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

 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Faricimab—F. Hoffmann-La Roche Ltd 
Protocol GR42691 Corneal Endothelial Cells Substudy, Version 2 
 
PROTOCOL 
TITLE: 
A CORNEAL ENDOTHELIAL CELLS SUBSTUDY 
IN ASSOCIATION WITH GR42691 STUDY 
(AVONELLE-X):  A MULTICENTER, OPEN-LABEL 
EXTENSION STUDY TO EVALUATE THE LONG-
TERM SAFETY AND TOLERABILITY OF 
FARICIMAB IN PATIENTS WITH NEOVASCULAR 
AGE-RELATED MACULAR DEGENERATION  
PROTOCOL NUMBER: GR42691 Corneal Endothelial Cells Substudy  
VERSION NUMBER: 
2 
IND NUMBER: 
119225 
NCT NUMBER: 
NCT04777201 
TEST PRODUCT: 
Faricimab (RO6867461) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
APPROVAL: 
See electronic signature and date stamp on final page 
of this document. 

 
Faricimab—F. Hoffmann-La Roche Ltd 
2/Protocol GR42691 Corneal Endothelial Cells Substudy, Version 2 
PROTOCOL HISTORY 
Protocol 
Version 
Date Final 
2 
See electronic date stamp on the final page of 
this document. 
1 
7 February 2022 

 
Faricimab—F. Hoffmann-La Roche Ltd 
3/Protocol GR42691 Corneal Endothelial Cells Substudy, Version 2 
PROTOCOL AMENDMENT, VERSION 2: 
RATIONALE 
Protocol GR42691 Corneal Endothelial Cells (CEC) Substudy has been amended 
following a health authority request to include additional description of the test product, 
faricimab. The inclusion criteria have also been updated to facilitate study recruitment. 
Changes to the protocol, along with a rationale for each change, are summarized below: 
 
Investigational sites have been updated from those within the United States only, to 
also include global sites, for recruitment purposes (Section 3.1.1).  
 
The inclusion criteria have been updated to include main Study GR42691 patients 
willing to participate in the CEC Substudy for at least 48 weeks and have at least the 
first CEC visit while enrolled in main Study GR42691, to support recruitment efforts 
(Section 4.1.1.1). 
 
The exclusion criteria were updated to clarify the excluded severity of Fuchs 
endothelial corneal dystrophy Grade  2 
 
Additional description of the Sponsor-supplied dosing form of the investigational 
medicinal product, faricimab, has been provided for clarity (new Sections 4.2.1.1, 
4.2.2, 4.2.2.2, and 4.2.3 have been added).   
 
Text has been added to inform investigators that if a patient’s  participation extends 
beyond the duration of the main study, faricimab will continue to be reimbursed until 
the patient completes the CEC Substudy for the study eye (Section 4.2.3). 
 
The primary Medical Monitor has been updated to 
, M.D. (Protocol 
Title Page, Protocol Amendment Acceptance Form, and Section 5.4.1). 
 
Text has been added to clarify the circumstances in which reimbursement will be 
provided for use in the fellow eye of anti-VEGF therapies that are licensed for ocular 
use (Section 4.3.1).  
 
Text has been added to refer investigators to the main Study GR42691 protocol for 
guidance for safety assessments while also informing sites that the CEC Substudy 
will continue adverse event reporting until patients have completed the Substudy 
regardless of the completion status of the main Study GR42691 (new Section 5 has 
been added; subsequent sections have been renumbered; Appendix 1, the 
Schedule of Activities has been updated to include these changes). 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 

 
Faricimab—F. Hoffmann-La Roche Ltd 
4/Protocol GR42691 Corneal Endothelial Cells Substudy, Version 2 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM ............................................ 7 
PROTOCOL SYNOPSIS ...................................................................................... 8 
1. 
BACKGROUND ............................................................................ 12 
1.1 
Background on Faricimab ........................................................ 12 
1.2 
Background on Corneal Endothelial Cells ............................... 12 
1.3 
Substudy Rationale and Benefit-Risk Assessment .................. 14 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 15 
2.1 
Substudy Objective .................................................................. 15 
2.1.1 
Primary Objective .................................................................... 15 
3. 
STUDY DESIGN ........................................................................... 15 
3.1 
Description of the Substudy ..................................................... 15 
3.1.1 
Overview of the Substudy ........................................................ 16 
3.1.2 
Enrollment................................................................................ 17 
3.1.3 
Corneal Endothelial Cells Assessments .................................. 17 
3.1.4 
Substudy or Study Withdrawal ................................................. 18 
3.2 
End of Substudy and Length of Substudy ................................ 18 
3.3 
Rationale for Substudy Design ................................................ 18 
3.3.1 
Rationale for Faricimab Dose and Schedule............................ 18 
3.3.2 
Rationale for Patient Population .............................................. 18 
3.3.3 
Rationale for Use of Patient Fellow Eye as the Comparator .... 18 
4. 
MATERIALS AND METHODS ...................................................... 19 
4.1 
Patients .................................................................................... 19 
4.1.1 
Inclusion Criteria ...................................................................... 19 
4.1.1.1 
General Inclusion Criteria ........................................................ 19 
4.1.1.2 
Ocular Inclusion Criteria .......................................................... 19 
4.1.2 
Exclusion Criteria ..................................................................... 19 
4.2 
Study Treatment and Other Treatments Relevant to the 
Substudy Design ...................................................................... 20 
4.2.1 
Study Treatment Formulation and Packaging ......................... 20 
4.2.1.1 
Faricimab ................................................................................. 20 

 
Faricimab—F. Hoffmann-La Roche Ltd 
5/Protocol GR42691 Corneal Endothelial Cells Substudy, Version 2 
4.2.2 
Investigational Medicinal Product Handling and 
Accountability ......................................................................... 21 
4.2.3 
Continued Access to Faricimab ............................................... 21 
4.3 
Concomitant Therapy .............................................................. 21 
4.3.1 
Permitted Therapy ................................................................... 21 
4.3.2 
Prohibited Therapy .................................................................. 21 
4.4 
Substudy Assessments ........................................................... 21 
4.4.1 
Informed Consent Forms and Screening Log .......................... 22 
4.4.2 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ......................................... 22 
4.4.3 
Vital Signs ................................................................................ 22 
4.4.4 
Ocular Assessments ................................................................ 22 
4.4.5 
Concurrent Ocular Procedures ................................................ 23 
4.5 
Treatment, Patient, Study, and Site Discontinuation ................ 23 
4.5.1 
Study Treatment Discontinuation ............................................. 23 
4.5.2 
Patient Discontinuation from the Study .................................... 23 
4.5.3 
Study Discontinuation .............................................................. 23 
4.5.4 
Site Discontinuation ................................................................. 23 
5. 
ASSESSMENT OF SAFETY ........................................................ 23 
5.1 
Safety Plan .............................................................................. 23 
5.2 
Safety Parameters and Definitions .......................................... 23 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters .................................................................... 23 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor .................................................................................... 23 
5.4.1 
Medical Monitors and Emergency Medical Contact ................ 23 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 24 
5.4.3 
Reporting Requirements for Pregnancies ................................ 24 
5.5 
Follow-Up of Patients after Adverse Events ............................ 24 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period...................................................................... 24 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees .............. 24 

