A Phase III, Multicenter, Randomized, Double-Masked, Active Comparator-Controlled Study to Evaluate the Efficacy and Safety of Faricimab (RO6867461) in Patients With Diabetic Macular Edema (RHINE)
Phase: PHASE3
Conditions: Diabetic Macular Edema
Sponsor: Hoffmann-La Roche

 
Official Title: 
 
A Phase III, Multicenter, Randomized, Double-Masked, Active 
Comparator-Controlled Study to Evaluate the Efficacy and Safety of 
Faricimab (RO6867461) in Patients With Diabetic Macular Edema 
(RHINE) 
NCT Number: NCT03622593 
Document Date: Protocol Version 3: 20-Jun-2019 
 
 

PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Faricimab—F. Hoffmann-La Roche Ltd
Protocol GR40398 (Rhine), Version 3
PROTOCOL
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, 
DOUBLE-MASKED, ACTIVE 
COMPARATORCONTROLLED STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF
FARICIMAB (RO6867461) IN PATIENTS WITH 
DIABETIC MACULAR EDEMA (RHINE)
PROTOCOL NUMBER:
GR40398
VERSION NUMBER:
3
EUDRACT NUMBER:
2017-005105-12
IND NUMBER:
119225
TEST PRODUCT:
Faricimab (RO6867461)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  4 June 2018
DATES AMENDED:
Version 2:  23 August 2018
Version 3:  See electronic date stamp below.
 
20-Jun-2019 19:31:21
Title
Approver's Name
Company Signatory
Date and Time (UTC)
Protocol Number: 
 Report Number: 
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PROTOCOL AMENDMENT, VERSION 3:
RATIONALE
Protocol GR40398 has been amended primarily for the following reasons:

RO6867461 received World Health Organization (WHO) status of a recommended 
International Nonproprietary Name (INN) of "faricimab" and will hereafter be referred 
to in the text as such. Note that in some figure legends, study titles, and appendices, 
the name "RO6867461" may still be referenced and should be read as synonymous 
with faricimab. This is a global change and is not shown in italics.

The Medical Monitor name has been updated to 
, M.D., Ph.D.
(protocol cover page, acceptance form, and Section 5.4.1). 

 
 

The study eye ocular exclusion criterion has been modified to include vitreomacular 
traction (Section 4.1.2.2), 
 
 

The concurrent ocular conditions exclusion criterion has been modified to include 
retinal embolus (Section 4.1.2.5).

A section for risks associated with aflibercept has been added (Section 5.1.3).

Study treatment interruption due to active or suspected infection has been 
expanded to include "suspected ocular or periocular infections" (Section 5.1.4.1, 
Table 2).

Criteria for study treatment interruption due to intraocular inflammation have been 
updated such that study treatment may be resumed subsequently as determined by 
the investigator (Section 5.1.4.1; Table 2).

Reporting of medication errors and associated adverse event in Section 5.4.4 was 
updated and moved to Section 5.3.5.12. The medication errors themselves will no 
longer be reported expeditiously (within 24 hours).  However, if they cause a serious 
adverse event or adverse event of special interest, these will continue to be reported 
in an expedited manner. 

The expedited reporting of medication errors and overdose has been removed from 
Section 5.4.  

Language has been updated to indicate that therapeutic or elective abortions are 
not considered adverse events unless performed because of an underlying maternal 
or embryofetal toxicity.  In such cases, the underlying toxicity should be reported as 
a serious adverse event.  Language has also been added to clarify that all abortions 
are to be reported on the paper Clinical Trial Pregnancy Reporting Form 
(Section 5.4.3.2).
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In addition, the following changes and/or clarifications have been made:

The secondary efficacy objective endpoint "change from baseline in CST over time"
has been further clarified to include "change from baseline in CST at 1 year"
(Section 2, Table 1).

An exploratory efficacy objective has been added to evaluate the efficacy of 
faricimab on anatomical outcome measures using SD-OCT to correspond to the
already existing endpoints of change from baseline in neurosensory CST and in 
total macular volume over time (Section 2, Table 1).

Information for the combined screening/Day 1 visit (Section 3.1.1.1) has been 
enriched to improve readability; text has also been added to clarify conditions for the 
screening process.

Information for the randomization and visit schedule (Section 3.1.1.3) has been 
enriched to promote understanding of protocol-specific requirements. 

 
 

The inclusion criterion for documented diagnosis of diabetes mellitus now includes 
examples of other injectable drugs (e.g., dulaglutide and liraglutide) 
(Section 4.1.1.1).

An additional example (micropulse laser) has been added to study eye macular 
laser exclusion criterion (Section 4.1.2.2).

A description for the sham procedure has been added to Section 4.3 for 
completeness.

Additional examples (argon/selective laser trabeculoplasty and ocular allergies) 
have been included as to when short-term use of topical ocular corticosteroids can 
be used (Section 4.4.1).

Details have been added to the descriptions for ocular images (Section 4.5.5).

It has been clarified that leftover samples will be destroyed no later than 5 years 
after the final Clinical Study Report has been completed (Section 4.5.7). 

As applicable throughout the protocol,
 
 to more accurately describe what the assays are measuring and to be 
consistent with the other sections of the protocol.

To improve content flow and readability, the optional aqueous and optional plasma 
samples text has been modified (Section 4.5.7.1).

Details have been added to provide a better description of potential biomarkers 
assessments that may be performed for this study (Section 4.5.7.2).  

Language has been added to clarify that, after withdrawal of consent for 
participation in the Research Biosample Repository (RBR), remaining RBR samples 
will be destroyed or will no longer be linked to the patient; details regarding 
instruction for patient withdrawal of consent to the testing of his or her RBR samples 
after closure of the site has been added (4.5.9.6).
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
On-study prohibited medications (already included in Section 4.4.2) are now also 
listed in Section 5.1.4.1, Table 2 for completeness. 

Bevacizumab (Avastin) for the fellow eye treatment has been added to 
Section 4.4.1 to clarify that only anti-VEGFs approved for ophthalmic use by the 
country regulatory agency are allowed to be administered to the fellow eye. 

To improve content flow and readability, the definition of adverse event reporting 
period was clarified (Section 5.6).

Language has been added for consistency with Roche's current data retention 
policy and to accommodate more stringent local requirements (if applicable) 
(Section 7.5).

Language has been added to indicate that the study will comply with applicable local, 
regional, and national laws (Section 8.1). 

Language has been revised to clarify that data posting will not be limited to two 
clinical trial registries and to clarify that redacted CSRs are provided only if 
requirements of Roche's global policy on data sharing have been met (Section 9.5).

The assessment for the
has been entered on separate line of schedule of activities 
(Appendix 1) for clarity.

For consistency with the body text, study details have been added and clarifications 
made to the schedule of activities (Appendix 1); in addition, minor formatting 
changes and corrections have been made.

Refraction data recording on the eCRF at specific timepoints has been added to 
Appendix 4.

Additional details have been added to the descriptions and processes for CFP and 
fundus fluorescein angiography (FFA) in Appendices 5 and 6, respectively.

The acronym for "CRC" to describe the central reading center has been introduced 
throughout the protocol.  This is a global change and is not shown in italics.
Additional minor changes and correction of typographical errors have been made to 
improve clarity and consistency.  Substantive new information appears in italics.  This 
amendment represents cumulative changes to the original protocol.
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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 13
PROTOCOL SYNOPSIS .................................................................................... 14
1.
BACKGROUND .......................................................................................... 31
1.1
Background on Diabetic Macular Edema............................... 31
1.2
Background on Faricimab...................................................... 32
1.3
Study Rationale and BenefitRisk Assessment..................... 33
1.3.1
Benefits.................................................................................. 33
1.3.2
Risks...................................................................................... 35
1.3.3
Conclusions........................................................................... 36
2.
OBJECTIVES AND ENDPOINTS ............................................................... 36
3.
STUDY DESIGN......................................................................................... 40
3.1
Description of the Study......................................................... 40
3.1.1
Overview of Study Design ..................................................... 40
3.1.1.1
Screening .............................................................................. 42
3.1.1.2
Screen-Failed Patients .......................................................... 43
3.1.1.3
Randomization and Visit Schedule........................................ 43
44
3.1.2
Treatment Schedule for Patients in the 
Personalized Treatment Interval Arm (Arm B)....................... 45
3.1.2.1
Study Drug Dosing Interval Determination............................. 45
3.1.2.2
Study Drug Dosing Intervals.................................................. 46
3.1.3
Additional Considerations for PTI Arm IxRS 
Study Drug Dosing Interval Decision ..................................... 46
3.1.3.1
Missed Study Drug Dosing Visit(s) ........................................ 46
3.1.3.2
Study Drug Interruption at Study Drug Dosing 
Visit(s).................................................................................... 47
3.1.3.3
Missing CST Value at Study Drug Dosing Visit ..................... 47
3.1.3.4
Missing BCVA Value at Study Drug Dosing Visit................... 47
3.1.4
Missed Study Drug Treatment Visit(s) for 
Patients in the Q8W Treatment Arms .................................... 47
48
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3.1.6
Independent Data Monitoring Committee .............................. 48
3.2
End of Study and Length of Study......................................... 49
3.3
Rationale for Study Design.................................................... 49
3.3.1
Rationale for Treatment Arms Dose and 
Schedule................................................................................ 49
3.3.1.1
Rationale for Faricimab Dose and Schedule ......................... 49
3.3.1.2
Rationale for Aflibercept Dose and Schedule ........................ 51
3.3.2
Rationale for Patient Population ............................................ 51
3.3.3
Rationale for Control Group................................................... 52
3.3.4
Rationale for Pharmacodynamic and Biomarker 
Assessments ......................................................................... 52
4.
MATERIALS AND METHODS .................................................................... 53
4.1
Patients.................................................................................. 53
4.1.1
Inclusion Criteria.................................................................... 53
4.1.1.1
General Inclusion Criteria ...................................................... 53
4.1.1.2
Ocular Inclusion Criteria for Study Eye.................................. 54
4.1.2
Exclusion Criteria................................................................... 55
4.1.2.1
General Exclusion Criteria..................................................... 55
4.1.2.2
Ocular Exclusion Criteria for Study Eye................................. 56
4.1.2.3
Ocular Exclusion Criteria for Fellow Eye 
(NonStudy Eye) ................................................................... 57
4.1.2.4
Exclusion Criteria for Both Eyes ............................................ 57
4.1.2.5
Concurrent Ocular Conditions Exclusion Criteria................... 57
4.2
Method of Treatment Assignment and Masking .................... 57
4.2.1
Treatment Assignment........................................................... 57
4.2.2
Masking ................................................................................. 58
4.2.2.1
Masked Roles........................................................................ 58
4.2.2.2
Unmasked Roles ................................................................... 59
4.2.2.3
Delegation Log....................................................................... 60
4.2.2.4
Role Switching........................................................................ 60
4.2.2.5
Study Backup Staff................................................................. 60
4.2.2.6
Masking of Vendors, Sponsor's Agents, and 
Laboratory Personnel ............................................................ 60
4.2.2.7
Patient Masking .................................................................... 61
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4.2.3
Unmasking............................................................................. 61
4.2.3.1
Single-Patient Emergency Unmasking .................................. 61
4.2.3.2
Single-Patient Non-Emergency Unmasking........................... 61
4.2.3.3
Single-Patient Unmasking for Health Authority 
Reporting Requirements........................................................ 61
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 62
4.3.1
Study Treatment Formulation, Packaging, 
and Handling ......................................................................... 62
4.3.1.1
Faricimab, Aflibercept and Sham........................................... 62
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 63
4.3.2.1
Dosage .................................................................................. 63
4.3.3
Administration........................................................................ 64
4.3.3.1
Faricimab or Aflibercept Intravitreal Injections or 
Sham Procedure.................................................................... 64
4.3.4
Study Treatment Preparation................................................. 64
4.3.5
Compliance............................................................................ 64
4.3.6
Investigational Medicinal Product Accountability ................... 64
4.3.7
Continued Access to Faricimab............................................. 65
4.4
Concomitant Therapy ............................................................ 66
4.4.1
Permitted Therapy................................................................. 66
4.4.2
Prohibited Therapy ................................................................ 67
4.5
Study Assessments ............................................................... 67
4.5.1
Informed Consent Forms and Screening Log........................ 68
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 68
4.5.3
Physical Examinations........................................................... 68
4.5.4
Vital Signs.............................................................................. 68
4.5.5
Ocular Assessments.............................................................. 69
4.5.6
Concurrent Ocular Procedures.............................................. 70
4.5.7
Laboratory, Biomarker, and Other 
Biological Samples ................................................................ 70
4.5.7.1
Optional Aqueous Humor and Optional Plasma 
Samples................................................................................. 71
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4.5.7.2
Optional Unscheduled Collection of Vitreous and 
Optional PK Samples ............................................................ 72
4.5.8
Patient-Reported Outcomes .................................................. 72
4.5.9
Optional Samples for Research Biosample 
Repository ............................................................................. 73
4.5.9.1
Overview of the Research Biosample Repository.................. 73
4.5.9.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 73
4.5.9.3
Sample Collection.................................................................. 74
4.5.9.4
Confidentiality........................................................................ 74
4.5.9.5
Consent to Participate in the Research 
Biosample Repository............................................................ 75
4.5.9.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 75
4.5.9.7
Monitoring and Oversight....................................................... 76
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 76
4.6.1
Study Treatment Discontinuation........................................... 76
4.6.2
Patient Discontinuation from Study........................................ 76
4.6.3
Study Discontinuation............................................................ 77
4.6.4
Site Discontinuation............................................................... 77
5.
ASSESSMENT OF SAFETY....................................................................... 78
5.1
Safety Plan ............................................................................ 78
5.1.1
Safety Assessments .............................................................. 78
5.1.2
Risks Associated with Faricimab ........................................... 79
5.1.3
Risks Associated with Aflibercept (Comparator).................... 79
5.1.4
Management of Patients Who Experience 
Adverse Events ..................................................................... 79
5.1.4.1
Treatment Interruption:  Dose Interruption and 
Treatment Discontinuation Criteria ........................................ 79
5.2
Safety Parameters and Definitions ........................................ 81
5.2.1
Adverse Events ..................................................................... 81
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 82
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 83
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5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 83
5.3.1
Adverse Event Reporting Period ........................................... 84
5.3.2
Eliciting Adverse Event Information....................................... 84
5.3.3
Assessment of Severity of Adverse Events ........................... 84
5.3.4
Assessment of Causality of Adverse Events ......................... 85
5.3.5
Procedures for Recording Adverse Events............................ 85
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 86
5.3.5.2
Adverse Events That Are Secondary to 
Other Events.......................................................................... 86
5.3.5.3
Persistent or Recurrent Adverse Events................................ 87
5.3.5.4
Abnormal Laboratory Values ................................................. 87
5.3.5.5
Abnormal Vital Sign Values ................................................... 88
5.3.5.6
Abnormal Liver Function Tests.............................................. 89
5.3.5.7
Deaths ................................................................................... 89
5.3.5.8
Preexisting Medical Conditions.............................................. 89
5.3.5.9
Worsening of Diabetic Macular Edema or 
Diabetic Retinopathy in the Study Eye .................................. 90
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 90
5.3.5.11
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 90
5.3.5.12
Reporting Requirements for Cases of Medication 
Error and Associated Adverse Events ................................... 90
5.3.5.13
Patient-Reported Outcome Data ........................................... 91
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 92
5.4.1
Emergency Medical Contacts................................................ 92
5.4.2
Reporting Requirements for Serious Adverse
Events and Adverse Events of Special Interest..................... 93
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 93
5.4.2.2
Events That Occur after Study Drug Initiation........................ 93
5.4.3
Reporting Requirements for Pregnancies.............................. 93
5.4.3.1
Pregnancies in Female Patients............................................ 93
5.4.3.2
Abortions ............................................................................... 94
5.4.3.3
Congenital Anomalies/Birth Defects ...................................... 94
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5.5
Follow-Up of Patients after Adverse Events .......................... 94
5.5.1
Investigator Follow-Up........................................................... 94
5.5.2
Sponsor Follow-Up ................................................................ 95
5.6
Adverse Events That Occur after the 
Adverse Event Reporting Period ........................................... 95
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 95
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 95
6.1
Determination of Sample Size ............................................... 96
6.2
Analysis Populations ............................................................. 97
6.2.1
Intent-to-Treat Population...................................................... 97
6.2.2
Treatment-Naive Population.................................................. 97
6.2.3
Per-Protocol Population......................................................... 98
6.2.4
Safety-Evaluable Population.................................................. 98
6.2.5
Pharmacokinetic-Evaluable Population ................................. 98
6.2.6
Immunogenicity-Analysis population ..................................... 98
6.3
Summaries of Conduct of Study............................................ 98
6.4
Summaries of Treatment Group Comparability ..................... 99
6.5
Efficacy Analyses .................................................................. 99
6.5.1
Primary Efficacy Endpoint...................................................... 99
6.5.2
Secondary Efficacy Endpoints............................................. 101
6.5.3
Exploratory Efficacy Endpoints............................................ 102
6.6
Safety Analyses................................................................... 103
6.7
Pharmacokinetic Analyses................................................... 103
6.8
Pharmacodynamic Analyses ............................................... 104
6.9
Immunogenicity Analyses.................................................... 104
6.10
Biomarker Analyses............................................................. 105
105
7.
DATA COLLECTION AND MANAGEMENT ............................................. 105
7.1
Data Quality Assurance....................................................... 105
7.2
Electronic Case Report Forms............................................. 105
7.3
Source Data Documentation................................................ 106
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7.4
Use of Computerized Systems ............................................ 106
7.5
Retention of Records........................................................... 107
8.
ETHICAL CONSIDERATIONS.................................................................. 107
8.1
Compliance with Laws and Regulations .............................. 107
8.2
Informed Consent................................................................ 107
8.3
Institutional Review Board or Ethics Committee.................. 108
8.4
Confidentiality...................................................................... 109
8.5
Financial Disclosure ............................................................ 109
9.
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION........................................................................... 110
9.1
Study Documentation .......................................................... 110
9.2
Protocol Deviations.............................................................. 110
9.3
Site Inspections ................................................................... 110
9.4
Administrative Structure....................................................... 110
9.5
Dissemination of Data and Protection of 
Trade Secrets...................................................................... 111
9.6
Protocol Amendments ......................................................... 112
10. REFERENCES ......................................................................................... 113
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LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 37
Table 2
Dose Interruption and Treatment Discontinuation Criteria .......... 80
Table 3
Adverse Event Severity Grading Scale ....................................... 84
Table 4
Causal Attribution Guidance ....................................................... 85
LIST OF FIGURES
Figure 1
Study Treatment Schema ........................................................... 41
Figure 2
Algorithm for IxRS-Determined Personalized Treatment 
Interval Study Drug Dosing Intervals........................................... 45
Figure 3
Graph-Based Testing Procedure for the Primary Endpoint....... 100
LIST OF APPENDICES
Appendix 1
Schedule of Activities................................................................ 116
Appendix 2
Unscheduled Safety Assessment Visit...................................... 127
Appendix 3
Grading Scale for Assessment of Anterior Chamber Flare or 
Cells and Vitreous Cell.............................................................. 128
Appendix 4
Refraction and Best-Corrected Visual Acuity Testing ............... 129
Appendix 5
Color Fundus Photography ....................................................... 130
Appendix 6
Fundus Fluorescein Angiography ............................................. 131
Appendix 7
Spectral-Domain Optical Coherence Tomography.................... 132
Appendix 8
Biological Sample Collection and Shipping Instructions............ 133
Appendix 9
National Eye Institute Visual Functioning Questionnaire25..... 135
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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, 
DOUBLE-MASKED, ACTIVE 
COMPARATORCONTROLLED STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF 
FARICIMAB (RO6867461) IN PATIENTS WITH 
DIABETIC MACULAR EDEMA (RHINE)
PROTOCOL NUMBER:
GR40398
VERSION NUMBER:
3
EUDRACT NUMBER:
2017-005105-12
IND NUMBER:
119225
TEST PRODUCT:
Faricimab (RO6867461)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form to your local study monitor.
Protocol Number: 
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PROTOCOL SYNOPSIS
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-MASKED, 
ACTIVE COMPARATORCONTROLLED STUDY TO EVALUATE 
THE EFFICACY AND SAFETY OF FARICIMAB (RO6867461) IN
PATIENTS WITH DIABETIC MACULAR EDEMA (RHINE)
PROTOCOL NUMBER:
GR40398
VERSION NUMBER:
3
EUDRACT NUMBER:
2017-005105-12
IND NUMBER:
119225
TEST PRODUCT:
Faricimab (RO6867461)
PHASE:
Phase III
INDICATION:
Diabetic macular edema
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, and pharmacokinetics of faricimab when dosed 
every 8 weeks (Q8W) and with a personalized treatment interval (PTI) regimen compared with 
aflibercept (Eylea®) monotherapy in patients with diabetic macular edema (DME).  Specific 
objectives and corresponding endpoints for the study are outlined in the following table.
In this protocol, study drug refers to faricimab or aflibercept (intended for the study eye) and 
study treatment refers to faricimab, aflibercept, or the sham procedure (see the protocol for 
further details).
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Objectives and Corresponding Endpoints
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of IVT 
injections of the 6-mg dose of 
faricimab on BCVA outcomes
Change from baseline in BCVA (as measured on
the ETDRS chart at a starting distance of 
4 meters) at 1 year a
Key Secondary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of faricimab
on DR severity outcomes
Proportion of patients with a 2-step DRS 
improvement from baseline on the ETDRS 
DRSS at Week 52
Secondary Efficacy Objectives
Corresponding Endpoints
To evaluate the efficacy of faricimab
on additional BCVA outcomes
Change from baseline in BCVA (as measured on
the ETDRS chart at a starting distance of 
4 meters) over time 
Proportion of patients gaining 15, 10, 5, or 
0 letters in BCVA from baseline over time 
Proportion of patients avoiding a loss of 15, 
105, or >0 letters in BCVA from baseline 
over time 
Proportion of patients gaining 15 letters or 
achieving BCVA of 84 letters over time
Proportion of patients with BCVA Snellen 
equivalent of 20/40 or better over time
Proportion of patients with BCVA Snellen 
equivalent of 20/200 or worse over time
To evaluate the efficacy of faricimab
on additional DR outcomes
Proportion of patients with a 2-step DRS 
improvement from baseline on the ETDRS DRSS 
over time
Proportion of patients with a 3-step DRS 
improvement from baseline on the ETDRS DRSS 
over time
Proportion of patients who develop new PDR 
over time 
To evaluate faricimab treatment 
intervals in the PTI arm
Proportion of patients in the PTI arm on a Q4W, 
Q8W, Q12W, or Q16W treatment interval at 
1 year and 2 years
Treatment intervals in the PTI arm over time
a The definition of 1 year is the average of the Week 48, 52, and 56 visits.
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Objectives and Corresponding Endpoints (cont.)
Secondary Efficacy Objectives (cont.)
Corresponding Endpoints (cont.)
To evaluate the efficacy of faricimab on 
anatomical outcome measures using 
SD-OCT
Change from baseline in CST at 1 year a
Change from baseline in CST over time
Proportion of patients with absence of DME (CST 
325 m for Spectralis SD-OCT, or 315 m for 
Cirrus SD-OCT or Topcon SD-OCT) over time
Proportion of patients with absence of intraretinal 
fluid over time
Proportion of patients with absence of subretinal 
fluid over time
Proportion of patients with absence of intraretinal 
fluid and subretinal fluid over time
To evaluate the efficacy of faricimab on 
patient-reported vision-related functioning
and quality of life using the NEI VFQ-25
Change from baseline in NEI VFQ-25 composite 
score over time
Safety Objective
Corresponding Endpoints
To evaluate the ocular and systemic 
safety and tolerability of faricimab
Incidence and severity of ocular adverse events
Incidence and severity of non-ocular 
adverse events
Exploratory Efficacy Objectives
Corresponding Endpoints
To further evaluate the efficacy of 
faricimab on additional DR outcomes
Proportion of patients with a 2-step or 3-step 
DRS worsening from baseline on ETDRS DRSS 
over time
Proportion of patients who receive vitrectomy or 
PRP over time during the study
To further evaluate the efficacy of 
faricimab on anatomical outcome 
measures using FFA and/or OCT-A c
Change from baseline in the macular and the total 
retinal area b of ischemic non-perfusion (capillary 
loss) over time
Change from baseline in vascular leakage in the 
macula and in the total retinal area b over time
Proportion of patients with resolution of vascular 
leakage in the macula and in the total retinal 
area b over time
To further evaluate the efficacy of 
faricimab on anatomical outcome 
measures using SD-OCT
Change from baseline neurosensory CST over 
time
Change from baseline in total macular volume over 
time
a The definition of 1 year is the average of the Week 48, 52, and 56 visits.
b The total retinal area is defined as 7-modified fields or 4-wide fields or ETDRS 7-field mask 
overlay on ultra-wide field (UWF; Optos) images in all study patients and as the entire 
UWF image, including peripheral areas in a subset of patients with Optos FFA.
c
In a subset of patients with OCT-A.
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Objectives and Corresponding Endpoints (cont.)
Exploratory Efficacy Objectives
(cont.)
Corresponding Endpoints
(cont.)
To further evaluate the efficacy of 
faricimab on patient-reported vision-
related functioning and quality of life 
using the NEI VFQ-25
Change from baseline in the NEI VFQ-25 Near 
Activities, Distance Activities, and Driving 
subscales at 1 year a
Proportion of patients with a 4-point 
improvement from baseline in NEI VFQ-25 
composite score at 1 year a
Pharmacokinetic Objective
Corresponding Endpoint
To characterize the systemic 
pharmacokinetics of faricimab
Plasma concentration of faricimab over time
Immunogenicity Objectives
Corresponding Endpoints

To evaluate the immune response to 
faricimab
Presence of ADAs during the study relative to 
the presence of ADAs at baseline

To evaluate potential effects of ADAs
Relationship between ADA status and efficacy, 
safety, or PK endpoints
Exploratory Pharmacokinetic, 
Pharmacodynamic, and Biomarker 
Objectives
Corresponding Endpoints
To identify biomarkers that are 
predictive of response to faricimab, 
are associated with progression to a 
more severe disease state, are 
associated with susceptibility to 
developing adverse events, can 
provide evidence of faricimab activity, 
or can increase the knowledge and 
understanding of disease biology
Concentration of biomarkers of angiogenesis 
and inflammation in aqueous humor (optional) at 
baseline and over time and their correlation with 
PK and/or primary and secondary endpoints at 
baseline and over time
Relationship between efficacy, safety, PK, 
immunogenicity,
 
Relationship between baseline anatomic 
measures and the change in BCVA or other 
endpoints (e.g., the frequency of study drug 
administration) over time
Relationship between anatomic measures and 
visual acuity
a The definition of 1 year is the average of the Week 48, 52, and 56 visits.
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Objectives and Corresponding Endpoints (cont.)
Exploratory Pharmacokinetic, 
Pharmacodynamic, and Biomarker 
Objectives (cont.)
Corresponding Endpoints (cont.)
To evaluate potential relationships 
between selected covariates and 
exposure to faricimab
Relationship between selected covariates and 
plasma or aqueous humor (optional) 
concentration or PK parameters for faricimab
To characterize the aqueous humor 
(optional) and vitreous (optional) 
pharmacokinetics of faricimab
Aqueous humor (optional) and vitreous 
(optional) concentration of faricimab over time
To evaluate the drug concentration 

To explore the concentrationeffect 
relationship for visual acuity and other 
endpoints (e.g., anatomical markers)
Pharmacokinetics of faricimab and the change 
in BCVA or other endpoints (e.g., anatomical 
markers) over time
ADAanti-drug antibody;
; 
BCVAbest-corrected visual acuity; CSTcentral subfield thickness; DRdiabetic retinopathy; 
DRSdiabetic retinopathy severity; DRSSDiabetic Retinopathy Severity Scale; 
ETDRSEarly Treatment Diabetic Retinopathy Study; FFAfundus fluorescein angiography; 
IVTintravitreal; NEI VFQ-25National Eye Institute 25-Item Visual Function Questionnaire; 
OCT-Aoptical coherence tomographyangiography; PDRproliferative diabetic retinopathy; 
PKpharmacokinetic; PRPpanretinal photocoagulation; PTIpersonalized treatment 
interval; Q4W every 4 weeks; Q8Wevery 8 weeks; Q12W every 12 weeks; Q16W every 
16 weeks; SD-OCTspectral-domain optical coherence tomography; 
 
Study Design
Description of Study
This is a Phase III, double-masked, multicenter, randomized, active comparatorcontrolled, 
parallel-group study, evaluating the efficacy, safety, pharmacokinetics, and optimal treatment 
frequency of faricimab administered by intravitreal (IVT) injection at 8-week intervals or PTI of 
approximately 100 weeks' duration (excluding the screening period) to patients with DME.  
Overview of Study Design
Approximately 900 patients will be randomized during the global enrollment phase of the study 
in a 1:1:1 ratio to one of three treatment arms at approximately 240 investigational sites globally.  
The study will randomize patients with DME who are naive to antivascular endothelial growth 
factor (anti-VEGF) therapy in the study eye and patients who have previously been treated with 
anti-VEGF therapy in the study eye, provided that the last treatment was at least 3 months prior 
to the Day 1 visit (the first study treatment).  Site investigators will be retina specialists or the 
equivalent outside of the United States.
The study treatment arms will be as follows:

Arm A (administered every 8 weeks [Q8W]) (n300):  Patients randomized to Arm A will 
receive 6-mg IVT faricimab injections every 4 weeks (Q4W) to Week 20, followed by 6-mg 
IVT faricimab injections Q8W to Week 96, followed by the final study visit at Week 100.

Arm B (PTI) (n300):  Patients randomized to Arm B will receive 6-mg IVT faricimab
injections every 4 weeks (Q4W) to at least Week 12, followed by PTI dosing (see the PTI 
dosing criteria below) of 6-mg IVT faricimab injections to Week 96, followed by the final 
study visit at Week 100.
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
Arm C (comparator arm) (administered Q8W) (n300): Patients randomized to Arm C will 
receive 2-mg IVT aflibercept injections Q4W to Week 16, followed by 2-mg IVT aflibercept 
injections Q8W to Week 96, followed by the final study visit at Week 100.
Patients in all three treatment arms will complete scheduled study visits Q4W for the entire 
study duration (100 weeks).  A sham procedure will be administered to patients in all three 
treatment arms at applicable visits to maintain masking among treatment arms.
Only one eye will be assigned as the study eye.  If both eyes are considered eligible, the eye 
with the worse best-corrected visual acuity (BCVA), as assessed at screening, will be selected 
as the study eye unless the investigator deems the other eye to be more appropriate for 
treatment in the study.
There will be a minimum of two investigators per site to fulfill the masking requirements of the 
study.  At least one investigator will be designated as the assessor physician who will be 
masked to each patient’s treatment assignment and who will evaluate ocular assessments.  At 
least one other investigator will be unmasked and will perform study treatments (see the 
protocol for additional masking details).
The study will consist of a screening period of up to 28 days (Days 28 to 1) in length and an 
approximately 96-week treatment period, followed by the final study visit at Week 100. 
A unique screening number will be assigned to each screened patient through an interactive 
voice or web-based response system (IxRS).
Screening
Informed consent must be administered and signed by a patient before any study-specific 
screening procedure is performed. Each consented patient must satisfy the eligibility criteria as 
applicable at screening and/or the Day 1 visit.  
Note: Some patients may require an extended screening period (more than 28 days) as a result 
of repeated evaluation of images or other issues.  Upon agreement with the Medical Monitor, 
the screening period may be extended by up to 5 business days in such cases.
In some countries/regions, the screening and Day 1 (randomization) visits may occur as a
combined visit if all assessments are completed and evaluated on the same day or within 2 
business days. When screening and the Day 1 visit are completed as a combined visit, the 
assessments listed for both visits should be conducted only once.  The following conditions 
have to be met for a combined visit to occur:


A historic hemoglobin A1c (HbA1c) value must be available from within 2 months prior to 
Day 1.  
If the screening and Day 1 visit are not completed on the same day (but rather within 2 business 
days), the following safety assessments must be repeated on the day of patient’s randomization 
and study treatment administration:  urine pregnancy test (if applicable), slitlamp examination, 
indirect ophthalmoscopy, and pre- and post-treatment intraocular pressure (IOP) measurements
(recorded on the Day 1 electronic Case Report Form [eCRF] and dated accordingly).
For all study patients, after screening has been completed, including all assessments listed 
for the Day 1 visit, eligible patients will have a randomization identification number assigned
through the IxRS and will be randomized in a 1:1:1 ratio in order that approximately 300 patients 
are randomized to each of the three treatment arms. Randomization will be stratified by
baseline BCVA Early Treatment Diabetic Retinopathy Study (ETDRS) letter score, as assessed 
on Day 1 (64 letters or better vs. 63 letters or worse), prior IVT anti-VEGF therapy (yes vs. no), 
and region (United States and Canada, Asia, and the rest of the world).
Screen-Failed Patients
Patients who are not eligible for enrollment (screen failures) may be eligible for re-screening 
for up to an additional two times during the enrollment period of the study. At re-screening, 
a new screening number will be assigned to each patient through the IxRS and all screening 
visit assessments will be performed.  At the Day 1 visit, fundus FFA images do not have to be 
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repeated, provided that the same eye is selected for the study eye at rescreening and acceptable 
FFA images were taken within 4 weeks before the new Day 1 visit (randomization) date.
Randomization and Visit Schedule
The first study treatment will be administered on the same day as randomization, which will be 
performed through the IxRS (i.e., at the Day 1 visit).  
Note:  If a site has an unexpected issue (e.g., the IxRS is not able to assign the study kit), a 
patient’s randomization and first study treatment may be administered within 2 business days 
of the Day 1 visit assessments, after consultation with the Medical Monitor.  The following 
assessments will be repeated on the day of randomization and study treatment:  urine 
pregnancy test (if applicable), slitlamp examination, indirect ophthalmoscopy, pre-treatment 
IOP measurements (recorded on the Day 1 eCRF and dated accordingly), and any new 
concomitant medications.
Randomized patients will have the first study treatment administered by the unmasked 
investigator on Day 1, followed by the safety assessments (finger-counting test and post-dose 
IOP measurement).  Afterwards, all study patients will also have a safety assessment visit on 
Day 7 (3 days) evaluated by the masked investigator.  At subsequent scheduled visits, 
patients will have pre-dose safety assessments evaluated by the masked investigator prior to 
receiving study treatment.  Study treatment administration and study-related assessments will 
occur Q4W (starting from Day 1), as outlined in the protocol.  The sham procedure will be 
delivered to patients in all arms throughout the study as applicable.
Patients will be instructed to contact the study site at any time if they have any health-related 
concerns. If warranted, patients will be asked to return to the clinic as soon as possible for an 
unscheduled safety assessment visit.  
All assessments (including study treatment) for a scheduled visit are to be performed on the 
same day, except those performed during the screening period.
Study treatment visits cannot occur earlier than 21 days after the previous study treatment visit.  
Missed study treatments will not be made up.
Note:  After the Day 1 visit, if a patient misses a study visit when ocular CFP and FFA images 
are to be obtained, or these images are not taken at the scheduled visit (e.g. equipment is 
broken), they must be obtained at the next scheduled visit the patient attends.  
If a patient misses more than two consecutive study treatment visits within any 24-week 
treatment period, the investigator and the Medical Monitor may consider discontinuing the 
patient from study treatment.  
Patients who are prematurely discontinued from study treatment but who agree to continue to 
participate in the study will be encouraged to undergo as many scheduled visits as possible,
with emphasis on completing the Week 48, 52, 56, and 100 visits.   
Study treatment visits will be scheduled Q4W (7 days) relative to the Day 1 visit date.
Patients who are discontinuing from the study prior to completion will be asked to return for an
early termination visit after a minimum of 28 days have elapsed following their last study 
treatment for monitoring of adverse events and early termination visit assessments. 
Patients who complete study treatment (i.e., the Week 96 visit) will return for the final study visit 
(Week 100) after a minimum of 28 days have elapsed from their last study treatment for 
monitoring of adverse events and final study visit assessments.  
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Treatment Schedule for Patients in the Personalized Treatment Interval Arm (Arm B)
Study drug dosing interval decisions in the PTI arm are automatically calculated by the IxRS 
based on the algorithm described in this section.  Study drug dosing visits are visits when a 
patient is assigned to receive faricimab. 
Study Drug Dosing Interval Determination 
Patients randomized to the PTI arm (Arm B) will be treated with faricimab on a Q4W dosing 
interval until at least the patient’s Week 12 visit, or a later visit when CST meets the predefined 
reference central subfoveal thickness (CST) threshold (CST 325 m for Spectralis SD-OCT, or 
315 m for Cirrus SD-OCT or Topcon SD-OCT), as determined by the CRC.  The reference 
CST (as defined in the protocol) is used at study drug dosing visits by the IxRS for the drug 
dosing interval decision-making.
After a patient’s initial reference CST is established, their study drug dosing interval will be 
increased by 4 weeks to an initial Q8W dosing interval by the IxRS.  From this point forward, the 
study drug dosing interval will be extended, reduced, or maintained based on assessments 
made at study drug dosing visits.  See the protocol for the algorithm used by the IxRS for 
interval decision-making, which is based on the relative change of the CST and BCVA 
compared with reference CST and reference BCVA.
Study Drug Dosing Intervals
The IxRS can adjust the study drug dosing interval by 4-week increments to a maximum of 
every 16 weeks (Q16W) and a minimum of Q4W.  The IxRS algorithm for the study drug 
treatment interval decision making is based on the relative change of the CST and absolute 
change in BCVA compared with the reference CST and BCVA, respectively.
Similar to Arms A and C, patients randomized to the PTI arm (Arm B) will receive a sham 
procedure at study visits when they are not receiving treatment with faricimab.
Additional Considerations for PTI Arm IxRS Study Drug Dosing Interval Decision
Sites will report missed study treatment visits and study treatment interruption visits to the IxRS 
for all patients (Arms A, B, and C) to preserve the masking.  The following algorithms are only 
applicable to patients in the PTI arm (Arm B) and are used by the IxRS to automatically 
determine study drug dosing intervals in the event of the following situations.  
Missed Study Drug Dosing Visit(s)
If a patient misses a study drug dosing visit, the IxRS will assign the patient to receive study 
drug dosing at the next scheduled study visit the patient attends.  A decision regarding the 
subsequent study drug dosing interval will be made by IxRS based on CST and BCVA 
assessments completed at the visit when study drug is administered, and any changes in the 
drug dosing interval will be based from the last assigned interval prior to the missed drug dosing 
visit.
Example:  If a patient was on an every 12-week (Q12W) drug dosing interval prior to missing 
the study drug dosing visit, then the IxRS decision to maintain, extend, or reduce the dosing 
interval will be made on the basis of the previously assigned drug interval (Q12W) along with 
CST and BCVA data obtained at the visit when the patient receives study drug.  If the data 
indicate that the patient should maintain the Q12W interval, then he or she will receive study 
drug 12 weeks after that visit.
Study Drug Interruption at Study Drug Dosing Visit(s)
If a patient's dosing has to be interrupted (e.g., because of an adverse event) at a study drug 
dosing visit, IxRS will assign the patient to receive study drug at the earliest subsequent study 
visit when the patient is permitted to resume study drug dosing.  The IxRS will be used to 
determine the next study drug dosing based on a Q8W interval unless the patient was treated 
on a Q4W interval prior to dose interruption.  In that case, the patient will be evaluated on the 
basis of the Q4W interval. 
Missing CST Value at Study Drug Dosing Visit
If a patient attends a study drug dosing visit, but the CST value is not available for any reason 
(e.g., optical coherence tomography [OCT] machine is not available or is broken), the IxRS will 
assign the patient to receive study drug at that visit.  Generally, the IxRS will maintain the 
previous drug dosing interval.  However, in the event of a concurrent 10-letter decrease 
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relative to the reference BCVA at that study drug dosing visit, the IxRS will reduce the study 
drug dosing interval by 4 weeks. 
Missing BCVA Value at Study Drug Dosing Visit
If a patient attends a study drug dosing visit, but the BCVA value is not available for any reason, 
the IxRS will assign the patient to receive study drug at that visit.  The IxRS will base the study 
drug dosing interval determination on CST value only.
Missed Study Drug Treatment Visit(s) for Patients in the Q8W Treatment Arms
If a patient randomized to treatment Arm A (faricimab Q8W) or Arm C (aflibercept Q8W) misses 
study drug dosing visit(s) after the Q4W initiating doses, the IxRS will assign the patient to 
receive faricimab or aflibercept at the next study visit he or she attends.  The Q8W drug 
treatment interval will be automatically reset by the IxRS from that visit forward, thus 4 weeks 
later, at the following study visit, the patient will receive sham.  
Independent Data Monitoring Committee
An independent Data Monitoring Committee (iDMC) will monitor safety and study conduct on an 
ongoing basis. Members of the iDMC will be external to the Sponsor and will follow a charter 
that outlines the iDMC's roles and responsibilities. 
The iDMC will meet approximately every 6 months (frequency adjustable if required) to evaluate 
unmasked ocular and systemic (non-ocular) safety events with an emphasis on the evaluation 
of the rate of ocular inflammation, increased IOP, endophthalmitis, arterial thromboembolic 
events, and clinically significant decreases in BCVA, which will be prepared for the committee
by an independent Data Coordinating Center (iDCC).  The iDMC may recommend stopping the 
study early for safety reasons. 
After reviewing the data, the iDMC will provide a recommendation to the Sponsor as described 
in the iDMC Charter.  Final decisions will rest with the Sponsor.
Any outcomes of these data reviews that affect study conduct will be communicated in a timely 
manner to the investigators for notification of their respective Institutional Review Boards/Ethics 
Committees.
Number of Patients
Approximately 900 patients will be randomized during the global enrollment phase of the study. 
Target Population
Inclusion Criteria
Patients must meet the following inclusion criteria for study entry. 
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Exclusion Criteria
Patients who meet any of the following exclusion criteria will be excluded from study entry.
General Exclusion Criteria
Patients who meet any of the following general exclusion criteria will be excluded from 
study entry:

Currently untreated diabetes mellitus or previously untreated patients who initiated oral or 
injectable anti-diabetic medication within 3 months prior to Day 1

History of allergy or hypersensitivity to active drug aflibercept and any of its excipients, 
fluorescein, or any study treatmentrelated mandatory ingredients (e.g., disinfectants, 
anesthetics, etc.; see the pharmacy manual for additional details) that is not amenable to 
treatment

History of a severe allergic reaction or anaphylactic reaction to a biologic agent or known 
hypersensitivity to any component of the faricimab or to aflibercept injections, study 
treatment procedure, dilating drops, or any of the anesthetic and antimicrobial preparations 
used by a patient during the study 

Active cancer within the past 12 months except for appropriately treated carcinoma in situ of 
the cervix, non-melanoma skin carcinoma, and prostate cancer with a Gleason score of 6
and a stable prostate-specific antigen for 12 months

Systemic treatment for suspected or active systemic infection
Ongoing use of prophylactic antibiotic therapy may be acceptable but has to be 
discussed with the Medical Monitor.

Renal failure requiring renal transplant, hemodialysis, or peritoneal dialysis or anticipated to 
require hemodialysis or peritoneal dialysis at any time during the study 

History of other disease, other non-diabetic metabolic dysfunction, physical examination 
finding, historical or current clinical laboratory finding giving reasonable suspicion of a
condition that contraindicates the use of the faricimab or aflibercept or that might affect 
interpretation of the results of the study or renders the patient at high risk for treatment 
complications in the opinion of the investigator 

Uncontrolled blood pressure (defined as systolic 180 mmHg and/or diastolic 100 mmHg 
while a patient is at rest)
If a patient’s initial reading exceeds these values, a second reading may be obtained 
later the same day or on another day during the screening period.  If the patient’s blood 
pressure is controlled by antihypertensive medication, the patient should be taking the 
same medication continuously for at least 30 days prior to Day 1.

Stroke (cerebral vascular accident) or myocardial infarction within 6 months prior to Day 1

Pregnancy or breastfeeding, or intention to become pregnant during the study
Women of childbearing potential must have a negative urine pregnancy test result within 
28 days prior to initiation of study treatment.  If the urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test.

