A Phase IIIb, Open-Label, Single-Arm Study in Patients With Neovascular Age-Related Macular Degeneration or Diabetic Macular Edema to Evaluate the Safety of the 6-mg Faricimab Prefilled Syringe
Phase: PHASE3
Conditions: Neovascular Age-related Macular Degeneration, Diabetic Macular Edema
Sponsor: Hoffmann-La Roche



CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
6-mg Faricimab Prefilled Syringe—F. Hoffmann-La Roche Ltd
Protocol GR43742, Version 1
PROTOCOL 
PROTOCOL TITLE: 
A PHASE IIIb, OPEN-LABEL, SINGLE-ARM STUDY 
IN PATIENTS WITH NEOVASCULAR 
AGE-RELATED MACULAR DEGENERATION OR 
DIABETIC MACULAR EDEMA TO EVALUATE THE 
SAFETY OF THE 6-MG FARICIMAB PREFILLED 
SYRINGE
PROTOCOL NUMBER: GR43742 
VERSION NUMBER: 
1 
TEST COMPOUND: 
Faricimab (RO6867461) 
STUDY PHASE: 
Phase IIIb 
EUDRACT NUMBER: 
Not applicable. 
IND NUMBER: 
119225 
NCT NUMBER: 
To be determined 
MEDICAL MONITOR: 
, M.D., Ph.D. 
SPONSOR’S NAME 
AND LEGAL 
REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd
Grenzacherstrasse 124
4070 Basel, Switzerland
APPROVAL: 
See electronic signature and date stamp on the final 
page of this document. 

6-mg Faricimab Prefilled Syringe—F. Hoffmann-La Roche Ltd 
2/Protocol GR43742, Version 1 
 
TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................... 6 
1. 
PROTOCOL SUMMARY ................................................................. 7 
1.1 
Synopsis .................................................................................... 7 
1.2 
Study Schema ........................................................................... 9 
1.3 
Schedule of Activities ............................................................... 10 
2. 
INTRODUCTION ........................................................................... 12 
2.1 
Study Rationale ....................................................................... 12 
2.2 
Background.............................................................................. 12 
2.3 
Benefit–Risk Assessment ........................................................ 13 
3. 
OBJECTIVES AND ENDPOINTS ................................................. 13 
4. 
STUDY DESIGN ........................................................................... 14 
4.1 
Overall Design ......................................................................... 14 
4.1.1 
Description of Study ................................................................. 14 
4.1.2 
Overview of Study Design and Procedure ............................... 14 
4.2 
Rationale for Study Design ...................................................... 15 
4.2.1 
Rationale for Study Population ................................................ 15 
4.2.2 
Rationale for Human Factors Observations ............................. 16 
4.3 
Justification for Dose ............................................................... 16 
4.4 
End of Study Definition ............................................................ 16 
4.5 
Duration of Participation .......................................................... 16 
5. 
STUDY POPULATION .................................................................. 16 
5.1 
Inclusion Criteria ...................................................................... 17 
5.1.1 
Inclusion Criteria for Health Care Providers ............................. 17 
5.1.2 
Inclusion Criteria for Patients ................................................... 17 
5.2 
Exclusion Criteria ..................................................................... 18 
5.2.1 
Exclusion Criteria for Patients .................................................. 18 
5.3 
Lifestyle Considerations ........................................................... 19 
5.3.1 
Meals and Dietary Restrictions ................................................ 19 
5.3.2 
Caffeine, Alcohol, and Tobacco ............................................... 19 
5.3.3 
Activity ..................................................................................... 19 

6-mg Faricimab Prefilled Syringe—F. Hoffmann-La Roche Ltd 
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5.3.4 
Contraception Requirements ................................................... 19 
5.4 
Screen Failures ........................................................................ 19 
6. 
STUDY TREATMENT, OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN, AND CONCOMITANT THERAPY ...... 20 
6.1 
Study Treatments Administered ............................................... 20 
6.2 
Preparation, Handling, Storage, and Accountability ................. 21 
6.3 
Treatment Assignment ............................................................. 21 
6.4 
Study Treatment Compliance .................................................. 22 
6.5 
Dose Modification .................................................................... 22 
6.6 
Continued Access to Study Treatment after the End of the 
Study ....................................................................................... 22 
6.7 
Treatment of Overdose ............................................................ 23 
6.8 
Concomitant Therapy .............................................................. 23 
6.8.1 
Permitted Therapy ................................................................... 23 
6.8.2 
Prohibited Therapy .................................................................. 24 
7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PATIENT DISCONTINUATION OR WITHDRAWAL ..................... 24 
7.1 
Discontinuation of Study Treatment ......................................... 24 
7.2 
Patient Discontinuation or Withdrawal from the Study ............. 24 
7.3 
Patients Lost to Follow-Up ....................................................... 25 
8. 
STUDY ASSESSMENTS AND PROCEDURES ........................... 25 
8.1 
Efficacy Assessments .............................................................. 26 
8.2 
Safety Assessments ................................................................ 26 
8.2.1 
Ocular Assessments ................................................................ 26 
8.2.2 
Pregnancy Testing ................................................................... 27 
8.3 
Adverse Events, Serious Adverse Events, and Other 
Safety Reporting ...................................................................... 27 
8.3.1 
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information .................................. 27 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events ...................................................................................... 28 
8.3.3 
Follow-Up of Adverse Events and Serious Adverse Events .... 28 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events ...................................................................................... 28 

6-mg Faricimab Prefilled Syringe—F. Hoffmann-La Roche Ltd
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8.3.5
Pregnancy................................................................................ 29
8.3.6
Cardiovascular and Death Events ........................................... 29
8.3.7
Anticipated Events Not Qualifying for Expedited Reporting ..... 29
8.3.8
Adverse Events of Special Interest .......................................... 30
8.3.9
Device Product Complaints (Including Failures and 
Malfunctions) ........................................................................... 30
8.3.10
Medical Monitors and Emergency Medical Contacts ............... 31
8.4
Pharmacokinetics .................................................................... 31
8.5
Pharmacodynamics ................................................................. 31
8.6
Genetics .................................................................................. 31
8.7
Biomarker Assessments .......................................................... 31
8.8
Immunogenicity Assessments ................................................. 31
8.9
Health Economics and Medical Resource Utilization ............... 31
8.10
Additional Assessments and Procedures 
Requiring Separate Consent or Performed 
Only at Participating Sites ........................................................ 32
9.
STATISTICAL CONSIDERATIONS .............................................. 32
9.1
Statistical Hypotheses ............................................................. 32
9.2
Sample Size Determination ..................................................... 32
9.3
Safety Analyses ....................................................................... 32
9.4
Summaries of Conduct of Study .............................................. 32
9.5
Interim Analysis ....................................................................... 32
9.6
Independent Data Monitoring Committee ................................ 32
10.
REFERENCES.............................................................................. 33
LIST OF TABLES 
Table 1
Schedule of Activities for Health Care Providers ......................... 10
Table 2
Schedule of Activities for Patients ............................................... 11
Table 
Study Treatment Description ....................................................... 20
LIST OF FIGURES 
Figure 1
Study Schema ............................................................................... 9

6-mg Faricimab Prefilled Syringe—F. Hoffmann-La Roche Ltd 
5/Protocol GR43742, Version 1 
 
LIST OF APPENDICES 
Appendix 1 
Regulatory, Ethical, and Study Oversight Considerations ........... 34 
Appendix 2 
Adverse Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ......................................... 41 
Appendix 3 
Safety Plan:  Management of Identified and Potential Risks ....... 57 
Appendix 4 
Contraceptive and Barrier Guidance ........................................... 60 
Appendix 5 
Reporting Requirements for Device Product Complaints ............ 63 
Appendix 6 
Clinical Safety Laboratory Tests ................................................. 65 
Appendix 7 
Grading Scale for Assessment of Anterior Chamber Flare or 
Cells and Vitreous Cell ................................................................ 66 
Appendix 8 
Refraction and Best-Corrected Visual Acuity Testing ................. 67 
Appendix 9 
Unscheduled Safety Assessment Visit ........................................ 68 
Appendix 10 
Abbreviations .............................................................................. 69 
 
 

 
Faricimab 6 mg Prefilled Syringe—F. Hoffmann-La Roche Ltd 
6/Protocol GR43742, Version 1 
PROTOCOL ACCEPTANCE FORM 
PROTOCOL TITLE: 
A PHASE IIIb, OPEN-LABEL, SINGLE-ARM STUDY 
IN PATIENTS WITH NEOVASCULAR 
AGE-RELATED MACULAR DEGENERATION OR 
DIABETIC MACULAR EDEMA TO EVALUATE THE 
SAFETY OF THE 6-MG FARICIMAB PREFILLED 
SYRINGE 
PROTOCOL NUMBER: GR43742 
VERSION NUMBER: 
1 
TEST COMPOUND: 
Faricimab (RO6867461) 
MEDICAL MONITOR: 
, M.D., Ph.D. 
SPONSOR NAME: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name  (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy 
of the signed form as instructed by your local study monitor. 
 