 
Faricimab—F. Hoffmann-La Roche Ltd 
6/Protocol GR42691 Corneal Endothelial Cells Substudy, Version 2 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 24 
6.1 
Determination of Sample Size ................................................. 24 
6.2 
Analysis Populations ................................................................ 24 
6.2.1 
Modified Intent-to-Treat Population .......................................... 24 
6.2.2 
Per-Protocol Population ........................................................... 25 
6.3 
Summaries of Conduct of Study .............................................. 25 
6.4 
Summaries of Demographic and Baseline Characteristics ...... 25 
6.5 
Imaging Analyses .................................................................... 26 
6.5.1 
Primary Efficacy Endpoint ........................................................ 26 
6.5.2 
Secondary Efficacy Endpoint ................................................... 26 
6.5.3 
Exploratory Efficacy Endpoints ................................................ 26 
6.5.3.1 
Subgroup Analyses .................................................................. 26 
6.6 
Interim Analysis ....................................................................... 26 
7. 
DATA COLLECTION AND MANAGEMENT ................................. 26 
8. 
ETHICAL CONSIDERATIONS ...................................................... 26 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ....................................................................... 27 
10. 
REFERENCES.............................................................................. 28 
 
 
LIST OF FIGURES 
Figure 1 
Substudy Assessment Schema .................................................. 17 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities .................................................................. 31 

 
Faricimab—F. Hoffmann-La Roche Ltd 
7/Protocol GR42691 Corneal Endothelial Cells Substudy, Version 2 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A CORNEAL ENDOTHELIAL CELLS SUBSTUDY IN 
ASSOCIATION WITH GR42691 STUDY 
(AVONELLE-X):  A MULTICENTER, OPEN-LABEL 
EXTENSION STUDY TO EVALUATE THE LONG-
TERM SAFETY AND TOLERABILITY OF 
FARICIMAB IN PATIENTS WITH NEOVASCULAR 
AGE-RELATED MACULAR DEGENERATION  
PROTOCOL NUMBER: GR42691 Corneal Endothelial Cells Substudy 
VERSION NUMBER: 
2 
IND NUMBER: 
119225 
NCT NUMBER: 
NCT04777201 
TEST PRODUCT: 
Faricimab (RO6867461) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor.   
 
 

 
Faricimab—F. Hoffmann-La Roche Ltd 
8/Protocol GR42691 Corneal Endothelial Cells Substudy, Version 2 
PROTOCOL SYNOPSIS 
TITLE: 
A CORNEAL ENDOTHELIAL CELLS SUBSTUDY IN 
ASSOCIATION WITH GR42691 STUDY (AVONELLE-X):  A 
MULTICENTER, OPEN-LABEL EXTENSION STUDY TO 
EVALUATE THE LONG-TERM SAFETY AND TOLERABILITY OF 
FARICIMAB IN PATIENTS WITH NEOVASCULAR AGE-RELATED 
MACULAR DEGENERATION  
PROTOCOL NUMBER: 
GR42691 Corneal Endothelial Cells Substudy  
VERSION NUMBER: 
2 
IND NUMBER: 
119225 
NCT NUMBER: 
NCT04777201 
TEST PRODUCT: 
Faricimab (RO6867461)  
PHASE: 
III (Long-term extension) 
INDICATION: 
Neovascular age-related macular degeneration 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
OBJECTIVES AND ENDPOINTS 
The primary objective for this substudy is to evaluate the impact of faricimab on corneal 
endothelial cell health on the basis of the following endpoints, as assessed by specular 
microscopy: 
 
Primary endpoint:  Percent change in corneal endothelial cell density (ECD) from baseline 
at Year 1 (defined as the earliest substudy visit closest to Week 52 occurring between 
Week 48 and Week 64) in the study eye as compared with the fellow eye  
 
Secondary endpoint:  Percent change in corneal ECD from baseline at substudy midpoint 
(defined as the earliest substudy visit closest to Week 24 occurring between Week 20 and 
Week 28) in the study eye as compared with the fellow eye 
 
Exploratory endpoints:  
– 
Percent change in the coefficient of variation (CV) of corneal endothelial cell area 
(standard deviation of the cell area/mean cell area) from baseline at substudy midpoint 
and Year 1 in the study eye as compared with the fellow eye 
– 
Percent change of hexagonal endothelial cells (HEX) from baseline at substudy 
midpoint and Year 1 in the study eye as compared with the fellow eye 
STUDY DESIGN 
DESCRIPTION OF STUDY 
The main Study GR42691 is a multicenter long-term extension study designed to evaluate the 
long-term safety and tolerability of intravitreal faricimab 6 mg administered at a personalized 
treatment interval (PTI) to patients with neovascular age-related macular degeneration (nAMD) 
who enrolled in and completed one of the Phase III studies, GR40306 and GR40844.  Patients 
enrolled in GR40306 or GR40844 were randomized in a 1:1 ratio to receive faricimab at a PTI 
up to Q16W (experimental arm) or aflibercept Q8W (comparator arm).  
This substudy is designed to evaluate the impact of intravitreal faricimab 6 mg administered at a 
PTI on the health of the corneal endothelial cells in patients with nAMD.  Fellow eyes of enrolled 
patients will be used as a comparator for corneal endothelial cells analyses. 
NUMBER OF PATIENTS 
Approximately 135 patients with nAMD will be enrolled at approximately 50 investigational 
global sites from the main Study GR42691. 