Participation in an investigational trial that involves treatment with any drug or device (with 
the exception of vitamins and minerals) within 3 months prior to Day 1 

Administration of systemic pro-angiogenic treatments, such as VEGF-based therapies for 
the peripheral or coronary ischemia (e.g., limb ischemia or myocardial infarction) within 
3 months or 5 half-lives prior to Day 1

Inability to comply with study or follow-up procedures

Requirement for continuous use of any medications and treatments indicated in the protocol 
(see Prohibited Therapy)
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Ocular Exclusion Criteria for Study Eye
Patients who meet any of the following exclusion criteria for the study eye will be excluded from 
study entry:

High-risk proliferative diabetic retinopathy (PDR) in the study eye, using any of the following 
established criteria for high-risk PDR:
–
Any vitreous or pre-retinal hemorrhage
–
Neovascularization elsewhere 1/2 disc area within an area equivalent to the mydriatic 
ETDRS 7 fields on clinical examination or on CFPs
–
Neovascularization at disc 1/3 disc area on clinical examination

Tractional retinal detachment, pre-retinal fibrosis, vitreomacular traction, or epiretinal 
membrane involving the fovea or disrupting the macular architecture in the study eye, 
 

Active rubeosis 

Uncontrolled glaucoma 

History of retinal detachment or macular hole (Stage 3 or 4) 

Aphakia or implantation of anterior chamber intraocular lens 

IVT anti-VEGF treatment within 3 months prior to Day 1 (applicable to patients whose study 
eyes were previously treated with IVT anti-VEGF agents) or any IVT anti-VEGF agents to 
study eye prior to Day 1 (applicable for patients who are treatment naive)

Treatment with panretinal photocoagulation (PRP) within 3 months prior to Day 1

Macular (focal, grid, or micropulse) laser within 3 months prior to Day 1

Any cataract surgery or treatment for complications of cataract surgery with steroids or YAG 
(yttrium-aluminum-garnet) laser capsulotomy within 3 months prior to Day 1

Any other intraocular surgery (e.g., corneal transplantation, glaucoma filtration, pars plana 
vitrectomy, corneal transplant, or radiotherapy) 

Any IVT or periocular (subtenon) corticosteroid treatment within 6 months prior to Day 1

Any use of medicated intraocular implants, including Ozurdex®, within 6 months of Day 1

Any use of Iluvien® implants at any time prior to Day 1

Treatment for other retinal diseases that can lead to macular edema
Ocular Exclusion Criteria for Fellow Eye (NonStudy Eye)
Patients who meet the following exclusion criterion for the fellow eye (nonstudy eye) will be 
excluded from study entry:

Non-functioning nonstudy eye, defined as either:
–
BCVA of hand motion or worse
–
No physical presence of nonstudy eye (i.e., monocular)
Exclusion Criteria for Both Eyes 
Patients who meet the following exclusion criterion for either eye will be excluded from study 
entry:

Prior administration of IVT faricimab in either eye

Any history of idiopathic or immune-mediated uveitis in either eye

Active ocular inflammation or suspected or active ocular or periocular infection in either eye 
on Day 1 
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Concurrent Ocular Conditions Exclusion Criteria
Patients who meet the following exclusion criteria related to concurrent ocular conditions will be 
excluded from study entry:

Any current or history of ocular disease other than DME that may confound assessment of 
the macula or affect central vision in the study eye (e.g., choroidal neovascularization, 
age-related macular degeneration, retinal vein occlusion, uveitis, angioid streaks, 
histoplasmosis, active or inactive cytomegalovirus, pathological myopia, retinal detachment, 
retinal embolus, macular traction, macular hole, and other) 

Any current ocular condition which, in the opinion of the investigator, is currently causing or 
could be expected to contribute to irreversible vision loss due to a cause other than DME in 
the study eye (e.g., foveal atrophy, foveal fibrosis, pigment abnormalities, dense subfoveal 
hard exudates, or other non-retinal conditions) 
End of Study
The study consists of two enrollment phases:  the global enrollment phase, during which
patients are recruited globally,
 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs, 
 The end of the study is expected to occur
approximately 100 weeks after the last patient is randomized.
Length of the Study
The total length of the study 
 from screening of the first patient 
to the LPLV for patients from the global enrollment phase is expected to be approximately 
38 months.
Investigational Medicinal Products
Test Products (Investigational Drugs)
Intravitreal Faricimab Injections
The 6-mg dose of faricimab will be evaluated in this study and will be administered intravitreally 
to patients randomized to receive faricimab Q8W or PTI during the 96-week treatment period.
Patients randomized to receive Q8W treatment will be administered 15 IVT injections of 
faricimab during the 96-week treatment period.  Treatment will consist of 6 initial injections 
(6 mg of faricimab Q4W to Week 20), followed by 9 maintenance injections (6 mg of faricimab
Q8W between Week 24 and Week 96). 
The number of IVT injections of faricimab administered to patients in the PTI arm will vary (see 
protocol for the retreatment criteria), but a minimum of 10 IVT injections of faricimab will be
administered to patients during the 96-week treatment period.  This will consist of minimum of 4 
initiating injections (6 mg of faricimab Q4W to Week 12), followed by minimum of 6 maintenance 
injections (6 mg of faricimab between Week 16 and Week 96). 
Comparator
Intravitreal Aflibercept (Active Comparator) Injections
A 2-mg dose of aflibercept (Arm C) will be administered intravitreally Q8W to patients 
randomized to the aflibercept treatment arm during the 96-week treatment period.  Patients will 
receive 15 IVT injections of aflibercept during the 96-week treatment period.  Treatment will 
consist of 5 initiating injections (2 mg of aflibercept Q4W to Week 16), followed by 
10 maintenance injections (2 mg of aflibercept Q8W between Week 20 and Week 96).
Sham Procedure
All three treatment arms (faricimab Q8W, faricimab PTI, and aflibercept Q8W) will maintain 
Q4W study visits for the 100-week study duration.  To preserve the randomized treatment arm 
masking, patients will have the sham procedure performed at study treatment visits when they 
are not treated with either faricimab or aflibercept as applicable per their treatment arm 
schedule.
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Statistical Methods
Primary Analysis
The primary efficacy endpoint is the change from baseline in BCVA averaged over Weeks 48, 
52, and 56.  The BCVA outcome measure is based on the ETDRS visual acuity chart assessed 
at a starting distance of 4 meters. 
The primary comparisons will be the pairwise comparisons between the active comparator 
(aflibercept Q8W) and each of the faricimab arms (Q8W and PTI). Additional analyses based 
on the per-protocol population will also be conducted.
For the two faricimab arms (Q8W and PTI), the following three hypotheses will be tested for 
each treatment group separately at an overall significance level of 0.05 using a graph-based 
testing procedure to control for the overall type I error rate:

Non-inferiority of faricimab compared with aflibercept Q8W in the intent-to-treat 
(ITT) population

Superiority of faricimab compared with aflibercept Q8W in the treatment-naive population

Superiority of faricimab compared with aflibercept Q8W in the ITT population
If the tests for one treatment sequence are all positive, then /2 will be propagated to the 
beginning of the other treatment sequence, which will be tested at a significance level of 
0.05.  Of note, non-inferiority will be tested one sided at half of the designated significance 
level.
The non-inferiority tests for the faricimab Q8W arm and the faricimab PTI arm compared with 
aflibercept Q8W arm will be conducted with a non-inferiority margin of 4 letters. For each 
faricimab group (Q8W or PTI) the null hypothesis, 
H0: faricimabaflibercept 4 letters, and the alternative hypothesis, 
Ha: faricimabaflibercept 4 letters, will be tested, for which faricimab and aflibercept are the expected 
change from baseline in BCVA averaged over Weeks 48, 52, and 56 for the treatment group in 
question (faricimab Q8W or PTI) and the active comparator (aflibercept Q8W), respectively.
The change from baseline averaged over Weeks 48, 52, and 56 will be compared between 
each faricimab arm and the aflibercept Q8W arm using a mixed-model repeated measures 
(MMRM) model. The model will include the change from baseline at Weeks 456 as the 
response variables and will include the categorical covariates of treatment group, visit, 
visit-by-treatment group interaction, the continuous baseline value for the response variable (in 
this case, baseline BCVA), as well as randomization stratification factors as fixed effects. 
Comparisons between each faricimab arm and the aflibercept Q8W arm will be made using a 
composite contrast over Weeks 48, 52, and 56. The MMRM model will assume an unstructured 
covariance structure. If there are convergence problems with the model, then a heterogeneous 
compound symmetry or an AR(1) covariance structure may be fitted.
Missing data will be implicitly imputed using the MMRM model, assuming a missing at random 
missing data mechanism (i.e., the probability that missing data are dependent on other 
observed variables but not on the missing data).  Data for patients who receive prohibited 
therapy will be censored at the timing of use of prohibited therapy. Data for patients who 
discontinue from study drug and do not receive any prohibited therapy after discontinuation of 
study drug will be included in the analysis.
Additional details about the planned analyses, as well as sensitivity analyses using other 
imputation methods for missing data, sensitivity analysis using the trimmed mean approach for
patients who receive prohibited therapy or discontinue study drug due to lack of efficacy or 
adverse events, sensitivity analyses of the per-protocol population, and subgroup analyses to 
assess the robustness of the primary endpoint results will be provided in the Statistical Analysis 
Plan.
Determination of Sample Size
Determination of sample size is based on patients enrolled in the global enrollment phase.  The 
global enrollment phase will enroll approximately 900 patients.  Patients will be randomized in a 
1:1:1 ratio to receive treatment with faricimab Q8W (Arm A), faricimab PTI (Arm B), or 
aflibercept Q8W (Arm C).  The primary comparisons will be the pairwise comparisons between 
the active comparator (aflibercept Q8W) and each of the faricimab arms (Q8W and PTI).  
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A sample size of approximately 300 patients in each arm will provide greater than 90% power to 
show non-inferiority of faricimab to aflibercept (pairwise comparisons between the active 
comparator and each of the faricimab arms) in the ITT population, using a non-inferiority margin 
of 4 letters and under the following assumptions:

Standard deviation (SD) of 11 letters for the change from baseline in BCVA averaged over 
Week 48, Week 52, and Week 56

Two-sample t-test

1.25% one-sided type I error rate

10% dropout rate
Assuming 75%90% of patients recruited will be treatment naive, approximately 225270 
treatment-naive patients will be enrolled per arm.  A sample size of 225270 patients per arm 
will provide greater than 80% power to show a 3.5-letter superiority of faricimab over aflibercept 
(pairwise comparisons between the active comparator and each of the faricimab arms) in the
treatment-naive population, using the same SD, test, and dropout assumptions above, and a 
two-sided type I error rate of 2.5%.
Furthermore, a sample size of approximately 300 patients per arm will provide greater than 
80% power to show a 3-letter superiority of faricimab over aflibercept (pairwise comparisons 
between the active comparator and each of the faricimab arms) in the ITT population, under the 
same SD, test, and dropout assumptions above, and a two-sided type I error rate of 2.5%.
The sample size may be adjusted as appropriate, based on a masked assessment of the 
pooled SD of the change in BCVA from baseline.  The assessment will be performed by the 
Sponsor at a specified timepoint prior to completing enrollment.  Details on the masked sample 
size re-estimation conducted, as well as actions and decisions made regarding changes in 
sample size will be documented in the Statistical Analysis Plan. The Sponsor will remain 
masked.  Other factors external to the study may also trigger a decision to modify the sample 
size. 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody
Ang-2
angiopoietin-2 
ANGPT2
angiopoietin-2 protein (gene)
BCVA
best-corrected visual acuity
CFP
color fundus photograph
CI
center involvement
CRC
central reading center
CST
central subfield thickness
DME
diabetic macular edema
DR
diabetic retinopathy
DRS
diabetic retinopathy severity
DRSS
Diabetic Retinopathy Severity Scale
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
ETDRS
Early Treatment Diabetic Retinopathy Study
FDA
Food and Drug Administration
FFA
fundus fluorescein angiography
GCP
Good Clinical Practice
HbA1c
hemoglobin A1c
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Council for Harmonisation
iDCC
independent Data Coordinating Center
iDMC
independent Data Monitoring Committee
IL-1b (-6)
interleukin-1b (-6)
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IOP
intraocular pressure
IRB
Institutional Review Board
ITT
intent to treat
IVT
intravitreal
IxRS
interactive voice or web-based response system
LPLV
last patient, last visit
MedDRA
Medical Dictionary for Regulatory Activities
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Abbreviation
Definition
MMRM
mixed-model repeated-measures (model)
nAMD
neovascular age-related macular degeneration
NEI VFQ-25
National Eye Institute Visual Functioning
Questionnaire25
NPDR
non-proliferative diabetic retinopathy
OCT-A
optical coherence tomographyangiography
PD
pharmacodynamic
PDR
proliferative diabetic retinopathy
PK
pharmacokinetic
PRO
patient-reported outcome
PRP
panretinal photocoagulation
PTI
personalized treatment interval 
Q4W
every 4 weeks
Q8W
every 8 weeks
Q12W
every 12 weeks
Q16W
every 16 weeks
RBR
Research Biosample Repository
SD
standard deviation
SD-OCT
spectral-domain optical coherence tomography
SOC
standard of care
SS-OCT
swept-source optical coherence tomography
UWF
ultra-wide field
ULN
upper limit of normal
VA
visual acuity
VEGF(-A)
vascular endothelial growth factor(A)
YAG
yttrium-aluminum-garnet
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1.
BACKGROUND
1.1
BACKGROUND ON DIABETIC MACULAR EDEMA
Diabetic macular edema (DME), a complication of diabetic retinopathy (DR), 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
(Henricsson et al. 1999; Johnson 2009) from non-proliferative DR (NPDR) to proliferative 
DR (PDR). DME 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), and if 
left untreated 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). In 2013, the worldwide 
population of people with diabetes was approximately 382 million, and it is estimated to 
grow to 592 million by 2035 (International Diabetes Federation 2013). 
With advances in imaging technology, DME is now often diagnosed by optical coherence 
tomography (OCT) rather than the traditional Early Treatment Diabetic Retinopathy 
Study (ETDRS) ophthalmoscopy-based criteria. 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 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 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).
Although macular laser used to be the standard of care (SOC) for treatment of DME, the 
development of anti-VEGF pharmacotherapy in the past 10 years has led to dramatic 
improvements in visual outcomes for patients with DME. 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 strong efficacy achieved with anti-VEGF therapies in DME, a significant 
proportion of patients do not experience clinically meaningful improvements in vision in 
the real world. Frequent IVT administration is required to achieve, and in some cases, to 
maintain the observed early benefits of DME treatment over a long period of time. 
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The current SOC for administration of anti-VEGF injections requires patients to undergo 
frequent clinical examinations and IVT injections. This imposes a significant burden on 
patients, caregivers, treating physicians, and the healthcare system. 
Large Phase III trials of anti-VEGF agents in DME demonstrated that after the first year 
of treatment, the number of injections needed for maintenance of vision gains can be 
decreased (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 predictive biomarkers of treatment frequency, the standard
anti-VEGF approach in DME still relies on frequent monitoring visits and places 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 high unmet medical need in DME.
1.2
BACKGROUND ON FARICIMAB
Faricimab (also known as RO6867461) is a humanized full-length bispecific IgG1
antibody that selectively neutralizes VEGF-A (hereafter referred to as "VEGF") and 
Ang-2, the key factors mediating pathophysiology of diabetic eye disease.  Faricimab
was developed using Roche’s CrossMab (monoclonal antibody) technology. The VEGF 
binding and the Ang-2 binding variable regions of faricimab bind to VEGF and Ang-2 
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 VEGF and Ang-2 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 VEGF and Ang-2, 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 improve visual and anatomical outcomes in DME and DR compared 
with anti-VEGF monotherapies.
Refer to the RO6867461 (faricimab) Investigator's Brochure for details on nonclinical
and clinical studies.
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1.3
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
The Phase III program will evaluate the efficacy, safety, and pharmacokinetics of 
faricimab when administered to patients every 8 weeks (Q8W) and with a personalized 
treatment interval (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) (i.e., the number of ETDRS 
letters). 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. 
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 and supports further evaluation of faricimab in Phase III DME studies.
Additionally, the efficacy, safety, and treatment frequency of IVT faricimab administration 
has been assessed in another retinal disease indication, neovascular age-related 
macular degeneration (nAMD), in one Phase I study (BP28936) and in two Phase II 
studies (BP29647 [AVENUE] and CR39521 [STAIRWAY]).
Based on the totality of evidence from the Phase II studies, and taking into account 
evidence from the preclinical models, it is anticipated that the well-established 
anti-VEGF mechanism of action combined with antiAng-2 targeting in the bispecific 
faricimab molecule will lead to improved efficacy and/or reduced injection burden 
compared with anti-VEGF monotherapy. This would represent an important advance for 
patients with DME.
1.3.1
Benefits
The clinical benefit of IVT faricimab injections for patients with DME was demonstrated 
in the Phase II study BP30099. The study met its primary efficacy endpoint, which was 
the mean change from baseline in BCVA at Week 24 in anti-VEGF treatmentnaive 
patients treated with faricimab compared with 0.3 mg of ranibizumab.
Study BP30099 enrolled 229 patients with DME. The study was originally designed to 
enroll anti-VEGF treatmentnaive patients. The protocol was subsequently amended to 
include an additional cohort of patients (n61) who were previously treated with 
anti-VEGF for DME to allow for the exploratory evaluation of the efficacy of faricimab in 
this population.
Anti-VEGF treatmentnaive patients were randomized equally into three treatment arms:  
6 mg of IVT faricimab, 1.5 mg of IVT faricimab, and 0.3 mg of IVT ranibizumab. Patients 
who were previously treated with anti-VEGF were randomized equally to receive either 6 
mg of IVT faricimab or 0.3 mg of IVT ranibizumab. Key demographic and ocular 
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baseline characteristics were generally well balanced. The study consisted of a 
treatment period (20 weeks in length) and an observational period (up to 16 weeks in 
length), for a total study duration of up to 36 weeks. Study treatment was administered
to patients by IVT injection at every-4-week (Q4W) intervals up to the last injection at
Week 20, with the primary endpoint assessed at Week 24. The observational period 
without treatment lasted up to 16 weeks from Week 20 to Week 36. The observation 
period allowed for exploration of the durability of pharmacodynamic (PD) effects after the 
last treatment.
The mean BCVA change from baseline in the anti-VEGF treatmentnaive patients 
treated with 6 mg of faricimab improved steadily over time, with patients experiencing an
average benefit of 3.6 letters (p0.03; 80% confidence interval [CI]: 1.5 to 5.6 letters)
over anti-VEGF monotherapy (adjusted for baseline variables) at Week 24 (1 month
after the last monthly dose administered at Week 20), which was statistically significant 
in a mixed-model repeated measures (MMRM) analysis. In this anti-VEGF 
treatmentnaive population, the mean change in BCVA from baseline in the 6-mg
faricimab group and the 1.5-mg faricimab group at Week 24 was 13.9 letters and 
11.7 letters, respectively, relative to 10.3 letters in the 0.3-mg ranibizumab group. The 
proportion of treatment-naive patients gaining 15 letters or more from baseline over time 
at Week 24 was 35.3% for the 0.3-mg ranibizumab group relative to 36.0% and 42.5% 
for the 1.5-mg and 6-mg faricimab groups, respectively. In addition to DME benefit,
higher rates of improvement in DR severity from baseline (as assessed on the ETDRS 
Diabetic Retinopathy Severity Scale [DRSS]) were also observed with faricimab
compared with anti-VEGF monotherapy in the antiVEGF treatmentnaive cohort, with 
27.7% and 38.6% of patients (1.5-mg and 6-mg faricimab, respectively) experiencing a 
2-step improvement from baseline to Week 24 compared with 12.2% in the 0.3-mg 
ranibizumab treatment cohort. 
For the previously anti-VEGFtreated population, the absolute change from baseline 
was 9.6 letters and 8.3 letters for the 6-mg faricimab group and the anti-VEGF group, 
respectively.  The difference of 1.3 letters was directionally similar to the 
treatment-naive cohort but was not statistically significant (p0.635; 80% CI:2.3 to 5.0). 
Additionally, the proportion of patients gaining 15 or more letters from baseline over time 
at Week 24 was 23.2% and 16.8% for the 6-mg faricimab and anti-VEGF SOC treatment 
arms, respectively. The anatomical outcomes showed directionally similar benefits for 
faricimab in this cohort.
Overall, the data from intent-to-treat (ITT) study population (both treatment-naive and 
previously anti-VEGFtreated patients) suggest consistent benefit of faricimab over anti-
VEGF monotherapy in the general DME population.
The outcomes in the off-treatment study observation period provided evidence of 
prolonged duration of effect with faricimab compared with anti-VEGF monotherapy.
Assessment of time to disease reactivation up to 16 weeks after the last dose showed 
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an improvement in the duration of the effect of faricimab over ranibizumab, as measured 
by the time to loss of 5 ETDRS letters because of DME and an increase 50 m in 
CST in the treatment-naive patient population in a dose-dependent manner.  This 
improvement in the duration of effect of faricimab over ranibizumab was also seen in the 
previously treated group and the overall patient group.
In summary, the data from Study BP30099 suggested a dose-related benefit favoring the 
6-mg dose of faricimab relative to the 1.5-mg dose, as measured by both the efficacy 
outcomes and duration of effect.  Based on these results, the 6-mg dose of faricimab
has been chosen for further clinical development in Phase III studies in patients with 
DME to explore its benefit compared with SOC IVT anti-VEGF treatment from the 
following perspectives:

Potential for superior efficacy outcomes in DME with 6 mg of IVT faricimab
compared with SOC IVT

Potential for prolonged treatment duration while achieving and maintaining 
comparable efficacy with 6 mg of IVT faricimab compared with SOC IVT
The Phase III clinical development program will enroll both patients with DME who are 
naive to anti-VEGF therapy in the study eye and patients who were previously treated 
with anti-VEGF therapy in the study eye to further explore outcomes on DME in both 
populations.
1.3.2
Risks
In the Phase I study (BP28936), single and multiple IVT administrations of faricimab
were well tolerated in patients with nAMD up to the highest dose tested, 6 mg. No 
deaths and no dose-limiting events were reported.
The Phase II study BP30099 in DME also showed an acceptable tolerability and safety 
profile, with no new or unexpected safety signals. No serious ocular or systemic 
adverse events considered related to treatment with faricimab were reported. The 
ocular and systemic safety findings for faricimab observed in the Phase II study were 
generally consistent with the safety profile reported in patients with DME who receive 
intravitreally administered anti-VEGF products.
Additionally, the safety of IVT faricimab administration has been assessed in patients 
with nAMD in two Phase II studies (BP29647 [AVENUE] and CR39521 [STAIRWAY]).
A total of 436 patients have been exposed to at least one dose of faricimab to date. No
unexpected safety signals have been identified in these studies that would change the 
anticipated safety profile in the Phase III DME program.
Based on the totality of evidence from the Phase I and Phase II studies, and taking into
account evidence from the murine and non-human primate preclinical and toxicology 
models, it is anticipated that the additional antiAng-2 mechanism of action of the 
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faricimab molecule will not lead to an increase in safety risks compared with IVT
anti-VEGF monotherapy.
Refer to the RO6867461 (faricimab) Investigator's Brochure for details on safety results
from nonclinical and clinical Phase I and Phase II studies.
1.3.3
Conclusions
The available Phase I and II efficacy and safety data showed a benefitrisk profile that 
supports further assessment of the efficacy and safety of 6 mg faricimab across various 
treatment intervals compared with anti-VEGF IVT monotherapy in a Phase III 
DME program.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, and pharmacokinetics of faricimab when 
dosed Q8W and with a PTI regimen compared with aflibercept (Eylea®) monotherapy in 
patients with DME.  Specific objectives and corresponding endpoints for the study are 
outlined in Table 1. An overview of the proposed statistical analyses is described in
Section 6.
In this protocol, study drug refers to faricimab or aflibercept (intended for the study eye) 
and study treatment refers to faricimab, aflibercept, or the sham procedure (see 
Section 4.3 for further details).
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Table 1
Objectives and Corresponding Endpoints
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of IVT 
injections of the 6-mg dose of 
faricimab on BCVA outcomes
Change from baseline in BCVA (as measured on
the ETDRS chart at a starting distance of 
4 meters) at 1 year a
Key Secondary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of faricimab
on DR severity outcomes
Proportion of patients with a 2-step DRS 
improvement from baseline on the ETDRS 
DRSS at Week 52
Secondary Efficacy Objectives
Corresponding Endpoints
To evaluate the efficacy of faricimab
on additional BCVA outcomes
Change from baseline in BCVA (as measured on
the ETDRS chart at a starting distance of 
4 meters) over time 
Proportion of patients gaining 15, 10, 5, or 
0 letters in BCVA from baseline over time
Proportion of patients avoiding a loss of 15, 
105, or >0 letters in BCVA from baseline 
over time
Proportion of patients gaining 15 letters or 
achieving BCVA of 84 letters over time
Proportion of patients with BCVA Snellen 
equivalent of 20/40 or better over time
Proportion of patients with BCVA Snellen 
equivalent of 20/200 or worse over time
To evaluate the efficacy of faricimab
on additional DR outcomes
Proportion of patients with a 2-step DRS 
improvement from baseline on the ETDRS DRSS
over time
Proportion of patients with a 3-step DRS 
improvement from baseline on the ETDRS DRSS 
over time
Proportion of patients who develop new PDR 
over time 
To evaluate faricimab treatment 
intervals in the PTI arm
Proportion of patients in the PTI arm on a Q4W, 
Q8W, Q12W, or Q16W treatment interval at 
1 year and 2 years
Treatment intervals in the PTI arm over time
a The definition of 1 year is the average of the Week 48, 52, and 56 visits.
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Table 1
Objectives and Corresponding Endpoints (cont.)
Secondary Efficacy Objectives (cont.)
Corresponding Endpoints (cont.)
To evaluate the efficacy of faricimab on 
anatomical outcome measures using 
SD-OCT
Change from baseline in CST at 1 year a
Change from baseline in CST over time
Proportion of patients with absence of DME (CST 
325 m for Spectralis SD-OCT, or 315 m for 
Cirrus SD-OCT or Topcon SD-OCT) over time
Proportion of patients with absence of intraretinal 
fluid over time
Proportion of patients with absence of subretinal fluid 
over time
Proportion of patients with absence of intraretinal 
fluid and subretinal fluid over time
To evaluate the efficacy of faricimab on 
patient-reported vision-related 
functioning and quality of life using the 
NEI VFQ-25
Change from baseline in NEI VFQ-25 composite 
score over time
Safety Objective
Corresponding Endpoints
To evaluate the ocular and systemic
safety and tolerability of faricimab
Incidence and severity of ocular adverse events
Incidence and severity of non-ocular 
adverse events
Exploratory Efficacy Objectives
Corresponding Endpoints
To further evaluate the efficacy of 
faricimab on additional DR outcomes
Proportion of patients with a 2-step or 3-step 
DRS worsening from baseline on ETDRS DRSS 
over time
Proportion of patients who receive vitrectomy or 
PRP over time during the study
To further evaluate the efficacy of 
faricimab on anatomical outcome 
measures using FFA and/or OCT-A c
Change from baseline in the macular and the total 
retinal area b of ischemic non-perfusion (capillary 
loss) over time
Change from baseline in vascular leakage in the 
macula and in the total retinal area b over time
Proportion of patients with resolution of vascular 
leakage in the macula and in the total retinal area
b over time
To further evaluate the efficacy of 
faricimab on anatomical outcome 
measures using SD-OCT
Change from baseline neurosensory CST over time 
Change from baseline in total macular volume over 
time
a The definition of 1 year is the average of the Week 48, 52, and 56 visits.
b The total retinal area is defined as 7-modified fields or 4-wide fields or ETDRS 7-field mask 
overlay on ultra-wide field (UWF; Optos) images in all study patients and as the entire 
UWF image, including peripheral areas in a subset of patients with Optos FFA.
c
In a subset of patients with OCT-A.
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Table 1
Objectives and Corresponding Endpoints (cont.)
Exploratory Efficacy Objectives
(cont.)
Corresponding Endpoints
(cont.)
To further evaluate the efficacy of 
faricimab on patient-reported vision-
related functioning and quality of life 
using the NEI VFQ-25
Change from baseline in the NEI VFQ-25 Near 
Activities, Distance Activities, and Driving 
subscales at 1 year a
Proportion of patients with a 4-point 
improvement from baseline in NEI VFQ-25 
composite score at 1 year a
Pharmacokinetic Objective
Corresponding Endpoint
To characterize the systemic 
pharmacokinetics of faricimab
Plasma concentration of faricimab over time
Immunogenicity Objectives
Corresponding Endpoints

To evaluate the immune response to 
faricimab
Presence of ADAs during the study relative to 
the presence of ADAs at baseline

To evaluate potential effects of ADAs
Relationship between ADA status and efficacy, 
safety, or PK endpoints
Exploratory Pharmacokinetic, 
Pharmacodynamic, and Biomarker 
Objectives
Corresponding Endpoints
To identify biomarkers that are 
predictive of response to faricimab, 
are associated with progression to a 
more severe disease state, are 
associated with susceptibility to 
developing adverse events, can 
provide evidence of faricimab activity, 
or can increase the knowledge and 
understanding of disease biology
Concentration of biomarkers of angiogenesis 
and inflammation in aqueous humor (optional) at 
baseline and over time and their correlation with 
PK and/or primary and secondary endpoints at 
baseline and over time
Relationship between efficacy, safety, PK, 
immunogenicity,
Relationship between baseline anatomic 
measures and the change in BCVA or other 
endpoints (e.g., the frequency of study drug 
administration) over time
Relationship between anatomic measures and 
visual acuity
a The definition of 1 year is the average of the Week 48, 52, and 56 visits.
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Table 1
Objectives and Corresponding Endpoints (cont.)
Exploratory Pharmacokinetic, 
Pharmacodynamic, and Biomarker 
Objectives (cont.)
Corresponding Endpoints (cont.)
To evaluate potential relationships 
between selected covariates and 
exposure to faricimab
Relationship between selected covariates and 
plasma or aqueous humor (optional) 
concentration or PK parameters for faricimab
To characterize the aqueous humor 
(optional) and vitreous (optional) 
pharmacokinetics of faricimab
Aqueous humor (optional) and vitreous (optional) 
concentration of faricimab over time
To evaluate the drug concentration 

To explore the concentrationeffect 
relationship for visual acuity and other 
endpoints (e.g., anatomical markers)
Pharmacokinetics of faricimab and the change in 
BCVA or other endpoints (e.g., anatomical 
markers) over time
ADAanti-drug antibody;
 BCVAbest-
corrected visual acuity; CSTcentral subfield thickness; DRdiabetic retinopathy; 
DRSdiabetic retinopathy severity; DRSSDiabetic Retinopathy Severity Scale; 
ETDRSEarly Treatment Diabetic Retinopathy Study; FFAfundus fluorescein angiography; 
IVTintravitreal; NEI VFQ-25National Eye Institute 25-Item Visual Function Questionnaire; 
OCT-Aoptical coherence tomographyangiography; PDRproliferative diabetic retinopathy; 
PKpharmacokinetic; PRPpanretinal photocoagulation; PTIpersonalized treatment interval; 
Q4W every 4 weeks; Q8Wevery 8 weeks; Q12W every 12 weeks; Q16W every 16 
weeks; SD-OCTspectral-domain optical coherence tomography;
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a Phase III, double-masked, multicenter, randomized, active 
comparatorcontrolled, parallel-group study, evaluating the efficacy, safety, 
pharmacokinetics, and optimal treatment frequency of faricimab administered by IVT
injection at 8-week intervals or PTI of approximately 100 weeks' duration (excluding the 
screening period) to patients with DME.  
3.1.1
Overview of Study Design
Approximately 900 patients will be randomized during the global enrollment phase of the 
study in a 1:1:1 ratio to one of three treatment arms (see Figure 1) at approximately 
240 investigational sites globally.  The study will randomize patients with DME who are
naive to anti-VEGF therapy in the study eye and patients who have previously been 
treated with anti-VEGF therapy in the study eye, provided that the last treatment was at 
least 3 months prior to the Day 1 visit (the first study treatment).  Site investigators will 
be retina specialists or the equivalent outside of the United States (see Section 4.2.2 for 
additional details).
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The study treatment arms will be as follows:

Arm A (administered Q8W) (n300):  Patients randomized to Arm A will receive 
6-mg IVT faricimab injections Q4W to Week 20, followed by 6-mg IVT faricimab
injections Q8W to Week 96, followed by the final study visit at Week 100.

Arm B (PTI) (n300):  Patients randomized to Arm B will receive 6-mg IVT faricimab
injections Q4W to at least Week 12, followed by PTI dosing (see the PTI dosing 
criteria below) of 6-mg IVT faricimab injections to Week 96, followed by the final 
study visit at Week 100.

Arm C (comparator arm) (administered Q8W) (n300): Patients randomized to 
Arm C will receive 2-mg IVT aflibercept injections Q4W to Week 16, followed by 
2-mg IVT aflibercept injections Q8W to Week 96, followed by the final study visit at 
Week 100.
Patients in all three treatment arms will complete scheduled study visits Q4W for the 
entire study duration (100 weeks). A sham procedure will be administered to patients in
all three treatment arms at applicable visits to maintain masking among treatment arms
(see Figure 1).
Figure 1 presents an overview of the study treatment design.  A schedule of activities is 
provided in Appendix 1.
Figure 1
Study Treatment Schema
IVTintravitreal; Q8Wevery 8 weeks; PTIpersonalized treatment interval (see Section 3.1.2 for 
additional details); Wweek.
a The definition of 1 year used for the primary efficacy endpointdefined as the change from 
baseline in BCVA, as measured on the ETDRS chart at a starting distance of 4 meters at 
1 yearis the average of the Week 48, 52, and 56 visits.
Only one eye will be assigned as the study eye.  If both eyes are considered eligible, the 
eye with the worse BCVA, as assessed at screening, will be selected as the study eye 
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unless the investigator deems the other eye to be more appropriate for treatment in the 
study.
There will be a minimum of two investigators per site to fulfill the masking requirements 
of the study.  At least one investigator will be designated as the assessor physician who 
will be masked to each patient’s treatment assignment and who will evaluate ocular 
assessments.  At least one other investigator will be unmasked and will perform study 
treatments (see Section 4.2.2 for additional masking details). 
The study will consist of a screening period of up to 28 days (Days 28 to 1) in length 
and an approximately 96-week treatment period, followed by the final study visit at 
Week 100. A unique screening number will be assigned to each screened patient 
through an interactive voice or web-based response system (IxRS).
3.1.1.1
Screening
Informed consent must be administered and signed by a patient before any 
study-specific screening procedure is performed. Each consented patient must satisfy 
the eligibility criteria as applicable at screening and/or the Day 1 visit (see Sections 4.1.1
and 4.1.2).  
Note: Some patients may require an extended screening period (more than 28 days) as 
a result of repeated evaluation of images or other issues.  Upon agreement with the 
Medical Monitor, the screening period may be extended by up to 5 business days in
such cases.
In some countries/regions, the screening and Day 1 (randomization) visits may occur as
a combined visit if all assessments are completed and evaluated on the same day or
within 2 business days. When screening and the Day 1 visit are completed as a 
combined visit, the assessments listed for both visits (see the schedule of activities in
Appendix 1) should be conducted only once. The following conditions have to be met 
for a combined visit to occur:


A historic hemoglobin A1c (HbA1c) value must be available from within 2 months prior 
to Day 1.
If the screening and Day 1 visit are not completed on the same day (but rather within 2 
business days), the following safety assessments must be repeated on the day of 
patient’s randomization and study treatment administration: urine pregnancy test (if 
applicable), slitlamp examination, indirect ophthalmoscopy, and pre- and post-treatment
intraocular pressure (IOP) measurements (recorded on the Day 1 electronic Case 
Report Form [eCRF] and dated accordingly).
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For all study patients, after screening has been completed, including all assessments 
listed for the Day 1 visit, eligible patients will have a randomization identification
number assigned through the IxRS and will be randomized in a 1:1:1 ratio in order that 
approximately 300 patients are randomized to each of the three treatment arms.
Randomization will be stratified by baseline BCVA ETDRS letter score, as assessed on 
Day 1 (64 letters or better vs. 63 letters or worse), prior IVT anti-VEGF therapy (yes vs. 
no), and region (United States and Canada, Asia, and the rest of the world).
3.1.1.2
Screen-Failed Patients
Patients who are not eligible for enrollment (screen failures) may be eligible for 
re-screening for up to an additional two times during the enrollment period of the study.
At re-screening, a new screening number will be assigned to each patient through the 
IxRS and all screening visit assessments will be performed. At the Day 1 visit, fundus
FFA images do not have to be repeated, provided that the same eye is selected for the 
study eye at rescreening and acceptable FFA images were taken within 4 weeks before
the new Day 1 visit (randomization) date.
3.1.1.3
Randomization and Visit Schedule
The first study treatment will be administered on the same day as randomization, which 
will be performed through the IxRS (i.e., at the Day 1 visit).  
Note: If a site has an unexpected issue (e.g., the IxRS is not able to assign the study kit), 
a patient’s randomization and first study treatment may be administered within 2
business days of the Day 1 visit assessments, after consultation with the Medical Monitor.  
The following assessments will be repeated on the day of randomization and study 
treatment: urine pregnancy test (if applicable), slitlamp examination, indirect 
ophthalmoscopy, pre-treatment IOP measurements (recorded on the Day 1 eCRF and 
dated accordingly), and any new concomitant medications.
Randomized patients will have the first study treatment administered by the unmasked 
investigator on Day 1, followed by the safety assessments (finger-counting test and 
post-dose IOP measurement). Afterwards, all study patients will also have a safety 
assessment visit on Day 7 (3 days) evaluated by the masked investigator.  At 
subsequent scheduled visits, patients will have pre-dose safety assessments evaluated
by the masked investigator prior to receiving study treatment.  Study treatment 
administration and study-related assessments will occur Q4W (starting from Day 1), 
as outlined in the schedule of activities (see Appendix 1).  The sham procedure will be 
delivered to patients in all arms throughout the study as applicable (see Figure 1).
Patients will be instructed to contact the study site at any time if they have any 
health-related concerns. If warranted, patients will be asked to return to the clinic as 
soon as possible for an unscheduled safety assessment visit (see Appendix 2).  
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All assessments (including study treatment) for a scheduled visit are to be performed on 
the same day, except those performed during the screening period.
Study treatment visits cannot occur earlier than 21 days after the previous study
treatment visit.  Missed study treatments will not be made up.
Note: After the Day 1 visit, if a patient misses a study visit when ocular CFP and FFA 
images are to be obtained (see Appendix 1), or these images are not taken at the 
scheduled visit (e.g., equipment is broken), they must be obtained at the next scheduled 
visit the patient attends.  
If a patient misses more than two consecutive study treatment visits within any 24-week 
treatment period, the investigator and the Medical Monitor may consider discontinuing 
the patient from study treatment.  
Patients who are prematurely discontinued from study treatment but who agree to 
continue to participate in the study will be encouraged to undergo as many scheduled 
visits as possible, with emphasis on completing the Week 48, 52, 56, and 100 visits.
Study treatment visits will be scheduled Q4W (7 days) relative to the Day 1 visit date.
Patients who are discontinuing from the study prior to completion will be asked to return
for an early termination visit after a minimum of 28 days have elapsed following their last 
study treatment for monitoring of adverse events and early termination visit assessments 
(see Appendix 1). 
Patients who complete study treatment (i.e., the Week 96 visit) will return for the final 
study visit (Week 100) after a minimum of 28 days have elapsed from their last study 
treatment for monitoring of adverse events and final study visit assessments (see 
Appendix 1).  
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3.1.2
Treatment Schedule for Patients in the Personalized 
Treatment Interval Arm (Arm B)
Study drug dosing interval decisions in the PTI arm are automatically calculated by the 
IxRS based on the algorithm described in this section. Study drug dosing visits are visits 
when a patient is assigned to receive faricimab. 
3.1.2.1
Study Drug Dosing Interval Determination 
Patients randomized to the PTI arm (Arm B) will be treated with faricimab on a Q4W 
dosing interval until at least the patient’s Week 12 visit, or a later visit when CST meets 
the predefined reference CST threshold (CST 325 m for Spectralis SD-OCT, or 
315 m for Cirrus SD-OCT or Topcon SD-OCT), as determined by the CRC.  The 
reference CST (as defined in Figure 2) is used at study drug dosing visits by the IxRS 
for the drug dosing interval decision-making.
After a patient’s initial reference CST is established, their study drug dosing interval will 
be increased by 4 weeks to an initial Q8W dosing interval by the IxRS.  From this point 
forward, the study drug dosing interval will be extended, reduced, or maintained based 
on assessments made at study drug dosing visits.  Figure 2 outlines the algorithm used 
by the IxRS for interval decision-making, which is based on the relative change of the 
CST and BCVA compared with reference CST and reference BCVA.
Figure 2
Algorithm for IxRS-Determined Personalized Treatment Interval
Study Drug Dosing Intervals 
All comparisons are made relative to the reference CST* and reference BCVA**.  The 
IxRS will determine the study drug dosing interval based on CST and BCVA data 
obtained from the study drug dosing visits. 
Interval extended by 4 weeks: 

If the CST value is increased or decreased by 10% without an associated 
10-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 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 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
*
Reference central subfield thickness (CST):  the CST value when the initial CST threshold 
criteria are met.  Reference CST is adjusted if CST decreases by 10% from the previous 
reference CST for two consecutive study 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.
**
Reference best-corrected visual acuity (BCVA): the mean of the three best BCVA scores 
obtained at any prior study drug dosing visit.
3.1.2.2
Study Drug Dosing Intervals
The IxRS can adjust the study drug dosing interval by 4-week increments to a maximum 
of every 16 weeks (Q16W) and a minimum of Q4W.  The IxRS algorithm for the study 
drug treatment interval decision making is based on the relative change of the CST and 
absolute change in BCVA compared with the reference CST and BCVA, respectively.
Similar to Arms A and C, patients randomized to the PTI arm (Arm B) will receive a 
sham procedure at study visits when they are not receiving treatment with faricimab.
3.1.3
Additional Considerations for PTI Arm IxRS Study Drug Dosing 
Interval Decision
Sites will report missed study treatment visits and study treatment interruption visits to 
the IxRS for all patients (Arms A, B, and C) to preserve the masking. The following 
algorithms are only applicable to patients in the PTI arm (Arm B) and are used by the 
IxRS to automatically determine study drug dosing intervals in the event of the following
situations.
3.1.3.1
Missed Study Drug Dosing Visit(s)
If a patient misses a study drug dosing visit, the IxRS will assign the patient to receive 
study drug dosing at the next scheduled study visit the patient attends. A decision 
regarding the subsequent study drug dosing interval will be made by IxRS based on 
CST and BCVA assessments completed at the visit when study drug is administered,
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and any changes in the drug dosing interval will be based from the last assigned interval
prior to the missed drug dosing visit.
Example:  If a patient was on an every 12-week (Q12W) drug dosing interval prior to 
missing the study drug dosing visit, then the IxRS decision to maintain, extend, or 
reduce the dosing interval will be made on the basis of the previously assigned drug 
interval (Q12W) along with CST and BCVA data obtained at the visit when the patient
receives study drug.  If the data indicate that the patient should maintain the Q12W 
interval, then he or she will receive study drug 12 weeks after that visit.
3.1.3.2
Study Drug Interruption at Study Drug Dosing Visit(s)
If a patient's dosing has to be interrupted (e.g., because of an adverse event) at a study 
drug dosing visit, IxRS will assign the patient to receive study drug at the earliest
subsequent study visit when the patient is permitted to resume study drug dosing. The
IxRS will be used to determine the next study drug dosing based on a Q8W interval
unless the patient was treated on a Q4W interval prior to dose interruption. In that case, 
the patient will be evaluated on the basis of the Q4W interval.
3.1.3.3
Missing CST Value at Study Drug Dosing Visit
If a patient attends a study drug dosing visit, but the CST value is not available for any 
reason (e.g., OCT machine is not available or is broken), the IxRS will assign the patient 
to receive study drug at that visit.  Generally, the IxRS will maintain the previous drug 
dosing interval.  However, in the event of a concurrent 10-letter decrease relative to the 
reference BCVA at that study drug dosing visit, the IxRS will reduce the study drug 
dosing interval by 4 weeks. 
3.1.3.4
Missing BCVA Value at Study Drug Dosing Visit
If a patient attends a study drug dosing visit, but the BCVA value is not available for any 
reason, the IxRS will assign the patient to receive study drug at that visit.  The IxRS will 
base the study drug dosing interval determination on CST value only.
3.1.4
Missed Study Drug Treatment Visit(s) for Patients in the 
Q8W Treatment Arms
If a patient randomized to treatment Arm A (faricimab Q8W) or Arm C (aflibercept Q8W) 
misses study drug dosing visit(s) after the Q4W initiating doses, the IxRS will assign the 
patient to receive faricimab or aflibercept at the next study visit he or she attends. The 
Q8W drug treatment interval will be automatically reset by the IxRS from that visit
forward, thus 4 weeks later, at the following study visit, the patient will receive sham. 
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3.1.6
Independent Data Monitoring Committee
An independent Data Monitoring Committee (iDMC) will monitor safety and study 
conduct on an ongoing basis. Members of the iDMC will be external to the Sponsor and 
will follow a charter that outlines the iDMC's roles and responsibilities. 
The iDMC will meet approximately every 6 months (frequency adjustable if required) to 
evaluate unmasked ocular and systemic (non-ocular) safety events with an emphasis on 
the evaluation of the rate of ocular inflammation, increased IOP, endophthalmitis, arterial 
thromboembolic events, and clinically significant decreases in BCVA, which will be 
prepared for the committee by an independent Data Coordinating Center (iDCC). The 
iDMC may recommend stopping the study early for safety reasons. 
After reviewing the data, the iDMC will provide a recommendation to the Sponsor as 
described in the iDMC Charter.  Final decisions will rest with the Sponsor.
Any outcomes of these data reviews that affect study conduct will be communicated in a 
timely manner to the investigators for notification of their respective Institutional Review 
Boards/Ethics Committees (IRBs/ECs).
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3.2
END OF STUDY AND LENGTH OF STUDY
The study consists of two enrollment phases: the global enrollment phase, during which 
patients are recruited globally,
 
 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs, 
  The end of the study is expected 
to occur approximately 100 weeks after the last patient is randomized.
The total length of the study
from screening of the first 
patient to the LPLV for patients from the global enrollment phase is expected to be 
approximately 38 months.
3.3
RATIONALE FOR STUDY DESIGN
A multicenter, double-masked, randomized, comparator-controlled trial design was 
selected to minimize bias in the evaluation of faricimab as a treatment for patients with 
DME. 
To ensure the safety of all patients during the conduct of the study, several safety 
assessments have been included, for example, regular ophthalmological monitoring and 
imaging assessments, adverse event monitoring (ocular and systemic), and laboratory 
safety tests (see Section 4.5 and Appendix 1 for a description of study assessments).
Optional aqueous humor samples will be collected from consenting patients in regions 
where optional sampling is approved, with the aim to further understand the ocular 
pharmacokinetics of faricimab as well as to assess biomarkers (see Section 3.3.4).
Single (Krohne et al. 2012) and multiple (Campochiaro et al. 2013) aqueous humor 
samplings have previously been instrumental in the understanding of ocular 
pharmacokinetics and VEGF suppression (Muether et al. 2012, 2013, 2014; Fauser 
et al. 2014; Fauser and Muether 2016; Hutton-Smith et al. 2017) and were safely applied 
in faricimab clinical studies in a total of 180 patients.
3.3.1
Rationale for Treatment Arms Dose and Schedule
3.3.1.1
Rationale for Faricimab Dose and Schedule
The 6-mg dose of faricimab will be administered to patients as initiating and 
maintenance doses in treatment Arm A and Arm B, as outlined in Section 3.1.1. 
Dose
The 6-mg dose of faricimab selected for this study is based on data from preclinical 
in vivo and toxicology models, clinical outcomes from Phase I and Phase II studies, and
supported by clinical pharmacokinetic (PK) and PD assessments.
The first-in-human study (BP28936) evaluated the safety and tolerability of single and 
multiple administration of faricimab to 24 patients with nAMD, at doses ranging from 0.5 
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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 faricimab and 6-mg faricimab) with 0.3-mg 
IVT ranibizumab.  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. 
As a result, the 6-mg faricimab dose has been chosen for further clinical development in 
Phase III studies in patients with DME. Refer to the RO6867461 (faricimab)
Investigator's Brochure for details on efficacy and safety results for the above-mentioned
nonclinical and clinical studies.
Schedule
The dosing schedule in the Phase III study is designed to allow the assessment of both 
efficacy and the optimal treatment frequency of the 6-mg IVT faricimab dose.  The 
dosing schedule is based on the clinical data from the Phase II study (BP30099 
[BOULEVARD]) and the PK and PD assessments of aqueous humor samples from a 
subset of patients with DME in the Phase II study BP30099.
The mechanism of action of faricimab is through neutralization of VEGF and Ang-2. PK
and PD assessments of aqueous humor samples from a subset of patients in
Study BP30099 demonstrated high suppression of VEGF and Ang-2 for 8 weeks or 
more with faricimab, fully supporting the Q8W dosing regimen with a potential to further 
extend the intervals between injections. 
An initiating phase with six IVT injections of 6-mg faricimab Q4W was selected for Arm A 
(faricimab Q8W). The rationale for the initial six Q4W doses is based on the continuous 
BCVA gains seen after each Q4W injection up to Week 24 in the Phase II study 
(BP30099). The maintenance dosing phase for patients in Arm A (faricimab Q8W) will 
consist of 6 mg of IVT faricimab administered to patients Q8W. The rationale for Q8W 
maintenance phase dosing is based on the evidence of the durability of the 6-mg
faricimab dose in the 16-week observation period of the Phase II study (after the last 
dose at Week 20 until the end of observation period at Week 36), and on the VEGF and 
Ang-2 target neutralization in the aqueous humor in a subset of patients. An additional
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rationale for the Q8W maintenance dosing schedule for patients in Arm A is that it 
matches the U.S., Japan, and E.U. approved interval for the active comparator Arm C 
(aflibercept Q8W) in the Phase III design.
Both the efficacy outcomes from the Phase II study and the variability in individual VEGF
and Ang-2 suppression times in the PK/PD aqueous humor assessments indicated a 
heterogeneous response to treatment and supported a flexible dosing regimen with 
intervals from Q4W to Q16W. The Phase II study (BP30099) time to disease 
re-activation data (time to a 50-m increase in CST or time to a 5-letter worsening in 
BCVA) following six Q4W doses demonstrated that although some patients with DME
may 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 structural 
model of PK/PD model characterizing the aqueous humorfree VEGF time course 
showed that there was a substantial proportion of patients with high aqueous humor
free-VEGF suppression for whom a Q12W or Q16W regimen could be sufficient to 
maintain efficacy.
As a result, the Phase III design will assess 6-mg IVT faricimab administered at PTIs to
patients in Arm B.  The PTI regimen aims to achieve maximum efficacy while reducing 
the IVT injection treatment burden in patients with DME. 
3.3.1.2
Rationale for Aflibercept Dose and Schedule
The 2-mg aflibercept doses will be administered to patients in treatment Arm C, as 
outlined in Section 3.1.1. The aflibercept dose and schedule used in this study are 
consistent with global recommended dosing posologies (e.g., in the United States, 
European Union, and Japan) DME product labeling for Eylea (aflibercept) (see 
Section 3.3.3).
3.3.2
Rationale for Patient Population
This study will be conducted in patients with decreased vision due to DME who meet all 
of the eligibility criteria for this protocol (for the inclusion and exclusion criteria, see 
Sections 4.1.1 and 4.1.2, respectively).
Patients who are both naive to anti-VEGF therapy in the study eye and those who have 
previously been treated with anti-VEGF therapy in the study eye will be randomized.
Inclusion of previously anti-VEGFtreated patients in the study will enable exploratory 
evaluation of the impact of previous IVT anti-VEGF treatment on the efficacy of faricimab.
The target for participation of previously anti-VEGFtreated patients will be capped at a 
minimum 10% and a maximum 25% of enrollment. The rationale for capping the
number of previously anti-VEGFtreated patients is based on the heterogeneous nature 
of this population with potentially a history of long-standing DME and irreversible retinal 
damage that may limit the possibility of detecting additional VA improvements.
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3.3.3
Rationale for Control Group
This study is an interventional study, aiming to evaluate the efficacy of faricimab
compared with a SOC anti-VEGF therapy, aflibercept, for patients with DME. Anti-VEGF 
therapy is a well-established SOC in patients with DME, and studies with an inactive 
comparator or macular laser treatment alone are no longer ethically acceptable 
alternatives given the improvements in visual and anatomical outcomes associated with 
anti-VEGF treatment. 
Aflibercept is an approved anti-VEGF treatment in patients with DME and has 
demonstrated improvement of BCVA in the target population in controlled, randomized 
clinical studies (Eylea® [aflibercept] U.S. Package Insert, Eylea® [aflibercept] E.U.
Summary of Product Characteristics, and Eylea® [aflibercept] Japan Package Insert).
Eylea is the only globally approved anti-VEGF therapy with a Q8W maintenance 
regimen, facilitating a comparison with the Q8W maintenance regimen of faricimab in 
treatment Arm A. 
3.3.4
Rationale for Pharmacodynamic and Biomarker Assessments
PD parameters comprise the primary target engagement markers
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 Muethe 2016; 
Hutton-Smith et al. 2017).  Therefore, to increase our understanding of the ocular 
pharmacokinetics and pharmacodynamics of faricimab and its relationship to PTIs, 
optional aqueous humor samples will be obtained from patients who provide additional 
optional consent to participate. Aqueous humor and vitreous humor samples will be 
measured at different timepoints for patients who consent in regions where optional 
sampling is approved. 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 such as cytokines 
 
may be analyzed in these 
specimens in an exploratory analysis.  The analysis of these entities aims at the 
investigation of the role of biochemical and biological processes, such as angiogenesis, 
inflammation, and oxidative stress in the pathogenesis of DR (Goldberg 2009; Kaul et al. 
2010) and DME (Campochiaro 2015) 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 the molecular targets unbound to faricimab
 
 will be measured in the systemic circulation as part of PD assessments at 
different timepoints for all patients and at two additional timepoints for patients who
consent in regions where optional sampling is approved.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Patient Selection and Sex Distribution
Approximately 900 patients with DR and macular edema secondary to diabetes mellitus 
(Type 1 and 2) will be randomized to the study. 
The study will recruit patients who are naive to anti-VEGF therapy in the study eye and 
those who have previously been treated with anti-VEGF therapy in the study eye.  Study 
participation of previously anti-VEGFtreated patients will be capped at a maximum 25% 
of enrollment. 
Only one eye will be assigned as the study eye. If both eyes are considered eligible, the 
eye with the worse BCVA, as assessed at screening, will be selected for the study eye 
unless the investigator deems the other eye to be more appropriate for treatment in the 
study.
The protocol allows enrollment of both men and women, provided the following entry 
criteria are met (see Sections 4.1.1 and 4.1.2).  
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry.
4.1.1.1
General Inclusion Criteria
Patients must meet the following general inclusion criteria for study entry:

Willingness and the ability to provide signed informed consent
Additionally, at U.S. sites, patients must provide Health Insurance Portability and 
Accountability Act (HIPAA) authorization, and in other countries, as applicable 
according to national laws.

