Clinical trial NCT04607148
Conditions: Macular Degeneration, Age-Related Geographic Atrophy
Sponsor: Genentech, Inc.
Start date: 2020-11-16; Completion date: 2022-11-14
Enrollment: 144 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the long-term safety and tolerability of intravitreal (ITV) injections of galegenimab (FHTR2163) administered every 4 weeks (Q4W) or every 8 weeks (Q8W) in participants with geographic atrophy (GA) secondary to age-related macular degeneration (AMD) who completed the parent study (NCT03972709/GR40973).

Detailed description:

Arms: arm 1: Participants will receive 20 milligrams (mg) galegenimab via ITV injection every 4 weeks (Q4W). arm 2: Participants will receive 20 mg galegenimab via ITV injection every 8 weeks (Q8W). arm 3: Participants will receive 10 mg galegenimab via ITV injection Q4W. arm 4: Participants will receive 10 mg galegenimab via ITV injection Q8W.
Interventions: intervention 1: Galegenimab
Intervention descriptions: intervention 1: Intravitreal (ITV) injections of galegenimab

Protocol documents:
Prot_SAP_000.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (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 Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered.
FHTR2163—Genentech, Inc.
Protocol GR42558, Version 4
PROTOCOL
TITLE:
A MULTICENTER, OPEN-LABEL EXTENSION 
STUDY TO EVALUATE THE LONG-TERM SAFETY 
AND TOLERABILITY OF INTRAVITREAL 
INJECTIONS OF FHTR2163 IN PATIENTS WITH 
GEOGRAPHIC ATROPHY SECONDARY TO 
AGE-RELATED MACULAR DEGENERATION
PROTOCOL NUMBER:
GR42558
VERSION NUMBER:
4
EUDRACT NUMBER:
Not applicable
IND NUMBER:
134632
NCT NUMBER:
NCT04507148
TEST PRODUCT:
FHTR2163 (RO7171009)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
Genentech, Inc.
DATE FINAL:
See electronic date stamp below
 
Company Signatory
Approver's Name
Title
Date and Time (UTC)
22-Sep-2021 15:49:27
 
Company Signatory
Approver's Name
Title
Date and Time (UTC)
22-Sep-2021 23:09:01


FHTR2163—Genentech, Inc.
2/Protocol GR42558, Version 4
PROTOCOL HISTORY
Version
Date Final
1
15 July 2020
2
10 October 2020
3
3 May 2021


FHTR2163—Genentech, Inc.
3/Protocol GR42558, Version 4
PROTOCOL AMENDMENT, VERSION 4: 
RATIONALE
Protocol GR42558 has been amended primarily to include two additional treatment arms 
to provide safety, tolerability, pharmacokinetic, pharmacodynamic biomarker, and 
immunogenicity data for intravitreal administration of FHTR2163 at 10 mg.

Two new treatment arms have been added to the study design; patients assigned to 
these arms will receive either 10 mg of FHTR2163 every 4 weeks (Q4W) or 10 mg 
of FHTR2163 every 8 weeks (Q8W), respectively.  Upon implementation of protocol 
Version 4, newly enrolling patients from the sham control arms of parent study 
GR40973 (hereafter referred to as the parent study) will be assigned to the new 
10 mg treatment arm that corresponds to the dosing frequency of each patient's 
original dosing schedule in the parent study (i.e., Q4W or Q8W).  No changes will be 
made to the dosing regimens of patients currently enrolled in Study GR42558
(Sections 3.1, 3.4.1, 4.3.2, 6.2, 6.3, 6.5, and 6.6; Figure 1).

Given that the changes in the study design could potentially unmask the parent 
study, an Internal Monitoring Committee has been added to monitor safety and 
study conduct during the masked period of the current study, which extends until 
database lock of the parent study (Sections 3.2, 4.2.2, and 5.1).

Additional aqueous humor sample collections have been added at Week 24 and 
Week 72 to assess if sufficient HtrA1 target inhibition is achieved at the 10 mg of 
FHTR2163 dose level, and additional serum pharmacokinetic (PK) and anti-drug 
antibody samples have been added at Week 24 and Week 72 to enable assessment 
of immunogenicity at the 10 mg of FHTR2163 dose level. These sample collections 
have been added for all treatment arms to maintain masking (Appendix 1 and 
Appendix 2).
Other changes made to the protocol are as follows:

Language around pre-injection prophylactic paracentesis procedures being 
performed outside of pre-specified aqueous humor collection visits has been added 
to the exclusion criteria, prohibited therapy criteria, and treatment interruption 
criteria.  Specifically, given that such pre-injection prophylactic paracentesis 
procedures are not pre-specified procedures in the Informed Consent Form and 
procedure sequelae could confound the interpretation of the study outcomes, 
pre-injection prophylactic paracentesis procedures have been added as an 
exclusionary criterion and as a prohibited therapy.  Treatment interruption criteria 
have been amended to indicate that if an enrolled patient is deemed to require a 
prophylactic paracentesis prior to study treatment administration, study treatment 
must be interrupted and may be resumed as determined by the investigator with 
consultation from the Medical Monitor.  In addition, permitted therapy criteria have
been clarified to allow for post-injection paracentesis as per clinical judgment.  


FHTR2163—Genentech, Inc.
4/Protocol GR42558, Version 4
Furthermore, treatment interruption criteria have been amended to indicate that if an 
enrolled patient has had three consecutive post-injection paracentesis procedures 
performed in the study eye for treatment of adverse events, study drug must be 
interrupted.  Study treatment may be resumed as determined by the investigator 
with consultation from the Medical Monitor (Sections 4.1.2, 4.4.1, 4.4.2, and 5.1.5; 
Table 1).

Guidelines for permitted therapy have been updated to clarify that in the event the 
non-study eye requires treatment for neovascular age-related macular degeneration
(nAMD), treatment with any FDA-approved intravitreal antivascular endothelial 
growth factor (anti-VEGF) treatment for nAMD may be administered (Section 4.4.1).

References to inclusion of caregiver reporting of patient health data has been 
removed for consistency with the Informed Consent Form (Sections 4.5.6 and 5.1.1; 
Appendix 1 and Appendix 2).

The Medical Monitor has been changed; applicable study summary pages and 
emergency medical contact information (Section 5.4.1) have been updated 
accordingly.

Guidelines for dose interruption and treatment discontinuation in the event of
intraocular inflammation have been updated (Section 5.1.5; Appendix 1 and 
Appendix 2).

A footnote has been added for aqueous humor and serum PK sample collections to 
clarify that these samples should be collected on Day 1 of the current study if the 
Day 1 visit does not coincide with the Week 76 visit in the parent study and these 
samples were not collected on Week 76 in accordance with the parent study 
(Appendix 1 and Appendix 2).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative
changes to the original protocol.


FHTR2163—Genentech, Inc.
5/Protocol GR42558, Version 4
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11
PROTOCOL SYNOPSIS .................................................................................... 12
1.
BACKGROUND .......................................................................................... 18
1.1
Background on Geographic Atrophy Secondary 
to Age-Related Macular Degeneration .................................. 18
1.2
Background on HtrA1 ............................................................ 19
1.3
Background on FHTR2163.................................................... 19
1.3.1
Summary of Nonclinical Studies of FHTR2163...................... 19
1.3.2
Summary of Clinical Studies of FHTR2163 ........................... 20
1.4
Study Rationale and Benefit–Risk Assessment..................... 21
2.
OBJECTIVES AND ENDPOINTS ............................................................... 21
2.1
Safety Objective (Primary Objective)..................................... 22
2.2
Pharmacokinetic Objectives .................................................. 22
2.3
Immunogenicity Objectives.................................................... 22
2.4
Biomarker Objectives............................................................. 22
3.
STUDY DESIGN......................................................................................... 23
3.1
Description of the Study......................................................... 23
3.2
Internal Monitoring Committee ...........................................24
3.3
End of Study.......................................................................... 24
3.4
Rationale for Study Design.................................................... 25
3.4.1
Rationale for FHTR2163 Dose and Schedule........................ 25
3.4.2
Rationale for Biomarker Assessments................................... 25
4.
MATERIALS AND METHODS .................................................................... 26
4.1
Patients.................................................................................. 26
4.1.1
Inclusion Criteria.................................................................... 26
4.1.2
Exclusion Criteria................................................................... 27
4.1.2.1
Ocular Exclusion Criteria ....................................................... 27
4.1.2.2
Concurrent Condition Exclusion Criteria................................ 28
4.2
Method of Treatment Assignment and Masking .................... 28
4.2.1
Treatment Assignment........................................................... 28


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6/Protocol GR42558, Version 4
4.2.2
Masking Throughout the Study ............................................. 29
4.2.3
Masking During the Masked Period of the Study ................. 29
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 29
4.3.1
Study Treatment Formulation and Packaging........................ 29
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 29
4.3.3
Investigational Medicinal Product Handling and 
Accountability ........................................................................ 30
4.3.4
Continued Access to FHTR2163 ........................................... 31
4.4
Concomitant Therapy ............................................................ 31
4.4.1
Permitted Therapy................................................................. 31
4.4.2
Prohibited Therapy ................................................................ 32
4.5
Study Assessments ............................................................... 32
4.5.1
Informed Consent Forms....................................................... 32
4.5.2
Physical Examinations........................................................... 33
4.5.3
Vital Signs.............................................................................. 33
4.5.4
Ocular Assessments.............................................................. 33
4.5.5
Ocular Imaging ...................................................................... 34
4.5.6
Follow-Up Calls ..................................................................... 34
4.5.7
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 35
4.5.8
Optional Samples for Research Biosample 
Repository ............................................................................. 36
4.5.8.1
Overview of the Research Biosample Repository.................. 36
4.5.8.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 37
4.5.8.3
Sample Collection.................................................................. 37
4.5.8.4
Confidentiality........................................................................ 37
4.5.8.5
Consent to Participate in the Research 
Biosample Repository............................................................ 38
4.5.8.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 38
4.5.8.7
Monitoring and Oversight....................................................... 39
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 39