 
6-mg Faricimab Prefilled Syringe—F. Hoffmann-La Roche Ltd 
7/Protocol GR43742, Version 1 
1. 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
 
PROTOCOL TITLE: 
A PHASE IIIb, OPEN-LABEL, SINGLE-ARM STUDY IN PATIENTS 
WITH NEOVASCULAR AGE-RELATED MACULAR 
DEGENERATION OR DIABETIC MACULAR EDEMA TO 
EVALUATE THE SAFETY OF THE 6-MG FARICIMAB PREFILLED 
SYRINGE 
  
STUDY RATIONALE 
The purpose of the clinical in-use study is to collect observations on the use of the 6-mg 
faricimab prefiled syringe (PFS) configuration to administer an intravitreal (IVT) injection to 
patients with either diabetic macular edema (DME) or neovascular age-related macular 
degeneration (nAMD) in an actual clinical use environment.  Observations will be collected 
during the preparation and administration of a 6-mg faricimab IVT injection using the PFS 
configuration in accordance with the Instructions for Use (IFU) in the intended use environment.  
The PFS configuration consists of the faricimab 6-mg PFS together with the co-packed injection 
filter needle (IFN).  
OBJECTIVES AND ENDPOINTS 
The primary objective of this study is to collect observations on healthcare providers (HCPs) 
using a PFS configuration in an actual clinical use environment to prepare and administer a 
6‑mg faricimab intravitreal injection to patients with either DME or nAMD and as instructed in 
the IFU.   
No patient-related efficacy or safety endpoints are planned for this study.  However, in 
accordance with Good Clinical Practices (GCPs), adverse events (AEs), adverse events of 
special interest (AESIs), and serious adverse events (SAEs) occurring during the 7-day study 
reporting period will be summarized. 
OVERALL DESIGN 
The 6-mg faricimab PFS clinical in-use study is a Phase IIIb, single-arm, open-label multicenter 
study in patients with nAMD or DME designed to assess the ability of the intended users, HCPs, 
to follow the IFU to perform an IVT injection using the 6-mg faricimab PFS configuration per the 
intended use.  The study will collect observations related to the use of the PFS configuration.   
The study will be conducted in ophthalmology clinical settings.  The focus of the usability 
observation will be on the HCP teams.  The HCP team will consist of a retina specialist and any 
assistants who participate in any stage of the PFS preparation and administration procedure.  
Approximately three HCP teams will participate in this study to administer a single IVT injection 
of 6-mg faricimab PFS (120 mg/mL drug concentration) using the PFS configuration for a total 
of approximately 35 participants.  
All patients will be required to have a current diagnosis of nAMD or DME with at least one eye 
eligible for 6-mg faricimab IVT injection, at the discretion of the retina specialist.  Both previously 
treated and treatment-naive patients will be eligible for enrollment.  Only one eye will be 
selected as the study eye.  If both eyes are eligible, the investigator will determine which eye 
will be selected for study treatment (study eye). 
The same retina specialist may act as the Principal Investigator and the HCP using the PFS 
configuration to administer faricimab.  Alternatively, a sub-investigator may perform the duties of 
the HCP.   
DISCLOSURE STATEMENT 
This is a single-group device feasibility study that is not masked. 
NUMBER OF PARTICIPANTS 
Approximately 35 evaluable patients with nAMD or DME will be enrolled in this study.  

 
6-mg Faricimab Prefilled Syringe—F. Hoffmann-La Roche Ltd 
8/Protocol GR43742, Version 1 
Note:  "Enrolled" means a participant's or their legally acceptable representative’s agreement to 
participate in a clinical study following completion of the informed consent process.  Potential 
participants who are screened for the purpose of determining eligibility for the study but do not 
participate in the study, are not considered enrolled, unless otherwise specified by the protocol. 
STUDY TREATMENT 
The investigational medicinal product for this study is 6-mg faricimab PFS. 
Patients will receive a single IVT injection of 0.05 mL of the 120-mg/mL faricimab (6-mg dose) 
formulation delivered via PFS with a co-packaged injection filter needle. 
DURATION OF PARTICIPATION 
The total duration of study participation for each patient is expected to be approximately 7 days. 
INDEPENDENT DATA MONITORING COMMITTEE 
An independent Data Monitoring Committee (iDMC) will not be used. 
 

 
6-mg Faricimab Prefilled Syringe—F. Hoffmann-La Roche Ltd 
9/Protocol GR43742, Version 1 
1.2 
STUDY SCHEMA 
Figure 1 Study Schema 
 
BCVA  best-corrected visual acuity; FPI  first patient in; HCP  health care provider; 
ICF  Informed Consent Form; IFU  Instructions for Use. 
Note:  There will be approximately 23 HCP teams, with 35 patients in total.  Study start 
corresponds with Day 1 (FPI).  Study end is 7 days after the injection in the last patient.  The 
injection procedure (study Day 1 in the schematic) can occur on different calendar days for 
different HCPs and different patients.  HCPs will review the IFU on their own before Day 1 of the 
study.  HCP interviews will be conducted on Day 1. 
*Baseline examinations consist of BCVA, slitlamp, and indirect ophthalmoscopy. 

 
6-mg Faricimab Prefilled Syringe—F. Hoffmann-La Roche Ltd 
12/Protocol GR43742, Version 1 
2. 
INTRODUCTION 
2.1 
STUDY RATIONALE 
The purpose of the clinical in-use study is to collect observations on the use of the 6-mg 
faricimab prefiled syringe (PFS) configuration to administer an intravitreal (IVT) injection 
to patients with either diabetic macular edema (DME) or neovascular age-related 
macular degeneration (nAMD) in an actual clinical use environment.  Observations will 
be collected during the preparation and administration of a 6-mg faricimab IVT injection 
using the PFS configuration in accordance with the Instructions for Use (IFU) in the 
intended use environment.   
The PFS configuration consists of the faricimab 6-mg PFS together with the co-packed 
injection filter needle (IFN).  
2.2 
BACKGROUND 
nAMD is a form of advanced AMD that causes rapid and severe visual loss and remains 
a leading cause of visual impairment in the elderly (Bourne et al. 2013; Wong et al. 
2014).  Treatment goals are to regain and maintain vision.  A key challenge with 
currently available antivascular endothelial growth factor (VEGF) treatments is the 
requirement for frequent and long-term administration to maintain vision gains 
(Heier et al. 2012; the Comparison of Age-Related Macular Degeneration Treatment 
Trials [CATT] Research Group 2016).  There remains an unmet need for more 
efficacious and durable treatment.  
DME, a complication of diabetic retinopathy (DR), can develop at any stage of the 
underlying disease of retinal microvasculature (Fong et al. 2004) and is a major cause of 
vision loss in working-age individuals.  Despite advances with the anti-VEGF approach 
in DME, a significant percentage of patients do not achieve normal vision or have 
adequate vision required to obtain a driver’s license, suggesting that anti-VEGF 
treatment alone does not address all the pathways underlying DME pathology. 
Faricimab is an intravitreously administered, humanized bispecific immunoglobulin G1 
(IgG1) antibody that selectively binds to angiopoietin-2 (Ang-2) and VEGF-A.  Vitreous 
concentrations of both Ang-2 and VEGF-A are upregulated in patients with diabetic eye 
disease, and to a lesser extent, in patients with nAMD.  Therefore, selective 
neutralization of both Ang-2 and VEGF may better stabilize pathological ocular 
vasculature in addition to further reducing leakage compared with anti-VEGF 
monotherapy.  This may result in further improvement of retinal function and durability of 
response for patients with DME, DR, and nAMD.  As of May 2022, the vial product 
configuration of faricimab (under the tradename Vabysmo) has been approved in the 
United States, United Kingdom, Canada, Japan, Thailand, Switzerland, and the United 
Arab Emirates for the treatment of nAMD and DME by injection into the eye. 

 
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6-mg Faricimab Prefilled Syringe—F. Hoffmann-La Roche Ltd 
14/Protocol GR43742, Version 1 
administer a 6-mg faricimab intravitreal injection to patients with either DME or nAMD 
and as instructed in the IFU.   
No patient-related efficacy or safety endpoints are planned for this study.  However, in 
accordance with Good Clinical Practices (GCPs), adverse events (AEs), adverse events 
of special interest (AESIs), and serious adverse events (SAEs) occurring during the 
7‑day study reporting period will be summarized.  
4. 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
4.1.1 
Description of Study 
The 6-mg faricimab PFS clinical in-use study is a Phase IIIb, single-arm, open-label, 
multicenter study in patients with nAMD or DME designed to assess the ability of the 
intended users, HCPs, to follow the IFU to perform an IVT injection using the 6-mg 
faricimab PFS configuration per the intended use.  The study will collect observations 
related to the use of the PFS configuration.   
The study will be conducted in ophthalmology clinical settings.  The focus of the usability 
observation will be on the HCP teams.  The HCP team will consist of a retina specialist 
and any assistants who participate in any stage of the PFS preparation and 
administration procedure.  Approximately three HCP teams will participate in this study 
to administer a single IVT injection of 6-mg faricimab PFS (120-mg/mL drug 
concentration) using the PFS configuration for a total of approximately 35 participants.  
All patients will be required to have a current diagnosis of nAMD or DME with at least 
one eye eligible for 6-mg faricimab IVT injection, at the discretion of the retina specialist.  
Both previously treated and treatment-naive patients will be eligible for enrollment.  Only 
one eye will be selected as the study eye.  If both eyes are eligible, the investigator will 
determine which eye will be selected for study treatment (study eye). 
The same retina specialist may act as the Principal Investigator and the HCP using the 
PFS configuration to administer faricimab.  Alternatively, a sub-investigator may perform 
the duties of the HCP.   
4.1.2 
Overview of Study Design and Procedure 
A study schema is provided in Section 1.2 (see Figure 1).  The schedules of activities 
are provided in Section 1.3 (see Table 1 and Table 2). 
The study will be set up to enable usability (human factors [HF]) observations related to 
the use of the PFS configuration.  This will be performed by the two HF observers who 
will be present at the study sites to observe each injection procedure.  In the 30 days 
prior to (or including) Day 1, patients will be screened for their eligibility to participate in 
the trial.  