 
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9/Protocol GR42691 Corneal Endothelial Cells Substudy, Version 2 
TARGET POPULATION 
Inclusion Criteria 
In addition to the inclusion criteria specified in the main Study GR42691 (see 
main Study GR42691 Section 4.1.1.1), patients must meet the following criteria:   
 
Signed Informed Consent for this substudy  
 
Must be able to participate for at least 48 weeks in the CEC Substudy and have at least 
the first CEC visit while enrolled in main Study GR42691 
General Inclusion Criteria 
Patients must meet the following ocular inclusion criterion for substudy entry:  
 
Difference of  10% in ECD at screening between the two eyes as measured by specular 
microscopy and determined by the independent reading center 
Exclusion Criteria 
In addition to all criteria specified in the main Study GR42691 protocol, patients will be excluded 
from this substudy if they meet the following criteria:  
FELLOW (NON-STUDY) EYE 
 
Prior and/or current administration of faricimab  
 
Prior administration of brolucizumab 
EITHER EYE 
 
Corneal ECD  1500 cells/mm2 in either eye at screening as determined by the independent 
corneal reading center 
 
Fuchs endothelial corneal dystrophy Grade  2  
 
Previous ocular trauma (blunt or penetrating) and/or corneal endothelial cell damage, 
including from blunt or surgical trauma (including complicated cataract surgery resulting in 
complicated lens placement such as anterior chamber intraocular lens, sulcus intraocular 
lens, aphakia, etc.) 
 
Any ocular condition that precludes obtaining an analyzable specular microscopy image 
 
Active or history of corneal edema 
 
Any active or history of corneal dystrophies, excluding Fuchs endothelial corneal 
dystrophy Grade  2 
 
Active or history of iridocorneal endothelial syndrome 
 
Active or history of pseudoexfoliation syndrome 
 
Active or history of herpetic keratitis or kerato-uveitis (including herpes simplex virus and 
herpes zoster virus) 
 
Intraocular laser therapy including selective laser trabeculoplasty, yttrium-aluminum garnet 
(YAG), prophylactic peripheral iridotomy within 1 year of screening, or YAG capsulotomy 
within 3 months of screening 
 
Prior vitrectomy surgery, submacular surgery, or other surgical intervention for age-related 
macular degeneration 
 
Prior pars plana vitrectomy surgery 
 
Previous intraocular device implantation excluding intraocular lenses  
 
Cataract surgery within 6 months of screening or planned for during the study 
 
History of glaucoma-filtering surgery, tube shunts, or microinvasive glaucoma surgery.  
Other types of prior glaucoma surgery are allowed providing that the surgery occur more 
than 6 months before screening 
 
Administration of topical Rho kinase inhibitors (e.g., Rhopressa eye drops) within 1 month 
prior to the screening visit 
 
Contact lens wear in either eye within 2 months of screening  

 
Faricimab—F. Hoffmann-La Roche Ltd 
10/Protocol GR42691 Corneal Endothelial Cells Substudy, Version 2 
 
History of corneal transplantation, including partial-thickness corneal grafts (e.g., Descemet 
membrane endothelial keratoplasty, Descemet stripping endothelial keratoplasty) 
 
Active or history of iridocorneal endothelial syndrome 
 
Active or history of pseudoexfoliation syndrome 
END OF SUBSTUDY 
The end of this substudy is defined as the date when the last patient, last visit occurs.   
LENGTH OF SUBSTUDY 
The end of the substudy is expected to occur approximately 48 weeks after the last substudy 
patient is enrolled. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
TEST PRODUCT (INVESTIGATIONAL DRUG) 
The investigational medicinal product(IMP) for this study is faricimab (test product).  
Faricimab will be supplied by the Sponsor as a sterile liquid for intravitreal injection in 
single-use glass vials.  
Each single-use, 2 mL glass vial contains 6 mg (nominal) of faricimab formulated as 120 
mg/mL in L-histidine/acetate buffer solution (approximately pH 5.5) containing sodium 
chloride, sucrose, L-methionine, and polysorbate 20 and is designed to provide a dose of 6 
mg/0.05 mL for intravitreal injection.  
STATISTICAL METHODS 
PRIMARY ANALYSIS 
The percent change in corneal ECD from baseline at Year 1 will be analyzed using the paired 
t-test.  The 95% confidence intervals for Year 1 values as well as change-from-baseline at 
Year 1 will be calculated. 
DETERMINATION OF SAMPLE SIZE   
No formal sample size calculations were performed for this substudy.  A planned enrollment of 
approximately 135 patients from the main Study GR42691 was selected in order to obtain data 
from at least 100 patients through Year 1 to account for patients with missing data (e.g., missed 
visits, lost to follow-up).  ECD, CV, and HEX will be assessed in the corneal endothelium 
evaluable set (Modified Intent to Treat [mITT] population), which includes all patients who were 
treated in the study eye and for whom specular microscopic images were interpretable in both 
the study and fellow eye both at baseline and at the substudy midpoint and/or Year 1 
evaluations.   
INTERIM ANALYSES 
No interim analysis is planned for this substudy. 
 

 
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11/Protocol GR42691 Corneal Endothelial Cells Substudy, Version 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AMD 
age-related macular degeneration 
Ang2 
angiopoietin-2 
BCVA 
best corrected visual acuity 
CEC 
Corneal Endothelial Cells 
CV 
coefficient of variation 
DME 
diabetic macular edema 
ECD 
endothelial cell density 
FDA 
Food and Drug Administration 
HEX 
hexagonal endothelial cells 
IMP 
investigational medicinal product 
mITT 
modified intent-to-treat 
nAMD 
neovascular age-related macular degeneration 
PTI 
personalized treatment interval 
Q8W 
every 8 weeks 
Q16W 
every 16 weeks 
VEGF 
vascular endothelial growth factor 
SD 
standard deviation 
YAG 
yttrium-aluminum garnet 