Age 18 years

Documented diagnosis of diabetes mellitus (Type 1 or Type 2), as defined by the 
American Diabetes Association or per WHO criteria and
–
Current regular use of insulin or other injectable drugs (e.g., dulaglutide and 
liraglutide) for the treatment of diabetes 
and/or
–
Current regular use of oral anti-hyperglycemic agents for the treatment of 
diabetes

HbA1c of 10% within 2 months prior to the Day 1 visit date
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
Ability and willingness to undertake all scheduled visits and assessments

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.

4.1.1.2
Ocular Inclusion Criteria for Study Eye
Patients must meet the following ocular inclusion criteria for the study eye for entry in 
the study:

Macular thickening secondary to DME involving the center of the fovea with CST
325 m, as measured on Spectralis SD-OCT, or 315 m, as measured on Cirrus 
SD-OCT or Topcon SD-OCT at screening

BCVA of 73 to 25 letters, inclusive (20/40 to 20/320 approximate Snellen equivalent),
using the ETDRS protocol at the initial testing distance of 4 meters (see the BCVA 
manual for additional details) on Day 1

Sufficiently clear ocular media and adequate pupillary dilatation to allow acquisition 
of good quality CFPs (including ETDRS 7 modified fields or 4 wide-angle fields to 
permit grading of DR and assessment of the retina) and other imaging modalities.
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4.1.2
Exclusion Criteria
Patients who meet any of the following exclusion criteria will be excluded from 
study entry.
4.1.2.1
General Exclusion Criteria
Patients who meet any of the following general exclusion criteria will be excluded from 
study entry:

Currently untreated diabetes mellitus or previously untreated patients who initiated
oral or injectable anti-diabetic medication within 3 months prior to Day 1

History of allergy or hypersensitivity to active drug aflibercept and any of its 
excipients, fluorescein, or any study treatmentrelated mandatory ingredients 
(e.g., disinfectants, anesthetics, etc.; see the pharmacy manual for additional 
details) that is not amenable to treatment

History of a severe allergic reaction or anaphylactic reaction to a biologic agent or
known hypersensitivity to any component of the faricimab or to aflibercept injections,
study treatment procedure, dilating drops, or any of the anesthetic and antimicrobial 
preparations used by a patient during the study

Active cancer within the past 12 months except for appropriately treated carcinoma 
in situ of the cervix, non-melanoma skin carcinoma, and prostate cancer with a
Gleason score of 6 and a stable prostate-specific antigen for 12 months

Systemic treatment for suspected or active systemic infection
Ongoing use of prophylactic antibiotic therapy may be acceptable but has to be 
discussed with the Medical Monitor.

Renal failure requiring renal transplant, hemodialysis, or peritoneal dialysis or 
anticipated to require hemodialysis or peritoneal dialysis at any time during the 
study 

History of other disease, other non-diabetic metabolic dysfunction, physical 
examination finding, historical or current clinical laboratory finding giving
reasonable suspicion of a condition that contraindicates the use of the faricimab or 
aflibercept or that might affect interpretation of the results of the study or renders the 
patient at high risk for treatment complications in the opinion of the investigator 

Uncontrolled blood pressure (defined as systolic 180 mmHg and/or diastolic 
100 mmHg while a patient is at rest)
If a patient’s initial reading exceeds these values, a second reading may be 
obtained later the same day or on another day during the screening period.  If the 
patient’s blood pressure is controlled by antihypertensive medication, the patient 
should be taking the same medication continuously for at least 30 days prior to 
Day 1.

Stroke (cerebral vascular accident) or myocardial infarction within 6 months prior to
Day 1
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
Pregnancy or breastfeeding, or intention to become pregnant during the study
Women of childbearing potential must have a negative urine pregnancy test 
result within 28 days prior to initiation of study treatment.  If the urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test.

Participation in an investigational trial that involves treatment with any drug or 
device (with the exception of vitamins and minerals) within 3 months prior to Day 1 

Administration of systemic pro-angiogenic treatments, such as VEGF-based 
therapies for the peripheral or coronary ischemia (e.g., limb ischemia or myocardial 
infarction) within 3 months or 5 half-lives prior to Day 1

Inability to comply with study or follow-up procedures

Requirement for continuous use of any medications and treatments indicated in 
Section 4.4.2, Prohibited Therapy
4.1.2.2
Ocular Exclusion Criteria for Study Eye
Patients who meet any of the following exclusion criteria for the study eye will be 
excluded from study entry:

High-risk PDR in the study eye, using any of the following established criteria for 
high-risk PDR:
–
Any vitreous or pre-retinal hemorrhage
–
Neovascularization elsewhere 1/2 disc area within an area equivalent to the 
mydriatic ETDRS 7 fields on clinical examination or on CFPs
–
Neovascularization at disc 1/3 disc area on clinical examination

Tractional retinal detachment, pre-retinal fibrosis, vitreomacular traction, or 
epiretinal membrane involving the fovea or disrupting the macular architecture in the 
study eye,

Active rubeosis 

Uncontrolled glaucoma 

History of retinal detachment or macular hole (Stage 3 or 4) 

Aphakia or implantation of anterior chamber intraocular lens

IVT anti-VEGF treatment within 3 months prior to Day 1 (applicable to patients 
whose study eyes were previously treated with IVT anti-VEGF agents) or any IVT 
anti-VEGF agents to study eye prior to Day 1 (applicable for patients who are 
treatment naive)

Treatment with panretinal photocoagulation (PRP) within 3 months prior to Day 1

Macular (focal, grid, or micropulse) laser within 3 months prior to Day 1

Any cataract surgery or treatment for complications of cataract surgery with steroids 
or YAG (yttrium-aluminum-garnet) laser capsulotomy within 3 months prior to Day 1

Any other intraocular surgery (e.g., corneal transplantation, glaucoma filtration, pars 
plana vitrectomy, corneal transplant, or radiotherapy) 
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
Any IVT or periocular (subtenon) corticosteroid treatment within 6 months prior to 
Day 1

Any use of medicated intraocular implants, including Ozurdex®, within 6 months of 
Day 1

Any use of Iluvien® implants at any time prior to Day 1

Treatment for other retinal diseases that can lead to macular edema
4.1.2.3
Ocular Exclusion Criteria for Fellow Eye (NonStudy Eye)
Patients who meet the following exclusion criterion for the fellow eye (nonstudy eye) 
will be excluded from study entry:

Non-functioning nonstudy eye, defined as either:
–
BCVA of hand motion or worse
–
No physical presence of nonstudy eye (i.e., monocular)
4.1.2.4
Exclusion Criteria for Both Eyes 
Patients who meet the following exclusion criterion for either eye will be excluded from 
study entry:

Prior administration of IVT faricimab in either eye

Any history of idiopathic or immune-mediated uveitis in either eye

Active ocular inflammation or suspected or active ocular or periocular infection in 
either eye on Day 1 
4.1.2.5
Concurrent Ocular Conditions Exclusion Criteria
Patients who meet the following exclusion criteria related to concurrent ocular conditions
will be excluded from study entry:

Any current or history of ocular disease other than DME that may confound 
assessment of the macula or affect central vision in the study eye (e.g., choroidal 
neovascularization, age-related macular degeneration, retinal vein occlusion, uveitis, 
angioid streaks, histoplasmosis, active or inactive cytomegalovirus, pathological 
myopia, retinal detachment, retinal embolus, macular traction, macular hole, and
other)

Any current ocular condition which, in the opinion of the investigator, is currently 
causing or could be expected to contribute to irreversible vision loss due to a cause 
other than DME in the study eye (e.g., foveal atrophy, foveal fibrosis, pigment 
abnormalities, dense subfoveal hard exudates, or other non-retinal conditions) 
4.2
METHOD OF TREATMENT ASSIGNMENT AND MASKING
4.2.1
Treatment Assignment
After written informed consent has been obtained, all patients will receive a screening 
number assigned through the IxRS.  A patient must satisfy all eligibility criteria (see 
Sections 4.1.1 and 4.1.2) prior to randomization through the IxRS. As part of the 
screening process, the CRC will evaluate CFPs and SD-OCT images to provide an 
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objective, masked assessment of patient eligibility. After all patient eligibility 
requirements are confirmed, site personnel will contact the IxRS at the Day 1 visit for 
assignment of a patient identification number (a separate number from the screening 
number). Patients will be randomized in a 1:1:1 ratio to one of three study treatment 
arms (faricimab Q8W, faricimab PTI, or aflibercept Q8W). After randomization and at 
each study treatment visit (i.e., including Day 1), the IxRS will assign the appropriate 
study treatment kit to be used. Patients will be randomized on the same day study 
treatment is to be initiated (the Day 1 visit).
Randomization will be stratified by the following baseline factors (Day 1):

Baseline BCVA ETDRS letter score (64 letters vs. 64 letters)

Prior IVT anti-VEGF treatment (yes vs. no)

Region (United States and Canada, Asia, and the rest of the world)
A stratified permuted-block randomization scheme will be used to obtain approximately a
1:1:1 ratio among the treatment groups overall and within each of the above strata. 
Patients who are not eligible for enrollment (screen failures) may be eligible for 
re-screening for up to an additional two times during the enrollment period of the study.
At re-screening, a new screening number will be assigned to each patient through the 
IxRS and all screening visit assessments will be performed. At the Day 1 visit, FFA 
images do not have to be repeated, provided the same eye is selected for the study eye 
at rescreening and CRC acceptable FFA images were taken within 4 weeks before the 
new Day 1 visit (randomization) date.
4.2.2
Masking
This is a double-masked study.  There must be a minimum of two investigators per site 
to fulfill the masking requirements of this study, and both are required to be present at 
each scheduled study visit.
4.2.2.1
Masked Roles
Principal Investigator
The Principal Investigator who will be a retina specialist (or the equivalent in ex-U.S. 
countries) must be in a masked role as he or she has to oversee the whole trial conduct 
at his or her site and must be masked to patients’ treatment assignment. In addition, the
Principal Investigator can assume any other masked role for which he or she qualifies
except for BCVA examiner tasks.
Assessor Physician
At least one investigator who will be a retina specialist (or the equivalent in ex-U.S. 
countries) will be designated as the assessor physician. He or she will be masked to 
patients’ treatment assignments and will evaluate all pre-treatment assessments, as well 
as all assessments performed at screening, Day 7, and at the final or early termination
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visit.   The assessor physician will also evaluate the causality of all adverse events
reported by the treatment administrator physician. If qualified, this role can take on any 
other masked role tasks except tasks performed by the BCVA examiner.
Photographer(s) and OCT Technician(s)
If qualified, the photographers and OCT technicians can share any other masked role 
tasks except tasks performed by the BCVA examiner.  
Study Coordinator(s)
If qualified, the study coordinator(s) can share any other masked role tasks except tasks 
performed by the BCVA examiner.  
BCVA Examiner 
The BCVA examiner will be masked to both the assigned treatment arm and the location 
(right vs. left) of the study eye.  The BCVA examiner will have no access to patients’ 
medical charts or the VA scores from a patient’s previous visits and may have access 
only to a patient’s refraction data from previous visits.  The BCVA examiner is not 
allowed to perform any other task involving direct patient care.
Phlebotomist
The phlebotomist’s tasks can be performed by a qualified masked or unmasked role
individual except for BCVA examiner role. 
4.2.2.2
Unmasked Roles
Treatment Administrator
At least one investigator will be designated as the treatment administrator and will be 
unmasked to the patients’ treatment assignment. The treatment administrator will be a 
retina specialist (or the equivalent in ex-U.S. countries).  In addition, ophthalmologists 
who have completed a minimum of 2 full years of ophthalmology residency (or 
equivalent in ex-U.S. countries) may be permitted to perform the role of the treatment
administrator following Sponsor approval. 
The treatment administrator(s) performing the study treatment administration (faricimab, 
aflibercept, or sham) will also perform the post-treatment administration vision testing 
(finger-counting and, if applicable, hand movement and/or light perception tests) and will 
treat adverse events that occur during or shortly after the study treatment administration.  
The person in this role, however, will not evaluate the causality of adverse events, which 
is the responsibility of the masked assessor physician(s).  The treatment administrator 
will also perform post-treatment IOP measurements, as well as optional aqueous humor 
sample collection. 
In addition, the qualifying treatment administrator can assist with and perform the
screening and Day 1 visit assessments.  The treatment administrator must not be 
involved in any other aspect of the study and must not divulge treatment assignment 
to anyone. 
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Unmasked Assistant(s) and Pharmacist
If desired, sites may have designated qualified unmasked assistant(s) who can,
e.g., assemble study treatment supplies, prepare sterile field, prepare the patient’s study 
eye for treatment, discard all injection materials (i.e., syringes and needles) immediately
following study treatment, and place vial in the kit box. The qualified unmasked 
assistant(s) can be assigned to measure post-dose IOP. If the site uses a pharmacy, 
then the unmasked role is also assigned to the pharmacist who can take on IMP-related 
tasks as applicable per delegation of authority log. In addition, qualifying unmasked 
assistant(s) can assist with and perform the screening and Day 1 visit assessments. 
Number of Unmasked Personnel per Site
Every effort must be made to limit the number of unmasked study personnel to ensure 
the integrity of this masked study.  There should be no more than six unmasked 
personnel (e.g., treatment administering physician[s] and assisting technician[s] if 
applicable) at an investigative site at one time.  In certain circumstances, the total 
number of unmasked personnel might be increased after discussion with and approval 
by the Medical Monitor. If the site is using a pharmacist, then this person may be in an 
unmasked role in addition to the unmasked staff at the site. 
Any other study assisting personnel not listed above will be in the masked roles. 
4.2.2.3
Delegation Log
All roles for each study staff member should be clearly documented in the Site 
Delegation Log.  The Site Delegation Log must be signed by the Principal Investigator.
4.2.2.4
Role Switching
Once personnel assigned to the designated unmasked role start performing that role
they cannot switch to a masked role during the study.  Switching from a masked role to 
an unmasked role may be possible and must be documented in the Delegation Log. 
4.2.2.5
Study Backup Staff
Sites are strongly advised to have backup staff for key study roles. In case of an 
emergency (e.g., an unscheduled safety visit), patients should be seen preferably by the 
assessor physician. If the assessor physician is unavailable, then any clinic physician 
present, including the physician in the treatment administrator role, should see the 
patient. 
4.2.2.6
Masking of Vendors, Sponsor's Agents, and 
Laboratory Personnel 
CRC personnel, study vendors, the Sponsor, and its agents will also be masked to 
treatment assignment, with the exception of individuals who require access to patient 
treatment assignments to fulfill their job roles during a clinical trial.  These roles include 
the clinical supply chain managers, sample handling staff, operational assay group 
personnel, IxRS service provider, drug accountability clinical research associates, the 
images coordinator, iDCC and iDMC members, and an internal unmasking statistician 
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(this person is from the Sponsor's unmasking group and will follow the Sponsor's 
standard operation procedures to audit the implementation of the randomization scheme 
and the treatment interval assignment by the IxRS vendor periodically during the 
conduct of the study; this person will not be involved in other study-related activities).
To maintain the masked design of the study, blood samples, optional aqueous humor 
samples, and optional vitreous humor samples obtained at the timepoints specified in 
the schedule of activities (see Appendix 1) will be obtained from consenting patients in 
any treatment arm.  The laboratories responsible for performing sample analyses will be 
unmasked to patients' treatment assignment to identify appropriate samples to be 
analyzed.  Unmasking for analysis of the relevant biosamples during the conduct of the 
study will be performed by personnel outside of the study team and according to the 
Sponsor’s internal standard procedures to ensure the integrity of the data.  The number 
of Roche representative(s) and delegates who are unmasked will be kept to the 
minimum required to address the objective of the biosample analysis.
4.2.2.7
Patient Masking 
Patients will be masked to treatment assignment during the study and until study 
closeout, until the Sponsor indicates that the study can be unmasked. 
4.2.3
Unmasking
4.2.3.1
Single-Patient Emergency Unmasking
If unmasking is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS. The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations.
4.2.3.2
Single-Patient Non-Emergency Unmasking
If the investigator wants to know the identity of study drug for any reason other than a 
medical emergency, he or she should contact the Medical Monitor directly.  The 
investigator should document and provide an explanation for any non-emergency 
unmasking.  The investigator will be able to break the treatment code by contacting 
the IxRS.
4.2.3.3
Single-Patient Unmasking for Health Authority 
Reporting Requirements
As per health authority reporting requirements, the Sponsor's Drug Safety representative
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the Drug Safety representative and 
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personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above) will remain masked to treatment assignment.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal product (IMP) for this study is faricimab (test product).
Aflibercept is being used as an active comparator in this study; therefore, aflibercept is 
also considered an IMP for this study when administered to the study eye.
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 
the anesthetized eye.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Faricimab, Aflibercept and Sham
4.3.1.1.1
Faricimab Formulation
Faricimab will be supplied by the Sponsor as a sterile liquid for IVT injection in 
single-use glass vials.
4.3.1.1.2
Aflibercept (Active Comparator) Formulation
Aflibercept will be supplied by the Sponsor as a sterile liquid for IVT injection in 
single-use glass vials.   
4.3.1.1.3
Sham Formulation
The sham vial is empty and will remain empty throughout the sham treatment. The 
sham is a procedure that mimics an IVT injection and involves the blunt end of an empty 
syringe (without a needle) being pressed against the anesthetized eye.
4.3.1.1.4
Faricimab, Aflibercept, and Sham Packaging and Handling
Faricimab drug product, aflibercept and sham packaging will be overseen by Roche's
Clinical Trial Supplies Department and bear labels with the identification required by 
local law, the protocol number, drug identification, and its concentration.
The packaging and labeling of faricimab drug product, aflibercept, and sham will be in 
accordance with Roche standards and local regulations.
Faricimab drug product, aflibercept, and sham must be stored according to the details on 
the product label and the information provided in the pharmacy manual.
For more detailed information on the formulation and handling of faricimab, aflibercept,
and sham, see the pharmacy manual. 
Upon arrival of the masked investigational products at the site, site personnel should 
check individual carton boxes for damage and verify proper identity, quantity, integrity of 
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seals and temperature conditions, and report any deviations or product complaints to the
unmasked monitor upon discovery.  Any product under investigation for integrity or 
temperature excursion should be quarantined by the IxRS, pending final assessment by 
the Sponsor.  
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.1.
4.3.2.1
Dosage
4.3.2.1.1
Intravitreal Faricimab Injections
The 6-mg dose of faricimab will be evaluated in this study and will be administered
intravitreally to patients randomized to receive faricimab Q8W or PTI during the 96-week 
treatment period (see the study treatment schema in Figure 1).
Patients randomized to receive Q8W treatment will be administered 15 IVT injections of
faricimab during the 96-week treatment period. Treatment will consist of 6 initial 
injections (6 mg of faricimab Q4W to Week 20), followed by 9 maintenance injections 
(6 mg of faricimab Q8W between Week 24 and Week 96). 
The number of IVT injections of faricimab administered to patients in the PTI arm will 
vary (see Section 3.1.2.1 for the retreatment criteria), but a minimum of 10 IVT injections 
of faricimab will be administered to patients during the 96-week treatment period. This 
will consist of minimum of 4 initiating injections (6 mg of faricimab Q4W to Week 12), 
followed by minimum of 6 maintenance injections (6 mg of faricimab between Week 16 
and Week 96). 
4.3.2.1.2
Intravitreal Aflibercept (Active Comparator) Injections
A 2-mg dose of aflibercept (Arm C) will be administered intravitreally Q8W to patients 
randomized to the aflibercept treatment arm during the 96-week treatment period (see 
Figure 1). Patients will receive 15 IVT injections of aflibercept during the 96-week 
treatment period. Treatment will consist of 5 initiating injections (2 mg of aflibercept 
Q4W to Week 16), followed by 10 maintenance injections (2 mg of aflibercept Q8W 
between Week 20 and Week 96).
4.3.2.1.3
Sham Procedure
All three treatment arms (faricimab Q8W, faricimab PTI, and aflibercept Q8W) will 
maintain Q4W study visits for the 100-week study duration. To preserve the randomized
treatment arm masking, patients will have the sham procedure performed at study 
treatment visits when they are not treated with either faricimab or aflibercept as 
applicable per their treatment arm schedule (see Figure 1).
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4.3.3
Administration
4.3.3.1
Faricimab or Aflibercept Intravitreal Injections or 
Sham Procedure
See the pharmacy manual for the pre-treatment procedures, the administration of 
faricimab, aflibercept, or sham and the post-treatment procedures for all treated patients.
4.3.4
Study Treatment Preparation
The pharmacist responsible for dispensing the study treatment, or designated unmasked 
site personnel, will prepare the correct study treatment (faricimab, aflibercept, or sham) 
as assigned through the IxRS.
Detailed stepwise instructions for the preparation of faricimab, aflibercept, or sham for 
administration, and mandatory materials to be used will be specified by the Sponsor and 
are detailed in the pharmacy manual.
A specified filter needle must be used for each dose preparation of faricimab or 
aflibercept according to the instructions provided in the pharmacy manual.  All materials 
to prepare and administer study treatments will be provided or reimbursed by the 
Sponsor, and no other material than specified should be used.
Vials of faricimab drug product and vials of aflibercept (the active comparator) are for 
single-use only (one injection preparation per patient per eye).  Vials used for one
patient must not be used for any other patient.  Partially used vials, remaining faricimab
drug product or aflibercept vials, as well as administration material must not be reused.  
4.3.5
Compliance
Any medication error, including drug overdose, should be noted on Adverse Event eCRF 
even if it did not result in any adverse event (see Adverse Event eCRF completion 
guidance and Section 5.3.5.12).
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Table 2 and Section 5.1.4.1.
4.3.6
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (faricimab, sham, and aflibercept) will be 
provided by the Sponsor.  The study site will acknowledge receipt of IMPs supplied by 
the Sponsor using the IxRS to confirm shipment condition and content.  Any damaged 
shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site’s method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
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the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.7
Continued Access to Faricimab
The Sponsor will offer continued access to Roche IMP (faricimab) free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive Roche IMP (faricimab) after completing the study if all
of the following conditions are met:

The patient has a sight-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them
A patient will not be eligible to receive Roche IMP (faricimab) after completing the study 
if any of the following conditions are met:

The Roche IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or would not
otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the IMP or data suggest that the IMP
is not effective for 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
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
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4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any prescription drugs or over-the-counter preparations
or procedures other than protocol-specified procedural medications (e.g., dilating drops 
or fluorescein dyes, proparacaine, or antimicrobials [if applicable]) used by a patient 
within 7 days preceding the Day 1 visit and through the conclusion of the patient’s study 
participation or early termination visit. Patients required to use therapy that is prohibited 
(see Section 4.4.2) will not be eligible for the study.
All concomitant medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF except for anti-VEGF therapy in the fellow eye that will 
be recorded on a separate eCRF. Concomitant ocular procedures performed on either 
eye during the study should be recorded in the Concurrent Ocular Procedures Log on
the eCRF.
4.4.1
Permitted Therapy
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 5.1.4.1, Table 2) may apply with cataract surgery

Short-term use of topical ocular corticosteroids after cataract surgery, yttrium-
aluminum garnet capsulotomy, peripheral iridotomy, argon/selective laser 
trabeculoplasty, or ocular allergic conditions

PRP 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 masked physician, randomized patients may have their fellow 
(nonstudy) eye treated with anti-VEGF therapy licensed for ocular use if they are 
diagnosed with an ocular condition for which the selected anti-VEGF therapy is 
approved by the country regulatory agency.  Consult with the region-specific anti-VEGF
prescribing information for the recommended dose and frequency of treatment. The 
Sponsor will cover the cost of approved licensed ocular anti-VEGF therapy in 
accordance with local regulations.  Note: Avastin (bevacizumab) is not licensed for 
ophthalmic use in any country; therefore, it is prohibited to be used.
If (per the masked investigator's judgment) treatment with anti-VEGF is to be given to 
the fellow (nonstudy) eye at the same visit as the study eye treatment, all study eye 
assessments (including study eye study treatment administration) must be completed
first.  If there are no safety concerns, the site may proceed with the fellow eye treatment
administered by the unmasked physician to preserve masking.
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Individual trays and sterile preparation must be separately prepared for each
eye treatment. 
Note:  If the fellow eye anti-VEGF treatment is performed outside of the study visit, 
then a qualified physician, either in masked or unmasked role, can administer the 
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 from use during a patient’s study treatment
participation.  Patients may be discontinued from study treatment and/or the study to
receive these therapies:

Systemic anti-VEGF therapy 

Systemic drugs known to cause macular edema (fingolimod, tamoxifen)

IVT anti-VEGF agents (other than study-assigned aflibercept or faricimab) in study 
eye 

IVT, periocular (subtenon), steroid implants (i.e., Ozurdex®, Iluvien®), or chronic 
topical ocular corticosteroids in study eye 

Treatment with Visudyne® in study eye

Administration of micropulse and focal or grid laser in study eye

Other experimental therapies (except those comprising vitamins and minerals)
Note:  patients who discontinue study treatment should be strongly encouraged to 
continue their study participation and undergo as many scheduled visits as possible, 
with emphasis on the Weeks 48, 52, 56, and 100 visits.
4.5
STUDY ASSESSMENTS
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities must be performed and documented for each patient.  Written informed 
consent will be obtained prior to initiation of any study procedures.  The screening 
evaluation will be performed within 28 days preceding the Day 1 visit (the day of the first 
study treatment).
Note: Some patients may require an extended screening period as a result of repeated 
evaluation of images or other issues.  Upon agreement with the Medical Monitor, the 
screening period may be extended for up to 5 business days for such cases.
All assessments (including the study treatment administration) for a scheduled visit 
are to be performed on the same day, except those performed during the screening period.
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4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening or re-screening
evaluations).  Informed Consent Forms for enrolled patients and for patients who are not 
subsequently enrolled will be maintained at the study site.
All screening and Day 1 visit evaluations must be completed and reviewed to confirm 
that patients meet all eligibility criteria before randomization at the Day 1 visit.  The 
investigator will maintain a screening log to record details about all patients screened 
and to confirm eligibility. Reasons for screening failure have to be documented in 
patients' source documents.
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data
Medical history, including clinically significant diseases, chronic and ongoing conditions 
(e.g., trauma, cancer, cardiovascular, cerebrovascular, and ophthalmic history),
surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, and smoking history will be recorded at baseline.  In addition, all medications 
(e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic 
remedies, nutritional supplements) used by a patient within 7 days prior to initiation of 
study treatment (the Day 1 visit) will be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity.  Race/ethnicity 
is recorded because of the potential contribution of this variable to differences in 
observed pharmacokinetics, pharmacodynamics, toxicity, and/or response to treatment
in retinal microvascular diseases (Zhang and Lai 2018).
4.5.3
Physical Examinations
A targeted physical examination should include an evaluation of the head, ears, nose 
and throat.  A patient’s height and weight will be recorded as well.  If any abnormalities 
are noted during the study, the patient may be referred to another doctor.
Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on 
the Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of temperature, respiratory rate, pulse rate, and 
systolic and diastolic blood pressure.  Vital signs will be taken with the patient in a 
seated position after resting for 5 minutes.
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4.5.5
Ocular Assessments
Ocular assessments include the following and will be performed for both eyes at
specified timepoints according 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 4)

Pre-treatment IOP measurement of both eyes (perform prior to dilating eyes)

Slitlamp examination (for grading scales for anterior and vitreous cells, see
Appendix 3)

Dilated binocular indirect high-magnification ophthalmoscopy

Finger-counting test followed by hand motion and light perception tests (when 
necessary) performed within approximately 15 minutes of post-study treatment in
the study eye only by the unmasked treatment administrator.

At study treatment visits, post-treatment IOP measurement in the study eye only at 
30 (15) minutes by qualified personnel assigned to the unmasked role. If there are 
no safety concerns after 30 (15) minutes following the study treatment, the patient 
will be permitted to leave the clinic.  If the IOP value is of concern to the treatment 
administrator, the patient will remain in the clinic and will be managed in accordance 
with this physician clinical judgment. The adverse event will be recorded on the 
Adverse Event eCRF as applicable. 
The method of IOP measurement used for a patient must remain consistent throughout 
the study.
Ocular Imaging 
The CRC(s) will provide sites with the CRC(s) manual and training materials for 
specified study ocular images.  Before any study images are obtained, site personnel, 
test images, systems and software (where applicable) will be certified and validated by 
the CRC(s) as specified in the CRC manual.  All ocular images results will be obtained 
by trained site personnel at the study sites and forwarded to the CRC(s) for independent 
analysis and/or storage (see Appendix 5, Appendix 6, and Appendix 7).
Note: After randomization, if a patient misses a study visit when ocular 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), they should be obtained at the next scheduled visit
the patient attends.
Ocular images include the following:

Mandatory CFP (7- or 4-wide fields; perform one of these methods for the patient 
consistently throughout the trial participation) of both eyes

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
FFA (preferred method is UWF (Optos) FFA if sites have capability; the sites 
without UWF (Optos) FFA to capture 7 or 4-wide fields using the same method 
consistently throughout the trial participation) of both eyes (if applicable, 
performed after blood samples are obtained)

SD-OCT or swept-source OCT (SS-OCT) images of both eyes
Certain SS-OCT machines may be acceptable; consult the CRC.  

Optional OCT-angiography (OCT-A) of both eyes at sites with OCT-A capabilities
and agreement by sites to take these images
Additional details on obtaining these images are included in the CRC manual.
4.5.6
Concurrent Ocular Procedures
Any ocular procedures performed on either eye during the study (from Day 1, post study 
treatment) will be recorded on the Concurrent Ocular Procedures Log on the eCRF.
4.5.7
Laboratory, Biomarker, and Other Biological Samples
At the scheduled visit, all samples must be obtained prior to study treatment and blood 
samples must be obtained prior to FFA assessments (if applicable).  Fasting is not
required prior to specimen collection.  The specimens will be forwarded to the central 
laboratory.  The central laboratory will either perform the analysis or forward samples to
the Sponsor or its designee for analysis and/or storage. Instructions for obtaining, 
processing, storing, and shipping of all specimens are provided in the laboratory manual.  
Laboratory supply kits will be provided to the sites by the central laboratory.  See 
Appendix 1 for sample collection timepoints and Appendix 8 for biological sample 
collection and shipping instructions.  
All samples obtained during screening from patients who are not randomized will be 
discarded. 
The following assessments will be performed:

Hematology:  hemoglobin, hematocrit, quantitative platelet count, RBC counts, WBC
counts, and differentials, including neutrophils, bands, lymphocytes, basophils, 
eosinophils, and monocytes (absolute)

Serum chemistry:  sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen, creatinine, calcium, phosphorus, total and direct bilirubin, total protein, 
albumin, ALP, AST, ALT, and uric acid

Urinalysis:  specific gravity, pH, blood, protein, ketones, glucose, bilirubin, 
urobilinogen, and microscopic examination (if any of the preceding urinalysis tests, 
other than glucose and ketones, are abnormal)

Coagulation:  activated partial thromboplastin time and prothrombin time
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
Urine pregnancy test at screening and 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. 

HbA1c

Plasma samples for measurement of anti-faricimab antibodies

Plasma samples to measure faricimab or aflibercept concentration (PK sample)

Unless the patient gives specific consent for his or her leftover plasma samples to be 
stored for optional exploratory research (see Section 4.5.9.1), the samples will be 
destroyed no later than 5 years after the final Clinical Study Report has been completed.  
The hematology, serum chemistry, urinalysis, coagulation, serum, urine pregnancy tests,
and HbA1c samples will be destroyed after their analysis during the study.
Drug concentration, 
will be determined in plasma using a 
validated immunoassay method.  Anti-drug antibodies (ADAs) will be detected in plasma
.
4.5.7.1
Optional Aqueous Humor and Optional Plasma Samples
Collection and submission of optional aqueous humor and optional plasma samples is
contingent upon 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 4.5.7.1) will not be applicable at that site. 
For patients who consent to provide aqueous humor sampling, the aqueous humor 
sample should be collected just prior to study treatment (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 lab manual for aqueous samples collection, storage, and transfer). 
All efforts should be made to obtain a baseline aqueous humor sample on Day 1 (pre-
dose).  The schedule of activities (see Appendix 1) provides guidance on recommended 
visits at which aqueous humor samples should be obtained.  Patients who are 
prematurely discontinued from study treatment but who agree to continue to participate 
in the study should discontinue collection of optional aqueous humor samples and any 
associated optional plasma samples.  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 or aflibercept,
 Data from these analyses will be used to develop better
predictive models for determining optimal patient treatment interval(s) and to support 
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selection of a dosing regimen for future clinical trials. Remaining samples will be 
analyzed for additional biomarkers, including those involved in angiogenesis 
 
 
 and inflammation 
 
to identify new therapeutic targets, better understand variability in patient 
responses to faricimab, and to support patient selection and/or stratification in future 
clinical trials.
At Day 7 and Week 32, sites will collect optional PK plasma samples for measurement 
of faricimab or aflibercept  concentration and optional PD plasma sample for  analysis 
of systemic
(see Appendix 1 and the Covance manual for 
PK/PD samples collection, storage, and transfer).
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.9.1), biological samples will be destroyed 
no later than 5 years after the final Clinical Study Report has been completed.
4.5.7.2
Optional Unscheduled Collection of Vitreous and Optional PK 
Samples
Elective vitrectomy for vitreous sample collection is not allowed in the study eye during a 
patient's study participation; however, if the surgery is medically necessary and the 
patient consents, a vitreous sample can be obtained from the study eye (see Appendix 8
for further details).  Associated PK plasma samples will be collected to measure faricimab 
or aflibercept concentration.  See the Covance manual for vitreous and PK sample 
collection, storage, and transfer.
Vitreous humor samples will be analyzed primarily for faricimab or aflibercept 
concentrations.  The remaining samples may be analyzed for
, as well as additional biomarkers, including those involved in 
angiogenesis 
 
 and inflammation 
 
 to identify new therapeutic targets, 
better understand variability in patient responses to faricimab, and to support patient 
selection and/or stratification in future clinical trials.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.9.5), biological samples will be destroyed 
no later than 5 years after the final Clinical Study Report has been completed.
4.5.8
Patient-Reported Outcomes
PROs will be assessed using the National Eye Institute Visual Functioning
Questionnaire25 (NEI VFQ-25) (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 
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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. 
The NEI VFQ-25 will be interviewer administered by the masked site staff (except for the 
VA examiner) prior to any other visit assessments being performed. Interviews will be 
conducted in the local language of the patient using linguistically validated translations.  
Patients may be excluded from completing the NEI VFQ-25 if a translation is not 
available in their spoken language. 
4.5.9
Optional Samples for Research Biosample Repository
4.5.9.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR specimens will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.9.2
Approval by the Institutional Review Board or 
Ethics Committee
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's IRB or EC and, if applicable, an appropriate regulatory 
body.  If a site has not been granted approval for RBR sampling, this section of the 
protocol (Section 4.5.9) will not be applicable at that site. The RBR portion of the
Informed Consent Form has to be agreed to and signed by the consenting patient before 
these samples can be collected and/or mandatory residual samples used. 
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4.5.9.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to response to faricimab, to 
improve the understanding of the biology of VEGF-A and Ang-2, or to better understand 
the targets or diseases (DR and DME):

Whole blood sample for DNA 

Residual aqueous humor sample

Residual vitreous sample

Residual plasma PD sample

Residual PK sample

Residual ADA sample
The whole blood sample for DNA may be sent to one or more laboratories for analysis
via WGS, next-generation sequencing, or other genomic analysis methods. 
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and exome,
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches.  Data will be analyzed in the 
context of this study but will also be explored in aggregate with data from other studies.  
The availability of a larger dataset will assist in identification of important pathways, 
guiding the development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  For all samples, the dates of consent should be recorded on the 
associated RBR eCRF.
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.9.4
Confidentiality
Specimens and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR specimens, data 
derived from these analyses will generally not be provided to study investigators or 
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patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.9.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research.
4.5.9.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR specimens have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining 
samples will be destroyed or will no longer be linked to the patient.  However, if RBR
specimens have been tested prior to withdrawal of consent, results from those tests will 
remain as part of the overall research data.  If a patient wishes to withdraw consent to 
the testing of his or her specimens, the investigator must inform the Medical Monitor in 
writing of the patient's wishes through use of the appropriate RBR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RBR Research 
Sample Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent 
to the testing of his or her RBR samples after closure of the site, the investigator must 
inform the Sponsor by emailing the study number and patient number to the following 
email address:
global_rcr-withdrawal@roche.com
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A patient's withdrawal from Study GR40398 does not, by itself, constitute withdrawal of 
specimens from the RBR.  Likewise, a patient's withdrawal from the RBR does not 
constitute withdrawal from Study GR40398.
4.5.9.7
Monitoring and Oversight
RBR specimens will be tracked in a manner consistent with Good Clinical Practice (GCP)
by a quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Occurrence of any medical condition that the investigator or Sponsor determines 
may jeopardize the patient’s safety if he or she continues to receive study treatment

Investigator or Sponsor determines it is in the best interest of the patient

Pregnancy
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. Patients who discontinue study treatment prematurely will not be 
replaced and will not be allowed to restart study treatment. However, they should be 
strongly encouraged to continue their study participation and undergo as many 
scheduled visits as possible, with emphasis on the Week 48, 52, 56, and 100 visits. 
4.6.2
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator and Sponsor have the right to withdraw a patient from the 
study at any time.  Reasons for withdrawal from the study may include, but are not 
limited to, the following:

Patient withdrawal of consent

Study termination or site closure

Any medical condition that the investigator determines may jeopardize the patient’s 
safety if he or she continues in the study 

Investigator or Sponsor determines it is in the best interest of the patient 
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
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.
If a patient discontinues from the study but has not withdrawn informed consent, the site 
should make every effort to continue to follow-up on serious adverse events, deaths, and 
adverse events of special interest.  In order to avoid loss to follow-up, the investigator 
should ask the patient at the study start for the contact information of a relative or friend 
who can be contacted in case the patient cannot be reached.  However, patients will not 
be followed for any reason after consent has been withdrawn. If a patient requests to be 
withdrawn from the study, this request must be documented in the source documents 
and signed by the investigator.  Patients who withdraw from the study will not be 
replaced.
Patients who discontinue from the study early but have not withdrawn consent should 
return for an early termination visit (see Appendix 1) after a minimum of 28 days have
elapsed following the last study treatment.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline 
for GCP

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
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5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Faricimab is not approved, and clinical development is ongoing.  The safety plan for 
patients in this study is based on clinical experience with faricimab in completed and 
ongoing studies. Please refer to the RO6867461 (faricimab) Investigator's Brochure for
a complete summary of safety information
5.1.1
Safety Assessments
The schedule of safety assessments to be performed during the study is provided in 
Appendix 1. After the first study treatment on Day 1, all patients will return for a safety 
assessment visit on Day 7 (3 days).  Patients will be instructed to contact the site at 
any time if they have any health-related concerns.  If warranted, patients will be asked to 
return to the clinic as soon as possible for an unscheduled safety assessment visit 
(see Appendix 2).
At sites where the masked investigator’s decision is for patients to receive pre- and 
post-injection antimicrobials, patients will also be asked whether they have taken the 
prescribed, self-administered, pre- and/or post-injection antimicrobials.  
A finger-counting test will be conducted for each patient within approximately 15 minutes 
following study treatment by the treatment administrator; hand motion and light 
perception tests will be performed when necessary.  
Following the study treatment, IOP will be measured in the study eye only at 
30 (15) minutes by qualified personnel assigned to the unmasked role. If there are no 
safety concerns after 30 (15) minutes following study treatment, the patient will be 
permitted to leave the clinic.  If the IOP value is of concern to the treatment administrator, 
the patient will remain in the clinic and will be managed in accordance with this physician
clinical judgment. The adverse event will be recorded on the Adverse Event eCRF as 
applicable.  
Note: If an anti-VEGF injection is administered to the nonstudy (fellow) eye at the 
same visit as the study eye study treatment (faricimab, aflibercept, or sham), the study 
eye treatment must be performed first (see Section 4.4.1 for additional details). 
Detailed ocular examinations, including indirect ophthalmoscopy and slitlamp 
examination, will be performed throughout the study. Blood samples for plasma study 
drug concentrations, antibodies to faricimab, and other biomarker samples (see 
Section 4.5.6 ) will be obtained from all patients at selected timepoints.  The optional 
aqueous humor and vitreous samples will be obtained from patients who consent to the
procedure and sample collection.
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An iDMC will monitor safety and study conduct on an ongoing basis (see Section 3.1.6
for additional details).
Patients who are discontinuing from the study prior to completion (Week 100) will be
asked to return for early termination visit assessments after a minimum of 28 days have 
elapsed following the last study treatment (see Appendix 1).  The visit will include 
assessment of all adverse events (serious and non-serious; ocular and non-ocular).  
Serious adverse events will be reported in compliance with GCP guidelines.
Treatment interruption and/or treatment discontinuation for adverse events will be 
determined using the criteria in Section 5.1.4.1, Table 2
5.1.2
Risks Associated with Faricimab
To date, no identified risks for faricimab have been observed.
Based on experience with aflibercept and other anti-VEGF therapies, potential risks of 
faricimab include intraocular inflammation, the intravitreal injection-related risks of 
infectious endophthalmitis, retinal detachment/tear, iatrogenic traumatic cataracts and
increased IOP, as well as the non-ocular risk of arterial thromboembolic events.  An
independent clinical events coding committee will be established to adjudicate 
thromboembolic events (myocardial infarcts, strokes, and deaths) reported during the 
study.
Please see the RO6867461 (faricimab) Investigator's Brochure for more details on the
risks of faricimab.
5.1.3
Risks Associated with Aflibercept (Comparator)
Important risks associated with aflibercept IVT injections are conjunctival hemorrhage, 
eye pain, reduced vision, endophthalmitis, intraocular inflammation, increased 
intraocular pressure, rhegmatogenous retinal detachment, retinal tear, and iatrogenic 
traumatic cataract.  Important potential risks associated with aflibercept treatment 
include arterial thromboembolic events and immunogenicity.
For full detail on risks associated with aflibercept, please see the Eylea® (aflibercept) 
Summary of Product Characteristics.
5.1.4
Management of Patients Who Experience Adverse Events
5.1.4.1
Treatment Interruption:  Dose Interruption and 
Treatment Discontinuation Criteria
Study treatment interruption and/or patient discontinuation from the study treatment for 
adverse events will be determined using the criteria listed in Table 2. If any of these 
criteria are met, treatment will be interrupted (or discontinued, if applicable) and will not 
be resumed earlier than the next scheduled study visit. The reason for study treatment 
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interruption/discontinuation should be recorded on the appropriate eCRF and, if 
applicable, on the Adverse Event eCRF.
Table 2
Dose Interruption and Treatment Discontinuation Criteria
Event
Criteria
Intraocular inflammation

Interrupt study treatment if intraocular 
inflammation (iritis, iridocyclitis or vitritis)
is 2in the study eye.  

Study treatment may be resumed 
subsequently as determined by the 
investigator 
Cataract surgery in the study eye

Interrupt study treatment after cataract 
surgery in study eye.  

Study treatment may be resumed no 
earlier than 28 days after an 
uncomplicated cataract surgery and no 
evidence of post-operational inflammation
at that time.  For cataract surgery with 
complications, study treatment may be 
permitted as determined by Medical 
Monitor and investigator.  
BCVA decrease

Interrupt study treatment if there is a study 
treatmentrelated decrease in BCVA of
30 letters in the study eye compared with 
the last assessment of BCVA prior to the 
most recent treatment.  

Study treatment may be permitted 
subsequently, as determined by the 
investigator.
Elevated IOP

Interrupt study treatment if 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 study treatment if a retinal break 
is present in the study eye.  

Study treatment may be resumed no 
earlier than 28 days after successful laser 
retinopexy, as determined by the 
investigator.
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Table 2
Dose Interruption and Treatment Discontinuation Criteria (cont.)
Event
Criteria
Rhegmatogenous retinal detachment or 
macular hole

Interrupt study treatment if 
rhegmatogenous retinal detachment or 
Stage 3 or 4 macular hole occurs in the 
study eye.

