Conditions: Diabetic Macular Edema
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1479
Healthy volunteers: no

Brief summary:
This is a multicenter long-term extension study designed to evaluate the long-term safety and tolerability of faricimab administered by intravitreal (IVT) injection at a personalized treatment interval (PTI) to participants who enrolled in and completed one of the two Phase III studies, GR40349 (NCT03622580) or GR40398 (NCT03622593), also referred to as the parent studies.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Faricimab intervention 2: Sham Procedure
Intervention descriptions: intervention 1: Faricimab will be administered by intravitreal (IVT) injection into the study eye according to the personalized treatment interval (PTI) dosing regimen. intervention 2: 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. The sham procedure will be administered to participants as appropriate during the first 16 weeks of this study in order to maintain the masking of the initial faricimab PTI.

Protocol document:
Prot_000.pdf: 
Official Title: 
A Multicenter, Open-Label Extension Study to Evaluate The Long-
Term Safety and Tolerability of Faricimab in Patients with Diabetic 
Macular Edema 
NCT Number: 
NCT04432831 
Document & Date: 
Protocol Version 3: 13-Dec-2021 


FINAL PROTOCOL APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Faricimab—F. Hoffmann-La Roche Ltd
Protocol GR41987, Version 3
PROTOCOL
TITLE:
A MULTICENTER, OPEN-LABEL EXTENSION 
STUDY TO EVALUATE THE LONG-TERM SAFETY 
AND TOLERABILITY OF FARICIMAB IN PATIENTS 
WITH DIABETIC MACULAR EDEMA
PROTOCOL NUMBER:
GR41987
VERSION NUMBER:
3
EUDRACT NUMBER:
2020-000402-29
IND NUMBER:
119,225
NCT NUMBER:
To be determined
TEST PRODUCT:
Faricimab (RO6867461)
MEDICAL MONITOR:
 M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
See electronic date stamp below.
 
Company Signatory
Approver's Name
Title
Date and Time (UTC)
13-Dec-2021 23:23:33


Faricimab—F. Hoffmann-La Roche Ltd
2/Protocol GR41987, Version 3
PROTOCOL HISTORY
Version
Date Final
2
13 May 2020
1
12 February 2020


Faricimab—F. Hoffmann-La Roche Ltd
3/Protocol GR41987, Version 3
PROTOCOL AMENDMENT, VERSION 3:
RATIONALE
Protocol GR41987 has been amended to include a Final End of Study visit, and extend 
the study to Week 108 for patients who receive their final dose of faricimab at Week 104, 
and to make other minor changes to improve clarity and consistency.  The main changes 
to the protocol, along with a rationale for each change, are summarized below:

Section 3.1.3.6 was added to clarify that it is not possible for a site to manually 
modify the PTI algorithm to adjust the faricimab treatment interval

Section 3.2 has been updated to reflect the addition of a Final End of Study visit
scheduled approximately 4 weeks after receipt of the final study dose of faricimab to 
enable adequate safety monitoring of patients following the final administration of 
study drug

Section 4.1.2 (exclusion criteria) and Appendix 1 have been updated to reconcile
the criterion currently described in the ICF relating to pregnancy

Section 4.4.2 (prohibited therapy) has been edited to clarify that continuous usage 
of topical ophthalmic corticosteroids for 100 days or more is considered prohibited 
therapy, and to add the use of kallidinogenase and other medications claiming to 
have an effect on macular pathology to the list of prohibited therapies.

Section 5.1.1 has been updated to reflect updated information on risks of faricimab 
according to the Investigator’s Brochure version 11.

Section 5.4.1 has been updated to reflect the Medical Monitor change for Western 
Hemisphere. 

Appendix 1 definitions for Year 1 and Year 2 were clarified to explain the specific 
time window for these annual visits, to avoid sites bringing patients back 
unnecessarily outside the PTI scheduling time point.
The following minor changes have been made per Roche guidelines: 

Language has been added to indicate that sites can confirm that appropriate 
temperature conditions have been maintained during IMP transit either by time 
monitoring (shipment arrival date and time) or temperature monitoring (Section 
4.3.3).

Language has been added to clarify that adverse events associated with a special 
situation that also qualify as adverse events of special interest should be reported 
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 name of a Roche policy on data sharing has been corrected (Section 9.6).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.


Faricimab—F. Hoffmann-La Roche Ltd
4/Protocol GR41987, Version 3
TABLE OF CONTENTS
PROTOCOL HISTORY ........................................................................................ 2
PROTOCOL ACCEPTANCE FORM .................................................................. 11
PROTOCOL SYNOPSIS .................................................................................... 12
1.
BACKGROUND .......................................................................................... 19
1.1
Background on Diabetic Macular Edema............................... 19
1.2
Background on Faricimab...................................................... 20
1.2.1
Phase III Faricimab Studies:  GR40349 
(YOSEMITE) and GR40398 (RHINE).................................... 21
1.3
Study Rationale and Benefit-Risk Assessment...................... 21
2.
OBJECTIVES AND ENDPOINTS ............................................................... 22
2.1
Primary Objective .................................................................. 22
2.2
Exploratory Objective............................................................. 22
2.3
Pharmacokinetic Objective .................................................... 23
2.4
Immunogenicity Objective...................................................... 23
2.5
Exploratory Biomarker Objectives ......................................... 23
3.
STUDY DESIGN......................................................................................... 23
3.1
Description of the Study......................................................... 23
3.1.1
Overview of Study Design ..................................................... 24
3.1.1.1
LTE Visit Schedule during the Masked Period....................... 26
3.1.1.2
LTE Visit Schedule following Masked Period......................... 26
3.1.2
Faricimab Dosing Schedule................................................... 26
3.1.2.1
Faricimab Personalized Treatment Interval ........................... 26
3.1.2.2
Faricimab Dosing Intervals—Phase III to LTE....................... 28
3.1.3
Additional Considerations for PTI IxRS Study 
DrugDosing Interval Decision .............................................. 29
3.1.3.1
Missed Faricimab Dosing Visits............................................. 29
3.1.3.2
Treatment Interruption ........................................................... 29
3.1.3.3
Missing CST Value at LTE Study Visit................................... 29
3.1.3.4
Missing BCVA Value at LTE Study Visit ................................ 29
3.1.3.5
Timely Reporting of BCVA and OCT data to 
eCRF, CRC, and IxRS........................................................... 30


Faricimab—F. Hoffmann-La Roche Ltd
5/Protocol GR41987, Version 3
3.1.3.6
Modifications to the PTI Algorithm ......................................... 30
3.2
End of Study and Length of Study......................................... 31
3.3
Rationale for Study Design.................................................... 31
3.3.1
Rationale for Faricimab Dose and Schedule ......................... 31
3.3.2
Rationale for Patient Population ............................................ 33
3.3.3
Rationale for Optional Biomarker Assessments .................... 33
4.
MATERIALS AND METHODS .................................................................... 34
4.1
Patients.................................................................................. 34
4.1.1
Inclusion Criteria.................................................................... 34
4.1.2
Exclusion Criteria................................................................... 35
4.2
Method of Treatment Assignment and Masking .................... 35
4.2.1
Masking Requirements during the Masked Period 
of LTE Study.......................................................................... 35
4.2.1.1
Masked Roles during the Masked Period of the 
LTE Study.............................................................................. 36
4.2.1.2
Unmasked Roles ................................................................... 37
4.2.1.3
Delegation Log ...................................................................... 37
4.2.1.4
Role Switching....................................................................... 37
4.2.1.5
Study Backup Staff ................................................................ 38
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 38
4.3.1
Study Treatment Formulation and Packaging........................ 38
4.3.1.1
Faricimab Formulation........................................................... 38
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 38
4.3.2.1
Faricimab Administration ....................................................... 38
4.3.2.2
Sham Administration ............................................................. 39
4.3.3
Investigational Medicinal Product Accountability ................... 39
4.3.4
Continued Access to Faricimab............................................. 40
4.4
Concomitant Therapy ............................................................ 41
4.4.1
Permitted Therapy................................................................. 41
4.4.2
Prohibited Therapy ................................................................ 42
4.5
Study Assessments ............................................................... 42
4.5.1
Informed Consent Forms....................................................... 43


Faricimab—F. Hoffmann-La Roche Ltd
6/Protocol GR41987, Version 3
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 43
4.5.3
Vital Signs.............................................................................. 43
4.5.4
Ocular Assessments.............................................................. 43
4.5.5
Concurrent Ocular Procedures.............................................. 44
4.5.6
Laboratory and Other Biological Samples ............................. 45
4.5.6.1
Optional Aqueous Humor and Associated 
Optional Plasma Samples ..................................................... 46
4.5.6.2
Optional Unscheduled Collection of Vitreous 
Humor and Associated Optional Plasma Samples ................ 47
4.5.7
Patient-Reported Outcomes .................................................. 47
4.5.7.1
Data Collection Methods for Patient-Reported 
Outcome Assessments.......................................................... 47
4.5.7.2
Description of PRO Instrument.............................................. 48
4.5.8
Optional Samples for Research Biosample 
Repository ............................................................................. 48
4.5.8.1
Overview of the Research Biosample Repository.................. 48
4.5.8.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 49
4.5.8.3
Sample collection .................................................................. 49
4.5.8.4
Confidentiality........................................................................ 50
4.5.8.5
Consent to Participate in the Research 
Biosample Repository............................................................ 50
4.5.8.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 51
4.5.8.7
Monitoring and Oversight....................................................... 51
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 51
4.6.1
Study Treatment Discontinuation........................................... 51
4.6.2
Patient Discontinuation from the Study.................................. 52
4.6.3
Study Discontinuation............................................................ 52
4.6.4
Site Discontinuation............................................................... 52
5.
ASSESSMENT OF SAFETY....................................................................... 53
5.1
Safety Plan ............................................................................ 53
5.1.1
Risks Associated with Faricimab ........................................... 53


Faricimab—F. Hoffmann-La Roche Ltd
7/Protocol GR41987, Version 3
5.1.2
Management of Patients Who Experience 
Adverse Events ..................................................................... 53
5.1.2.1
Treatment Interruption ........................................................... 53
5.2
Safety Parameters and Definitions ........................................ 54
5.2.1
Adverse Events ..................................................................... 55
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 55
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 56
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 57
5.3.1
Adverse Event Reporting Period ........................................... 57
5.3.2
Eliciting Adverse Event Information....................................... 57
5.3.3
Assessment of Severity of Adverse Events ........................... 57
5.3.4
Assessment of Causality of Adverse Events ......................... 58
5.3.5
Procedures for Recording Adverse Events............................ 59
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 59
5.3.5.2
Adverse Events That Are Secondary to Other 
Events.................................................................................... 60
5.3.5.3
Persistent or Recurrent Adverse Events................................ 60
5.3.5.4
Abnormal Laboratory Values ................................................. 60
5.3.5.5
Abnormal Vital Sign Values ................................................... 61
5.3.5.6
Abnormal Liver Function Tests.............................................. 62
5.3.5.7
Deaths ................................................................................... 62
5.3.5.8
Preexisting Medical Conditions.............................................. 62
5.3.5.9
Lack of Efficacy or Worsening of Diabetic 
Macular Edema or Diabetic Retinopathy in the 
Study Eye .............................................................................. 63
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 63
5.3.5.11
Cases of Accidental Overdose or Medication 
Error....................................................................................... 63
5.3.5.12
Patient-Reported Outcome Data ........................................... 65
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 65
5.4.1
Medical Monitors and Emergency Medical 
Contacts ................................................................................ 66


Faricimab—F. Hoffmann-La Roche Ltd
8/Protocol GR41987, Version 3
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 67
5.4.2.1
Events That Occur after Study Drug Initiation........................ 67
5.4.3
Reporting Requirements for Pregnancies.............................. 67
5.4.3.1
Pregnancies in Female Patients............................................ 67
5.4.3.2
Abortions ............................................................................... 67
5.4.3.3
Congenital Anomalies/Birth Defects ...................................... 68
5.5
Follow-Up of Patients after Adverse Events .......................... 68
5.5.1
Investigator Follow-Up........................................................... 68
5.5.2
Sponsor Follow-Up ................................................................ 68
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 68
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees.......................................................... 69
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 69
6.1
Determination of Sample Size ............................................... 69
6.2
Analysis Populations ............................................................. 69
6.2.1
Intent-to-Treat Population...................................................... 69
6.2.2
Per-Protocol Population......................................................... 70
6.2.3
Safety-Evaluable Population.................................................. 70
6.2.4
Pharmacokinetic Population .................................................. 70
6.2.5
Immunogenicity Population.................................................... 70
6.3
Summaries of Conduct of Study............................................ 70
6.4
Summaries of Demographic and Baseline 
Characteristics....................................................................... 71
6.5
Safety Analyses..................................................................... 71
6.6
Exploratory efficacy analyses ................................................ 71
6.6.1
Intercurrent Events ................................................................ 72
6.6.2
Endpoints (Variables) ............................................................ 72
6.7
Pharmacokinetic Analyses..................................................... 73
6.8
Immunogenicity Analyses...................................................... 73
6.9
Biomarker Analyses............................................................... 74
6.10
Interim Analysis ..................................................................... 74


Faricimab—F. Hoffmann-La Roche Ltd
9/Protocol GR41987, Version 3
7.
DATA COLLECTION AND MANAGEMENT ............................................... 74
7.1
Data Quality Assurance......................................................... 74
7.2
Electronic Case Report Forms............................................... 74
7.3
Source Data Documentation.................................................. 75
7.4
Use of Computerized Systems .............................................. 75
7.5
Retention of Records............................................................. 76
8.
ETHICAL CONSIDERATIONS.................................................................... 76
8.1
Compliance with Laws and Regulations ................................ 76
8.2
Informed Consent.................................................................. 76
8.3
Institutional Review Board or Ethics Committee.................... 77
8.4
Confidentiality........................................................................ 78
8.5
Financial Disclosure .............................................................. 79
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 79
9.1
Study Documentation ............................................................ 79
9.2
Protocol Deviations................................................................ 79
9.3
Management of Study Quality ............................................... 79
9.4
Site Inspections ..................................................................... 80
9.5
Administrative Structure......................................................... 80
9.6
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 80
9.7
Protocol Amendments ........................................................... 81
10. REFERENCES ........................................................................................... 82


Faricimab—F. Hoffmann-La Roche Ltd
10/Protocol GR41987, Version 3
LIST OF TABLES
Table 1
Dose Interruption and Treatment Discontinuation Criteria .......... 54
Table 2
Adverse Event Severity Grading Scale ....................................... 58
Table 3
Causal Attribution Guidance ....................................................... 58
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 25
Figure 2
Algorithm for IxRS-Determined Personalized Treatment 
Interval Study Drug Dosing Intervals........................................... 27
LIST OF APPENDICES
Appendix 1
Schedule of Activities................................................................. 85
Appendix 2
Unscheduled Safety Assessment Visit....................................... 90
Appendix 3
Refraction and Best-Corrected Visual Acuity Testing ................ 91
Appendix 4
Grading Scale for Assessment of Anterior Chamber Flare or 
Cells and Vitreous Cell................................................................ 92
Appendix 5
Color Fundus Photography ........................................................ 93
Appendix 6
Fundus Fluorescein Angiography .............................................. 94
Appendix 7
Spectral-Domain Optical Coherence Tomography..................... 95
Appendix 8
Biological Sample Collection and Shipping Instructions............. 96
Appendix 9
National Eye Institute Visual Functioning Questionnaire25...... 98


Faricimab—F. Hoffmann-La Roche Ltd
11/Protocol GR41987, Version 3
PROTOCOL ACCEPTANCE FORM
TITLE:
A MULTICENTER, OPEN-LABEL EXTENSION 
STUDY TO EVALUATE THE LONG-TERM SAFETY 
AND TOLERABILITY OF FARICIMAB IN PATIENTS 
WITH DIABETIC MACULAR EDEMA
PROTOCOL NUMBER:
GR41987
VERSION NUMBER:
3
EUDRACT NUMBER:
2020-000402-29
IND NUMBER:
119,225
NCT NUMBER:
To be determined
TEST PRODUCT:
Faricimab (RO6867461)
MEDICAL MONITOR:
 M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator's Name  (print)
Principal Investigator's Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form to your local study monitor.


Faricimab—F. Hoffmann-La Roche Ltd
12/Protocol GR41987, Version 3
PROTOCOL SYNOPSIS
TITLE:
A MULTICENTER, OPEN-LABEL EXTENSION STUDY TO 
EVALUATE THE LONG-TERM SAFETY AND TOLERABILITY OF 
FARICIMAB IN PATIENTS WITH DIABETIC MACULAR EDEMA
PROTOCOL NUMBER:
GR41987
VERSION NUMBER:
3
EUDRACT NUMBER:
2020-000402-29
IND NUMBER:
119,225
NCT NUMBER:
To be determined
TEST PRODUCT:
Faricimab (RO6867461)
PHASE:
III (Long-term extension)
INDICATION:
Diabetic macular edema
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This long-term extension (LTE) study will evaluate the long-term safety, tolerability, and efficacy
of intravitreal (IVT) faricimab in patients with diabetic macular edema who have completed
either of the Phase III (GR40349 or GR40398) studies. Additional assessments relating to
pharmacokinetics, immunogenicity, and biomarkers will be performed.  Specific objectives and 
corresponding endpoints for the study are outlined below.
Primary Objective
The primary objective is to evaluate the 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 systemic (non-ocular) adverse events.
Exploratory Objective
The exploratory objective of this study is to assess the long-term efficacy of IVT faricimab for 
the management of diabetic eye disease in all patients participating in the LTE study on the 
basis of the following endpoints (Note: Where mentioned, “over time” refers to the change from 
the parent study Day 1 and the LTE study Day 1 visit):

Change in best-corrected visual acuity (BCVA) over time as measured using the Early 
Treatment Diabetic Retinopathy Study chart at a starting distance of 4 meters

Change in central subfield thickness (CST) over time as measured by spectral-domain 
optical coherence tomography

Proportion of patients with presence of central retina intraretinal fluid, subretinal fluid, and
both over time

Number of faricimab injections received during the LTE study

The proportion of patients on a every 4 weeks (Q4W), every 8 weeks, every 12 weeks, and 
every 16 weeks treatment interval during the study


Faricimab—F. Hoffmann-La Roche Ltd
13/Protocol GR41987, Version 3

Proportion of patients with a 2- or 3-step improvement in their Diabetic Retinopathy 
Severity Scale (DRSS) score over time

Proportion of patients with a 2- or 3-step worsening in their DRSS score over time

Proportion of patients who develop new proliferative diabetic retinopathy over time

Change in patient-reported vision-related functioning and quality of life over time 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
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 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 biomarkers), or can increase the knowledge and understanding of 
disease biology, on the basis of the following endpoints:

Relationship between anatomic measures at baseline or during the course of the study and 
the change in visual acuity or other endpoints (e.g., the frequency of study drug 
administration) over time from the start of the LTE study
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 (GR40349 or GR40398), 
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 96-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 100 visit in Studies GR40349 and GR40398).  
The end of study 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.  If the end-of-study visit of the parent study 
and enrollment visit for this extension study cannot be completed on the same day, the 
investigator must contact the Sponsor for further discussion prior to scheduling the extension 
study enrollment visit.