 
Faricimab—F. Hoffmann-La Roche Ltd 
12/Protocol GR42691 Corneal Endothelial Cells Substudy, Version 2 
1. 
BACKGROUND 
1.1 
BACKGROUND ON FARICIMAB 
See main Study GR42691 Section 1.2. 
1.2 
BACKGROUND ON CORNEAL ENDOTHELIAL CELLS  
The corneal endothelium is a single layer of cells lining the posterior portion of the 
cornea that regulates the health and optical transparency of the cornea 
(Van den Bogerd et al. 2019).  The structural and functional integrity of the corneal 
endothelium can be impacted by a variety of extrinsic and intrinsic factors, including 
genetics, race, age, corneal dystrophy, ocular trauma, intraocular surgery, ultraviolet 
radiation, and intraocular infection.  Morphological changes in the corneal endothelium 
occur throughout life, including a significant decline in corneal endothelial cell density 
(ECD) and percentage of hexagonal cells with age (Bourne et al. 1997; 
Zavala et al. 2013).  At birth, human ECD is approximately 5000 to 6000 cells/mm2, and 
gradually decreases to about 3500 cells/mm2 by 5 years of age, 3000 cells/mm2 by 
14 to 20 years of age, and 2500 cells/mm2 in late adulthood due to an age-related 
increase in the corneal cell dimensions and normal senescence of the endothelial cells 
(Chaurasia and Vanathi 2021).  Changes in normal human corneal endothelium in adult 
patients were studied for over 10 years and showed a calculated rate of cell loss at 
approximately 0.6% per year (Bourne et al. 1997).  Additional factors can influence or 
induce corneal endothelial cell loss as seen, for example, by the exacerbation of loss 
following cataract surgery.  Cell loss rates up to 10 years following cataract surgery 
(phacoemulsification) were reported as 2.5% per year, which is four times higher than 
the average rate due to the aging process alone (Choi and Han 2019).  The greatest 
corneal endothelial cell loss occurs primarily in the first 1 to 3 months following cataract 
surgery (Bourne et al. 1997; Beato et al. 2021) and stabilizes approximately 6 months 
post-operatively (Dick et al. 1996; Bourne et al. 2004; Lass et al 2019; 
Kelkar et al. 2020).  
Specular microscopy is an imaging modality that allows for direct assessment of the 
corneal ECD and morphology and is routinely used in the assessment of corneal 
endothelial cell health (Chaurasia and Vanathi 2021).  Variables studied in the specular 
microscopy examination include ECD, percentage of hexagonal endothelial cells (HEX), 
and coefficient of variation (CV) of cell area and collectively allow the clinician to 
interpret the health status of the corneal endothelial cells (Chaurasia and Vanathi 2021).  
Human corneal endothelium consists of a monolayer of hexagonal cells situated in the 
posterior surface of the cornea (Schmedt et al. 2012) and healthy cornea has 
approximately 60% of HEX (Chaurasia and Vanathi 2021).  The percentage of HEX 
decreases (pleomorphism) and the CV of cell area increases (polymegathism) with age 
and endothelial cell attrition due to various causes (Chaurasia and Vanathi 2021).  
Corneal ECD is an important clinical parameter that enables assessment of the risk of 
functional decompensation of cornea and evaluation of the functional reserve of the 

 
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13/Protocol GR42691 Corneal Endothelial Cells Substudy, Version 2 
corneal endothelium in individual patients.  Clinical observations indicate that an ECD of 
about 400 to 600 cells/mm2 is a threshold at which corneal decompensation develops 
resulting in corneal edema accompanied by loss of corneal transparency 
(Arici et al 2014).  The most common causes for corneal endothelial decompensation 
include cataract surgery or intraocular lens implantation-related complications and Fuchs 
endothelial corneal dystrophy (Ong Tone et al 2021).   
Angiogenic Privilege of Corneal Endothelium   
Maintenance of homeostasis between pro- and anti-angiogenic factors in the cornea 
regulates processes such as endothelial cell proliferation, survival, and apoptosis 
(Menzel-Severing 2012).  In a recent literature search, no peer-reviewed literature was 
found showing Tie2 receptor expression on corneal endothelial cells.  Tie2 receptor 
expression is absent on normal corneal endothelial cells, except in the instances of 
pathological corneal neovascularization.  In this situation, Tie2 can be found expressed 
in the cornea only on the pathologically infiltrating vascular cells (Yan et al. 2017).  
Although high levels of Ang2 expression were detected in pathologically vascularized 
corneas, Ang2 levels in the corneal endothelial cells of normal corneas are low 
(Ferrari et al. 2016), and increased levels in the experimental pathological 
neovascularization corneal models could be reduced with anti-Ang2 treatment 
(Ferrari et al. 2016; Zhang et al. 2017).  Under certain conditions (such as corneal injury 
or chemical burn, viral infection, other corneal inflammatory disorders, or surgical 
sutures in a predisposed high-risk corneal graft recipient), pathological triggers may tilt 
the balance between angiogenic and anti-angiogenic factors and lead to activation of the 
angiogenic cascade, resulting in neovascularization of the normally avascular cornea 
and overexpression of angiogenic growth receptors (Azar 2006).  The majority of data on 
angiogenic factor expression in the cornea in the literature is related to the expression of 
pro-angiogenic factors and their receptors in pathologically neovascularized corneal 
tissue, and not in normal corneal tissue. 
Potential Corneal Endothelial Cell Interactions with Intraocular Anti-VEGF 
Treatment 
Medications administered via the intravitreal route can be eliminated from the vitreous 
body through both the blood-retinal barrier and the aqueous humor outflow, thus 
intravitreal medication can come in contact with corneal endothelial cells 
(Philipp et al. 2000; Del Amo et al. 2017; Lass et al. 2018).  It has been postulated that 
VEGF receptors expressed in the corneal endothelium are in direct contact with the 
aqueous humor; therefore, anti-VEGF agents may potentially impact VEGF pathway 
dynamics within the aqueous humor and corneal endothelium (Menzel-Severing 2012; 
Guzel et al. 2015).   
Both in vitro and in vivo studies have set out to address the potential influence of 
anti-VEGF antibodies on corneal endothelial cells.  For instance, in vitro analysis of 
human donor corneas in the presence of anti-VEGF treatment showed no cytotoxic 
effects on the corneal endothelium up to 4 weeks post-treatment (Merz et al. 2018).   

 
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14/Protocol GR42691 Corneal Endothelial Cells Substudy, Version 2 
Though anti-VEGF has been detected in aqueous humor following intravitreal injections 
(Wang et al. 2014; Celik et al. 2015; Hsu et al. 2016), a number of clinical studies have 
concluded that there is no substantial impact on the health of the corneal endothelium.  
No significant differences in corneal ECD, CV, and percent of HEX were identified in 
patients with neovascular age-related macular degeneration (nAMD) in comparisons 
preceding and either immediately following aflibercept loading doses (Atilgan et al. 2020) 
or after single dose of aflibercept at 1-, 3-, and 6-months follow-up (Muto and 
Machida 2019).  Additionally, RE-VIEW was a Phase IV, open-label, single-arm study 
that evaluated corneal endothelial cell health by specular microscopy in eyes treated 
with repeated intravitreal aflibercept injection (Lass et al. 2018).  Patients with nAMD 
received aflibercept intravitreal injections every 8 weeks (Q8W) after 3 monthly doses 
and had specular microscopy assessments performed at baseline and Weeks 24 and 
52.  RE-VIEW concluded that repeated intravitreal aflibercept injections compared to 
untreated fellow eyes had no significant impact on ECD, CV, and percent HEX at 1-year 
follow-up (Lass et al. 2018).  Similarly, studies specifically using ranibizumab for 
intravitreal injections showed no significant impact on ECD, CV, and percentage of HEX 
up to 1-month (Joshi et al. 2019) and 6-months after injection (Perez-Rico et al. 2010).  
Conversely, a retrospective study of patients with age-related macular degeneration 
(AMD) receiving repeated treatments of either aflibercept or ranibizumab detected a 
statistically significant ECD loss from baseline up to 6-months after the first treatment 
(Urban et al. 2020); however, the authors noted that they had comparable 
measurements to multiple other studies where no statistically significant changes were 
detected.  Collectively, safety analyses of pivotal trials for ranibizumab have detected no 
corneal toxicity and a majority of studies have shown that intravitreal anti-VEGF has no 
significant effect on the health of corneal endothelial cells.   
Similarly, safety analyses from the Phase III studies GR40306 (TENAYA) and GR40844 
(LUCERNE) of faricimab in patients with nAMD and from the Phase III studies GR40349 
(YOSEMITE) and GR40398 (RHINE) of faricimab in patients with diabetic macular 
edema (DME) did not identify any clinically detectable cornea-related events that could 
be indicative of corneal endothelial cell toxicity, such as corneal edema; however, the 
direct impact of faricimab on the density of the corneal endothelium analyzed by 
specular microscopy has not yet been investigated. 
1.3 
SUBSTUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
The four faricimab Phase III studies (GR40306 and GR40844 in patients with nAMD, 
and GR40349 and GR40398 in patients with DME) showed that faricimab 6 mg at 
intervals of up to every 16 weeks (Q16W) was non-inferior to aflibercept 2 mg Q8W for 
the primary endpoint of change from baseline in mean best corrected visual acuity 
(BCVA) at 1 year.  Overall, all four studies indicated that faricimab was generally well 
tolerated and had a comparable safety profile to aflibercept, and a positive benefit-risk 
was established.  