 
6-mg Faricimab Prefilled Syringe—F. Hoffmann-La Roche Ltd 
15/Protocol GR43742, Version 1 
As part of the information package sent in preparation for the study, each clinical study 
site will be provided with the IFU.  Approximately 3 days prior to Day 1, HCPs will be 
expected to familiarize themselves with the documentation in advance and will be asked 
to confirm that they have read the IFU by signing an acknowledgement on Day 1.  The 
HF observer and the additional observer will not provide a demonstration or training to 
HCP participants. 
The HF observers will pre-brief the HCPs prior to the HF observations.  When the patient 
is ready, the HF observers will be introduced to the patient in the administration room.  
The HF observers will be positioned such that they can clearly observe the entire 
preparation and administration process.  The HCP team (i.e., retina specialist alone or 
retina specialist with assistant/technician, as per local procedure) will be asked to open 
the folding box only when the HF observers are present and to perform all preparation 
and administration steps in view of the HF observers.  The PFS configuration should be 
prepared for use immediately prior to the injection, as described in the IFU.  The HF 
observers will remain at a distance specified by the HCPs or facility and will not interrupt 
or interfere with the procedure.  The HF observers will document HCP’s performance 
using an assessment checklist and all administration procedures will be recorded on 
video to facilitate subsequent HF analysis of observations. 
HF observers will ask for good visibility of all activities.  To enable assessment of dose 
setting accuracy, HCPs will be asked to pause briefly during every procedure in order to 
turn and show the set dose to the observers for a closer look and brief video recording.   
Should the HF observers see any HCP actions of potential safety concerns related to 
safe PFS use, they will not intervene, as it is considered the responsibility of the HCPs to 
ensure patient safety based on clinical judgement.  However, participating HCPs are 
expected to remain aware of any potential safety concerns (should they arise due to 
PFS use) and take preventative actions.  
Following the completion of each IVT injection, the HF observers will conduct a follow-up 
interview with the HCPs to discuss observations.  No questions will be asked in the 
presence of patients or other site staff.  Interview questions will focus on identifying 
reasons for observed actions.  HCPs will be reminded of the complaints procedure for 
reporting observations of device failures or malfunctions (Appendix 5). 
See Table 1 and Table 2 for the schedules of activities performed by the HCP during the 
study.  
4.2 
RATIONALE FOR STUDY DESIGN 
4.2.1 
Rationale for Study Population 
Patients with nAMD and DME have been selected for inclusion in this study given that 
these indications are being investigated in the Phase III program (Studies GR40306 and 
GR40844 in nAMD, and Studies GR40349 and GR40398 in DME).  As of May 2022, the 

 
6-mg Faricimab Prefilled Syringe—F. Hoffmann-La Roche Ltd 
16/Protocol GR43742, Version 1 
faricimab (under the tradename Vabysmo) vial product configuration has been 
approved in the United States, United Kingdom, Canada, Japan, Thailand, Switzerland, 
and the United Arab Emirates for the treatment of nAMD and DME by injection into the 
eye.  Licensing applications are currently under health authority review for faricimab in 
these indications in other countries. 
4.2.2 
Rationale for Human Factors Observations 
The purpose of the usability observations is to observe the use of the PFS configuration 
in an actual clinical use environment to assess if there are any safety concerns 
remaining related to the future commercial use of the device components.  At the time of 
the study, the PFS configuration (i.e., its device components) will have gone through full 
technical development, including design validation to ensure the safety of the PFS and 
the IFN.  However, the PFS configuration will not have received market approval at this 
time.  
4.3 
JUSTIFICATION FOR DOSE 
The 6-mg dose of faricimab in the PFS has been selected to align with the dose that has 
been studied in the Phase III program in patients with nAMD (Studies GR40306 and 
GR40844) and DME (Studies GR40349 and GR40398).  The formulation, concentration, 
and intended injection volume will also remain the same as those used in the Phase III 
program. 
4.4 
END OF STUDY DEFINITION 
A patient is considered to have completed the study if he or she has completed all 
phases of the study, including the safety telephone call 7 days after administration of the 
PFS injection. 
The end of this study is defined as the date when approximately 35 patients have 
received injections, all HCP participants have completed their interviews with the HF 
observers, and the 7-day ( 1 day) reporting period after the PFS injection in the last 
patient has passed.  It is expected that the duration of the investigation (length of study 
plus enrollment period) will be approximately 1.5 months. 
In addition, the Sponsor may decide to terminate the study at any time. 
4.5 
DURATION OF PARTICIPATION 
The total duration of study participation for each patient is expected to be approximately 
7 days. 
5. 
STUDY POPULATION 
Approximately 35 patients with nAMD or DME will be enrolled in this study. 

 
6-mg Faricimab Prefilled Syringe—F. Hoffmann-La Roche Ltd 
17/Protocol GR43742, Version 1 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA 
5.1.1 
Inclusion Criteria for Health Care Providers 
Criteria necessary for a retina specialist to participate in the clinical in-use study are the 
following: 
 
Valid medical license to practice in the United States 
 
Previous experience performing faricimab IVT injections using the vial and syringe 
procedure 
Note that only the retina specialist or suitably-qualified retina fellows are 
allowed to perform the injection. 
 
Ability to pre-screen and recruit patients with nAMD or DME indicated for faricimab 
IVT therapy within a reasonable time frame ( 30 days) 
 
Ability to schedule the required baseline examinations and faricimab PFS injection 
procedures, and undergo clinical in-use evaluation within a relatively short time 
frame ( 7 days) 
 
All additional HCPs (i.e., retina specialists nurses, assistants, or technicians) involved in 
the faricimab PFS preparation or injection procedure will be included in the study 
observations and the post-procedure interviews.  All participating retina specialists and 
additional HCPs will be asked to sign an informed consent form regarding the 
observations to be conducted before commencing with injection preparation.  
5.1.2 
Inclusion Criteria for Patients  
Patients are eligible to be included in the study only if all of the following criteria apply: 
 
Signed Informed Consent Form  
 
Age  18 years at the time of signing Informed Consent Form 
 
Willing and able to comply with clinic visits and study-related procedures (e.g., video 
recording during the injection procedure) 
 
For female patients of childbearing potential:  agreement to remain abstinent (refrain 
from heterosexual intercourse) or use contraception, and agree to refrain from 
donating eggs, as defined below: 
Patients must remain abstinent or use contraceptive methods with a failure rate 
of   1% per year during the treatment period and for 3 months after the final 
dose of faricimab.  Patients must refrain from donating eggs during this same 
period. 
A female patient is considered to be of childbearing potential if she is 
postmenarchal, has not reached a postmenopausal state ( 12 continuous 
months of amenorrhea with no identified cause other than menopause), and is 
not permanently infertile due to surgery (i.e., removal of ovaries, fallopian 

 
6-mg Faricimab Prefilled Syringe—F. Hoffmann-La Roche Ltd 
18/Protocol GR43742, Version 1 
tubes, and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  Per this definition, a woman with a tubal ligation is 
considered to be of childbearing potential.  The definition of childbearing 
potential may be adapted for alignment with local guidelines or regulations. 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices.  
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the 
individual.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not adequate methods of 
contraception.  If required per local guidelines or regulations, locally recognized 
adequate methods of contraception and information about the reliability of 
abstinence will be described in the local Informed Consent Form. 
 
Patients who have a confirmed diagnosis of nAMD (any subtype) or DME in one or 
both eyes by the study site investigator (only one eye will be selected as the study 
eye, as determined by the retina specialist) with onset at any time prior to study start 
 
Patients whose study eye is deemed to be indicated for faricimab IVT treatment at 
the discretion of the retina specialist 
 
Patients with historical optical coherence tomography (OCT) data available for the 
study eye within 30 days prior to Day 1. 
 
5.2 
EXCLUSION CRITERIA 
5.2.1 
Exclusion Criteria for Patients 
Patients are excluded from the study if any of the following criteria apply: 
 
Pregnancy or breastfeeding, or intention to become pregnant during the study or 
within 3 months after the final dose of faricimab 
Female patients of childbearing potential must have a negative urine 
pregnancy test result during screening and on Day 1. 
 
Requirement on Day 1 for continuous use of any medications and treatments 
indicated in Section 6.8.2, Prohibited Therapy 
 
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 
 
Stroke (cerebral vascular accident) or myocardial infarction within 6 months prior to 
Day 1 
 
History of a severe allergic reaction or anaphylactic reaction to a biologic agent or 
known hypersensitivity to any component of the faricimab PFS injection, study-
related procedure preparations, or any of the anesthetic and antimicrobial 
preparations used by a participant during the study 
 
History of other disease, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding giving reasonable suspicion of a condition that 

 
6-mg Faricimab Prefilled Syringe—F. Hoffmann-La Roche Ltd 
19/Protocol GR43742, Version 1 
contraindicates the use of faricimab or renders the patient at high risk for treatment 
complications in the opinion of the investigator 
 
Uncontrolled hypertension (systolic blood pressure 180 mmHg and/or diastolic 
blood pressure 100 mmHg while a patient is at rest) 
 
Systemic treatment for suspected or active systemic infection on Day 1 
 
Patients legally blind in the study eye on Day 1 (legal blindness:  Best-corrected 
visual acuity [BCVA] of 20/200 or less). 
 