Faricimab—F. Hoffmann-La Roche Ltd
14/Protocol GR41987, Version 3
Approximately 1800 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, GR40349 and 
GR40398. 
Eligible patients who choose to enroll into the LTE study will have monthly, masked, study visits 
for the first 4 months of the study (Day 1 through to Week 16). During the masked period,
patients and physicians will only be masked to the faricimab treatment interval.  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.
Number of Patients
Approximately 1800 patients are expected to participate in this extension 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 GR40349 (YOSEMITE) or GR40398 
(RHINE), 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 acceptable contraceptive methods that result in a failure 
rate of 1% per year during the treatment period and for at least 3 months after the final
dose of study treatment
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements.
Examples of acceptable contraceptive methods include bilateral tubal ligation, male 
sterilization; hormonal contraceptives that inhibit ovulation, hormone-releasing 
intrauterine devices and copper intrauterine devices.
Contraception methods that do not result in a failure rate of 1% per year such as 
male or female condom with or without spermicide; and cap, diaphragm, or sponge 
with spermicide are not acceptable.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  If a patient is 
usually not sexually active but becomes active, they, with their partner, must comply 
with the contraceptive requirements of the study.
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 IVT injection 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.


Faricimab—F. Hoffmann-La Roche Ltd
15/Protocol GR41987, Version 3

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 treatment procedure, 
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 4 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.
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, 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.


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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 96 visit in one of the parent studies 
GR40349 (YOSEMITE) or GR40398 (RHINE).
Interim Analyses 
No formal interim analysis is planned.  Data cuts may be performed at appropriate timepoints 
for inclusion in the submission with the main studies, for example, to support the safety profile.  
An interim analysis may be performed for internal stakeholder data presentations/conference 
presentations/ publications/market authorization purposes.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody
Ang-2
angiopoietin-2 
BCVA
best-corrected visual acuity
CFP
color fundus photograph
CRC
central reading center
CST
central subfield thickness
DME
diabetic macular edema
DR
diabetic retinopathy
DRSS
Diabetic Retinopathy Severity Scale
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
ICH
International Council for Harmonisation
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IOP
intraocular pressure
IRB
Institutional Review Board
ITT
intent to treat
IVT
intravitreal
IxRS
interactive web-based response system
LTE
long-term extension
MedDRA
Medical Dictionary for Regulatory Activities
NEI VFQ-25
National Eye Institute Visual Functioning 
Questionnaire25
NPDR
non-proliferative diabetic retinopathy
OCT
optical coherence tomography
OCT-A
optical coherence tomographyangiography
PD
pharmacodynamic
PDR
proliferative diabetic retinopathy
PI
Principal Investigator


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Abbreviation
Definition
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
UWF
ultra-wide field
ULN
upper limit of normal
VA
visual acuity
VEGF(-A)
vascular endothelial growth factor(-A)
WGS
whole genome sequencing


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1.
BACKGROUND
1.1
BACKGROUND ON DIABETIC MACULAR EDEMA
Diabetic macular edema (DME) is a complication of diabetic retinopathy (DR) and can 
develop at any stage of the underlying disease of retinal microvasculature (Fong et al.
2004).  DME occurs with increasing frequency as the underlying DR worsens from 
non-proliferative DR (NPDR) to proliferative DR (PDR) (Henricsson et al. 1999; 
Johnson 2009).  DME affects central vision and is the most common cause of moderate 
and severe visual impairment in patients with DR (Ciulla et al. 2003; Davidson et al.
2007; Leasher et al. 2016). If left untreated, DME can lead to a loss of 10 or more letters 
in visual acuity (VA) within 2 years in approximately 50% of patients (Ferris and Patz 
1984; Ciulla et al. 2003).  DME affects approximately 14% of patients with diabetes and 
can be found in patients with both Type 1 and Type 2 diabetes (Girach and 
Lund-Andersen 2007). The global prevalence of DME is estimated to be around 7.5%, 
affecting 21 million individuals (Yau et al. 2012). In 2019, the worldwide population of 
people living with diabetes was approximately 463 million, and is estimated to grow to 
548 million by 2045 (International Diabetes Federation 2019), thus the global burden on 
DME is expected to increase significantly.
On a molecular level, DME is a result of a vascular endothelial growth 
factorA (VEGF-A) mediated increase in vessel permeability, and loss of pericytes
consequent to hypoxia-mediated release of pro-angiogenic, hyperpermeability, and 
pro-inflammatory mediators (Antonetti et al. 1999).  VEGF-A also upregulates a 
homeostatic factor, angiopoietin-2 (Ang-2), which acts as an antagonist of the Tie2 
receptor tyrosine kinase on endothelial cells, counteracting vessel stabilization 
maintained through Ang-1dependent Tie2 activation.  Therefore, Ang-2 acts as a 
vascular destabilization factor, rendering the vasculature more elastic and amenable to 
endothelial barrier breakdown and sprouting.  The excess of Ang-2 and VEGF-A in the 
retinal tissues promotes vessel destabilization, vascular leakage, and 
neovascularization.  Ang-2 is also involved in inflammatory pathways, such as 
lymphocyte recruitment.  In summary, both VEGF-A and Ang-2 are recognized as key 
factors mediating diabetic eye disease pathogenesis (Aiello et al. 1994; Davis et al.
1996; Maisonpierre et al. 1997; Gardner et al. 2002; Joussen et al. 2002; Fiedler et al.
2003).
Until recently, focal macular laser was the first line of therapy in the treatment of DME,
but the development of anti-VEGF biologics in the last 10 years has led to dramatic 
improvements in visual outcomes for patients with DME (Diabetic Retinopathy Clinical 
Research Network et al. 2010).  Currently available anti-VEGF therapies for DME 
include ranibizumab and aflibercept.  Other available approved options for the treatment 
of DME include periocular or intravitreal (IVT) steroids and steroid implants.
Despite the significant improvements in both vision and anatomical outcomes achieved 
with anti-VEGF injections in DME, the current standard-of-care for management requires 


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patients to undergo frequent clinical examinations and IVT injections.  This imposes a 
significant burden on patients, caregivers, treating physicians, and the healthcare 
system.  Thus, in the real world, the average number of injections received, and the 
consequent improvements in vision are lower than in clinical trials (Fong et al. 2018, 
Hodzic-Hadzibegovic et al. 2018, Stefanickova et al. 2018, Ziemssen et al. 2018, 
Farinha et al. 2019).
Large Phase III trials of anti-VEGF agents in DME demonstrated that after the first year 
of treatment, fewer injections are needed for maintenance of vision gains (Diabetic 
Retinopathy Clinical Research Network et al. 2010; Schmidt-Erfurth et al. 2014; Elman 
et al. 2015).  However, to achieve optimal outcomes in the absence of validated 
biomarkers to predict treatment frequency, the standard anti-VEGF approach in DME 
still relies on frequent monitoring visits, placing a substantial burden on patients and 
healthcare providers.  In addition, anti-VEGF monotherapy does not fully address other 
pathways, including inflammation and pericyte destabilization, that contribute to 
worsening of diabetic eye disease.
New treatments that target additional pathways and that lead to reduced burden of IVT 
injections are needed to address these unmet medical needs in DME.
1.2
BACKGROUND ON FARICIMAB
Faricimab is a humanized full-length bispecific IgG1 antibody that selectively neutralizes 
Ang-2 and VEGF-A (hereafter referred to as "VEGF"), the key factors mediating 
pathophysiology of diabetic eye disease.  Faricimab was developed using Roche’s 
CrossMab (monoclonal antibody) technology.  The Ang-2 and VEGF binding variable 
regions of faricimab bind to Ang-2 and VEGF independently and simultaneously with 
high affinity.  The Fc portion of faricimab was engineered for ophthalmic use through 
inactivation of effector function (FcR) and elimination of binding to the neonatal receptor 
(FcRn) that has the potential to reduce systemic exposure following IVT injection.
The concentrations of both Ang-2 and VEGF in the vitreous were shown to be 
upregulated in patients with DR (Rangasamy et al. 2011; Park et al. 2014).  In vivo 
pharmacological evaluations in spontaneous and induced mouse and non-human 
primate models of neovascularization and in models of intraocular inflammation (uveitis) 
confirmed the improved anti-angiogenic and anti-inflammatory effects of faricimab 
treatment compared with anti-VEGF monotherapy.
Based on the novel mechanism of action of faricimab through selective neutralization of 
both Ang-2 and VEGF, and based on the pathophysiology of diabetic eye disease, it is 
hypothesized that faricimab may lead to stabilization of the pathological ocular 
vasculature and to improved visual and anatomical outcomes in DME and DR compared 
with anti-VEGF monotherapies.


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Refer to the Faricimab (RO6867461) Investigator's Brochure for details on nonclinical 
and clinical studies.
1.2.1
Phase III Faricimab Studies: GR40349 (YOSEMITE) and 
GR40398 (RHINE)
The Sponsor is currently investigating the efficacy and safety of faricimab 6 mg in 
DME in two identical, global Phase III, randomized, double-masked, active 
comparator-controlled trials. Approximately 1800 patients have been randomized 
in a 1:1:1 ratio to one of three treatment arms.  The studies include both patients with 
DME who were naive to anti-VEGF therapy in the study eye and patients who have 
previously been treated with anti-VEGF therapy in the study eye.
The Phase III study treatment arms are as follows:

Arm A (administered every 8 weeks [Q8W]) (n600):  Patients randomized to 
Arm A will have received faricimab 6-mg IVT injections every 4 weeks (Q4W) to 
Week 20, followed by faricimab 6-mg IVT injections Q8W to Week 96, followed by 
the final study visit at Week 100.

Arm B (personalized treatment interval [PTI]) (n600):  Patients randomized to 
Arm B will have received faricimab 6-mg IVT injections Q4W to at least Week 12, 
followed by PTI dosing of faricimab 6-mg IVT injections to Week 96, followed by the 
final study visit at Week 100.

Arm C (comparator arm; administered Q8W) (n600):  Patients randomized to 
Arm C will have received aflibercept 2-mg IVT injections Q4W to Week 16, followed 
by aflibercept 2-mg IVT injections Q8W to Week 96, followed by the final study visit 
at Week 100.
The aim of the Phase III program is to evaluate the efficacy, safety, and 
pharmacokinetics of faricimab when administered to patients at Q8W intervals and with 
a PTI regimen compared with aflibercept (Eylea®) monotherapy in patients with DME.  
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 optical coherence tomography [SD-OCT], color fundus 
photographs [CFPs], fundus fluorescein angiography [FFA]), and other imaging 
modalities to assess both DME and DR outcomes.  In addition, safety, patient-reported 
outcomes (PROs), and the pharmacokinetics of faricimab will be assessed.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
The Phase II study (BP30099 [BOULEVARD]) provided preliminary evidence of a 
positive benefitrisk profile for the use of 6-mg IVT injections of faricimab for patients 
with DME. Further evidence for the efficacy, safety, and tolerability of the drug in this 
patient group will be generated in the pivotal Phase III studies, GR40349 (YOSEMITE) 
and GR40398 (RHINE).


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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 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 DME.
2.
OBJECTIVES AND ENDPOINTS
This long-term extension (LTE) study will evaluate the long-term safety, tolerability, and 
efficacy of IVT faricimab in patients with DME who have completed either of the 
Phase III (GR40349 or GR40398) studies. Additional assessments relating to
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.
2.1
PRIMARY OBJECTIVE
The primary objective is to evaluate the 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 systemic (non-ocular) adverse events.
2.2
EXPLORATORY OBJECTIVE
The exploratory objective of this study is to assess the long-term efficacy of IVT 
faricimab for the management of diabetic eye disease in all patients participating in the 
LTE study on the basis of the following endpoints (Note: Where mentioned, “over time”
refers to the change from the parent study Day 1 and the LTE study Day 1 visit):

Change in BCVA over time as measured using the Early Treatment Diabetic 
Retinopathy Study (ETDRS) chart at a starting distance of 4 meters

Change in central subfield thickness (CST) over time as measured by SD-OCT

Proportion of patients with presence of central retina intraretinal fluid, subretinal 
fluid, and both over time

Number of faricimab injections received during the LTE study

The proportion of patients on a Q4W, Q8W, every 12 weeks (Q12W), and every 
16 weeks (Q16W) treatment interval during the study

Proportion of patients with a 2- or 3-step improvement in their Diabetic 
Retinopathy Severity Scale (DRSS) score over time

Proportion of patients with a 2- or 3-step worsening in their DRSS score over 
time

Proportion of patients who develop new PDR over time


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
Change in patient-reported vision-related functioning and quality of life over time 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
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 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 or during the course of the 
study and the change in visual acuity or other endpoints (e.g., the frequency of 
study drug administration) over time from the start of the LTE study
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 (GR40349 or GR40398), 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 96-week treatment period are not eligible for 
enrollment in this extension study.


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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 100 visit in Studies GR40349 and 
GR40398).  Patients will be enrolled into the extension study using an interactive 
web-based response system (IxRS).
The end of study 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 assessments in Appendix 1).  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 1800 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, GR40349 and GR40398. 
Patients will be required to attend study assessment visits at intervals as scheduled by 
the IxRS system based on the PTI algorithm (see below). Figure 1 outlines the study 
design, and the schedule of activities is provided in Appendix 1 and Appendix 2.


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Figure 1
Study Schema
LTElong-term extension; PTIpersonalized treatment interval; Q8W every 8 weeks.
In the LTE study, all patients will move from the Phase III parent study arm to a faricimab PTI arm.  Refer to Sections 3.1.1.1 and 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 Sections 4.1.1 and 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 4 months of the study (Day 1 through to Week 16; see Figure 1).
During the masked period, patients and physicians will only be masked to the faricimab 
treatment interval. 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 optical coherence tomography CST values obtained at dosing visits.
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.
3.1.2.1
Faricimab Personalized Treatment Interval
The PTI algorithm is the same as that used in the Phase III studies and uses anatomical 
(i.e., CST) and functional (i.e., BCVA) data obtained at dosing visits to determine the 
next interval for faricimab dosing. Faricimab dosing intervals can be adjusted in 4-week 
increments to a maximum of Q16W and a minimum of Q4W. The PTI algorithm is based 
on the relative change of the CST and absolute change in BCVA compared with the 
reference CST and BCVA, respectively (see Figure 2).


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Figure 2
Algorithm for IxRS-Determined Personalized Treatment Interval 
Study Drug Dosing Intervals
BCVA best-corrected visual acuity; CST central subfield thickness; IxRSinteractive voice or 
web-based response system; SD-OCTspectral-domain optical coherence tomography.
* Reference CST:  the CST value when the initial CST threshold criteria (CST 325 m for 
Spectralis SD-OCT, or 315 m for Cirrus SD-OCT or Topcon SD-OCT) are met.  The 
reference CST is adjusted if CST decreases by 10% from the previous reference CST for two 
consecutive drug-dosing visits and the values obtained are within 30 m.  The CST value 
obtained at the latter visit will serve as the new reference CST, starting immediately at that 
visit. CST values from the parent study will be used as appropriate in the reference CST 
calculations.
** Reference BCVA:  the mean of the three best BCVA values obtained at any prior drug-dosing 
visit, which will include parent study data.
The study drug dosing interval will be adjusted based on comparisons made to reference 
CST and reference BCVA data captured in the parent study. The algorithm used by 
IxRS for interval decision-making is based on the relative change of the CST and 
BCVA compared with the reference CST and reference BCVA as follows (see Figure 2):
Interval extended by 4 weeks

If the CST value is increased or decreased by 10% without an associated 
10-letter BCVA decrease
Interval maintained

If the CST is decreased by 10% or

CST value is increased or decreased by 10% with an associated 10-letter 
BCVA decrease or

CST value is increased between 10% and 20% without an associated 5-letter 
BCVA decrease
Interval extended
by 4 weeks 
0%
+10%
-10%
+20%
-20%
-5
Interval reduced 
by 8 weeks 
Interval
maintained
Interval reduced
by 4 weeks
-10
Change in BCVA
Compared with Reference BCVA **
Change in CST Compared with Reference CST *
Interval maintained
0


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Interval reduced by 4 weeks

If the CST value is increased between 10% and 20% with an associated 5- to 
10-letter BCVA decrease or

CST value is increased by 20% without an associated 10-letter BCVA decrease
Interval reduced by 8 weeks

If the CST value is increased by 10% with an associated 10-letter 
BCVA decrease
3.1.2.2
Faricimab Dosing Intervals—Phase III to LTE
As described in Section 1.2, the parent Phase III studies (GR40349 or GR40398) include
patients randomized in a 1:1:1 fashion to one of three regimens: a fixed interval 
faricimab dosing regimen (Arm A: faricimab Q8W), faricimab administered according to a 
PTI (Arm B: faricimab PTI), and a fixed interval comparator arm (Arm C: 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 Q8W), who have had their last 
dose of faricimab at Week 92 of the parent study (see Figure 1), will have a 
faricimab dose on Day 1 of the LTE study and will then be eligible to have their 
subsequent faricimab dosing interval extended, reduced, or maintained based on 
the PTI algorithm. 
Patients from this arm who (e.g., because of dose holds/missed visits in the parent 
study) received a faricimab dose at Week 96 in the parent study, will not receive a 
faricimab dose on Day 1 of the LTE study. Instead, these patients will be dosed 
8 weeks after the final dose in the parent study (i.e., at Week 4 of the LTE study)
and will then be eligible to have their subsequent dosing interval extended, reduced,
or maintained on the basis of the PTI algorithm.

