visit is a faricimab dosing visit. 
x The finger-counting test should be conducted within approximately 15 minutes after treatment administration to the study eye. 

Appendix 1: Schedule of Activities 
 
Faricimab—F. Hoffmann-La Roche Ltd 
95/Protocol GR42691, Version 3 
y Post-treatment IOP to be measured in the study eye post-study treatment administration by qualified personnel assigned to the unmasked role 
during the masked period.  If there are safety concerns, the patient should be managed in accordance with the investigator’s clinical judgment.  
Any adverse events will be recorded on the Adverse Event eCRF. 
z All adverse events will be reported until the final study visit or until the early treatment/study termination visit (if applicable).  After this period, 
the Sponsor should be notified if the investigator becomes aware of any serious adverse events that are believed to be related to prior study 
drug treatment (see Section 5.6).  The investigator should follow each adverse event until the event has resolved to baseline grade or better, 
the event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be 
made to follow all serious adverse events considered to be related to study drug or trial-related procedures until a final outcome can be 
reported. 
aa Record any concomitant medications (i.e., any prescription medications or over-the-counter preparations other than protocol-specified 
procedural medications such as proparacaine, etc.) used by a patient until the conclusion of the patient’s study participation or early 
treatment/study termination visit. 
bb Record all concurrent ocular procedures performed on the study or non-study eye up until the final study visit or early treatment/study 
termination visit (if applicable). 

 
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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 
Pregnancy test 
Best-corrected visual acuity (assessed at a 4-meter starting distance) b 
Slitlamp examination 
Dilated binocular indirect high-magnification ophthalmoscopy 
FFA, CFP, ICGA (if applicable), and OCT imaging 
IOP c 
Adverse events d 
Concurrent ocular procedures 
Concomitant medications 
FFA  fundus fluorescein angiography; CFP  color fundus photograph; 
ICGA  indocyanine green angiography; IOP  intraocular pressure; 
OCT  optical coherence tomography. 
Note:  Unscheduled safety visits should only be used for the assessment of 
adverse events and are not intended for standard-of-care procedures. 
a Patients will be instructed to contact the investigator at any time if they 
have any health-related concerns.  Investigators may ask the patient to 
return to the clinic for an unscheduled safety assessment visit if there are 
any concerns.  Assessments performed at unscheduled safety visits are at 
the discretion of the investigator.  It is recommended to perform ocular 
assessments on both eyes.  
b Perform finger counting test followed by hand motion and light perception 
tests when necessary. 
c The method used for the IOP measurement for a patient must remain 
consistent throughout the study. 
d Adverse event causality to be evaluated by the masked physician in the 
assessor role. 
 

 
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Appendix 3  
Grading Scale for Assessment of Anterior Chamber Flare or 
Cells and Vitreous Cells 
Anterior Chamber Flare 
Grade 
Description 
0 
None 
1   
Faint 
2   
Moderate (iris and lens details clear) 
3   
Marked (iris and lens details hazy) 
4   
Intense (fibrin or plastic aqueous) 
 
Anterior Chamber Cells 
Grade 
Cells in Field a 
0 
 1 
0.5   
15 
1   
615 
2   
1625 
3   
2650 
4   
 50 
a Field size is a 1-mm slit beam. 
 
Vitreous Cells 
Grade 
Number of Vitreous Cells 
0 
No cells 
0.5   
110 
1   
1120 
2   
2130 
3   
31100 
4   
 101a 
a There is an error in the publication.  This should read 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 BCVA examiner must be masked to each patient’s study (treated) eye and 
treatment interval assignment for the duration of the study.  BCVA 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 visual acuity (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 
BCVA 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.  

 
Faricimab—F. Hoffmann-La Roche Ltd 
100/Protocol GR42691, Version 3 
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 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 acquired 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.   
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:  Optional optical coherence tomographyangiography (OCT-A) images will be 
collected at the sites with OCT-A capabilities and forwarded to the CRC. 
EQUIPMENT 
See the CRC manual.  Only electronically exportable digital image files will be accepted 
(i.e., print outs of SD-OCT images are not acceptable). 
Note:  Certain swept source optical coherence tomography machines may be acceptable 
to use; consult the CRC 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 concentrations (pharmacokinetics), 
anti-faricimab antibodies, pregnancy test, optional blood DNA sample, and optional 
aqueous humor, vitreous, and blood samples will be obtained at the timepoints specified 
in the protocol (see Section 4.5.6 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. 
A pharmacokinetic and/or pharmacodynamic blood sample (for plasma preparation) 
should also be collected and shipped as specified in the central laboratory manual. 
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.  

Appendix 9: Biological Sample Collection and Shipping Instructions 
 
Faricimab—F. Hoffmann-La Roche Ltd 
104/Protocol GR42691, Version 3 
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.  The 
remaining samples may be analyzed for free Ang-2 and free VEGF-A concentrations, as 
well as possibly other biomarkers.

 
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Appendix 10  
National Eye Institute 25-Item Visual Function Questionnaire 
 

Appendix 10:  National Eye Institute 25-Item Visual Function Questionnaire 
 
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Appendix 10:  National Eye Institute 25-Item Visual Function Questionnaire 
 
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Appendix 10:  National Eye Institute 25-Item Visual Function Questionnaire 
 
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Appendix 10:  National Eye Institute 25-Item Visual Function Questionnaire 
 
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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 
 
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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 
 
Faricimab—F. Hoffmann-La Roche Ltd 
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Appendix 10:  National Eye Institute 25-Item Visual Function Questionnaire 
 
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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 
 
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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 
 
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Signature Page for Prot GR42691 (AVONELLE-X) faricimab v3 - Published
System identifier: RIM-CLIN-446138
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14-Jul-2022 14:35:23 GMT+0000
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