History of or any current clinically relevant intraocular inflammation or ocular 
inflammatory reaction (any grading from trace and greater is excluded), including 
non-infectious uveitis or infectious uveitis, or sterile inflammatory reaction after 
previous IVT injections with any agent in either eye  
 
Suspected or active ocular or periocular infection in either eye on Day 1 
 
History of or any current indication of excessive bleeding and recurrent 
hemorrhages, including any prior excessive intraocular or subconjunctival bleeding 
or hemorrhages after IVT injection or intraocular procedures in either eye 
 
Uncontrolled glaucoma in the study eye 
 
Treatment with any IVT injection in the study eye within the 27 days prior to Day 1 
 
Any invasive intraocular surgery, prior long-acting therapeutic agent, or ocular drug 
release device implantation (approved or investigational) in the study eye at any 
time during the 3 months prior to Day 1 
 
Treatment with panretinal photocoagulation, laser retinopexy or macular (focal, grid, 
or micropulse) laser in the study eye within one month prior to Day 1 
 
5.3 
LIFESTYLE CONSIDERATIONS 
5.3.1 
Meals and Dietary Restrictions 
This study has no meal or dietary restrictions. 
5.3.2 
Caffeine, Alcohol, and Tobacco 
This study has no caffeine, alcohol, or tobacco restrictions. 
5.3.3 
Activity 
This study has no activity restrictions. 
5.3.4 
Contraception Requirements 
During the study, patients must use contraception or take other precautions as described 
in Section 5.1. 
5.4 
SCREEN FAILURES 
Individuals who do not meet the criteria for participation in this study (screen failure) 
cannot be re-screened.  The investigator will record reasons for screen failure in the 
screening log (see Section 8). 

 
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21/Protocol GR43742, Version 1 
6.2 
PREPARATION, HANDLING, STORAGE, AND 
ACCOUNTABILITY 
The Investigatonal Medicinal Product (IMP) required for completion of this study will be 
provided by the Sponsor.  The study site (i.e., investigator or other authorized personnel 
[e.g., pharmacist]) is responsible for maintaining records of IMP delivery to the site, IMP 
inventory at the site, IMP use by each patient, and return of unused IMP, thus enabling 
reconciliation of all IMP received, and for ensuring that patients are provided with doses 
specified by the protocol. 
The study site should follow all instructions included with each shipment of IMP.  The 
study site will acknowledge receipt of IMP supplied by the Sponsor by returning the 
appropriate documentation form to confirm the shipment condition and content.  
Any damaged shipments will be replaced.  The investigator or designee must confirm 
that appropriate temperature conditions have been maintained during transit, either by 
time monitoring (shipment arrival date and time) or temperature monitoring, for the IMP 
received and that any discrepancies have been reported and resolved before use of the 
IMP.  The IMP must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions, with 
access limited to the investigator and authorized staff. 
Only patients enrolled in the study may receive the IMP, and only authorized staff may 
supply or administer the IMP. 
The IMP will be returned to the Sponsor with the appropriate documentation, as per 
agreement.  
Accurate records of the IMP received at, dispensed from, and returned to the Sponsor by 
the study site should be recorded on the drug accountability log. 
Refer to the Instructions for Use and/or the pharmacy manual for information on IMP 
preparation, storage, handling, and accountability.  
Of note, each single-dose PFS will provide a usable amount to deliver a single dose of 
6 mg faricimab in a volume of 0.05 mL via IVT injection, using the co-packaged IFN.  
The PFS and co-packaged IFN utilized in this study are fully representative of the 
presentation intended for commercialization.   
6.3 
TREATMENT ASSIGNMENT 
This is a non-randomized, open-label study.  After eligibility has been established for a 
patient and written informed consent has been obtained, the study site will obtain the 
patient's identification number from the Sponsor.  All participants will receive 6-mg 
faricimab with the PFS configuration. 

 
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6-mg Faricimab Prefilled Syringe—F. Hoffmann-La Roche Ltd 
24/Protocol GR43742, Version 1 
 
The onset of increased IOP and/or glaucoma in the study eye during a patient’s 
study participation should be treated as clinically indicated.  
 
The use of topical antimicrobials, anesthesia, and steroids in the study eye and in 
the fellow eye is permitted at the discretion of the investigator. 
 
6.8.2 
Prohibited Therapy 
At the discretion of the investigator, patients may continue to receive all medications and 
standard treatments administered for other conditions.  However, after the study drug 
administration on Day 1 the following medications and treatments are prohibited during 
study participation: 
 
Systemic anti-VEGF therapy 
 
IVT anti-VEGF agents in the study eye  
 
Planned (non-emergency) ocular or systemic surgical interventions 
 
Concurrent use of any macular photocoagulation or photodynamic therapy with 
verteporfin in the study eye 
 
Other experimental therapies (except those comprising vitamins and minerals) 
 
In addition, the investigator should contact the Medical Monitor if questions arise 
regarding medications not listed above. 
7. 
DISCONTINUATION OF STUDY TREATMENT AND PATIENT 
DISCONTINUATION OR WITHDRAWAL 
Study and site closure is described in Appendix 1 
. 
7.1 
DISCONTINUATION OF STUDY TREATMENT 
Discontinuation of study treatment is not applicable because each patient will receive 
only one study treatment administration. 
7.2 
PATIENT DISCONTINUATION OR WITHDRAWAL FROM THE 
STUDY 
A patient may withdraw from the study at any time at his or her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. 
The primary reason for discontinuation from the study should be documented on the 
appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator. 
The patient will be permanently discontinued both from the study treatment and from the 
study at that time. 

 
6-mg Faricimab Prefilled Syringe—F. Hoffmann-La Roche Ltd 
25/Protocol GR43742, Version 1 
If a patient withdraws consent from the study, the Sponsor may retain and continue to 
use any data collected before withdrawal of consent.  Patients who withdraw from the 
study will be replaced. 
7.3 
PATIENTS LOST TO FOLLOW-UP 
A patient will be considered lost to follow-up if he or she repeatedly is unable to be 
contacted by the study site. 
The following actions must be taken if a patient fails to be contactable by the study site: 
 
The site must attempt to contact the patient and reschedule the missed visit as soon 
as possible and counsel the patient on the importance of maintaining the assigned 
visit schedule.  If the patient is unable or unwilling to comply with study visits, site 
personnel should assess reasons the patient is unable or unwilling to participate, 
and determine if there are ways to support patient participation.  
 
Before a patient is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the patient (when possible, three telephone calls 
and, if necessary, a certified letter to the patient’s last known mailing address or 
local equivalent methods).  These contact attempts should be documented in the 
patient’s medical record. 
 
In the event that the patient continues to be unreachable, he or she will be 
considered lost to follow-up and will be withdrawn from the study. 
 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Written informed consent for participation in the study must be obtained from the 
patients before performing any study-related procedures (including screening 
evaluations).  Informed Consent Forms for enrolled patients and for patients who are not 
subsequently enrolled will be maintained at the study site.  Informed Consent Forms for 
the HCPs participating in the HF observations will be collected and maintained by the HF 
observers during their visits at the study sites, and need to be signed before 
commencing to unpack and prepare the device for use. 
Study procedures and their timing are summarized in the schedule of activities (see 
Section 1.3).  Protocol waivers or exemptions are not allowed. 
Urgent safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness. 
Adherence to the study design requirements, including those specified in the schedule of 
activities, is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
patients meet all eligibility criteria.  The investigator will maintain a detailed record of all 

 
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6-mg Faricimab Prefilled Syringe—F. Hoffmann-La Roche Ltd 
30/Protocol GR43742, Version 1 
8.3.8 
Adverse Events of Special Interest 
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 the investigator becomes aware 
of the event; see Section A25 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 A27.6) 
 
Suspected transmission of an infectious agent by a study treatment, 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 treatment is suspected. 
 
Sight-threatening adverse events:  An adverse event is considered to be sight-
threatening and should be reported expeditiously if it meets one or more of the 
following criteria: 
– 
It causes a decrease of  30 letters in visual acuity (VA) score using Early 
Treatment Diabetic Retinopathy Study (ETDRS) or greater than 0.6 using 
LogMAR or more than 6 lines using Snellen (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 A2-7 and 
Appendix 7 for intraocular inflammation terms and definitions). 
 
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. 
Descriptions of risks and management of the above-listed adverse events are provided 
in Appendix 3 
. 
8.3.9 
Device Product Complaints (Including Failures and 
Malfunctions) 
In this study, 6-mg faricimab single-use PFS with co-packaged injection filter needle is 
considered a drug-device combination product.  The biologic constituent part is 

6-mg Faricimab Prefilled Syringe—F. Hoffmann-La Roche Ltd
31/Protocol GR43742, Version 1
faricimab.  The device constituent parts are the prefilled syringe with the extended finger 
flange and the coupled plunger as well as and the injection filter needle.  The 
investigator must report all medical device complaints (including failures and 
malfunctions) and any associated adverse events to the Sponsor, as described in 
Appendix 5 . 
8.3.10 
Medical Monitors and Emergency Medical Contacts 
Contact Information for All Sites
Medical Monitor (Primary): 
, M.D., Ph.D. 
Mobile Telephone No.: 
Medical Monitor (Secondary): 
, M.D., Ph.D. 
Mobile Telephone No.: 
To ensure the safety of study patients, an Emergency Medical Call Center will be 
available 24 hours per day, 7 days per week, in case the above-listed contacts cannot 
be reached.  The Emergency Medical Call Center will connect the investigator with an 
Emergency Medical Contact, provide medical translation service if necessary, and track 
all calls.  Contact information, including toll-free numbers for the Emergency Medical Call 
Center, will be distributed to investigators.  
8.4 
PHARMACOKINETICS 
Pharmacokinetic parameters will not be evaluated in this study. 
8.5 
PHARMACODYNAMICS 
Pharmacodynamic biomarker assessments will not be performed in this study. 
8.6 
GENETICS 
Genetic biomarker assessments will not be performed in this study. 
8.7 
BIOMARKER ASSESSMENTS 
Biomarker assessments will not be performed in this study. 
8.8 
IMMUNOGENICITY ASSESSMENTS 
Immunogenicity assessments will not be performed in this study. 
8.9 
HEALTH ECONOMICS AND MEDICAL RESOURCE 
UTILIZATION 
Health economics and medical resource utilization assessments will not be performed in 
this study.  