Patients previously randomized to Arm B (faricimab PTI) will remain on their 
previously calculated faricimab interval at entry to the LTE study.

Patients previously randomized to Arm C (aflibercept Q8W) who have had their last 
dose of aflibercept at Week 96 of the parent study (see Figure 1) will have a dose of 
faricimab at Week 4 of the LTE study, and will then be eligible to have their 
subsequent faricimab dosing interval extended, reduced, or maintained based on 
the PTI algorithm.
Patients in this arm who (e.g., because of dose holds/missed visits in the parent 
study) received their last aflibercept dose at Week 92 of the parent study will have a 
faricimab dose on Day 1 of the LTE study. These patients will then be eligible to 
have their subsequent dosing interval extended, reduced, or maintained based on 
the PTI algorithm.
Note:  During the masked period of the LTE study (from Day 1 through to Week 16; 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.


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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 the CST and 
BCVA data captured at the 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.
Once treatment is resumed, the IxRS will determine the next dosing interval based on a 
Q8W interval unless the patient was treated on a Q4W interval prior to dose interruption.  
In that case, the patient will be evaluated on the basis of the Q4W interval.
3.1.3.3
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, the IxRS will assign the patient to 
receive faricimab as scheduled at that visit and maintain the previous faricimab dosing 
interval.  However, if at that visit the patient shows a concurrent 10-letter decrease 
relative to the reference BCVA, the IxRS will reduce the faricimab dosing interval by 
4 weeks. 
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 assign the patient to 
receive faricimab as scheduled at that visit and base the next faricimab dosing interval 
on the CST value only.


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3.1.3.5
Timely Reporting of BCVA and OCT data to eCRF, CRC, and 
IxRS
For the duration of the LTE study, a central reading center (CRC) will be used to read 
the optical coherence tomography (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 
dispensed according to the PTI dispensing schedule. If a patient is deemed to have 
DME that requires immediate treatment, the patient will need to be withdrawn from 
faricimab study treatment and treated with standard care. 
If a patient discontinues from faricimab study treatment, they should, where possible, 
attend at least their Year 1 and Year 2 visits, if not already completed. No other study 
visits will be required. Please note that the Sponsor will not reimburse 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 faricimab study treatment. 


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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 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 their 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 system will issue a confirmation email if that was final 
treatment visit.  Upon confirmation of the final study treatment via IxRS, patients are 
expected to attend an end of study visit between 2835 days after their final study 
treatment visit date. 
In addition, 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 a Phase III multicenter, randomized, comparator-controlled,
double-masked study of faricimab in patients with DME.
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.
Dose
The 6-mg dose of faricimab selected for the parent study was based on preclinical 
in vivo and toxicology models, data from Phase I and Phase II studies, and is supported 
by clinical PK and PD assessments.
The first-in-human study (BP28936) evaluated the safety and tolerability of single and 
multiple administration of faricimab to 24 patients with neovascular age-related macular 
degeneration, at doses ranging from 0.5 mg to 6 mg.  The selection of these doses was 
based on nonclinical findings and absolute IVT doses administered in toxicology studies.  
The 6-mg dose of faricimab was the highest feasible dose of faricimab, and single and 
multiple doses of up to 6 mg were well tolerated.
The Phase II study (BP30099 [BOULEVARD]) provided evidence of a positive 
benefitrisk profile for IVT faricimab in patients with DME (n229 enrolled).  The study 
compared two doses of IVT faricimab (1.5-mg and 6-mg) with 0.3-mg IVT ranibizumab.  


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The effects of 6-mg IVT faricimab on the primary endpoint of the mean change from 
baseline in BCVA in the anti-VEGF treatmentnaive DME patient subset 
(n168 enrolled) were statistically significant and clinically important compared with 
0.3-mg IVT ranibizumab.  The efficacy of faricimab was supported by additional 
secondary BCVA and anatomical DME and DR outcomes in the overall Phase II 
population and demonstrated a consistent advantage over anti-VEGF monotherapy with 
ranibizumab across both dose levels.  Both doses of faricimab, 6 mg and 1.5 mg, were 
well tolerated and did not result in any new or unexpected safety signals.
The 6-mg faricimab dose was chosen for further clinical development in Phase III studies 
in patients with DME.  Refer to the Faricimab (RO6867461) Investigator's Brochure for 
details on efficacy and safety results for the above-mentioned nonclinical and clinical 
studies.
Schedule
The dosing schedule in the LTE study will continue with a PTI regimen.  The mechanism 
of action of faricimab is through neutralization of Ang-2 and VEGF.  Ocular 
pharmacokinetics and pharmacodynamics have been investigated in Phase I and II 
studies of faricimab. Aqueous humor free-Ang-2 and free-VEGF concentrations were 
measured to support the assessments of the primary mode of action and the clinical 
durability potential of faricimab.  Overall, the 6-mg faricimab dose at a Q8W interval 
suppressed aqueous humor free-VEGF levels for 8 weeks post-dose, supporting at least 
a Q8W dosing regimen for faricimab at 6 mg with respect to ocular VEGF suppression.  
A high suppression of free-Ang-2 levels was also observed, lasting for at least 
68 weeks post-dose of faricimab.
Both the efficacy outcomes from the Phase II study (BP30099) and the variability in 
individual Ang-2 and VEGF suppression times in the PK/PD aqueous humor 
assessments indicated a heterogeneous response to treatment and support a flexible 
dosing regimen with intervals ranging from Q4W to Q16W.
In Study BP30099, the time to disease reactivation (defined as either a 50-m increase 
in CST or time to a 5-letter worsening in BCVA) following six Q4W doses demonstrated
that, whilst some patients with DME might require more frequent dosing, most patients 
with DME may need less intensive treatment and may need as little as Q12W or Q16W 
dosing.  Additionally, the PK/PD model characterizing the aqueous humor free-VEGF 
time course showed that there was a substantial proportion of patients with high 
suppression of VEGF, for whom a Q12W or Q16W regimen could be sufficient to 
maintain efficacy. As a result, the Phase III design includes a treatment arm assessing
6-mg IVT faricimab administered in accordance to a PTI regimen.
Real world evidence suggests that the improvements in visual acuity achieved in the 
clinical trial setting with anti-VEFG monotherapy are not always replicated in clinical 
practice, potentially due to the reduced frequency of injections administered in clinical 


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practice (Blinder et al. 2017; Hodzic-Hadzibegovic et al. 2018; Stefanickova et al. 2018;
Ziemssen et al. 2018). The PTI regimen aims to optimize efficacy while reducing the IVT 
injection treatment burden in patients with DME, 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 DME who have completed the parent Phase III 
study (GR40349 or GR40398), 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.
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.  Aqueous humor samplings have previously been 
demonstrated to be instrumental in improving our understanding of the relationships 
between ocular pharmacokinetics, VEGF suppression, and duration of clinical efficacy 
(Muether et al. 2012, 2013, 2014; Fauser et al. 2014; Fauser and Muether 2016; 
Hutton-Smith et al. 2017).  Therefore, to increase our understanding of the ocular 
pharmacokinetics and pharmacodynamics of faricimab and the relationship to dosing 
interval, optional aqueous humor samples will be obtained at different timepoints from 
patients who provide additional optional consent to participate in regions where optional 
sampling is approved.  Aqueous humor and vitreous humor samples will be measured 
for free VEGF and free Ang-2, and data from these analyses will be used to develop 
better predictive models for determining optimal PTIs by means of longitudinal target 
engagement assessments in these surrogate specimens.
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 DME 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.


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The concentration of free VEGF and Ang-2 will be measured in plasma to assess the 
systemic target suppression following IVT faricimab injection. 
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 1800 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, GR40349 and GR40398.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Previous enrollment in and completion of Study GR40349 (YOSEMITE) or GR40398 
(RHINE), 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 acceptable contraceptive methods that result in a 
failure rate of 1% per year during the treatment period and for at least 3 months
after the final dose of study treatment
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of amenorrhea 
with no identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus). The definition of childbearing 
potential may be adapted for alignment with local guidelines or requirements.
Examples of acceptable contraceptive methods include bilateral tubal ligation, 
male sterilization; hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices and copper intrauterine devices.
Contraception methods that do not result in a failure rate of 1% per year such 
as male or female condom with or without spermicide; and cap, diaphragm, or 
sponge with spermicide are not acceptable.
The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient.  If a patient
is usually not sexually active but becomes active, they, with their partner, must 
comply with the contraceptive requirements of the study.


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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 IVT injection 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 treatment 
procedure, 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.
As outlined in Section 3.1, there will be a masked period in the early phase of the LTE 
study. 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 the masked period, patients will be advised that at masked study 
visits they will either receive faricimab or sham injection. After the Week 16 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.
Please note, as detailed in Section 4.2.1.1, throughout the entire study period, the 
retinal physician is expected to assess adverse events, which includes assigning 
causality and severity of the event.
4.2.1
Masking Requirements during the Masked Period of LTE Study
To fulfil the masking requirements, LTE study assessments will be performed by an 
investigator masked to the patients’ faricimab treatment interval, whilst treatment 


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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 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 should 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, with the exception of being a 
VA examiner.
Assessor Physician
Sites are permitted to have at least one additional investigator designated as a masked 
assessor physician, who will be an ophthalmologist with an expertise in the retinal 
subspecialty.  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 VA 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.
BCVA Examiner 
For the duration of the LTE study, to minimise bias, the VA 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 VA examiner may 
have access to a patient’s refraction data from previous visits.  The VA 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. 


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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 will be a
retina specialist (or the equivalent in ex-U.S. countries). In addition, ophthalmologists
who have completed a minimum of 2 full years of ophthalmology residency (or the
equivalent in ex-U.S. countries) may be permitted to perform the role of the treatment
administrator following Sponsor approval.
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 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.
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. 


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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.
The sham is a procedure that mimics an IVT injection to preserve the study masking, 
and involves the blunt end of an empty syringe, without a needle, being pressed against 
an anaesthetized eye.
4.3.1
Study Treatment Formulation and Packaging
4.3.1.1
Faricimab Formulation
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, refer to the 
pharmacy manual.
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 faricimab preparation, storage, 
and administration.
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.
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.


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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 
4 months of the study and will have the sham procedure performed at these visits when 
they are not treated with faricimab.
4.3.3
Investigational Medicinal Product 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.


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Only patients enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs.
The IMP 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 the Sponsor-supplied IMP 
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 the IMP received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the drug accountability log.
Refer to the pharmacy manual and/or the Faricimab Investigator's Brochure for 
information on IMP handling, including preparation and storage, and accountability.
4.3.4
Continued Access to Faricimab
The Sponsor will offer continued access to Roche IMP (faricimab) free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive Roche IMP (faricimab) after completing the study if all
of the following conditions are met:

The patient has a sight-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them
A patient will not be eligible to receive Roche IMP (faricimab) after completing the study 
if any of the following conditions are met:

The Roche IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the IMP or data suggest that the IMP
is not effective for DME

The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
DME

Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country


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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 for anti-VEGF therapy in 
the fellow eye that should be recorded on a separate Fellow Eye anti-VEGF 
Administration eCRF.  Concomitant ocular procedures performed on either eye during 
the study should be recorded in the Concurrent Ocular Procedures eCRF.
4.4.1
Permitted Therapy 
Patients who use maintenance therapies should continue their use.  Of note, the 
following are some common therapies that are permitted:

Onset of ocular hypertension or glaucoma in the study eye during a patient’s study 
participation should be treated as clinically indicated

Onset of cataract or posterior capsular opacification in either eye during a patient’s 
study participation may be treated as clinically indicated.  Dose interruption criteria 
(see Section 5.1.2.1 and Table 1) may apply with cataract surgery.

Short-term use of topical ocular corticosteroids after cataract surgery, 
yttrium-aluminum garnet capsulotomy, peripheral iridotomy, argon/selective laser 
trabeculoplasty, or for ocular allergic conditions

Panretinal photocoagulation may be allowed for the treatment of DR after discussion 
with the Medical Monitor
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 with the region-specific 
anti-VEGF prescribing information for the recommended dose and frequency of 
treatment. The Sponsor will cover the cost of an 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 support fellow-eye treatment with faricimab.
Any exceptions for ongoing reimbursement of other anti-VEGF therapies must 
be approved by the Sponsor. 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.


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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 trial.
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.
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 the LTE study. If necessary, patients
may be discontinued from faricimab treatment and/or the LTE study to receive these 
therapies:

Systemic anti-VEGF therapy 

Systemic drugs known to cause macular edema (fingolimod, tamoxifen)

IVT anti-VEGF agents (other than faricimab) in study eye 

IVT, periocular (subtenon), steroid implants (i.e., Ozurdex®, Iluvien®), or chronic 
topical ocular corticosteroids in study eye (defined as continuous usage for
100 days or longer).

Treatment with Visudyne® in study eye

Administration of micropulse and focal or grid laser in 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 attend LTE annual visits (Year 1 and Year 2) visits, 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.  
All activities should be performed and documented for each patient.


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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, 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.
Concomitant medication information will be obtained at each visit.
4.5.3
Vital Signs
Vital signs will be collected as part of the schedule of assessments for the Week 100 
visit of the parent study, and will not be obtained again for this extension study.
4.5.4
Ocular Assessments
Ocular assessments include the following and will be performed on both eyes at 
specified timepoints in accordance to the schedule of activities in Appendix 1:

Refraction and BCVA assessed on ETDRS chart at a starting distance of 4 meters 
(perform prior to dilating eyes; see Appendix 3)

Pre-treatment IOP measurement of both eyes (perform prior to dilating eyes)

Slitlamp examination (for grading scales for anterior and vitreous cells, see
Appendix 4)

Dilated binocular indirect high-magnification ophthalmoscopy

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 post-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.


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NB: 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
software) that have been certified by the CRC. The method for obtaining CRC 
certification is detailed in the CRC manual. Photographers/study imaging technicians 
should obtain CRC certification prior to acquiring any LTE study images.
All ocular images obtained by trained and CRC certified site personnel should be 
forwarded to the CRC as soon as possible (see Section 3.1.3.5 and Appendix 1,
Appendix 5 [CFP], Appendix 6 [FFA], and Appendix 7 [SD-OCT]).
If a patient misses a study visit when CFP and FFA images are scheduled (see 
Appendix 1) or the images are not taken at the scheduled visit (e.g., due to broken 
equipment), the images should be obtained the next time the patient attends.
Ocular images include the following:

CFP in both eyes (7- or 4-ETDRS fields; method used for each patient should be 
consistent with that used in the parent study and remain consistent throughout the 
duration of the LTE study) 

Optional ultra-wide field (UWF) CFP of both eyes (to be undertaken in patients for 
whom consent was obtained and images acquired in the parent study)

FFA of both eyes (preferred method is UWF FFA if sites have capability; sites 
without UWF should capture 7- or 4-field ETDRS as per the parent study and use the 
same method consistently throughout their LTE study participation). FFA should be 
performed after blood samples obtained (if applicable).

SD-OCT or swept-source OCT images of both eyes (to be undertaken using the 
same device as that used in the parent study)

Optional OCT-angiography (OCT-A) of both eyes at sites with OCT-A capabilities and 
agreement by sites to take these images (to be undertaken using the same device as 
that used in the parent study)
Refer to the CRC manual for additional details regarding obtaining above images.
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.


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4.5.6
Laboratory and Other Biological Samples
At the 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.  Laboratory supply kits 
will be provided to the sites by the central laboratory.  See Appendix 1 for sample 
collection timepoints and Appendix 8 for biological sample collection and shipping 
instructions.
The following samples will be sent to the central laboratory or to the Sponsor or a 
designee for analysis and/or storage:

Urine pregnancy test prior to each study treatment for women of childbearing 
potential, including those who have had tubal ligation
If positive, perform the 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
Drug concentration, will be determined in plasma using a validated immunoassay 
method.  Anti-drug antibodies (ADAs) will be detected in plasma using a validated 
bridging ELISA.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.8), biological samples will be destroyed 
no later than the time of completion of the final Clinical Study Report, with the following 
exceptions:

Plasma samples collected for PK or immunogenicity analysis may be needed for 
additional immunogenicity characterization; therefore, these samples will be 
destroyed no later than 5 years after the final Clinical Study Report has been 
completed.

Optional aqueous humor samples collected for biomarker research will be destroyed 
no later than 5 years after the final Clinical Study Report has been completed

Optional plasma samples (if aqueous humor sample is collected)

Optional vitreous humor samples
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.
4.5.6.1
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. 
For patients who consent to provide 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 8
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 (see Appendix 1) provides guidance on 
recommended visits at which aqueous humor samples should be obtained.  Patients 
who are prematurely discontinued from study treatment but who agree to continue to 
participate in the study should discontinue collection of optional aqueous humor samples 
and any associated optional plasma samples.  However, (unscheduled) sampling may 
be performed at other or additional planned visits at the discretion of the investigator and 
in agreement with the participating patient.
Aqueous humor samples will be analyzed for faricimab, free VEGF-A, and free Ang-2 
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 samples for measurement of faricimab concentration 
(see Appendix 1 and the Covance manual for sample collection, storage, and transfer). 