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7/Protocol GR42558, Version 4
4.6.1
Study Treatment Discontinuation........................................... 39
4.6.2
Patient Discontinuation from the Study.................................. 40
4.6.3
Study Discontinuation............................................................ 40
4.6.4
Site Discontinuation............................................................... 40
5.
ASSESSMENT OF SAFETY....................................................................... 41
5.1
Safety Plan ............................................................................ 41
5.1.1
Potential Risks Associated with FHTR2163........................... 41
5.1.1.1
Potential Ocular Risks ........................................................... 41
5.1.1.2
Potential Systemic Risks ....................................................... 43
5.1.2
Risks Associated with Intravitreal Route of 
Administration........................................................................ 44
5.1.3
Risks Associated with Aqueous Humor Sampling 
through Anterior Chamber Paracentesis................................ 44
5.1.4
Management of Patients Who Experience 
Adverse Events Associated with Intravitreal 
Injection ................................................................................. 44
5.1.5
Management Guidelines and Treatment 
Interruption and Treatment Discontinuation 
Criteria................................................................................... 45
5.2
Safety Parameters and Definitions ........................................ 47
5.2.1
Adverse Events ..................................................................... 48
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 48
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 49
5.2.4
Selected Adverse Events....................................................... 50
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 50
5.3.1
Adverse Event Reporting Period ........................................... 50
5.3.2
Eliciting Adverse Event Information....................................... 51
5.3.3
Assessment of Severity of Adverse Events ........................... 51
5.3.4
Assessment of Causality of Adverse Events ......................... 52
5.3.5
Procedures for Recording Adverse Events............................ 52
5.3.5.1
Adverse Events of Ocular Infection and 
Inflammation.......................................................................... 53
5.3.5.2
Increased Intraocular Pressure Values.................................. 53


FHTR2163—Genentech, Inc.
8/Protocol GR42558, Version 4
5.3.5.3
Abnormal Findings on Ocular Imaging .................................. 54
5.3.5.4
Diagnosis versus Signs and Symptoms................................. 54
5.3.5.5
Adverse Events That Are Secondary to Other 
Events.................................................................................... 54
5.3.5.6
Persistent or Recurrent Adverse Events................................ 55
5.3.5.7
Abnormal Laboratory Values ................................................. 55
5.3.5.8
Abnormal Vital Sign Values ................................................... 56
5.3.5.9
Abnormal Liver Function Tests.............................................. 57
5.3.5.10
Deaths ................................................................................... 57
5.3.5.11
Preexisting Medical Conditions.............................................. 57
5.3.5.12
Worsening of Geographic Atrophy in Study Eye.................... 58
5.3.5.13
Hospitalization or Prolonged Hospitalization.......................... 58
5.3.5.14
Cases of Accidental Overdose or Medication 
Error....................................................................................... 58
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 60
5.4.1
Emergency Medical Contacts................................................ 60
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 60
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 60
5.4.2.2
Events That Occur after Study Drug Initiation........................ 61
5.4.3
Reporting Requirements for Pregnancies.............................. 61
5.4.3.1
Pregnancies in Female Patients............................................ 61
5.4.3.2
Abortions ............................................................................... 62
5.4.3.3
Congenital Anomalies/Birth Defects ...................................... 62
5.5
Follow-Up of Patients after Adverse Events .......................... 62
5.5.1
Investigator Follow-Up........................................................... 62
5.5.2
Sponsor Follow-Up ................................................................ 63
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 63
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees.......................................................... 63


FHTR2163—Genentech, Inc.
9/Protocol GR42558, Version 4
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 64
6.1
Determination of Sample Size ............................................... 64
6.2
Summaries of Conduct of Study............................................ 64
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 64
6.4
Safety Analyses..................................................................... 64
6.5
Pharmacokinetic Analyses..................................................... 65
6.6
Immunogenicity Analyses...................................................... 65
6.7
Biomarker Analyses............................................................... 65
6.8
Interim Analyses .................................................................... 65
7.
DATA COLLECTION AND MANAGEMENT ............................................... 65
7.1
Data Quality Assurance......................................................... 65
7.2
Electronic Case Report Forms............................................... 66
7.3
Source Data Documentation.................................................. 66
7.4
Use of Computerized Systems .............................................. 67
7.5
Retention of Records............................................................. 67
8.
ETHICAL CONSIDERATIONS.................................................................... 68
8.1
Compliance with Laws and Regulations ................................ 68
8.2
Informed Consent.................................................................. 68
8.3
Institutional Review Board or Ethics Committee.................... 69
8.4
Confidentiality........................................................................ 69
8.5
Financial Disclosure .............................................................. 70
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 70
9.1
Study Documentation ............................................................ 70
9.2
Protocol Deviations................................................................ 71
9.3
Site Inspections ..................................................................... 71
9.4
Administrative Structure......................................................... 71
9.5
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 71
9.6
Protocol Amendments ........................................................... 72
10. REFERENCES ........................................................................................... 73


FHTR2163—Genentech, Inc.
10/Protocol GR42558, Version 4
LIST OF TABLES
Table 1
Management Guidelines and Treatment Interruption and 
Treatment Discontinuation Criteria.............................................. 46
Table 2
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in WHO Toxicity Grading Scale ..................... 51
Table 3
Causal Attribution Guidance ....................................................... 52
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 24
LIST OF APPENDICES
Appendix 1
Schedule of Activities for Q4W Arms .......................................... 76
Appendix 2
Schedule of Activities for Q8W Arms .......................................... 85
Appendix 3
Best Corrected Visual Acuity Testing.......................................... 89
Appendix 4
Low-Luminance Best Corrected Visual Acuity Testing................ 90
Appendix 5
Grading Scale for Assessment of Anterior Chamber Flare or 
Cells and Vitreous Cells.............................................................. 91
Appendix 6
Post-Injection Procedures for All Patients................................... 92
Appendix 7
Color Fundus Photography ......................................................... 93
Appendix 8
Fundus Autofluorescence ........................................................... 94
Appendix 9
Near Infrared Imaging................................................................. 95
Appendix 10
Spectral Domain Optical Coherence Tomography...................... 96
Appendix 11
Optical Coherence Tomography Angiography ............................ 97
Appendix 12
Fluorescein Angiography ............................................................ 98
Appendix 13
Anterior Chamber Paracentesis and Aqueous Humor 
Sampling Procedures.................................................................. 99
Appendix 14
WHO Toxicity Grading Scale for Determining the Severity of 
Adverse Events......................................................................... 101


FHTR2163—Genentech, Inc.
11/Protocol GR42558, Version 4
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A MULTICENTER, OPEN-LABEL EXTENSION 
STUDY TO EVALUATE THE LONG-TERM SAFETY 
AND TOLERABILITY OF INTRAVITREAL 
INJECTIONS OF FHTR2163 IN PATIENTS WITH 
GEOGRAPHIC ATROPHY SECONDARY TO 
AGE-RELATED MACULAR DEGENERATION
PROTOCOL NUMBER:
GR42558
VERSION NUMBER:
4
EUDRACT NUMBER:
Not applicable
IND NUMBER:
134632
NCT NUMBER:
NCT04507148
TEST PRODUCT:
FHTR2163 (RO7171009)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
Genentech, Inc.
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 PPD.


FHTR2163—Genentech, Inc.
12/Protocol GR42558, Version 4
PROTOCOL SYNOPSIS
TITLE:
A MULTICENTER, OPEN-LABEL EXTENSION STUDY TO 
EVALUATE THE LONG-TERM SAFETY AND TOLERABILITY OF 
INTRAVITREAL INJECTIONS OF FHTR2163 IN PATIENTS WITH 
GEOGRAPHIC ATROPHY SECONDARY TO AGE-RELATED
MACULAR DEGENERATION
PROTOCOL NUMBER:
GR42558
VERSION NUMBER:
4
EUDRACT NUMBER:
Not applicable
IND NUMBER:
134632
NCT NUMBER:
NCT04507148
TEST PRODUCT:
FHTR2163 (RO7171009)
PHASE:
II
INDICATION:
Geographic atrophy secondary to age-related macular degeneration
SPONSOR:
Genentech, Inc.
OBJECTIVES AND ENDPOINTS
The primary objective of this open-label extension (OLE) study is to evaluate the long-term 
safety and tolerability of intravitreal (ITV) injections of 20 mg of FHTR2163 and ITV injections 
of 10 mg of FHTR2163 administered every 4 weeks (Q4W) or every 8 weeks (Q8W) in eligible 
patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD) 
who completed Study GR40973 (hereafter referred to as the parent study).  Specific objectives 
and corresponding endpoints for the study are outlined below.
Safety Objective (Primary Objective)
The safety objective for this study (primary objective) is to evaluate the long-term safety and 
tolerability of FHTR2163 on the basis of the following endpoints:

Incidence and severity of ocular adverse events

Incidence and severity of systemic (non-ocular) adverse events 
Pharmacokinetic Objectives
The pharmacokinetic (PK) objective for this study is to evaluate the observed trough 
concentration following 20 mg of FHTR2163 and 10 mg of FHTR2163 administered by ITV 
injection Q4W or Q8W on the basis of the following endpoint:

Serum and aqueous humor concentration of FHTR2163 at specified timepoints
The exploratory PK objective for this study is to evaluate potential relationships between drug 
exposure and the safety of FHTR2163 on the basis of the following endpoint:

Relationship between serum and/or aqueous humor concentration for FHTR2163 and 
clinically relevant safety endpoints
Immunogenicity Objectives
The immunogenicity objective for this study is to evaluate the immune response to FHTR2163 
on the basis of the following endpoint:

Prevalence of serum anti-drug antibodies (ADAs) at baseline and incidence of serum ADAs 
during the study 


FHTR2163—Genentech, Inc.
13/Protocol GR42558, Version 4
The exploratory immunogenicity objective for this study is to evaluate potential effects of ADAs 
on the basis of the following endpoint:

Relationship between ADA status and safety or PK endpoints
Biomarker Objectives
The exploratory imaging biomarker objective for this study is to evaluate GA disease status, in 
the study population and in subgroups based on HTRA1 risk-variant carrier status as 
determined in the parent study, on the basis of the following endpoint:

Change in GA area from parent study baseline and from OLE study baseline, as measured 
by fundus autofluorescence (FAF) imaging and determined by a central reading center 
consisting of graders and ophthalmologists experienced in the conduct of clinical trials
The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that 
are predictive of response to FHTR2163, are associated with rate of progression to a more 
severe disease state, are associated with susceptibility to developing adverse events, can 
provide evidence of FHTR2163 activity, or can increase the knowledge and understanding of 
disease biology and drug safety, on the basis of the following endpoints:

Relationship between biomarkers in plasma and aqueous humor and safety, PK, 
immunogenicity, or other biomarker endpoints

Relationship between retinal imaging metrics (e.g., metrics from FAF, spectral domain 
optical coherence tomography, optical coherence tomography angiography) and safety, PK, 
immunogenicity, or other biomarker endpoints
STUDY DESIGN
Description of Study
Study GR42558 is a multicenter, OLE study to evaluate the long-term safety and tolerability of 
ITV injections of FHTR2163 in patients with GA who completed the parent study.  Patients who 
discontinued from the parent study or discontinued from study treatment prior to completion of 
the final (Week 76) visit are not eligible for enrollment in this OLE study.  
Patients who consent to participate in the OLE study will be screened for eligibility upon 
completion of the parent study (i.e., Week 76 visit).  The Week 76 visit will serve as the final visit 
for the parent study and the first (Day 1) visit for the OLE study (i.e., the two visits are to be 
conducted on the same day), and all Week 76 assessments must be completed prior to 
conducting Day 1 assessments.  If all assessments for the Day 1 visit cannot be completed on 
the same day as the Week 76 visit, patients may return to the clinic within 28 days to complete 
the Day 1 visit.  If a patient is not able to complete the Day 1 visit within 28 days, the 
investigator must contact the Medical Monitor for further discussion prior to scheduling the 
Day 1 visit.
Patients will receive 20 mg of FHTR2163 or 10 mg of FHTR2163 by ITV injection in the same 
eye selected for injections in the parent study (referred to as the "study eye") Q4W or Q8W for 
approximately 144 weeks.  Dosing frequency will remain consistent with each patient's original 
dosing schedule in the parent study (i.e., Q4W or Q8W).  Upon implementation of protocol 
Version 4, all eligible patients in the sham control arms of the parent study that are newly 
enrolling in the OLE study will receive 10 mg of FHTR2163 (Q4W or Q8W).  Patients 
currently enrolled in the OLE study (i.e. enrolled prior to implementation of protocol 
Version 4) will continue receiving their current dosing regimen for the remainder of the 
study.
Number of Patients
Approximately 360 patients are expected to participate in the OLE study.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Completion of the parent study (GR40973) through the Week 76 visit without early 
treatment discontinuation


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14/Protocol GR42558, Version 4

Sufficiently clear ocular media, adequate pupillary dilation, and fixation to permit acceptable 
fundus imaging

Ability to comply with the study protocol

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate of 
1% per year during the treatment period and for 28 days after the final dose of 
FHTR2163.  
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis).  The definition of 
childbearing potential may be adapted for alignment with local guidelines or 
regulations.
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.  If required per local guidelines or 
regulations, locally recognized acceptable methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form.
Ocular Inclusion Criteria:  Study Eye

If the study eye best corrected visual acuity (BCVA) letter score is 69 letters (Snellen 
equivalent of 20/40 or better), the non-study eye must have a BCVA letter score of 44 
letters (Snellen equivalent of 20/125 or better) on visit Day 1 OLE/Week 76 of parent study.
Ocular Inclusion Criteria:  Non-Study Eye

The non-study eye must have a BCVA letter score of 44 letters (Snellen equivalent of 
20/125 or better) if the study eye BCVA letter score is 69 letters (Snellen equivalent of 
20/40 or better) on visit Day 1 OLE/Week 76 of parent study. 
Exclusion Criteria
Ocular Exclusion Criteria
Patients who meet any of the following ocular criteria will be excluded from study entry:

Active uveitis and/or vitritis (grade trace or above) in either eye

Active, infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye

Active or history of choroidal neovascularization in study eye that requires anti-VEGF 
treatment

Active or recent history (i.e., since enrollment in parent study) of optic neuritis in either eye

Retinal pigment epithelium tear that involves the macula in either eye

Moderate or severe non-proliferative diabetic retinopathy in either eye

Proliferative diabetic retinopathy in either eye

Central serous retinopathy in either eye

Recent history of recurrent infectious or inflammatory ocular disease in either eye

Recent history of idiopathic or autoimmune-associated uveitis in either eye


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
Any concurrent ocular or intraocular condition in the study eye that contraindicates the use 
of an investigational drug or may affect interpretation of the study results or may render the 
patient at high risk for treatment complications
Note that medical history (e.g., clinically significant increased intraocular pressure 
meeting sight-threatening criteria) that will require the patient to receive 
pre-injection prophylactic paracentesis prior to the study treatment administration 
in the study eye is exclusionary.
Concurrent Condition Exclusion Criteria
Patients who meet any of the following concurrent condition criteria will be excluded from study 
entry:

Recent history of any disease, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding that gives reasonable suspicion of a disease or condition that 
contraindicates the use of FHTR2163, that might affect interpretation of the results of the 
study, or that renders the patient at high risk of treatment complications

Recent history of a severe allergic reaction or anaphylactic reaction to a biologic agent or 
known hypersensitivity to any component of the investigational drug

Requirement for continuous use of any medication or treatment indicated as a prohibited 
therapy in this study

Medical condition that may be associated with a clinically significant risk for bleeding

Recent history of cerebral vascular accident or transient ischemic attack

Pregnant or breastfeeding, or intending to become pregnant during the study or within 
28 days after the final dose of FHTR2163
Women of childbearing potential must have a negative urine pregnancy test result at 
the Day 1 visit, prior to initiation of study drug.

Active systemic or localized infection requiring medical treatment that, in the opinion 
of the investigator, could interfere with study conduct
End of Study
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs.  LPLV 
is expected to occur approximately 144 weeks after the last patient is enrolled in the study.
INVESTIGATIONAL MEDICINAL PRODUCTS
Patients will receive 20 mg of FHTR2163 or 10 mg of FHTR2163 by ITV injection in the study 
eye at a dosing frequency that is consistent with the patient's original dosing schedule in the 
parent study (i.e., Q4W or Q8W).
STATISTICAL METHODS
Primary Analysis
The safety analysis population will consist of all patients enrolled in this study who received at 
least one dose of study drug.  
Safety will be assessed through descriptive summaries of adverse events, ocular assessments 
(e.g., inflammation, intraocular pressure, best corrected visual acuity), clinical laboratory 
evaluations, ocular imaging, and immunogenicity against FHTR2163.
Verbatim descriptions of adverse events will be summarized by mapped term, appropriate 
thesaurus level, and toxicity grade (severity) if applicable. 
Determination of Sample Size
This study is open to all patients who completed FHTR2163 treatment and follow-up through the 
final (Week 76) visit of the parent study and meet the eligibility criteria.  Accordingly, the sample 
size for this study is not based on a formal sample size calculation.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody
AMD
age-related macular degeneration
BCVA
best corrected visual acuity
CARASIL
cerebral autosomal recessive arteriopathy with 
subcortical infarcts and leukoencephalopathy
CFP
color fundus photograph
CNV
choroidal neovascularization
CRO
contract research organization
DKK3
Dickkopf-related protein 3
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
ETDRS
Early Treatment Diabetic Retinopathy Study
FA
fluorescein angiography
FAF
fundus autofluorescence
GA
geographic atrophy
GLP
Good Laboratory Practice
HIPAA
Health Insurance Portability and Accountability Act
HRB
hyperreflective band
HtrA1
high-temperature requirement A1
ICH
International Council for Harmonisation
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IOI
intraocular inflammation
IOP
intraocular pressure
IRB
Institutional Review Board
ITV
intravitreal
IWRS
interactive web-based response system
LPLV
last patient, last visit
MD
multiple-dose
nAMD
neovascular AMD
NI
near infrared (images)
OCT-A
optical coherence tomography angiography
OLE
open-label extension
PD
pharmacodynamic


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Abbreviation
Definition
PK
pharmacokinetic
Q4W
every 4 weeks
Q8W
every 8 weeks
RBR
Research Biosample Repository
RPE
retinal pigment epithelium
SAD
single ascending dose
SD-OCT
spectral domain optical coherence tomography
ULN
upper limit of normal
VA
visual acuity
VEGF
vascular endothelial growth factor
WES
whole exome sequencing
WGS
whole genome sequencing
YAG
yttrium aluminum garnet