 
6-mg Faricimab Prefilled Syringe—F. Hoffmann-La Roche Ltd 
32/Protocol GR43742, Version 1 
8.10 
ADDITIONAL ASSESSMENTS AND PROCEDURES 
REQUIRING SEPARATE CONSENT OR PERFORMED 
ONLY AT PARTICIPATING SITES 
There are no additional assessments and procedures requiring separate consent or 
performed only at participating sites. 
9. 
STATISTICAL CONSIDERATIONS 
9.1 
STATISTICAL HYPOTHESES 
No formal statistical hypotheses will be tested for this study.   
9.2 
SAMPLE SIZE DETERMINATION 
Because the study aims to assess the safety of 6-mg faricimab PFS and no formal 
hypothesis testings are planned, there are no formal statistical considerations or analysis 
plan used to determine sample size.  With approximately 12 patients per HCP team and 
at minimum three teams of HCPs, approximately 35 patients (at minimum 30 patients) 
with either nAMD or DME will enable evaluation of the safety of the 6-mg faricimab PFS 
per intended use. 
9.3 
SAFETY ANALYSES 
Descriptive statistics will be used to describe the incidence and severity of ocular and 
non-ocular adverse event data collected during the study and will also be summarized 
by the Investigator. 
9.4 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment, study treatment administration and discontinuation from the study, along 
with the reason for study discontinuation, will be summarized by the Investigator in the 
final study report.  Major protocol deviations, including major deviations with regard to 
the inclusion and exclusion criteria, will be summarized.  
9.5 
INTERIM ANALYSIS 
No interim analysis is planned.   
9.6 
INDEPENDENT DATA MONITORING COMMITTEE 
There is no independent Data Monitoring Committee for this study. 

 
6-mg Faricimab Prefilled Syringe—F. Hoffmann-La Roche Ltd 
33/Protocol GR43742, Version 1 
10. 
REFERENCES 
Bourne RR, Stevens GA, White RA, et al. Causes of vision loss worldwide, 19902010: 
a systematic analysis. Lancet Glob Health 2013;1:e33949. 
[CATT] Comparison of Age-related Macular Degeneration Treatments Trials Research 
Group, Maguire MG, Martin DF, et al. Five-year outcomes with anti-vascular 
endothelial growth factor treatment of neovascular age-related macular 
degeneration: The Comparison of Age-Related Macular Degeneration Treatments 
Trials. Ophthalmology 2016;123:175161. 
Fong DS, Aiello LP, Ferris FL 3rd, et al. Diabetic retinopathy. Diabetes Care 
2004;27:254053. 
Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet 
age-related macular degeneration. Ophthalmology 2012;119:253748. 
Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and 
disease burden projection for 2020 and 2040: a systematic review and 
meta-analysis. Lancet Glob Health 2014;2:e10616.  
 

Appendix 1:  Regulatory, Ethical, and Study Oversight Considerations 
6-mg Faricimab Prefilled Syringe—F. Hoffmann-La Roche Ltd 
35/Protocol GR43742, Version 1 
A11. 
REGULATORY AND ETHICAL CONSIDERATIONS 
This study will be conducted in accordance with the protocol and with the following: 
 
Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences international ethical guidelines 
 
Applicable International Council for Harmonisation (ICH) Guideline for Good Clinical 
Practice 
 
Applicable laws and regulations 
 
The protocol, patient Informed Consent Form, Investigator's Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an Institutional Review 
Board or Ethics Committee (IRB/EC) by the investigator and reviewed and approved by 
the IRB/EC before the study is initiated. 
Any substantial amendments to the protocol will require IRB/EC and health authority 
approval (as locally required) before implementation of changes, with the exception of 
administrative changes or changes necessary to eliminate an immediate hazard to study 
patients. 
The investigator will be responsible for the following: 
 
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 
 
Notifying the IRB/EC of serious adverse events or other significant safety findings, as 
required by IRB/EC procedures 
 
Providing oversight of the conduct of the study at the site and ensuring adherence to 
requirements of 21 CFR (U.S. sites only), the ICH Guideline for Good Clinical 
Practice, the IRB/EC, Regulation (E.U.) No. 536/2014 (E.U. sites only), and all other 
applicable local regulations 
 
A12. 
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 definition of end of study in 
Section 4.4). 

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A13. 
INFORMED CONSENT PROCESS 
Health Care Provider Consent 
Consent forms will be provided in English and must be signed and dated by the HCP 
before his or her participation in the study.   
Patient Informed Consent 
The investigator or authorized designee will explain the nature of the study, including the 
risks and benefits, to the patient or his or her legally authorized representative and 
answer all questions regarding the study. 
Patients must be informed that their participation is voluntary.  Patients or their legally 
authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50 (U.S. sites only), the ICH Guideline for Good 
Clinical Practice, and the IRB/EC. 
The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
Informed Consent Form. 
If the Informed Consent Form is revised (through an amendment or an addendum) to 
communicate information that might affect a patient's willingness to continue in the 
study, the patient or the patient's legally authorized representative must re-consent by 
signing the most current version of the Informed Consent Form or the addendum, in 
accordance with applicable laws and IRB/EC policy. 
A copy of each Informed Consent Form must be provided to the patient or the patient’s 
legally authorized representative. 
A14. 
DATA PROTECTION 
Patients will be assigned a unique identifier by the Sponsor.  Any patient records or 
datasets that are transferred to the Sponsor will contain the identifier only; the patient's 
name or any information that would make the patient identifiable will not be transferred. 
Patients must be informed that their personal study-related data will be used by the 
Sponsor in accordance with local data protection law.  The level of disclosure must also 
be explained to patients, who will be required to give consent for their data to be used as 
described in the Informed Consent Form. 

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Patients must be informed that their medical records may be examined by auditors or 
other authorized individuals representing the Sponsor or Sponsor collaborators and 
licensees, by appropriate IRB/EC members, and by inspectors from health authorities. 
A15. 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.  
TEAM Consulting will observe, record, and analyze human factors observations on 
behalf of the Sponsor. 
Approximately 3 sites in the United States will participate to enroll approximately 
35 patients.  An interactive voice or web-based response system (IxRS) will not be used.  
Sites will receive logs to manage patient enrollment and study IMP accountability. 
Electronic data capture will be used and sites will report and submit data to the Sponsor 
though this system. 
A16. 
DISSEMINATION OF CLINICAL STUDY DATA 
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.  For more information, refer to the Roche Global Policy on Sharing of 
Clinical Study Information at the following website: 
www.roche.com/roche global policy on sharing of clinical study information.pdf 
 
A17. 
DATA QUALITY ASSURANCE 
All patient data relating to the study will be recorded on printed forms (if applicable) or 
electronic Case Report Forms (CRFs) unless transmitted to the Sponsor or designee 
electronically (e.g., laboratory data).  The investigator is responsible for verifying that 
data entries are accurate and correct by physically or electronically signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. 

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Monitoring details describing strategy, including definition of study critical data items and 
processes (e.g., risk-based initiatives in operations and quality such as risk management 
and mitigation strategies and analytical risk-based monitoring), methods, responsibilities, 
and requirements, including handling of non-compliance issues and monitoring 
techniques (central, remote, or on-site monitoring), are provided prior to study 
initiation, in the various functional monitoring plans (including, but not limited to, Quality 
Tolerance Limit Management Plan and Trial Monitoring Plan). 
The Sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
The Sponsor assumes accountability for actions delegated to other individuals 
(e.g., contract research organizations). 
Study monitors will perform ongoing monitoring activities as specified in the Trial 
Monitoring Plan to confirm that data entered into the CRF by authorized site personnel 
are accurate, complete, and verifiable from source documents; that the safety and rights 
of patients are being protected; and that the study is being conducted in accordance with 
the currently approved protocol and any other study agreements, the ICH Guideline for 
Good Clinical Practice, and all applicable regulatory requirements. 
Records and documents pertaining to the conduct of this study, including signed 
Informed Consent Forms, must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention 
period.  No records may be destroyed during the retention period without the written 
approval of the Sponsor.  No records may be transferred to another location or party 
without written notification to the Sponsor. 
The Sponsor will retain study data for 25 years after the final study results have been 
reported or for the length of time required by relevant national or local health authorities, 
whichever is longer. 
A18. 
SOURCE DOCUMENTS 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator’s site. 
Data reported on the CRF or entered on the electronic Case Report Form (eCRF) that 
are transcribed from source documents must be consistent with the source documents, 
or the discrepancies must be explained.  The investigator may need to request previous 
medical records or transfer records, depending on the study.  Also, current medical 
records must be available. 