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Faricimab will be quantified in plasma using validated immunoassay methods.
Remaining plasma samples may be analysed for additional biomarkers.
Refer to Section 4.5.6 for details on duration of sample storage, use of samples after 
patient withdrawal, confidentiality standards for data, and availability of data from 
biomarker analyses.
4.5.6.2
Optional Unscheduled Collection of 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 of the protocol (Section 4.5.6.2) 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 8
for further details).  Approximately 0.5 mL of undiluted vitreous humor should be 
collected using an aseptic procedure and sterile field and according to local guidelines.
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 VEGF-A and free Ang-2 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.
Refer to Section 4.5.6 for details on duration of sample storage, use of samples after 
patient withdrawal, confidentiality standards for data, and availability of data from 
biomarker analyses.
4.5.7
Patient-Reported Outcomes
The NEI VFQ-25 will be completed to assess the treatment benefit of faricimab.
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,
instruments will be administered before the patient receives any information on disease 
status and prior to the administration of study treatment, unless otherwise specified.


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The NEI VFQ-25, translated into the local language as appropriate, will be provided by 
the Sponsor to enable instruments 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 PRO Instrument
PROs will be assessed using the NEI VFQ-25 (Mangione et al. 2001) (see Appendix 9).  
The NEI VFQ-25 captures a patient’s perception of vision-related functioning and 
vision-related quality of life.  The core measure includes 25 items that comprise 
11 vision-related subscales and one item on general health.  In this study, an additional 
six 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.


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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.
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, vitreous, and plasma 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.


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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.
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.


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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.
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 faricimab 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 faricimab treatment

Investigator or Sponsor determination that faricimab 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.


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Patients who discontinue from faricimab treatment but remain in the study for 
follow up must attend an unscheduled visit 2835 days after their last 
faricimab dose, and be encouraged to attend both the Year 1 and Year 2 visits if 
not already completed.
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
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 withdraw from the study will not be replaced.
Patients who discontinue from the study prior to the end of study must return 
to the clinic for a treatment discontinuation visit 2835 days after the final 
dose of faricimab 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


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
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY 
5.1
SAFETY PLAN
Faricimab is not approved, and clinical development is ongoing.  The safety plan for 
patients in this study is based on clinical experience with faricimab in completed and 
ongoing studies.  The anticipated important safety risks for faricimab are outlined below.  
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.
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.
Potential risks of faricimab include intraocular inflammation, the intravitreal 
injection-related risks of infectious endophthalmitis, retinal detachment/tear, iatrogenic 
traumatic cataracts, and transient increased IOP, as well as 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 1.  If any of these criteria are 
met, treatment will be interrupted (or discontinued, if appropriate).  The reason for study 
treatment interruption/discontinuation should be recorded on the appropriate eCRF and, 
if applicable, on the Adverse Event eCRF.


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Table 1
Dose Interruption and Treatment Discontinuation Criteria
Event 
Criteria
Intraocular 
inflammation

Interrupt 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.
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 Medical Monitor and investigator.
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 after 
discussion with Medical Monitor.
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.
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 performing other protocol-specified tests that are 
deemed critical to the safety evaluation of the study.


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Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.8
and 5.3.5.9 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
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 
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The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; see 
Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.6)

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;
laser or retinal cryopexy with gas; or a medication) to prevent permanent loss of 
sight.
–
It is associated with severe intraocular inflammation (i.e., endophthalmitis, 
4anterior chamber cell/flare, or 4vitritis; see Section 5.3.5 and Appendix 4 for 
intraocular inflammation grading scales).


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All of the above listed sight-threatening adverse events should be reported as serious 
adverse events, listing the underlying cause (if known) of the event as the primary 
event term.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).
For adverse events that occur during or shortly after study treatment 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 initiation of study drug, all adverse events will be reported until the final study visit 
at Year 2.  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 2 provides guidance for assessing adverse event severity.


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Table 2
Adverse Event Severity Grading Scale
Severity
Description
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating with inability to work or to perform normal daily activity
Note:  Regardless of severity, some events may also meet seriousness criteria.  
Refer to definition of a serious adverse event (see Section 5.2.2).
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (see also 
Table 3).

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
Table 3
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).


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For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
For the purposes of reporting events of infection and inflammation, see 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 RBCs or WBCs or the result of any ocular 
disorder, should not be recorded as an adverse event.
5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.


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5.3.5.2
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
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)


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
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5upper limit of normal (ULN) associated with 
cholestasis), only the diagnosis (i.e., cholestasis) should be recorded on the Adverse 
Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 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.


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Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2).
5.3.5.7
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the Day 1 visit for this study. 
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 


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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 Diabetic Macular Edema or
Diabetic Retinopathy in the Study Eye
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on changes in BCVA and OCT criteria and changes observed 
in the DRSS. In rare cases, the determination of clinical progression will be based on 
symptomatic deterioration.  However, every effort should be made to document 
progression through use of objective criteria.  If there is any uncertainty as to whether an 
event is due to disease progression, it should be reported as an adverse event.
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 


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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).  
During the Masked Phase (i.e., Day 1Week 16):
All special situations associated with the masked study treatment, regardless of 
whether they result in an adverse event, should be recorded on the Adverse 
Event eCRF in a masked manner as described below:

For medication error enter “Medication Error” on the Adverse Event eCRF 
as the primary event term and check the “Medication error” box (see eCRF 
Completion Guidelines for additional details).

For intercepted medication error enter “intercepted Medication Error” on 
the Adverse Event eCRF as the primary event term and check the 
“Medication Error” box (see eCRF Completion Guidelines for additional 
details).
Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria (see Section 5.2.2) or it is adverse event of special interest 
(see Section 5.2.3), the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.3.1).  
Adverse events associated with special situations should be recorded as 
described below:

Enter the adverse event caused by the medication error as primary adverse 
event term on Adverse Event eCRF.  Check the "Medication Error" box.
As an example, a special situation that resulted in a headache would require 
two entries on the Adverse Event eCRF, one entry to report the medication 
error and one entry to report the headache.  The “Medication Error" box would 
need to be checked for both.
During the Open-Label Phase (i.e., Week 20 onwards):
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.


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
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.

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)


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
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.
5.4.1
Medical Monitors and Emergency Medical Contacts
Contact Information for Eastern Hemisphere 
Medical Monitor/Emergency Medical Contact:
 M.D. 
Telephone No.:
Mobile Telephone No.:
Contact information for Western Hemisphere
Medical Monitor/Emergency Medical Contact:
 M.D., Ph.D.
Mobile Telephone No.:
Contact Information for Western Hemisphere
Medical Monitor/Emergency Medical Contact:
 M.D., Ph.D.
Mobile Telephone No.:
Contact Information for Asia-Pacific
Medical Monitor/Emergency Medical Contact:
 M.D., Ph.D.
Telephone No.:
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
be available 24 hours per day, 7 days per week, in case the above-listed contacts 
cannot be reached.  The Emergency Medical Call Center will connect the investigator 
with an Emergency Medical Contact, provide medical translation service if necessary, 
and track all calls.  Contact information, including toll-free numbers for the Emergency 
Medical Call Center, will be distributed to investigators.


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5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until the final visit at Year 2. 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.
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 inform the investigator immediately 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, 


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and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
5.4.3.3
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
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 


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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.
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 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 96 visit in one of the 
parent studies GR40349 (YOSEMITE) or GR40398 (RHINE) (see Sections 4.1.1 and 
4.1.2).
6.2
ANALYSIS POPULATIONS
6.2.1
Intent-to-Treat Population
The Intent-to-Treat (ITT) population will comprise all eligible patients enrolled into this 
LTE study. For analyses using the parent study treatment group, patients will be 
grouped according to the treatment assigned at randomization in the parent study.


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6.2.2
Per-Protocol Population
The per-protocol population is defined as all ITT patients who received at least one 
injection of faricimab and who do not have a major protocol violation. 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 patients who enroll in the LTE, 
regardless of whether they received faricimab treatment during the LTE. 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 96 visit as follows (similar 
algorithm used in the parent studies):

If the only active treatment received in the parent study by a patient in the study eye 
was aflibercept, the patient’s parent study treatment group will be aflibercept Q8W.

If the only active treatment received in the parent study by a patient in the study eye 
was faricimab, the patient’s parent study treatment group will be as randomized if 
the patient was randomized to one of the faricimab arms.

If a patient received in the parent study a combination of different active treatments 
(faricimab and aflibercept) in the study eye, the patient’s parent study 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 ITT population and presented 
overall, and by parent study treatment group. The number and percentage of patients 
who enroll (including from which parent study), discontinue, or complete the LTE study 
will be summarized overall, and by country and site.  Reasons for premature study 
withdrawal will be listed and summarized.  Enrollment and major protocol deviations will 
be listed and evaluated for their potential effects on the interpretation of the study 
results.


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6.4
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics will be summarized using the ITT 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 come from the parent 
study and the LTE study. Descriptive statistics for continuous data will include number 
of observations, arithmetic mean, standard deviation, 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 from the parent study and the LTE study presented overall, and by parent 
treatment group for the safety-evaluable population.
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 
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, 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 (SAP).
6.6
EXPLORATORY EFFICACY ANALYSES
The exploratory efficacy analyses will be based on the ITT population.  Additional 
analyses based on the per-protocol population will also be conducted for the 
BCVA score and CST analyses over time.


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Summary measures will be as follows:

For proportions:
Overall for the whole LTE study cohort
Difference in proportions between each of the two faricimab arms (Q8W and PTI) 
and the aflibercept (Q8W) arm

For continuous variables:
Overall for the whole LTE study cohort
Difference in adjusted mean between each of the two faricimab arms (Q8W and 
PTI) and the aflibercept (Q8W) arm and overall
6.6.1
Intercurrent Events
The following intercurrent events will be taken into consideration if the event occurred 
until the clinical cutoff date

Discontinuation of study treatment due to adverse events or lack of efficacy

Use of prohibited therapy in the study eye
If a patient discontinues from study treatment due to adverse events or lack of efficacy, 
or receives any prohibited systemic treatment or prohibited therapy in the study eye, a 
treatment policy estimand approach will be followed where all observed values will be 
used regardless of the occurrence of intercurrent event.
6.6.2
Endpoints (Variables)
All efficacy endpoints will be assessed over time, and at 1- and 2-year timepoints in the 
LTE study. Change from baseline will be calculated from Day 1 of the parent study and 
from the Day 1 of this LTE study.
The following endpoints will be included in the exploratory efficacy analyses:

Change in BCVA over time as measured using the ETDRS chart at a starting 
distance of 4 meters

Change in CST over time as measured by SD-OCT

Proportion of patients with presence of central retina intraretinal fluid, subretinal
fluid, and both over time

Number of faricimab injections received during the LTE study

The proportion of patients on a Q4W, Q8W, Q12W, and Q16W treatment interval 
during the study

Proportion of patients with a 2- or 3-step improvement in their DRSS score 
over time

Proportion of patients with a 2- or 3-step worsening in their DRSS score over 
time

Proportion of patients who develop new PDR over time


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
Change in patient-reported vision-related functioning and quality of life over time as 
assessed using the NEI VFQ-25 composite score, the near activity subscale score, 
the distance activities subscale score, and driving subscale score
Missing data will be implicitly imputed using a mixed-model repeated measures model, 
assuming a missing-at-random missing data mechanism (i.e., the probability that 
missing data are dependent on other observed variables but not on the missing data).
Additional details about the planned analyses, as well as sensitivity analyses using other 
imputation methods for missing data and sensitivity analyses of the per-protocol 
population will be provided in the SAP.
6.7
PHARMACOKINETIC ANALYSES
The PK analyses will be performed using the PK population. 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 inter-individual 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.
The number and proportion of ADA-positive patients and ADA-negative patients at 
parent study baseline Day 1 (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.


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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.  Data cuts may be performed at appropriate 
timepoints for inclusion in the submission with the main studies, for example, to support 
the safety profile. An interim analysis may be performed for internal stakeholder 
data presentations/conference presentations/publications/market authorization 
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 
Centre Images will be sent directly to the Sponsor, using the Sponsor's standard 
procedures to handle and process the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data
will be consistent with the Sponsor's standard procedures.
PRO data will be collected on paper questionnaires.  The data from the questionnaires 
will be entered into the EDC system by site staff.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.


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All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
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.


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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. Food and Drug 
Administration regulations and applicable local, state, and federal laws.  Studies 
conducted in the European Union or European Economic Area will comply with the E.U.
Clinical Trial Directive (2001/20/EC) and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
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.  


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Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
If the Consent Forms are revised (through an amendment or an addendum) while a 
patient is participating in the study, the patient or a legally authorized representative 
must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB/EC policy.  For any updated or 
revised Consent Forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient's
legally authorized representative.  All signed and dated Consent Forms must remain in
each patient's study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
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 


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requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.7).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  
In addition, redacted Clinical Study Reports and other summary reports will be provided 
upon request (see Section 9.5).


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8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
MANAGEMENT OF STUDY QUALITY
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  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.


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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 550 sites globally participated in the parent studies, and these same sites 
will enroll approximately 1800 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:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.


Faricimab—F. Hoffmann-La Roche Ltd
81/Protocol GR41987, Version 3
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).


Faricimab—F. Hoffmann-La Roche Ltd
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10.
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patients with diabetic retinopathy and other retinal disorders. N Engl J Med
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Antonetti DA, Lieth E, Barber AJ, et al. Molecular mechanisms of vascular permeability 
in diabetic retinopathy. Semin Ophthalmol 1999;14:2408.
Blinder KJ, Dugel PU, Chen S, et al. Anti-VEGF treatment of diabetic macular edema in 
clinical practice: effectiveness and patterns of use (ECHO Study Report 1).
Clin Ophthalmol 2017;11:393–401.
Ciulla TA, Amador AG, Zinman B. Diabetic retinopathy and diabetic macular edema: 
pathophysiology, screening and novel therapies. Diabetes Care 2003;26:265364.
Davidson JA, Ciulla TA, McGill JB, et al. How the diabetic eye loses vision. Endocrine 
2007;32:10716.
Davis S, Aldrich TH, Jones PF, et al. Isolation of angiopoietin-1, a ligand for the TIE2 
receptor, by secretion-trap expression cloning. Cell 1996;87:11619.
Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, et al. 
Randomized trial evaluating ranibizumab plus prompt or deferred laser or 
triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 
2010:117:106477. 
Elman MJ, Ayala A, Bressler NM, et al. Intravitreal ranibizumab for diabetic macular 
edema with prompt versus deferred laser treatment: 5-year randomized trial 
results. Ophthalmology 2015;122:37581.
Eylea® (aflibercept) European Summary of Product Characteristics, Bayer AG. 
Eylea® (aflibercept) Japanese Package Insert, Santen Pharmaceutical Co., Ltd.
Eylea® (aflibercept) U.S. Package Insert, Regeneron Pharmaceuticals, Inc.
Farinha C, Martins A, Neves A, et al. Ranibizumab for the treatment of diabetic macular 
oedema in the real-world clinical setting in Portugal: A multicentre study. 
Ophthalmologica 2019;241:18.
Fauser S, Muether PS. Clinical correlation to differences in ranibizumab and aflibercept 
vascular endothelial growth factor suppression times. Br J Ophthalmol 
2016;100:14948.
Fauser S, Schwabecker V, Muether PS. Suppression of intraocular vascular endothelial 
growth factor during aflibercept treatment of age-related macular degeneration. 
Am J Ophthalmol 2014;158:5326.
Ferris FL 3rd, Patz A. Macular edema. A complication of diabetic retinopathy. 
Surv Ophthamol 1984;28 (Suppl 2):45261.


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Fiedler U, Krissl T, Koidl S, et al. Angiopoietin-1 and angipoietin-2 share the same 
binding domains in the Tie-2 receptor involving the first Ig like loop and the 
epidermal growth factor-like repeats. J Biol Chem 2003;278:17217.
Fong DS, Aiello LP, Ferris FL 3rd, et al. Diabetic retinopathy. Diabetes Care
2004;27:254053.
Fong DS, Luong TQ, Contreras R, et al. Treatment patterns and 2-year vision outcomes 
with bevacizumab in diabetic macular edema: an analysis from a large U.S. 
Integrated health care system. Retina 2018;38:18308.
Gardner TW, Antonetti DA, Barber AJ, et al. Diabetic retinopathy: more than meets the 
eye. Surv Ophthalmol 2002;47(Suppl 2):S25362.
Girach A, Lund-Andersen H. Diabetic macular oedema: a clinical overview. Int J Clin 
Practice 2007;61:8897.
Henricsson M, Sellman A, Tyrberg M, et al. Progression to proliferative retinopathy and 
macular oedema requiring treatment. Assessment of the alternative classification 
of the Wisconsin Study. Acta Ophthalmol Scand 1999;77:21823.
Hodzic-Hadzibegovic D, Sander BA, Monberg TJ, et al. Diabetic macular oedema 
treated with intravitreal anti-vascular endothelial growth factor - 2-4 years follow-up 
of visual acuity and retinal thickness in 566 patients following Danish national 
guidelines. Acta Ophthalmol 2018;96:26778.
Hutton-Smith LA, Gaffney EA, Byrne HM, et al. Ocular pharmacokinetics of therapeutic 
antibodies given by intravitreal injection: estimation of retinal permeabilities using a 
3-compartment semi-mechanistic model. Mol Pharm 2017;14:26906.
International Diabetes Federation. IDF diabetes altas. 9th edition 2019 [resource on the 
Internet]. 2019 [cited: January 2020]. Available from: 
https://www.idf.org/e-library/epidemiology-research/diabetes-atlas/159-idf-diabetes-
atlas-ninth-edition-2019.html.
Johnson MW. Etiology and treatment of macular edema. Am J Ophthalmol 
2009;147:1121.
Joussen AM, Poulaki V, Qin W, et al. Retinal vascular endothelial growth factor induces 
intercellular adhesion molecule-1 and endothelial nitric oxide synthase expression 
and initiates early diabetic retinal leukocyte adhesion in vivo. Am J Pathol 
2002;160:5019.
Leasher JL, Bourne RR, Flaxman SR, et al. Global estimates on the number of people 
blind or visually impaired by diabetic retinopathy: a meta-analysis from 1990 to 
2010. Diabetes Care 2016;39:16439.
Maisonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural antagonist for Tie2 
that disrupts in vivo angiogenesis. Science 1997;277:5560.