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1.
BACKGROUND
1.1
BACKGROUND ON GEOGRAPHIC ATROPHY SECONDARY TO 
AGE-RELATED MACULAR DEGENERATION
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in 
people aged 50 years or older in the developed world (Friedman et al. 2004).  The 
majority of the visual loss occurs in the advanced stage of AMD, which has two clinical 
forms:  1) a non-exudative form, geographic atrophy (GA), which is characterized by loss 
of photoreceptors, retinal pigment epithelium (RPE), and choriocapillaris; and 2) an 
exudative or wet form, known as neovascular AMD (nAMD), which is characterized by 
choroidal neovascularization (CNV) (Sunness et al. 1999; Lindblad et al. 2009).  The 
prevalence of GA increases exponentially with age and approximately quadruples per 
decade beyond 50 years of age (Rudnicka et al. 2012).  The estimated prevalence of GA 
in populations of European ancestry at 70 years of age is 0.70%, rising to 2.91% at 
80 years of age and 11.29% at 90 years of age (Rudnicka et al. 2012).
In the early stages of GA, patients typically show minimal changes in central visual 
acuity (VA).  However, while central VA may not yet be affected, patients often still 
experience significant symptoms from visual dysfunction, such as dense parafoveal 
scotomas (e.g., leading to difficulties with face recognition), delayed dark adaptation, 
reduced contrast sensitivity, and a decrease in reading rate (Sunness et al. 1995, 1996, 
1999).  In the later stages, as the GA lesion expands into the fovea, a profound 
decrease in central VA occurs with a decline in activities of daily living (Lindblad and 
Clemons 2005).  Moreover, GA is bilateral in most patients with advanced AMD 
(Sunness et al. 1999; Lindblad et al. 2009).  As such, GA is a significant cause of both 
moderate and severe central visual loss.
Currently, there are no approved treatments for GA secondary to AMD, and a significant 
unmet medical need exists for treatment of this serious condition.  In Chroma 
(Study GX29176) and Spectri (Study GX29185), the largest Phase III studies of GA 
conducted to date, lampalizumab (anticomplement factor D) did not result in a 
reduction of GA lesion area versus sham during 48 weeks of treatment (Holz et al. 
2018).  Other more recent Phase II studies have reported positive results:  the BEACON 
study evaluating the brimonidine drug delivery system (Allergan), the FILLY study 
evaluating APL-2, a synthetic cyclic peptide conjugated to a polyethylene glycol polymer 
that binds specifically to C3 and C3b (Apellis 2018), and the GATHER1 study
evaluating avacincaptad pegol, an inhibitor of the cleavage of C5 and formation of 
terminal fragments C5a and C5b (Jaffe et al. 2020).


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1.2
BACKGROUND ON HTRA1
The HTRA1 gene, located in chromosomal region 10q26, was one of the first AMD 
genetic loci identified, and this finding has been replicated in multiple studies employing
linkage analysis or genome-wide association (Weeks et al. 2001; Fritsche et al. 2016).  
A single nucleotide polymorphism (rs10490924) in the promoter region of HTRA1 is the 
most likely causal variant, or tags the causal variant, for AMD at 10q26 (DeWan et al. 
2006; Yang et al. 2006) and is estimated to confer a population attributable risk of 49.3% 
(Yang et al. 2006).  Transcription of HTRA1 has been shown to be increased in 
association with the risk allele (Yang et al. 2006).
HtrA1 is a member of the mammalian HtrA serine protease family (Clausen et al. 2002).  
HtrA1 has been shown to cleave a large number of potential substrates, many of which 
are extracellular matrix proteins (Grau et al. 2006).  In transgenic mice, overexpression 
of HtrA1 in RPE cells recapitulated cardinal features associated with advanced AMD, 
including choroidal vasculopathy and severe degeneration of elastic laminae of the 
Bruch’s membrane (Jones et al. 2011; Kumar et al. 2014).  At the molecular level, this 
phenotype appears to result from HtrA1-induced breakdown of extracellular matrix 
protein associated with RPE, Bruch’s membrane, and choroid (Jones et al. 2011; 
Vierkotten et al. 2011; Kumar et al. 2014).  In the human retina, HtrA1 is expressed by 
RPE cells (DeWan et al. 2006; Yang et al. 2006), and unpublished studies conducted by 
Genentech revealed that its expression is increased in the area peri-lesional to the GA.
1.3
BACKGROUND ON FHTR2163
FHTR2163 (RO7171009) is a Fab of a humanized monoclonal antibody directed against 
the HtrA1 protein (Tom et al. 2020). FHTR2163 was shown to bind with an equilibrium 
dissociation constant of 0.13 nM to human HtrA1.  The HtrA1 protease is functional only 
as a trimer.  Full inhibition of the enzymatic activity of trimeric HtrA1 requires three 
separate anti-HtrA1 Fabs to bind each HtrA1 subunit (Ciferri et al. 2015).  By inhibiting 
HtrA1 protease activity, treatment with FHTR2163 may represent a novel therapeutic 
option for the treatment of GA.
1.3.1
Summary of Nonclinical Studies of FHTR2163 
In Good Laboratory Practice (GLP) repeat-dose toxicity studies, FHTR2163 was 
generally well tolerated in cynomolgus monkeys following bilateral intravitreal (ITV) 
doses every 2 weeks in studies of up to 6 months in duration at doses of up to 
12.5 mg/eye in a 750 mOsm/kg formulation.  Hyperreflective bands (HRBs) were noted 
on spectral domain optical coherence tomography (SD-OCT) imaging in the fovea of 
some eyes that were dosed with vehicle or FHTR2163.  HRBs were transient, confined 
to the fovea, and not correlated with functional (full-field electroretinography) or 
histopathologic abnormalities.  These findings suggest that HRBs may be related to the 
volume and/or number of ITV injections, and are not due to FHTR2163 (Booler et al. 
2019; Covance Laboratories Inc. report 2018 [available upon request]).  Ocular effects 
associated with FHTR2163 were limited to ocular inflammation, which was considered to 


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be procedure related and/or secondary to specific immune-mediated response to a 
humanized protein. Ocular inflammation was associated with the presence of systemic 
anti-drug antibodies (ADAs), was not considered to be related to the pharmacologic
action of FHTR2163, and showed reversibility by the end of the 1-month recovery 
period. No systemic effects were observed in evaluated parameters, including safety 
pharmacology endpoints (cardiovascular, respiratory, or behavioral). The 
no-observed-adverse-effect level in the 6-month GLP repeat-dose toxicity study was 
considered to be 12.5 mg/eye in a 750 mOsm/kg formulation administered as a single 
50-µL ITV injection every 2 weeks.  
Overall, the nonclinical studies demonstrated that FHTR2163 has an acceptable 
pharmacokinetic (PK) and safety profile to support long-term dosing in humans.  Refer to 
the FHTR2163 Investigator’s Brochure for details on nonclinical studies.
1.3.2
Summary of Clinical Studies of FHTR2163 
Clinical studies of FHTR2163 to date consist of one completed Phase I study (GR39821) 
and one ongoing Phase II study (GR40973 [GAllego]).
Study GR39821 is a completed, Phase I, open-label, first-in-human study that 
investigated the ocular and systemic safety, tolerability, pharmacokinetics, and 
immunogenicity of FHTR2163 in patients with GA secondary to AMD.  A total of 
28 patients were enrolled in the study:  15 patients during the single ascending dose 
(SAD) stage and 13 patients during the multiple-dose (MD) stage. During the SAD 
stage, patients received single ITV injections of FHTR2163 at doses ranging from 1 to 
20 mg.  During the MD stage, patients received up to three ITV injections of FHTR2163 
at a dose of 20 mg (maximum dose tested in the SAD stage) and a frequency of one
injection every 4 weeks (Q4W).  FHTR2163 was well tolerated during the study.  There 
were no observed dose-limiting toxicities or ocular serious adverse events, and there 
were no observed systemic or ocular adverse events assessed as related to study drug. 
Following single or multiple ITV injections, FHTR2163 exhibited flip-flop kinetics, with 
serum concentrations low relative to aqueous humor concentrations.  The apparent 
serum and aqueous humor half-life had a range of 3.068.67 days across all individuals, 
which is consistent with other Fabs administered by ITV injection.  Pharmacodynamic 
(PD) changes were assessed in aqueous humor by measuring levels of cleaved DKK3, 
an endogenous substrate of HtrA1, as a PD biomarker of FHTR2163 inhibition of HtrA1 
protease activity (Tom et al. 2020). Dose-dependent inhibition of DKK3 cleavage by 
FHTR2163 was observed in the SAD cohorts.  Higher doses of FHTR2163 yielded 
longer duration of HtrA1 inhibition, and at the 20-mg dose, inhibition of DKK3 cleavage 
was sustained for at least 8 weeks after a single ITV administration.  In the MD stage, 
DKK3 cleavage remained inhibited throughout the treatment period with FHTR2163.  
Following the final dose at Week 8, inhibition was maintained through Day 112 (Week 
16; 8 weeks after the final dose), with an upward trend towards baseline levels of 
DKK3 cleavage by Day 133 (Week 19; 11 weeks after the final dose).  The DKK3 