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Definition of what constitutes source data and its origin can be found in the Trial 
Monitoring Plan. 
A19. 
STUDY AND SITE CLOSURE 
The Sponsor or designee reserves the right to close the study site or terminate the study 
at any time for any reason at the sole discretion of the Sponsor.  Study sites will be 
closed upon study completion.  A study site is considered closed when all required 
documents and study supplies have been collected and a site closure visit has been 
performed. 
The investigator may initiate site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or investigator may include, 
but are not limited to, the following: 
 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the Sponsor's procedures, or the ICH Guideline 
for Good Clinical Practice 
 
Inadequate recruitment of patients by the investigator 
 
Discontinuation of further study treatment development 
 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform 
the investigators, the IRBs/ECs, the health authorities, and any contract research 
organizations used for the study of the reason for termination or suspension, as 
specified by the applicable regulatory requirements.  The investigator shall promptly 
inform the patients and should ensure appropriate patient therapy and/or followup-. 
A110. 
PUBLICATION POLICY 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission.  This allows the Sponsor to protect proprietary information and to 
provide comments. 
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of results of multicenter studies only in their entirety and not as 
individual site 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. 

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40/Protocol GR43742, Version 1 
A111. 
PROTOCOL DEVIATIONS 
The integrity and potential deviations of all human factors (HF) aspects of the study, 
including HF observations, will be documented and explained by the HF observers. 
The investigator should document and explain any other non-HF related protocol 
deviations.  The investigator should promptly report any deviations that might have an 
impact on patient safety and data integrity to the Sponsor and to the IRB/EC in 
accordance with established IRB/EC policies and procedures.  The Sponsor will review 
all protocol deviations and assess whether any represent a serious breach of Good 
Clinical Practice guidelines and require reporting to health authorities.  As per the 
Sponsor's standard operating procedures, prospective requests to deviate from the 
protocol, including requests to waive protocol eligibility criteria, are not allowed. 
 

 
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Appendix 2  
Adverse Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting 
 
 
 
 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
A2-1 
Definition of Adverse Event...................................................... 43 
A2-2 
Definition of Serious Adverse Event ........................................ 44 
A2-3 
Recording and Follow-Up of Adverse Events and/or 
Serious Adverse Events .......................................................... 45 
A2-3.1 
Adverse Event and Serious Adverse Event Recording ............ 45 
A2-3.2 
Assessment of Severity ........................................................... 46 
A2-3.3 
Assessment of Causality ......................................................... 46 
A2-3.4 
Follow-up of Adverse Events and Serious Adverse Events ..... 47 
A2-3.4.1 
Investigator Follow-Up ............................................................. 47 
A2-3.4.2 
Sponsor Follow-Up .................................................................. 48 
A2-4 
Reporting of Serious Adverse Events ...................................... 48 
A2-4.1 
Serious Adverse Event Reporting to The Sponsor via an 
Electronic Collection Tool ........................................................ 48 
A2-4.2 
Serious Adverse Event Reporting to The Sponsor via 
Paper CRF ............................................................................... 48 
A2-5 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 49 
A2-5.1 
Events That Occur Prior to Study Treatment Initiation ............. 49 
A2-5.2 
Events That Occur After Study Treatment Initiation ................. 49 
A2-6 
Reporting Adverse Events That Occur after the Adverse 
Event Reporting Period ............................................................ 49 
A2-7 
Procedures for Recording Adverse Events .............................. 50 
A2-7.1 
Diagnosis Versus Signs And Symptoms .................................. 51 
A2-7.2 
Adverse Events that are Secondary to Other Events ............... 51 
A2-7.3 
Persistent of Recurrent Adverse Events .................................. 51 
A2-7.4 
Abnormal Laboratory Values ................................................... 52 
A2-7.5 
Abnormal Vital Sign Values ..................................................... 53 
A2-7.6 
Abnormal Liver Function Tests ................................................ 53 
A2-7.7 
Deaths ..................................................................................... 54 

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A2-7.8 
Preexisting Medical Conditions ................................................ 54 
A2-7.9 
Unexpected Worsening of nAMD or DME in the Study Eye .... 54 
A2-7.10 
Hospitalization or Prolonged Hospitalization ............................ 55 
A2-7.11 
Requirements for Cases of Accidental Overdose or 
Medication Error ...................................................................... 55 
 

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Follow-Up, and Reporting 
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A2-1 
DEFINITION OF ADVERSE EVENT 
Adverse Event Definition 
An adverse event is any untoward medical occurrence in a patient or clinical study 
patient temporally associated with the use of a study treatment, whether or not 
considered related to the study treatment. 
Note:  An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention. 
Events Meeting the Adverse Event Definition 
The following events meet the definition of adverse event: 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease) 
 
Exacerbation of a chronic or intermittent preexisting condition, including either an 
increase in frequency and/or intensity of the condition 
 
New condition detected or diagnosed after study treatment administration, even 
though it may have been present before the start of the study 
 
Signs, symptoms, or clinical sequelae of a suspected drugdrug interaction 
 
Signs, symptoms, or clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication 
Overdose per se will not be reported as an adverse event or serious adverse 
event unless it is an intentional overdose taken with possible suicidal or 
self‑harming intent.  Such overdoses should be reported regardless of 
sequelae. 
 
Events NOT Meeting the Definition of Adverse Event 
The following events do not meet the definition of adverse event: 
 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the patient’s condition 
 
The disease or disorder being studied or expected progression, signs, or 
symptoms of the disease or disorder being studied, unless more severe than 
expected for the patient’s condition 
 
Medical or surgical procedure (e.g., endoscopy, appendectomy) 

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The condition that leads to the procedure is the adverse event. 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
 
Anticipated day-to-day fluctuations of a preexisting disease or condition present 
or detected at the start of the study that do not worsen 
 
A2-2 
DEFINITION OF SERIOUS ADVERSE EVENT 
If an event is not an adverse event per the definition in Section A2-1, it cannot be a 
serious adverse event even if serious conditions are met (e.g., hospitalization for signs 
or symptoms of the disease under study, death due to progression of disease). 
A serious adverse event is defined as any untoward medical occurrence that, at any 
dose: 
 
Results in death 
 
Is life threatening 
The term "life-threatening" in the definition of "serious" refers to an event in 
which the patient was at risk of death at the time of the event.  It does not refer 
to an event that hypothetically might have caused death if it were more severe. 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the patient has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting.  Complications that occur during 
hospitalization are adverse events.  If a complication prolongs hospitalization or 
fulfills any other seriousness criteria, the event is serious.  When in doubt as to 
whether "hospitalization" occurred or was necessary, the adverse event should 
be considered serious. 
Hospitalization for elective treatment of a preexisting condition that did not 
worsen from baseline is not considered an adverse event. 
 
Results in persistent disability or incapacity 
The term "disability" means a substantial disruption of a person’s ability to 
conduct normal life functions. 
This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) that may interfere with 
or prevent everyday life functions but do not constitute a substantial disruption. 
 
Is a congenital anomaly or birth defect 
 
Other situations: 

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Medical or scientific judgment should be exercised in deciding whether serious 
adverse event reporting is appropriate in other situations such as important 
medical events that may not be immediately life threatening or result in death or 
hospitalization but may jeopardize the patient or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition.  These events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development 
of drug dependency or drug abuse. 
 
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, see Section A2-3.2); 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 electronic Case Report Form (eCRF). 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after the investigator becomes aware of the 
event) (see Section A2-5 for reporting instructions). 
A2-3 
RECORDING AND FOLLOW-UP OF ADVERSE EVENTS 
AND/OR SERIOUS ADVERSE EVENTS 
A2-3.1 
Adverse Event and Serious Adverse Event Recording 
When an adverse event or serious adverse event occurs, it is the responsibility of the 
investigator to review all documentation (e.g., hospital progress notes, laboratory 
reports, and diagnostics reports) related to the event. 
The investigator will then record all relevant adverse event or serious adverse event 
information on the eCRF. 
It is not acceptable for the investigator to send photocopies of the patient’s medical 
records to the Sponsor in lieu of completion of the Adverse Event eCRF. 
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor.  In this case, all patient identifiers, with the exception of the patient 
number, will be redacted on the copies of the medical records before submission to 
the Sponsor. 

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The investigator will attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis (not the 
individual signs or symptoms) will be documented as the adverse event or serious 
adverse event. 
A2-3.2 
Assessment of Severity 
The investigator will make an assessment of the severity of each adverse event and 
serious adverse event during the study and assign it to one of the categories in 
Table A2-1. 
Table A2-1  
Adverse Event Severity Grading Scale 
Severity 
Description 
Mild 
An event that is easily tolerated by the patient, causing minimal discomfort and 
not interfering with everyday activities 
Moderate 
An event that causes sufficient discomfort and interferes with normal everyday 
activities 
Severe 
An event that prevents normal everyday activities 
An adverse event that is assessed as severe should not be confused with a 
serious adverse event.  Severe is a category utilized for rating the severity 
of an event, and both adverse events and serious adverse events can be 
assessed as severe. 
An event is defined as "serious" when it meets at least one of the 
predefined outcomes as described in the definition of a serious adverse 
event, NOT when it is rated as severe. 
 