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84/Protocol GR41987, Version 3
Mangione CM, Lee PP, Gutierrez PR, et al. Development of the 25-Item National Eye 
Institute Visual Function Questionnaire. Arch Ophthamol. 2001;119:10508.
Muether PS, Droege KM, Fauser S. Vascular endothelial growth factor suppression 
times in patients with diabetic macular oedema treated with ranibizumab. 
Br J Ophthalmol 2014;98:17981.
Muether PS, Hermann MM, Droge K, et al. Long-term stability of vascular endothelial 
growth factor suppression time under ranibizumab treatment in age-related 
macular degeneration. Am J Ophthalmol 2013;156:98993.e2.
Muether PS, Hermann MM, Viebahn U, et al. Vascular endothelial growth factor in 
patients with exudative age-related macular degeneration treated with 
ranibizumab. Ophthalmology 2012;119:20826.
Park SW, Yun JH, Kim JH, et al. Angiopoietin 2 induces pericyte apoptosis via 31 
integrin signaling in diabetic retinopathy. Diabetes 2014;63:305768.
Rangasamy S, Srinivasan R, Maestras J, et al. A potential role for angiopoietin 2 in the 
regulation of blood-retinal barrier in diabetic retinopathy. Invest Ophthamol Vis Sci 
2011;52:378491.
Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept injection for 
neovascular age-related macular degeneration: ninety-six-week results of the 
VIEW studies. Ophthalmology 2014;121:193201.
Stefanickova J, Cunha-Vaz J, Ulbig M, et al.). A noninterventional study to monitor 
patients with diabetic macular oedema starting treatment with ranibizumab 
(POLARIS). Acta Ophthalmol 2018;96:e9429.
Yau JW, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors of 
diabetic retinopathy. Diabetes Care 2012;35:55664.
Ziemssen F, Wachtlin J, Kuehlewein L, et al. Intravitreal ranibizumab therapy for diabetic 
macular edema in routine practice: two-year real-life data from a 
non-interventional, multicenter study in Germany. Diabetes Ther 2018;9:227189.


Faricimab—F. Hoffmann-La Roche Ltd
85/Protocol GR41987, Version 3
Appendix 1
Schedule of Activities
Day 1 a
Week 4
Week 8
Week 12 Week 16 PTI interval Year 1 b
Year 2 b
Final end of 
study visit c
ET Visit d
Visit Window (days)
(7)
(7)
(7)
(7)
2835 days 
after last 
dose
(2835 days 
after last 
study
treatment)
Main informed consent e
x
Optional aqueous, vitreous and blood sample 
informed consent e
x
Optional (RBR) residual samples and 
DNA whole blood sample informed consent e
x
Review of inclusion and exclusion criteria
x
Vital signs f
(x) g
x
x
NEI VFQ-25 g
(x) g
x
x
x
Refraction and BCVA assessment i
(x) g
x
x
x
x
x
x
x
x
x
Pre-treatment IOP j
(x) g
x
x
x
x
x
x
x
x
Urine pregnancy test k
(x) g
x
x
x
x
x
x
x
x
x
Mandatory plasma PK sample l
(x) g
x
x
x
x
x
Mandatory plasma ADA sample l
(x) g
x
x
x
x
x
Optional aqueous humor sample m
x
x
x
x
x
PK plasma sample (only if optional aqueous 
humor sample is collected) m
x
x
Optional PD plasma sample (if aqueous 
humor sample is collected) m
x
x
x
x
Optional whole blood sample for DNA n
(x)


Appendix 1: Schedule of Activities
Faricimab—F. Hoffmann-La Roche Ltd
86/Protocol GR41987, Version 3
Day 1 a
Week 4
Week 8
Week 12 Week 16 PTI interval Year 1 b
Year 2 b
Final end of 
study visit c
ET Visit d
Visit Window (days)
(7)
(7)
(7)
(7)
2835 days 
after last 
dose
(2835 days 
after last 
study
treatment)
Optional vitreous humor sample o
Can be collected if vitrectomy is necessary.
PK plasma sample (only if optional vitreous 
humor sample is collected) o
Collect if vitreous humor sample is collected.
Slit-lamp examination
(x) g
x
x
x
x
x
x
x
x
x
Indirect ophthalmoscopy
(x) g
x
x
x
x
x
x
x
x
x
SD-OCT o
(x) g
x
x
x
x
x
x
x
x
x
Optional OCT-A q
(x) g
x
x
x
FFA r
(x) s
x
x
x
CFP r
(x) s
x
x
x
x
Optional UWF CFP r
(x) s
x
x
x
x
Administration of study treatment t
x
x
x
x
x
x
x
x
Finger-counting test u
x
x
x
x
x
x
x
x
IOP (post-study treatment) v
x
x
x
x
x
x
x
x
Adverse events w
x
x
x
x
x
x
x
x
x
x
Concomitant medications x
(x) g
x
x
x
x
x
x
x
x
x
Concurrent ocular procedures y
(x) g
x
x
x
x
x
x
x
x
x


Appendix 1: Schedule of Activities
Faricimab—F. Hoffmann-La Roche Ltd
87/Protocol GR41987, Version 3
ADAanti-drug antibody; BCVAbest-corrected visual acuity; CFPcolor fundus photograph; CRCcentral reading center; eCRFelectronic 
Case Report Form; ET early termination; FFAfundus fluorescein angiography; IOPintraocular pressure; IxRSinteractive voice or web-based 
response system; LTElong-term extension; NEI VFQ-25National Eye Institute Visual Functioning Questionnaire25; OCT-Aoptical coherence 
tomographyangiography; PDpharmacodynamic; PK pharmacokinetic; PTIpersonalized treatment interval; RBRResearch Biosample 
Repository; SD-OCT spectral-domain optical coherence tomography; UWFultra-wide field.
Notes:  All ocular assessments are to be performed for both eyes unless noted otherwise.  All assessments must be performed on the 
same day.
a The LTE study Day 1 visit and the parent Phase III study Week 100 visit should be on the same day. If this is not possible, the Day 1 LTE visit 
should be within 2 business days of the Phase III Week 100 visit.
b Annual visits are defined as the scheduled PTI visit that is earliest (between Week 48 and Week 64) relative to 52 weeks (for Year 1) and 
earliest (between Week 96 and Week 104) relative to 104 weeks (for Year 2) from Day 1. If, due to the patient’s faricimab PTI,
there are multiple options for Year 1 or Year 2 visits, IxRS will advise the site that the earliest scheduled visit between Week 48 and 
Week 64 should be considered the Year 1 visit and that the earliest scheduled visit between Weeks 96 and 104 should be considered 
the Year 2 visit.
If the earliest scheduled visit is missed, then the next visit within the period should be considered the annual 
visit.
c Patients who undertake their Year 2 visit at Week 96 or Week 100 but are on a PTI that requires them to return at Week 100 
and/or Week 104 should also attend these scheduled study visits and attend their Final End of Study visit 2835 days after 
their final dose of study treatment.
Further information regarding the Year 2 visit will be provided by the study team.
d Patients who discontinue the study prior to the final study visit at Year 2 and have not withdrawn consent should return for an ET visit 
2835 days after receipt of the last study treatment.
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 Blood, Aqueous Humor, Vitreous Humor Samples Informed Consent Form as well as Optional 
(RBR) Informed Consent Form for residual samples and whole blood DNA sample collection can be signed either at the parent study Week 96 
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.  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 parent Phase III study Week 100 visit.  Assessment may need to be performed again if the LTE Day 1 
visit is conducted on a different day to parent study Week 100 visit; see Section 3.1
h To be administered by masked site staff (except for the visual acuity 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.


Appendix 1: Schedule of Activities
Faricimab—F. Hoffmann-La Roche Ltd
88/Protocol GR41987, Version 3
i
Refraction and BCVA assessments should be performed prior to pupil dilation. Assessments to be performed on both eyes. Study eye 
refraction data to be entered in appropriate eCRF log on Day 1, Year 1, and Year 2 only. 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.
j
Pre-treatment IOP should be measured before pupillary dilation at each study visit, and at the ET visit, if applicable. 
k Urine pregnancy test should be performed on women of childbearing potential, including those who have had tubal ligation, at each study 
treatment visit.  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.
l
Samples should be collected prior to study treatment administration, and, if scheduled, FFA. If samples are missed at a scheduled visit, 
they may be collected at the next scheduled visit. This does not apply to missed Week 8 samples, as Week 12 is also a sampling 
visit.
m 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 prior to study treatment administration. If applicable, samples may be collected after FFA. Please collect associated optional plasma 
PK PD samples at the indicated timepoints if aqueous humor sample is collected.  Missed aqueous humor samples and associated optional 
plasma samples will not be made up at the next scheduled visit.
n Optional whole blood sample collection only in patients for whom optional sample was not collected in the parent study. If the optional whole 
blood DNA sample was not collected in the parent study, and is not obtained at 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 DNA samples will be collected from patients who give specific consent to participate in this 
optional research.
o 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.
p Parent study CRC certified equipment to be used. SD-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.
q Parent study CRC certified equipment to be used. Only at sites with OCT-A capabilities.
r
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.


Appendix 1: Schedule of Activities
Faricimab—F. Hoffmann-La Roche Ltd
89/Protocol GR41987, Version 3
s
Images will be collected as part of parent Phase III study Week 96 visit and do not need to be repeated unless the image was not collected at the 
parent study Week 96 visit.
t
During the masked period of the LTE study, patients will receive either faricimab or sham injection.  Refer to Sections 3.1, 4.2, and 4.3 for further 
details. 
u The finger-counting test should be conducted after treatment administration to the study eye.
v 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.
w All adverse events will be reported until the final study visit or until the ET 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.
x 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 ET visit.
y Record all concurrent ocular procedures performed on the study or nonstudy eye up until the final study visit or ET visit (if applicable).


Faricimab—F. Hoffmann-La Roche Ltd
90/Protocol GR41987, Version 3
Appendix 2
Unscheduled Safety Assessment Visit
Assessments (at the discretion of the investigator) a
Vital signs (blood pressure, respiration rate, pulse, and temperature)
Best-corrected visual acuity (assessed at a 4-meter starting distance) b
Slitlamp examination
Dilated binocular indirect high-magnification ophthalmoscopy
Intraocular pressure c
Adverse events d
Concurrent ocular procedures
Concomitant medications
Hematology, serum chemistry panel, and coagulation as deemed appropriate by the 
investigator
Ocular imaging, as necessary
IOPintraocular pressure.
a Patients will be instructed to contact the investigator at any time if they have any 
health-related concerns.  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 during the masked period.
Please note, unscheduled safety visits should only be utilized for the 
assessment of adverse events and are not to be used for standard of 
care procedures.


Faricimab—F. Hoffmann-La Roche Ltd
91/Protocol GR41987, Version 3
Appendix 3
Refraction and Best-Corrected Visual Acuity Testing
SCOPE
The refraction and best-corrected visual acuity (BCVA) assessment must be conducted 
before pupil dilation.  The refraction and BCVA will be measured by trained and certified 
personnel at the study sites.  Both refraction and BCVA will be assessed at every study 
visit. However, only study eye refraction from Day 1, Year 1, and Year 2 visit will be 
entered to refraction specific electronic Case Report Form (eCRF).  The 
BCVA assessment data will be entered to BCVA specific eCRF from every study visit.  
The visual acuity (VA) examiner must be masked to each patient’s study (treated) 
eye and treatment interval assignment for the duration of the study.  VA will be 
measured at the intervals specified in the protocol (see Appendix 1).
EQUIPMENT
The following are needed to conduct the examination:

Examination lane of adequate dimensions to allow testing at required distances 
(4- and 1-meter lanes)

Standard chair with a firm back

Set of three Precision Vision or Lighthouse distance acuity charts as applicable per 
country and region (see the BCVA manual for details)

Retro-Illuminated box

Study frame

Study lens set 
Note:  for additional details, see the BCVA specification manual.
TRAINING AND CERTIFICATION
A VA specifications document, procedure manual, and training materials will be provided 
to the investigational sites, and examiner certification will be obtained from a third party 
vendor.  The VA examination room also must be certified before any VA examinations 
are performed.


Faricimab—F. Hoffmann-La Roche Ltd
92/Protocol GR41987, Version 3
Appendix 4
Grading Scale for Assessment of Anterior Chamber Flare
or Cells and Vitreous Cell
Anterior Chamber Flare
Grade
Description
0
None
1
Faint
2
Moderate (iris and lens details clear)
3
Marked (iris and lens details hazy)
4
Intense (fibrin or plastic aqueous)
Anterior Chamber Cells
Grade
Cells in Field a
0
1
0.5
15
1
615
2
1625
3
2650
4
50
a Field size is a 1-mm slit beam.
Vitreous Cells
Grade
Number of Vitreous Cells
0
No cells
0.5
110
1
1120
2
2130
3
31100
4
101
From:  The Standardization of Uveitis Nomenclature (SUN) Working Group criteria.  Reference:  
Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred 
practice patterns of uveitis management. Surv Ophthalmol 2016;61:117.


Faricimab—F. Hoffmann-La Roche Ltd
93/Protocol GR41987, Version 3
Appendix 5
Color Fundus Photography
SCOPE
Stereo color fundus photography (CFP) using 7-modified field or 4-wide field imaging will 
be performed on both eyes by trained and central reading center (CRC) certified 
personnel.  CFP will be performed at baseline (Day 1) and at the intervals specified in 
the schedule of activities (see Appendix 1).
Sites that have ultra-wide field (UWF) CFP (e.g., Optos) capabilities, and have agreed 
to performing these, will collect additional UWP images of both eyes starting at baseline 
(Day 1) and at the intervals specified in the schedule of activities (Appendix 1).
EQUIPMENT
See the CRC manual.
PROCEDURES
The CRC will provide a study manual and training materials.  The fundus photographer 
and photography equipment will be certified by the CRC before any study images are 
taken.  See the CRC manual for further details.


Faricimab—F. Hoffmann-La Roche Ltd
94/Protocol GR41987, Version 3
Appendix 6
Fundus Fluorescein Angiography
SCOPE
Fundus fluorescein angiography (FFA) using the preferred ultra-wide field (UWF; 
Optos) imaging, if available, or otherwise using 7- or 4-wide field imaging, will be 
performed on both eyes at the study sites by central reading center (CRC) certified
trained personnel.  FFA will be obtained at baseline (Day 1) and at the intervals specified 
in the protocol (see Appendix 1).
EQUIPMENT
Digital angiograms must be acquired for the study.
Film-based angiography is not acceptable.
UWF is the preferred method for FFA.  Study sites without UWF equipment and 
certification must use 7- or 4-wide field FFA capture as described in the CRC manual.
DIGITAL IMAGING SYSTEMS AND CERTIFICATION
Digital imaging systems are required.  The system and software at the site will be 
certified by the CRC prior to obtaining any study angiograms.
PROCEDURES
The CRC will provide a study manual and training materials.  Photographers, systems, 
and software will be certified prior to obtaining angiograms of patients.


Faricimab—F. Hoffmann-La Roche Ltd
95/Protocol GR41987, Version 3
Appendix 7
Spectral-Domain Optical Coherence Tomography
SCOPE
Spectral-domain optical coherence tomography (SD-OCT) will be performed at the study 
sites by trained, central reading center (CRC) certified personnel.  SD-OCT imaging will 
be performed for each patient at the intervals specified in the protocol (see Appendix 1).
SD-OCT images of both eyes obtained at protocol-specified visits will be forwarded to 
the CRC.
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 CRC will provide the study manual and training materials.  SD-OCT operators, 
systems, and software will be certified prior to any evaluation of patients.


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Appendix 8
Biological Sample Collection and Shipping Instructions
BIOLOGICAL SAMPLES
Biological samples for the assessment of faricimab concentrations (pharmacokinetics), 
pharmacodynamics, anti-faricimab antibodies, blood DNA sample, laboratory 
assessment (hematology, serum chemistry, coagulation), and optional aqueous humor 
and vitreous samples will be obtained at the timepoints specified in the protocol (see 
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 treatment administrator from patients who consent to the procedure and 
sample acquisition.  An aqueous humor sample will be collected before the patient’s 
study eye treatment at the visits as indicated in Appendix 1.  Please refer to the central 
laboratory manual for additional details regarding sample collection and shipping 
information.
OPTIONAL UNSCHEDULED COLLECTION OF VITREOUS HUMOR 
SAMPLE COLLECTION
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.
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 VEGF and Ang-2 concentrations, and 
possibly other biomarkers.


Appendix 8: Biological Sample Collection and Shipping Instructions
Faricimab—F. Hoffmann-La Roche Ltd
97/Protocol GR41987, Version 3
BIOLOGICAL SAMPLES STORAGE DURATION
The hematology, serum chemistry, coagulation, serum, and urine pregnancy tests 
samples will be destroyed no later than the time of completion of the final Clinical Study 
Report.
Unless the patient gives specific Research Biosample Repository consent for his or her 
remaining samples to be stored for optional exploratory research (see Section 4.5.8), the 
rest of the biological samples will be destroyed no later than 5 years after the final 
Clinical Study Report has been completed.