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cleavage results provided information on the duration of target coverage by FHTR2163
and supported administration of FHTR2163 Q4W or every 8 weeks (Q8W) in the 
Phase II study.
Refer to the FHTR2163 Investigator’s Brochure for further details on clinical studies.
1.4
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT
This open-label extension (OLE) study will evaluate the long-term safety and tolerability 
of ITV injections of FHTR2163 in patients with GA secondary to AMD. Currently, there 
are no approved treatments to slow or stop the progression of GA secondary to AMD 
and associated vision loss.  FHTR2163 is a first-in-class inhibitor of HtrA1 in clinical 
development, and as such there are no published data on the clinical benefit of this 
mechanism for the treatment of GA secondary to AMD. 
The clinical experience with FHTR2163 consists of data from the Phase I first-in-human 
study (GR39821) and emerging data from the ongoing Phase II study (GR40973), as 
described in Section 1.3.2 and the FHTR2163 Investigator’s Brochure. Given the early 
phase of development, the safety profile of FHTR2163 in humans is not fully understood 
at this time.  This OLE study will complement the Phase II parent study (GR40973), 
permitting the evaluation of long-term safety and tolerability of FHTR2163 in patients 
who have completed that study. In addition, this OLE study will provide an opportunity 
for eligible patients undergoing sham injections in Study GR40973 to receive 
FHTR2163. 
Data from completed nonclinical pharmacology, PK, and toxicology studies, data from
the completed Phase I study (GR39821), and emerging safety data from the ongoing 
Phase II study (GR40973) support the continued clinical development of FHTR2163 in
patients with GA secondary to AMD (see Sections 1.3.1 and 1.3.2).  There are no
identified risks for FHTR2163 to date.  Potential risks are described in Section 5.1.1.  
Several measures are being taken in this study to mitigate possible safety concerns, 
including strict inclusion and exclusion criteria (see Section 4.1), physical examinations 
(see Section 4.5.2), regular ocular assessments (see Section 4.5.4), and regular ocular 
imaging (see Section 4.5.5). Because of the high unmet medical need for new 
treatments for GA secondary to AMD and the safety profile of FHTR2163 observed in 
both nonclinical and clinical studies to date, the benefitrisk of FHTR2163 is favorable 
and supportive of its continued use in this OLE study.
2.
OBJECTIVES AND ENDPOINTS
The primary objective of this study is to evaluate the long-term safety and tolerability 
of ITV injections of 20 mg of FHTR2163 and ITV injections of 10 mg of FHTR2163 
administered Q4W or Q8W in eligible patients with GA secondary to AMD who 
completed Study GR40973 (hereafter referred to as the parent study). Specific 
objectives and corresponding endpoints for the study are outlined below.


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2.1
SAFETY OBJECTIVE (PRIMARY OBJECTIVE)
The safety objective for this study (primary objective) is to evaluate the long-term safety 
and tolerability of FHTR2163 on the basis of the following endpoints:

Incidence and severity of ocular adverse events, with severity determined according 
to the scale in Section 5.3.3

Incidence and severity of systemic (non-ocular) adverse events, with severity 
determined according to the WHO toxicity scale (or the alternative scale in 
Section 5.3.3, if appropriate)
2.2
PHARMACOKINETIC OBJECTIVES
The PK objective for this study is to evaluate the observed trough concentration 
following 20 mg of FHTR2163 and 10 mg of FHTR2163 administered by ITV injection
Q4W or Q8W on the basis of the following endpoint:

Serum and aqueous humor concentration of FHTR2163 at specified timepoints
The exploratory PK objective for this study is to evaluate potential relationships between 
drug exposure and the safety of FHTR2163 on the basis of the following endpoint:

Relationship between serum and/or aqueous humor concentration for FHTR2163 
and clinically relevant safety endpoints
2.3
IMMUNOGENICITY OBJECTIVES
The immunogenicity objective for this study is to evaluate the immune response to 
FHTR2163 on the basis of the following endpoint:

Prevalence of serum ADAs at baseline and incidence of serum ADAs during the 
study 
The exploratory immunogenicity objective for this study is to evaluate potential effects of 
ADAs on the basis of the following endpoint:

Relationship between ADA status and safety or PK endpoints
2.4
BIOMARKER OBJECTIVES
The exploratory imaging biomarker objective for this study is to evaluate GA disease 
status, in the study population and in subgroups based on HTRA1 risk-variant carrier 
status as determined in the parent study, on the basis of the following endpoint:

Change in GA area from parent study baseline and from OLE study baseline, as 
measured by fundus autofluorescence (FAF) imaging and determined by a central 
reading center consisting of graders and ophthalmologists experienced in the 
conduct of clinical trials


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The exploratory biomarker objective for this study is to identify and/or evaluate 
biomarkers that are predictive of response to FHTR2163, are associated with rate of 
progression to a more severe disease state, are associated with susceptibility to 
developing adverse events, can provide evidence of FHTR2163 activity, or can increase 
the knowledge and understanding of disease biology and drug safety, on the basis of the 
following endpoints:

Relationship between biomarkers in plasma and aqueous humor (listed in 
Section 4.5.7) and safety, PK, immunogenicity, or other biomarker endpoints

Relationship between retinal imaging metrics (e.g., metrics from FAF, SD-OCT, 
optical coherence tomography angiography [OCT-A]) and safety, PK, 
immunogenicity, or other biomarker endpoints
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
Study GR42558 is a multicenter, OLE study to evaluate the long-term safety and 
tolerability of ITV injections of FHTR2163 in patients with GA who completed the parent 
study. Patients who discontinued from the parent study or discontinued from study 
treatment prior to completion of the final (Week 76) visit are not eligible for enrollment in 
this OLE study. Approximately 360 patients are expected to participate in the OLE 
study.  
Patients who consent to participate in the OLE study will be screened for eligibility upon 
completion of the parent study (i.e., Week 76 visit).  The Week 76 visit will serve as the 
final visit for the parent study and the first (Day 1) visit for the OLE study (i.e., the two 
visits are to be conducted on the same day), and all Week 76 assessments must be 
completed prior to conducting Day 1 assessments.  If all assessments for the Day 1 visit 
cannot be completed on the same day as the Week 76 visit, patients may return to the 
clinic within 28 days to complete the Day 1 visit.  If a patient is not able to complete the 
Day 1 visit within 28 days, the investigator must contact the Medical Monitor for further 
discussion prior to scheduling the Day 1 visit.
Patients will receive 20 mg of FHTR2163 or 10 mg of FHTR2163 by ITV injection in the 
same eye selected for injections in the parent study (referred to as the "study eye") Q4W 
or Q8W for approximately 144 weeks.  Dosing frequency will remain consistent with 
each patient's original dosing schedule in the parent study (i.e., Q4W or Q8W).  Upon 
implementation of protocol Version 4, all eligible patients in the sham control arms of 
the parent study that are newly enrolling in the OLE study will receive 10 mg of 
FHTR2163 (Q4W or Q8W; see Figure 1).  Patients currently enrolled in the OLE study 
(i.e. enrolled prior to implementation of protocol Version 4) will continue receiving 
their current dosing regimen for the remainder of the study.
Figure 1 presents an overview of the study design.  Schedules of activities are provided 
in Appendix 1 and Appendix 2.




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3.4
RATIONALE FOR STUDY DESIGN
3.4.1
Rationale for FHTR2163 Dose and Schedule
In the MD stage of the Phase I study (GR39821), patients received three 20-mg doses of 
FHTR2163 (maximum dose tested) by ITV injection Q4W.  The 20-mg dose and the 
Q4W interval were found to be well tolerated (see the FHTR2163 Investigator’s 
Brochure).  The Phase II parent study is evaluating the 20-mg FHTR2163 dose at both a 
Q4W interval and a Q8W interval, to assess the relationship between dosing interval and 
efficacy, and potentially enable a longer dosing interval, which is a major priority for 
patients, caregivers, and physicians in this disease indication.
On the basis of the observed serum and aqueous PK data, estimated vitreal drug 
concentrations for a typical patient treated with 20 mg of FHTR2163 Q8W are 
maintained above the 50% inhibitory concentration of 3.58 nM established in a 
cynomolgus monkey PK/PD study (16-0265). In addition, the Q8W dosing interval is 
supported by the observed PD biomarker data from aqueous humor samples collected 
during the Phase I study (GR39821), which suggest inhibition of HtrA1 activity through at 
least 8 weeks following a 20-mg dose (see Section 1.3.2).
All patients will receive either 20 mg of FHTR2163 or 10 mg of FHTR2163 and will 
continue on the same dosing schedule as they were assigned in the parent study
(Q4W or Q8W).  Upon implementation of protocol Version 4, all eligible patients in the 
sham control arms of the parent study that are newly enrolling in the OLE study will 
receive 10 mg of FHTR2163 (Q4W or Q8W; see Figure 1). This approach will provide 
safety, tolerability, pharmacokinetic, pharmacodynamic biomarker, and immunogenicity 
data for ITV administration of 10 mg of FHTR2163 at two different treatment regimens
(i.e., Q4W and Q8W). 
The 10 mg of FHTR2163 dose level (Q4W or Q8W) proposed for the alternative dosing
regimen is supported by the observed serum and aqueous PK data from the Phase I 
study, as the estimated vitreal drug concentrations for a typical patient treated with 
10 mg of FHTR2163 are also maintained above the 50% inhibitory concentration of 
3.58 nM established in the cynomolgus monkey PK/PD study.  The observed PD 
biomarker data from aqueous humor samples collected during the Phase I study also 
suggest inhibition of HtrA1 activity through at least 8 weeks following a 10-mg dose.
3.4.2
Rationale for Biomarker Assessments
AMD is a heterogeneous disease, and HtrA1 expression, as well as associated 
downstream activity, may vary among patients.  Therefore, all patients may not respond 
similarly to treatment with FHTR2163.  Plasma biomarker samples collected at baseline
and during the treatment period will be analyzed to evaluate response to FHTR2163 and
to identify patients who may be more likely to respond to FHTR2163 for future studies.