 
Faricimab—F. Hoffmann-La Roche Ltd 
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Although previous studies showed that anti-VEGF treatments do not significantly affect 
the health of the corneal endothelium (Benítez-Herreros et al. 2010; 
Perez-Rico et al. 2010; Joshi et al. 2019), the impact of faricimab, which inhibits both 
VEGF and Ang-2, on corneal endothelial cells has not been studied.  
The aim of this substudy to main long-term extension Study GR42691 is to evaluate the 
corneal endothelial cells in the study eyes of patients with nAMD receiving faricimab to 
fulfill a U.S. Food and Drug Administration (FDA) post-marketing requirement.  The 
fellow eyes of the same patients will serve as the controls, and will be permitted to 
receive standard of care anti-VEGF treatment (if needed). 
2. 
OBJECTIVES AND ENDPOINTS 
This substudy will evaluate the impact of faricimab on corneal endothelial cells in 
patients with nAMD.  Specific objectives and corresponding endpoints for this substudy 
are outlined in the sections below. 
2.1 
SUBSTUDY OBJECTIVE 
2.1.1 
Primary Objective 
The primary objective for this substudy is to evaluate the impact of faricimab on corneal 
endothelial cell health on the basis of the following endpoints, as assessed by specular 
microscopy: 
 
Primary endpoint:  Percent change in corneal endothelial cell density from baseline 
at Year 1 (defined as the earliest substudy visit closest to Week 52 occurring 
between Week 48 and Week 64) in the study eye as compared with the fellow eye  
 
Secondary endpoint:  Percent change in corneal endothelial cell density from 
baseline at substudy midpoint (defined as the earliest substudy visit closest to 
Week  24 occurring between Week 20 and Week 28) in the study eye as compared 
with the fellow eye 
 
Exploratory endpoints:  
– 
Percent change in the coefficient of variation of corneal endothelial cell area 
(standard deviation of the cell area/mean cell area) from baseline at substudy 
midpoint and Year 1 in the study eye as compared with the fellow eye 
– 
Percent change of hexagonal endothelial cells from baseline at substudy 
midpoint and Year 1 in the study eye as compared with the fellow eye 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE SUBSTUDY 
The main Study GR42691 is a multicenter long-term extension study designed to 
evaluate the long-term safety and tolerability of intravitreal faricimab 6 mg administered 
at a PTI to patients with nAMD who enrolled in and completed one of the Phase III 
studies, GR40306 and GR40844.  Patients enrolled in GR40306 or GR40844 were 

 
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randomized in a 1:1 ratio to receive faricimab at a PTI up to Q16W (experimental arm) or 
aflibercept Q8W (comparator arm).  
This substudy is designed to evaluate the impact of intravitreal faricimab 6 mg 
administered at a PTI on the health of the corneal endothelial cells in patients with 
nAMD.  Fellow eyes of enrolled patients will be used as a comparator for corneal 
endothelial cells analyses. 
3.1.1 
Overview of the Substudy  
Approximately 135 patients with nAMD will be enrolled at approximately 
50 investigational global sites from the main Study GR42691.  Study GR42691 patients 
must have at least 48 weeks remaining in Study GR42691. 
Patients in the main Study GR42691 will be eligible to screen for participation in this 
substudy.  During the substudy screening visit, eligibility to participate will be determined 
based on the inclusion and exclusion criteria for this substudy. 
Patients who do not meet the criteria for participation in this substudy (screen failure) 
may qualify for one re-screening opportunity (for a total of two screenings per patient) at 
the investigator's discretion.  Patients are not required to re-sign the consent form if they 
are re-screened within 90 days after previously signing the consent form.  The 
investigator will maintain a record of reasons for screen failure ( Section 4.4.1). 
Figure 1 presents an overview of the substudy design.  A schedule of activities is 
provided in Appendix 1. 

 
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17/Protocol GR42691 Corneal Endothelial Cells Substudy, Version 2 
Figure 1 Substudy Assessment Schema 
 
D1  Day 1; PRN  pro renata (as needed); PTI  personalized treatment interval; Scrn  screening 
visit. 
Substudy midpoint data collection timepoint is defined as the earliest substudy visit closest to 
Week 24 occurring between Week 20 and Week 28.  Year 1 data collection timepoint is defined 
as the earliest substudy visit closest to Week 52 occurring between Week 48 and Week 64. 
 
3.1.2 
Enrollment 
Each consented patient must satisfy all eligibility criteria of the main Study GR42691 
(see main Study GR42691 Sections 4.1.1 and 4.1.2), and the eligibility criteria of this 
substudy (see Section 4.1.1 and Section 4.1.2), including receipt of all substudy 
screening images and confirmation of substudy eligibility by the independent corneal 
reading center.   
3.1.3 
Corneal Endothelial Cells Assessments  
When possible, patients will follow the scheduled assessments per the main protocol 
(see main Study GR42691 Appendix 1).  However, for some patients, an additional visit 
may need to be scheduled in between main protocol visits for the substudy midpoint 
visit.  Substudy patients will undergo specular microscopy imaging in both eyes to 
assess number/density of corneal endothelial cells at screening, substudy midpoint, and 
Year 1 prior to the application of any topical ophthalmic anesthetic, tonometry, or any 
other study treatment. 
Patients should attend all scheduled visits; however, if there are extenuating 
circumstances that preclude attendance at a scheduled visit, the patient may come in for 
specular microscopy imaging at an unscheduled visit up to 4 weeks after the missed 
visit.   