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Appendix 9
National Eye Institute Visual Functioning Questionnaire25


Appendix 9: National Eye Institute Visual Functioning Questionnaire25
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Appendix 9: National Eye Institute Visual Functioning Questionnaire25
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Appendix 9: National Eye Institute Visual Functioning Questionnaire25
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Appendix 9: National Eye Institute Visual Functioning Questionnaire25
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Appendix 9: National Eye Institute Visual Functioning Questionnaire25
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Appendix 9: National Eye Institute Visual Functioning Questionnaire25
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Appendix 9: National Eye Institute Visual Functioning Questionnaire25
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Appendix 9: National Eye Institute Visual Functioning Questionnaire25
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Appendix 9: National Eye Institute Visual Functioning Questionnaire25
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Appendix 9: National Eye Institute Visual Functioning Questionnaire25
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Appendix 9: National Eye Institute Visual Functioning Questionnaire25
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Appendix 9: National Eye Institute Visual Functioning Questionnaire25
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Appendix 9: National Eye Institute Visual Functioning Questionnaire25
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SAP_001.pdf: 
Official Title: 
A Multicenter, Open-Label Extension Study to Evaluate The Long-
Term Safety and Tolerability of Faricimab in Patients with Diabetic 
Macular Edema 
NCT Number: 
NCT04432831 
Document & Date: 
SAP Version 2: 26-Jan-2024 


STATISTICAL ANALYSIS PLAN APPROVAL 
SPONSOR: 
LEGAL REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd
Grenzacherstrasse 124
4070 Basel, Switzerland
DATE FINAL: 
See electronic date stamp on the last page of this 
document  
CONFIDENTIAL 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
Faricimab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GR41987, version 2 
STATISTICAL ANALYSIS PLAN 
STUDY TITLE: 
A MULTICENTER, OPEN-LABEL EXTENSION 
STUDY TO EVALUATE THE LONG-TERM SAFETY 
AND TOLERABILITY OF FARICIMAB IN PATIENTS 
WITH DIABETIC MACULAR EDEMA 
STUDY NUMBER: 
GR41987 
STUDY NAME:  
RHONE-X 
VERSION NUMBER: 
2 
ROCHE COMPOUND: 
Faricimab (RO6867461) 
EUDRACT NUMBER: 
2020-000402-29 
IND NUMBER: 
119225 
NCT NUMBER: 
NCT04432831
PLAN PREPARED BY: 
 


 
 
Faricimab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GR41987, version 2 
2 
STATISTICAL ANALYSIS PLAN VERSION HISTORY 
This Statistical Analysis Plan (SAP) was developed based on Roche SAP model 
document V2.0. 
SAP Version 
Approval Date 
Based on Protocol  
(Version, Approval Date) 
1 
see electronic date stamp 
on the last page of this 
document 
Version 3, dated 13 Dec 2021 
2 
see electronic date stamp 
on the last page of this 
document 
Version 3, dated 13 Dec 2021 
 
 
 


 
 
Faricimab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GR41987, version 2 
3 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE 
 
This Statistical Analysis Plan (SAP) has been amended to incorporate the following 
changes: 
Section 
Description of Change 
3 
3 
Removed definition of per protocol population 
Re-defined safety evaluable population 
4.1 
Restructured section for better clarity and consistency 
4.4 
Added additional details of the analyses of exploratory endpoints. 
4.6 
Added additional details of immunogenicity analyses 
 
Additional minor changes have been made throughout to improve clarity and consistency.


 
 
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Statistical Analysis Plan GR41987, version 2 
4 
 
TABLE OF CONTENTS 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION ............................................................................. 8 
1.1 
Objectives and Endpoints .......................................................... 9 
1.1.1 
Primary Objective ...................................................................... 9 
1.1.2 
Exploratory Efficacy Objectives ............................................... 10 
1.1.3 
Pharmacokinetic Objectives..................................................... 11 
1.1.4 
Immunogenicity Objectives ...................................................... 11 
1.1.5 
Exploratory Biomarker Objectives ............................................ 11 
1.2 
Study Design ........................................................................... 11 
1.2.1 
Treatment Assignment and Blinding ........................................ 15 
1.2.2 
Independent Review Facility .................................................... 16 
1.2.3 
Data Monitoring ....................................................................... 16 
2. 
STATISTICAL HYPOTHESES AND SAMPLE SIZE 
DETERMINATION ........................................................................ 17 
2.1 
Statistical Hypotheses ............................................................. 17 
2.2 
Sample Size Determination ..................................................... 17 
3. 
ANALYSIS SETS .......................................................................... 17 
4. 
STATISTICAL ANALYSES ........................................................... 18 
4.1 
General Considerations ........................................................... 18 
4.2 
Analysis to Support the Primary Objective ............................... 19 
4.2.1 
Endpoint to Support the Primary Objective .............................. 19 
4.2.2 
Main Analytical Approach ........................................................ 20 
4.2.3 
Sensitivity Analysis .................................................................. 21 
4.2.4 
Supplementary Analysis .......................................................... 21 
4.2.4.1 
Subgroup Analyses for Primary Endpoint(s) ............................ 21 
4.3 
Secondary Endpoint Analysis .................................................. 21 
4.4 
Exploratory Analysis ................................................................ 21 
4.4.1 
Continuous Exploratory Endpoints ........................................... 22 
4.4.2 
Binary Exploratory Endpoints................................................... 23 


 
 
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Statistical Analysis Plan GR41987, version 2 
5 
4.5 
Other Safety Analyses ............................................................. 24 
4.5.1 
Extent of Exposure .................................................................. 25 
4.5.2 
Adverse Events ........................................................................ 25 
4.5.3 
Additional Safety Assessments ................................................ 25 
4.5.3.1 
Ocular Assessments ................................................................ 25 
4.5.3.2 
Laboratory Data ....................................................................... 25 
4.5.3.3 
Vital Signs ................................................................................ 26 
4.6 
Other Analyses ........................................................................ 26 
4.6.1 
Summaries of Conduct of Study .............................................. 26 
4.6.2 
Summaries of Demographics and Baseline Characteristics .... 26 
4.6.3 
Pharmacokinetic Analyses ....................................................... 27 
4.6.4 
Immunogenicity Analyses ........................................................ 27 
4.6.5 
Biomarkers Analyses ............................................................... 29 
4.6.6 
Analyses for COVID-19 ........................................................... 29 
4.6.7 
Study Conduct Analyses for COVID-19 ................................... 29 
4.6.8 
Safety Analyses for COVID-19 ................................................ 29 
4.7 
Interim Analyses ...................................................................... 31 
5. 
SUPPORTING DOCUMENTATION .............................................. 32 
6. 
REFERENCES.............................................................................. 32 
 
 
LIST OF TABLES 
Table 1 
Participant Analysis Sets ............................................................ 17 
Table 2 
Roche COVID-19 SMQ (narrow) Preferred Terms for 
Confirmed Cases ........................................................................ 31 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 13 
Figure 2 
Algorithm for IxRS-Determined Personalized Treatment 
Interval Study Drug Dosing Intervals ........................................... 15 
 


 
 
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Statistical Analysis Plan GR41987, version 2 
6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Description 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
ANCOVA 
analysis of covariance 
Ang-2 
angiopoietin-2 (protein)  
anti-VEGF 
anti-vascular endothelial growth factor 
APTC 
Anti-Platelet Trialists’ Collaboration 
ATE 
arterial thromboembolic event 
BCVA 
best-corrected visual acuity 
CI 
confidence interval 
COVID-19 
Coronavirus Disease 
CRC 
Central Reading Center 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CST 
central subfield thickness 
eCRF 
electronic Case Report Form 
DME  diabetic macular edema 
DR 
Diabetic Retinopathy 
DRSS 
Diabetic Retinopathy Severity Scale 
ET 
Early Termination 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FFA 
Fundus Fluorescein Angiography 
ILM 
IRF 
internal limiting membrane 
Intra-retinal Fluid 
IOI 
intraocular inflammation 
IOP 
intraocular pressure 
IVT 
intravitreal 
IxRS 
interactive voice or web-based response system 
LTE 
long-term extension 
MedDRA 
Medical Dictionary for Regulatory Activities 
NEI VFQ-25 
National Eye Institute Visual Function Questionnaire 25 
OCT 
Optical Coherence Tomography 
OCT-A 
Optical Coherence Tomography-Angiography 


 
 
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Statistical Analysis Plan GR41987, version 2 
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PD 
pharmacodynamic 
PK 
pharmacokinetic 
PT 
preferred term 
PTI 
personalized treatment interval 
Q4W 
every 4 weeks 
Q8W 
every 8 weeks 
Q12W 
every 12 weeks 
Q16W 
every 16 weeks 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD-OCT 
Spectral-Domain Optical Coherence Tomography 
SMQ 
standardized MedDRA queries 
SS-OCT 
Swept-Source Optical Coherence Tomography 
UWP 
Ultra-wide photography 
VA 
visual acuity 
VEGF (-A) 
vascular endothelial growth factor (-A) 


 
 
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Statistical Analysis Plan GR41987, version 2 
8 
1. 
INTRODUCTION 
Diabetic macular edema (DME), a complication of diabetic retinopathy (DR), can 
develop at any stage of the underlying disease of retinal microvasculature. DME occurs 
with increasing frequency as the underlying DR worsens from non-proliferative DR to 
proliferative DR (PDR). DME is the most common cause of moderate and severe visual 
impairment in patients with DR and affects approximately 14% of patients with diabetes. 
On a molecular level, DME is a result of a vascular endothelial growth factorA 
(VEGF-A)mediated increase in vessel permeability and loss of pericytes. VEGF also 
upregulates a homeostatic factor, angiopoietin-2 (Ang-2), counteracting vessel 
stabilization. In summary, both Ang-2 and VEGF-A are recognized as key factors 
mediating diabetic eye disease pathogenesis. The development of anti-VEGF 
pharmacotherapy in the past decade has led to dramatic improvements in visual 
outcomes for patients with DME. Despite these advancements, a significant proportion 
of patients do not experience clinically meaningful improvements in vision in the real 
world. The current standard of care for administration of anti-VEGF injections requires 
patients to undergo frequent clinical examinations and intravitreal (IVT) injections 
imposing a significant burden on patients, caregivers, and treating physicians. In 
addition, anti-VEGF monotherapy does not fully address other pathways, including 
inflammation and pericyte destabilization, that contribute to worsening of diabetic eye 
disease. Consequently, patients on anti-VEGF monotherapy may not be gaining as 
much vision as they could. Taken together, new treatments that target additional 
pathways could address the above unmet medical needs by improving visual acuity (VA) 
outcomes and reducing the burden of IVT injections in DME.  
Faricimab is a humanized full-length bispecific immunoglobulin 1 antibody that 
selectively neutralizes Ang-2 and VEGF-A. The Ang-2 binding and the VEGF binding 
variable regions of faricimab bind to Ang-2 and VEGF independently and simultaneously 
with high affinity. Based on this novel mechanism of action of faricimab, and existing 
evidence of upregulated concentrations of both Ang-2 and VEGF in the vitreous in 
patients with DR, it is hypothesized that faricimab may lead to stabilization of the 
pathological ocular vasculature and to improve visual and anatomical outcomes in DME 
and DR compared with anti-VEGF monotherapies. The available Phase I and II efficacy 
and safety data showed a benefitrisk profile that supports further assessment of the 
efficacy, durability, and safety of faricimab compared with anti-VEGF IVT monotherapy 
in a Phase III setting.  The Phase 3 studies YOSEMITE (GR40349) and RHINE 
(GR40398) were identically designed registrational studies that investigated the efficacy, 
safety and pharmacokinetics of faricimab given at Q8W intervals or with a PTI regimen 
compared with aflibercept monotherapy in patients with DME. The primary analysis of 
these Phase III studies demonstrated that patients treated with faricimab Q8W or PTI 
had a non-inferior mean change from baseline in BCVA at Week 48/52/56 compared 
with patients treated with aflibercept Q8W. The mean change in BCVA from baseline 


 
 
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Statistical Analysis Plan GR41987, version 2 
9 
was comparable over time across faricimab Q8W, faricimab PTI, and aflibercept Q8W 
arms through Week 100.  In addition, the majority of faricimab-treated patients ( 70%) 
were on an extended dosing regimen (every 12 weeks [Q12W] or Q16W) at Week 52.  
The purpose of this document is to provide details of the planned analyses for inclusion 
in the clinical study report of the Phase III long term extension (LTE) Study GR41987 
(RHONE-X).  In this Statistical Analysis Plan, ‘study drug’ refers to faricimab whereas 
‘study treatment’ refers to faricimab or the sham procedure in the masked period. 
The analysis plan and the endpoints specified in this document supersede the analysis 
plan described in the study protocol.  This document will address analysis for efficacy, 
safety, immunogenicity, biomarkers and pharmacokinetics.  Detailed specifications of 
tables, figures and listings are provided in separate documents.  
1.1 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the long term safety and tolerability of intravitreal (IVT) faricimab 
in patients with DME who have completed either of the Phase III (GR40349 or 
GR40398) studies, also referred to as the parent studies. 
Eligible patients who choose to enroll into the LTE study will have monthly, masked, 
study visits for the first 4 months of the study (Day 1 through to Week 16).  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 Personalized Treatment Interval (PTI) algorithm.  See 
Section 1.2 for details on the study design.  
The primary objective is to evaluate the long-term ocular and systemic safety and 
tolerability of faricimab on the basis of the incidence and severity of ocular and 
non‑ocular adverse events.  
Additional assessments relating to efficacy, pharmacokinetics, immunogenicity, and 
biomarkers will be performed.  
All efficacy endpoints will be assessed at selected timepoints, including at the 1 and 
2 year timepoints in the LTE study. 
1.1.1 
Primary Objective 
The primary objective for this study is to evaluate the long-term ocular and systemic 
safety and tolerability of faricimab in all patients who have enrolled in this LTE study, 


 
 
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Statistical Analysis Plan GR41987, version 2 
10 
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 
 
1.1.2 
Exploratory Efficacy Objectives 
The exploratory efficacy objective of this study is to assess the long-term efficacy of IVT 
faricimab for the management of diabetic eye disease in all patients who have enrolled 
in this LTE study on the basis of the following endpoints: 
 
Change from baseline in best-corrected visual acuity (BCVA) over time as 
measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at a 
starting distance of 4 meters  
 
Change from baseline in central subfield thickness (CST) over time 
– 
CST is defined as the distance between ILM and BM, as measured in μm as 
assessed by Central Reading Center (CRC). CST for Cirrus spectral-domain 
optical coherence tomography (SD-OCT) or Topcon SD-OCT were 
standardized to Spectralis SD-OCT by the central reading center. 
 
Proportion of patients with absence of intraretinal fluid over time 
 
Proportion of patients with absence of subretinal fluid over time 
 
Proportion of patients with absence of both intraretinal fluid and subretinal fluid over 
time 
 
Proportion of patients with absence of DME over time 
– 
Absence of DME is defined as achieving a CST of  325 microns 
 
Proportion of patients on a Q4W, Q8W, Q12W, or Q16W treatment during the study: 
– 
Treatment interval at a given visit is defined as the treatment interval decision 
followed at that visit.  If the visit is not an active dosing visit, treatment interval is 
defined as the treatment interval the patient is on at that visit 
 
Proportion of patients with: 
– 
 2-step DRS improvement from baseline on the ETDRS DRSS over time 
– 
 3-step DRS improvement from baseline on the ETDRS DRSS over time 
 
Proportion of patients with:  
– 
 2-step DRS worsening from baseline on the ETDRS DRSS over time 
– 
 3-step DRS worsening from baseline on the ETDRS DRSS over time 
 
Proportion of patients who develop new PDR over time 
 
Change from baseline in patient-reported vision-related functioning and quality of life 
over time as assessed using the National Eye Institute Visual Functioning 


 
 
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Statistical Analysis Plan GR41987, version 2 
11 
Questionnaire 25‑item (NEI VFQ-25) composite score, the near activity subscale 
score, the distance activities subscale score, and driving subscale score 
 
1.1.3 
Pharmacokinetic Objectives 
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 
 
1.1.4 
Immunogenicity Objectives 
The immunogenicity objective for this study is to evaluate the immune response to 
faricimab on the basis of the following endpoints: 
 
Presence of anti-drug antibodies (ADAs) at baseline 
 
Incidence of ADAs during the study from the start of the LTE. 
 
See Section 4.6.4 for the definition of baseline for immunogenicity analyses. 
1.1.5 
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 baseline anatomic measures and the change in BCVA or 
other endpoints (e.g., the frequency of faricimab administration) over time.  Over 
time refers to the study period starting from LTE Day 1 
 
1.2 
STUDY DESIGN 
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 (GR40349 or GR40398).  Patients in the parent 
studies who discontinued from the study or study treatment prior to completion of the 
96‑week treatment period are not eligible for enrollment in this extension study. 


 
 
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Statistical Analysis Plan GR41987, version 2 
12 
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 100 visit in Studies GR40349 and 
GR40398).  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 100) 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.  Assessments that are required for the Week 100 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. 
Total 1479 patients have been enrolled in this extension study after completion of the 
parent studies and will all follow a single faricimab 6 mg PTI regimen. 
 
Patients previously randomized to Arm A (faricimab Q8W) who have had their last 
dose of faricimab at Week 92 of the parent study (see Figure 1) will have a dose of 
faricimab at Day 1 of the LTE study, and will then be eligible to have their 
subsequent faricimab dosing based on the PTI algorithm. 
Patients in this arm who (e.g., because of dose holds/missed visits in the parent 
study) received a faricimab dose at Week 96 in the parent study, will not receive a 
faricimab dose on Day 1 of the LTE study. Instead, these patients will be dosed 
8 weeks after the final dose in the parent study (i.e., at Week 4 of the LTE study) 
and will then be eligible to have their subsequent dosing interval extended, reduced, 
or maintained on the basis of the PTI algorithm. 
 
Patients previously randomized to Arm B (faricimab PTI up to Q16W) will continue  
their previously assigned treatment interval and will then be eligible to have their 
subsequent faricimab dosing based on the PTI algorithm.  
 