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Biomarkers in aqueous humor may reflect aspects of pathology or treatment response 
that cannot be detected in blood (Kersten et al. 2018).  In nonclinical models and in the 
Phase I study (GR39821), FHTR2163 reduced levels of cleaved DKK3, an aqueous 
humor biomarker related to HtrA1 activity (Tom et al. 2020).  Aqueous humor samples 
will be collected to measure levels of FHTR2163 and biomarkers related to HtrA1, GA,
and/or AMD to support the evaluation of PK and PD effects. The method for aqueous 
humor sample collection in patients receiving ITV injection of therapeutic products has 
been shown to be generally safe and well tolerated when performed by experienced 
ophthalmologists (Van der Lelij and Rothova 1997; Trivedi et al. 2011; Kitazawa et al. 
2017).  Complication rates were less than 1% with no long-term sequelae and no effect 
on VA.  
Aqueous humor and plasma biomarker data will be analyzed in the context of this study 
but will also be explored in aggregate with data from other studies.  This aggregate 
analysis may increase the knowledge and understanding of GA and inform the 
development of new therapeutic targets.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 360 patients with GA secondary to AMD who completed study treatment 
and the Week 76 visit in the parent study will be enrolled at approximately 
75 investigative sites located in the United States in this OLE study.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Completion of the parent study (GR40973) through the Week 76 visit without early 
treatment discontinuation

Sufficiently clear ocular media, adequate pupillary dilation, and fixation to permit 
acceptable fundus imaging

Ability to comply with the study protocol

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate 
of 1% per year during the treatment period and for 28 days after the final dose 
of FHTR2163.  


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A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.  
If required per local guidelines or regulations, locally recognized acceptable 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form.
Ocular Inclusion Criteria: Study Eye

If the study eye best corrected visual acuity (BCVA) letter score is 69 letters 
(Snellen equivalent of 20/40 or better), the non-study eye must have a BCVA letter 
score of 44 letters (Snellen equivalent of 20/125 or better) on visit Day 1 
OLE/Week 76 of parent study.
Ocular Inclusion Criteria: Non-Study Eye

The non-study eye must have a BCVA letter score of 44 letters (Snellen equivalent 
of 20/125 or better) if the study eye BCVA letter score is 69 letters (Snellen 
equivalent of 20/40 or better) on visit Day 1 OLE/Week 76 of parent study. 
4.1.2
Exclusion Criteria
4.1.2.1
Ocular Exclusion Criteria
Patients who meet any of the following ocular criteria will be excluded from study entry:

Active uveitis and/or vitritis (grade trace or above) in either eye

Active, infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye

Active or history of CNV in study eye that requires anti-VEGF treatment

Active or recent history (i.e., since enrollment in parent study) of optic neuritis in 
either eye

RPE tear that involves the macula in either eye

Moderate or severe non-proliferative diabetic retinopathy in either eye

Proliferative diabetic retinopathy in either eye

Central serous retinopathy in either eye

Recent history of recurrent infectious or inflammatory ocular disease in either eye


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
Recent history of idiopathic or autoimmune-associated uveitis in either eye

Any concurrent ocular or intraocular condition in the study eye that contraindicates 
the use of an investigational drug or may affect interpretation of the study results or 
may render the patient at high risk for treatment complications
Note that medical history (e.g., clinically significant increased intraocular 
pressure meeting sight-threatening criteria) that will require the patient to 
receive pre-injection prophylactic paracentesis prior to the study treatment 
administration in the study eye is exclusionary.
4.1.2.2
Concurrent Condition Exclusion Criteria
Patients who meet any of the following concurrent condition criteria will be excluded from 
study entry:

Recent history of any disease, metabolic dysfunction, physical examination finding, 
or clinical laboratory finding that gives reasonable suspicion of a disease or 
condition that contraindicates the use of FHTR2163, that might affect interpretation 
of the results of the study, or that renders the patient at high risk of treatment 
complications

Recent history of a severe allergic reaction or anaphylactic reaction to a biologic 
agent or known hypersensitivity to any component of the investigational drug

Requirement for continuous use of any medication or treatment indicated as a 
prohibited therapy in this study (see Section 4.4.2)

Medical condition that may be associated with a clinically significant risk for bleeding

Recent history of cerebral vascular accident or transient ischemic attack

Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 28 days after the final dose of FHTR2163
Women of childbearing potential must have a negative urine pregnancy test 
result at the Day 1 visit, prior to initiation of study drug.

Active systemic or localized infection requiring medical treatment that, in the opinion 
of the investigator, could interfere with study conduct
4.2
METHOD OF TREATMENT ASSIGNMENT AND MASKING
4.2.1
Treatment Assignment
This is a non-randomized study.  After initial written informed consent has been 
obtained and eligibility has been established for a patient, the site will obtain the 
patient's treatment assignment from an interactive web-based response system 
(IWRS).  Patients will retain the same patient number that was assigned in the parent 
study.
Patients will receive either 20 mg of FHTR2163 or 10 mg of FHTR2163 by ITV 
injection in the same study eye selected for injections in the parent study and at a 
dosing frequency that is consistent with the patient's original dosing schedule in the 
parent study (i.e., Q4W or Q8W).


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4.2.2
Masking Throughout the Study
The best corrected visual acuity (BCVA) examiner will be masked to study eye
assignment throughout the study.  The BCVA examiner will be permitted to perform only 
the refraction and the following study assessments: BCVA, low-luminance BCVA, and 
pretreatment intraocular pressure (IOP).  The BCVA examiner will also be masked to the 
BCVA scores from the patient’s previous visits and will only have access to a patient’s 
refraction data from previous visits.  Other site study staff will not be masked to study 
eye assignment or patient treatment assignment.
4.2.3
Masking During the Masked Period of the Study
The study will be masked until database lock of the parent study.  After the masked 
period, the study will follow an open-label design.
The central reading center review team, consisting of graders and ophthalmologists 
experienced in the conduct of clinical trials, will be masked to patient treatment 
assignment during the masked period of the study.  The central reading center will 
conduct masked independent review of CFP, FAF, NI, SD-OCT, and OCT-A images to 
provide an objective assessment of image evaluations.  Contract research organization 
personnel, including clinical research associates, will not be masked to patient 
treatment assignment.
Patients will be masked to their treatment assignment (10 mg of FHTR2163 or 20 mg of 
FHTR2163).  Sponsor personnel (except for IMC members) will be masked to treatment 
assignment until after database lock of the parent study, unless there is a need to 
unmask as determined by the IMC. Personnel responsible for PK/PD sample 
management, assays, and analysis may be unmasked as needed (i.e., to evaluate PK 
relationship to an adverse event). 
For regulatory reporting purposes and if required by local health authorities, the 
Sponsor will break the treatment code for all serious, unexpected suspected adverse 
reactions that are considered by the investigator or Sponsor to be related to study drug.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal product (IMP) for this study is FHTR2163.
4.3.1
Study Treatment Formulation and Packaging
FHTR2163 will be supplied by the Sponsor.  Information on the formulation and 
packaging are provided in the pharmacy manual.
4.3.2
Study Treatment Dosage, Administration, and Compliance
Patients will receive 20 mg of FHTR2163 or 10 mg of FHTR2163 by ITV injection in the 
study eye at a dosing frequency that is consistent with the patient's original dosing 
schedule in the parent study (i.e., Q4W or Q8W).  




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to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the drug accountability log.
Refer to the pharmacy manual and/or the FHTR2163 Investigator's Brochure for 
information on IMP handling, including preparation and storage, and accountability. 
4.3.4
Continued Access to FHTR2163
Currently, the Sponsor (Genentech, a member of the Roche Group) does not have any 
plans to provide Genentech IMP (FHTR2163) or any other study treatments to patients 
who have completed the study.  The Sponsor may evaluate whether to continue 
providing FHTR2163 in accordance with the Roche Global Policy on Continued Access 
to Investigational Medicinal Product, available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-
counter drugs) other than protocol-specified procedural medications (e.g., dilating drops, 
proparacaine) used by a patient in addition to protocol-mandated treatment through the 
final visit.  All such medications should be reported to the investigator and recorded on 
the Concomitant Medications eCRF.
4.4.1
Permitted Therapy 
In general, investigators may manage patients' preexisting conditions or new-onset
conditions as clinically indicated and per local standard practice, with the exception of 
prohibited therapies defined in Section 4.4.2.  Of note, the following are some common 
therapies that are permitted:

Treatments as clinically indicated for onset of ocular hypertension or glaucoma are 
permitted in either eye during study participation

Treatments as clinically indicated for onset of cataract or posterior capsular 
opacification are permitted in either eye during study participation
Treatment interruption criteria may apply with cataract surgery (see 
Section 5.1.5).

Corticosteroids (ITV, subtenon, topical, device implant, oral, or IV) 

Patients who use hormone-replacement therapy or other maintenance therapy 
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
Anti-VEGF treatment in the non-study eye is permitted
Intravitreal administration of FDA-approved anti-VEGF agents is permitted 
at the discretion of the evaluating investigator if a patient's non-study eye 
requires treatment for nAMD.  Treatment in the non-study eye may be 
administered at the same visit as the study eye treatment; however, all study 
assessments and study eye treatment per protocol should be completed prior to 
anti-VEGF administration in the non-study eye.  Individual trays and sterile 
preparation must be separately prepared for each eye treatment.