Study treatment may be subsequently 
permitted after discussion with Medical 
Monitor.  
Active or suspected infection

Interrupt study treatment if active or 
suspected ocular or periocular infections 
are present (e.g., infectious conjunctivitis, 
infectious keratitis, infectious scleritis, or 
endophthalmitis) in either eye 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 study treatment 
discontinuation.
BCVAbest-corrected visual acuity; IOPintraocular pressure.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for GCP, an adverse event is any untoward medical 
occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution.  An adverse event can therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.8
and 5.3.5.9 for more information)
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
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 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to the Adverse 
Event Grading Scale; see Section 5.3.3, Table 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 site staff to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
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5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.6)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

Sight-threatening adverse events:  an adverse event is considered to be 
sight-threatening and should be reported expeditiously if it meets one or more of the 
following criteria:
–
It causes a decrease of 30 letters in VA score (compared with the last 
assessment of VA prior to the most recent assessment) lasting more than 
1 hour.
–
It requires surgical or medical intervention (i.e., conventional surgery, 
vitrectomy, vitreous tap, or biopsy with IVT injection of anti-infective treatments, 
or laser or retinal cryopexy with gas, or a medication) to prevent permanent loss 
of sight.
–
It is associated with severe intraocular inflammation (i.e., endophthalmitis, 
4anterior chamber cell/flare, or 4vitritis; see Section 5.3.5 and Appendix 3 for 
intraocular inflammation grading scales).
All of the above listed sight-threatening adverse events should be reported as serious 
adverse events, listing the underlying cause (if known) of the event as the primary 
event term.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigators 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
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during or shortly after study treatment, the unmasked investigator may assess the 
seriousness and severity of the event, but event causality will be assessed by the 
investigator who is in the masked role. 
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until the final study visit 
at Week 100. For patients who terminate study treatment and from the study early, all 
adverse events will be reported up to the early termination visit. For patients who 
discontinue study treatment early (prior to Week 96 treatment) but continue to participate 
in the study, adverse events will be reported until their last or final study visit.  
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
Table 3 provides guidance for assessing adverse event severity.
Table 3
Adverse Event Severity Grading Scale
Severity
Description
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating with inability to work or to perform normal daily activity
Note:  Regardless of severity, some events may also meet seriousness criteria.  
Refer to definition of a serious adverse event (see Section 5.2.2).
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5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (see also 
Table 4).  Note: Only the masked investigator will assess all adverse event causality.

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event
Table 4
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
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For the purposes of reporting events of infection and inflammation, 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, aqueous pigmented cells visible on slitlamp examination that are 
caused by dilation and are not RBCs or WBCs or the result of any ocular disorder should 
not be recorded as an adverse event.
5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.2
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.
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
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
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If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP 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.
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).
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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 screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study. When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
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5.3.5.9
Worsening of Diabetic Macular Edema or Diabetic Retinopathy
in the Study Eye
Medical occurrences or symptoms of deterioration that are anticipated as part of study 
eye DME or DR should be recorded as an adverse event if judged by the investigator to 
have unexpectedly worsened in severity or frequency or changed in nature at any time
during the study.  When recording an unanticipated worsening of DME or DR on the 
Adverse Event eCRF, it is important to convey the concept that the condition has 
changed by including applicable descriptors (e.g., "accelerated worsening of diabetic 
macular edema").  The expedited reporting requirements for associated sight threatening 
events (listed in the Section 5.2.3) will apply.  
5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.11
Adverse Events Associated with an Overdose or Error in 
Drug Administration
No safety data related to overdosing of faricimab are available.
5.3.5.12
Reporting Requirements for Cases of Medication Error and 
Associated Adverse Events
Medication Error Definition and Reporting
Medication error, including the error intercepted prior to administration and accidental 
overdose (hereafter collectively referred to as "special situations"), are defined as 
follows: 

Medication error is accidental deviation in the administration of a drug.  In some 
cases, a medication error may be intercepted prior to administration of the drug.
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
Accidental overdose is accidental administration of a drug in a quantity that is 
higher than the assigned dose. 
Special situations are not in themselves adverse events but may result in adverse 
events.  All special situations associated with the masked study treatment, regardless of 
whether they result in an adverse event, should be recorded on the Adverse Event eCRF 
in masked manner as described below:
For medication error, enter “Medication Error” on the Adverse Event eCRF as 
the primary event term and check the “Medication error” box (see eCRF 
Completion Guidelines for additional details).
For intercepted medication error enter “Intercepted Medication Error” on the 
Adverse Event eCRF as the primary event term and check the “Medication 
error” box (see eCRF Completion Guidelines for additional details).
Reporting of Adverse Events Resulting from Special Situation
Each adverse event associated with a special situation should be recorded separately on 
the Adverse Event eCRF.  If the associated adverse event fulfills seriousness criteria 
(see Section 5.2.2) or it is adverse event of special interest (see Section 5.2.3), the event 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).   Adverse events associated with special 
situations should be recorded as described below:

Enter the adverse event caused by the medication error as primary adverse event 
term on Adverse Event eCRF.  Check the "Medication error" box.
As an example, a special situation that resulted in a headache would require two entries 
on the Adverse Event eCRF, one entry to report the medication error and one entry to 
report the headache.  The “Medication error" box would need to be checked for both 
entries.
5.3.5.13
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.
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5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for Western Hemisphere
Medical Monitor/Roche Medical Responsible:
, M.D., Ph.D.
Mobile Telephone No.:
Medical Monitor Contact Information for Eastern Hemisphere
Medical Monitor/Roche Medical Responsible:
, MB, Ch.B.
Telephone No.:
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
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7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events, and adverse events of special 
interest will be reported until the final study visit at Week 100. 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 to immediately inform the 
investigator if they become pregnant during the study or within 3 months after the last
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 
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discontinue study drug and counsel the patient, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy
becomes available.  
5.4.3.2
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal 
or embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
5.4.3.3
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source 
data verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
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5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE 
ADVERSE EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (see
definition in Section 5.3.1) if the event is believed to be related to prior study drug 
treatment. 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 using the following reference document for 
IMPs:

RO6867461 (faricimab) Investigator's Brochure

Aflibercept (Eylea) E.U. Summary of Product Characteristics
The Sponsor will compare the severity of each event and the cumulative event
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
Approximately 900 patients will be randomized in the global enrollment phase of this 
study. 
 
 
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The primary analyses of this study will include patients enrolled during the global 
enrollment phase; 
 
The primary analyses will be performed when all patients from the global enrollment 
phase have either completed the study through Week 56 or have discontinued from the 
study prior to Week 56, whichever comes later (i.e., timing is defined as the primary 
analysis after the LPLV), and all data collected prior to the primary LPLV in the global 
enrollment phase are in the database and have been cleaned and verified.
Results of the primary analyses, summarized by treatment group, may be reported to the 
public before completion of the study. However, patients, masked study site personnel, 
and CRC personnel will remain masked to individual treatment assignment until the 
study is completed, the database is locked, and the study analyses are final.
The final analysis will be performed when all patients from the global enrollment phase 
have either completed the study through Week 100 or have discontinued early from the 
study, all data from the global enrollment phase are in the database, and the database is 
locked.
Unless otherwise specified, the analyses described in this section are based on patients 
enrolled during the global enrollment phase 
. Details of 
the planned analyses, including any additional analyses needed to support 
country-specific or regional marketing applications, will be provided in the Statistical 
Analysis Plan. 
6.1
DETERMINATION OF SAMPLE SIZE
Determination of sample size is based on patients enrolled in the global enrollment 
phase. The global enrollment phase will enroll approximately 900 patients. Patients will 
be randomized in a 1:1:1 ratio to receive treatment with faricimab Q8W (Arm A), 
faricimab PTI (Arm B), or aflibercept Q8W (Arm C). The primary comparisons will be the 
pairwise comparisons between the active comparator (aflibercept Q8W) and each of the 
faricimab arms (Q8W and PTI). 
A sample size of approximately 300 patients in each arm will provide greater than 90% 
power to show non-inferiority of faricimab to aflibercept (pairwise comparisons between 
the active comparator and each of the faricimab arms) in the ITT population, using a 
non-inferiority margin of 4 letters and under the following assumptions:

Standard deviation (SD) of 11 letters for the change from baseline in BCVA 
averaged over Week 48, Week 52, and Week 56

Two-sample t-test

1.25% one-sided type I error rate

10% dropout rate
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Assuming 75%90% of patients recruited will be treatment naive, approximately 
225270 treatment-naive patients will be enrolled per arm. A sample size of 225270 
patients per arm will provide greater than 80% power to show a 3.5-letter superiority of 
faricimab over aflibercept (pairwise comparisons between the active comparator and 
each of the faricimab arms) in the treatment-naive population, using the same SD, test,
and dropout assumptions above, and a two-sided type I error rate of 2.5%.
Furthermore, a sample size of approximately 300 patients per arm will provide greater 
than 80% power to show a 3-letter superiority of faricimab over aflibercept (pairwise 
comparisons between the active comparator and each of the faricimab arms) in the ITT
population, under the same SD, test, and dropout assumptions above, and a two-sided 
type I error rate of 2.5%.
The sample size may be adjusted as appropriate, based on a masked assessment of the 
pooled SD of the change in BCVA from baseline.  The assessment will be performed by 
the Sponsor at a specified timepoint prior to completing enrollment.  Details on the 
masked sample size re-estimation conducted, as well as actions and decisions made 
regarding changes in sample size will be documented in the Statistical Analysis Plan. 
The Sponsor will remain masked.  Other factors external to the study may also trigger a 
decision to modify the sample size. 
 
 
6.2
ANALYSIS POPULATIONS
The analysis populations used in this section, such as the ITT population, are based on 
patients enrolled during the global enrollment phase and will not include the 
 unless otherwise specified.
6.2.1
Intent-to-Treat Population
The ITT population will comprise all patients who are randomized in the study. For 
analyses based on this patient population, patients will be grouped according to the 
treatment assigned at randomization.
6.2.2
Treatment-Naive Population
The treatment-naive population is defined as all patients randomized in the study who 
have not received any IVT anti-VEGF agents in the study eye prior to Day 1. For 
analyses based on this patient population, patients will be grouped according to the 
treatment assigned at randomization.
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6.2.3
Per-Protocol Population
The per-protocol population is defined as all patients randomized in the study who 
receive at least one dose of study treatment and who do not have a major protocol 
violation. For analyses based on this patient population, patients will be grouped 
according to the treatment assigned at randomization.
6.2.4
Safety-Evaluable Population
The safety-evaluable population will comprise all patients who receive at least one 
injection of active study treatment (faricimab or aflibercept).  For analyses based on this 
patient population, patients will be grouped according to the actual treatment received up 
to the Week 56 visit as follows.

If the only active treatment received by a patient in the study eye is aflibercept, the 
patient’s treatment group will be aflibercept Q8W. 

If the only active treatment received by a patient in the study eye is faricimab, the 
patient’s treatment group will be as randomized if the patient is randomized to one 
of the faricimab arms; otherwise, the patient’s treatment group will be faricimab
Q8W. 

If a patient received a combination of different active treatments (faricimab and 
aflibercept) in the study eye, the patient’s treatment group will be as randomized.
6.2.5
Pharmacokinetic-Evaluable Population
The PK analyses will include safety-evaluable patients who have at least one plasma 
sample, and if sufficient dosing information (dose and dosing time) is available, with 
patients grouped according to treatment received (as defined in the previous section). 
6.2.6
Immunogenicity-Analysis population
The immunogenicity analysis population will consist of all patients with at least one 
plasma sample for anti-drug antibody assessment.  Patients will be grouped according to 
treatment received or, if no treatment is received prior to study discontinuation, 
according to treatment assigned.
6.3
SUMMARIES OF CONDUCT OF STUDY
Summaries of conduct of study will be based on the ITT population.
The number of patients randomized will be tabulated by country, site, and treatment arm. 
Patient disposition (the number of patients randomized, treated, and completing through 
the primary endpoint timing, as well as of end of study) will be tabulated by treatment 
arm. Premature study drug discontinuation and study discontinuation, as well as
reasons for discontinuations, will be summarized. Eligibility criteria exceptions and other 
major protocol deviations will be summarized by treatment arm.
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6.4
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics such as age, sex, race/ethnicity, region, 
baseline vital sign measurements, laboratory test results, and baseline disease 
characteristics (such as, baseline BCVA, ocular assessments, and medical history) will 
be summarized by treatment as assigned for the ITT population using means, SDs, 
medians, and ranges for continuous variables, and counts and proportions for 
categorical variables, as appropriate.
Exposure to study drug (number of treatments and duration of treatment) will be 
summarized by treatment arm for the safety-evaluable population.
6.5
EFFICACY ANALYSES
The primary and secondary efficacy analyses will be based on the ITT population and 
the treatment-naive population, unless otherwise specified. For both the ITT population
and the treatment-naive population, patients will be grouped according to the treatment 
assigned at randomization. Additional analyses based on the per-protocol population 
will also be conducted for the primary and the key secondary endpoints.
The primary comparisons will be the pairwise comparisons between the active 
comparator (aflibercept Q8W) and each of the faricimab arms (Q8W and PTI).
Continuous outcomes will be analyzed using a MMRM model. Binary secondary 
endpoints will be analyzed using stratified estimation for binomial proportions. Additional 
details are provided in Sections 6.5.1 and 6.5.2.
6.5.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline in BCVA averaged over 
Weeks 48, 52, and 56. The BCVA outcome measure is based on the ETDRS VA chart 
assessed at a starting distance of 4 meters. 
The primary comparisons will be the pairwise comparisons between the active 
comparator (aflibercept Q8W) and each of the faricimab arms (Q8W and PTI). Additional 
analyses based on the per-protocol population will also be conducted.
For the two faricimab arms (Q8W and PTI), the following three hypotheses will be tested
for each treatment group separately at an overall significance level of 0.05 using a 
graph-based testing procedure (Bretz et al. 2009, 2011) to control for the overall type I 
error rate:

Non-inferiority of faricimab compared with aflibercept Q8W in the ITT population

Superiority of faricimab compared with aflibercept Q8W in the 
treatment-naive population

Superiority of faricimab compared with aflibercept Q8W in the ITT population
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The order in which hypothesis tests for the primary endpoint will be performed is 
illustrated in Figure 3, with arrows denoting the direction of -propagation. If the tests for 
one treatment sequence are all positive, then /2 will be propagated to the beginning of 
the other treatment sequence, which will be tested at a significance level of 0.05.
Of note, non-inferiority will be tested one sided at half of the designated significance 
level shown in Figure 3.
Figure 3
Graph-Based Testing Procedure for the Primary Endpoint
PTIpersonalized treatment interval; Q8W every 8 weeks.
Note: 0.05.
The non-inferiority tests for the faricimab Q8W arm and the faricimab PTI arm compared 
with aflibercept Q8W arm will be conducted with a non-inferiority margin of 4 letters. For 
each faricimab group (Q8W or PTI) the null hypothesis, 
H0: faricimabaflibercept 4 letters, and the alternative hypothesis, 
Ha: faricimabaflibercept 4 letters, will be tested, for which faricimab and aflibercept are the
expected change from baseline in BCVA averaged over Weeks 48, 52, and 56 for the 
treatment group in question (faricimab Q8W or PTI) and the active comparator 
(aflibercept Q8W), respectively.
The change from baseline averaged over Weeks 48, 52, and 56 will be compared 
between each faricimab arm and the aflibercept Q8W arm using a MMRM model. The 
model will include the change from baseline at Weeks 456 as the response variables 
and will include the categorical covariates of treatment group, visit, visit-by-treatment 
group interaction, the continuous baseline value for the response variable (in this case, 
baseline BCVA), as well as randomization stratification factors as fixed effects. 
Comparisons between each faricimab arm and the aflibercept Q8W arm will be made 
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using a composite contrast over Weeks 48, 52, and 56. The MMRM model will assume 
an unstructured covariance structure. If there are convergence problems with the model, 
then a heterogeneous compound symmetry or an AR(1) covariance structure may be 
fitted.
Missing data will be implicitly imputed using the MMRM model, assuming a missing at
random missing data mechanism (i.e., the probability that missing data are dependent 
on other observed variables but not on the missing data). Data for patients who receive 
prohibited therapy will be censored at the timing of use of prohibited therapy. Data for 
patients who discontinue from study drug and do not receive any prohibited therapy after 
discontinuation of study drug will be included in the analysis.
Additional details about the planned analyses, as well as sensitivity analyses using other 
imputation methods for missing data, sensitivity analysis using the trimmed mean 
approach for patients who receive prohibited therapy or discontinue study drug due to 
lack of efficacy or adverse events, sensitivity analyses of the per-protocol population,
and subgroup analyses to assess the robustness of the primary endpoint results will be 
provided in the Statistical Analysis Plan.
Non-Inferiority Margin
Non-inferiority hypothesis testing for the primary endpoint of the change from baseline in 
BCVA averaged over Weeks 48, 52, and 56 will be performed using a 4-letter 
non-inferiority margin based on the VISTA and VIVID aflibercept pivotal DME studies.  
These studies compared aflibercept to laser control.  The 4-letter non-inferiority margin 
also preserves approximately 50% of the least estimated benefit of aflibercept over 
control in both VISTA and VIVID studies individually.
The VISTA study randomized 466 patients in the United States and the VIVID study 
randomized 406 patients in Europe, Japan, and Australia. At Week 52, in VISTA, 
patients receiving 2 mg of aflibercept Q8W gained 10.7 letters from baseline compared 
with 0.2 letters for patients in the control arm. The corresponding results from the VIVID
study were a gain of 10.7 letters for aflibercept versus 1.2 letters for the control arm.
The non-inferiority margin should be small enough to allow a conclusion that the new 
treatment is not inferior to the active control to an unacceptable extent on the basis of a
combination of clinical judgment and statistical reasoning. From a clinical perspective, 
the non-inferiority margin should be fewer than 5 letters given that a loss of 5 letters (one 
ETDRS line) between treatments would be considered clinically relevant.
6.5.2
Secondary Efficacy Endpoints
The key secondary endpoint is the proportion of patients with a 2-step improvement in 
DR severity from baseline on the ETDRS DRSS at Week 52.
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Additional secondary endpoints are listed in Section 2, Table 1. For all secondary 
endpoints measured on a continuous scale, the same analysis method and data 
handling rules as described in Section 6.5.1 for the primary endpoint will be used. For 
binary secondary endpoints, the proportion of patients in each treatment group and the 
overall difference in proportions between treatment groups will be estimated using the 
weighted average of the observed proportions and the differences in observed 
proportions over the strata defined by randomization factors using the Cochran-Mantel-
Haenszel weights (Cochran 1954; Mantel and Haenszel 1959).  CIs of the proportion of 
patients in each treatment group and the overall difference in proportions between 
treatment groups will be calculated using the normal approximation to the weighted 
proportions (Mehrota and Railkar 2000). Superiority will be assessed, as appropriate,
using a Cochran-Mantel-Haenszel test stratified by the randomization stratification 
factors.
All secondary endpoints will be assessed at 1 year and at additional timepoints over time 
during the study. For the purpose of analysis, the definition of 1 year is the average of 
the Week 48, 52, and 56 visits.
Additional details regarding the plan for the secondary endpoint analyses will be
provided in the Statistical Analysis Plan.
6.5.3
Exploratory Efficacy Endpoints
Details regarding the exploratory efficacy endpoints will be provided in the Statistical 
Analysis Plan.
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6.6
SAFETY ANALYSES
Safety analyses will be based on the safety-evaluable population.
Safety will be assessed through descriptive summary of ocular and systemic (non-ocular)
adverse events, deaths, and ocular assessments (e.g., IOP). Clinically significant 
laboratory abnormalities and clinically significant vital sign abnormalities will be reported 
as adverse events and evaluated as part of the adverse event assessments.
At the time of the primary analysis, safety summaries will be summarized based on the 
complete Week 56 data in the safety-evaluable population. In addition, summaries for 
ongoing safety data (after Week 56 and up to a single specified clinical cutoff date) in the 
safety-evaluable population will also be summarized. At the time of the final analysis, 
safety summaries will be produced based on cumulative Week 100 data in the 
safety-evaluable population.
Verbatim descriptions of treatment-emergent adverse events will be mapped to Medical 
Dictionary for Regulatory Activities (MedDRA) thesaurus terms, and their incidence and 
severity will be summarized by treatment arm. A treatment-emergent adverse event is
defined as any new adverse event reported or any worsening of an existing condition on
or after the first dose of study drug. Adverse events will be tabulated by System Organ 
Class and preferred term.  In addition, summaries will be generated for serious adverse 
events, deaths, adverse events leading to discontinuation of study drug, adverse events 
of special interest, and adverse events judged to be related to study treatment.
Separate summaries will be prepared for systemic (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 baseline in pre-dose IOP 
measurements and changes between pre-dose and post-dose IOP measurements will 
also be summarized. 
Additional details regarding the safety analysis plan will be provided in the Statistical 
Analysis Plan.
6.7
PHARMACOKINETIC ANALYSES
PK analyses will be performed in the PK-evaluable population. 
A non-linear mixed-effects modeling approach (with NONMEM software [Beal and 
Sheiner 1998]) will be used to analyze the concentrationtime data for faricimab and
aflibercept. Population and individual primary PK parameters (i.e., clearances and 
volumes) will be estimated. The plasma data collected in this study may be pooled with 
aqueous humor drug concentrations and with data collected in previous studies as 
appropriate to update the current population-PK model. The model may be revised if 
necessary. A covariate modeling approach emphasizing parameter estimation will be 
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implemented for the covariate model development. Potential covariateparameter
relationships will be identified based on mechanistic plausibility and exploratory graphics.  
Inferences about covariate effects and their clinical relevance will be based on the 
resulting parameter estimates and measures of estimation precision (asymptotic 
standard errors). PK parameters such as area under the concentrationtime curve and 
maximum concentration will be derived from the individual post-hoc predictions.
The result of this analysis will be reported in a separate document from the Clinical 
Study Report. 
6.8
PHARMACODYNAMIC ANALYSES
PD analyses will be based on the safety-evaluable population.  PD biomarkers and the 
change from baseline values (absolute or percent change as appropriate) will be 
summarized by treatment arm and timepoint. 
The data collected from this study may be pooled with data from previous studies.  The 
effect of exposure or dosing information on BCVA, aqueous humor
will be explored using a longitudinal model approach.  The influence of
various baseline covariates on model parameters will be investigated. The PKPD or 
dosePD relationship will be characterized. Additional PD markers, such as anatomical 
endpoints, may be included. Additional details about the PK and PD analyses will be 
provided in the Modeling Analysis Plan. The results will be reported in a separate 
document from the Clinical Study Report.
6.9
IMMUNOGENICITY ANALYSES
Immunogenicity analyses will be based on the immunogenicity analysis population.
The number and proportion of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after drug administration (post-baseline incidence) 
will be summarized by treatment group.  When determining the post-baseline incidence, 
patients will considered to be ADA positive if they are ADA negative or have missing 
data at baseline but who develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA positive at baseline and the titer 
of one or more post-dose samples is greater than the titer of the baseline sample by a 
scientifically reasonable margin (details to be provided in the Statistical Analysis Plan).
Patients will be 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.
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported using descriptive statistics.
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6.10
BIOMARKER ANALYSES
Biomarker analyses will be based on the safety-evaluable population.
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.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and CRC reports 
and images will be sent directly to the Sponsor, using the Sponsor’s standard 
procedures to handle and process the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
PRO data will be collected on paper questionnaires. The data from the questionnaires 
will be entered into the EDC system by site staff.
7.2
ELECTRONIC CASE REPORT FORMS
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
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At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the data is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered on the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly on 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 Clinical Study Report has been 
completed 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 GCP and 
the principles of the Declaration of Helsinki, or the applicable laws and regulations of the 
country in which the research is conducted, whichever affords the greater protection to 
the individual.  The study will comply with the requirements of the ICH E2A guideline 
(Clinical Safety Data Management:  Definitions and Standards for Expedited Reporting).  
Studies conducted in the United States or under a U.S. Investigational New Drug (IND) 
Application will comply with U.S. FDA regulations and applicable local, state, and federal 
laws.  Studies conducted in the European or European Economic Area will comply with 
the E.U. Clinical Trial Directive (2001/20/EC), and applicable local, regional, and 
national laws.
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form will be provided to each site.  If 
applicable, it will be provided in a certified translation of the local language.  The 
Sponsor or its designee must review and approve any proposed deviations from the 
Sponsor's sample Informed Consent Forms or any alternate consent forms proposed by 
the site (collectively, the "Consent Forms") before IRB/EC submission.  The final 
IRB/EC-approved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
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consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient before his or her 
participation in the study.  The case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient. All signed and 
dated Consent Forms must remain in each patient’s study file or in the site file and must 
be available for verification by study monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization
to allow use and disclosure of personal health information in compliance with the U.S. 
HIPAA of 1996.  If the site utilizes a separate Authorization Form for patient 
authorization for use and disclosure of personal health information under the HIPAA 
regulations, the review, approval, and other processes outlined above apply except that 
IRB review and approval may not be required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
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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 datasets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted clinical study reports and other summary reports will be provided upon 
request.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
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study and for 1 year after completion of the study (see the definition of end of study in 
Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes 
to data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of GCP guidelines and require reporting to 
health authorities.  As per the Sponsor's standard operating procedures, prospective 
requests to deviate from the protocol, including requests to waive protocol eligibility 
criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Approximately 225 sites globally will participate to enroll approximately 900 patients.  
Enrollment will occur through an IxRS.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5. 
An iDMC will be employed to monitor and evaluate patient safety throughout the study.  
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9.5
DISSEMINATION OF DATA AND PROTECTION OF 
TRADE SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both 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, provided the requirements of Roche's global policy on data sharing have been 
met.  For more information, refer to the Roche Global Policy on Sharing of Clinical Trials
Data at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
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9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).
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10.
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et al. Three-year follow-up of a randomized trial comparing focal/grid 
photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch 
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triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 
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growth factor during aflibercept treatment of age-related macular degeneration.
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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.
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intercellular adhesion molecule-1 and endothelial nitric oxide synthase expression 
and initiates early diabetic retinal leukocyte adhesion in vivo. Am J Path 
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pathogenic link in diabetes? Curr Diabetes Rev 2010;6:294303.
Krohne TU, Liu Z, Holz FG, et al. Intraocular pharmacokinetics of ranibizumab following 
a single intravitreal injection in humans. Am J Ophthalmol 2012;154:6826.
Leasher JL, Bourne RR, Flaxman SR, et al., Vision Loss Expert Group of the Global 
Burden of Disease Study. Global estimates on the number of people blind or 
visually impaired by diabetic retinopathy: a meta-analysis from 1990 to 2010.
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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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binomial trials. Stat Med 2000;19:811–25.
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, Dröge 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;63:93057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. doi: 10.1167/iovs.10-6386.
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.
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age-related macular degeneration. Biomed Res Int 2018;110 [cited: 18 May 2018]. 
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Appendix 1
Schedule of Activities
Screening through Week 52 and Early Termination
Visit Window (days)
Screening
Visit Day
Visit Week
ET
Visit b
1a
7
4
8
12
16
20
24
28
32
36
40
44
48
52
–28 to 1
NA
(3)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(28)
Main informed consent c
x
Optional aqueous, vitreous
and blood sample informed 
consent c
x
x
Optional (RBR) residual
samples and DNA whole 
blood sample informed 
consent c
x
x
Review of inclusion and 
exclusion criteria
x
x
Demographics (age, sex, and 
self-reported race/ethnicity)
x
Medical and surgical history
including tobacco history d
x
Physical examination e 
x
x
Body weight and height
x
Vital signs f 
x
x
x
NEI VFQ-25 g
x
x
x
x
Refraction and BCVA h
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Pre-treatment IOP i
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urine pregnancy test j, k 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
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Appendix 1
Schedule of Activities (cont.)
Screening through Week 52 and Early Termination
Visit Window (days)
Screening
Visit Day
Visit Week
ET
Visit b
1a
7
4
8
12
16
20
24
28
32
36
40
44
48
52
–28 to 1
NA
(3)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(28)
Whole blood sample 
(hematology, coagulation 
[aPTT and PT], serum 
chemistry, and urinalysis) j, l
x
x l
HbA1c j
x
x
x
Optional aqueous humor 
sample for biomarkers m 
x
x
x
x
x
x
Optional PK plasma sample 
(if aqueous humor sample is 
collected) j, m
x
x
Optional PD plasma sample 
(if aqueous humor sample is 
collected) j, m
x
x
Optional vitreous humor 
sample for biomarkers n
Can be collected if vitrectomy is necessary
Optional PK plasma sample (if 
vitreous humor sample is 
collected) j, n
Collect PK sample if vitreous humor sample is collected
Optional whole blood sample 
for DNA j, o
x
Mandatory plasma
PK sample j, p
x
x
x
x
x
Mandatory plasma
PD sample j, p
x
x
x
x
x
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Appendix 1
Schedule of Activities (cont.)
Screening through Week 52 and Early Termination
Visit Window (days)
Screening
Visit Day
Visit Week
ET
Visit b
1a
7
4
8
12
16
20
24
28
32
36
40
44
48
52
–28 to 1
NA
(3)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(28)
Mandatory plasma 
ADA sample j, p
x
x
x
x
x
Slitlamp examination
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Indirect ophthalmoscopy
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
SD-OCT q
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Optional OCT-A q, r
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
FFA q
(x) q
x
x
x
x
CFP q
x
x
x
x
q
x
(x) q
x
x
x
Administration of study 
treatment s
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Finger-counting test t
x
x
x
x
x
x
x
x
x
x
x
x
x
x
IOP (post-study treatment) u
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events v
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant medications w
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concurrent ocular procedures x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ADAanti-drug antibody; Ang-2angiopoietin-2; BCVAbest-corrected visual acuity; CFPcolor fundus photograph; CRC central reading center; 
DMEdiabetic macular edema; eCRFelectronic Case Report Form; ETearly termination; FFAfundus fluorescein angiography; HbA1chemoglobin A1C; 
ICFInformed Consent Form; IOPintraocular pressure; NEI VFQ-Q25National Eye Institute 25-Item Visual Functioning Questionnaire; OCT-Aoptical 
coherence tomographyangiography; PDpharmacodynamic; PKpharmacokinetic; RBRResearch Biosample Repository; SD-OCTspectral-domain optical 
coherence tomography; SOCstandard of care;
; VAvisual acuity; VEGF-Avascular endothelial growth factorA.
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Appendix 1
Schedule of Activities (cont.)
Screening through Week 52 and Early Termination
Notes:  All ocular assessments are to be performed for both eyes unless noted otherwise.  All assessments are to be performed on the same day, except 
those at screening.  All study visits will be scheduled relative to the date of the Day 1 visit (first study treatment).  For the study visits windows, the sites 
should utilize patient’s study visit calculator posted on DrugDev.
There must be a minimum of 21 days between study treatment visits occurring from the Day 1 visit through the Week 96 visit.  The final study visit at Week 
100 should not occur earlier than 28 days after the last study treatment.  The fellow eye anti-VEGF treatment approved by the country regulatory agency for 
ocular use may be covered by the Sponsor as long as the patient remains in the study (see Section 4.4.1).  The fellow eye anti-VEGF treatments after the ET 
visit or the final study visit (Week 100) will not be covered by the Sponsor.
a
The screening and Day 1 (randomization) visits may occur as a combined visit if all assessments are completed and evaluated within 2 business days.  The 
following two conditions must be met for the combined visit to occur:  prior communication with the CRC so the screening images are evaluated in 
expedited manner; and availability of the historical HbA1c data (obtained within 2 months prior to Day 1 visit; it is permissible to use site’s own 
HbA1c analyzer with print-out results).  There is no need to wait for Covance sample results.  When screening and randomization are combined and 
performed in 1 day, assessments listed for both visits should be conducted only once.  If the combined visit is conducted within 2 business days, then the 
following safety assessments will be repeated on the day of patient’s randomization and study treatment administration:  urine pregnancy test (if 
applicable), slitlamp examination, indirect ophthalmoscopy, and pre-treatment IOP measurements (recorded on the Day 1 eCRF and dated accordingly). 
Verify that patient did not start on any prohibited medication.
b
Patients who are discontinuing from the study early (prior to the final study visit at Week 100) but have not withdrawn consent should return for an ET visit 
after a minimum of 28 days have elapsed following their last study treatment.
c
Informed consent must be administered and documented before any study-specific screening procedure is performed and may be obtained more than 
28 days before initiation of study treatment at the Day 1 visit.  The optional Blood, Aqueous Humor, Vitreous Humor Samples Informed Consent Form as 
well as Optional (RBR) Informed Consent Form for residual samples and whole blood DNA sample collection can be signed either at the screening or Day 1 
visit prior to sample collection. 
d
Medical history, including clinically significant diseases, chronic and ongoing conditions (e.g., trauma, cancer, cardiovascular, cerebrovascular, and 
ophthalmic history), surgeries, cancer history (including prior cancer therapies and procedures), reproductive status, smoking history, and height and 
weight will be recorded at baseline. 
e
A targeted physical examination should include an evaluation of the head, ears, nose and throat.  If any abnormalities are noted during the study, the 
patient may be referred to another doctor.  Changes from baseline abnormalities should be recorded in patient notes. New or worsened clinically significant 
abnormalities should be recorded as adverse events on the Adverse Event eCRF.
f
Vital signs include measurement of temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressure; at the Day 1 visit, vital signs should 
be recorded before study treatment. Vital signs will be measured with the patient in a seated position after resting for 5 minutes.
g
To be administered by the masked site staff (except for the VA examiner) prior to any other visit assessments being performed on that day.
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Appendix 1
Schedule of Activities (cont.)
Screening through Week 52 and Early Termination
h
Perform the assessments prior to dilating the eyes.  Both refraction and BCVA will be assessed at every study visit for both eyes.  However, only study 
eye refraction from the Day 1, Week 56 and Week 96 visits will be entered on the refraction-specific eCRF.  The BCVA assessment data for both eyes 
will be entered on the BCVA-specific eCRF from every study visit.  The study eye visual acuity score from each study treatment visit must be 
entered to IxRS after each visit; IxRS needs the data to assign the correct study treatment at future visits.  
i
Perform the assessments prior to dilating the eyes at screening and at each study visit, and if applicable, at the ET visit.
j
Obtain prior to FFA (if applicable) and prior to study treatment. 
k
Starting at screening, collect and perform the urine pregnancy test for women of childbearing potential, including those who have had tubal ligation, at each 
study treatment visit.  If positive, collect the serum pregnancy sample and forward it to the central laboratory for testing.  If the serum pregnancy test is 
positive, do not administer study treatment.
l
Hematology includes hemoglobin, hematocrit, quantitative platelet count, RBC counts, WBC counts, and differentials, including neutrophils, lymphocytes, 
bands, eosinophils, basophils, and monocytes (absolute).  Serum chemistry panel includes sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen, creatinine, calcium, phosphorus, total and direct bilirubin, total protein, albumin, ALP, AST, ALT, and uric acid. Urinalysis includes specific gravity, 
pH, blood, protein, ketones, glucose, bilirubin, urobilinogen, and microscopic examination (if any of the preceding urinalysis tests, other than glucose and 
ketones, are abnormal). If the screening and Day 1 (randomization) visits occur as a combined visit, a historic HbA1c value must be available from within 
2 months prior to Day 1.  If the screening and Day 1 visits are performed separately, then these samples collections can be done at either visit based on 
investigator judgment, but historical (obtained within 2 months of Day 1 visit) or current HbA1c results must be available at Day 1 prior to 
randomization to confirm eligibility.
m If a patient consents to collection of optional aqueous humor sample, collect the sample at indicated timepoints prior to study treatment administration.  It is 
permissible to collect aqueous humor sample after FFA was performed at applicable visits.  Associated optional PK and PD plasma samples have to be 
collected at the Day 7 and Week 32 visits.  See the central lab manual for additional details.  Not applicable for a site that has not been granted 
approval by a site's Institutional Review Board or Ethics Committee.  
n
If vitrectomy is medically necessary and the patient consents, a vitreous sample can be obtained from the study eye.  Associated PK blood sample (for 
plasma preparation) should also be collected and shipped to the central lab.  Vitreous humor and PK samples will be analyzed primarily for faricimab 
concentrations and may also be analyzed for aflibercept concentrations.  The remaining samples may be analyzed for 
 
and possibly other biomarkers.
o
If the optional whole blood DNA sample is not obtained at the assigned visit (Day 1), the sample may be collected at any subsequent study visit when a 
blood draw is being performed for other purposes as specified (e.g., PK, ADA).  This sample collection is not applicable for a site that has not been granted 
approval by the country regulators or site's Institutional Review Board or Ethics Committee. The DNA samples will be collected from patients who give 
specific consent to participate in this optional research. 
p
At specified visits, the mandatory plasma PK, PD, and ADA samples will be collected prior to FFA assessment (if applicable) and prior to study 
treatment.  
Protocol Number: 
 Report Number: 
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GR40398
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Faricimab—F. Hoffmann-La Roche Ltd
121/Protocol GR40398 (Rhine), Version 3
Appendix 1
Schedule of Activities (cont.)
Screening through Week 52 and Early Termination
q
The CRC will review SD-OCT (certain SS-OCT equipment may be acceptable; consult CRC) and 7-modified field or 4-wide field CFP images obtained at 
screening for determination of patient eligibility. 
 outputs from all types of imaging assessments will be sent to the relevant CRC.  The preferred method for FFA collection is UWF 
(Optos) at sites with capability, and 7 or 4-wide fields at all the other sites.  See the CRC manual for additional details.  The baseline FFA may be 
obtained either at screening or the Day 1 visit, but it is recommended to obtain it at the Day 1 visit if both eyes appear eligible to become the study eye.  
The FFA images should be obtained after lab samples have been collected.   Note:  After randomization, if a patient misses a study visit when CFP or FFA 
ocular images are scheduled or these images are not taken at the scheduled visit (e.g. equipment is broken), they must be obtained at the next scheduled 
visit the patient attends.  Please remember to forward OCT images to the CRC immediately after the visit as they need to be evaluated and 
data submitted to the IxRS by the CRC before the next study visit.  If the OCT image was missed due to a missed visit or not taken, then 
notify the CRC immediately so they can inform IxRS that the expected data will not be available.
r
To be conducted at sites with OCT-A capability.  
s
At study treatment visits, randomized patients will receive faricimab at some visits and sham at other visits or aflibercept at some visits and sham at other 
visits.  The timing of these treatments will depend on the treatment arm to which they are randomized, which will be masked. 
t
The finger-counting test should be conducted within approximately 15 minutes of study treatment administration for the study eye only by the unmasked 
investigator.
u
Post-treatment IOP measurement in the study eye only at 30 (15) minutes to be performed by qualified personnel assigned to the unmasked role.  If there 
are no safety concerns after 30 (15) minutes following the study treatment, the patient will be permitted to leave the clinic.  If the IOP value is of concern to 
the investigator, the patient will remain in the clinic and will be managed in accordance with the investigator’s clinical judgment.  The adverse event will be 
recorded on the Adverse Event eCRF as applicable.   
v
After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated intervention 
should be reported.  After initiation of study treatment (Day 1), all adverse events will be reported until the final study visit or if applicable until the ET visit.  
After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event 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.
w 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 within 7 days preceding Day 1 and through the conclusion of the patient’s study participation or 
ET visit.  
x
Record all concurrent ocular procedures performed on the study or nonstudy eye between the Day 1 visit after study treatment and the final study visit or 
ET visit.
Protocol Number: 
 Report Number: 
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Faricimab—F. Hoffmann-La Roche Ltd
122/Protocol GR40398 (Rhine), Version 3
Appendix 1
Schedule of Activities (cont.)
Week 56 through Week 100 and Early Termination
Visit Window (days)
Week Visit 
ET 
Visit a
56
60
64
68
72
76
80
84
88
92
96
100
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(28 and 
35)
(28)
Physical examination b 
x
x
Vital signs c
x
x
NEI VFQ-25 d
x
x
Refraction and BCVA e
x
x
x
x
x
x
x
x
x
x
x
x
x
Pre-treatment IOP f
x
x
x
x
x
x
x
x
x
x
x
x
x
Urine pregnancy 
test g, h
x
x
x
x
x
x
x
x
x
x
x
x
x
Whole blood sample 
(hematology, coagulation 
[aPTT and PT], serum 
chemistry, and 
urinalysis) g, i
x
HbA1c g
x
x
Optional aqueous humor 
sample for biomarkers j
x
x
x
x
x
Protocol Number: 
 Report Number: 
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Faricimab—F. Hoffmann-La Roche Ltd
123/Protocol GR40398 (Rhine), Version 3
Appendix 1
Schedule of Activities (cont.)
Week 56 through Week 100 and Early Termination
Visit Window (days)
Week Visit 
ET 
Visit a
56
60
64
68
72
76
80
84
88
92
96
100
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(28 and 
35)
(28)
Optional vitreous humor 
sample for biomarkers k
Can be collected if vitrectomy is necessary.
Optional PK plasma 
sample (if vitreous 
humor sample is 
collected) g,k
Collect PK sample if vitreous humor sample is collected
Mandatory plasma PK 
sample g
x
x
x
Mandatory plasma 
PD sample g
x
x
x
Mandatory plasma 
ADA sample g
x
x
x
Slitlamp examination
x
x
x
x
x
x
x
x
x
x
x
x
x
Indirect ophthalmoscopy
x
x
x
x
x
x
x
x
x
x
x
x
x
SD-OCT l or SS-OCT (if 
applicable)
x
x
x
x
x
x
x
x
x
x
x
x
x
Optional OCT-A l, m
x
x
x
x
x
x
x
x
x
x
x
x
x
FFA l
x
x
CFP l
x
x
l
x
x
Protocol Number: 
 Report Number: 
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Faricimab—F. Hoffmann-La Roche Ltd
124/Protocol GR40398 (Rhine), Version 3
Appendix 1
Schedule of Activities (cont.)
Week 56 through Week 100 and Early Termination
Visit Window (days)
Week Visit 
ET 
Visit a
56
60
64
68
72
76
80
84
88
92
96
100
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(28 and 
35)
(28)
Administration of study 
treatment n
x
x
x
x
x
x
x
x
x
x
x
Finger-counting test o
x
x
x
x
x
x
x
x
x
x
x
IOP post-treatment p
x
x
x
x
x
x
x
x
x
x
x
Adverse events q
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant 
medications r
x
x
x
x
x
x
x
x
x
x
x
x
x
Concurrent ocular
procedures s
x
x
x
x
x
x
x
x
x
x
x
x
x
ADAanti-drug antibody; BCVAbest-corrected visual acuity; CFPcolor fundus photograph; DMEdiabetic macular edema; eCRFelectronic Case Report 
Form; ETearly termination; FFAfundus fluorescein angiography; HbA1chemoglobin A1C; IOPintraocular pressure; 
NEI VFQ-Q25National Eye Institute 25-Item Visual Functioning Questionnaire; OCT-Aoptical coherence tomographyangiography; PDpharmacodynamic; 
PKpharmacokinetic; SD-OCTspectral-domain optical coherence tomography; SOCstandard of care;
; VAvisual acuity; VEGF-
Avascular endothelial growth factorA.
Notes:  All ocular assessments are to be performed for both eyes unless noted otherwise.  All assessments are to be performed on the same day.  All study 
visits will be scheduled relative to the date of the Day 1 visit (first study treatment).  There must be a minimum of 21 days between all study treatment visits 
occurring at the Day 1 visit through the Week 100 visit.  
The fellow eye anti-VEGF treatment approved by the country regulatory agency for ocular use may be covered by the Sponsor as long as the patient 
remains in the study (see Section 4.4.1).  The fellow eye anti-VEGF treatment after the ET visit or the final study visit (Week 100) will not be covered by the 
Sponsor.
a
Patients who are discontinuing from the study early (prior to the final study visit at Week 100) but have not withdrawn consent should return for an ET visit 
after a minimum of 28 days have elapsed following the last study treatment.
Protocol Number: 
 Report Number: 
Clinical Study Report: faricimab - F. Hoffmann-La Roche Ltd
GR40398
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Faricimab—F. Hoffmann-La Roche Ltd
125/Protocol GR40398 (Rhine), Version 3
Appendix 1
Schedule of Activities (cont.)
Week 56 through Week 100 and Early Termination
b
A targeted physical examination should include an evaluation of the head, ears, nose, and throat.  If any abnormalities are noted during the 
study, the patient may be referred to another doctor. Changes from baseline abnormalities should be recorded in patient notes. New or 
worsened clinically significant abnormalities should be recorded as adverse events on the Adverse Event eCRF.
c
Vital signs include measurement of temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressure; at the Day 1 visit,
vital signs should be recorded before study treatment.  Vital signs will be measured with the patient in a seated position after resting for 
5 minutes.
d
To be administered by the masked site staff (except for the VA examiner) prior to any other visit assessments being performed on that day.
e
Perform the assessments prior to dilating the eyes.  Both refraction and BCVA will be assessed at every study visit for both eyes.  
However, only study eye refraction from the Day 1, Week 56 and Week 96 visits will be entered on the refraction-specific eCRF.  The 
BCVA assessment data for both eyes will be entered on the BCVA-specific eCRF from every study visit.  The study eye visual acuity
score from each study treatment visit must be entered to IxRS at the visit; IxRS needs the data to assign the correct study 
treatment at future visits.
f
Perform the assessments prior to dilating the eyes and prior to study treatment.
g
Obtain prior to FFA (if applicable) and prior to study treatment. 
h
Starting at screening, collect and perform the urine pregnancy test for women of childbearing potential, including those who have had tubal 
ligation, at each study treatment visit. If positive, collect the serum pregnancy sample and forward it to the central laboratory for testing.  
If the serum pregnancy test is positive, do not administer study treatment.
i
Hematology includes hemoglobin, hematocrit, quantitative platelet count, RBC counts, WBC counts, and differentials, including neutrophils, 
lymphocytes, bands, eosinophils, basophils, and monocytes (absolute).  Serum chemistry panel includes sodium, potassium, chloride, 
bicarbonate, glucose, blood urea nitrogen, creatinine, calcium, phosphorus, total and direct bilirubin, total protein, albumin, ALP, AST, ALT, 
and uric acid. Urinalysis includes specific gravity, pH, blood, protein, ketones, glucose, bilirubin, urobilinogen, and microscopic examination 
(if any of the preceding urinalysis tests, other than glucose and ketones, are abnormal).
j
If a patient consents to collection of optional aqueous humor sample, collect the sample at indicated timepoints prior to study treatment 
administration.  It is acceptable to collect aqueous sample after FFA was performed at applicable visits.  Not applicable for a site that has 
not been granted approval by a site's Institutional Review Board or Ethics Committee.
k
If vitrectomy is medically necessary and the patient consents, a vitreous sample can be obtained from the study eye.  Associated PK blood 
sample (for plasma preparation) should also be collected and shipped to the central lab.  Vitreous humor and PK samples will be analyzed 
primarily for faricimab concentrations and may also be analyzed for aflibercept concentrations.  The remaining samples may be analyzed for 
and possibly other biomarkers.
Protocol Number: 
 Report Number: 
Clinical Study Report: faricimab - F. Hoffmann-La Roche Ltd
GR40398
1102957
125

Faricimab—F. Hoffmann-La Roche Ltd
126/Protocol GR40398 (Rhine), Version 3
Appendix 1
Schedule of Activities (cont.)
Week 56 through Week 100 and Early Termination
l
The outputs from imaging assessments will be sent to the CRC.  See the CRC manual for additional details. Note: After randomization, if a 
patient misses a study visit when ocular CFP
and FFA images are scheduled or these images are not 
taken at the scheduled visit (e.g., equipment is broken), they must be obtained at the next scheduled visit the patient attends.  Please 
remember to forward OCT images to the CRC immediately after the visit as they need to be evaluated and data submitted 
to the IxRS by the CRC before the next study visit.  If the OCT image was missed due to a missed visit or not taken, then 
notify the CRC immediately so they can inform IxRS that the expected data will not be available.
m To be conducted at sites with OCT-A capability. 
n
At study treatment visits, randomized patients will receive study drug at some visits and sham at other visits or aflibercept at some visits and 
sham at other visits. The timing of these treatments will depend on the treatment arm to which patients are randomized, which will be 
masked. 
o
The finger-counting test should be conducted within approximately 15 minutes of study treatment administration for the study eye only by 
the unmasked investigator.
p
Post-treatment IOP measurement in the study eye only at 30 (15) minutes to be performed by qualified personnel assigned to the 
unmasked role. If there are no safety concerns after 30 (15) minutes following the study treatment, the patient will be permitted to leave 
the clinic.  If the IOP value is of concern to the investigator, the patient will remain in the clinic and will be managed in accordance with the 
investigator’s clinical judgment. The adverse event will be recorded on the Adverse Event eCRF as applicable.
q
After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study treatment (Day 1), all adverse events will be reported until the patient’s last or final 
study visit or, if applicable, until the ET visit.  After this period, the Sponsor should be notified if the investigator becomes aware of any 
serious adverse event 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.
r
Record any concomitant medications (i.e., any prescription medications or over-the-counter preparations other than protocol-specified 
procedural medications such as proparacaine, etc.) used by the patient within 7 days preceding Day 1 and through the conclusion of the 
patient’s study participation or the ET visit.
s
Record all concurrent ocular procedures performed on the study or nonstudy eye between the Day 1 visit after study treatment and the 
final study visit or the ET visit.
Protocol Number: 
 Report Number: 
Clinical Study Report: faricimab - F. Hoffmann-La Roche Ltd
GR40398
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127/Protocol GR40398 (Rhine), 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 e
Ocular imaging, as necessary
IOPintraocular pressure.
a Patients will be instructed to contact the investigator at any time if they have 
any health-related concerns.  If warranted, patients will be asked to return to 
the clinic as soon as possible for an unscheduled safety assessment visit.  
Assessments performed at unscheduled safety visits are at the discretion of 
the investigator. It is recommended to perform ocular assessments on both 
eyes.
b Perform finger-counting test followed by hand motion and light perception 
tests when necessary.
c The method used for the IOP measurement for a patient must remain 
consistent throughout the study.
d Adverse event causality to be evaluated by the masked physician in the 
assessor role.
e Hematology includes hemoglobin, hematocrit, quantitative platelet count, 
RBC counts, WBC counts, and differentials, including neutrophils, 
lymphocytes, bands, eosinophils, basophils, and monocytes (absolute).  
Serum chemistry panel includes sodium, potassium, chloride, bicarbonate, 
glucose, blood urea nitrogen, creatinine, calcium, phosphorus, total and 
direct bilirubin, total protein, albumin, ALP, AST, ALT, and uric acid.  
Protocol Number: 
 Report Number: 
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128/Protocol GR40398 (Rhine), Version 3
Appendix 3
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.
Protocol Number: 
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Appendix 4
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, Week 56, and Week 96 visit will 
be entered to Refraction specific 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 arm assignment.  VA will be 
measured at the intervals specified in the protocol (see Appendix 1).
EQUIPMENT
The following are needed to conduct the examination:

Examination lane of adequate dimensions to allow testing at required distances
(4- and 1-meter lanes)

Standard chair with a firm back

Set of three Precision Visionor Lighthouse distance acuity charts as applicable 
per country and region (see the BCVA manual for details)

Retro-Illuminated box

Study frame

Study lens set

Note:  for additional details, see the BCVA specification manual.
TRAINING AND CERTIFICATION
A VA specifications document, procedure manual, and training materials will be provided 
to the investigational sites, and examiner certification will be obtained from a third party 
vendor.  The VA examination room also must be certified before any VA examinations 
are performed.
Protocol Number: 
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Appendix 5
Color Fundus Photography
SCOPE
Stereo color fundus photographs using 7-modified field or 4-wide field imaging will be 
obtained from both eyes by trained personnel at the study sites.  Fundus photography 
will be performed at baseline (screening) and at the intervals specified in the schedule of 
activities (see Appendix 1).  Analysis (if applicable) of fundus photographs will be 
performed by the central reading center (CRC).
EQUIPMENT
See the CRC manual.
PROCEDURE
The CRC will provide a study manual and training materials.  The fundus photographer 
and photography equipment will be certified by the CRC before any study images are 
taken.  See the CRC manual for further details.
Protocol Number: 
 Report Number: 
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Appendix 6
Fundus Fluorescein Angiography
SCOPE
Fundus fluorescein angiography 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 trained personnel who are certified by the central 
reading center (CRC).  The fundus fluorescein angiograms will be obtained at baseline 
(at screening or on Day 1) and at the intervals specified in the protocol (see Appendix 1).  
Analysis (if applicable) of fundus fluorescein angiograms will be performed by the CRC.
EQUIPMENT
Digital angiograms must be used while conducting an angiographic evaluation for the 
study.
Film-based angiography is not acceptable.
UWF (Optos) is the preferred method for fundus fluorescein angiography (FFA) 
capture.  The study sites without Optos 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.  This certification and 
validation process will ensure that the CRC will be able to correctly calculate the 
required measurements.
PROCEDURES
The CRC will provide a study manual and training materials.  Photographers, systems, 
and software will be certified prior to obtaining angiograms of patients.
Protocol Number: 
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Appendix 7
Spectral-Domain Optical Coherence Tomography
SCOPE
Spectral-domain optical coherence tomography (SD-OCT) will be performed at the study 
sites by trained personnel who are certified by the central reading center (CRC).  
SD-OCT imaging will be performed for each patient at the intervals specified in the 
protocol (see Appendix 1).
The SD-OCT images of both eyes will be obtained at protocol-specified visits and will be 
forwarded to the CRC.
Note: The optional images will be collected at the sites with optical coherence 
tomographyangiography capabilities and forwarded to the CRC.
EQUIPMENT
Equipment utilized during this study is described in the CRC manual.  The ability to 
transfer images to electronically exportable digital files is required (i.e., no printed 
SD-OCT images will be sent to the CRC).
Note:  Certain swept-source optical coherence tomography (SS-OCT) machines may be 
acceptable to use; consult the CRC for further details.
PROCEDURES AND CERTIFICATION
The CRC will provide the study manual and training materials.  SD-OCT operators, 
systems, and software will be certified prior to any evaluation of patients.
Protocol Number: 
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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 urinalysis), hemoglobin A1C
(HbA1c), 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 treating physician from patients who consent to the procedure and sample 
acquisition.  An aqueous humor sample will be collected before the patient’s study eye 
treatment at the visits as indicated in Appendix 1. Please refer to the central laboratory
manual for additional details regarding sample collection and shipping information. 
OPTIONAL UNSCHEDULED COLLECTION OF VITREOUS HUMOR 
SAMPLE COLLECTION
Elective vitrectomy is not allowed in the study eye during a patient's study participation.  
However, if the surgery is medically necessary and the patient consents, a vitreous 
sample can be collected from the study eye. Either masked or unmasked investigators 
can collect the sample. Approximately 0.5 mL of undiluted vitreous humor should be 
collected using an aseptic procedure and sterile field and according to local guidelines 
and shipped as specified in the central laboratory manual. 
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Appendix 8
Biological Sample Collection and Shipping Instructions (cont.)
A pharmacokinetic blood sample (for plasma preparation) should also be collected and 
shipped as specified in the central laboratory manual.
Vitreous humor samples will be analyzed primarily for faricimab concentrations and may 
also be analyzed for aflibercept concentrations.  The remaining samples may be 
analyzed for
 and possibly other biomarkers.
BIOLOGICAL SAMPLES STORAGE DURATION
The hematology, serum chemistry, urinalysis, coagulation, serum, urine pregnancy tests,
and HbA1c samples will be destroyed after their analysis during the study.
Unless the patient gives specific Research Biosample Repository consent for his or her 
remaining samples to be stored for optional exploratory research (see Section 4.5.9.5), 
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
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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RO6867461—F. Hoffmann-La Roche Ltd
2/Protocol GR40398, Version 2
PROTOCOL AMENDMENT, VERSION 2:
RATIONALE
Protocol GR40398 has been amended to include additional prohibited medications 
(Section 4.4.2) and more detailed examples of contraceptive methods for females of 
childbearing potential (Section 4.1.1.1) to enhance patient safety and to comply with 
health authority requests, enabling this protocol to be conducted globally.
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.
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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.
RO6867461—F. Hoffmann-La Roche Ltd
Protocol GR40398, Version 1
PROTOCOL
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, 
DOUBLE-MASKED, ACTIVE 
COMPARATORCONTROLLED STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF
RO6867461 IN PATIENTS WITH DIABETIC 
MACULAR EDEMA (RHINE)
PROTOCOL NUMBER:
GR40398
VERSION NUMBER:
1
EUDRACT NUMBER:
2017-005105-12
IND NUMBER:
119225
TEST PRODUCT:
RO6867461
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
See electronic date stamp below.
 
04-Jun-2018 21:20:32
Title
Approver's Name
Company Signatory
Date and Time (UTC)
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 Report Number: 
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TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................. 10
PROTOCOL SYNOPSIS .................................................................................... 11
1.
BACKGROUND .......................................................................................... 27
1.1
Background on Diabetic Macular Edema............................... 27
1.2
Background on RO6867461 .................................................. 28
1.3
Study Rationale and BenefitRisk Assessment..................... 29
1.3.1
Benefits.................................................................................. 29
1.3.2
Risks...................................................................................... 31
1.3.3
Conclusions........................................................................... 32
2.
OBJECTIVES AND ENDPOINTS ............................................................... 32
3.
STUDY DESIGN......................................................................................... 36
3.1
Description of the Study......................................................... 36
3.1.1
Overview of Study Design ..................................................... 36
3.1.1.1
Screening .............................................................................. 38
3.1.1.2
Screen-Failed Patients .......................................................... 39
3.1.1.3
Randomization and Visit Schedule........................................ 39
41
3.1.2
Treatment Schedule for Patients in the 
Personalized Treatment Interval Arm (Arm B)....................... 41
3.1.2.1
Study Drug Dosing Interval Determination............................. 41
3.1.2.2
Study Drug Dosing Intervals.................................................. 43
3.1.3
Additional Considerations for PTI Arm IxRS 
Study Drug Dosing Interval Decision ..................................... 43
3.1.3.1
Missed Study Drug Dosing Visit(s) ........................................ 43
3.1.3.2
Study Drug Interruption at Study Drug Dosing 
Visit(s).................................................................................... 43
3.1.3.3
Missing CST Value at Study Drug Dosing Visit ..................... 43
3.1.3.4
Missing BCVA Value at Study Drug Dosing Visit................... 44
3.1.4
Missed Study Drug Treatment Visit(s) for 
Patients in the Q8W Treatment Arms .................................... 44
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3.1.5
Timely Reporting of BCVA Scores, CST Values, 
Missed Study Treatment Visits, or Study 
Treatment Interruptions for All Study Patients ....................... 44
3.1.6
Independent Data Monitoring Committee .............................. 44
3.2
End of Study and Length of Study......................................... 45
3.3
Rationale for Study Design.................................................... 45
3.3.1
Rationale for Treatment Arms Dose and 
Schedule................................................................................ 45
3.3.1.1
Rationale for RO6867461 Dose and Schedule...................... 45
3.3.1.2
Rationale for Aflibercept Dose and Schedule ........................ 47
3.3.2
Rationale for Patient Population ............................................ 47
3.3.3
Rationale for Control Group................................................... 48
3.3.4
Rationale for Pharmacodynamic and Biomarker 
Assessments ......................................................................... 48
4.
MATERIALS AND METHODS .................................................................... 49
4.1
Patients.................................................................................. 49
4.1.1
Inclusion Criteria.................................................................... 49
4.1.1.1
General Inclusion Criteria ...................................................... 50
4.1.1.2
Ocular Inclusion Criteria for Study Eye.................................. 50
4.1.2
Exclusion Criteria................................................................... 51
4.1.2.1
General Exclusion Criteria..................................................... 51
4.1.2.2
Ocular Exclusion Criteria for Study Eye................................. 52
4.1.2.3
Ocular Exclusion Criteria for Fellow Eye 
(NonStudy Eye) ................................................................... 53
4.1.2.4
Exclusion Criteria for Both Eyes ............................................ 53
4.1.2.5
Concurrent Ocular Conditions Exclusion Criteria................... 53
4.2
Method of Treatment Assignment and Masking .................... 54
4.2.1
Treatment Assignment........................................................... 54
4.2.2
Masking ................................................................................. 55
4.2.2.1
Masked Roles........................................................................ 55
4.2.2.2
Unmasked Roles ................................................................... 56
4.2.2.3
Delegation Log ..................................................................... 57
4.2.2.4
Role Switching...................................................................... 57
4.2.2.5
Study Backup Staff ............................................................... 57
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4.2.2.6
Masking of Vendors, Sponsor's Agents, and 
Laboratory Personnel ............................................................ 57
4.2.2.7
Patient Masking.................................................................... 57
4.2.3
Unmasking............................................................................. 58
4.2.3.1
Single-Patient Emergency Unmasking .................................. 58
4.2.3.2
Single-Patient Non-Emergency Unmasking........................... 58
4.2.3.3
Single-Patient Unmasking for Health Authority 
Reporting Requirements........................................................ 58
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 58
4.3.1
Study Treatment Formulation, Packaging, 
and Handling ......................................................................... 58
4.3.1.1
RO6867461, Aflibercept and Sham....................................... 58
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 59
4.3.2.1
Dosage .................................................................................. 59
4.3.3
Administration........................................................................ 60
4.3.3.1
RO6867461 or Aflibercept Intravitreal Injections 
or Sham Procedure ............................................................... 60
4.3.4
Study Treatment Preparation................................................. 60
4.3.5
Compliance............................................................................ 61
4.3.6
Investigational Medicinal Product Accountability ................... 61
4.3.7
Continued Access to RO6867461 ......................................... 61
4.4
Concomitant Therapy ............................................................ 62
4.4.1
Permitted Therapy................................................................. 62
4.4.2
Prohibited Therapy ................................................................ 63
4.5
Study Assessments ............................................................... 63
4.5.1
Informed Consent Forms and Screening Log........................ 64
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 64
4.5.3
Physical Examinations........................................................... 64
4.5.4
Vital Signs.............................................................................. 64
4.5.5
Ocular Assessments.............................................................. 65
4.5.6
Concurrent Ocular Procedures.............................................. 66
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4.5.7
Laboratory, Biomarker, and Other 
Biological Samples ................................................................ 66
4.5.7.1
Optional Aqueous Humor Samples ....................................... 67
4.5.7.2
Optional Unscheduled Collection of Vitreous 
Samples................................................................................. 68
4.5.8
Patient-Reported Outcomes .................................................. 68
4.5.9
Optional Samples for Research Biosample 
Repository ............................................................................. 68
4.5.9.1
Overview of the Research Biosample Repository.................. 68
4.5.9.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 69
4.5.9.3
Sample Collection.................................................................. 69
4.5.9.4
Confidentiality........................................................................ 70
4.5.9.5
Consent to Participate in the Research 
Biosample Repository............................................................ 70
4.5.9.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 71
4.5.9.7
Monitoring and Oversight....................................................... 71
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 71
4.6.1
Study Treatment Discontinuation........................................... 71
4.6.2
Patient Discontinuation from Study........................................ 72
4.6.3
Study Discontinuation............................................................ 72
4.6.4
Site Discontinuation............................................................... 73
5.
ASSESSMENT OF SAFETY....................................................................... 73
5.1
Safety Plan ............................................................................ 73
5.1.1
Safety Assessments .............................................................. 73
5.1.2
Risks Associated with RO6867461........................................ 74
5.1.3
Management of Patients Who Experience 
Adverse Events ..................................................................... 74
5.1.3.1
Treatment Interruption:  Dose Interruption and 
Treatment Discontinuation Criteria ........................................ 74
5.2
Safety Parameters and Definitions ........................................ 76
5.2.1
Adverse Events ..................................................................... 76
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 77
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5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 77
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 78
5.3.1
Adverse Event Reporting Period ........................................... 78
5.3.2
Eliciting Adverse Event Information....................................... 79
5.3.3
Assessment of Severity of Adverse Events ........................... 79
5.3.4
Assessment of Causality of Adverse Events ......................... 79
5.3.5
Procedures for Recording Adverse Events............................ 80
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 81
5.3.5.2
Adverse Events That Are Secondary to 
Other Events.......................................................................... 81
5.3.5.3
Persistent or Recurrent Adverse Events................................ 82
5.3.5.4
Abnormal Laboratory Values ................................................. 82
5.3.5.5
Abnormal Vital Sign Values ................................................... 83
5.3.5.6
Abnormal Liver Function Tests.............................................. 83
5.3.5.7
Deaths ................................................................................... 84
5.3.5.8
Preexisting Medical Conditions.............................................. 84
5.3.5.9
Worsening of Diabetic Macular Edema or 
Diabetic Retinopathy in the Study Eye .................................. 84
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 84
5.3.5.11
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 85
5.3.5.12
Patient-Reported Outcome Data ........................................... 85
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 85
5.4.1
Emergency Medical Contacts................................................ 86
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 87
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 87
5.4.2.2
Events That Occur after Study Drug Initiation........................ 87
5.4.3
Reporting Requirements for Pregnancies.............................. 87
5.4.3.1
Pregnancies in Female Patients............................................ 87
5.4.3.2
Abortions ............................................................................... 88
5.4.3.3
Congenital Anomalies/Birth Defects ...................................... 88
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5.4.4
Expedited Reporting Requirements for Cases of 
Medication Error .................................................................... 88
5.5
Follow-Up of Patients after Adverse Events .......................... 89
5.5.1
Investigator Follow-Up........................................................... 89
5.5.2
Sponsor Follow-Up ................................................................ 89
5.6
Adverse Events That Occur after the 
Adverse Event Reporting Period ........................................... 89
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 90
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 90
6.1
Determination of Sample Size ............................................... 91
6.2
Analysis Populations ............................................................. 92
6.2.1
Intent-to-Treat Population...................................................... 92
6.2.2
Treatment-Naive Population.................................................. 92
6.2.3
Per-Protocol Population......................................................... 92
6.2.4
Safety-Evaluable Population.................................................. 93
6.2.5
Pharmacokinetic-Evaluable Population ................................. 93
6.2.6
Immunogenicity-Analysis population ..................................... 93
6.3
Summaries of Conduct of Study............................................ 93
6.4
Summaries of Treatment Group Comparability ..................... 93
6.5
Efficacy Analyses .................................................................. 94
6.5.1
Primary Efficacy Endpoint...................................................... 94
6.5.2
Secondary Efficacy Endpoints............................................... 96
6.5.3
Exploratory Efficacy Endpoints.............................................. 97
6.6
Safety Analyses..................................................................... 97
6.7
Pharmacokinetic Analyses..................................................... 98
6.8
Pharmacodynamic Analyses ................................................. 98
6.9
Immunogenicity Analyses...................................................... 99
6.10
Biomarker Analyses............................................................... 99
99
7.
DATA COLLECTION AND MANAGEMENT ............................................. 100
7.1
Data Quality Assurance....................................................... 100
7.2
Electronic Case Report Forms............................................. 100
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7.3
Source Data Documentation................................................ 100
7.4
Use of Computerized Systems ............................................ 101
7.5
Retention of Records........................................................... 101
8.
ETHICAL CONSIDERATIONS.................................................................. 102
8.1
Compliance with Laws and Regulations .............................. 102
8.2
Informed Consent................................................................ 102
8.3
Institutional Review Board or Ethics Committee.................. 103
8.4
Confidentiality...................................................................... 103
8.5
Financial Disclosure ............................................................ 104
9.
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION........................................................................... 104
9.1
Study Documentation .......................................................... 104
9.2
Protocol Deviations.............................................................. 104
9.3
Site Inspections ................................................................... 105
9.4
Administrative Structure....................................................... 105
9.5
Dissemination of Data and Protection of 
Trade Secrets...................................................................... 105
9.6
Protocol Amendments ......................................................... 106
10. REFERENCES ......................................................................................... 107
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 33
Table 2
Dose Interruption and Treatment Discontinuation Criteria .......... 75
Table 3
Adverse Event Severity Grading Scale ....................................... 79
Table 4
Causal Attribution Guidance ....................................................... 80
LIST OF FIGURES
Figure 1
Study Treatment Schema ........................................................... 38
Figure 2
Algorithm for IxRS-Determined Personalized Treatment 
Interval Study Drug Dosing Intervals........................................... 42
Figure 3
Graph-Based Testing Procedure for the Primary Endpoint......... 95
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LIST OF APPENDICES
Appendix 1
Schedule of Activities................................................................ 110
Appendix 2
Unscheduled Safety Assessment Visit...................................... 120
Appendix 3
Grading Scale for Assessment of Anterior Chamber Flare or 
Cells and Vitreous Cell.............................................................. 121
Appendix 4
Best-Corrected Visual Acuity Testing........................................ 123
Appendix 5
Color Fundus Photography ....................................................... 124
Appendix 6
Fundus Fluorescein Angiography ............................................. 125
Appendix 7
Spectral-Domain Optical Coherence Tomography.................... 126
Appendix 8
Biological Sample Collection and Shipping Instructions............ 127
Appendix 9
National Eye Institute Visual Functioning Questionnaire25..... 129
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PROTOCOL ACCEPTANCE FORM
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, 
DOUBLE-MASKED, ACTIVE 
COMPARATORCONTROLLED STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF    
RO6867461 IN PATIENTS WITH DIABETIC 
MACULAR EDEMA (RHINE)
PROTOCOL NUMBER:
GR40398
VERSION NUMBER:
1
EUDRACT NUMBER:
2017-005105-12
IND NUMBER:
119225
TEST PRODUCT:
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.
Protocol Number: 
 Report Number: 
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11/Protocol GR40398, Version 1
PROTOCOL SYNOPSIS
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-MASKED, 
ACTIVE COMPARATORCONTROLLED STUDY TO EVALUATE 
THE EFFICACY AND SAFETY OF RO6867461 IN PATIENTS WITH 
DIABETIC MACULAR EDEMA (RHINE)
PROTOCOL NUMBER:
GR40398
VERSION NUMBER:
1
EUDRACT NUMBER:
2017-005105-12
IND NUMBER:
119225
TEST PRODUCT:
RO6867461
PHASE:
Phase III
INDICATION:
Diabetic macular edema
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, and pharmacokinetics of RO6867461 when dosed 
every 8 weeks (Q8W) and with a personalized treatment interval (PTI) regimen compared with 
aflibercept (Eylea®) monotherapy in patients with diabetic macular edema (DME).  Specific 
objectives and corresponding endpoints for the study are outlined in the following table.
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Objectives and Corresponding Endpoints
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of IVT 
injections of the 6-mg dose of 
RO6867461 on BCVA outcomes
Change from baseline in BCVA (as measured on
the ETDRS chart at a starting distance of 
4 meters) at 1 year a
Key Secondary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of 
RO6867461 on DR severity outcomes
Proportion of patients with a 2-step DRS 
improvement from baseline on the ETDRS 
DRSS at Week 52
Secondary Efficacy Objectives
Corresponding Endpoints
To evaluate the efficacy of 
RO6867461 on additional BCVA 
outcomes
Change from baseline in BCVA (as measured on
the ETDRS chart at a starting distance of 
4 meters) over time 
Proportion of patients gaining 15, 10, 5, or 
0 letters in BCVA from baseline over time 
Proportion of patients avoiding a loss of 15, 
105, or >0 letters in BCVA from baseline 
over time 
Proportion of patients gaining 15 letters or 
achieving BCVA of 84 letters over time
Proportion of patients with BCVA Snellen 
equivalent of 20/40 or better over time
Proportion of patients with BCVA Snellen 
equivalent of 20/200 or worse over time
To evaluate the efficacy of 
RO6867461 on additional DR 
outcomes
Proportion of patients with a 2-step DRS 
improvement from baseline on the ETDRS DRSS 
over time
Proportion of patients with a 3-step DRS 
improvement from baseline on the ETDRS DRSS 
over time
Proportion of patients who develop new PDR 
over time 
To evaluate RO6867461 treatment 
intervals in the PTI arm
Proportion of patients in the PTI arm on a Q4W, 
Q8W, Q12W, or Q16W treatment interval at 
1 year and 2 years
Treatment intervals in the PTI arm over time
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Objectives and Corresponding Endpoints (cont.)
Secondary Efficacy Objectives 
(cont.)
Corresponding Endpoints (cont.)
To evaluate the efficacy of 
RO6867461 on anatomical outcome 
measures using SD-OCT
Change from baseline in CST over time
Proportion of patients with absence of DME (CST 
325 m for Spectralis SD-OCT, or 315 m for 
Cirrus SD-OCT or Topcon SD-OCT) over time
Proportion of patients with absence of intraretinal 
fluid over time
Proportion of patients with absence of subretinal 
fluid over time
Proportion of patients with absence of intraretinal 
fluid and subretinal fluid over time
To evaluate the efficacy of 
RO6867461 on patient-reported 
vision-related functioning and quality 
of life using the NEI VFQ-25
Change from baseline in NEI VFQ-25 composite 
score over time
Safety Objective
Corresponding Endpoints
To evaluate the ocular and systemic 
safety and tolerability of RO6867461
Incidence and severity of ocular adverse events
Incidence and severity of non-ocular 
adverse events
Exploratory Efficacy Objectives
Corresponding Endpoints
To further evaluate the efficacy of 
RO6867461 on additional DR 
outcomes
Proportion of patients with a 2-step or 3-step 
DRS worsening from baseline on ETDRS DRSS 
over time
Proportion of patients who receive vitrectomy or 
PRP over time during the study
To further evaluate the efficacy of 
RO6867461 on anatomical outcome 
measures using FFA and/or OCT-A
Change from baseline in total area of macular 
non-perfusion and macular ischemia over time
Change from baseline in total area of vascular 
leakage over time
Proportion of patients with resolution of macular 
leakage over time
Change from baseline CST neurosensory over 
time (as measured on SD-OCT)
Change from baseline in total macular volume 
over time (as measured on SD-OCT)
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Objectives and Corresponding Endpoints (cont.)
Exploratory Efficacy Objectives
(cont.)
Corresponding Endpoints
(cont.)
To further evaluate the efficacy of 
RO6867461 on patient-reported 
vision-related functioning and quality 
of life using the NEI VFQ-25
Change from baseline in the NEI VFQ-25 Near 
Activities, Distance Activities, and Driving 
subscales at 1 year a
Proportion of patients with a 4-point 
improvement from baseline in NEI VFQ-25 
composite score
Pharmacokinetic Objective
Corresponding Endpoint
To characterize the systemic 
pharmacokinetics of RO6867461
Plasma concentration of RO6867461 over time
Immunogenicity Objectives
Corresponding Endpoints

To evaluate the immune response to 
RO6867461
Presence of ADAs during the study relative to 
the presence of ADAs at baseline

To evaluate potential effects of ADAs
Relationship between ADA status and efficacy, 
safety, or PK endpoints
Exploratory Pharmacokinetic, 
Pharmacodynamic, and Biomarker 
Objectives
Corresponding Endpoints
To identify biomarkers that are 
predictive of response to RO6867461, 
are associated with progression to a 
more severe disease state, are 
associated with susceptibility to 
developing adverse events, can 
provide evidence of RO6867461 
activity, or can increase the 
knowledge and understanding of 
disease biology
Concentration of biomarkers of angiogenesis 
and inflammation in aqueous humor (optional) at 
baseline and over time and their correlation with 
PK and/or primary and secondary endpoints at 
baseline and over time
Relationship between efficacy, safety, PK, 
immunogenicity,
Relationship between baseline anatomic 
measures and the change in BCVA or other 
endpoints (e.g., the frequency of study drug 
administration) over time
Relationship between anatomic measures and 
visual acuity
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Objectives and Corresponding Endpoints (cont.)
Exploratory Pharmacokinetic, 
Pharmacodynamic, and Biomarker 
Objectives (cont.)
Corresponding Endpoints (cont.)
To evaluate potential relationships 
between selected covariates and 
exposure to RO6867461
Relationship between selected covariates and 
plasma or aqueous humor (optional) 
concentration or PK parameters for RO6867461
To characterize the aqueous humor 
(optional) and vitreous (optional) 
pharmacokinetics of RO6867461
Aqueous humor (optional) and vitreous 
(optional) concentration of RO6867461
over time
To evaluate the drug concentration 

To explore the concentrationeffect 
relationship for visual acuity and other 
endpoints (e.g., anatomical markers)
Pharmacokinetics of RO6867461 and the 
change in BCVA or other endpoints (e.g., 
anatomical markers) over time
ADAanti-drug antibody;
 
BCVAbest-corrected visual acuity; CSTcentral subfield thickness; DRdiabetic retinopathy; 
DRSdiabetic retinopathy severity; DRSSDiabetic Retinopathy Severity Scale; 
ETDRSEarly Treatment Diabetic Retinopathy Study; FFAfundus fluorescein angiography; 
IVTintravitreal; NEI VFQ-25National Eye Institute 25-Item Visual Function Questionnaire; 
OCT-Aoptical coherence tomographyangiography; PDRproliferative diabetic retinopathy; 
PKpharmacokinetic; PRPpanretinal photocoagulation; PTIpersonalized treatment 
interval; Q4W every 4 weeks; Q8Wevery 8 weeks; Q12W every 12 weeks; Q16W every 
16 weeks; SD-OCTspectral-domain optical coherence tomography;
 
a The definition of 1 year for the primary endpoint is the average of the Week 48, 52, and 56 
visits.
Study Design
Description of Study
This is a Phase III, double-masked, multicenter, randomized, active comparatorcontrolled, 
parallel-group study, evaluating the efficacy, safety, pharmacokinetics, and optimal treatment 
frequency of RO6867461 administered by intravitreal (IVT) injection at 8-week intervals or PTI 
of approximately 100 weeks' duration (excluding the screening period) to patients with DME.  
Overview of Study Design
Approximately 900 patients will be randomized during the global enrollment phase of the study 
in a 1:1:1 ratio to one of three treatment arms at approximately 240 investigational sites globally.  
The study will randomize patients with DME who are naive to antivascular endothelial growth 
factor (anti-VEGF) therapy in the study eye and patients who have previously been treated with 
anti-VEGF therapy in the study eye, provided that the last treatment was at least 3 months prior 
to the Day 1 visit (the first study treatment).  Site investigators will be retina specialists or the 
equivalent outside of the United States.
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The study treatment arms will be as follows:

Arm A (administered every 8 weeks [Q8W]) (n300):  Patients randomized to Arm A will 
receive 6-mg IVT RO6867461 injections every 4 weeks (Q4W) to Week 20, followed by 
6-mg IVT RO6867461 injections Q8W to Week 96, followed by the final study visit at 
Week 100.

Arm B (PTI) (n300):  Patients randomized to Arm B will receive 6-mg IVT RO6867461
injections every 4 weeks (Q4W) to at least Week 12, followed by PTI dosing (see the PTI 
dosing criteria below) of 6-mg IVT RO6867461 injections to Week 96, followed by the final 
study visit at Week 100.

Arm C (comparator arm) (administered Q8W) (n300): Patients randomized to Arm C will 
receive 2-mg IVT aflibercept injections Q4W to Week 16, followed by 2-mg IVT aflibercept 
injections Q8W to Week 96, followed by the final study visit at Week 100.
Patients in all three treatment arms will complete scheduled study visits Q4W for the entire 
study duration (100 weeks).  A sham procedure will be administered to patients in all three 
treatment arms at applicable visits to maintain masking among treatment arms.
Only one eye will be assigned as the study eye.  If both eyes are considered eligible, the eye 
with the worse best-corrected visual acuity (BCVA), as assessed at screening, will be selected 
as the study eye unless the investigator deems the other eye to be more appropriate for 
treatment in the study.
There will be a minimum of two investigators per site to fulfill the masking requirements of the 
study.  At least one investigator will be designated as the assessor physician who will be 
masked to each patient’s treatment assignment and who will evaluate ocular assessments.  At 
least one other investigator will be unmasked and will perform study treatments. 
The study will consist of a screening period of up to 28 days (Days 28 to 1) in length and an 
approximately 96-week treatment period, followed by the final study visit at Week 100. 
A unique screening number will be assigned to each screened patient through an interactive 
voice or web-based response system (IxRS).
Screening
Informed consent must be administered and signed by a patient before any study-specific 
screening procedure is performed. Each consented patient must satisfy the eligibility criteria as 
applicable at screening and/or the Day 1 visit.  
Note: Some patients may require an extended screening period (more than 28 days) as a result 
of repeated evaluation of images or other issues.  Upon agreement with the Medical Monitor, 
the screening period may be extended by up to 5 business days in such cases.
The screening and Day 1 (randomization) visits may occur as a combined visit if all 
assessments are completed and evaluated on the same day or within 2 business days. When
screening and the Day 1 visit are completed on the same day, the assessments listed for both 
visits should be conducted only once.  A historic hemoglobin A1c (HbA1c) value must be 
available from within 2 months of Day 1 to enable screening and randomization to occur on the 
same day.  If a historic value is used, receipt of screening laboratory results would not be 
required prior to randomization.  If the screening and Day 1 visit are not completed on the same 
day (but rather within 2 business days), the following safety assessments will be repeated on 
the day of patient’s randomization and study treatment administration:  slitlamp examination, 
indirect ophthalmoscopy, and pre- and post-treatment intraocular pressure (IOP) measurements
(recorded on the Day 1 electronic Case Report Form [eCRF] and dated accordingly).
After screening has been completed, eligible patients will have a randomization identification 
number assigned through the IxRS and will be randomized in a 1:1:1 ratio in order that 
approximately 300 patients are randomized to each of the three treatment arms.
Randomization will be stratified by baseline BCVA Early Treatment Diabetic Retinopathy Study
(ETDRS) letter score, as assessed on Day 1 (64 letters or better vs. 63 letters or worse), prior 
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IVT anti-VEGF therapy (yes vs. no), and region (United States and Canada, Asia, and the rest 
of the world).
Randomization and Visit Schedule
The first study treatment will be administered on the same day as randomization, which will be 
performed through the IxRS (i.e., at the Day 1 visit).  
Note:  If a site has an unexpected issue (e.g., the IxRS is not able to assign the study kit), a
patient’s first study treatment may be administered within 2 business days of the Day 1 visit
after consultation with the Medical Monitor.  The following assessments will be repeated on the 
day of study treatment: slitlamp examination, indirect ophthalmoscopy, and pre- and 
post-treatment IOP measurements (recorded on the Day 1 eCRF and dated accordingly).
Starting at the Day 1 visit, randomized patients will have study treatment administered Q4W by 
the unmasked investigator that will be followed by the safety assessments (finger-counting test 
and post-dose IOP measurement).  After the Day 1 visit, patients will also have safety 
assessments evaluated by the masked investigator prior to receiving study treatment.  Patients 
will be instructed to contact the study site at any time if they have any health-related concerns.
If warranted, patients will be asked to return to the clinic as soon as possible for an unscheduled 
safety assessment visit.  
All assessments (including study treatment) for a scheduled visit are to be performed on the 
same day, except those performed during the screening period.
Study treatment visits cannot occur earlier than until a full 21 days have elapsed after the 
previous study treatment visit.  Missed study treatments will not be made up.
Note: After the Day 1 visit, if a patient misses a study visit when ocular images are to be 
obtained, the images must be obtained at the next scheduled visit the patient attends.  
If a patient misses more than two consecutive study treatment visits within any 24-week 
treatment period, the investigator and the Medical Monitor may consider discontinuing the 
patient from study treatment.  
For study masking requirements, see Section 4.2.  
Patients who are prematurely discontinued from study treatment but who agree to continue to 
participate in the study will be encouraged to undergo as many scheduled visits as possible,
with emphasis on completing the Week 48, 52, 56, and 100 visits.   
Study treatment visits will be scheduled Q4W (7 days) relative to the Day 1 visit date.
Patients who discontinue from the study prior to completion will be asked to return for an early 
termination visit after a minimum of 28 days have elapsed following their last study treatment for 
monitoring of adverse events and early termination visit assessments. 
Patients who complete study treatment (i.e., the Week 96 visit) will return for the final study visit 
(Week 100) after a minimum of 28 days have elapsed from their last study treatment for 
monitoring of adverse events and final study visit assessments.  
Treatment Schedule for Patients in the Personalized Treatment Interval Arm (Arm B)
Study drug dosing interval decisions in the PTI arm are automatically calculated by the IxRS 
based on the algorithm described in this section.  Study drug dosing visits are visits when a 
patient is assigned to receive RO6867461. 
Study Drug Dosing Interval Determination 
Patients randomized to the PTI arm (Arm B) will be treated with RO6867461 on a Q4W dosing 
interval until the patient’s Week 12 visit or later CST meets the predefined reference central 
subfoveal thickness (CST) threshold (CST 325 m for Spectralis SD-OCT, or 315 m for 
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Cirrus SD-OCT or Topcon SD-OCT).  The reference CST is used at study drug dosing visits by 
the IxRS for interval decision-making.
After a patient’s initial reference CST is established, their study drug dosing interval will be 
increased by 4 weeks to an initial Q8W dosing interval by the IxRS.  From this point forward, the 
study drug dosing interval will be extended, reduced, or maintained based on assessments 
made at study drug dosing visits.  See Section 3.1.2.1, Figure 2, for the algorithm used by the 
IxRS for interval decision-making, which is based on the relative change of the CST and BCVA 
compared with reference CST and BCVA.
Study Drug Dosing Intervals
The IxRS can adjust the study drug dosing interval by 4-week increments to a maximum of 
every 16 weeks (Q16W) and a minimum of Q4W.
Patients whose drug dosing interval is reduced from Q16W to a shorter interval because of 
disease activity will not be allowed to return to a Q16W interval but may be eligible for Q12W, 
Q8W, or Q4W interval, depending on disease activity. 
Patients whose drug dosing interval is reduced from Q16W to a shorter interval because of
study treatment interruption at the study drug dosing visit will be allowed to re-initiate the Q16W 
interval. 
Similar to Arms A and C, patients randomized to the PTI arm (Arm B) will receive a sham 
procedure at study visits when they are not receiving treatment with RO6867461.
Additional Considerations for PTI Arm IxRS Study Drug Dosing Interval Decision
Sites will report missed study visits (except of Day 7 visit) and study drug interruption visits to 
the IxRS for all patients (Arms A, B, and C) to preserve the masking.  The following algorithms 
are only applicable to patients in the PTI arm (Arm B) and are used by the IxRS to automatically 
determine study drug intervals in the event of the following situations.  
Missed Study Drug Dosing Visit(s)
If a patient misses a study drug dosing visit, the IxRS will assign the patient to receive study 
drug dosing at the next scheduled study visit the patient attends.  A decision regarding the 
subsequent study drug dosing interval will be made by the IxRS based on CST and BCVA 
assessments completed at the visit when study drug is administered, and any changes in the 
drug dosing interval will be based from the last assigned interval prior to the missed drug dosing 
visit.
Example:  If a patient was on the every Q12W drug dosing interval prior to missing the study 
drug dosing visit, then the IxRS decision to maintain, extend, or reduce the dosing interval will 
be made on the basis of the previously assigned drug interval along with CST and BCVA data 
obtained at the visit when the patient receives study drug.  If the data indicate that the patient 
should maintain the Q12W interval, then he or she will receive study drug 12 weeks after that 
visit.
Study Drug Interruption at Study Drug Dosing Visit(s)
If a patient's dosing has to be interrupted (e.g., because of an adverse event) at a study drug 
dosing visit, IxRS will assign the patient to receive study drug dosing at the earliest subsequent 
study visit when the patient is permitted to resume study drug dosing.  The IxRS will be used to 
determine the next study drug dosing based on a Q8W interval unless the patient was treated 
on a Q4W interval prior to dose interruption.  In that case, the patient will be evaluated on the 
basis of the Q4W interval. 
Missing CST Value at Study Drug Dosing Visit
If a patient attends a study drug dosing visit, but the CST value is not available for any reason 
(e.g., optical coherence tomography [OCT] machine is not available or is broken), the IxRS will 
assign the patient to receive study drug at that visit.  Generally, the IxRS will maintain the 
previous drug dosing interval.  However, in the event of a concurrent 10-letter decrease 
relative to the reference BCVA at that study drug dosing visit, the IxRS will reduce the study 
drug dosing interval by 4 weeks. 
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Missing BCVA Value at Study Drug Dosing Visit
If a patient attends a study drug dosing visit, but the BCVA value is not available for any reason 
(e.g., patient refuses BCVA examination), the IxRS will assign the patient to receive study drug 
at that visit.  The IxRS will base the study drug dosing interval determination on CST only.
Missed Study Drug Treatment Visit(s) for Patients in the Q8W Treatment Arms
If a patient randomized to treatment Arm A (RO6867461 Q8W) or Arm C (aflibercept Q8W) 
misses study drug treatment visit(s), the IxRS will assign the patient to receive RO6867461 or 
aflibercept at the next study visit he or she attends.  The Q8W drug treatment interval will be 
automatically reset by IxRS from that visit forward, thus 4 weeks later, at the following study 
visit, the patient will receive sham.  
Timely Reporting of BCVA Scores, CST Values, Missed Study Treatment Visits, or 
Study Treatment Interruptions for All Study Patients
Starting at the Day 1 visit, patients’ BCVA scores in all randomized treatment arms (Arms A, B, 
and C) from each study treatment visit have to be reported by the sites to the IxRS in a timely 
manner (ideally, within 24 hours of obtaining them).  Similarly, OCT images obtained at each 
study treatment visit have to be forwarded to the central reading center in a timely manner 
(ideally, within 24 hours of obtaining them).  Sites will report in a timely manner in the IxRS the 
study treatment visits that patients miss. Sites will report in the IxRS the study treatment 
interruption(s) in order that the correct study treatment (study drug or sham) can be assigned by 
the system to a patient for a future study treatment visit. 
Independent Data Monitoring Committee
An independent Data Monitoring Committee (iDMC) will monitor safety and study conduct on an 
ongoing basis. Members of the iDMC will be external to the Sponsor and will follow a charter 
that outlines the iDMC's roles and responsibilities. 
The iDMC will meet approximately every 6 months (frequency adjustable if required) to evaluate 
unmasked ocular and systemic (non-ocular) safety events with an emphasis on the evaluation 
of the rate of ocular inflammation, increased IOP, endophthalmitis, arterial thromboembolic 
events, and clinically significant decreases in BCVA, which will be prepared for the committee
by an independent Data Coordinating Center (iDCC).  The iDMC may recommend stopping the 
study early for safety reasons. 
After reviewing the data, the iDMC will provide a recommendation to the Sponsor as described 
in the iDMC Charter.  Final decisions will rest with the Sponsor.
Any outcomes of these data reviews that affect study conduct will be communicated in a timely 
manner to the investigators for notification of their respective Institutional Review Boards/Ethics 
Committees.
Number of Patients
Approximately 900 patients will be randomized during the global enrollment phase of the study. 
Target Population
Inclusion Criteria
Patients must meet the following inclusion criteria for study entry. 
General Inclusion Criteria
Patients must meet the following general inclusion criteria for study entry:

Willingness and the ability to provide signed informed consent
Additionally, at U.S. sites, patients must provide Health Insurance Portability and 
Accountability Act authorization, and in other countries, as applicable according to 
national laws.

Age 18 years

Documented diagnosis of diabetes mellitus (Type 1 or Type 2), as defined by the 
American Diabetes Association or per WHO criteria and 
–
Current regular use of insulin for the treatment of diabetes 
and/or
–
Current regular use of oral anti-hyperglycemic agents for the treatment of diabetes
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
Renal failure requiring renal transplant, hemodialysis, or peritoneal dialysis within 6 months 
prior to Day 1 or anticipated to require hemodialysis or peritoneal dialysis at any time during 
the study 

History of other disease, other non-diabetic metabolic dysfunction, physical examination 
finding, or clinical laboratory finding giving reasonable suspicion of a condition that 
contraindicates the use of the RO6867461 or aflibercept or that might affect interpretation of 
the results of the study or renders the patient at high risk for treatment complications in the 
opinion of the investigator 

Uncontrolled blood pressure (defined as systolic 180 mmHg and/or diastolic 100 mmHg 
while a patient is at rest)
If a patient’s initial reading exceeds these values, a second reading may be obtained 
later the same day or on another day during the screening period.  If the patient’s blood 
pressure is controlled by antihypertensive medication, the patient should be taking the 
same medication continuously for at least 30 days prior to Day 1.

Cerebral vascular accident or myocardial infarction within 6 months prior to Day 1

Pregnancy or breastfeeding, or intention to become pregnant during the study
Women of childbearing potential must have a negative urine pregnancy test result within 
28 days prior to initiation of study treatment.  If the urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test.