 
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3.1.4 
Substudy or Study Withdrawal 
If the patient withdraws from the substudy only, then the patient may remain in the main 
Study GR42691.   
If the patient withdraws from the main Study GR42691, then the patient will also be 
withdrawn from this substudy.   
If the patient discontinues treatment in the main Study GR42691 but remains in the main 
Study  GR42691 for follow-up, then the patient will remain in this substudy.  All patients 
who remain in this substudy will be strongly encouraged to complete specular 
microscopy imaging at substudy midpoint and Year 1. 
3.2 
END OF SUBSTUDY AND LENGTH OF SUBSTUDY 
The end of this substudy is defined as the date when the last patient, last visit occurs.  
The end of the substudy is expected to occur approximately 48 weeks after the last 
substudy patient is enrolled. 
In addition, the Sponsor may decide to terminate the substudy at any time. 
3.3 
RATIONALE FOR SUBSTUDY DESIGN 
3.3.1 
Rationale for Faricimab Dose and Schedule 
See main Study GR42691 Section 3.3.1. 
3.3.2 
Rationale for Patient Population 
The patient population for this substudy mirrors the patient population of the main Study 
GR42691, with the exceptions listed in Section 4.1.1 for Inclusion Criteria and 
Section 4.1.2 for Exclusion Criteria. 
The aim of this substudy is to assess whether the health of corneal endothelial cells is 
affected by faricimab in eyes of patients with nAMD, and therefore the patient population 
for this substudy, which includes patients with nAMD who will receive faricimab in 
one eye with fellow eye as a control comparison, is appropriate. 
3.3.3 
Rationale for Use of Patient Fellow Eye as the Comparator 
Documented changes occur in the morphology, cell density, and percent hexagonal cells 
in the corneal endothelium due to the natural progression of aging (Bourne et al. 1997).  
Large inter-patient variability in corneal endothelium morphology can be due to factors 
such as age, gender, ethnicity, and ocular and non-ocular disorders (Carlson et al. 1988; 
Snellingen et al. 2001; Shi et al. 2019); therefore, comparison of corneal endothelial 
cells’ health between two eyes of the same patient (one eye treated with faricimab, the 
other eye without) is appropriate to account for changes that would typically occur in a 
given patient.  

 
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Current evidence suggests that intravitreally administered anti-VEGF agents, as 
described in Section 1.2, have no negative impact on corneal endothelial health.  
However, safety data have shown that treatment with brolucizumab is associated with 
intraocular inflammation that could lead to retinal vasculitis or retinal artery occlusion.  
Therefore, patients who previously received brolucizumab in the fellow eye will be 
excluded (see Section 4.1.2) but there will be no other specific exclusion of patients who 
have received previous treatment in the fellow eye with other intravitreal anti-VEGF 
agents.   
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
The planned enrollment is approximately 135 patients with nAMD who meet eligibility 
criteria for both the main Study GR42691 and this substudy.   
4.1.1 
Inclusion Criteria 
4.1.1.1 
General Inclusion Criteria 
In addition to the inclusion criteria specified in the main Study GR42691 (see main 
Study GR42691 Section 4.1.1.1), patients must meet the following criteria:   
 
Signed Informed Consent for this substudy  
Must be able to participate for at least 48 weeks in the CEC Substudy and have at least 
the first CEC visit while enrolled in the main Study GR42691. 
  
4.1.1.2 
Ocular Inclusion Criteria 
Patients must meet the following ocular inclusion criterion for substudy entry:  
 
Difference of  10% in ECD at screening between the two eyes as measured by 
specular microscopy and determined by the independent reading center 
 
4.1.2 
Exclusion Criteria 
In addition to all criteria specified in the main Study GR42691 protocol, patients will be 
excluded from this substudy if they meet the following criteria:  
Fellow (Non-Study) Eye 
 
Prior and/or current administration of faricimab  
 
Prior administration of brolucizumab 
 
Either Eye 
 
Corneal ECD  1500 cells/mm2 in either eye at screening as determined by the 
independent corneal reading center 
 
Fuchs endothelial corneal dystrophy Grade  2  
 
Previous ocular trauma (blunt or penetrating) and/or corneal endothelial cell 
damage, including from blunt or surgical trauma (including complicated cataract 
surgery resulting in complicated lens placement such as anterior chamber 
intraocular lens, sulcus intraocular lens, aphakia, etc.) 

 
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 
Any ocular condition that precludes obtaining an analyzable specular microscopy 
image 
 
Active or history of corneal edema 
 
Any active or history of corneal dystrophies, excluding Fuchs endothelial corneal 
dystrophy Grade  2 
 
Active or history of iridocorneal endothelial syndrome 
 
Active or history of pseudoexfoliation syndrome 
 
Active or history of herpetic keratitis or kerato-uveitis (including herpes simplex virus 
and herpes zoster virus) 
 
Intraocular laser therapy including selective laser trabeculoplasty, yttrium-aluminum 
garnet (YAG), prophylactic peripheral iridotomy within 1 year of screening, or YAG 
capsulotomy within 3 months of screening 
 
Prior vitrectomy surgery, submacular surgery, or other surgical intervention for AMD 
 
Prior pars plana vitrectomy surgery 
 
Previous intraocular device implantation excluding intraocular lenses  
 
Cataract surgery within 6 months of screening or planned for during the study 
 
History of glaucoma-filtering surgery, tube shunts, or microinvasive glaucoma 
surgery.  Other types of prior glaucoma surgery are allowed providing that the 
surgery occur more than 6 months before screening 
 
Administration of topical Rho kinase inhibitors (e.g., Rhopressa eye drops) within 
1 month prior to the screening visit 
 
Contact lens wear in either eye within 2 months of screening  
 
History of corneal transplantation, including partial-thickness corneal grafts 
(e.g., Descemet membrane endothelial keratoplasty, Descemet stripping endothelial 
keratoplasty) 
 
Active or history of iridocorneal endothelial syndrome 
 
Active or history of pseudoexfoliation syndrome 
 
4.2 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE SUBSTUDY DESIGN 
The investigational medicinal product (IMP) for this study is faricimab (test product).  
4.2.1 
Study Treatment Formulation and Packaging 
4.2.1.1 
Faricimab 
Faricimab will be supplied by the Sponsor as a sterile liquid for intravitreal injection in 
single-use glass vials.  
Each single-use, 2 ‑mL glass vial contains 6 mg (nominal) of faricimab formulated as 
120 mg/mL in L-histidine/acetate buffer solution (approximately pH 5.5) containing 
sodium chloride, sucrose, L-methionine, and polysorbate 20 and is designed to provide a 