Paracentesis in the study eye after study drug administration is permitted per 
clinical judgment for treatment of adverse events
For patients with a history of repeated paracentesis after study drug 
administration, refer to treatment interruption criteria (see Table 1).
4.4.2
Prohibited Therapy
The following medications and therapies are prohibited during the study, and patients 
who receive any of the following therapies may have study treatment interrupted or 
discontinued and/or may be discontinued from the study (see Section 5.1.5):

Systemic anti-VEGF agents

ITV anti-VEGF agents in the study eye

Concurrent non-study eye treatment with unapproved anti-VEGF therapy for 
nAMD 

Systemic or IV immunomodulatory therapy (e.g., azathioprine, methotrexate, 
mycophenolate mofetil, cyclosporine, cyclophosphamide, anti-tumor necrosis factor 
agents, eculizumab, tocilizumab)

Treatment with photodynamic therapy in either eye

Other experimental therapies, including, but not limited to, stem-cell treatments, 
gene therapy, and long-acting delivery platforms or formulations

Prophylactic paracentesis in the study eye prior to study treatment administration 
(not including anterior chamber paracentesis to enable collection of aqueous humor 
samples)
For patients that require prophylactic paracentesis prior to study drug 
administration, refer to treatment interruption criteria (see Table 1).
4.5
STUDY ASSESSMENTS 
Schedules of activities to be performed during the study are provided in Appendix 1 and 
Appendix 2.  All activities should be performed and documented for each patient.  
4.5.1
Informed Consent Forms 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures.  Informed Consent Forms for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site.


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Week 76 evaluations in the parent study must be completed and reviewed to confirm 
that patients meet all eligibility criteria prior to enrollment at the Day 1 visit in this 
extension study.  The investigator will maintain a log to record details of all patients who 
sign the Informed Consent Form to document each patient’s eligibility or ineligibility to be 
enrolled in the study, as applicable.
4.5.2
Physical Examinations
A targeted physical examination should include an evaluation of the head, eyes, ears, 
nose, throat, and cranial nerves.  The patient’s weight will be measured as well.  Any 
abnormality identified at Day 1 (screening) should be recorded on the General Medical 
History and Baseline Conditions eCRF.  If any abnormalities are noted during the study, 
the patient may be referred to their primary care physician or an appropriate specialist 
for further evaluation.  Changes from baseline abnormalities should be recorded in 
patient notes.  New or worsened clinically significant abnormalities should be recorded 
as adverse events on the Adverse Event eCRF.
4.5.3
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position after resting for 
5 minutes, and temperature.
4.5.4
Ocular Assessments
Ocular assessments will include the following, to be performed on both eyes (with the 
exception of post-injection safety assessments) at timepoints specified in the schedules
of activities (see Appendix 1 and Appendix 2).  A detailed examination to evaluate for 
signs of intraocular inflammation (IOI) should be performed prior to any study drug 
administration. 

BCVA assessment as determined by Early Treatment Diabetic Retinopathy Study 
(ETDRS) chart at a starting distance of 4 m
Perform assessment prior to dilating eyes.  Refer to Appendix 3 and the Clinical 
Edge Visual Acuity Certification Procedure Manual for more information on BCVA 
assessments.

Low-luminance BCVA assessment as determined by ETDRS chart at a starting 
distance of 4 m under low-luminance conditions
Perform assessment prior to dilating eyes.  Refer to Appendix 4 and the Clinical 
Edge Visual Acuity Certification Procedure Manual for more information on 
low-luminance BCVA assessments.

Pre-injection IOP measurement 
Perform assessment prior to dilating eyes.  The method of IOP measurement 
used for a patient must remain consistent throughout the study.


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
Slit-lamp examination
Perform examination prior to dilating eyes.  Refer to Appendix 5 for grading 
scales for anterior chamber flare or cells and vitreous cells.

Dilated binocular indirect high-magnification ophthalmoscopy examination

Finger-counting test, followed by hand motion and light perception tests when 
necessary, performed for the study eye within 15 minutes after study drug injection 
(see Appendix 6)

Post-injection IOP measurement in the study eye between 30 and 50 minutes after 
injection on study treatment visit days 
If there are no safety concerns, the patient will be discharged from the clinic. If 
the IOP is increased by 10 mmHg compared with the pre-injection 
measurement or is of concern to the investigator, the IOP will be measured again 
at 6080 minutes after injection.  If the IOP value remains a concern to the 
investigator, the patient will remain in the clinic and will be treated as necessary 
in accordance with the investigator’s clinical judgment prior to the patient’s 
discharge (see Section 5.3.5.2 for guidance on recording adverse events of 
increased IOP).
The method of IOP measurement used for a patient must remain consistent 
throughout the study.
4.5.5
Ocular Imaging
Ocular images to be obtained during the study include the following:

Digital color fundus photographs (CFPs) of both eyes (see Appendix 7)

FAF images of both eyes (see Appendix 8)

Near infrared (NI) images of both eyes (see Appendix 9)

SD-OCT images of both eyes (see Appendix 10)

OCT-A images of both eyes (for sites with OCT-A capabilities) (see Appendix 11)
Both eyes will be dilated prior to ocular imaging. Additional details on obtaining these 
images are included in the Central Reading Center Manual.
4.5.6
Follow-Up Calls
After each study treatment visit, the site must contact the patient 14 (5) days after each 
treatment visit and query for adverse events; particularly any signs or symptoms of 
decreased visual acuity and/or inflammation (e.g., painful red eye, floaters, scotoma, 
pain).  If the patient reports any concerning signs and/or symptoms, the patient must be 
evaluated by the investigator as soon as possible.


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4.5.7
Laboratory, Biomarker, and Other Biological Samples
Fasting is not required prior to specimen collection.  The specimens will be sent to a
central laboratory.  The central laboratory will either perform the analysis or send the
samples to the Sponsor or a designee for analysis and/or storage.
Samples will be collected for the following analyses:

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, and 
other cells)

Chemistry panel (serum):  sodium, potassium, glucose, BUN or urea, creatinine, 
total protein, albumin, total and direct bilirubin, ALP, ALT, and AST

Coagulation:  INR, aPTT, and PT

Lipids:  cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides

Pregnancy test
All women of childbearing potential will have a urine pregnancy test prior to 
each study drug injection.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test.

PK analysis (serum and aqueous humor)

Immunogenicity analysis (serum)

Exploratory biomarker research (plasma and aqueous humor)
Exploratory biomarker research may include, but will not be limited to, cleaved 
DKK3 and other biomarkers associated with HtrA1, GA, and/or AMD.  Research 
may involve extraction of cell-free DNA.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.8), biological samples will be destroyed 
no later than the time of completion of the final Clinical Study Report, with the following 
exceptions:

Serum and aqueous humor samples collected for PK or immunogenicity analysis 
may be needed for additional immunogenicity characterization and for PK or 
immunogenicity assay development and validation; therefore, these samples will be 
destroyed no later than 5 years after the final Clinical Study Report has been 
completed.

Blood and aqueous humor samples collected for biomarker research and biomarker 
assay development will be destroyed no later than 15 years after the final Clinical 
Study Report has been completed.


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However, the storage period will be in accordance with the Institutional Review Board or 
Ethics Committee (IRB/EC)approved Informed Consent Form and applicable laws 
(e.g., health authority requirements).
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis, including data on genomic variants, will be subject to 
the confidentiality standards described in Section 8.4.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
4.5.8
Optional Samples for Research Biosample Repository
4.5.8.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives:

To study the association of biomarkers with efficacy or disease progression

To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation

To increase knowledge and understanding of disease biology and drug safety

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
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4.5.8.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 4.5.8) will 
not be applicable at that site.
4.5.8.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to FHTR2163, diseases, or 
drug safety:

Leftover blood, serum, plasma, and aqueous humor samples and any derivatives 
thereof (e.g., DNA, RNA, proteins, peptides)
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via whole genome sequencing (WGS), whole exome sequencing 
(WES), or other genomic analysis methods. Genomics is increasingly informing 
researcher's understanding of disease pathobiology.  WGS and WES provide a 
comprehensive characterization of the genome and exome, respectively, and, along with 
clinical data collected in this study, may increase the opportunity for developing new 
therapeutic approaches or new methods for monitoring efficacy and safety or predicting 
which patients are more likely to respond to a drug or develop adverse events.
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/ECapproved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.8.4
Confidentiality
RBR samples and associated data will be labeled with a unique patient identification 
number.


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Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.8.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the Sample Informed 
Consent/Withdrawal eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research.
4.5.8.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the Sample Informed 
Consent/Withdrawal eCRF.  If a patient wishes to withdraw consent to the testing of his 


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or her RBR samples after closure of the site, the investigator must inform the Sponsor by 
emailing the study number and patient number to the following email address:
global_rcr-withdrawal@roche.com
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study.
4.5.8.7
Monitoring and Oversight
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Pregnancy

Unacceptable toxicity

Any event that meets treatment discontinuation criteria defined in Table 1 in 
Section 5.1.5.
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced and will not be allowed to resume study treatment.  However, they should be 
strongly encouraged to stay in the study and undergo as many scheduled visits as 
possible.