Participation in an investigational trial that involves treatment with any drug or device (with 
the exception of vitamins and minerals) within 3 months prior to Day 1 

Administration of systemic pro-angiogenic treatments, such as VEGF-based therapies for 
the peripheral or coronary ischemia (e.g., limb ischemia or myocardial infarction) within 
3 months or 5 half-lives prior to Day 1

Inability to comply with study or follow-up procedures

Requirement for continuous use of any medications and treatments indicated in 
Section 4.4.2, Prohibited Therapy
Ocular Exclusion Criteria for Study Eye
Patients who meet any of the following exclusion criteria for the study eye will be excluded from 
study entry:

High-risk proliferative diabetic retinopathy (PDR) in the study eye, using any of the following 
established criteria for high-risk PDR:
–
Any vitreous or pre-retinal hemorrhage
–
Neovascularization elsewhere 1/2 disc area within an area equivalent to the mydriatic 
ETDRS 7 fields on clinical examination or on CFPs
–
Neovascularization at disc 1/3 disc area on clinical examination

Tractional retinal detachment, pre-retinal fibrosis, or epiretinal membrane involving the 
fovea or disrupting the macular architecture in the study eye

Active rubeosis 

Uncontrolled glaucoma 

History of retinal detachment or macular hole (Stage 3 or 4) 

Aphakia or implantation of anterior chamber intraocular lens 

IVT anti-VEGF treatment within 3 months prior to Day 1 (applicable to patients whose study 
eyes were previously treated with IVT anti-VEGF agents) or any IVT anti-VEGF agents to 
study eye prior to Day 1 (applicable for patients who are treatment naive)

Treatment with panretinal photocoagulation (PRP) within 3 months prior to Day 1

Macular (focal or grid) laser within 3 months prior to Day 1

Any cataract surgery or treatment for complications of cataract surgery with steroids or YAG 
(yttrium-aluminum-garnet) laser capsulotomy within 3 months prior to Day 1
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Patients randomized to receive Q8W treatment will be administered 15 IVT injections of 
RO6867461 during the 96-week treatment period.  Treatment will consist of 6 initial injections 
(6 mg of RO6867461 Q4W to Week 20), followed by 9 maintenance injections (6 mg of 
RO6867461 Q8W between Week 24 and Week 96). 
The number of IVT injections of RO6867461 administered to patients in the PTI arm will vary, 
but a minimum of 10 IVT injections of RO6867461 will be administered to patients during the 
96-week treatment period.  This will consist of minimum of 4 initiating injections (6 mg of 
RO6867461 Q4W to Week 12), followed by minimum of 6 maintenance injections (6 mg of 
RO6867461 between Week 16 and Week 96). 
Comparator
Intravitreal Aflibercept Injections 
A 2-mg dose of aflibercept (Arm C) will be administered intravitreally Q8W to patients 
randomized to the aflibercept treatment arm during the 96-week treatment period.  Patients will 
receive 15 IVT injections of aflibercept during the 96-week treatment period.  Treatment will 
consist of 5 initiating injections (2 mg of aflibercept Q4W to Week 16), followed by 
10 maintenance injections (2 mg of aflibercept Q8W between Week 20 and Week 96).
Non-Investigational Medicinal Products
All three treatment arms (RO6867461 Q8W, RO6867461 PTI, and aflibercept Q8W) will 
maintain Q4W study visits for the 100-week study duration.  To preserve the randomized 
treatment arm masking, patients will have the sham procedure performed at study treatment 
visits when they are not treated with either RO6867461 or aflibercept as applicable per their 
treatment arm schedule.
Statistical Methods
Primary Analysis
The primary efficacy endpoint is the change from baseline in BCVA averaged over Weeks 48, 
52, and 56.  The BCVA outcome measure is based on the ETDRS visual acuity chart assessed 
at a starting distance of 4 meters. 
The primary comparisons will be the pairwise comparisons between the active comparator 
(aflibercept Q8W) and each of the RO6867461 arms (Q8W and PTI). Additional analyses 
based on the per-protocol population will also be conducted.
For the two RO6867461 arms (Q8W and PTI), the following three hypotheses will be tested for 
each treatment group separately at an overall significance level of 0.05 using a graph-based 
testing procedure to control for the overall type I error rate:

Non-inferiority of RO6867461 compared with aflibercept Q8W in the intent-to-treat 
(ITT) population

Superiority of RO6867461 compared with aflibercept Q8W in the treatment-naive population

Superiority of RO6867461 compared with aflibercept Q8W in the ITT population
If the tests for one treatment sequence are all positive, then /2 will be propagated to the 
beginning of the other treatment sequence, which will be tested at a significance level of 
0.05.  Of note, non-inferiority will be tested one sided at half of the designated significance 
level.
The non-inferiority tests for the RO6867461 Q8W arm and the RO6867461 PTI arm compared 
with aflibercept Q8W arm will be conducted with a non-inferiority margin of 4 letters. For each 
RO6867461 group (Q8W or PTI) the null hypothesis, 
H0: RO6867461aflibercept 4 letters, and the alternative hypothesis, 
Ha: RO6867461aflibercept 4 letters, will be tested, for which RO6867461 and aflibercept are the 
expected change from baseline in BCVA averaged over Weeks 48, 52, and 56 for the treatment 
group in question (RO6867461 Q8W or PTI) and the active comparator (aflibercept Q8W), 
respectively.
The change from baseline averaged over Weeks 48, 52, and 56 will be compared between 
each RO6867461 arm and the aflibercept Q8W arm using a mixed-model repeated measures 
(MMRM) model. The model will include the change from baseline at Weeks 456 as the 
response variables and will include the categorical covariates of treatment group, visit, 
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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
CI
center involvement
CST
central subfield thickness
DME
diabetic macular edema
DR
diabetic retinopathy
DRS
diabetic retinopathy severity
DRSS
Diabetic Retinopathy Severity Scale
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
ETDRS
Early Treatment Diabetic Retinopathy Study
FDA
Food and Drug Administration
FFA
fundus fluorescein angiography
GCP
Good Clinical Practice
HbA1c
hemoglobin A1c
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Council for Harmonisation
iDCC
independent Data Coordinating Center
iDMC
independent Data Monitoring Committee
IL-1b (-6)
interleukin-1b (-6)
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IOP
intraocular pressure
IRB
Institutional Review Board
ITT
intent to treat
IVT
intravitreal
IxRS
interactive voice or web-based response system
LPLV
last patient, last visit
MedDRA
Medical Dictionary for Regulatory Activities
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Abbreviation
Definition
MMRM
mixed-model repeated-measures (model)
nAMD
neovascular age-related macular degeneration
NEI VFQ-25
National Eye Institute Visual Functioning
Questionnaire25
NPDR
non-proliferative diabetic retinopathy
OCT-A
optical coherence tomographyangiography
PD
pharmacodynamic
PDR
proliferative diabetic retinopathy
PK
pharmacokinetic
PRO
patient-reported outcome
PRP
panretinal photocoagulation
PTI
personalized treatment interval 
Q4W
every 4 weeks
Q8W
every 8 weeks
Q12W
every 12 weeks
Q16W
every 16 weeks
RBR
Research Biosample Repository
SD
standard deviation
SD-OCT
spectral-domain optical coherence tomography
SOC
standard of care
SS-OCT
swept-source optical coherence tomography
ULN
upper limit of normal
VA
visual acuity
VEGF(-A)
vascular endothelial growth factor(A)
YAG
yttrium-aluminum-garnet
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1.
BACKGROUND
1.1
BACKGROUND ON DIABETIC MACULAR EDEMA
Diabetic macular edema (DME), a complication of diabetic retinopathy (DR), 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
(Henricsson et al. 1999; Johnson 2009) from non-proliferative DR (NPDR) to proliferative 
DR (PDR). DME 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), and if 
left untreated 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). In 2013, the worldwide 
population of people with diabetes was approximately 382 million, and it is estimated to 
grow to 592 million by 2035 (International Diabetes Federation 2013). 
With advances in imaging technology, DME is now often diagnosed by optical coherence 
tomography (OCT) rather than the traditional Early Treatment Diabetic Retinopathy 
Study (ETDRS) ophthalmoscopy-based criteria. 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 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 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).
Although macular laser used to be the standard of care (SOC) for treatment of DME, the 
development of anti-VEGF pharmacotherapy in the past 10 years has led to dramatic 
improvements in visual outcomes for patients with DME. 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 strong efficacy achieved with anti-VEGF therapies in DME, a significant 
proportion of patients do not experience clinically meaningful improvements in vision in 
the real world. Frequent IVT administration is required to achieve, and in some cases, to 
maintain the observed early benefits of DME treatment over a long period of time. 
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The current SOC for administration of anti-VEGF injections requires patients to undergo 
frequent clinical examinations and IVT injections. This imposes a significant burden on 
patients, caregivers, treating physicians, and the healthcare system. 
Large Phase III trials of anti-VEGF agents in DME demonstrated that after the first year 
of treatment, the number of injections needed for maintenance of vision gains can be 
decreased (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 predictive biomarkers of treatment frequency, the standard 
anti-VEGF approach in DME still relies on frequent monitoring visits and places 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 high unmet medical need in DME.
1.2
BACKGROUND ON RO6867461
RO6867461 is a humanized full-length bispecific IgG1 antibody that selectively 
neutralizes VEGF-A and Ang-2, the key factors mediating pathophysiology of diabetic 
eye disease. RO6867461 was developed using Roche’s CrossMab (monoclonal 
antibody) technology. The VEGF binding and the Ang-2 binding variable regions of 
RO6867461 bind to VEGF and Ang-2 simultaneously and with high affinity. The Fc 
portion of RO6867461 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 VEGF and Ang-2 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 RO6867461
treatment compared with anti-VEGF monotherapy.
Based on the novel mechanism of action of RO6867461 through selective neutralization 
of both VEGF and Ang-2, and based on the pathophysiology of diabetic eye disease, it is 
hypothesized that RO6867461 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.
Refer to the RO6867461 Investigator's Brochure for details on nonclinical and 
clinical studies.
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1.3
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
The Phase III program will evaluate the efficacy, safety, and pharmacokinetics of 
RO6867461 when administered to patients every 8 weeks (Q8W) and with a 
personalized treatment interval (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) (i.e., the 
number of ETDRS letters). 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 RO6867461 will be assessed. 
The Phase II study (BP30099 [BOULEVARD]) provided preliminary evidence of a 
positive benefitrisk profile for the use of 6-mg IVT injections of RO6867461 for patients 
with DME and supports further evaluation of RO6867461 in Phase III DME studies.
Additionally, the efficacy, safety, and treatment frequency of IVT RO6867461
administration has been assessed in another retinal disease indication, neovascular 
age-related macular degeneration (nAMD), in one Phase I study (BP28936) and in two 
Phase II studies (BP29647 [AVENUE] and CR39521 [STAIRWAY]).
Based on the totality of evidence from the Phase II studies, and taking into account 
evidence from the preclinical models, it is anticipated that the well-established 
anti-VEGF mechanism of action combined with antiAng-2 targeting in the bispecific 
RO6867461 molecule will lead to improved efficacy and/or reduced injection burden 
compared with anti-VEGF monotherapy. This would represent an important advance for 
patients with DME.
1.3.1
Benefits
The clinical benefit of IVT RO6867461 injections for patients with DME was 
demonstrated in the Phase II study BP30099. The study met its primary efficacy 
endpoint, which was the mean change from baseline in BCVA at Week 24 in anti-VEGF
treatmentnaive patients treated with RO6867461 compared with 0.3 mg of 
ranibizumab.
Study BP30099 enrolled 229 patients with DME. The study was originally designed to 
enroll anti-VEGF treatmentnaive patients. The protocol was subsequently amended to 
include an additional cohort of patients (n61) who were previously treated with 
anti-VEGF for DME to allow for the exploratory evaluation of the efficacy of RO6867461
in this population.
Anti-VEGF treatmentnaive patients were randomized equally into three treatment arms:  
6 mg of IVT RO6867461, 1.5 mg of IVT RO6867461, and 0.3 mg of IVT ranibizumab.
Patients who were previously treated with anti-VEGF were randomized equally to
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receive either 6 mg of IVT RO6867461 or 0.3 mg of IVT ranibizumab. Key demographic 
and ocular baseline characteristics were generally well balanced. The study consisted 
of a treatment period (20 weeks in length) and an observational period (up to 16 weeks
in length), for a total study duration of up to 36 weeks. Study treatment was 
administered to patients by IVT injection at every-4-week (Q4W) intervals up to the last 
injection at Week 20, with the primary endpoint assessed at Week 24. The 
observational period without treatment lasted up to 16 weeks from Week 20 to Week 36. 
The observation period allowed for exploration of the durability of pharmacodynamic 
(PD) effects after the last treatment.
The mean BCVA change from baseline in the anti-VEGF treatmentnaive patients 
treated with 6 mg of RO686746 improved steadily over time, with patients experiencing 
an average benefit of 3.6 letters (p0.03; 80% confidence interval [CI]: 1.5 to 5.6 letters)
over anti-VEGF monotherapy (adjusted for baseline variables) at Week 24 (1 month
after the last monthly dose administered at Week 20), which was statistically significant 
in a mixed-model repeated measures (MMRM) analysis. In this anti-VEGF 
treatmentnaive population, the mean change in BCVA from baseline in the 6-mg
RO6867461 group and the 1.5-mg RO6867461 group at Week 24 was 13.9 letters and 
11.7 letters, respectively, relative to 10.3 letters in the 0.3-mg ranibizumab group. The 
proportion of treatment-naive patients gaining 15 letters or more from baseline over time 
at Week 24 was 35.3% for the 0.3-mg ranibizumab group relative to 36.0% and 42.5% 
for the 1.5-mg and 6-mg RO6867461 groups, respectively. In addition to DME benefit,
higher rates of improvement in DR severity from baseline (as assessed on the ETDRS 
Diabetic Retinopathy Severity Scale [DRSS]) were also observed with RO6867461 
compared with anti-VEGF monotherapy in the antiVEGF treatmentnaive cohort, with 
27.7% and 38.6% of patients (1.5-mg and 6-mg RO6867461, respectively) experiencing
a 2-step improvement from baseline to Week 24 compared with 12.2% in the 0.3-mg 
ranibizumab treatment cohort. 
For the previously anti-VEGFtreated population, the absolute change from baseline 
was 9.6 letters and 8.3 letters for the 6-mg RO6867461 group and the anti-VEGF group, 
respectively.  The difference of 1.3 letters was directionally similar to the 
treatment-naive cohort but was not statistically significant (p0.635; 80% CI:2.3 to 5.0). 
Additionally, the proportion of patients gaining 15 or more letters from baseline over time 
at Week 24 was 23.2% and 16.8% for the 6-mg RO6867461 and anti-VEGF SOC 
treatment arms, respectively. The anatomical outcomes showed directionally similar 
benefits for RO6867461 in this cohort.
Overall, the data from intent-to-treat (ITT) study population (both treatment-naive and 
previously anti-VEGFtreated patients) suggest consistent benefit of RO6867461 over 
anti-VEGF monotherapy in the general DME population.
The outcomes in the off-treatment study observation period provided evidence of 
prolonged duration of effect with RO6867461 compared with anti-VEGF monotherapy.
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Assessment of time to disease reactivation up to 16 weeks after the last dose showed 
an improvement in the duration of the effect of RO6867461 over ranibizumab, as 
measured by the time to loss of 5 ETDRS letters because of DME and an increase
50 m in CST in the treatment-naive patient population in a dose-dependent manner.  
This improvement in the duration of effect of RO6867461 over ranibizumab was also 
seen in the previously treated group and the overall patient group.
In summary, the data from Study BP30099 suggested a dose-related benefit favoring the 
6-mg dose of RO6867461 relative to the 1.5-mg dose, as measured by both the efficacy 
outcomes and duration of effect.  Based on these results, the 6-mg dose of RO6867461 
has been chosen for further clinical development in Phase III studies in patients with 
DME to explore its benefit compared with SOC IVT anti-VEGF treatment from the 
following perspectives:

Potential for superior efficacy outcomes in DME with 6 mg of IVT RO6867461
compared with SOC IVT

Potential for prolonged treatment duration while achieving and maintaining 
comparable efficacy with 6 mg of IVT RO6867461 compared with SOC IVT
The Phase III clinical development program will enroll both patients with DME who are 
naive to anti-VEGF therapy in the study eye and patients who were previously treated 
with anti-VEGF therapy in the study eye to further explore outcomes on DME in both 
populations.
1.3.2
Risks
In the Phase I study (BP28936), single and multiple IVT administrations of RO6867461 
were well tolerated in patients with nAMD up to the highest dose tested, 6 mg. No 
deaths and no dose-limiting events were reported.
The Phase II study BP30099 in DME also showed an acceptable tolerability and safety 
profile, with no new or unexpected safety signals. No serious ocular or systemic 
adverse events considered related to treatment with RO6867461 were reported. The 
ocular and systemic safety findings for RO6867461 observed in the Phase II study were 
generally consistent with the safety profile reported in patients with DME who receive 
intravitreally administered anti-VEGF products.
Additionally, the safety of IVT RO6867461 administration has been assessed in patients 
with nAMD in two Phase II studies (BP29647 [AVENUE] and CR39521 [STAIRWAY]).
A total of 436 patients have been exposed to at least one dose of RO6867461 to date. 
No unexpected safety signals have been identified in these studies that would change 
the anticipated safety profile in the Phase III DME program.
Based on the totality of evidence from the Phase I and Phase II studies, and taking into
account evidence from the murine and non-human primate preclinical and toxicology 
models, it is anticipated that the additional antiAng-2 mechanism of action of the 
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RO6867461 molecule will not lead to an increase in safety risks compared with IVT
anti-VEGF monotherapy.
Refer to the RO6867461 Investigator's Brochure for details on safety results from
nonclinical and clinical Phase I and Phase II studies.
1.3.3
Conclusions
The available Phase I and II efficacy and safety data showed a benefitrisk profile that 
supports further assessment of the efficacy and safety of 6 mg RO6867461 across
various treatment intervals compared with anti-VEGF IVT monotherapy in a Phase III 
DME program.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, and pharmacokinetics of RO6867461 when 
dosed Q8W and with a PTI regimen compared with aflibercept (Eylea®) monotherapy in 
patients with DME.  Specific objectives and corresponding endpoints for the study are 
outlined in Table 1. An overview of the proposed statistical analyses is described in
Section 6.
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Table 1
Objectives and Corresponding Endpoints
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of IVT 
injections of the 6-mg dose of 
RO6867461 on BCVA outcomes
Change from baseline in BCVA (as measured on
the ETDRS chart at a starting distance of 
4 meters) at 1 year a
Key Secondary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of 
RO6867461 on DR severity outcomes
Proportion of patients with a 2-step DRS 
improvement from baseline on the ETDRS 
DRSS at Week 52
Secondary Efficacy Objectives
Corresponding Endpoints
To evaluate the efficacy of 
RO6867461 on additional BCVA 
outcomes
Change from baseline in BCVA (as measured on
the ETDRS chart at a starting distance of 
4 meters) over time 
Proportion of patients gaining 15, 10, 5, or 
0 letters in BCVA from baseline over time
Proportion of patients avoiding a loss of 15, 
105, or >0 letters in BCVA from baseline 
over time
Proportion of patients gaining 15 letters or 
achieving BCVA of 84 letters over time
Proportion of patients with BCVA Snellen 
equivalent of 20/40 or better over time
Proportion of patients with BCVA Snellen 
equivalent of 20/200 or worse over time
To evaluate the efficacy of 
RO6867461 on additional DR 
outcomes
Proportion of patients with a 2-step DRS 
improvement from baseline on the ETDRS DRSS
over time
Proportion of patients with a 3-step DRS 
improvement from baseline on the ETDRS DRSS 
over time
Proportion of patients who develop new PDR 
over time 
To evaluate RO6867461 treatment 
intervals in the PTI arm
Proportion of patients in the PTI arm on a Q4W, 
Q8W, Q12W, or Q16W treatment interval at 
1 year and 2 years
Treatment intervals in the PTI arm over time
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Table 1
Objectives and Corresponding Endpoints (cont.)
Secondary Efficacy Objectives (cont.)
Corresponding Endpoints (cont.)
To evaluate the efficacy of 
RO6867461 on anatomical outcome 
measures using SD-OCT
Change from baseline in CST over time
Proportion of patients with absence of DME (CST 
325 m for Spectralis SD-OCT, or 315 m for 
Cirrus SD-OCT or Topcon SD-OCT) over time
Proportion of patients with absence of intraretinal 
fluid over time
Proportion of patients with absence of subretinal 
fluid over time
Proportion of patients with absence of intraretinal 
fluid and subretinal fluid over time
To evaluate the efficacy of 
RO6867461 on patient-reported 
vision-related functioning and quality 
of life using the NEI VFQ-25
Change from baseline in NEI VFQ-25 composite 
score over time
Safety Objective
Corresponding Endpoints
To evaluate the ocular and systemic
safety and tolerability of RO6867461
Incidence and severity of ocular adverse events
Incidence and severity of non-ocular 
adverse events
Exploratory Efficacy Objectives
Corresponding Endpoints
To further evaluate the efficacy of 
RO6867461 on additional DR 
outcomes
Proportion of patients with a 2-step or 3-step 
DRS worsening from baseline on ETDRS DRSS 
over time
Proportion of patients who receive vitrectomy or 
PRP over time during the study
To further evaluate the efficacy of 
RO6867461 on anatomical outcome 
measures using FFA and/or OCT-A
Change from baseline in total area of macular 
non-perfusion and macular ischemia over time
Change from baseline in total area of vascular 
leakage over time
Proportion of patients with resolution of macular 
leakage over time
Change from baseline CST neurosensory over 
time (as measured on SD-OCT)
Change from baseline in total macular volume 
over time (as measured on SD-OCT)
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Table 1
Objectives and Corresponding Endpoints (cont.)
Exploratory Efficacy Objectives
(cont.)
Corresponding Endpoints
(cont.)
To further evaluate the efficacy of 
RO6867461 on patient-reported 
vision-related functioning and quality 
of life using the NEI VFQ-25
Change from baseline in the NEI VFQ-25 Near 
Activities, Distance Activities, and Driving 
subscales at 1 year a
Proportion of patients with a 4-point 
improvement from baseline in NEI VFQ-25 
composite score
Pharmacokinetic Objective
Corresponding Endpoint
To characterize the systemic 
pharmacokinetics of RO6867461
Plasma concentration of RO6867461 over time
Immunogenicity Objectives
Corresponding Endpoints

To evaluate the immune response to 
RO6867461
Presence of ADAs during the study relative to 
the presence of ADAs at baseline

To evaluate potential effects of ADAs
Relationship between ADA status and efficacy, 
safety, or PK endpoints
Exploratory Pharmacokinetic, 
Pharmacodynamic, and Biomarker 
Objectives
Corresponding Endpoints
To identify biomarkers that are 
predictive of response to RO6867461, 
are associated with progression to a 
more severe disease state, are 
associated with susceptibility to 
developing adverse events, can 
provide evidence of RO6867461 
activity, or can increase the 
knowledge and understanding of 
disease biology
Concentration of biomarkers of angiogenesis 
and inflammation in aqueous humor (optional) at 
baseline and over time and their correlation with 
PK and/or primary and secondary endpoints at 
baseline and over time
Relationship between efficacy, safety, PK, 
immunogenicity,
 
Relationship between baseline anatomic 
measures and the change in BCVA or other 
endpoints (e.g., the frequency of study drug 
administration) over time
Relationship between anatomic measures and 
visual acuity
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Table 1
Objectives and Corresponding Endpoints (cont.)
Exploratory Pharmacokinetic, 
Pharmacodynamic, and Biomarker 
Objectives (cont.)
Corresponding Endpoints (cont.)
To evaluate potential relationships 
between selected covariates and 
exposure to RO6867461
Relationship between selected covariates and 
plasma or aqueous humor (optional) 
concentration or PK parameters for RO6867461
To characterize the aqueous humor 
(optional) and vitreous (optional) 
pharmacokinetics of RO6867461
Aqueous humor (optional) and vitreous 
(optional) concentration of RO6867461
over time
To evaluate the drug concentration 

To explore the concentrationeffect 
relationship for visual acuity and other 
endpoints (e.g., anatomical markers)
Pharmacokinetics of RO6867461 and the 
change in BCVA or other endpoints (e.g., 
anatomical markers) over time
ADAanti-drug antibody;
 
BCVAbest-corrected visual acuity; CSTcentral subfield thickness; DRdiabetic retinopathy; 
DRSdiabetic retinopathy severity; DRSSDiabetic Retinopathy Severity Scale; 
ETDRSEarly Treatment Diabetic Retinopathy Study; FFAfundus fluorescein angiography; 
IVTintravitreal; NEI VFQ-25National Eye Institute 25-Item Visual Function Questionnaire; 
OCT-Aoptical coherence tomographyangiography; PDRproliferative diabetic retinopathy; 
PKpharmacokinetic; PRPpanretinal photocoagulation; PTIpersonalized treatment 
interval; Q4W every 4 weeks; Q8Wevery 8 weeks; Q12W every 12 weeks; Q16W every 
16 weeks; SD-OCTspectral-domain optical coherence tomography;
a The definition of 1 year for the primary endpoint is the average of the Week 48, 52, and 56 
visits.
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a Phase III, double-masked, multicenter, randomized, active 
comparatorcontrolled, parallel-group study, evaluating the efficacy, safety, 
pharmacokinetics, and optimal treatment frequency of RO6867461 administered by IVT
injection at 8-week intervals or PTI of approximately 100 weeks' duration (excluding the 
screening period) to patients with DME.  
3.1.1
Overview of Study Design
Approximately 900 patients will be randomized during the global enrollment phase of the 
study in a 1:1:1 ratio to one of three treatment arms (see Figure 1) at approximately 
240 investigational sites globally.  The study will randomize patients with DME who are
naive to anti-VEGF therapy in the study eye and patients who have previously been 
treated with anti-VEGF therapy in the study eye, provided that the last treatment was at 
least 3 months prior to the Day 1 visit (the first study treatment).  Site investigators will 
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be retina specialists or the equivalent outside of the United States (see Section 4.2.2 for 
additional details).
The study treatment arms will be as follows:

Arm A (administered Q8W) (n300):  Patients randomized to Arm A will receive 
6-mg IVT RO6867461 injections Q4W to Week 20, followed by 6-mg IVT 
RO6867461 injections Q8W to Week 96, followed by the final study visit at 
Week 100.

Arm B (PTI) (n300):  Patients randomized to Arm B will receive 6-mg IVT 
RO6867461 injections Q4W to at least Week 12, followed by PTI dosing (see the
PTI dosing criteria below) of 6-mg IVT RO6867461 injections to Week 96, followed 
by the final study visit at Week 100.

Arm C (comparator arm) (administered Q8W) (n300): Patients randomized to 
Arm C will receive 2-mg IVT aflibercept injections Q4W to Week 16, followed by 
2-mg IVT aflibercept injections Q8W to Week 96, followed by the final study visit at 
Week 100.
Patients in all three treatment arms will complete scheduled study visits Q4W for the 
entire study duration (100 weeks). A sham procedure will be administered to patients in
all three treatment arms at applicable visits to maintain masking among treatment arms
(see Figure 1).
Figure 1 presents an overview of the study treatment design.  A schedule of activities is 
provided in Appendix 1.
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Figure 1
Study Treatment Schema
IVTintravitreal; Q8Wevery 8 weeks; PTIpersonalized treatment interval (see Section 3.1.2 for 
additional details); Wweek.
a The definition of 1 year used for the primary efficacy endpointdefined as the change from 
baseline in BCVA, as measured on the ETDRS chart at a starting distance of 4 meters at 
1 yearis the average of the Week 48, 52, and 56 visits.
Only one eye will be assigned as the study eye.  If both eyes are considered eligible, the 
eye with the worse BCVA, as assessed at screening, will be selected as the study eye 
unless the investigator deems the other eye to be more appropriate for treatment in the 
study.
There will be a minimum of two investigators per site to fulfill the masking requirements 
of the study.  At least one investigator will be designated as the assessor physician who 
will be masked to each patient’s treatment assignment and who will evaluate ocular 
assessments.  At least one other investigator will be unmasked and will perform study 
treatments (see Section 4.2.2 for additional masking details). 
The study will consist of a screening period of up to 28 days (Days 28 to 1) in length 
and an approximately 96-week treatment period, followed by the final study visit at 
Week 100. A unique screening number will be assigned to each screened patient 
through an interactive voice or web-based response system (IxRS).
3.1.1.1
Screening
Informed consent must be administered and signed by a patient before any 
study-specific screening procedure is performed. Each consented patient must satisfy 
the eligibility criteria as applicable at screening and/or the Day 1 visit (see Sections 4.1.1
and 4.1.2).  
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Note: Some patients may require an extended screening period (more than 28 days) as 
a result of repeated evaluation of images or other issues.  Upon agreement with the 
Medical Monitor, the screening period may be extended by up to 5 business days in
such cases.
The screening and Day 1 (randomization) visits may occur as a combined visit if all 
assessments are completed and evaluated on the same day or within 2 business days.
When screening and the Day 1 visit are completed on the same day, the assessments 
listed for both visits (see the schedule of activities in Appendix 1) should be conducted 
only once. A historic hemoglobin A1c (HbA1c) value must be available from within 
2 months prior to Day 1 to enable screening and randomization to occur on the same 
day. If a historic value is used, receipt of screening laboratory results would not be 
required prior to randomization. If the screening and Day 1 visit are not completed on 
the same day (but rather within 2 business days), the following safety assessments will 
be repeated on the day of patient’s randomization and study treatment administration:
slitlamp examination, indirect ophthalmoscopy, and pre- and post-treatment intraocular 
pressure (IOP) measurements (recorded on the Day 1 electronic Case Report Form 
[eCRF] and dated accordingly).
After screening has been completed, eligible patients will have a randomization 
identification number assigned through the IxRS and will be randomized in a 1:1:1 ratio 
in order that approximately 300 patients are randomized to each of the three treatment 
arms. Randomization will be stratified by baseline BCVA ETDRS letter score, as 
assessed on Day 1 (64 letters or better vs. 63 letters or worse), prior IVT anti-VEGF 
therapy (yes vs. no), and region (United States and Canada, Asia, and the rest of the 
world).
3.1.1.2
Screen-Failed Patients
Patients who are not eligible for enrollment (screen failures) may be eligible for 
re-screening for up to an additional two times during the enrollment period of the study.
At re-screening, a new screening number will be assigned to each patient through the 
IxRS and all screening visit assessments will be performed. At the Day 1 visit, fundus
FFA images do not have to be repeated, provided that acceptable FFA images are 
received by the central reading center within 4 weeks before the new Day 1 visit 
(randomization) date.
3.1.1.3
Randomization and Visit Schedule
The first study treatment will be administered on the same day as randomization, which 
will be performed through the IxRS (i.e., at the Day 1 visit).  
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Note: If a site has an unexpected issue (e.g., the IxRS is not able to assign the study kit), 
a patient’s first study treatment may be administered within 2 business days of the Day 1 
visit after consultation with the Medical Monitor.  The following assessments will be 
repeated on the day of study treatment: slitlamp examination, indirect ophthalmoscopy, 
and pre- and post-treatment IOP measurements (recorded on the Day 1 eCRF and 
dated accordingly).
Starting at the Day 1 visit, randomized patients will have study treatment administered 
Q4W by the unmasked investigator that will be followed by the safety assessments 
(finger-counting test and post-dose IOP measurement). After the Day 1 visit, patients 
will also have safety assessments (see Appendix 1) evaluated by the masked 
investigator prior to receiving study treatment (for additional details about masking, see 
Section 4.2).  Patients will be instructed to contact the study site at any time if they have 
any health-related concerns. If warranted, patients will be asked to return to the clinic as 
soon as possible for an unscheduled safety assessment visit (see Appendix 2).  
All assessments (including study treatment) for a scheduled visit are to be performed on 
the same day, except those performed during the screening period.
Study treatment visits cannot occur earlier than until a full 21 days have elapsed after 
the previous study treatment visit.  Missed study treatments will not be made up.
Note: After the Day 1 visit, if a patient misses a study visit when ocular images are to be 
obtained (see Appendix 1), the images must be obtained at the next scheduled visit the 
patient attends.  
If a patient misses more than two consecutive study treatment visits within any 24-week 
treatment period, the investigator and the Medical Monitor may consider discontinuing 
the patient from study treatment.  
For study masking requirements, see Section 4.2.  
Patients who are prematurely discontinued from study treatment but who agree to 
continue to participate in the study will be encouraged to undergo as many scheduled 
visits as possible, with emphasis on completing the Week 48, 52, 56, and 100 visits.
Study treatment visits will be scheduled Q4W (7 days) relative to the Day 1 visit date.
Patients who discontinue from the study prior to completion will be asked to return for an 
early termination visit after a minimum of 28 days have elapsed following their last study 
treatment for monitoring of adverse events and early termination visit assessments (see 
Appendix 1). 
Patients who complete study treatment (i.e., the Week 96 visit) will return for the final 
study visit (Week 100) after a minimum of 28 days have elapsed from their last study 
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treatment for monitoring of adverse events and final study visit assessments (see 
Appendix 1).  
3.1.2
Treatment Schedule for Patients in the Personalized 
Treatment Interval Arm (Arm B)
Study drug dosing interval decisions in the PTI arm are automatically calculated by the 
IxRS based on the algorithm described in this section. Study drug dosing visits are visits 
when a patient is assigned to receive RO6867461. 
3.1.2.1
Study Drug Dosing Interval Determination 
Patients randomized to the PTI arm (Arm B) will be treated with RO6867461 on a Q4W 
dosing interval until the patient’s Week 12 visit or later CST meets the predefined 
reference CST threshold (CST 325 m for Spectralis SD-OCT, or 315 m for Cirrus 
SD-OCT or Topcon SD-OCT).  The reference CST is used at study drug dosing visits by 
the IxRS for interval decision-making.
After a patient’s initial reference CST is established, their study drug dosing interval will 
be increased by 4 weeks to an initial Q8W dosing interval by the IxRS.  From this point 
forward, the study drug dosing interval will be extended, reduced, or maintained based 
on assessments made at study drug dosing visits.  Figure 2 outlines the algorithm used 
by the IxRS for interval decision-making, which is based on the relative change of the 
CST and BCVA compared with reference CST and BCVA.
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Figure 2
Algorithm for IxRS-Determined Personalized Treatment Interval
Study Drug Dosing Intervals 
All comparisons are made relative to the reference CST* and reference BCVA**.  The 
IxRS will determine the study drug dosing interval based on CST and BCVA data 
obtained from the study drug dosing visits. 
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 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
*
Reference center subfoveal thickness (CST):  the CST value when the initial CST threshold 
criteria are met. Reference CST is adjusted if CST decreases by 10% from the previous 
reference CST for two consecutive study 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.
**
Reference best-corrected visual acuity (BCVA): the mean of the three best BCVA scores 
obtained at any prior study drug dosing visit.
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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3.1.2.2
Study Drug Dosing Intervals
The IxRS can adjust the study drug dosing interval by 4-week increments to a maximum 
of every 16 weeks (Q16W) and a minimum of Q4W.
Similar to Arms A and C, patients randomized to the PTI arm (Arm B) will receive a 
sham procedure at study visits when they are not receiving treatment with RO6867461.
3.1.3
Additional Considerations for PTI Arm IxRS Study Drug Dosing 
Interval Decision
Sites will report missed study visits (except of Day 7 visit) and study drug interruption
visits to the IxRS for all patients (Arms A, B, and C) to preserve the masking. The 
following algorithms are only applicable to patients in the PTI arm (Arm B) and are used 
by the IxRS to automatically determine study drug intervals in the event of the following
situations.
3.1.3.1
Missed Study Drug Dosing Visit(s)
If a patient misses a study drug dosing visit, the IxRS will assign the patient to receive 
study drug dosing at the next scheduled study visit the patient attends. A decision 
regarding the subsequent study drug dosing interval will be made by IxRS based on 
CST and BCVA assessments completed at the visit when study drug is administered,
and any changes in the drug dosing interval will be based from the last assigned interval
prior to the missed drug dosing visit.
Example:  If a patient was on the every 12 weeks (Q12W) drug dosing interval prior to 
missing the study drug dosing visit, then the IxRS decision to maintain, extend, or 
reduce the dosing interval will be made on the basis of the previously assigned drug 
interval along with CST and BCVA data obtained at the visit when the patient receives
study drug.  If the data indicate that the patient should maintain the Q12W interval, then 
he or she will receive study drug 12 weeks after that visit.
3.1.3.2
Study Drug Interruption at Study Drug Dosing Visit(s)
If a patient's dosing has to be interrupted (e.g., because of an adverse event) at a study 
drug dosing visit, IxRS will assign the patient to receive study drug dosing at the earliest
subsequent study visit when the patient is permitted to resume study drug dosing. The
IxRS will be used to determine the next study drug dosing based on a Q8W interval
unless the patient was treated on a Q4W interval prior to dose interruption. In that case, 
the patient will be evaluated on the basis of the Q4W interval.
3.1.3.3
Missing CST Value at Study Drug Dosing Visit
If a patient attends a study drug dosing visit, but the CST value is not available for any 
reason (e.g., OCT machine is not available or is broken), the IxRS will assign the patient 
to receive study drug at that visit.  Generally, the IxRS will maintain the previous drug 
dosing interval.  However, in the event of a concurrent 10-letter decrease relative to the 
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reference BCVA at that study drug dosing visit, the IxRS will reduce the study drug 
dosing interval by 4 weeks. 
3.1.3.4
Missing BCVA Value at Study Drug Dosing Visit
If a patient attends a study drug dosing visit, but the BCVA value is not available for any 
reason (e.g., patient refuses BCVA examination), the IxRS will assign the patient to 
receive study drug at that visit.  The IxRS will base the study drug dosing interval 
determination on CST only.
3.1.4
Missed Study Drug Treatment Visit(s) for Patients in the 
Q8W Treatment Arms
If a patient randomized to treatment Arm A (RO6867461 Q8W) or Arm C (aflibercept 
Q8W) misses study drug treatment visit(s) after the Q4W initiating doses, the IxRS will 
assign the patient to receive RO6867461 or aflibercept at the next study visit he or she 
attends. The Q8W drug treatment interval will be automatically reset by the IxRS from 
that visit forward, thus 4 weeks later, at the following study visit, the patient will receive 
sham. 
3.1.5
Timely Reporting of BCVA Scores, CST Values, Missed 
Study Treatment Visits, or Study Treatment Interruptions for 
All Study Patients
Starting at the Day 1 visit, patients’ BCVA scores in all randomized treatment arms 
(Arms A, B, and C) from each study treatment visit have to be reported by the sites to 
the IxRS in a timely manner (ideally, within 24 hours of obtaining them).  Similarly, OCT 
images obtained at each study treatment visit have to be forwarded to the central 
reading center in a timely manner (ideally, within 24 hours of obtaining them). Sites will 
report in a timely manner in the IxRS the study treatment visits that patients miss.
Sites will report in the IxRS the study treatment interruption(s) in order that the correct 
study treatment (study drug or sham) can be assigned by the system to a patient for a 
future study treatment visit.
3.1.6
Independent Data Monitoring Committee
An independent Data Monitoring Committee (iDMC) will monitor safety and study 
conduct on an ongoing basis. Members of the iDMC will be external to the Sponsor and 
will follow a charter that outlines the iDMC's roles and responsibilities. 
The iDMC will meet approximately every 6 months (frequency adjustable if required) to 
evaluate unmasked ocular and systemic (non-ocular) safety events with an emphasis on 
the evaluation of the rate of ocular inflammation, increased IOP, endophthalmitis, arterial 
thromboembolic events, and clinically significant decreases in BCVA, which will be 
prepared for the committee by an independent Data Coordinating Center (iDCC). The 
iDMC may recommend stopping the study early for safety reasons. 
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After reviewing the data, the iDMC will provide a recommendation to the Sponsor as 
described in the iDMC Charter.  Final decisions will rest with the Sponsor.
Any outcomes of these data reviews that affect study conduct will be communicated in a 
timely manner to the investigators for notification of their respective Institutional Review 
Boards/Ethics Committees (IRBs/ECs).
3.2
END OF STUDY AND LENGTH OF STUDY
The study consists of two enrollment phases: the global enrollment phase, during which 
patients are recruited globally,
 
 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs, 
  The end of the study is expected 
to occur approximately 100 weeks after the last patient is randomized.
The total length of the study
from screening of the first 
patient to the LPLV for patients from the global enrollment phase is expected to be 
approximately 46 months.
3.3
RATIONALE FOR STUDY DESIGN
A multicenter, double-masked, randomized, comparator-controlled trial design was 
selected to minimize bias in the evaluation of RO6867461 as a treatment for patients 
with DME. 
To ensure the safety of all patients during the conduct of the study, several safety 
assessments have been included, for example, regular ophthalmological monitoring and 
imaging assessments, adverse event monitoring (ocular and systemic), and laboratory 
safety tests (see Section 4.5 and Appendix 1 for a description of study assessments).
Optional aqueous humor samples will be collected from consenting patients in regions 
where optional sampling is approved, with the aim to further understand the ocular 
pharmacokinetics of RO6867461 as well as to assess biomarkers (see Section 3.3.4).
Single (Krohne et al. 2012) and multiple (Campochiaro et al. 2013) aqueous humor 
samplings have previously been instrumental in the understanding of ocular 
pharmacokinetics and VEGF suppression (Muether et al. 2012, 2013, 2014; Fauser 
et al. 2014; Fauser and Muether 2016; Hutton-Smith et al. 2017) and were safely applied 
in RO6867461 clinical studies in a total of 180 patients.
3.3.1
Rationale for Treatment Arms Dose and Schedule
3.3.1.1
Rationale for RO6867461 Dose and Schedule
The 6-mg dose of RO6867461 will be administered to patients as initiating and 
maintenance doses in treatment Arm A and Arm B, as outlined in Section 3.1.1. 
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Dose
The 6-mg dose of RO6867461 selected for this study is based on data from preclinical 
in vivo and toxicology models, clinical outcomes from Phase I and Phase II studies, and
supported by clinical pharmacokinetic (PK) and PD assessments.
The first-in-human study (BP28936) evaluated the safety and tolerability of single and 
multiple administration of RO6867461 to 24 patients with nAMD, at doses ranging from 
0.5 mg to 6 mg. The selection of these doses was based on nonclinical findings and 
absolute IVT doses administered in toxicology studies. The 6-mg dose of RO6867461
was the highest feasible dose of RO6867461, 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 RO6867461 in patients with DME (n229 enrolled). The study 
compared two doses of IVT RO6867461 (1.5-mg RO6867461 and 6-mg RO6867461)
with 0.3-mg IVT ranibizumab.  The effects of 6-mg IVT RO6867461 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 RO6867461 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 RO6867461, 
6 mg and 1.5 mg, were well tolerated and did not result in any new or unexpected 
safety signals. 
As a result, the 6-mg RO6867461 dose has been chosen for further clinical development 
in Phase III studies in patients with DME. Refer to the 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 Phase III study is designed to allow the assessment of both 
efficacy and the optimal treatment frequency of the 6-mg IVT RO6867461 dose.  The 
dosing schedule is based on the clinical data from the Phase II study (BP30099 
[BOULEVARD]) and the PK and PD assessments of aqueous humor samples from a 
subset of patients with DME in the Phase II study BP30099.
The mechanism of action of RO6867461 is through neutralization of VEGF and Ang-2. 
PK and PD assessments of aqueous humor samples from a subset of patients in
Study BP30099 demonstrated high suppression of VEGF and Ang-2 for 8 weeks or 
more with RO6867461, fully supporting the Q8W dosing regimen with a potential to 
further extend the intervals between injections. 
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An initiating phase with six IVT injections of 6-mg RO6867461 Q4W was selected for 
Arm A (RO6867461 Q8W). The rationale for the initial six Q4W doses is based on the 
continuous BCVA gains seen after each Q4W injection up to Week 24 in the Phase II 
study (BP30099). The maintenance dosing phase for patients in Arm A (RO6867461 
Q8W) will consist of 6 mg of IVT RO6867461 administered to patients Q8W. The 
rationale for Q8W maintenance phase dosing is based on the evidence of the durability 
of the 6-mg RO6867461 dose in the 16-week observation period of the Phase II study 
(after the last dose at Week 20 until the end of observation period at Week 36), and on 
the VEGF and Ang-2 target neutralization in the aqueous humor in a subset of patients.
An additional rationale for the Q8W maintenance dosing schedule for patients in Arm A 
is that it matches the U.S., Japan, and E.U. approved interval for the active comparator 
Arm C (aflibercept Q8W) in the Phase III design.
Both the efficacy outcomes from the Phase II study and the variability in individual VEGF
and Ang-2 suppression times in the PK/PD aqueous humor assessments indicated a 
heterogeneous response to treatment and supported a flexible dosing regimen with 
intervals from Q4W to Q16W. The Phase II study (BP30099) time to disease 
re-activation data (time to a 50-m increase in CST or time to a 5-letter worsening in 
BCVA) following six Q4W doses demonstrated that although some patients with DME
may 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 structural 
model of PK/PD model characterizing the aqueous humorfree VEGF time course 
showed that there was a substantial proportion of patients with high aqueous humor
free-VEGF suppression for whom a Q12W or Q16W regimen could be sufficient to 
maintain efficacy.
As a result, the Phase III design will assess 6-mg IVT RO6867461 administered at PTIs
to patients in Arm B.  The PTI regimen aims to achieve maximum efficacy while reducing 
the IVT injection treatment burden in patients with DME. 
3.3.1.2
Rationale for Aflibercept Dose and Schedule
The 2-mg aflibercept doses will be administered to patients in treatment Arm C, as 
outlined in Section 3.1.1. The aflibercept dose and schedule used in this study are 
consistent with global recommended dosing posologies (e.g., in the United States, 
European Union, and Japan) DME product labeling for Eylea (aflibercept) (see 
Section 3.3.3).
3.3.2
Rationale for Patient Population
This study will be conducted in patients with decreased vision due to DME who meet all 
of the eligibility criteria for this protocol (for the inclusion and exclusion criteria, see 
Sections 4.1.1 and 4.1.2, respectively).
Patients who are both naive to anti-VEGF therapy in the study eye and those who have 
previously been treated with anti-VEGF therapy in the study eye will be randomized.
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Inclusion of previously anti-VEGFtreated patients in the study will enable exploratory 
evaluation of the impact of previous IVT anti-VEGF treatment on the efficacy of 
RO6867461. The target for participation of previously anti-VEGFtreated patients will be
capped at a minimum 10% and a maximum 25% of enrollment. The rationale for 
capping the number of previously anti-VEGFtreated patients is based on the 
heterogeneous nature of this population with potentially a history of long-standing DME 
and irreversible retinal damage that may limit the possibility of detecting additional VA 
improvements.
3.3.3
Rationale for Control Group
This study is an interventional study, aiming to evaluate the efficacy of RO6867461 
compared with a SOC anti-VEGF therapy, aflibercept, for patients with DME. Anti-VEGF 
therapy is a well-established SOC in patients with DME, and studies with an inactive 
comparator or macular laser treatment alone are no longer ethically acceptable 
alternatives given the improvements in visual and anatomical outcomes associated with 
anti-VEGF treatment. 
Aflibercept is an approved anti-VEGF treatment in patients with DME and has 
demonstrated improvement of BCVA in the target population in controlled, randomized 
clinical studies (Eylea® [aflibercept] U.S. Package Insert, Eylea® [aflibercept] E.U.
Summary of Product Characteristics, and Eylea® [aflibercept] Japan Package Insert).
Eylea is the only globally approved anti-VEGF therapy with a Q8W maintenance 
regimen, facilitating a comparison with the Q8W maintenance regimen of RO6867461 in 
treatment Arm A. 
3.3.4
Rationale for Pharmacodynamic and Biomarker Assessments
PD parameters comprise the primary target engagement markers 
, and 
additional biomarkers. 
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 Muethe 2016; 
Hutton-Smith et al. 2017).  Therefore, to increase our understanding of the ocular 
pharmacokinetics and pharmacodynamics of RO6867461 and its relationship to PTIs, 
optional aqueous humor samples will be obtained from patients who provide additional 
optional consent to participate. Aqueous humor and vitreous humor samples will be 
measured at different timepoints for patients who consent in regions where optional 
sampling is approved. 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. 
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The concentration of the molecular targets unbound to RO6867461 (
 
) will be measured in the systemic circulation as part of PD assessments at 
different timepoints for all patients and at two timepoints for patients who consent in 
regions where optional sampling is approved.
Moreover, other biochemical entities such as cytokines 
 
may be analyzed in these 
specimens in an exploratory analysis.  The analysis of these entities aims at the 
investigation of the role of biochemical and biological processes, such as angiogenesis, 
inflammation, and oxidative stress in the pathogenesis of DR (Goldberg 2009; Kaul et al. 
2010) and DME (Campochiaro 2015) and in the response to RO6867461 treatment. 
Given that these biomarkers may also have prognostic value, their potential association 
with disease progression will also be explored.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Patient Selection and Sex Distribution
Approximately 900 patients with DR and macular edema secondary to diabetes mellitus 
(Type 1 and 2) will be randomized to the study. 
The study will recruit patients who are naive to anti-VEGF therapy in the study eye and 
those who have previously been treated with anti-VEGF therapy in the study eye.  Study 
participation of previously anti-VEGFtreated patients will be capped at a maximum 25% 
of enrollment. 
Only one eye will be assigned as the study eye. If both eyes are considered eligible, the 
eye with the worse BCVA, as assessed at screening, will be selected for the study eye 
unless the investigator deems the other eye to be more appropriate for treatment in the 
study.
The protocol allows enrollment of both men and women, provided the entry criteria are 
met.  However, women who are pregnant or breastfeeding will be excluded from the 
study.  The remaining inclusion and exclusion criteria apply to both male and female 
patients and pertain to issues of patient health performance and safety.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry.
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4.1.1.1
General Inclusion Criteria
Patients must meet the following general inclusion criteria for study entry:

Willingness and the ability to provide signed informed consent
Additionally, at U.S. sites, patients must provide Health Insurance Portability and 
Accountability Act (HIPAA) authorization, and in other countries, as applicable 
according to national laws.

Age 18 years

Documented diagnosis of diabetes mellitus (Type 1 or Type 2), as defined by the 
American Diabetes Association or per WHO criteria and
–
Current regular use of insulin for the treatment of diabetes
and/or
–
Current regular use of oral anti-hyperglycemic agents for the treatment of 
diabetes

HbA1c of 10% within 2 months prior to the Day 1 visit date

Ability and willingness to undertake all scheduled visits and assessments

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use acceptable contraceptive methods 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.
The following are acceptable contraceptive methods: bilateral tubal ligation, 
male sterilization; hormonal contraceptives that inhibit ovulation, hormone-
releasing intrauterine devices; copper intrauterine devices; male or female 
condom with or without spermicide; and cap, diaphragm, or sponge with 
spermicide.
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.

4.1.1.2
Ocular Inclusion Criteria for Study Eye
Patients must meet the following ocular inclusion criteria for the study eye for entry in 
the study:

Macular thickening secondary to DME involving the center of the fovea with CST
325 m, as measured on Spectralis SD-OCT, or 315 m, as measured on Cirrus 
SD-OCT or Topcon SD-OCT at screening
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
BCVA of 73 to 25 letters, inclusive (20/40 to 20/320 approximate Snellen equivalent),
using the ETDRS protocol at the initial testing distance of 4 meters (see the BCVA 
manual for additional details) on Day 1

Sufficiently clear ocular media and adequate pupillary dilatation to allow acquisition 
of good quality CFPs (including ETDRS 7 modified fields or 4 wide-angle fields to 
permit grading of DR and assessment of the retina) and other imaging modalities.
4.1.2
Exclusion Criteria
Patients who meet any of the following exclusion criteria will be excluded from 
study entry.
4.1.2.1
General Exclusion Criteria
Patients who meet any of the following general exclusion criteria will be excluded from 
study entry:

Currently untreated diabetes mellitus or previously untreated patients who initiated
oral anti-diabetic medication or insulin within 3 months prior to Day 1

History of allergy or hypersensitivity to active drug aflibercept and any of its 
excipients, fluorescein, or any study treatmentrelated mandatory ingredients 
(e.g., disinfectants, anesthetics, etc.; see the pharmacy manual for additional 
details) that is not amenable to treatment

History of a severe allergic reaction or anaphylactic reaction to a biologic agent or
known hypersensitivity to any component of the RO6867461 or to aflibercept 
injections, study treatment procedure, dilating drops, or any of the anesthetic and 
antimicrobial drops used by a patient during the study

Active cancer within the past 12 months except for appropriately treated carcinoma 
in situ of the cervix, non-melanoma skin carcinoma, and prostate cancer with a
Gleason score of 6 and a stable prostate-specific antigen for 12 months

Systemic treatment for suspected or active systemic infection
Ongoing use of prophylactic antibiotic therapy may be acceptable but has to be 
discussed with the Medical Monitor.