 
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21/Protocol GR42691 Corneal Endothelial Cells Substudy, Version 2 
dose of 6 mg/0.05 mL for intravitreal injection.  Refer to the pharmacy manual for 
detailed instructions on drug preparation, storage, and administration. 
4.2.2 
Investigational Medicinal Product Handling and 
Accountability 
See main Study GR42691 Section 4.3.3.  
4.2.3 
Continued Access to Faricimab 
See main Study GR42691 Section 4.3.4. If a patient’s participation extends beyond the 
duration of the main study faricimab  will continue to be reimbursed until the patient 
completes the CEC Substudy for the study eye. 
4.3 
CONCOMITANT THERAPY 
See main Study GR42691 Section 4.4. 
4.3.1 
Permitted Therapy  
See main Study GR42691 Section 4.4.1. As faricimab is made commercially available 
globally, the requirements for ongoing reimbursement of other anti-VEGF therapies 
licensed for ocular use that are used in the fellow eye have been revised, and 
reimbursement must be approved by the Sponsor unless the patient is enrolled in the 
CEC Substudy. Reimbursements will cease if the patient is discontinued from the 
faricimab study treatment or once the patient has completed the trial or the CEC 
substudy, whichever occurs last. 
4.3.2 
Prohibited Therapy 
See main Study GR42691 Section 4.4.2. 
Administration of topical Rho kinase inhibitors (e.g., Rhopressa eye drops) during the 
substudy and for at least 1 month prior to screening is prohibited. 
Administration of the following therapies to the fellow eye is also prohibited during the 
substudy: 
 
faricimab 
 
brolucizumab (Beovu®) 
 
bevacizumab (Avastin®) 
 
Port Delivery System implantation (Susvimo™) 
 
4.4 
SUBSTUDY ASSESSMENTS  
The schedule of activities to be performed during the substudy is provided in 
Appendix 1.  All activities should be performed and documented for each patient. 

 
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4.4.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the substudy must be obtained before 
performing any substudy-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. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a detailed record of 
all patients screened, to document eligibility or record reasons for screening failure, as 
applicable. 
4.4.2 
Medical History, Baseline Conditions, Concomitant Medication, 
and Demographic Data 
See main Study GR42691 Section 4.5.2 for the medical history, baseline conditions and 
demographic data.  
4.4.3 
Vital Signs 
See main Study GR42691 Section 4.5.3. 
4.4.4 
Ocular Assessments 
See main Study GR42691 Section 4.5.4. 
Ocular Imaging 
A corneal reading center will provide sites with the corneal reading center manual and 
training materials for specified substudy ocular images.  Before any substudy images are 
obtained, site personnel, test images, systems, and software (where applicable) will be 
certified and validated by the reading center as specified in the corneal reading center 
manual.  All ocular image results will be obtained by trained site personnel at the study 
sites and forwarded to the corneal reading center for independent analysis and/or 
storage and will later be transferred to the Sponsor. 
If a patient misses all the substudy visits within the visit window in which specular 
microscopy imaging can be scheduled (i.e., Weeks 20 through 28 for substudy midpoint 
and Weeks 48 through 64 for Year 1), the images should be obtained at an unscheduled 
visit up to 4 weeks after the last missed visit of the window (i.e., Week 28 for substudy 
midpoint and Week 64 for Year 1) or at the next scheduled in-person main 
Study GR42691 visit, whichever comes first.  If the images need to be repeated due to 
quality reasons, this should be done within the visit window or within 4 weeks, whichever 
comes first. 
Scans of both eyes will be collected from all substudy patients, according to the corneal 
reading center image acquisition protocol. 

 
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4.4.5 
Concurrent Ocular Procedures 
See main Study GR42691 Section 4.5.5. 
4.5 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.5.1 
Study Treatment Discontinuation 
See Section 3.1.4 and main Study GR42691 Section 4.6.1. 
4.5.2 
Patient Discontinuation from the Study 
See main Study GR42691 Section 4.6.2. 
4.5.3 
Study Discontinuation 
See Section 3.1.4 and main Study GR42691 Section 4.6.3. 
4.5.4 
Site Discontinuation 
See main Study GR42691 Section 4.6.4. 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
See main Study GR42691 Section 5.1. If a patient’s duration on the CEC Substudy 
extends beyond the duration of the main study, safety data will continue to be collected 
per the same reporting mechanism, which will remain available until the final CEC 
visit.  
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
See main Study GR42691 Section 5.2. 
5.3 
METHODS AND TIMING FOR CAPTURING AND 
ASSESSING SAFETY PARAMETERS 
See main Study GR42691 Section 5.3. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
See main Study GR42691 Section 5.4. 
5.4.1 
Medical Monitors and Emergency Medical Contact 
Contact Information for All Sites 
Medical Monitor/Emergency Medical Contact: 
 (Primary) 
Mobile Telephone No.: 
 

 
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5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
See main Study GR42691 Section 5.4.2. If a patient’s duration on the CEC Substudy 
extends beyond the duration of the main study, safety data will continue to be collected 
per the same reporting mechanism, which will remain available until the final CEC 
visit. 
5.4.3 
Reporting Requirements for Pregnancies 
See main Study GR42691 Section 5.4.3. 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
See main Study GR42691 Section 5.5. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
See main Study GR42691 Section 5.6. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES 
See main Study GR42691 Section 5.7. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
6.1 
DETERMINATION OF SAMPLE SIZE 
No formal sample size calculations were performed for this substudy.  A planned 
enrollment of approximately 135 patients from the main Study GR42691 was selected in 
order to obtain data from at least 100 patients through Year 1 to account for patients with 
missing data (e.g., missed visits, lost to follow-up).  ECD, CV, and HEX will be assessed 
in the corneal endothelium evaluable set (modified intent-to-treat [mITT] population), 
which includes all patients who were treated in the study eye and for whom specular 
microscopic images were interpretable in both the study and fellow eye both at baseline 
and at the substudy midpoint and/or Year 1 evaluations.   
For additional details, refer to main Study GR42691.  
6.2 
ANALYSIS POPULATIONS 
6.2.1 
Modified Intent-to-Treat Population 
The mITT population will comprise all eligible patients enrolled into this substudy who 
received at least one injection of faricimab during the substudy.  For analyses using the 
GR40306 or GR40844 (hereinafter referred to as main Phase III study) treatment group, 
patients will be grouped according to the treatment assigned at randomization in the 
main Phase III study.  In the main Phase III studies, patients were randomized to one of 