Patients previously randomized to Arm C (aflibercept Q8W) who have had their last 
dose of aflibercept at Week 96 of the parent study (see Figure 1) will have a dose of 
faricimab at Week 4 of the LTE study, and will then be eligible to have their 
subsequent faricimab dosing based on the PTI algorithm. Patients in this arm who 
(e.g., because of dose holds/missed visits in the parent study) received their last 
aflibercept dose at Week 92 of the parent study will have a faricimab dose on Day 1 
of the LTE study.  These patients will then be eligible to have their subsequent 
dosing based on the PTI algorithm. 
 
In this extension study, the study eye will be the same as that in the parent studies, 
GR40349 and GR40398. 


 
 
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Statistical Analysis Plan GR41987, version 2 
13 
Patients will be required to attend monthly study assessment visits between Day 1 and 
Week 16 (the masked period of the study) in order to preserve masking of a patient’s 
treatment assignment in the parent study.  From Week 20 until approximately Week 104, 
patients will attend study visits at intervals as scheduled by the IxRS system based on 
the PTI algorithm.   
Annual visits are defined as the scheduled PTI visit that is earliest (between Week 48 
and Week 64) relative to 52 weeks (for Year 1) and earliest (between Week 96 and 
Week 104) relative to 104 weeks (for Year 2) from Day 1. If, due to the patient’s 
faricimab PTI, there are multiple options for Year 1 or Year 2 visits, IxRS will advise the 
site that the earliest scheduled visit between Week 48 and Week 64 should be 
considered the Year 1 visit and that the earliest scheduled visit between Weeks 96 and 
104 should be considered the Year 2 visit. If the earliest scheduled visit is missed, then 
the next visit within the period should be considered the annual visit. 
Patients who undertake their Year 2 visit at Week 96 or Week 100 but are on a PTI that 
requires them to return at Week 100 and/or Week 104 should also attend these 
scheduled study visits and attend their Final End of Study visit (FEOS) 28-35 days after 
their final dose of study treatment. For the study schema, see Figure 1. Figure 1 has 
FEOS shaded to represent dosing but there is no dosing at this visit. 
Figure 1 Study Schema 
 
LTE  long-term extension; PTI  personalized treatment interval; Q8W  every 8 weeks; 
SFU  safety follow-up. 
  


 
 
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14 
Patients who discontinue study treatment will be encouraged to continue their study 
participation and attend LTE annual visits (Year 1 and Year 2), as outlined in the 
schedule of activities.  In addition to this, patients will return to the clinic for an 
unscheduled visit a minimum of 28 days after receiving the final dose of study drug. 
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 4 months of the study (Day 1 through to Week 16; see Figure 1)  
and they will receive sham injections at study visits at which they are not scheduled to 
receive faricimab.  During the masked period, patients and physicians will only be 
masked to the faricimab treatment interval (if faricimab or sham is administered).   
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. 
Personalized Treatment Interval Algorithm 
An IxRS system will be used to calculate a patient’s PTI interval. The PTI algorithm is 
the same as that used in the Phase III studies. The PTI uses patient’s BCVA and CST 
data obtained at dosing visits during both the parent study and the LTE to determine the 
next interval for faricimab dosing intervals can be extended in 4‑week increments to a 
maximum of Q16W, maintained, or reduced to a minimum of Q4W as mentioned below 
in Figure 2. 


 
 
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Statistical Analysis Plan GR41987, version 2 
15 
Figure 2 Algorithm for IxRS-Determined Personalized Treatment Interval 
Study Drug Dosing Intervals 
 
BCVA  Best Corrected Visual Acuity; CST  Central Subfield Thickness; IxRS  Interactive voice 
or web-based Response System. 
  
The final analysis will be performed when all patients have either completed the study 
through Year 2 or have discontinued early from the study, whichever comes later, all 
data are in the database, and cleaning and verification of critical variables have been 
completed. 
1.2.1 
Treatment Assignment and Blinding 
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 number and kit 
assignments from the IxRS.  In this extension study, the patient number will be the same 
as that assigned in the parent studies. 
As outlined in Section 3.1 of the protocol, there will be a masked period in the early 
phase of the LTE study (Day 1 to Week 16).  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 16 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. 


 
 
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Further details about masked roles during the masked period of the LTE study can be 
found in Section 4.2.1.1 of the protocol. 
1.2.2 
Independent Review Facility 
Ocular Imaging  
The protocol for image acquisition for the LTE study is the same as that used in the 
parent Phase III studies.  All ocular images are obtained by site personnel and imaging 
systems (including software) that have been certified by the CRC.  All ocular images 
obtained by trained and CRC certified site personnel are to be forwarded to the CRC for 
independent analysis and storage.  
Ocular images include the following: 
 
CFP in both eyes (7- or 4-ETDRS fields; method used for each patient should be  
 
consistent with that used in the parent study and remain consistent throughout the 
duration of the LTE study)  
 
Optional ultra-wide field (UWF) CFP of both eyes (to be undertaken in patients for 
whom consent was obtained and images acquired in the parent study) 
 
FFA of both eyes (preferred method is UWF FFA if sites have capability; sites  
 
without UWF should capture 7- or 4-field ETDRS as per the parent study and use 
the same method consistently throughout their LTE study participation). FFA should 
be performed after blood samples obtained (if applicable). 
 
SD-OCT or swept-source OCT images of both eyes (to be undertaken using the  
 
same device as that used in the parent study) 
 
Optional OCT-angiography (OCT-A) of both eyes at sites with OCT-A capabilities 
and agreement by sites to take these images (to be undertaken using the same 
device as that used in the parent study) 
 
The data resulting from this review of ocular images are forwarded to the Sponsor and 
additionally, the SD-OCT CST values are forwarded to the IxRS for treatment interval 
determination. 
Anti-Platelet Trialists’ Collaboration (APTC)  
Potential APTC events that are identified during the study are externally adjudicated on 
an ongoing basis.  A dossier of available information on each case of interest is provided 
to the external expert adjudicators for their review and assessment.  
1.2.3 
Data Monitoring 
Not Applicable 


 
 
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2. 
STATISTICAL HYPOTHESES AND SAMPLE SIZE 
DETERMINATION 
2.1 
STATISTICAL HYPOTHESES  
No formal statistical hypothesis will be tested. 
2.2 
SAMPLE SIZE DETERMINATION 
No formal sample size calculations were performed for this LTE study.  This study is 
open to all patients who complete study treatment and the Week 100 visit in one of the 
parent studies GR40349 (YOSEMITE) or GR40398 (RHINE).  
3. 
ANALYSIS SETS 
The participant analysis sets for the purposes of analyses are defined in Table 1. 
Table 1 
Participant Analysis Sets 
Participant Analysis Set 
Description 
Efficacy evaluable 
All eligible patients enrolled into this study.  
For analyses using the parent study treatment group, patients 
will be grouped according to the treatment assigned at 
randomization in the parent study. 
All data starting from the LTE baseline will be used for efficacy 
analyses. 
Safety-Evaluable 
The safety-evaluable population will comprise all patients who 
enroll in the LTE, and receive at least one dose of faricimab 
during the LTE. For analyses using the parent study treatment 
group, patients will be grouped according to the actual 
treatment received in the parent study up to the Week 96 visit, 
as explained in the Section 4.1. 
All data starting from the date of first administration of faricimab 
will be used for safety analyses. 
Pharmacokinetic-Evaluable 
Safety-evaluable patients who have at least one plasma 
sample, and if sufficient dosing information (dose and dosing 
time) is available.  
For analyses based on the parent study treatment groups, 
patients will be grouped according to the actual treatment 
received in the parent study (see Section 4.1).  


 
 
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Table 1 
Participant Analysis Sets (cont.) 
Participant Analysis Set 
Description 
Immunogenicity-evaluable 
All patients with at least one plasma sample for ADA 
assessment. 
The immunogenicity prevalence set will consist of all patients 
who received faricimab with at least one determinant anti-drug 
antibody (ADA against faricimab) assessment. The 
immunogenicity incidence set will consist of all patients who 
received faricimab with at least one determinant ADA 
assessment after the initiation of faricimab treatment. 
For analyses based on the parent study treatment groups, 
patients will be grouped according to the actual treatment 
received in the parent study (see Section 4.1). All data starting 
from the LTE baseline will be used for immunogenicity 
analyses. 
ADA  anti‑drug antibody; LTE  long-term extension. 
  
4. 
STATISTICAL ANALYSES 
Unless otherwise specified, the analyses described in this section are based on patients 
enrolled in this LTE study. 
The analyses timing for final analyses are provided in Section 1.2.  
4.1 
GENERAL CONSIDERATIONS 
Safety analyses will be based on the safety-evaluable population.  
Safety summary tables will include all events collected in this LTE study from the first 
dose of faricimab. Additional listings will be provided for events that occurred from the 
LTE enrollment to the first faricimab dose  for all enrolled patients. 
Unless otherwise noted, the exploratory efficacy analyses will be based on the 
efficacy‑evaluable population and will be presented overall and by parent study 
treatment group for the whole LTE study cohort for both binary and continuous 
endpoints.  The exploratory efficacy analyses will be based on all available observations 
collected during the LTE study. Baseline will be defined as Day 1 of this study for 
patients randomized to faricimab Q8W or faricimab PTI in the parent study and as the 
first day of faricimab treatment in the LTE for patients randomized to aflibercept in the 
parent study.  Patients with missing baseline assessments will not be imputed.   
Continuous outcomes will be analyzed descriptively and additionally BCVA and CST 
outcomes will be analyzed using an Analysis of Covariance (ANCOVA) model. Binary 
endpoints will be analyzed descriptively and using stratified estimation for binomial 
proportions. The estimates and confidence intervals (CIs) will be provided for the mean 


 
 
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(for continuous variables) or proportion (for binary variables). Separate listings will be 
provided to present efficacy data collected from LTE Day 1 to the first faricimab dose in 
patients randomized to aflibercept in the parent study by parent study treatment group. 
For safety 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 
96 visit as follows (similar algorithm used in the parent studies): 
 
If the only active treatment received in the parent study by a patient in the study eye 
was aflibercept, the patient’s parent study treatment group will be aflibercept Q8W. 
 
If the only active treatment received in the parent study by a patient in the study eye 
was faricimab, the patient’s parent study treatment group will be as randomized if 
the patient was randomized to one of the faricimab arms. 
 
If a patient received in the parent study a combination of different active treatments 
(faricimab and aflibercept) in the study eye, the patient’s parent study treatment 
group will be as randomized.  
 
For the purpose of visit scheduling, Year 1 is defined as the scheduled PTI visit that is 
earliest (between Week 48 and Week 64). Year 2 is defined as the scheduled PTI visit 
that is earliest (between Week 96 and Week 104) from Day 1 of the LTE study.  If the 
earliest scheduled visit is missed, then the next visit within the period should be 
considered the annual visit.  
Data collected in scheduled and unscheduled visits will be mapped to visits that appear 
in the schedule of assessments per the protocol using the actual study day of 
assessment.  For any study visit starting from Week 4, if there are multiple values in the 
same visit window, the value closest to the target study day will be mapped to the visit 
and used as the analysis value corresponding to that visit. For example: for the visit 
corresponding to Week 52 (target study day 364), the assessment within the visit 
window (349377 days) which is closest to study day 364 will be mapped to study visit 
Week 52 as the analysis value. Details of target study day and analysis window for each 
scheduled visit will be provided in Module 2 of the Data Analysis Plan. 
4.2 
ANALYSIS TO SUPPORT THE 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. 
4.2.1 
Endpoint to Support the Primary Objective 
The primary safety objective will be evaluated on the safety-evaluable population on the 
basis of the incidence and severity of ocular and non-ocular adverse events (AEs).  All 
verbatim AEs terms will be coded using the latest version of Medical Dictionary for 
Regulatory Activities (MedDRA).  


 
 
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Only treatment-emergent AEs will be summarized.  A treatment emergent adverse event 
is defined as any new adverse event reported or any worsening of an existing condition 
on or after the first dose of faricimab. Adverse events with missing onset date will be 
considered to be treatment emergent.  Adverse events with partially missing onset date 
will also be included as treatment emergent when the month (if it was recorded) and the 
year occur on or later than the month and year of the start date of the reporting period.   
Clinically significant laboratory abnormalities and clinically significant vital sign 
abnormalities will be reported as adverse events and evaluated as part of the adverse 
event assessments. 
Missing data for safety analyses will not be imputed.  
4.2.2 
Main Analytical Approach 
AEs will be tabulated by System Organ Class and Preferred Term and presented overall, 
and by parent study treatment group. 
For ocular AEs, events in the study eye and fellow eye will be summarized separately.  
Frequency tables, including patient incidence rates by parent study treatment arm, will 
be provided for the events listed below.  In addition, graphical presentations will be 
included, as applicable: 
 
Ocular AEs and serious adverse events (SAEs)  
 
Non-ocular AEs and SAEs   
 
Adverse events of special interest (AESI) defined as follows:  
– 
Cases of potential drug-induced liver injury that include elevated alanine 
aminotransferase or aspartate aminotransferase in combination with either an 
elevated bilirubin or clinical jaundice, as defined by Hy's Law (see Section 5.2.3 
of the protocol) 
– 
Suspected transmission of an infectious agent by the study drug  
– 
Sight-threatening AEs (see Section 5.2.3 of the protocol for definitions) 
 
AEs leading to discontinuation of study treatment 
 
AEs leading to discontinuation from the study 
 
AEs leading to study treatment interruption 
 
Treatment related ocular AEs and SAEs as determined by the Investigator 
 
Non-ocular adverse events of arterial thromboembolic event (ATE) and 
cerebrovascular haemorrhagic adverse events 
 
Externally adjudicated APTC events 
 
Intraocular inflammation (IOI)  


 
 
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 
Retinal vascular occlusive disease  
 
Deaths  
 
As there is no standardized MedDRA queries (SMQ) encompassing the medical 
concepts of IOI or retinal vascular occlusive disease, the definitions will be assessed 
based on the review of clinical database preferred terms (PTs) or reported AEs from 
clinical database prior to data cut and final database lock, and with subsequent MedDRA 
version updates, to ensure no event terms are missed.  
Ocular AEs and non-ocular AEs which occurred from the LTE enrollment to the first 
faricimab dose will be listed separately for all enrolled patients. 
4.2.3 
Sensitivity Analysis 
Not Applicable 
4.2.4 
Supplementary Analysis 
Not Applicable 
4.2.4.1 
Subgroup Analyses for Primary Endpoint(s) 
Not Applicable 
4.3 
SECONDARY ENDPOINT ANALYSIS 
Not Applicable. 
4.4 
EXPLORATORY ANALYSIS 
The exploratory efficacy analyses will be based on the efficacy-evaluable population and 
will be presented overall and by parent study treatment group for the whole LTE study 
cohort for both binary and continuous endpoints.  The analyses will be based on all 
available observations.  No formal statistical hypothesis will be tested. Missing data will 
not be imputed.  
For patients randomized to aflibercept in the parent study, baseline is defined as the last 
value collected before the first faricimab injection in the LTE study.  For patients 
randomized to faricimab Q8W or faricimab PTI in the parent study, baseline is defined as 
the value collected at parent study Week 100/study Day 1 prior to any LTE study 
assessments.  If LTE study Day 1 is  2 business days but  28 days from parent study 
Week 100 (delayed Day 1 visit), the following exploratory efficacy assessments must be 
repeated and the Day 1 value is considered the baseline value: 
 
BCVA 
 
Optical Coherence Tomography (OCT) measures  
 


 
 
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In case of a delayed Day 1 visit, non- Case Report Form (CRF) Day 1 imaging data will 
be transferred to the Sponsor.  Otherwise, if Day 1  2 business days from parent study 
Week 100, values will be pulled from the parent study Week 100 for the analysis. 
Descriptive summaries for the continuous endpoints will include the number of 
observations, arithmetic mean, SD, median, Q1, Q3, minimum, and maximum.   
Separate listings will be provided to present efficacy data collected from LTE Day 1 to 
the first faricimab dose in patients randomized to aflibercept in the parent study. 
Additional details of the analysis of each exploratory endpoint are given in the sections 
below. 
4.4.1 
Continuous Exploratory Endpoints 
Change from baseline in BCVA and CST 
The change from baseline in BCVA and CST will be summarized descriptively as well as 
using an Analysis of Covariance (ANCOVA) model with adjustment for parent study 
stratification factors of baseline BCVA score (64 letters or better vs. 63 letters or worse), 
prior IVT anti-VEGF therapy (yes vs. no), region (U.S. and Canada, Asia, and the rest of 
the world), parent study treatment arm (faricimab 6mg Q8W, faricimab 6mg PTI and 
aflibercept 2mg Q8W) and baseline value (continuous). 
The analysis of change from baseline in BCVA and CST will be presented at monthly 
intervals during the masked period, and at Year 1 (Y1), 18 months and Year 2 (Y2) 
timepoints. The 18 month time point has been added as an intermediate time point 
midway between the annual assessment timepoints for continuity in reporting of BCVA 
and CST outcomes. The calculation of the analysis value corresponding to Y1, 
18 months and Y2 timepoints will be done at patient level and is as described below.  
 
Analysis value at Year 1 is calculated as an average of values corresponding to all 
available visits (one value for each visit, mapped as described in Section 4.1) within 
the Year 1 visit window i.e., Week 48 to Week 64 
 
Analysis value at 18 months is calculated as an average of values corresponding to 
all available visits (one value for each visit, mapped as described in Section 4.1) 
within the 18 month visit window i.e., Week 72 to Week 88 
 
Analysis value at Year 2 is calculated as an average of values corresponding to all 
available visits (one value for each visit, mapped as described in Section 4.1) within 
the Year 2 visit window i.e., Week 96 to Week 104. 
 
This averaging will be done for both the BCVA and CST endpoints. The rationale for 
using this approach is to reduce bias arising from variability due to multiple assessments 
of BCVA and CST in the annual visit windows, especially from patients on a shorter PTI.  