Renal failure requiring renal transplant, hemodialysis, or peritoneal dialysis within 
6 months prior to Day 1 or anticipated to require hemodialysis or peritoneal dialysis 
at any time during the study 

History of other disease, other non-diabetic metabolic dysfunction, physical 
examination finding, or clinical laboratory finding giving reasonable suspicion of a 
condition that contraindicates the use of the RO6867461 or aflibercept or that might 
affect interpretation of the results of the study or renders the patient at high risk for 
treatment complications in the opinion of the investigator 

Uncontrolled blood pressure (defined as systolic 180 mmHg and/or diastolic 
100 mmHg while a patient is at rest)
If a patient’s initial reading exceeds these values, a second reading may be 
obtained later the same day or on another day during the screening period.  If the 
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patient’s blood pressure is controlled by antihypertensive medication, the patient 
should be taking the same medication continuously for at least 30 days prior to 
Day 1.

Cerebral vascular accident or myocardial infarction within 6 months prior to Day 1

Pregnancy or breastfeeding, or intention to become pregnant during the study
Women of childbearing potential must have a negative urine pregnancy test 
result within 28 days prior to initiation of study treatment.  If the urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test.

Participation in an investigational trial that involves treatment with any drug or 
device (with the exception of vitamins and minerals) within 3 months prior to Day 1 

Administration of systemic pro-angiogenic treatments, such as VEGF-based 
therapies for the peripheral or coronary ischemia (e.g., limb ischemia or myocardial 
infarction) within 3 months or 5 half-lives prior to Day 1

Inability to comply with study or follow-up procedures

Requirement for continuous use of any medications and treatments indicated in 
Section 4.4.2, Prohibited Therapy
4.1.2.2
Ocular Exclusion Criteria for Study Eye
Patients who meet any of the following exclusion criteria for the study eye will be 
excluded from study entry:

High-risk PDR in the study eye, using any of the following established criteria for 
high-risk PDR:
–
Any vitreous or pre-retinal hemorrhage
–
Neovascularization elsewhere 1/2 disc area within an area equivalent to the 
mydriatic ETDRS 7 fields on clinical examination or on CFPs
–
Neovascularization at disc 1/3 disc area on clinical examination

Tractional retinal detachment, pre-retinal fibrosis, or epiretinal membrane involving 
the fovea or disrupting the macular architecture in the study eye

Active rubeosis 

Uncontrolled glaucoma 

History of retinal detachment or macular hole (Stage 3 or 4) 

Aphakia or implantation of anterior chamber intraocular lens

IVT anti-VEGF treatment within 3 months prior to Day 1 (applicable to patients 
whose study eyes were previously treated with IVT anti-VEGF agents) or any IVT 
anti-VEGF agents to study eye prior to Day 1 (applicable for patients who are 
treatment naive)

Treatment with panretinal photocoagulation (PRP) within 3 months prior to Day 1

Macular (focal or grid) laser within 3 months prior to Day 1
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
Any cataract surgery or treatment for complications of cataract surgery with steroids 
or YAG (yttrium-aluminum-garnet) laser capsulotomy within 3 months prior to Day 1

Any other intraocular surgery (e.g., corneal transplantation, glaucoma filtration, pars 
plana vitrectomy, corneal transplant, or radiotherapy) 

Any IVT or periocular (subtenon) corticosteroid treatment within 6 months prior to 
Day 1

Any use of medicated intraocular implants, including Ozurdex®, within 6 months of 
Day 1

Any use of Iluvien® implants at any time prior to Day 1

Treatment for other retinal diseases that can lead to macular edema
4.1.2.3
Ocular Exclusion Criteria for Fellow Eye (NonStudy Eye)
Patients who meet the following exclusion criterion for the fellow eye (nonstudy eye) 
will be excluded from study entry:

Non-functioning nonstudy eye, defined as either:
–
BCVA of hand motion or worse
–
No physical presence of nonstudy eye (i.e., monocular)
4.1.2.4
Exclusion Criteria for Both Eyes 
Patients who meet the following exclusion criterion for either eye will be excluded from 
study entry:

Prior administration of IVT RO6867461 in either eye

Any history of idiopathic or immune-mediated uveitis in either eye

Active ocular inflammation or suspected or active ocular or periocular infection in 
either eye on Day 1 
4.1.2.5
Concurrent Ocular Conditions Exclusion Criteria
Patients who meet the following exclusion criteria related to concurrent ocular conditions 
will be excluded from study entry:

Any current or history of ocular disease other than DME that may confound 
assessment of the macula or affect central vision in the study eye (e.g., choroidal 
neovascularization, age-related macular degeneration, retinal vein occlusion, uveitis, 
angioid streaks, histoplasmosis, active or inactive cytomegalovirus, pathological 
myopia, retinal detachment, macular traction, macular hole, and other)

Any current ocular condition which, in the opinion of the investigator, is currently 
causing or could be expected to contribute to irreversible vision loss due to a cause 
other than DME in the study eye (e.g., foveal atrophy, foveal fibrosis, pigment 
abnormalities, dense subfoveal hard exudates, or other non-retinal conditions) 
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4.2
METHOD OF TREATMENT ASSIGNMENT AND MASKING
4.2.1
Treatment Assignment
After written informed consent has been obtained, all patients will receive a screening 
number assigned through the IxRS.  A patient must satisfy all eligibility criteria (see 
Sections 4.1.1 and 4.1.2) prior to randomization through the IxRS. As part of the 
screening process, the central reading center will evaluate CFPs and SD-OCT images to 
provide an objective, masked assessment of patient eligibility. After all patient eligibility 
requirements are confirmed, site personnel will contact the IxRS at the Day 1 visit for 
assignment of a patient identification number (a separate number from the screening 
number). Patients will be randomized in a 1:1:1 ratio to one of three study treatment 
arms (RO6867461 Q8W, RO6867461 PTI, or aflibercept Q8W). After randomization and 
at each study treatment visit (i.e., including Day 1), the IxRS will assign the appropriate 
study treatment kit to be used. Patients will be randomized on the same day study 
treatment is to be initiated (the Day 1 visit).
Randomization will be stratified by the following baseline factors (Day 1):

Baseline BCVA ETDRS letter score (64 letters vs. 64 letters)

Prior IVT anti-VEGF treatment (yes vs. no)

Region (United States and Canada, Asia, and the rest of the world)
A stratified permuted-block randomization scheme will be used to obtain approximately a
1:1:1 ratio among the treatment groups overall and within each of the above strata. 
Patients who are not eligible for enrollment (screen failures) may be eligible for 
re-screening for up to an additional two times during the enrollment period of the study.
At re-screening, a new screening number will be assigned to each patient through the 
IxRS and all screening visit assessments will be performed. At the Day 1 visit, FFA 
images do not have to be repeated, provided the central reading center's FFA images 
were obtained within 4 weeks before the new Day 1 visit (randomization) date.
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4.2.2
Masking
This is a double-masked study.  There must be a minimum of two investigators per site 
to fulfill the masking requirements of this study, and both are required to be present at 
each scheduled study visit.
4.2.2.1
Masked Roles
Principal Investigator
The Principal Investigator who will be a retina specialist (or the equivalent in ex-U.S. 
countries) must be in a masked role as he or she has to oversee the whole trial conduct 
at his or her site and must be masked to patients’ treatment assignment. In addition, the
Principal Investigator can assume any other masked role for which he or she qualifies
except for BCVA examiner tasks.
Assessor Physician
At least one investigator who will be a retina specialist (or the equivalent in ex-U.S. 
countries) will be designated as the assessor physician. He or she will be masked to 
patients’ treatment assignments and will evaluate all pre-treatment assessments, as well 
as all assessments performed at screening, Day 7, and at the final or early termination
visit.   The assessor physician will also evaluate the causality of all adverse events
reported by the treatment administrator physician. If qualified, this role can take on any 
other masked role tasks except tasks performed by the BCVA examiner.
Photographer(s) and OCT Technician(s)
If qualified, the photographers and OCT technicians can share any other masked role 
tasks except tasks performed by the BCVA examiner.  
Study Coordinator(s)
If qualified, the study coordinator(s) can share any other masked role tasks except tasks 
performed by the BCVA examiner.  
BCVA Examiner 
The BCVA examiner will be masked to both the assigned treatment arm and the location 
(right vs. left) of the study eye.  The BCVA examiner will have no access to patients’ 
medical charts or the VA scores from a patient’s previous visits and may have access 
only to a patient’s refraction data from previous visits.  The BCVA examiner is not 
allowed to perform any other task involving direct patient care.
Phlebotomist
The phlebotomist’s tasks can be performed by a qualified masked or unmasked role
individual except for BCVA examiner role. 
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4.2.2.2
Unmasked Roles
Treatment Administrator
At least one investigator will be designated as the treatment administrator and will be 
unmasked to the patients’ treatment assignment. The treatment administrator will be a 
retina specialist (or the equivalent in ex-U.S. countries).  Qualified ophthalmologists
(including retina fellows) may be permitted to perform the role of the treatment 
administrator following Sponsor approval. 
The treatment administrator(s) performing the study treatment administration 
(RO6867461, aflibercept, or sham) will also perform the post-treatment administration 
vision testing (finger-counting and, if applicable, hand movement and/or light perception
tests) and will treat adverse events that occur during or shortly after the study treatment 
administration.  The person in this role, however, will not evaluate the causality of 
adverse events, which is the responsibility of the masked assessor physician(s).  The 
treatment administrator will also perform post-treatment IOP measurements, as well as 
optional aqueous humor sample collection. 
In addition, the qualifying treatment administrator can assist with and perform the
screening and Day 1 visit assessments.  The treatment administrator must not be 
involved in any other aspect of the study and must not divulge treatment assignment 
to anyone. 
Unmasked Assistant(s) and Pharmacist
If desired, sites may have designated qualified unmasked assistant(s) who can,
e.g., assemble study treatment supplies, prepare sterile field, discard all injection 
materials (i.e., syringes and needles) immediately following study treatment, and place 
vial in the kit box. The qualified unmasked assistant(s) can be assigned to measure 
post-dose IOP. If the site uses a pharmacy, then the unmasked role is also assigned to 
the pharmacist who can take on IMP-related tasks as applicable per delegation of 
authority log. In addition, qualifying unmasked assistant(s) can assist with and perform
the screening and Day 1 visit assessments. 
Number of Unmasked Personnel per Site
Every effort must be made to limit the number of unmasked study personnel to ensure 
the integrity of this masked study.  There should be no more than six unmasked 
personnel (e.g., treatment administering physician[s] and assisting technician[s] if 
applicable) at an investigative site at one time.  In certain circumstances, the total 
number of unmasked personnel might be increased after discussion with and approval 
by the Medical Monitor. If the site is using a pharmacist, then this person may be in an 
unmasked role in addition to the unmasked staff at the site. 
Any other study assisting personnel not listed above will be in the masked roles. 
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4.2.2.3
Delegation Log
All roles for each study staff member should be clearly documented in the Site 
Delegation Log.  The Site Delegation Log must be signed by the Principal Investigator.
4.2.2.4
Role Switching
Once personnel assigned to the designated unmasked role start performing that role
they cannot switch to a masked role during the study.  Switching from a masked role to 
an unmasked role may be possible and must be documented in the Delegation Log. 
4.2.2.5
Study Backup Staff
Sites are strongly advised to have backup staff for key study roles. In case of an 
emergency (e.g., an unscheduled safety visit), patients should be seen preferably by the 
assessor physician. If the assessor physician is unavailable, then any clinic physician 
present, including the physician in the treatment administrator role, should see the 
patient. 
4.2.2.6
Masking of Vendors, Sponsor's Agents, and 
Laboratory Personnel 
Central reading center personnel, study vendors, the Sponsor, and its agents will also be 
masked to treatment assignment, with the exception of individuals who require access to 
patient treatment assignments to fulfill their job roles during a clinical trial.  These roles 
include the clinical supply chain managers, sample handling staff, operational assay 
group personnel, IxRS service provider, drug accountability clinical research associates, 
the images coordinator, iDCC and iDMC members, and an internal unmasking 
statistician (this person is from the Sponsor's unmasking group and will follow the 
Sponsor's standard operation procedures to audit the implementation of the 
randomization scheme and the treatment interval assignment by the IxRS 
vendor periodically during the conduct of the study; this person will not be involved in 
other study-related activities).
To maintain the masked design of the study, blood samples, optional aqueous humor 
samples, and optional vitreous humor samples obtained at the timepoints specified in 
the schedule of activities (see Appendix 1) will be obtained from consenting patients in 
any treatment arm.  The laboratories responsible for performing sample analyses will be 
unmasked to patients' treatment assignment to identify appropriate samples to be 
analyzed.  Unmasking for analysis of the relevant biosamples during the conduct of the 
study will be performed by personnel outside of the study team and according to the 
Sponsor’s internal standard procedures to ensure the integrity of the data.  The number 
of Roche representative(s) and delegates who are unmasked will be kept to the 
minimum required to address the objective of the biosample analysis.
4.2.2.7
Patient Masking 
Patients will be masked to treatment assignment during the study and until study 
closeout, until the Sponsor indicates that the study can be unmasked. 
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4.2.3
Unmasking
4.2.3.1
Single-Patient Emergency Unmasking
If unmasking is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS. The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations.
4.2.3.2
Single-Patient Non-Emergency Unmasking
If the investigator wants to know the identity of study drug for any reason other than a 
medical emergency, he or she should contact the Medical Monitor directly.  The 
investigator should document and provide an explanation for any non-emergency 
unmasking.  The investigator will be able to break the treatment code by contacting 
the IxRS.
4.2.3.3
Single-Patient Unmasking for Health Authority 
Reporting Requirements
As per health authority reporting requirements, the Sponsor's Drug Safety representative
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the Drug Safety representative and 
personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above) will remain masked to treatment assignment.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal product (IMP) for this study is RO6867461 (test product) 
and will be referred to as either study drug or by the International Non-Proprietary Name 
or RO number throughout this protocol.
Aflibercept is being used as an active comparator in this study; therefore, aflibercept is 
also considered an IMP for this study. 
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
RO6867461, Aflibercept and Sham
4.3.1.1.1
RO6867461 Formulation
RO6867461 will be supplied by the Sponsor as a sterile liquid for IVT injection in 
single-use glass vials.
4.3.1.1.2
Aflibercept (Active Comparator) Formulation
Aflibercept will be supplied by the Sponsor as a sterile liquid for IVT injection in 
single-use glass vials.   
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4.3.1.1.3
Sham Formulation
The sham vial is empty and will remain empty throughout the sham treatment. The 
sham is a procedure that mimics an IVT injection and involves the blunt end of an empty 
syringe (without a needle) being pressed against the anesthetized eye.
4.3.1.1.4
RO6867461, Aflibercept, and Sham Packaging and Handling
RO6867461 drug product, aflibercept and sham packaging will be overseen by Roche's
Clinical Trial Supplies Department and bear labels with the identification required by 
local law, the protocol number, drug identification, and its concentration.
The packaging and labeling of RO6867461 drug product, aflibercept, and sham will be in 
accordance with Roche standards and local regulations.
RO6867461 drug product, aflibercept, and sham must be stored according to the details 
on the product label and the information provided in the pharmacy manual.
For more detailed information on the formulation and handling of RO6867461, 
aflibercept, and sham, see the pharmacy manual. 
Upon arrival of the masked investigational products at the site, site personnel should 
check individual carton boxes for damage and verify proper identity, quantity, integrity of 
seals and temperature conditions, and report any deviations or product complaints to the
unmasked monitor upon discovery.  Any product under investigation for integrity or 
temperature excursion should be quarantined by the IxRS, pending final assessment by 
the Sponsor.  
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.1.
4.3.2.1
Dosage
4.3.2.1.1
Intravitreal RO6867461 Injections
The 6-mg dose of RO6867461 will be evaluated in this study and will be administered
intravitreally to patients randomized to receive RO6867461 Q8W or PTI during the 
96-week treatment period (see the study treatment schema in Figure 1).
Patients randomized to receive Q8W treatment will be administered 15 IVT injections of
RO6867461 during the 96-week treatment period. Treatment will consist of 6 initial 
injections (6 mg of RO6867461 Q4W to Week 20), followed by 9 maintenance injections 
(6 mg of RO6867461 Q8W between Week 24 and Week 96). 
The number of IVT injections of RO6867461 administered to patients in the PTI arm will 
vary (see Section 3.1.2.1 for the retreatment criteria), but a minimum of 10 IVT injections 
of RO6867461 will be administered to patients during the 96-week treatment period. 
This will consist of minimum of 4 initiating injections (6 mg of RO6867461 Q4W to 
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Week 12), followed by minimum of 6 maintenance injections (6 mg of RO6867461 
between Week 16 and Week 96). 
4.3.2.1.2
Intravitreal Aflibercept (Active Comparator) Injections
A 2-mg dose of aflibercept (Arm C) will be administered intravitreally Q8W to patients 
randomized to the aflibercept treatment arm during the 96-week treatment period (see 
Figure 1). Patients will receive 15 IVT injections of aflibercept during the 96-week 
treatment period. Treatment will consist of 5 initiating injections (2 mg of aflibercept 
Q4W to Week 16), followed by 10 maintenance injections (2 mg of aflibercept Q8W 
between Week 20 and Week 96).
4.3.2.1.3
Sham Procedure
All three treatment arms (RO6867461 Q8W, RO6867461 PTI, and aflibercept Q8W) will 
maintain Q4W study visits for the 100-week study duration. To preserve the randomized
treatment arm masking, patients will have the sham procedure performed at study 
treatment visits when they are not treated with either RO6867461 or aflibercept as 
applicable per their treatment arm schedule (see Figure 1).
4.3.3
Administration
4.3.3.1
RO6867461 or Aflibercept Intravitreal Injections or 
Sham Procedure
See the pharmacy manual for the pre-treatment procedures, the administration of 
RO6867461, aflibercept, or sham and the post-treatment procedures for all treated 
patients.
4.3.4
Study Treatment Preparation
The pharmacist responsible for dispensing the study treatment, or designated unmasked 
site personnel, will prepare the correct study treatment (RO6867461, aflibercept, or 
sham) as assigned through the IxRS.
Detailed stepwise instructions for the preparation of RO6867461, aflibercept, or sham for 
administration, and mandatory materials to be used will be specified by the Sponsor and 
are detailed in the pharmacy manual.
A specified filter needle must be used for each dose preparation of RO6867461 or 
aflibercept according to the instructions provided in the pharmacy manual.  All materials 
to prepare and administer study treatments will be provided or reimbursed by the 
Sponsor, and no other material than specified should be used.
Vials of RO6867461 drug product and vials of aflibercept (the active comparator) are for 
single-use only (one injection preparation per patient per eye).  Vials used for one
patient must not be used for any other patient.  Partially used vials, remaining
RO6867461 drug product or aflibercept vials, as well as administration material must not 
be reused.  
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4.3.5
Compliance
Any medication error, including drug overdose, should be noted on Adverse Event eCRF 
even if it did not result in any adverse event (see Adverse Event eCRF completion 
guidance and Section 5.4.4).
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Table 2 and Section 5.1.3.1.
4.3.6
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (RO6867461, sham, and aflibercept) will 
be provided by the Sponsor.  The study site will acknowledge receipt of IMPs supplied 
by the Sponsor using the IxRS to confirm shipment condition and content.  Any 
damaged shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site’s method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.7
Continued Access to RO6867461
The Sponsor will offer continued access to Roche IMP (RO6867461) 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 (RO6867461) 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 (RO6867461) after completing the 
study if any of the following conditions are met:

The Roche IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or would not
otherwise create a financial hardship for the patient)
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
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
The Roche Global Policy on Continued Access to Investigational Medicinal Product is
available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any prescription drugs or over-the-counter preparations
or procedures other than protocol-specified procedural medications (e.g., dilating drops 
or fluorescein dyes, proparacaine, or antimicrobials [if applicable]) used by a patient 
within 7 days preceding the Day 1 visit and through the conclusion of the patient’s study 
participation or early termination visit. Patients required to use therapy that is prohibited 
(see Section 4.4.2) will not be eligible for the study.
All concomitant medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF except for anti-VEGF therapy in the fellow eye that will 
be recorded on a separate eCRF. Concomitant ocular procedures performed on either 
eye during the study should be recorded in the Concurrent Ocular Procedures Log on
the eCRF.
4.4.1
Permitted Therapy
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 5.1.3.1, Table 2) may apply with cataract surgery.

Short-term use of topical corticosteroids after cataract surgery, yttrium-aluminum 
garnet capsulotomy, or peripheral iridotomy

PRP 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 masked physician, randomized patients may have their fellow 
(nonstudy) eye treated with anti-VEGF if they are diagnosed with an ocular condition 
for which the selected anti-VEGF therapy is approved in the country.  Consult with the 
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region-specific anti-VEGF prescribing information for the recommended dose and 
frequency of treatment. If the cost of approved anti-VEGF therapy for the fellow eye 
causes a financial hardship for the patient, the Sponsor will cover the cost of the therapy 
in accordance with local regulations.
Note: If (per the masked investigator's judgment) treatment with anti-VEGF is to be 
given to the fellow (nonstudy) eye at the same visit as the study eye treatment, all study 
eye assessments (including study eye study treatment administration) should be 
completed first.  If there are no safety concerns, the site may proceed with the fellow eye 
treatment administered by the unmasked physician to preserve masking.
Individual trays and sterile preparation must be separately prepared for each
eye treatment. 
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 from use during a patient’s study treatment, 
and patients will be discontinued from study treatment and/or the study to receive these 
therapies:

Systemic anti-VEGF therapy 

IVT anti-VEGF agents (other than study-assigned aflibercept or RO6867461) in 
study eye 

IVT, periocular (subtenon), steroid implants (i.e., Ozurdex®, Illuvien®), or chronic 
topical (ocular) corticosteroids in study eye 

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)
4.5
STUDY ASSESSMENTS
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities must be performed and documented for each patient.  Written informed 
consent will be obtained prior to initiation of any study procedures.  The screening 
evaluation will be performed within 28 days preceding the Day 1 visit (the day of the first 
study treatment).
Note: Some patients may require an extended screening period as a result of repeated 
evaluation of images or other issues.  Upon agreement with the Medical Monitor, the 
screening period may be extended for up to 5 business days for such cases.
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4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening or re-screening
evaluations).  Informed Consent Forms for enrolled patients and for patients who are not 
subsequently enrolled will be maintained at the study site.
All screening and Day 1 visit evaluations must be completed and reviewed to confirm 
that patients meet all eligibility criteria before randomization at the Day 1 visit.  The 
investigator will maintain a screening log to record details about all patients screened 
and to confirm eligibility. Reasons for screening failure have to be documented in 
patients' source documents.
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data
Medical history, including clinically significant diseases, chronic and ongoing conditions 
(e.g., trauma, cancer, cardiovascular, cerebrovascular, and ophthalmic history),
surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, and smoking history will be recorded at baseline.  In addition, all medications 
(e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic 
remedies, nutritional supplements) used by a patient within 7 days prior to initiation of 
study treatment (the Day 1 visit) will be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity.  Race/ethnicity 
is recorded because of the potential contribution of this variable to differences in 
observed pharmacokinetics, pharmacodynamics, toxicity, and/or response to treatment
in retinal microvascular diseases (Zhang and Lai 2018).
4.5.3
Physical Examinations
A targeted physical examination should include an evaluation of the head, ears, nose 
and throat.  A patient’s height and weight will be recorded as well.  If any abnormalities 
are noted during the study, the patient may be referred to another doctor.
Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on 
the Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of temperature, respiratory rate, pulse rate, and 
systolic and diastolic blood pressure.  Vital signs will be taken with the patient in a 
seated position after resting for 5 minutes.
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4.5.5
Ocular Assessments
Ocular assessments include the following and will be performed at specified timepoints 
according to the schedule of activities in Appendix 1:

BCVA assessed on ETDRS chart at a starting distance of 4 meters (perform prior to 
dilating eyes; see Appendix 4)

Pre-treatment IOP measurement of both eyes (perform prior to dilating eyes)

Slitlamp examination (for grading scales for anterior and vitreous cells, see
Appendix 3)

Dilated binocular indirect high-magnification ophthalmoscopy

Finger-counting test followed by hand motion and light perception tests (when 
necessary) performed within 15 minutes of post-study treatment in the study eye 
only by the unmasked treatment administrator.

At study treatment visits, post-treatment IOP measurement in the study eye only 
within 30 (15) minutes by qualified personnel assigned to the unmasked role. If
there are no safety concerns after 30 (15) minutes following the study treatment, 
the patient will be permitted to leave the clinic.  If the IOP value is of concern to the 
treatment administrator, the patient will remain in the clinic and will be managed in 
accordance with this physician clinical judgment. The adverse event will be 
recorded on the Adverse Event eCRF as applicable. 
The method of IOP measurement used for a patient must remain consistent throughout 
the study.
Ocular Imaging 
The central reading center(s) will provide sites with the central reading center(s) manual 
and training materials for specified study ocular images.  Before any study images are 
obtained, site personnel, test images, systems and software (where applicable) will be 
certified and validated by the reading center(s) as specified in the central reading center 
manual.  All ocular images results will be obtained by trained site personnel at the study 
sites and forwarded to the central reading center(s) for independent analysis and/or 
storage (see Appendix 5, Appendix 6, and Appendix 7).
Note: After randomization, if a patient misses a study visit when ocular images are 
scheduled (see Appendix 1), the images should be obtained at the next scheduled visit
the patient attends. 
Ocular images include the following:

CFP of both eyes

FFA of both eyes (performed after laboratory samples are obtained)

SD-OCT or swept-source OCT (SS-OCT) images of both eyes
Certain SS-OCT machines may be acceptable; see the central reading center 
manual.  
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
Optional OCT-angiography (OCT-A) of both eyes at sites with OCT-A capabilities
Additional details on obtaining these images are included in the central reading 
center manual.
4.5.6
Concurrent Ocular Procedures
Any ocular procedures performed on either eye during the study (from Day 1, post study 
treatment) will be recorded on the Concurrent Ocular Procedures Log on the eCRF.
4.5.7
Laboratory, Biomarker, and Other Biological Samples
At the scheduled visit, specimens should be obtained prior to study eye treatment and 
FFA assessments (if applicable).  Fasting is not required prior to specimen collection.  
The specimens will be forwarded to the central laboratory.  The central laboratory will 
either perform the analysis or forward samples to the Sponsor or its designee for 
analysis and/or storage. Instructions for obtaining, processing, storing, and shipping of 
all specimens are provided in the laboratory manual.  Laboratory supply kits will be 
provided to the sites by the central laboratory.  See Appendix 1 for sample collection 
timepoints and Appendix 8 for biological sample collection and shipping instructions.  
All samples obtained during screening from patients who are not randomized will be 
discarded. 
The following assessments will be performed:

Hematology:  hemoglobin, hematocrit, quantitative platelet count, RBC counts, WBC
counts, and differentials, including neutrophils, bands, lymphocytes, basophils, 
eosinophils, and monocytes (absolute)

Serum chemistry:  sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen, creatinine, calcium, phosphorus, total and direct bilirubin, total protein, 
albumin, ALP, AST, ALT, and uric acid

Urinalysis:  specific gravity, pH, blood, protein, ketones, glucose, bilirubin, 
urobilinogen, and microscopic examination (if any of the preceding urinalysis tests, 
other than glucose and ketones, are abnormal)

Coagulation:  activated partial thromboplastin time and prothrombin time

Urine pregnancy test at screening and 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. 

HbA1c

Plasma samples for measurement of anti-RO6867461 antibodies
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
Plasma samples to measure RO6867461 or aflibercept concentration (mandatory 
and optional samples from patients who consent to aqueous humor sampling)

and additional 
biomarkers (PD sample), mandatory and optional samples from patients who 
consent to aqueous humor sampling
These samples (except for hematology, serum chemistry, urinalysis, coagulation, serum,
urine pregnancy tests, and HbA1c that will be destroyed after their analysis during the 
study) will be stored for up to 5 years after the date of final closure of the associated 
clinical database.
Drug concentration, 
will be determined in plasma using a 
validated immunoassay method.  Anti-drug antibodies (ADAs) will be detected in plasma
.
4.5.7.1
Optional Aqueous Humor Samples
Collection and submission of optional aqueous humor 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 4.5.7.1) will not be applicable at that site. 
For patients who consent to provide aqueous humor sampling, the aqueous humor 
sample should be collected just prior to study treatment by a qualified unmasked 
treatment administrator, using an aseptic procedure and sterile field and according to 
local guidelines (see Appendix 8 for further details). All efforts should be made to obtain
a baseline aqueous humor sample on Day 1 (pre-dose).  The schedule of activities (see 
Appendix 1) provides guidance on recommended visits at which aqueous humor 
samples should be obtained.  Patients who are prematurely discontinued from study 
treatment but who agree to continue to participate in the study should discontinue 
collection of optional aqueous humor samples and any associated optional plasma 
samples.  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 RO6867461 or aflibercept,
. 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 
 
 
 and inflammation 
 
to identify new therapeutic targets, better understand variability in patient 
responses to RO6867461, and to support patient selection and/or stratification in future 
clinical trials.
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Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.9.1), biological samples will be destroyed 
no later than 5 years after the final Clinical Study Report has been completed.
4.5.7.2
Optional Unscheduled Collection of Vitreous Samples
Elective vitrectomy for vitreous sample collection is not allowed in the study eye during a 
patient's study participation; however, if the surgery is medically necessary and the 
patient consents, a vitreous sample can be obtained from the study eye (see Appendix 8
for further details).  
Vitreous humor samples will be analyzed primarily for RO6867461 or aflibercept
concentrations.  The remaining samples may be analyzed for 
 
, and possibly other biomarkers.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.9.5), biological samples will be destroyed 
no later than 5 years after the final Clinical Study Report has been completed.
4.5.8
Patient-Reported Outcomes
PROs will be assessed using the National Eye Institute Visual Functioning
Questionnaire25 (NEI VFQ-25) (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. 
The NEI VFQ-25 will be interviewer administered by the masked site staff (except for the 
VA examiner) prior to any other visit assessments being performed. Interviews will be 
conducted in the local language of the patient using linguistically validated translations.  
Patients may be excluded from completing the NEI VFQ-25 if a translation is not 
available in their spoken language. 
4.5.9
Optional Samples for Research Biosample Repository
4.5.9.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR specimens will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
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Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.9.2
Approval by the Institutional Review Board or 
Ethics Committee
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's IRB or EC and, if applicable, an appropriate regulatory 
body.  If a site has not been granted approval for RBR sampling, this section of the 
protocol (Section 4.5.9) will not be applicable at that site. The RBR portion of the 
Informed Consent Form has to be agreed to and signed by the consenting patient before 
these samples can be collected and/or mandatory residual samples used. 
4.5.9.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to response to RO6867461, 
to improve the understanding of the biology of VEGF-A and Ang-2, or to better 
understand the targets or diseases (DR and DME):

Whole blood sample for DNA 

Residual aqueous humor sample

Residual vitreous sample

Residual plasma PD sample

Residual PK sample

Residual ADA sample
The whole blood sample for DNA may be sent to one or more laboratories for analysis
via WGS, next-generation sequencing, or other genomic analysis methods. 
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and exome,
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches.  Data will be analyzed in the 
context of this study but will also be explored in aggregate with data from other studies.  
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The availability of a larger dataset will assist in identification of important pathways, 
guiding the development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  For all samples, the dates of consent and specimen collection 
should be recorded on the associated RBR eCRF.
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.9.4
Confidentiality
Specimens and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR specimens, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.9.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature.
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The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research.
4.5.9.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR specimens have the right to withdraw their 
consent at any time for any reason.  However, if RBR specimens have been tested prior 
to withdrawal of consent, results from those tests will remain as part of the overall 
research data.  If a patient wishes to withdraw consent to the testing of his or her 
specimens, the investigator must inform the Medical Monitor in writing of the patient's 
wishes through use of the appropriate RBR Subject Withdrawal Form and, if the trial is 
ongoing, must enter the date of withdrawal on the RBR Research Sample Withdrawal of 
Informed Consent eCRF.  The patient will be provided with instructions on how to 
withdraw consent after the trial is closed.  A patient's withdrawal from Study GR40398
does not, by itself, constitute withdrawal of specimens from the RBR.  Likewise, a 
patient's withdrawal from the RBR does not constitute withdrawal from Study GR40398.
4.5.9.7
Monitoring and Oversight
RBR specimens will be tracked in a manner consistent with Good Clinical Practice (GCP)
by a quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Occurrence of any medical condition that the investigator or Sponsor determines 
may jeopardize the patient’s safety if he or she continues to receive study treatment

Investigator or Sponsor determines it is in the best interest of the patient

Pregnancy
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. Patients who discontinue study treatment prematurely will not be 
replaced and will not be allowed to restart study treatment. However, they should be 
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strongly encouraged to continue their study participation and undergo as many 
scheduled visits as possible, with emphasis on the Week 48, 52, 56, and 100 visits. 
4.6.2
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator and Sponsor have the right to withdraw a patient from the 
study at any time.  Reasons for withdrawal from the study may include, but are not 
limited to, the following:

Patient withdrawal of consent

Study termination or site closure

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 

Investigator or Sponsor determines it is in the best interest of the patient 

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.
If a patient discontinues from the study but has not withdrawn informed consent, the site 
should make every effort to continue to follow-up on serious adverse events, deaths, and 
adverse events of special interest.  In order to avoid loss to follow-up, the investigator 
should ask the patient at the study start for the contact information of a relative or friend 
who can be contacted in case the patient cannot be reached.  However, patients will not 
be followed for any reason after consent has been withdrawn. If a patient requests to be 
withdrawn from the study, this request must be documented in the source documents 
and signed by the investigator.  Patients who withdraw from the study will not be 
replaced.
Patients who discontinue from the study early but have not withdrawn consent should 
return for an early termination visit (see Appendix 1) after a minimum of 28 days have
elapsed following the last study treatment.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
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4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline 
for GCP

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
RO6867461 is not approved, and clinical development is ongoing.  The safety plan for 
patients in this study is based on clinical experience with RO6867461 in completed and 
ongoing studies. Please refer to the RO6867461 Investigator's Brochure for a complete 
summary of safety information
5.1.1
Safety Assessments
The schedule of safety assessments to be performed during the study is provided in 
Appendix 1. After the first study treatment on Day 1, all patients will return for a safety 
assessment visit on Day 7 (3 days).  Patients will be instructed to contact the site at 
any time if they have any health-related concerns.  If warranted, patients will be asked to 
return to the clinic as soon as possible for an unscheduled safety assessment visit 
(see Appendix 2).
At sites where the masked investigator’s decision is for patients to receive pre- and 
post-injection antimicrobials, patients will also be asked whether they have taken the 
prescribed, self-administered, pre- and/or post-injection antimicrobials.  
A finger-counting test will be conducted for each patient within 15 minutes following 
study treatment by the treatment administrator; hand motion and light perception tests 
will be performed when necessary.  
Following the study treatment, IOP will be measured in the study eye only within 
30 (15) minutes by qualified personnel assigned to the unmasked role. If there are no 
safety concerns after 30 (15) minutes following study treatment, the patient will be 
permitted to leave the clinic.  If the IOP value is of concern to the treatment administrator, 
the patient will remain in the clinic and will be managed in accordance with this physician
clinical judgment. The adverse event will be recorded on the Adverse Event eCRF as
applicable.  
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Note: If an anti-VEGF injection is administered to the nonstudy (fellow) eye at the 
same visit as the study eye study treatment (RO6867461, aflibercept, or sham), the
study eye treatment must be performed first (see Section 4.4.1 for additional details). 
Detailed ocular examinations, including indirect ophthalmoscopy and slitlamp 
examination, will be performed throughout the study. Blood samples for plasma study 
drug concentrations, antibodies to RO6867461, and other biomarker samples (see 
Section 4.5.6) will be obtained from all patients at selected timepoints.  The optional 
aqueous humor and vitreous samples will be obtained from patients who consent to the
procedure and sample collection.
An iDMC will monitor safety and study conduct on an ongoing basis (see Section 3.1.5
for additional details).
Patients are discontinued from the study prior to completion (Week 100) will be asked to 
return for early termination visit assessments after a minimum of 28 days have elapsed
following the last study treatment (see Appendix 1).  The visit will include assessment of 
all adverse events (serious and non-serious; ocular and non-ocular).  Serious adverse 
events will be reported in compliance with GCP guidelines.
Treatment interruption and/or treatment discontinuation for adverse events will be 
determined using the criteria in Section 5.1.3.1, Table 2
5.1.2
Risks Associated with RO6867461
To date, no identified risks for RO6867461 have been observed.
Based on experience with aflibercept and other anti-VEGF therapies, potential risks of 
RO6867461 include intraocular inflammation, the intravitreal injection-related risks of 
infectious endophthalmitis, retinal detachment/tear, iatrogenic traumatic cataracts and
increased IOP, as well as the systemic risk of arterial thromboembolic events.  An 
independent clinical events coding committee will be established to adjudicate 
thromboembolic events (myocardial infarcts, strokes, and vascular deaths) reported 
during the study.
Please see the RO6867461 Investigator's Brochure for more details on the risks of 
RO6867461.
5.1.3
Management of Patients Who Experience Adverse Events
5.1.3.1
Treatment Interruption:  Dose Interruption and 
Treatment Discontinuation Criteria
Study treatment interruption and/or patient discontinuation from the study treatment for 
adverse events will be determined using the criteria listed in Table 2. If any of these 
criteria are met, treatment will be interrupted (or discontinued, if applicable) and will not 
be resumed earlier than the next scheduled study visit. The reason for study treatment 
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interruption/discontinuation should be recorded on the appropriate eCRF and, if 
applicable, on the Adverse Event eCRF.
Table 2
Dose Interruption and Treatment Discontinuation Criteria
Event
Criteria
Intraocular inflammation

Interrupt study treatment if intraocular 
inflammation (iritis, iridocyclitis or vitritis) 
is 2in the study eye.

Patients with 2intraocular inflammation 
may be allowed to resume study 
treatment subsequently as determined by 
Medical Monitor and Investigator 
Cataract surgery in the study eye

Interrupt study treatment after cataract 
surgery in study eye.  

Study treatment may be resumed no 
earlier than 28 days after an 
uncomplicated cataract surgery and no 
evidence of post-operational inflammation
at that time.  For cataract surgery with 
complications, study treatment may be 
permitted as determined by Medical 
Monitor and investigator.  
BCVA decrease

Interrupt study treatment if there is a study 
treatmentrelated decrease in BCVA of
30 letters in the study eye compared with 
the last assessment of BCVA prior to the 
most recent treatment.  

Study treatment may be permitted 
subsequently, as determined by the 
investigator.
Elevated IOP

Interrupt study treatment if 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 study treatment if a retinal break 
is present in the study eye.  

Study treatment may be resumed no 
earlier than 28 days after successful laser 
retinopexy, as determined by the 
investigator.
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Table 2
Dose Interruption and Treatment Discontinuation Criteria (cont.)
Event
Criteria
Rhegmatogenous retinal detachment or 
macular hole

Interrupt study treatment if 
rhegmatogenous retinal detachment or 
Stage 3 or 4 macular hole occurs.

Study treatment may be subsequently 
permitted after discussion with Medical 
Monitor.  
Active infection

Interrupt study treatment if any of the 
following are present:  infectious 
conjunctivitis, infectious keratitis, infectious 
scleritis, or endophthalmitis in either eye or 
if the patient requires treatment for an 
active systemic infection.
BCVAbest-corrected visual acuity; IOPintraocular pressure.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for GCP, an adverse event is any untoward medical 
occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution.  An adverse event can therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.8
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
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
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening-invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to 
the Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.10)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to the Adverse 
Event Grading Scale; see Section 5.3.3, Table 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 site staff to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.6)
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
Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

Sight-threatening adverse events:  an adverse event is considered to be 
sight-threatening and should be reported expeditiously if it meets one or more of the 
following criteria:
–
It causes a decrease of 30 letters in VA score (compared with the last 
assessment of VA prior to the most recent assessment) lasting more than 
1 hour.
–
It requires surgical or medical intervention (i.e., conventional surgery, 
vitrectomy, vitreous tap, or biopsy with IVT injection of anti-infective treatments, 
or laser or retinal cryopexy with gas, or a medication) to prevent permanent loss 
of sight.
–
It is associated with severe intraocular inflammation (i.e., endophthalmitis, 
4anterior chamber cell/flare, or 4vitritis; see Section 5.3.5 and Appendix 3 for 
intraocular inflammation grading scales).
All of the above listed sight-threatening adverse events should be reported as serious 
adverse events, listing the underlying cause (if known) of the event as the primary 
event term.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigators will 
make an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4). For adverse events that occur
during or shortly after study treatment, the unmasked investigator may assess the 
seriousness and severity of the event, but event causality will be assessed by the 
investigator who is in the masked role. 
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
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After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until the final study visit 
at Week 100. For patients who terminate study treatment and from the study early, all 
adverse events will be reported up to the early termination visit. For patients who 
discontinue study treatment early (prior to Week 96 treatment) but continue to participate 
in the study, adverse events will be reported until their last or final study visit.  
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
Table 3 provides guidance for assessing adverse event severity.
Table 3
Adverse Event Severity Grading Scale
Severity
Description
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating with inability to work or to perform normal daily activity
Note:  Regardless of severity, some events may also meet seriousness criteria.  
Refer to definition of a serious adverse event (see Section 5.2.2).
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (see also 
Table 4).  Note: Only the masked investigator will assess all adverse event causality.

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)
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
Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event
Table 4
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
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 (trace or greater)
Active inflammation in the vitreous should be clinically differentiated from cellular 
debris from prior episodes of inflammation, hemorrhage, or other causes.
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
Endophthalmitis:  diffuse intraocular inflammation predominantly involving the 
vitreous cavity but also involving the anterior chamber, implying a suspected 
underlying infectious cause
If possible, a sample for culture should be taken prior to initiating antibiotic 
treatment for presumed endophthalmitis.  Results of bacterial or fungal cultures, 
treatment given, and final ophthalmologic outcome should also be provided in the 
details section of the Adverse Event eCRF.
Note:  Trace benign, aqueous pigmented cells visible on slitlamp examination that are 
caused by dilation and are not RBCs or WBCs or the result of any ocular disorder should 
not be recorded as an adverse event.
5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.2
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

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.
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5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP 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."
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Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other causes 
of hyperbilirubinemia is considered to be an indicator of severe liver injury (as defined by 
Hy's Law).  Therefore, investigators must report as an adverse event the occurrence of 
either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
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).
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5.3.5.7
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.9
Worsening of Diabetic Macular Edema or Diabetic Retinopathy
in the Study Eye
Medical occurrences or symptoms of deterioration that are anticipated as part of study 
eye DME or DR should be recorded as an adverse event if judged by the investigator to 
have unexpectedly worsened in severity or frequency or changed in nature at any time
during the study.  When recording an unanticipated worsening of DME or DR on the 
Adverse Event eCRF, it is important to convey the concept that the condition has 
changed by including applicable descriptors (e.g., "accelerated worsening of diabetic 
macular edema").  The expedited reporting requirements for associated sight threatening 
events (listed in the Section 5.2.3) will apply.  
5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
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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
Adverse Events Associated with an Overdose or Error in 
Drug Administration
No safety data related to overdosing of RO6867461 are available.
See Section 5.4.4 for additional medication error reporting details. 
5.3.5.12
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  Sites are not expected to review the 
PRO data for adverse events.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)

Medication errors, including overdose (see Section 5.4.4 for details on reporting 
requirements)
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The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for Western Hemisphere
Medical Monitor/Roche Medical Responsible:
, M.D., Ph.D.
Mobile Telephone No.:
Medical Monitor Contact information for Western Hemisphere
Medical Monitor/Roche Medical Responsible:
, M.D., Ph.D.
Mobile Telephone No.:
Medical Monitor Contact Information for Eastern Hemisphere
Medical Monitor/Roche Medical Responsible:
, M.D.
Mobile Telephone No.:
Medical Monitor Contact Information for Eastern Hemisphere
Medical Monitor/Roche Medical Responsible:
, M.D., M.Sc., 
MB, Ch.B.
Telephone No.:
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
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5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events, and adverse events of special 
interest will be reported until the final study visit at Week 100. 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 to immediately inform the 
investigator if they become pregnant during the study or after the last 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 
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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
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).
5.4.3.3
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).
5.4.4
Expedited Reporting Requirements for Cases of
Medication Error
Medication error, including accidental overdose (hereafter collectively referred to as 
"special situations"), are defined as follows: 

Medication error: accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose
Special situations are not in themselves adverse events but may result in adverse 
events.  
All special situations associated with the masked study treatment, regardless of whether 
they result in an adverse event, should be recorded on the Adverse Event eCRF in 
masked manner and reported to the Sponsor immediately (i.e., no more than 24 hours 
after learning of the event) 
Special situations should be recorded as described below:

Medication error, including accidental overdose and intercepted medication error:  
Enter “Medication Error ” on Adverse Event eCRF as the primary event term and 
check the “Medication error” box.
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Each adverse event associated with a special situation should be recorded separately 
on the Adverse Event eCRF.  If the associated adverse event fulfills seriousness criteria, 
the event should be reported to the Sponsor immediately (i.e., no more than 24 hours 
after learning of the event; see Section 5.4.2).  Adverse events associated with special 
situations should be recorded as described below:

Enter the adverse event caused by the medication error as primary adverse event
term on Adverse Event eCRF.  Check the "Medication error" box.
As an example, a special situation that resulted in a headache would require two entries 
on the Adverse Event eCRF, one entry to report the medication error and one entry to 
report the headache.  The  "Medication error" box would need to be checked for both 
entries.
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source 
data verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE 
ADVERSE EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as
the final study visit for patients who complete study treatment, i.e., the Week 96 visit; for 
the patients who discontinue study treatment early but continue to participate in the 
study, the adverse events reporting period is until their last or final study visit) if the 
event is believed to be related to prior study drug treatment. The investigator should 
report these events directly to the Sponsor or its designee, either by faxing or by 
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scanning and emailing the paper Clinical Trial Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form using the fax number or email address provided to 
investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document for 
IMPs:

RO6867461 Investigator's Brochure

Aflibercept (Eylea) local prescribing information, such as the E.U. Summary of 
Product Characteristics, U.S. prescribing information or Package Insert, or other 
applicable local product labeling 
The Sponsor will compare the severity of each event and the cumulative event
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
Approximately 900 patients will be randomized in the global enrollment phase of this 
study. 
 
 
The primary analyses of this study will include patients enrolled during the global 
enrollment phase; 
 
The primary analyses will be performed when all patients from the global enrollment 
phase have either completed the study through Week 56 or have discontinued from the 
study prior to Week 56, whichever comes later (i.e., timing is defined as the primary 
analysis after the LPLV), and all data collected prior to the primary LPLV in the global 
enrollment phase are in the database and have been cleaned and verified.
Results of the primary analyses, summarized by treatment group, may be reported to the 
public before completion of the study. However, patients, masked study site personnel, 
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and central reading center personnel will remain masked to individual treatment 
assignment until the study is completed, the database is locked, and the study analyses 
are final.
The final analysis will be performed when all patients from the global enrollment phase 
have either completed the study through Week 100 or have discontinued early from the 
study, all data from the global enrollment phase are in the database, and the database is 
locked.
Unless otherwise specified, the analyses described in this section are based on patients 
enrolled during the global enrollment phase 
 Details of 
the planned analyses, including any additional analyses needed to support 
country-specific or regional marketing applications, will be provided in the Statistical 
Analysis Plan. 
6.1
DETERMINATION OF SAMPLE SIZE
Determination of sample size is based on patients enrolled in the global enrollment 
phase. The global enrollment phase will enroll approximately 900 patients. Patients will 
be randomized in a 1:1:1 ratio to receive treatment with RO6867461 Q8W (Arm A), 
RO6867461 PTI (Arm B), or aflibercept Q8W (Arm C). The primary comparisons will be 
the pairwise comparisons between the active comparator (aflibercept Q8W) and each of 
the RO6867461 arms (Q8W and PTI). 
A sample size of approximately 300 patients in each arm will provide greater than 90% 
power to show non-inferiority of RO6867461 to aflibercept (pairwise comparisons 
between the active comparator and each of the RO6867461 arms) in the ITT population, 
using a non-inferiority margin of 4 letters and under the following assumptions:

Standard deviation (SD) of 11 letters for the change from baseline in BCVA 
averaged over Week 48, Week 52, and Week 56

Two-sample t-test

1.25% one-sided type I error rate

10% dropout rate
Assuming 75%90% of patients recruited will be treatment naive, approximately 
225270 treatment-naive patients will be enrolled per arm. A sample size of 225270 
patients per arm will provide greater than 80% power to show a 3.5-letter superiority of 
RO6867461 over aflibercept (pairwise comparisons between the active comparator and 
each of the RO6867461 arms) in the treatment-naive population, using the same SD, 
test, and dropout assumptions above, and a two-sided type I error rate of 2.5%.
Furthermore, a sample size of approximately 300 patients per arm will provide greater 
than 80% power to show a 3-letter superiority of RO6867461 over aflibercept (pairwise 
comparisons between the active comparator and each of the RO6867461 arms) in the 
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ITT population, under the same SD, test, and dropout assumptions above, and a 
two-sided type I error rate of 2.5%.
The sample size may be adjusted as appropriate, based on a masked assessment of the 
pooled SD of the change in BCVA from baseline.  The assessment will be performed by 
the Sponsor at a specified timepoint prior to completing enrollment.  Details on the 
masked sample size re-estimation conducted, as well as actions and decisions made 
regarding changes in sample size will be documented in the Statistical Analysis Plan. 
The Sponsor will remain masked.  Other factors external to the study may also trigger a 
decision to modify the sample size. 
 