A2-3.3 
Assessment of Causality 
The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each adverse event or serious adverse event. 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out. 
The investigator will use clinical judgment to determine the relationship. 
Alternative causes, such as underlying diseases, concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment 
administration, will be considered and investigated. 
The investigator will also consult the Investigator’s Brochure and/or prescribing 
information (for marketed products) in his or her assessment. 

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For each adverse event or serious adverse event, the investigator must document in the 
medical notes that he or she has reviewed the adverse event or serious adverse event 
and has provided an assessment of causality. 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report to the Sponsor.  
However, it is very important that the investigator always make an assessment of 
causality for every event before the initial transmission of the serious adverse event data 
to the Sponsor. 
The investigator may change his or her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated causality 
assessment. 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
A2-3.4 
Follow-up of Adverse Events and Serious Adverse Events 
A2-3.4.1 
Investigator Follow-Up 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor to elucidate the nature and/or causality of the adverse event or serious adverse 
event as fully as possible.  This may include additional laboratory tests or investigations, 
histopathologic examinations, or consultation with other health care professionals. 
If a patient dies during participation in the study or during a recognized follow-up period, 
the investigator will provide the Sponsor with a copy of any post-mortem findings, 
including histopathology. 
New or updated information should be recorded on the originally completed Adverse 
Event eCRF.  For serious adverse events and adverse events of special interest, the 
investigator must report new significant follow-up information to the Sponsor immediately 
(i.e., no more than 24 hours after the investigator becomes aware of the information).  
New significant information includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event's outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 

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During the adverse event reporting period (defined in Section 8.3.1), 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. 
A2-3.4.2 
Sponsor Follow-Up 
For serious adverse events and adverse events of special interest, 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. 
A2-4 
REPORTING OF SERIOUS ADVERSE EVENTS 
A2-4.1 
Serious Adverse Event Reporting to The Sponsor via an 
Electronic Collection Tool 
The primary mechanism for reporting a serious adverse event to the Sponsor will be the 
electronic data collection tool, as described in Section A2-5. 
If the electronic system is unavailable, the site will use the paper Clinical Trial Adverse 
Event/Special Situations Form, as described in Section A2-5, to report the event within 
24 hours. 
The site will enter the serious adverse event data into the electronic system as soon as it 
becomes available. 
After the study is completed at a given site, the electronic data collection tool will be 
taken off line to prevent the entry of new data or changes to existing data. 
If a site receives a report of a new serious adverse event from a study patient or 
receives updated data on a previously reported serious adverse event after the 
electronic data collection tool has been taken off line, the site can report this information 
on a paper Clinical Trial Adverse Event/Special Situations Form, as described in 
Section A2-5. 
A2-4.2 
Serious Adverse Event Reporting to The Sponsor via Paper 
CRF 
Under certain circumstances, serious adverse events may be reported to the Sponsor 
through use of a paper Clinical Trial Adverse Event/Special Situations Form, as 
described in Section A2-5. 

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A2-5 
REPORTING REQUIREMENTS FOR SERIOUS ADVERSE 
EVENTS AND ADVERSE EVENTS OF SPECIAL INTEREST 
A2-5.1 
Events That Occur Prior to Study Treatment Initiation 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention (e.g., biopsy, 
discontinuation of medications) should be reported.  The paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
the investigator becomes aware of the event), either by faxing or by scanning and 
emailing the form, using the fax number or email address provided to investigators. 
A2-5.2 
Events That Occur After Study Treatment Initiation 
After initiation of study treatment, serious adverse events and adverse events of special 
interest will be reported until Day 7 after injection administration.  Investigators should 
record all case details that can be gathered immediately (i.e., within 24 hours after the 
investigator becomes aware 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 Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
the investigator becomes aware of the event), either by faxing or by scanning and 
emailing the form, using the fax number or email address provided to investigators.  
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system.  
Instructions for reporting serious adverse events that occur later than Day 7 after 
injection administration are provided in Section A2-6. 
A2-6 
REPORTING 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 
Day 7 after injection administration), if the event is believed to be related to prior 
exposure to study treatment.  These events should be reported through use of the 
Adverse Event eCRF.  However, if the EDC system is not available, the investigator 
should report these events directly to the Sponsor or its designee, either by faxing or by 
scanning and emailing the paper Clinical Trial Adverse Event/Special Situations Form, 
using the fax number or email address provided to investigators. 

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A2-7 
PROCEDURES FOR RECORDING ADVERSE EVENTS 
When an adverse event occurs, it is the responsibility of the investigator to review all 
documentation related to the event (e.g., hospital progress notes, laboratory reports, and 
diagnostics reports).  The investigator will then record all relevant adverse event 
information on the Adverse Event eCRF.  It is not acceptable for the investigator to send 
photocopies of the patient's medical records to the Medical Monitor in lieu of completion 
of the eCRF.  Investigators should use correct medical terminology and 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 of the 
Adverse Event eCRF. 
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor.  In this case, all patient identifiers, with the exception of the patient 
number, will be redacted on the copies of the medical records before submission to the 
Sponsor. 
For the purposes of reporting events of infection and inflammation, the following are 
examples of terms and definitions to be used: 
 
Iritis:  the presence of inflammatory cells in the anterior chamber 
The presence of aqueous flare alone will not constitute iritis but should be 
documented as an anterior chamber flare for adverse event reporting 
purposes. 
 
Iridocyclitis:  the presence of inflammatory cells in both the aqueous and vitreous 
 
Vitritis:  the presence of active inflammation in the vitreous, demonstrated by the 
presence of inflammatory cells  
Active inflammation in the vitreous should be clinically differentiated from 
cellular debris from prior episodes of inflammation, hemorrhage, or other 
causes. 
 
Endophthalmitis:  diffuse intraocular inflammation predominantly involving the 
vitreous cavity but also involving the anterior chamber, implying a suspected 
underlying infectious cause  
If possible, a sample for culture should be taken prior to initiating antibiotic 
treatment for presumed endophthalmitis.  Results of bacterial or fungal 
cultures, treatment given, and final ophthalmologic outcome should also be 
provided in the Details section of the Adverse Event eCRF. 
 
Note:  Trace, benign, pigmented cells in the anterior chamber visible on slitlamp 
examination caused by dilation, and are not red blood cells or white blood cells or the 
result of any ocular disorder, should not be recorded as an adverse event. 

Appendix 2:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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A2-7.1 
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. 
A2-7.2 
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. 
A2-7.3 
Persistent of 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 the investigator becomes aware that the event became 

Appendix 2:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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serious; see Section A2-5 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. 
A2-7.4 
Abnormal Laboratory Values 
Not every abnormal laboratory value qualifies as an adverse event.  A laboratory value 
abnormality that is associated with the underlying disease should not be reported as an 
adverse event unless judged by the investigator to be more severe than expected.  A 
laboratory value abnormality that is not associated with the underlying disease 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., dose 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." 

Appendix 2:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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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 A2-7.3 for 
details on recording persistent adverse events). 
A2-7.5 
Abnormal Vital Sign Values 
Not every abnormal vital sign value qualifies as an adverse event.  A vital sign 
abnormality that is associated with the underlying disease should not be reported as an 
adverse event unless judged by the investigator to be more severe than expected.  A 
vital sign abnormality that is not associated with the underlying disease 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., dose 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 (e.g., 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 A2-7.3 for 
details on recording persistent adverse events). 
A2-7.6 
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 A2-7.4) 

Appendix 2:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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and reported to the Sponsor immediately (i.e., no more than 24 hours after the 
investigator becomes aware of the event), either as a serious adverse event or an 
adverse event of special interest (see Section A2-5). 
A2-7.7 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 8.3.1), regardless of relationship to study treatment, must be recorded on 
the Adverse Event eCRF and immediately reported to the Sponsor (see Section A2-5). 
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 A2-6. 
A2-7.8 
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"). 
A2-7.9 
Unexpected Worsening of nAMD or DME in the Study Eye 
Medical occurrences or symptoms of deterioration that are anticipated as part of nAMD 
or DME should not be recorded as adverse events.  However, deterioration that is 
judged by the investigator to have unexpectedly worsened in severity or frequency or 
changed in nature at any time during the study should be recorded as an adverse event.  
When recording an unanticipated worsening of neovascular age-related macular 
degeneration (nAMD) or diabetic macular edema (DME) on the Adverse Event eCRF, it 
is important to convey the concept that the condition has changed by including 

Appendix 2:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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applicable descriptors (e.g., "accelerated worsening of neovascular age-related macular 
degeneration"; “accelerated worsening of diabetic macular edema"). 
A2-7.10 
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 A2-2), 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 patient was hospitalized for an elective procedure that was planned 
prior to the study, was scheduled during the study despite the fact that the 
condition had not worsened, or was scheduled during the study when 
treatment became necessary because of the expected normal progression 
of the condition 
– 
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 
 
A2-7.11 
Requirements for Cases of Accidental Overdose or Medication 
Error 
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations") are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
 
Note:  Special situations are not in themselves adverse events, but may result in 
adverse events.   
Each adverse event associated with a special situation should be recorded separately 
on the Adverse Event eCRF.  If the associated adverse event fulfills seriousness criteria 

Appendix 2:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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or qualifies as an adverse event of special interest, the event should be reported to the 
Sponsor immediately (i.e., no more than 24 hours after the investigator becomes aware 
of the event; see Section A2-5).  For 6-mg faricimab PFS, adverse events associated 
with special situations should be recorded as described below for each situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
As an example, an accidental overdose that resulted in a headache would require 
two entries on the Adverse Event eCRF, one entry to report the accidental overdose 
and one entry to report the headache.  The "Accidental overdose" and "Medication 
error" boxes would need to be checked for both entries. 
All special situations associated with 6-mg faricimab PFS, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF as described 
below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 
 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 