 
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two regimens:  faricimab administered up to Q16W or aflibercept administered at a fixed 
interval of Q8W.  
6.2.2 
Per-Protocol Population 
The per-protocol population is defined as all mITT patients who do not have a major 
protocol violation that impact the efficacy evaluation in the substudy.  For analyses using 
the main Phase III study treatment group, patients will be grouped according to the 
treatment assigned at randomization in the main Phase III study. 
6.3 
SUMMARIES OF CONDUCT OF STUDY 
Summaries of conduct of study will be based on the mITT population and will be 
presented overall and by main Phase III study treatment group.  The number and 
percentage of patients who enroll (including from which treatment group of the main 
Phase III study) will be summarized by site.  The number and percentage of patients 
who enroll in (including from which treatment group of the main Phase III study), 
discontinue from, or complete this substudy will be also summarized.  Reasons for 
premature substudy withdrawal will be listed and summarized.  Eligibility criteria 
exceptions and other major protocol deviations will be listed and evaluated for their 
potential impact on the interpretation of the substudy results.   
6.4 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline disease characteristics will be summarized using the mITT 
population and will be presented overall and by main study Phase III treatment group. 
 
Demographic data (e.g., sex and race or ethnicity) will originate from the main 
Phase III studies.  
 
Baseline ocular and non-ocular disease characteristics (e.g., baseline BCVA, central 
subfield thickness [CST]) will be done both with values originating from the main 
Phase III study treatment group and from the main study GR42691 study overall.   
 
Baseline ocular characteristics collected at the substudy screening visit will be 
summarized by eye (study eye versus control eye). 
Exposure to study drug (number of treatments and duration of treatment) will be 
summarized as the exposure during the substudy only.  Exposure will be presented 
overall and by main Phase III study treatment groups for the safety-evaluable 
population. 
The difference between study eye and fellow eye ECD, CV, and HEX will be 
summarized by using means, standard deviations, medians, and ranges for study and 
fellow eye at baseline.  Descriptive statistics for continuous data will include number of 
observations, arithmetic mean, SD, median, minimum, and maximum.  Descriptive 
statistics for categorical data will include frequency and/or percent. 

 
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6.5 
IMAGING ANALYSES 
Imaging analyses will be performed among the subset of patients who had an 
interpretable baseline specular microscopic image in both eyes and at least 
one post-baseline specular microscopic image for both eyes either at substudy midpoint 
and/or at Year 1.  
6.5.1 
Primary Efficacy Endpoint 
The percent change in corneal ECD from baseline at Year 1 will be analyzed using the 
paired t-test.  The 95% confidence intervals for Year 1 values as well as 
change-from-baseline at Year 1 will be calculated. 
6.5.2 
Secondary Efficacy Endpoint 
The percent change in corneal ECD from baseline at substudy midpoint will be analyzed 
using the paired t-test.  The 95% confidence intervals for baseline and substudy 
midpoint values as well as for change-from-baseline at substudy midpoint will be 
calculated. 
6.5.3 
Exploratory Efficacy Endpoints 
The percent change in CV of corneal endothelial cell area and percent change of HEX 
cells from baseline at substudy midpoint and Year 1 will be analyzed using the paired 
t-test.  The 95% confidence intervals for baseline, substudy midpoint, and Year 1 values 
as well as for change-from-baseline at each timepoint will be calculated. 
6.5.3.1 
Subgroup Analyses 
The percent change in corneal ECD from baseline at Year 1, the percent change in CV 
of corneal endothelial cell area from baseline at substudy midpoint and Year 1, and the 
percent change of HEX cells from baseline at substudy midpoint and Year 1 will be 
analyzed separately using the paired t-test within each of the following subgroups: 
 
Baseline age ( 65,  65 to  75, and  75 years)  
 
Number of faricimab injections received during substudy ( 5,  5 injections)  
 
6.6 
INTERIM ANALYSIS  
No interim analysis is planned for this substudy. 
7. 
DATA COLLECTION AND MANAGEMENT 
See main Study GR42691 Section 7. 
8. 
ETHICAL CONSIDERATIONS 
See main Study GR42691 Section 8. 

 
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9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
See main Study GR42691 Section 9. 

 
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10. 
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Faricimab—F. Hoffmann-La Roche Ltd 
30/Protocol GR42691 Corneal Endothelial Cells Substudy, Version 2 
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Faricimab—F. Hoffmann-La Roche Ltd 
31/Protocol GR42691 Corneal Endothelial Cells Substudy, Version 2 
Appendix 1 Schedule of Activities 
Assessments 
Screening and Enrollment Visit a, b 
Substudy 
Midpoint a, c 
Year 1 a, d 
(Final Substudy Visit) 
Unscheduled Visit 
Substudy (Week[s]) 
1 
20 to 28 
48 to 64 
Visit window (days) a 
Any week within main Study 
GR42691 and  7 days after last 
anti-VEGF or other IVT injection in 
either eye  
 
 
 
Informed consent e 
x 
 
 
 
Review of inclusion and 
exclusion criteria 
x 
 
 
 
Specular microscopy f 
x 
x 
x 
x 
IVT  intravitreal; VEGF  vascular endothelial growth factor. 
a Refer to main Study GR42691 Schedule of Activities (Appendix 1) for main study assessments, visit schedule, and study visit 
windows.  Please note that substudy visits will also be based on the patient’s personalized treatment interval determined during 
the main Study GR42691.   
b Screening and enrollment visit will be Day 1 of this substudy. 
c Substudy midpoint assessment is defined as the earliest substudy visit closest to Week 24 occurring between Week 20 and 
Week 28. However, patients are allowed to complete the CEC visit at any time between Week 20 and Week 28. 
d Year 1 assessment is defined as the earliest substudy visit closest to Week 52 occurring between Week 48 and Week 64. 
e Patients must sign the substudy Informed Consent Form prior to performing protocol-mandated assessments.  Consent may be 
obtained on or prior to the screening visit. However, patients are allowed to complete the Corneal Endothelial Cells study visit 
at any time between Week 48 and Week 64. 
f Perform specular microscopy for both eyes prior to application of any topical ophthalmic anesthetic, tonometry, or any other 
study treatment on the same day for the evaluation of endothelial cell density.  Specular microscopy imaging must be performed 
prior to study treatment administration. 
 

Signature Page for Protocol - GR42691 - VABYSMO - v2 -  Published
System identifier: RIM-CLIN-456968
Approval Task
Company Signatory
02-Nov-2022 19:57:49 GMT+0000