 
6.2
ANALYSIS POPULATIONS
The analysis populations used in this section, such as the ITT population, are based on 
patients enrolled during the global enrollment phase and will not include the 
 unless otherwise specified.
6.2.1
Intent-to-Treat Population
The ITT population will comprise all patients who are randomized in the study. For 
analyses based on this patient population, patients will be grouped according to the 
treatment assigned at randomization.
6.2.2
Treatment-Naive Population
The treatment-naive population is defined as all patients randomized in the study who 
have not received any IVT anti-VEGF agents in the study eye prior to Day 1. For 
analyses based on this patient population, patients will be grouped according to the 
treatment assigned at randomization.
6.2.3
Per-Protocol Population
The per-protocol population is defined as all patients randomized in the study who 
receive at least one dose of study treatment and who do not have a major protocol 
violation. For analyses based on this patient population, patients will be grouped 
according to the treatment assigned at randomization.
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6.2.4
Safety-Evaluable Population
The safety-evaluable population will comprise all patients who receive at least one 
injection of active study treatment (RO6867461 or aflibercept).  For analyses based on 
this patient population, patients will be grouped according to the actual treatment 
received up to the Week 56 visit as follows.

If the only active treatment received by a patient in the study eye is aflibercept, the 
patient’s treatment group will be aflibercept Q8W. 

If the only active treatment received by a patient in the study eye is RO6867461, the 
patient’s treatment group will be as randomized if the patient is randomized to one 
of the RO6867461 arms; otherwise, the patient’s treatment group will be 
RO6867461 Q8W. 

If a patient received a combination of different active treatments (RO6867461 and 
aflibercept) in the study eye, the patient’s treatment group will be as randomized.
6.2.5
Pharmacokinetic-Evaluable Population
The PK analyses will include safety-evaluable patients who have at least one plasma 
sample, and if sufficient dosing information (dose and dosing time) is available, with 
patients grouped according to treatment received (as defined in the previous section). 
6.2.6
Immunogenicity-Analysis population
The immunogenicity analysis population will consist of all patients with at least one 
plasma sample for anti-drug antibody assessment.  Patients will be grouped according to 
treatment received or, if no treatment is received prior to study discontinuation, 
according to treatment assigned.
6.3
SUMMARIES OF CONDUCT OF STUDY
Summaries of conduct of study will be based on the ITT population.
The number of patients randomized will be tabulated by country, site, and treatment arm. 
Patient disposition (the number of patients randomized, treated, and completing through 
the primary endpoint timing, as well as of end of study) will be tabulated by treatment 
arm. Premature study drug discontinuation and study discontinuation, as well as 
reasons for discontinuations, will be summarized. Eligibility criteria exceptions and other 
major protocol deviations will be summarized by treatment arm.
6.4
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics such as age, sex, race/ethnicity, region, 
baseline vital sign measurements, laboratory test results, and baseline disease 
characteristics (such as, baseline BCVA, ocular assessments, and medical history) will 
be summarized by treatment as assigned for the ITT population using means, SDs, 
medians, and ranges for continuous variables, and counts and proportions for 
categorical variables, as appropriate.
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Exposure to study treatment (number of study treatments and duration of treatment) will 
be summarized by treatment for the safety-evaluable population.
6.5
EFFICACY ANALYSES
The primary and secondary efficacy analyses will be based on the ITT population and 
the treatment-naive population, unless otherwise specified. For both the ITT population
and the treatment-naive population, patients will be grouped according to the treatment 
assigned at randomization. Additional analyses based on the per-protocol population 
will also be conducted for the primary and the key secondary endpoints.
The primary comparisons will be the pairwise comparisons between the active 
comparator (aflibercept Q8W) and each of the RO6867461 arms (Q8W and PTI).
Continuous outcomes will be analyzed using a MMRM model. Binary secondary 
endpoints will be analyzed using stratified estimation for binomial proportions. Additional 
details are provided in Sections 6.5.1 and 6.5.2.
6.5.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline in BCVA averaged over 
Weeks 48, 52, and 56. The BCVA outcome measure is based on the ETDRS VA chart 
assessed at a starting distance of 4 meters. 
The primary comparisons will be the pairwise comparisons between the active 
comparator (aflibercept Q8W) and each of the RO6867461 arms (Q8W and PTI).
Additional analyses based on the per-protocol population will also be conducted.
For the two RO6867461 arms (Q8W and PTI), the following three hypotheses will be 
tested for each treatment group separately at an overall significance level of 0.05 
using a graph-based testing procedure (Bretz et al. 2009, 2011) to control for the overall 
type I error rate:

Non-inferiority of RO6867461 compared with aflibercept Q8W in the ITT population

Superiority of RO6867461 compared with aflibercept Q8W in the 
treatment-naive population

Superiority of RO6867461 compared with aflibercept Q8W in the ITT population
The order in which hypothesis tests for the primary endpoint will be performed is 
illustrated in Figure 3, with arrows denoting the direction of -propagation. If the tests for 
one treatment sequence are all positive, then /2 will be propagated to the beginning of 
the other treatment sequence, which will be tested at a significance level of 0.05.
Of note, non-inferiority will be tested one sided at half of the designated significance 
level shown in Figure 3.
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Figure 3
Graph-Based Testing Procedure for the Primary Endpoint
PTIpersonalized treatment interval; Q8W every 8 weeks.
Note: 0.05.
The non-inferiority tests for the RO6867461 Q8W arm and the RO6867461 PTI arm 
compared with aflibercept Q8W arm will be conducted with a non-inferiority margin of 
4 letters. For each RO6867461 group (Q8W or PTI) the null hypothesis, 
H0: RO6867461aflibercept 4 letters, and the alternative hypothesis, 
Ha: RO6867461aflibercept 4 letters, will be tested, for which RO6867461 and aflibercept are the
expected change from baseline in BCVA averaged over Weeks 48, 52, and 56 for the 
treatment group in question (RO6867461 Q8W or PTI) and the active comparator 
(aflibercept Q8W), respectively.
The change from baseline averaged over Weeks 48, 52, and 56 will be compared 
between each RO6867461 arm and the aflibercept Q8W arm using a MMRM model. 
The model will include the change from baseline at Weeks 456 as the response 
variables and will include the categorical covariates of treatment group, visit, visit-by-
treatment group interaction, the continuous baseline value for the response variable (in 
this case, baseline BCVA), as well as randomization stratification factors as fixed effects. 
Comparisons between each RO6867461 arm and the aflibercept Q8W arm will be made 
using a composite contrast over Weeks 48, 52, and 56. The MMRM model will assume 
an unstructured covariance structure. If there are convergence problems with the model, 
then a heterogeneous compound symmetry or an AR(1) covariance structure may be 
fitted.
Missing data will be implicitly imputed using the MMRM model, assuming a missing at
random missing data mechanism (i.e., the probability that missing data are dependent 
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on other observed variables but not on the missing data). Data for patients who receive 
prohibited therapy will be censored at the timing of use of prohibited therapy. Data for 
patients who discontinue from study drug and do not receive any prohibited therapy after 
discontinuation of study drug will be included in the analysis.
Additional details about the planned analyses, as well as sensitivity analyses using other 
imputation methods for missing data, sensitivity analysis using the trimmed mean 
approach for patients who receive prohibited therapy or discontinue study drug due to 
lack of efficacy or adverse events, sensitivity analyses of the per-protocol population,
and subgroup analyses to assess the robustness of the primary endpoint results will be 
provided in the Statistical Analysis Plan.
Non-Inferiority Margin
Non-inferiority hypothesis testing for the primary endpoint of the change from baseline in 
BCVA averaged over Weeks 48, 52, and 56 will be performed using a 4-letter 
non-inferiority margin based on the VISTA and VIVID aflibercept pivotal DME studies.  
These studies compared aflibercept to laser control.  The 4-letter non-inferiority margin 
also preserves approximately 50% of the least estimated benefit of aflibercept over 
control in both VISTA and VIVID studies individually.
The VISTA study randomized 466 patients in the United States and the VIVID study 
randomized 406 patients in Europe, Japan, and Australia. At Week 52, in VISTA, 
patients receiving 2 mg of aflibercept Q8W gained 10.7 letters from baseline compared 
with 0.2 letters for patients in the control arm. The corresponding results from the VIVID
study were a gain of 10.7 letters for aflibercept versus 1.2 letters for the control arm.
The non-inferiority margin should be small enough to allow a conclusion that the new 
treatment is not inferior to the active control to an unacceptable extent on the basis of a
combination of clinical judgment and statistical reasoning. From a clinical perspective, 
the non-inferiority margin should be fewer than 5 letters given that a loss of 5 letters (one 
ETDRS line) between treatments would be considered clinically relevant.
6.5.2
Secondary Efficacy Endpoints
The key secondary endpoint is the proportion of patients with a 2-step improvement in 
DR severity from baseline on the ETDRS DRSS at Week 52.
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Additional secondary endpoints are listed in Section 2, Table 1. For all secondary 
endpoints measured on a continuous scale, the same analysis method and data 
handling rules as described in Section 6.5.1 for the primary endpoint will be used. For 
binary secondary endpoints, the proportion of patients in each treatment group and the 
overall difference in proportions between treatment groups will be estimated using the 
weighted average of the observed proportions and the differences in observed 
proportions over the strata defined by randomization factors using the Cochran-Mantel-
Haenszel weights (Cochran 1954; Mantel and Haenszel 1959).  CIs of the proportion of 
patients in each treatment group and the overall difference in proportions between 
treatment groups will be calculated using the normal approximation to the weighted 
proportions (Mehrota and Railkar 2000). Superiority will be assessed, as appropriate,
using a Cochran-Mantel-Haenszel test stratified by the randomization stratification 
factors.
All secondary endpoints will be assessed at 1 year and at additional timepoints over time 
during the study. For the purpose of analysis, the definition of 1 year is the average of 
the Week 48, 52, and 56 visits.
Additional details regarding the plan for the secondary endpoint analyses will be
provided in the Statistical Analysis Plan.
6.5.3
Exploratory Efficacy Endpoints
Details regarding the exploratory efficacy endpoints will be provided in the Statistical 
Analysis Plan.
6.6
SAFETY ANALYSES
Safety analyses will be based on the safety-evaluable population.
Safety will be assessed through descriptive summary of ocular and systemic (non-ocular)
adverse events, deaths, and ocular assessments (e.g., IOP). Clinically significant 
laboratory abnormalities and clinically significant vital sign abnormalities will be reported 
as adverse events and evaluated as part of the adverse event assessments.
At the time of the primary analysis, safety summaries will be summarized based on the 
complete Week 56 data in the safety-evaluable population. In addition, summaries for 
ongoing safety data (after Week 56 and up to a single specified clinical cutoff date) in the 
safety-evaluable population will also be summarized. At the time of the final analysis, 
safety summaries will be produced based on cumulative Week 100 data in the 
safety-evaluable population.
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Verbatim descriptions of treatment-emergent adverse events will be mapped to Medical 
Dictionary for Regulatory Activities (MedDRA) thesaurus terms, and their incidence and 
severity will be summarized by treatment arm. A treatment-emergent adverse event is
defined as any new adverse event reported or any worsening of an existing condition on
or after the first dose of study drug. Adverse events will be tabulated by System Organ 
Class and preferred term.  In addition, summaries will be generated for serious adverse 
events, deaths, adverse events leading to discontinuation of study drug, adverse events 
of special interest, and adverse events judged to be related to study treatment.
Separate summaries will be prepared for systemic (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 baseline in pre-dose IOP 
measurements and changes between pre-dose and post-dose IOP measurements will 
also be summarized. 
Additional details regarding the safety analysis plan will be provided in the Statistical 
Analysis Plan.
6.7
PHARMACOKINETIC ANALYSES
PK analyses will be performed in the PK-evaluable population. 
A non-linear mixed-effects modeling approach (with NONMEM software [Beal and 
Sheiner 1998]) will be used to analyze the concentrationtime data for RO6867461 and
aflibercept. Population and individual primary PK parameters (i.e., clearances and 
volumes) will be estimated. The plasma data collected in this study may be pooled with 
aqueous humor drug concentrations and with data collected in previous studies as 
appropriate to update the current population-PK model. The model may be revised if 
necessary. A covariate modeling approach emphasizing parameter estimation will be 
implemented for the covariate model development. Potential covariateparameter 
relationships will be identified based on mechanistic plausibility and exploratory graphics.  
Inferences about covariate effects and their clinical relevance will be based on the 
resulting parameter estimates and measures of estimation precision (asymptotic 
standard errors). PK parameters such as area under the concentrationtime curve and 
maximum concentration will be derived from the individual post-hoc predictions.
The result of this analysis will be reported in a separate document from the Clinical 
Study Report. 
6.8
PHARMACODYNAMIC ANALYSES
PD analyses will be based on the safety-evaluable population.  PD biomarkers and the 
change from baseline values (absolute or percent change as appropriate) will be 
summarized by treatment arm and timepoint. 
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The data collected from this study may be pooled with data from previous studies.  The 
effect of exposure or dosing information on BCVA, aqueous humor 
 
will be explored using a longitudinal model approach. The influence of various baseline
covariates on model parameters will be investigated. The PKPD or dosePD 
relationship will be characterized. Additional PD markers, such as anatomical endpoints, 
may be included. Additional details about the PK and PD analyses will be provided in 
the Modeling Analysis Plan. The results will be reported in a separate document from 
the Clinical Study Report.
6.9
IMMUNOGENICITY ANALYSES
Immunogenicity analyses will be based on the immunogenicity analysis population.
The number and proportion of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after drug administration (post-baseline incidence) 
will be summarized by treatment group.  When determining the post-baseline incidence, 
patients will considered to be ADA positive if they are ADA negative or have missing 
data at baseline but who develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA positive at baseline and the titer 
of one or more post-dose samples is greater than the titer of the baseline sample by a 
scientifically reasonable margin (details to be provided in the Statistical Analysis Plan).
Patients will be considered to be ADA negative if they are ADA negative or have missing 
data at baseline and all post-baseline samples are negative, or if they are ADA positive 
at baseline but do not have any post-baseline samples with a titer that is greater than the 
titer of the baseline sample by a scientifically reasonable margin such as 4-fold (if 
1:2 dilution steps are applied).
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported using descriptive statistics.
6.10
BIOMARKER ANALYSES
Biomarker analyses will be based on the safety-evaluable population.
Analyses will be performed to identify biomarkers that are predictive of response to 
RO6867461, are associated with progression to a more severe disease state, are 
associated with susceptibility to developing adverse events, can provide evidence of 
RO6867461 activity, or can increase the knowledge and understanding of disease 
biology.
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7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and central 
reading center reports and images will be sent directly to the Sponsor, using the 
Sponsor’s standard procedures to handle and process the electronic transfer of these 
data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
PRO data will be collected on paper questionnaires. The data from the questionnaires 
will be entered into the EDC system by site staff.
7.2
ELECTRONIC CASE REPORT FORMS
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the data is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered on the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
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transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly on the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO data (if applicable), Informed Consent 
Forms, laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for at least 15 years after completion or discontinuation of the 
study or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, subject 
to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
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8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for GCP and 
the principles of the Declaration of Helsinki, or the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the 
individual.  The study will comply with the requirements of the ICH E2A guideline 
(Clinical Safety Data Management:  Definitions and Standards for Expedited Reporting).  
Studies conducted in the United States or under a U.S. Investigational New Drug (IND) 
Application will comply with U.S. FDA regulations and applicable local, state, and federal 
laws.  Studies conducted in the European or European Economic Area will comply with 
the E.U. Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form will be provided to each site.  If 
applicable, it will be provided in a certified translation of the local language.  The 
Sponsor or its designee must review and approve any proposed deviations from the 
Sponsor's sample Informed Consent Forms or any alternate consent forms proposed by 
the site (collectively, the "Consent Forms") before IRB/EC submission.  The final 
IRB/EC-approved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient 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.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
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informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient. All signed and 
dated Consent Forms must remain in each patient’s study file or in the site file and must 
be available for verification by study monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization
to allow use and disclosure of personal health information in compliance with the U.S. 
HIPAA of 1996.  If the site utilizes a separate Authorization Form for patient 
authorization for use and disclosure of personal health information under the HIPAA 
regulations, the review, approval, and other processes outlined above apply except that 
IRB review and approval may not be required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in datasets 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.
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Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted clinical study reports and other summary reports will be provided upon 
request.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
study and for 1 year after completion of the study (see the definition of end of study in 
Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes 
to data.
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 
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policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of GCP guidelines and require reporting to 
health authorities.  As per the Sponsor's standard operating procedures, prospective 
requests to deviate from the protocol, including requests to waive protocol eligibility 
criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Approximately 225 sites globally will participate to enroll approximately 900 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.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
An iDMC will be employed to monitor and evaluate patient safety throughout the study.  
9.5
DISSEMINATION OF DATA AND PROTECTION OF 
TRADE SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses, in clinical trial registries of the U.S. National Institutes of Health and the 
European Medicines Agency, and in peer-reviewed journals. The Sponsor will comply 
with all requirements for publication of study results.  Study data may be shared with 
others who are not participating in this study, and redacted clinical study reports and 
other summary reports will be provided upon request (see Section 8.4 for more details).  
For more information, refer to the Roche Global Policy on Sharing of Clinical Trials Data 
at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
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 
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the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).
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10.
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Muether PS, Hermann MM, Dröge 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;63:93057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. doi: 10.1167/iovs.10-6386.
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.
Zhang X, Lai TYY. Baseline predictors of visual acuity outcome in patients with wet 
age-related macular degeneration. Biomed Res Int 2018;110 [cited: 18 May 2018]. 
Available from: https:doi.org/10.1155/2018/9640131. 
Protocol Number: 
 Report Number: 
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Appendix 1
Schedule of Activities
Table 1
Study Flowchart:  Day 1, Day 7, Week 4 through Week 52, and Early Termination
Visit Window (days)
Screening
Visit Day
Visit Week
ET
Visit b
1a
7
4
8
12
16
20
24
28
32
36
40
44
48
52
–28 to 1
NA
(3)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(28)
Main informed consent c
x
Optional aqueous, vitreous
and blood sample informed 
consent c
x
x
Optional (RBR) residual
samples and DNA whole 
blood sample informed 
consent c
x
x
Review of inclusion and 
exclusion criteria
x
x
Demographics (age, sex, and 
self-reported race/ethnicity)
x
Medical and surgical history
including tobacco history d
x
Physical examination e 
x
x
Body weight and height
x
Vital signs f 
x
x
x
NEI VFQ-25 g
x
x
x
x
BCVA h
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Pre-treatment IOP i
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urine pregnancy test j, k 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
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111/Protocol GR40398, Version 1
Appendix 1
Schedule of Activities (cont.)
Table 1
Study Flowchart:  Day 1, Day 7, Week 4 through Week 52, and Early Termination (cont.)
Visit Window (days)
Screening
Visit Day
Visit Week
ET
Visit b
1a
7
4
8
12
16
20
24
28
32
36
40
44
48
52
–28 to 1
NA
(3)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(28)
Whole blood sample 
(hematology, coagulation 
[aPTT and PT], serum 
chemistry, and urinalysis) j, l
x
HbA1C j
x
x
x
Optional aqueous humor 
sample j, m 
x
x
x
x
x
x
Optional vitreous humor 
sample j, n
Can be collected if vitrectomy is necessary
Optional whole blood sample 
for DNA j, o
x
Plasma PK sample j, o 
x
x
x
x
x
Optional PK plasma sample 
(if aqueous humor sample is 
collected) j, m
x
x
Plasma PD sample j, o
x
x
x
x
x
Optional PD plasma sample (if 
aqueous humor sample is 
collected) j, m
x
x
Plasma ADA sample j, o
x
x
x
x
x
Slitlamp examination
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Indirect ophthalmoscopy
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
SD-OCT p
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Optional OCT-A p, q
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Protocol Number: 
 Report Number: 
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RO6867461—F. Hoffmann-La Roche Ltd
112/Protocol GR40398, Version 1
Appendix 1
Schedule of Activities (cont.)
Table 1
Study Flowchart:  Day 1, Day 7, Week 4 through Week 52, and Early Termination (cont.)
Visit Window (days)
Screening
Visit Day
Visit Week
ET
Visit b
1a
7
4
8
12
16
20
24
28
32
36
40
44
48
52
–28 to 1
NA
(3)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(28)
FFA p
x
x
x
x
CFP p
x
x
x
x
Administration of study 
treatment r
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Finger-counting test s
x
x
x
x
x
x
x
x
x
x
x
x
x
x
IOP (post-study treatment) t
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events u
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant medications v
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concurrent ocular procedures w
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ADAanti-drug antibody; Ang-2angiopoietin-2; BCVAbest-corrected visual acuity; CFPcolor fundus photograph; DMEdiabetic macular edema; 
eCRFelectronic Case Report Form; ETearly termination; FFAfundus fluorescein angiography; HbA1Chemoglobin A1C; ICFInformed Consent Form;
IOPintraocular pressure; NEI VFQ-Q25National Eye Institute 25-Item Visual Functioning Questionnaire; OCT-Aoptical coherence tomographyangiography; 
PDpharmacodynamic; PKpharmacokinetic; RBRResearch Biosample Repository; SD-OCTspectral-domain optical coherence tomography; SOCstandard 
of care; VAvisual acuity; VEGF-Avascular endothelial growth factorA.
Notes:  All ocular assessments are to be performed for both eyes unless noted otherwise. All assessments are to be performed on the same day, except those 
at screening. All study visits will be scheduled relative to the date of the Day 1 visit (first study treatment).
There must be a minimum of 21 days between study treatment visits occurring from the Day 1 visit through the Week 96 visit.  The final study visit at Week 100 
should not occur earlier than 28 days after the last study treatment. SOC treatment for DME in the fellow eye may be provided by the Sponsor as long as the 
patient remains in the study (see Section 4.4.1).  SOC treatments after the ET visit or the final study visit (Week 100) will not be supplied by the Sponsor.
a
The screening and Day 1 (randomization) visits may occur as a combined visit if all assessments are completed and evaluated within 2 business days.  
Informed consent must be administered and signed by a patient before any study-specific screening procedure is performed.  When screening and 
randomization are combined and performed in 1 day, assessments listed for both visits should be conducted only once.  If the combined visit is conducted
within 2 business days, then the following safety assessments will be repeated on the day of patient’s randomization and study treatment administration:  
slitlamp examination, indirect ophthalmoscopy, and pre- and post-treatment IOP measurements (recorded on the Day 1 eCRF and dated accordingly). 
b
Patients who are discontinuing from the study early (prior to the final study visit at Week 100) but have not withdrawn consent should return for an ET visit 
after a minimum of 28 days have elapsed following their last study treatment.
Protocol Number: 
 Report Number: 
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113/Protocol GR40398, Version 1
Appendix 1
Schedule of Activities (cont.)
Table 1
Study Flowchart:  Day 1, Day 7, Week 4 through Week 52, and Early Termination (cont.)
c
Informed consent must be administered and documented before any study-specific screening procedure is performed and may be obtained more than 
28 days before initiation of study treatment at the Day 1 visit.  The optional Blood, Aqueous Humor, Vitreous Humor Samples Informed Consent Form as 
well as Optional (RBR) Informed Consent Form for residual samples and whole blood DNA sample collection can be signed either at the screening or Day 1 
visit prior to sample collection.
d
Medical history, including clinically significant diseases, chronic and ongoing conditions (e.g., trauma, cancer, cardiovascular, cerebrovascular, and 
ophthalmic history), surgeries, cancer history (including prior cancer therapies and procedures), reproductive status, and smoking history, will be recorded 
at baseline. 
e
A targeted physical examination should include an evaluation of the head, ears, nose and throat.  If any abnormalities are noted during the study, the 
patient may be referred to another doctor.  Changes from baseline abnormalities should be recorded in patient notes. New or worsened clinically significant 
abnormalities should be recorded as adverse events on the Adverse Event eCRF.
f
Vital signs include measurement of temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressure; at the Day 1 visit, vital signs should 
be recorded before study treatment. Vital signs will be measured with the patient in a seated position after resting for 5 minutes.
g
To be administered by the masked site staff (except for the VA examiner) prior to any other visit assessments being performed on that day.
h
Perform the assessments prior to dilating the eyes.
i
Perform the assessments prior to dilating the eyes at screening and at each study visit, and if applicable, at the ET visit.
j
Obtain prior to FFA (if applicable) and prior to study treatment. 
k
Starting on Day 1, collect and perform the urine pregnancy test for women of childbearing potential, including those who have had tubal ligation, at each 
study treatment visit. If positive, collect the serum pregnancy sample and forward it to the central laboratory for testing.  If the serum pregnancy test is 
positive, do not administer study treatment.
l
Hematology includes hemoglobin, hematocrit, quantitative platelet count, RBC counts, WBC counts, and differentials, including neutrophils, lymphocytes, 
bands, eosinophils, basophils, and monocytes (absolute).  Serum chemistry panel includes sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen, creatinine, calcium, phosphorus, total and direct bilirubin, total protein, albumin, ALP, AST, ALT, and uric acid. Urinalysis includes specific gravity, 
pH, blood, protein, ketones, glucose, bilirubin, urobilinogen, and microscopic examination (if any of the preceding urinalysis tests, other than glucose and 
ketones, are abnormal). If the screening and Day 1 (randomization) visits occur as a combined visit, a historic HbA1c value must be available from within 
2 months prior to Day 1. In this instance, results from the screening samples are not required for randomization.
m If a patient consents to collection of optional aqueous humor sample, collect the sample at indicated timepoints prior to study treatment administration.  Not 
applicable for a site that has not been granted approval by a site's Institutional Review Board or Ethics Committee. 
n
If vitrectomy is medically necessary and the patient consents, a vitreous sample can be obtained from the study eye.  A PK blood sample (for plasma 
preparation) should also be collected and shipped to the Sponsor.  Vitreous humor samples will be analyzed primarily for RO6867461 concentrations and 
may also be analyzed for aflibercept concentrations.  The remaining samples may be analyzed for
and possibly other 
biomarkers.
Protocol Number: 
 Report Number: 
Clinical Study Report: faricimab - F. Hoffmann-La Roche Ltd
GR40398
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114/Protocol GR40398, Version 1
Appendix 1
Schedule of Activities (cont.)
Table 1
Study Flowchart:  Day 1, Day 7, Week 4 through Week 52, and Early Termination (cont.)
o
If the optional whole blood DNA sample is not obtained at the assigned visit (Day 1), the sample may be collected at any subsequent study visit when a 
blood draw is being performed for other purposes as specified (e.g., PK, ADA).  This sample collection is not applicable for a site that has not been granted 
approval by the country regulators or site's Institutional Review Board or Ethics Committee. The DNA samples will be collected from patients who give 
specific consent to participate in this optional research. At specified visits, the plasma PK, PD, and ADA samples will be collected prior to study treatment. 
p
The central reading center will review SD-OCT and CFP images obtained at screening for determination of patient eligibility.  At all subsequent visits, 
outputs from all types of imaging assessments will be sent to the relevant central reading center.  See the central reading center manual for additional 
details. Note: After randomization, if a patient misses a study visit when ocular images are scheduled, the images should be obtained at the next 
scheduled visit the patient attends. The baseline FFA may be obtained either at the screening or the Day 1 visit.
q
To be conducted at sites with OCT-A capability. 
r
At study treatment visits, randomized patients will receive study drug at some visits and sham at other visits or aflibercept at some visits and sham at other 
visits. The timing of these treatments will depend on the treatment arm to which they are randomized, which will be masked. 
s
The finger-counting test should be conducted within 15 minutes of study treatment administration for the study eye only by the unmasked investigator.
t
Post-treatment IOP measurement in the study eye only within 30 (15) minutes to be performed by qualified personnel assigned to the unmasked role. If 
there are no safety concerns after 30 (15) minutes following the study treatment, the patient will be permitted to leave the clinic.  If the IOP value is of 
concern to the investigator, the patient will remain in the clinic and will be managed in accordance with the investigator’s clinical judgment. The adverse 
event will be recorded on the Adverse Event eCRF as applicable.   
u
After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated intervention 
should be reported.  After initiation of study treatment (Day 1), all adverse events will be reported until the final study visit or if applicable until the ET visit.  
After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event 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.
v
Record any concomitant medications (i.e., any prescription medications or over-the-counter preparations other than protocol-specified procedural 
medications such as proparacaine, etc.) used by a patient within 7 days preceding Day 1 and through the conclusion of the patient’s study participation or 
ET visit.
w Record all concurrent ocular procedures performed on the study or nonstudy eye between the Day 1 visit after study treatment and the final study visit or 
ET visit.
Protocol Number: 
 Report Number: 
Clinical Study Report: faricimab - F. Hoffmann-La Roche Ltd
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Appendix 1
Schedule of Activities (cont.)
Table 2
Study Flowchart:  Week 56 through Week 100 and Early Termination
Visit Window (days)
Week Visit 
ET 
Visit a
56
60
64
68
72
76
80
84
88
92
96
100
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(28 and 
35)
(28)
Physical examination b 
x
x
Vital signs c
x
x
NEI VFQ-25 d
x
x
BCVA e
x
x
x
x
x
x
x
x
x
x
x
x
x
Pre-treatment IOP f
x
x
x
x
x
x
x
x
x
x
x
x
x
Urine pregnancy 
test g, h
x
x
x
x
x
x
x
x
x
x
x
x
x
Whole blood sample 
(hematology, coagulation 
[aPTT and PT], serum 
chemistry, and 
urinalysis) g, i
x
HbA1C g
x
x
Optional aqueous humor 
sample f, j
x
x
x
x
x
Protocol Number: 
 Report Number: 
Clinical Study Report: faricimab - F. Hoffmann-La Roche Ltd
GR40398
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RO6867461—F. Hoffmann-La Roche Ltd
116/Protocol GR40398, Version 1
Appendix 1
Schedule of Activities (cont.)
Table 2
Study Flowchart:  Week 56 through Week 100 and Early Termination (cont.)
Visit Window (days)
Week Visit 
ET 
Visit a
56
60
64
68
72
76
80
84
88
92
96
100
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(28 and 
35)
(28)
Optional vitreous humor 
sample f, k
Can be collected if vitrectomy is necessary.
Plasma PK sample f, k
x
x
x
Plasma PD sample f, k
x
x
x
Plasma ADA sample f, k
x
x
x
Slitlamp examination
x
x
x
x
x
x
x
x
x
x
x
x
x
Indirect ophthalmoscopy
x
x
x
x
x
x
x
x
x
x
x
x
x
SD-OCT l
x
x
x
x
x
x
x
x
x
x
x
x
x
Optional OCT-A l, m
x
x
x
x
x
x
x
x
x
x
x
x
x
FFA l
x
x
CFP l
x
x
Administration of study 
treatment n
x
x
x
x
x
x
x
x
x
x
x
Finger-counting test o
x
x
x
x
x
x
x
x
x
x
x
IOP post-treatment p
x
x
x
x
x
x
x
x
x
x
x
Adverse events q
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant 
medications r
x
x
x
x
x
x
x
x
x
x
x
x
x
Concurrent ocular 
procedures s
x
x
x
x
x
x
x
x
x
x
x
x
x
Protocol Number: 
 Report Number: 
Clinical Study Report: faricimab - F. Hoffmann-La Roche Ltd
GR40398
1102957
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RO6867461—F. Hoffmann-La Roche Ltd
117/Protocol GR40398, Version 1
Appendix 1
Schedule of Activities (cont.)
Table 2
Study Flowchart:  Week 56 through Week 100 and Early Termination (cont.)
ADAanti-drug antibody; BCVAbest-corrected visual acuity; CFPcolor fundus photograph; DMEdiabetic macular edema; eCRFelectronic 
Case Report Form; ETearly termination; FFAfundus fluorescein angiography; HbA1Chemoglobin A1C; IOPintraocular pressure; 
NEI VFQ-Q25National Eye Institute 25-Item Visual Functioning Questionnaire; OCT-Aoptical coherence tomographyangiography; 
PDpharmacodynamic; PKpharmacokinetic; SD-OCTspectral-domain optical coherence tomography; SOCstandard of care; VAvisual 
acuity; VEGF-Avascular endothelial growth factorA.
Notes:  All ocular assessments are to be performed for both eyes unless noted otherwise. All assessments are to be performed on the same 
day.  All study visits will be scheduled relative to the date of the Day 1 visit (first study treatment).  There must be a minimum of 21 days 
between all study treatment visits occurring at the Day 1 visit through the Week 100 visit.  
SOC treatment for DME in the fellow (nonstudy) eye may be provided by the Sponsor as long as the patient remains in the study (see 
Section 4.4.1).  SOC treatment after the ET visit or the final study visit (Week 100) will not be supplied by the Sponsor.
a
Patients who are discontinuing from the study early (prior to the final study visit at Week 100) but have not withdrawn consent should return 
for an ET visit after a minimum of 28 days have elapsed following the last study treatment.
b
A targeted physical examination should include an evaluation of the head, ears, nose, and throat.  If any abnormalities are noted during the 
study, the patient may be referred to another doctor. Changes from baseline abnormalities should be recorded in patient notes. New or 
worsened clinically significant abnormalities should be recorded as adverse events on the Adverse Event eCRF.
c
Vital signs include measurement of temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressure; at the Day 1 visit,
vital signs should be recorded before study treatment.  Vital signs will be measured with the patient in a seated position after resting for 
5 minutes.
d
To be administered by the masked site staff (except for the VA examiner) prior to any other visit assessments being performed on that day.
e
Perform the assessments prior to dilating the eyes.
f
Perform the assessments prior to dilating the eyes, prior to the study treatment, and at the final or ET visit.
g
Obtain prior to FFA (if applicable) and prior to study treatment. 
h
Starting on Day 1, collect and perform the urine pregnancy test for women of childbearing potential, including those who have had tubal 
ligation, at each study treatment visit. If positive, collect the serum pregnancy sample and forward it to the central laboratory for testing.  
If the serum pregnancy test is positive, do not administer study treatment.
Protocol Number: 
 Report Number: 
Clinical Study Report: faricimab - F. Hoffmann-La Roche Ltd
GR40398
1102957
277

RO6867461—F. Hoffmann-La Roche Ltd
118/Protocol GR40398, Version 1
Appendix 1
Schedule of Activities (cont.)
Table 2
Study Flowchart:  Week 56 through Week 100 and Early Termination (cont.)
i
Hematology includes hemoglobin, hematocrit, quantitative platelet count, RBC counts, WBC counts, and differentials, including neutrophils, 
lymphocytes, bands, eosinophils, basophils, and monocytes (absolute).  Serum chemistry panel includes sodium, potassium, chloride, 
bicarbonate, glucose, blood urea nitrogen, creatinine, calcium, phosphorus, total and direct bilirubin, total protein, albumin, ALP, AST, ALT, 
and uric acid. Urinalysis includes specific gravity, pH, blood, protein, ketones, glucose, bilirubin, urobilinogen, and microscopic examination 
(if any of the preceding urinalysis tests, other than glucose and ketones, are abnormal).
j
If a patient consents to collection of optional aqueous humor sample, collect the sample at indicated timepoints prior to study treatment 
administration.  Not applicable for a site that has not been granted approval by a site's Institutional Review Board or Ethics Committee.
k
If vitrectomy is medically necessary and the patient consents, a vitreous sample can be obtained from the study eye.  A PK blood sample 
(for plasma preparation) should also be collected and shipped to the Sponsor.  Vitreous humor samples will be analyzed primarily for 
RO6867461 concentrations and may also be analyzed for aflibercept concentrations.  The remaining samples may be analyzed for 
and possibly other biomarkers.
l
The outputs from imaging assessments will be sent to the central reading center.  See the central reading center manual for additional 
details. Note: After randomization, if a patient misses a study visit when ocular images are scheduled, the images should be obtained at 
the next scheduled visit the patient attends.
m To be conducted at sites with OCT-A capability. 
n
At study treatment visits, randomized patients will receive study drug at some visits and sham at other visits or aflibercept at some visits and 
sham at other visits. The timing of these treatments will depend on the treatment arm to which patients are randomized, which will be 
masked. 
o
The finger-counting test should be conducted within 15 minutes of study treatment administration for the study eye only by the unmasked 
investigator.
p
Post-treatment IOP measurement in the study eye only within 30 (15) minutes to be performed by qualified personnel assigned to the 
unmasked role. If there are no safety concerns after 30 (15) minutes following the study treatment, the patient will be permitted to leave 
the clinic.  If the IOP value is of concern to the investigator, the patient will remain in the clinic and will be managed in accordance with the 
investigator’s clinical judgment. The adverse event will be recorded on the Adverse Event eCRF as applicable.
Protocol Number: 
 Report Number: 
Clinical Study Report: faricimab - F. Hoffmann-La Roche Ltd
GR40398
1102957
278

RO6867461—F. Hoffmann-La Roche Ltd
119/Protocol GR40398, Version 1
Appendix 1
Schedule of Activities (cont.)
Table 2
Study Flowchart:  Week 56 through Week 100 and Early Termination (cont.)
q
After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study treatment (Day 1), all adverse events will be reported until 28 days after their last 
study treatment.  After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event 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.
r
Record any concomitant medications (i.e., any prescription medications or over-the-counter preparations other than protocol-specified 
procedural medications such as proparacaine, etc.) used by the patient within 7 days preceding Day 1 and through the conclusion of the 
patient’s study participation or the ET visit.
s
Record all concurrent ocular procedures performed on the study or nonstudy eye between the Day 1 visit after study treatment and the
final study visit or the ET visit.
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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 e
IOPintraocular pressure.
a Patients will be instructed to contact the investigator at any time if they have 
any health-related concerns.  If warranted, patients will be asked to return to 
the clinic as soon as possible for an unscheduled safety assessment visit.  
Assessments performed at unscheduled safety visits are at the discretion of 
the investigator. It is recommended to perform ocular assessments on both 
eyes.
b Perform finger-counting test followed by hand motion and light perception 
tests when necessary.
c The method used for the IOP measurement for a patient must remain 
consistent throughout the study.
d Adverse event causality to be evaluated by the masked physician in the 
assessor role.
e Hematology includes hemoglobin, hematocrit, quantitative platelet count, 
RBC counts, WBC counts, and differentials, including neutrophils, 
lymphocytes, bands, eosinophils, basophils, and monocytes (absolute).  
Serum chemistry panel includes sodium, potassium, chloride, bicarbonate, 
glucose, blood urea nitrogen, creatinine, calcium, phosphorus, total and 
direct bilirubin, total protein, albumin, ALP, AST, ALT, and uric acid.  
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Appendix 3
Grading Scale for Assessment of Anterior Chamber Flare
or Cells and Vitreous Cell
Table 1
Grading Scale for Anterior Chamber Flare or Cells
Grade
Description
Flare
0
No protein is visible in the anterior chamber when viewed by an experienced 
observer using slitlamp biomicroscopy; a small, bright, focal slit-beam of white 
light; and high magnification.
Trace
Trace amount of protein is detectable in the anterior chamber.  This protein is 
visible only with careful scrutiny by an experienced observer using slitlamp 
biomicroscopy; a small, bright, focal slit-beam of white light; and high 
magnification.
1
Slight amount of protein is detectable in the anterior chamber:  the presence of 
protein in the anterior chamber is immediately apparent to an experienced 
observer using slitlamp biomicroscopy and high magnification, but such protein 
is detected only with careful observation with the naked eye and a small, bright, 
focal slit-beam of white light.
23
Moderate amount of protein is detectable in the anterior chamber.  These 
grades are similar to 1but the opacity would be readily visible to the naked eye 
of an observer using any source of a focused beam of white light.  This is a 
continuum of moderate opacification, with 2being less apparent than 3.
4
A large amount of protein is detectable in the anterior chamber.  This grade is 
similar to 3, but the density of the protein approaches that of the lens.  
Additionally, frank fibrin deposition is frequently seen in acute circumstances.  It 
should be noted that because fibrin may persist for a period of time after partial 
or complete restoration of the bloodaqueous barrier, it is possible to have 
resorbing fibrin present with lower numeric assignations for flare (e.g., 1flare 
with fibrin).
Cells
0
No cells are seen in any optical section when a large slit-amp beam is swept 
across the anterior chamber.
Trace
Few (13) cells are observed when the slitlamp beam is swept across the 
anterior chamber.  When the instrument is held stationary, not every optical 
section contains circulating cells.
1
310 cells per optical section are seen when the slitlamp beam is swept across 
the anterior chamber.  When the instrument is held stationary, every optical 
section contains circulating cells.
2
1025 cells are seen when the slitlamp beam is swept across the anterior 
chamber.  When the instrument is held stationary, every optical section contains 
circulating cells.
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Appendix 3
Grading Scale for Assessment of Anterior Chamber Flare 
or Cells and Vitreous Cell (cont.)
Table 1
Grading Scale for Anterior Chamber Flare or Cells (cont.)
Grade
Description
3
2550 cells are seen when the slitlamp beam is swept across the anterior chamber.  
When the instrument is held stationary, every optical section contains circulating 
cells.  Keratic precipitates or cellular deposits on the anterior lens capsule may be 
present.
4
More than 50 cells are seen when the slitlamp beam is swept across the anterior 
chamber.  When the instrument is held stationary, every optical section contains 
cells, or hypopyon is noted.  As for fibrin deposition, hypopyon may persist for some 
period of time after the active exudation of cells into the anterior chamber has 
diminished or ceased entirely, making it possible to have 1circulating cells in the 
anterior chamber with a resolving hypopyon.
Modified from:  Hogan et al. (1959).
Table 2
Grading Scale for Vitreous Cells
Cells in Retro-Illuminated Field
Description
Grade
0
Clear
0
120
Few opacities
Trace
2150
Scattered opacities
1
51100
Moderate opacities
2
101250
Many opacities
3
251
Dense opacities
4
Modified from:  Nussenblatt et al. (1996).
REFERENCES
Hogan MH, Kimura SJ, Thygeson P. Signs and symptoms of uveitis. I. Anterior uveitis. 
Am J Ophthalmol 1959;47(5, Part 2):15570.
Nussenblatt RB, Whitcup SM, Palestine AG. Uveitis: fundamentals and clinical practice. 
In: Nussenblatt RB, Whitcup SM, Palestine AG, editors. Examination of the 
patient with uveitis. 2nd revised edition. St Louis: Mosby, 1996; 64.
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Appendix 4
Best-Corrected Visual Acuity Testing
SCOPE
The best-corrected visual acuity (BCVA) assessment must be conducted before pupil
dilation.  BCVA will be measured by trained and certified personnel at the study sites.  
The visual acuity (VA) examiner must be masked to each patient’s study (treated) eye 
and treatment arm assignment.  VA will be measured at the intervals specified in the 
protocol (see Appendix 1).
EQUIPMENT
The following are needed to conduct the examination:

Examination lane of adequate dimensions to allow testing at required distances
(4- and 1-meter lanes)

Standard chair with a firm back

Set of three Precision Visionor Lighthouse distance acuity charts as applicable 
per country and region (see the BCVA manual for details)

Retro-Illuminated box

Study frame

Study lens set
TRAINING AND CERTIFICATION
A VA specifications document, procedure manual, and training materials will be provided 
to the investigational sites, and examiner certification will be obtained from a third party 
vendor.  The VA examination room also must be certified before any VA examinations 
are performed.
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Appendix 5
Color Fundus Photography
SCOPE
Stereo color fundus photographs will be obtained from both eyes by trained personnel at 
the study sites.  Fundus photography will be performed at the intervals specified in the 
schedule of activities (see Appendix 1).  Analysis (if applicable) of fundus photographs 
will be performed by the central reading center.
EQUIPMENT
See the central reading center manual.
PROCEDURE
The central reading center will provide a study manual and training materials.  The 
fundus photographer and photography equipment will be certified by the central reading 
center before any study images are taken.  See the central reading center manual for 
further details.
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Appendix 6
Fundus Fluorescein Angiography
SCOPE
Fundus fluorescein angiography will be performed on both eyes at the study sites by 
trained personnel who are certified by the central reading center.  The fundus fluorescein 
angiograms will be obtained at the intervals specified in the protocol (see Appendix 1).  
Analysis (if applicable) of fundus fluorescein angiograms will be performed by the central 
reading center.
EQUIPMENT
Digital angiograms must be used while conducting an angiographic evaluation for the 
study.
Film-based angiography is not acceptable.
DIGITAL IMAGING SYSTEMS AND CERTIFICATION
Digital imaging systems are required.  The system and software at the site will be 
certified by the central reading center prior to obtaining any study angiograms.  This 
certification and validation process will ensure that the central reading center will be able 
to correctly calculate the required measurements.
PROCEDURES
The central reading center will provide a study manual and training materials.  
Photographers, systems, and software will be certified prior to obtaining angiograms 
of patients.
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Appendix 7
Spectral-Domain Optical Coherence Tomography
SCOPE
Spectral-domain optical coherence tomography (SD-OCT) will be performed at the study 
sites by trained personnel who are certified by the central reading center.  SD-OCT 
imaging will be performed for each patient at the intervals specified in the protocol (see
Appendix 1).
The SD-OCT images of both eyes will be obtained at protocol-specified visits and will be 
forwarded to the central reading center.
Note: The optional images will be collected at the sites with optical coherence 
tomographyangiography capabilities and forwarded to the central reading center.
EQUIPMENT
Equipment utilized during this study is described in the central reading center manual.  
The ability to transfer images to electronically exportable digital files is required 
(i.e., no printed SD-OCT images will be sent to the central reading center).
PROCEDURES AND CERTIFICATION
The central reading center 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 RO6867461 concentrations 
(pharmacokinetics), pharmacodynamics, anti-RO6867461 antibodies, blood DNA 
sample, laboratory assessment (hematology, serum chemistry, coagulation, and 
urinalysis), hemoglobin A1C (HgA1C), 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 treating physician from patients who consent to the procedure and sample 
acquisition.  An aqueous humor sample will be collected before the patient’s study eye 
treatment at the visits as indicated in Appendix 1. Please refer to the central laboratory
manual for additional details regarding sample collection and shipping information. 
OPTIONAL UNSCHEDULED COLLECTION OF VITREOUS HUMOR 
SAMPLE COLLECTION
Elective vitrectomy is not allowed in the study eye during a patient's study participation.  
However, if the surgery is medically necessary and the patient consents, a vitreous 
sample can be collected from the study eye. Either masked or unmasked investigators 
can collect the sample. Approximately 0.5 mL of undiluted vitreous humor should be 
collected using an aseptic procedure and sterile field and according to local guidelines 
and shipped as specified in the central laboratory manual. 
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Appendix 8
Biological Sample Collection and Shipping Instructions (cont.)
A pharmacokinetic blood sample (for plasma preparation) should also be collected and 
shipped as specified in the central laboratory manual.
Vitreous humor samples will be analyzed primarily for RO6867461 concentrations and 
may also be analyzed for aflibercept concentrations.  The remaining samples may be 
analyzed for 
, and possibly other biomarkers.
BIOLOGICAL SAMPLES STORAGE DURATION
The hematology, serum chemistry, urinalysis, coagulation, serum, urine pregnancy tests,
and HbA1c samples will be destroyed after their analysis during the study.
Unless the patient gives specific Research Biosample Repository consent for his or her 
remaining samples to be stored for optional exploratory research (see Section 4.5.9.5), 
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
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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Appendix 9
National Eye Institute Visual Functioning Questionnaire25 
(cont.)
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