 
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Appendix 3  
Safety Plan:  Management of Identified and Potential Risks 
Table of Contents  
A3-1 
Risks Associated with faricimab……………..…56 
 
 

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A3-1 
RISKS ASSOCIATED WITH FARICIMAB 
Faricimab is currently approved in the United States, United Kingdom, Japan, Thailand, 
Switzerland, and the United Arab Emirates for the treatment of nAMD and DME by 
injection into the eye.  Clinical development is ongoing.  The safety plan for patients in 
this study is based on clinical experience with faricimab in completed and ongoing 
studies.  The anticipated important safety risks for faricimab are outlined below.  Please 
refer to the Faricimab Investigator's Brochure for a complete summary of safety 
information.  
Several measures will be taken to ensure the safety of study patients.  Following 6-mg 
faricimab intravitreal (IVT) injection using the PFS configuration, patients will undergo 
post-treatment observation according to standard clinical practice.  Patients will remain 
at the clinic for approximately 30 minutes after the injection.  Intraocular pressure (IOP) 
will be measured in the study eye at 30 ( 15) minutes after treatment.  If there are no 
safety concerns after 30 ( 15) minutes following treatment, patients will be allowed to 
leave the clinic.  If any safety concerns or immediate toxicity is noted, the patient will 
remain at the clinic and will be treated according to the designated physician’s clinical 
judgment.  If applicable, the adverse event and treatment of adverse event (if applicable) 
will be reported on the appropriate electronic Case Report Forms (eCRFs).   
All patients will be contacted by study site personnel 3 ( 1) days and 7 ( 1) days after 
the injection to elicit reports of any adverse events that may have occurred (e.g., 
decrease in vision, eye pain, unusual redness, or any other new ocular symptoms) in the 
study eye.  Patients will also be asked whether they have taken the prescribed, 
self -administered, post-injection antimicrobial treatments (if applicable) for their study 
eye as directed by the investigator. 
If warranted during the 7-day safety follow-up period, patients will be asked to return to 
the clinic as soon as possible for an unscheduled safety assessment visit and will be 
instructed to contact the investigator at any time should they have any health related 
concerns.  Refer to Appendix 9 for information on assessments required at unscheduled 
safety visits. 
The safety plan for patients in this study consists of monitoring of safety events 
(including adverse events, serious adverse events, and adverse events of special 
interest) during the study period.  Faricimab drug in the PFS has the same formulation 
and concentration, and is injected at the same dose, volume, route of administration, 
and injection procedure as the faricimab supplied in a vial configuration and studied in 
the Phase III program. 
The risks associated with faricimab are published in the Investigator’s Brochure.  These 
risks of faricimab include, but are not limited to, intraocular inflammation and increased 

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IOP.  Refer to the current version of the Faricimab Investigator's Brochure for more 
details on the risks of faricimab. 

 
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Appendix 4  
Contraceptive and Barrier Guidance 
TABLE OF CONTENTS 
 
A4 1. 
Pregnancies in Female patients 
A4 2. 
Abortions 
A4 3. 
Abnormal Pregnancy Outcomes 
 
 

Appendix 4:  Contraceptive and Barrier Guidance 
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A41. 
PREGNANCIES IN FEMALE PATIENTS 
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 3 months after the final dose of faricimab.  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 the investigator becomes aware 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 electronic Case Report Form (eCRF).  The investigator should 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 or 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.   
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 
follow-up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 
A4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 the 
investigator becomes aware of the event; see Section A2-5). 
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 the investigator becomes aware of the event; see 
Section A2-5).  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.  

Appendix 4:  Contraceptive and Barrier Guidance 
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A43. 
ABNORMAL PREGNANCY OUTCOMES 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomaly, birth defect, ectopic pregnancy) in a female patient exposed to 
study treatment 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 the investigator becomes aware of the event; see Section A2-5). 

 
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Appendix 5  
Reporting Requirements for Device Product Complaints  
TABLE OF CONTENTS 
A5-1 
Reporting Requirements for Device Product Complaints ......... 64 
 
 

Appendix 5:  Reporting Requirements for Medical Device Complaints 
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A5-1 
Reporting Requirements for Device Product Complaints (Including 
Device Failures and Malfunctions) 
In this study, the 6-mg faricimab prefilled syringe (PFS) with co-packaged injection filter 
needle is considered a drug-device combination product.  The investigator must report 
all device deficiencies related to the PFS and the IFN to the Sponsor in the form of a 
medical device complaint.  A device deficiency is an inadequacy of a medical device with 
respect to its identity, quality, durability, reliability, safety, or performance, and it can 
include malfunctions, use errors, and inadequate labeling.  In reporting a medical device 
complaint, the investigator should document as much information according to the 
medical device complaints procedure, including the product batch number, and forward 
the form to the Sponsor immediately (i.e., no more than 24 hours after the investigator 
becomes aware of the event) (refer to the Instructions for Use for further details on 
device use and expected functioning).  If the medical device deficiency results in an 
adverse event to the study patient, the event must be reported on the Adverse Event 
electronic Case Report Form (eCRF) and submitted through the electronic data system.  
If the event fulfills seriousness criteria, the Adverse Event eCRF must be completed 
immediately (i.e., no more than 24 hours after the investigator becomes aware of the 
event), as outlined in Section A2-5. 

 
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Appendix 6  
Clinical Safety Laboratory Tests 
The tests detailed in Table A6-1 will be performed by the local laboratory. 
Protocol-specific requirements for inclusion and exclusion of patients are detailed in 
Section 5. 
Additional tests may be performed at any time during the study if determined to be 
necessary by the investigator or if required by local regulations. 
Table A6-1 Protocol-Required Safety Laboratory Assessments 
Local Laboratory Test 
 Pregnancy test 
All women of childbearing potential will have a urine pregnancy test at screening and 
Day 1. 

 
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Appendix 7  
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  
Source:  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.

 
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Appendix 8  
Refraction and Best-Corrected Visual Acuity Testing 
SCOPE 
Refraction and best-corrected visual acuity (BCVA) assessment must be conducted 
before pupil dilation.  BCVA data for study eyes should be entered in appropriate eCRF 
log. 
BCVA may be assessed on any standard visual acuity (VA) chart according to local 
practice.  The Early Treatment Diabetic Retinopathy Study (ETDRS) chart is 
recommended, but Snellen and LogMAR are also acceptable.  
Note:  the chart used to measure a participant’s VA on Day 1 must remain consistent for 
the duration of the patient’s participation in this study. 

 
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Appendix 9  
Unscheduled Safety Assessment Visit 
Assessmentsa 
Mandatory assessments: 
Best-corrected visual acuity b, c  
Slitlamp examination 
Dilated binocular indirect high-magnification ophthalmoscopy  
Intraocular pressure c  
Adverse events d 
 
Assessments at the discretion of the Investigator e: 
 
Concurrent ocular procedures 
Concomitant medications 
Hematology, serum chemistry panel, and coagulation as deemed appropriate by the 
investigator  
Ocular imaging, as necessary  
a Participants will be instructed to contact the investigator at any time if they have 
any health related concerns.  If warranted, Investigators may ask the participant 
to return to the clinic for an unscheduled safety assessment visit during the study 
period.  Best-corrected visual acuity (BCVA), slitlamp, intraocular pressure (IOP), 
and indirect ophthalmoscopy examinations must be conducted at unscheduled 
safety visits.  All other assessments 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.  BCVA should assessed at a 4-meter starting distance when 
using Early Treatment Diabetic Retinopathy Study (ETDRS) chart or equivalent 
starting distance per local practice guidelines if using Snellen or LogMAR. 
c The method used for the BCVA and intraocular pressure measurement for a 
participant must remain consistent throughout the study. 
d Adverse event causality to be evaluated by an ophthalmologist. 
e If additional assessments (at the discretion of the Investigator) are performed per 
standard of care, please add the following information to the adverse event 
additional case details field:  describe the assessments performed (e.g., 
inflammatory laboratory panel, SD-OCT, etc.) and describe any relevant findings 
that could help contextualize the adverse event. 
 
  

 
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Appendix 10  
Abbreviations 
Abbreviation or Term 
Definition 
Ang-2 
angiopoietin-2 
BCVA 
best-corrected visual acuity 
CATT 
Comparison of Age-Related Macular 
Degeneration Treatment Trials  
COVID-19 
coronavirus disease 2019 
DME 
diabetic macular edema 
DR 
diabetic retinopathy 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
HCP 
health care provider 
HF 
human factors 
ICH 
International Council for Harmonisation 
iDMC 
independent Data Monitoring Committee 
IFN 
injection filter needle 
IFU 
Instructions for Use 
Ig 
Immunoglobulin 
IMP 
investigational medicinal product 
IOP 
intraocular pressure 
IRB 
Institutional Review Board 
IVT 
Intravitreal 
nAMD 
neovascular age-related macular 
degeneration 
OCT 
optical coherence tomography 
PFS 
prefilled syringe 
ULN 
upper limit of normal 
VA 
visual acuity 
VEGF 
vascular endothelial growth factor 
 

Signature Page for Protocol - GR43742 - VABYSMO - v1 - Global - Published
System identifier: RIM-CLIN-444535
Approval Task
Company Signatory
29-Jun-2022 01:19:11 GMT+0000