 
 
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A sensitivity analysis of change from baseline in BCVA and CST will be performed using 
the ANCOVA model with adjustment for parent study stratification factors of baseline 
BCVA score (64 letters or better vs. 63 letters or worse), prior IVT anti-VEGF therapy 
(yes vs. no), region (U.S. and Canada, Asia, and the rest of the world), parent study 
treatment arm (faricimab 6mg Q8W, faricimab 6mg PTI and aflibercept 2mg Q8W) and 
baseline value (continuous). For this analysis, the first data point in the analysis window 
corresponding to the Year 1, 18 month and Year 2 timepoints respectively will be used 
as the response variable as follows:  
 
Analysis value at Year 1 will be the value corresponding to the earliest visit (one 
value per visit, mapped as described in Section 4.1) available in the Year 1 visit 
window – Week 48 to Week 64 
 
Analysis value at Month 18 will be the value corresponding to the earliest visit (one 
value per visit, mapped as described in Section 4.1) available in the 18 month visit 
window – Week 72 to Week 88 
 
Analysis value at Year 2 will be the value corresponding to the earliest visit (one 
value per visit, mapped as described in Section 4.1) available in the Year 2 visit 
window – Week 96 to Week 104 
 
Non-standard BCVA data (assessed by Early Treatment Diabetic Retinopathy Study 
[ETDRS] BCVA testing with prior visit refraction, test performed by unmasked certified 
ETDRS BCVA assessor, or by uncertified experienced ETDRS BCVA assessor, or 
Snellen data) due to COVID-19 restrictions and collected in the COVID-19 
Non-Protocol-Specified Visual Acuity Testing eCRF will be excluded from all the 
analyses.  Invalid BCVA will be excluded from the analyses. 
Change from baseline in NEI-VFQ 25 patient reported outcome 
The change from baseline in NEI-VFQ 25 composite score, the near activity subscale 
score, the distance activities subscale score, and driving subscale score will be 
summarized descriptively at Year 1 and Year 2 timepoints respectively. 
4.4.2 
Binary Exploratory Endpoints 
Binary endpoints will be summarized using frequency and/or percentage. The proportion 
of patients in each treatment group will be estimated using the weighted average of the 
observed proportions over the strata defined by the parent study stratification factors of 
baseline BCVA score (64 letters or better vs. 63 letters or worse), prior IVT anti-VEGF 
therapy (yes vs. no), region (U.S. and Canada, Asia, and the rest of the world) and 
parent study treatment arm (faricimab 6mg Q8W, faricimab 6mg PTI and aflibercept 
2 mg Q8W) using the Cochran Mantel-Haenszel (CMH) weights (Cochran 1954; Mantel 
and Haenszel 1959). Confidence intervals of the proportion of patients in each treatment 
group will be calculated using the normal approximation to the weighted proportions 
(Mehrotra and Railkar 2000).  All CIs will be two-sided and at the 95% level.  No formal 
statistical hypothesis will be tested so no p-values will be provided. 


 
 
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The following binary exploratory endpoints will be summarized descriptively.  
 
Proportion of patients with absence of intraretinal fluid at Year 1 and Year 2.  
 
Proportion of patients with absence of both intraretinal fluid and subretinal fluid at 
Year 1 and Year 2 
 
Proportion of patients with absence of DME at Year 1, 18 months and Year 2 
– 
Absence of DME is defined as achieving a CST of  325 microns 
 
Proportion of patients on a Q4W, Q8W, Q12W, or Q16W treatment at Year 1 and 
Year 2: 
– 
Treatment interval at a given visit is defined as the treatment interval decision 
followed at that visit.  If the visit is not an active dosing visit, treatment interval is 
defined as the treatment interval the patient is on at that visit 
– 
For durability analyses, Year 2 analysis window is defined as Week 92 to Week 
104 to include patients on Q16W treated at Week 92. 
– 
The last observed PTI in the visit window for Year 1 and Year 2 will be used as 
the patient’s PTI at that time point as this is expected to represent the treatment 
interval at the end of long term faricimab treatment. For a patient with a missed 
Year 2 visit, the PTI calculated at the visit previous to the scheduled Year 2 visit 
will be the last calculated PTI for the patient. 
 
Proportion of patients with: 
– 
 2-step DRS improvement from baseline on the ETDRS DRSS at Week 16, 
Year 1 and Year 2 
– 
 3-step DRS improvement from baseline on the ETDRS DRSS at Week 16, 
Year 1 and Year 2 
 
Proportion of patients with:  
– 
 2-step DRS worsening from baseline on the ETDRS DRSS at Week 16, 
Year 1 and Year 2 
– 
 3-step DRS worsening from baseline on the ETDRS DRSS at Week 16, 
Year 1 and Year 2 
 
Proportion of patients who develop new PDR at Week 16, Year 1 and Year 2 
 
4.5 
OTHER SAFETY ANALYSES 
All the safety analyses will be performed on the safety-evaluable population and 
presented overall and by parent study treatment group. 
Patients will be grouped according to the actual treatment received in the parent study 
up to Week 96. 


 
 
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4.5.1 
Extent of Exposure 
Exposure to study drug (number of study drug administrations and duration of treatment) 
will be summarized overall and by parent study treatment group for the study eye in the 
safety evaluable population. All data starting from the date of first faricimab injection in 
the LTE will be included in the analyses. Baseline will be the date of first administration 
of faricimab in the LTE study. 
Duration of treatment is the time from the first faricimab administration in the LTE study 
to the earlier of  
 
the date of treatment discontinuation or  
 
date of study treatment completion during the entire study. 
 
The number of dose interruptions along with the reason for interruption and the number 
of interruptions per patient will be summarized using counts and percentages. 
4.5.2 
Adverse Events 
All the details about AEs analysis are provided in Section 4.2.2.   
4.5.3 
Additional Safety Assessments  
4.5.3.1 
 
Ocular Assessments 
Results of the following ocular assessments will be summarized by eye (study vs. fellow) 
using descriptive summaries and graphical presentations (as applicable): 
 
Intraocular pressure (IOP) 
 
Slit lamp examination 
 
Indirect ophthalmoscopy 
 
Changes from baseline in pre-dose IOP measurements will be summarized overall and 
by parent study treatment group over time. 
Baseline is defined as the first day of faricimab treatment for all patients enrolled in the 
LTE study. 
Changes between pre-dose and post-dose IOP measurements will also be summarized 
over time, overall and by parent study treatment group.  The presence of IOI and 
vitreous hemorrhage, as determined on slit lamp examination and/or indirect 
ophthalmoscopy, will be tabulated by grade (according to grading scales for flares and 
cells in Appendix 3 of the protocol).  The presence of retinal break or detachment as 
determined from indirect ophthalmoscopy will be tabulated. 
4.5.3.2 
 
Laboratory Data 
There is no laboratory data collection scheduled at study visits other than PK and ADA 
samples. No general summary is planned.  


 
 
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4.5.3.3 
 
Vital Signs 
Vital signs will be collected as part of the parent Phase III Week 100 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 100 visit. 
Vital signs will include measurements of temperature, respiratory rate, pulse rate, and 
systolic and diastolic blood pressure.  No general summary is planned. 
4.6 
OTHER ANALYSES 
4.6.1 
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.  Patient disposition (the number of patients 
enrolled, treated, and completing the study) will be summarized overall and by parent 
study treatment group. Premature study drug discontinuation and study discontinuation, 
as well as reasons for discontinuations, will be summarized. 
The impact of Coronavirus disease (COVID-19) will be assessed by using metrics 
reported in Section 4.6.6. 
Major protocol deviations will be summarized by parent study treatment arm and overall. 
Patient listings of major protocol deviations may also be provided. 
Concurrent ocular procedures, concomitant systemic medications, ocular medications 
for the study eye, and ocular medications for the fellow eye will be summarized 
separately overall and by parent study treatment group. The summaries will be based on 
medications given at or after the first faricimab dose in the LTE study. 
4.6.2 
Summaries of Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using the 
efficacy‑evaluable population and presented overall and by parent study treatment 
group.  Demographic data (e.g., age, sex, and race/ethnicity) and medical history will 
originate from the parent study.  Baseline disease characteristics (e.g., baseline BCVA, 
ocular assessments) will be summarized for the LTE study baseline. 
For the summaries of demographics and baseline characteristics, for patients 
randomized to aflibercept in the parent study, LTE baseline is defined as the last value 
collected before the first faricimab injection in the study. 
For patients randomized to faricimab Q8W or faricimab PTI in the parent study, LTE 
baseline is defined as the value collected at parent study Week 100/study Day 1 prior to 


 
 
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any study assessments.  If study Day 1 is  2 business days but  28 days from parent 
study Week 100, BCVA and ocular assessments (slit lamp examination, pre-dose IOP 
and indirect ophthalmoscopy) must be repeated at Day 1 and the Day 1 value is 
considered the baseline value. 
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. 
4.6.3 
Pharmacokinetic Analyses 
PK analyses will be based on the pharmacokinetic-evaluable population. 
For PK analyses, plasma concentration data from the date of first faricimab 
administration in the LTE study will be used for analysis. 
The analyses will be summarized overall and by parent study treatment group using 
descriptive statistics. 
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, 
the data of this study may be pooled with data from previous studies. The results will be 
reported separately from the Clinical Study Report.  Details of the population PK 
analyses will be described in a Modeling and Simulation Analysis Plan. 
4.6.4 
Immunogenicity Analyses  
Immunogenicity analyses will be based on the immunogenicity – evaluable population. 
Immunogenicity data will be reported by the treatment arm of the parent study and for All 
patients. 
The following properties of each sample will be listed by patient: ADA status (from the 
confirmatory assay): ADA positive (yes) or ADA negative (no) and titer value for the ADA 
positive sample. 
ADA summaries will be based on data from Day 1 of parent studies to the FEOS visit of 
the LTE study. Baseline will be defined as the last available assessment obtained prior 
to the first administration of faricimab in the parent study for patients randomized to 
faricimab Q8W or faricimab PTI in the parent study, and as the last assessment before 
the first administration of faricimab treatment in the LTE for patients randomized to 
aflibercept in the parent study.  


 
 
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The following results will be summarized overall and by parent study treatment group, for 
patients enrolled in the LTE study: 
 
The number and proportion of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence).  
 
The number and proportion of ADA-positive patients and ADA-negative patients 
after LTE enrollment (post-baseline incidence).  
 
Treatment-boosted ADA-positive: number and percent of patients with at least one 
treatment-boosted ADA-positive sample.  The numerator is the number of patients 
with an ADA-positive sample at baseline and with post-baseline samples with a titer 
that is equal or greater than 4-fold baseline titer.  The denominator is the total 
number of patients in the immunogenicity incidence set. 
 
Treatment-induced ADA-positive: number and percent of patients with at least one 
treatment-induced ADA-positive sample.  The numerator is the number of patients 
with an ADA-negative or missing sample at baseline and any post-baseline positive 
sample.  The denominator is the total number of patients in the immunogenicity 
incidence set.  Among the treatment –induced ADA positive, the number of patients 
with transient (ADA positive result detected (a) at only one post-baseline sampling 
time point [excluding last time point] OR (b) at 2 or more timepoints during treatment 
where the first and last ADA positive samples are separated by a period of 16 
weeks, irrespective of any negative samples in between) and persistent (ADA 
positive result detected (a) at the last post-baseline sampling time point, OR (b) at 2 
or more time points during treatment where the first and last ADA positive samples 
are separated by a period of  16 weeks, irrespective of any negative samples in 
between) will be listed. 
 
Treatment-unaffected ADA-positive patient: number and percent of patients with an 
ADA-positive baseline sample (level of pre-existing ADAs) that does not change 
following drug administration.  The numerator is the number of patients with ADA 
positive sample and with all post-baseline titers lower than 4-fold the ADA-positive 
baseline titer.  The denominator is the total number of patients in the 
immunogenicity incidence set. 
 
ADA-negative: number and percent of patients without positive ADA during the 
study period or if they are ADA positive at baseline but without positive ADA post 
baseline (numerator).  The denominator is the total number of patients in the 
immunogenicity incidence set. 
 
ADA incidence (i.e., ADA-positive in %): number and percent of patients with at 
least one treatment-induced or treatment-boosted ADA-positive sample.  The 
numerator is the number of patients positive for boosted or induced ADA.  The 
denominator is the total number of patients in the immunogenicity incidence set. 
 
The following summaries, both overall and by time point (including baseline) will be 
provided using the Immunogenicity prevalence set, according to treatment received. For 


 
 
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summaries by time point, the numerator is the number of patients at that time point with 
determinant samples.  
ADA prevalence: number and percent of patients with at least one ADA-positive sample 
at any time point (including baseline).  The numerator is the number of ADA positive 
patients at selected time points and overall timepoints.  The denominator is the total 
number of evaluable patients in the study at corresponding timepoints.  
The safety, efficacy and PK, will be summarized by ADA status group.  
4.6.5 
Biomarkers Analyses 
Biomarker analyses will be based on the safety-evaluable population.   
Analyses may 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. 
All data from LTE baseline will be included in the analysis.  Details of the biomarker 
analyses will be described in a separate analysis plan. 
The results from these analyses will be reported in a document separate from the 
Clinical Study Report (CSR).  
4.6.6 
Analyses for COVID-19 
Based on the first reports of COVID-19 infection globally, the Sponsor determined that 
the window for all analyses of COVID-19 associated events would start from 
1 December 2019. 
The impact of COVID-19 will be assessed for study conduct and safety events. 
4.6.7 
Study Conduct Analyses for COVID-19 
In order to assess the impact of COVID-19 on study conduct, the following metrics will 
be recorded: 
 
BCVA not performed per protocol (non-standard BCVA) due to COVID-19 or related 
precautions 
 
Major protocol deviations associated with COVID-19 directly or indirectly 
 
Discontinuations from treatment and/or study due to COVID-19 
 
4.6.8 
Safety Analyses for COVID-19 
Following the MedDRA 25.1 release, a COVID-19 SMQ (narrow) is available. 


 
 
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This SMQ includes terms relevant to COVID-19 infection.  Patients with AEs from this 
COVID-19  SMQ (narrow) will be considered to have a confirmed or suspected 
COVID‑19 infection (Table 2). 
For the patients identified from the search as having confirmed or suspected COVID-19 
infection, outputs to evaluate safety events will be produced as follows: 
 
Summary table and listing of confirmed and suspected COVID-19 AEs 
 
In addition to presenting the suspected/confirmed COVID-19 infections, the Sponsor 
developed a broad search strategy for AEs associated with COVID-19 infection to further 
evaluate the confirmed events of COVID-19 and reported AEs that could be considered 
complications of the disease.  This search strategy includes both the AEs of a confirmed 
or suspected COVID-19 infection and any AEs considered associated with COVID-19.  
The Sponsor identified associated AEs as those reported  7 days before  and  30 days 
after any reported AE suggesting a confirmed COVID-19 infection (PTs listed in 
Table 2).  AEs suspected of being caused by COVID-19 as per electronic Case Report 
Form (eCRF) will be considered associated with COVID-19 as well. 
For the patients identified as having COVID-19 associated AEs, outputs to evaluate 
these safety events will be produced as follows: 
 
Summary table and listing of COVID-19 Associated Events: including all of the 
above confirmed/suspected COVID-19 infections plus AEs suspected of being 
caused by COVID-19 as per eCRF and, for those patients with  confirmed COVID-
19 infection or positive polymerase chain reaction test flag, any other AEs occurring 
within  7 days before and  30 days after start date of all the confirmed COVID-19 
events in Table 2. 
 
Summary table and listing of AEs suspected of being caused by COVID-19 as per 
eCRF 
 
In addition, the following outputs will be produced: 
 
Listing of Adverse Events associated with COVID-19 Leading to Study Treatment 
Discontinuation 
 
Listing of Adverse Events associated with COVID-19 Leading to Study 
Discontinuation 
 
Listing of Adverse Events associated with COVID-19 Resulting in Death 


 
 
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Table 2 
Roche COVID-19 SMQ (narrow) Preferred Terms for Confirmed 
Cases 
Preferred Terms for Confirmed Cases 
Asymptomatic COVID-19 
Breakthrough COVID-19 
Congenital COVID-19 
Coronavirus infection 
Coronavirus pneumonia 
Coronavirus test positive 
COVID-19 
COVID-19 immunisation 
COVID-19 pneumonia 
COVID-19 prophylaxis 
COVID-19 treatment 
Exposure to SARS-CoV-2 
Multisystem inflammatory syndrome 
Multisystem inflammatory syndrome in adults 
Multisystem inflammatory syndrome in children 
Occupational exposure to SARS-CoV-2 
Post-acute COVID-19 syndrome 
SARS-CoV-2 antibody test positive 
SARS-CoV-2 carrier 
SARS-CoV-2 RNA decreased 
SARS-CoV-2 RNA fluctuation 
SARS-CoV-2 RNA increased 
SARS-CoV-2 sepsis 
SARS-CoV-2 test false negative 
SARS-CoV-2 test positive 
SARS-CoV-2 viraemia 
Suspected COVID-19 
Thrombosis with thrombocytopenia syndrome 
Vaccine derived SARS-CoV-2 infection 
COVID‑19  coronavirus Disease 2019; RNA  ribonucleic acid; SARS‑CoV‑2  severe acute 
respiratory syndrome coronavirus 2; SMQ  standardized Medical Dictionary for Regulatory 
Activities (MedDRA) queries 
  
4.7 
INTERIM ANALYSES  
Interim analyses may be conducted.  Details of the analyses will be described in Module 
2 of the Data Analysis Plan. 


 
 
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5. 
SUPPORTING DOCUMENTATION 
This section is not applicable since there is no additional supporting document. 
6. 
REFERENCES 
Not Applicable. 


Signature Page for Statistical Analysis Plan - GR41987
System identifier: RIM-CLIN-519587
Approval Task
Company Signatory
26-Jan-2024 15:47:08 GMT+0000