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4.6.2
Patient Discontinuation from the Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following:

Patient withdrawal of consent

Study termination or site closure

Adverse event

Loss to follow-up

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
who withdraw from the study will not be replaced.
Patients who discontinue from the study prematurely will return to the clinic for an early 
termination visit after at least 30 days have lapsed following the final dose of study 
treatment (see Appendix 1 and Appendix 2).
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory

Data recording is inaccurate or incomplete
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording


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
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
FHTR2163 is not approved, and clinical development is ongoing.  The safety plan for 
patients in this study is based on nonclinical studies, the anticipated mechanism of 
action, clinical experience with the completed Phase I study (GR39821), and emerging 
safety data from the ongoing Phase II study (GR40973).  Nonclinical toxicology and 
safety studies revealed minimal ocular inflammation that demonstrated complete or 
partial recovery, and no systemic adverse effects were observed.  In addition, 
FHTR2163 was well tolerated in the Phase I study (GR39821), with no ocular serious 
adverse events, dose-limiting toxicities, or adverse events of special interest reported.  
The anticipated important safety risks for FHTR2163 are outlined in Section 5.1.1.  Refer 
to the FHTR2163 Investigator's Brochure for further details.  Risks associated with ITV 
injections and aqueous humor sampling are described in Section 5.1.2 and Section 
5.1.3, respectively.
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  Review of unmasked safety data will 
be performed by an IMC (see Section 3.2).  Patients will be instructed to contact the 
investigator at any time if they have any health-related concerns.  If warranted, patients 
will be asked to return to the clinic as soon as possible for an unscheduled safety 
assessment visit (see Appendix 1 and Appendix 2).  In addition, guidelines for managing 
adverse events, including guidelines for treatment interruption or discontinuation, are 
provided in Sections 5.1.4 and 5.1.5.  Adverse events should be reported to the Sponsor 
in accordance with instructions provided in Section 5.2 5.6.
5.1.1
Potential Risks Associated with FHTR2163
5.1.1.1
Potential Ocular Risks
Ocular Inflammation
In repeat-dose, GLP toxicology studies of up to 6 months in duration in cynomolgus 
monkeys, an anterior and posterior intraocular inflammatory response was observed in 
animals treated with FHTR2163.  The observed inflammation was consistent with a 
generalized non-specific immune response to a heterologous protein, rather than direct 
effects of FHTR2163, because of the character and localization of the inflammation and 
because the incidence and/or severity of inflammation generally lacked a relationship to 
dose.  The inflammation noted during optical coherence tomography, ophthalmic 
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In the Phase I clinical study (GR39821) there was one patient with 2 non-serious
Grade 1 iritis events. Both events resolved with topical treatment and the patient
completed the study with no changes in study drug administration.
In the ongoing Phase II clinical study GR40973, there have been reports of inflammation 
of the anterior chamber only, posterior chamber only, as well as combined anterior and 
posterior chamber. These include two serious cases of vitritis, and one serious case of 
uveitis; and non-serious recurrent vitritis events that lead to study discontinuation. The 
mechanism is not fully understood at this point.
As of 26 March 2021, there have been no reports of IOI in the ongoing Phase II study 
GR42558. 
Refer to the FHTR2163 Investigator's Brochure for more details on ocular inflammation 
events in the completed and ongoing clinical studies.
The safety plan includes detailed ocular examinations, including BCVA testing, slit-lamp 
examinations, indirect ophthalmoscopy, and SD-OCT imaging at regular intervals 
throughout the study to evaluate for potential ocular adverse events. A follow-up call 
14 (5) days after all study drug administrations is required to query for adverse events; 
particularly any signs or symptoms of decreased visual acuity and/or inflammation (e.g., 
painful red eye, floaters, scotoma, pain); if the patient reports any concerning signs 
and/or symptoms, the patient must be evaluated by the investigator as soon as possible.
In case of non-infectious IOI, consider performing CFP/FA (widefield CFP/FA or 
standard CFP/FA with peripheral sweeps is preferred) and SD-OCT.  A uveitis lab 
workup, as per clinical judgment, should also be considered.  Additionally, consider 
treatment with corticosteroids if appropriate, based on the individual patient presentation 
and comorbidities (e.g., diabetes, systemic hypertension), and consider referring patient 
to a uveitis specialist and/or rheumatologist, per clinical judgment.
Management guidelines and treatment interruption and treatment discontinuation criteria
for ocular inflammation are presented in Section 5.1.5 (see Table 1).
IOI-Associated Retinal Vasculitis
In the ongoing clinical study GR40973, there have been two investigator-reported cases 
of IOI-associated retinal vasculitis as of 23 March 2021.  One case reported IOI with 
associated retinal sheathing of the arteries, with an initial decrease in visual acuity that is 
subsequently recovering with corticosteroid treatment.  The other case reported uveitis 
with mild vasculitis (retinal venous) and optic nerve head leakage seen on FA, with no 
impact on visual acuity.  These events occurred after administration of a single and of 
two doses of masked study drug, respectively, and were treated with corticosteroids. 


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IOI has been reported with other FDA-approved intravitreal agents for the treatment of 
wet AMD; it is typically mild, sterile and resolves with corticosteroid eye drops. 
Brolucizumab was the first approved anti-VEGF therapy associated with non-infectious
retinal vasculitis after intravitreal therapy.  These events have been reported up to 
8 weeks after the first brolucizumab injection, making a direct toxic or infectious cause 
unlikely, and suggesting an immune-mediated mechanism, potentially autoimmunity 
(Baumal et al. 2020).
It is important to recognize and diagnose IOI-associated retinal vasculitis and to 
distinguish it from other causes of uveitis, endophthalmitis, and embolic causes of retinal 
artery occlusion. Patients with IOI should be followed up closely, and treated 
appropriately, realizing that some may progress and potentially show signs of retinal 
vasculitis (Baumal et al. 2020). 
The safety plan is described above for ocular inflammation.
Management guidelines and treatment interruption and treatment discontinuation criteria 
IOI-associated retinal vasculitis are presented in Section 5.1.5 (Table 1).
5.1.1.2
Potential Systemic Risks
Systemic side effects of FHTR2163 are not anticipated, according to data from the 
nonclinical studies and the Phase I clinical study.  Observed systemic levels of 
FHTR2163 following multiple ITV administrations of 20 mg in the Phase I study 
(GR39821) were less than 0.2 g/mL on average at maximum concentration and are 
estimated to be at least 7,500-fold lower than vitreal FHTR2163 concentrations.  On the 
basis of the binding affinity of FHTR2163, baseline systemic HtrA1 levels, and systemic 
concentrations of FHTR2163 following ITV administration at the 20-mg dose, complete 
inhibition of systemic HtrA1 is not expected.
There is a rare human disease called cerebral autosomal recessive arteriopathy with 
subcortical infarcts and leukoencephalopathy (CARASIL) that is characterized by 
complete loss of HtrA1 activity due to a loss-of-function mutation in the HTRA1 gene.  
The main clinical manifestations of CARASIL are ischemic stroke or stepwise 
deterioration in brain function, progressive dementia, premature baldness, and onset of 
severe low back pain, spondylosis deformans, or disc herniations.  Even with complete 
loss of HtrA1 activity from birth, the onset of clinical signs and symptoms do not manifest 
until 20 to 45 years of age (Hara et al. 2009; Fukutake 2011). 
On the basis of the extended time course for the onset of CARASIL as well as the 
expectation that systemic exposures of FHTR2163 after ITV administration will not result 
in complete inhibition of systemic HtrA1, it is highly unlikely that patients will exhibit signs 
and/or symptoms of CARASIL after ITV administration of FHTR2163.


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5.1.2
Risks Associated with Intravitreal Route of Administration
Potential ocular safety issues currently thought to be associated with the ITV route of 
administration include decreased BCVA, conjunctival hemorrhage, ocular inflammation 
(see Appendix 5 for grading scales for anterior chamber flare or cells and vitreous cells), 
intraocular infection (endophthalmitis), transient and/or sustained elevation of IOP, 
transient vision loss, cataract development or progression, retinal or vitreous 
hemorrhage, and retinal break or detachment.  Section 5.1.4 provides details on 
monitoring for adverse events associated with ITV injections, and Section 5.1.5 provides 
management guidelines and treatment interruption and treatment discontinuation 
criteria.
5.1.3
Risks Associated with Aqueous Humor Sampling through 
Anterior Chamber Paracentesis
Patients will undergo anterior chamber paracentesis to enable collection of aqueous 
humor samples for analysis of ocular FHTR2163 pharmacokinetics and for exploratory 
biomarker research.  Potential ocular safety issues may include cataract development or 
progression, anterior chamber hemorrhage, decreased IOP and/or hypotony, and 
decreased BCVA.  There have also been rare reports of serious complications, including 
endophthalmitis and corneal abscess.
The procedure will be performed by experienced ophthalmologists familiar with aqueous 
humor sampling through anterior chamber paracentesis (see Appendix 13 for sampling 
procedures), and patients will be monitored closely for occurrence of potential adverse 
events associated with the procedure.
5.1.4
Management of Patients Who Experience Adverse Events
Associated with Intravitreal Injection
Patients will remain at the clinic for at least 30 minutes after each FHTR2163 injection.  
IOP will be measured in both eyes before injection and in the study eye 3050 minutes 
after injection.  If there are no safety concerns, the patient will be discharged from the 
clinic.  If the IOP is increased by 10 mmHg compared with the pre-injection 
measurement or is of concern to the investigator, the IOP will be measured again at 
6080 minutes post-injection. If the IOP value remains a concern to the investigator, the 
patient will remain in the clinic and will be treated as necessary, in accordance with 
investigator’s clinical judgment, prior to the patient’s discharge. See Section 5.3.5.2 for 
guidance on adverse event reporting. In the study eye, a finger-counting test, followed 
by hand motion and light perception tests when necessary, will be performed by the 
investigator within 15 minutes after each FHTR2163 injection.
In addition, patients will be instructed by study site personnel about warning signs and 
symptoms, including decrease in vision, eye pain, unusual redness, or any other new 
ocular symptoms in the study eye. If warranted, patients will be asked to return to the 
clinic as soon as possible for an unscheduled safety assessment visit (see Appendix 1


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and Appendix 2) and will be instructed to contact the investigator at any time should they 
have any health-related concerns.  Please see Section 5.1.5 for management guidelines 
and treatment interruption and treatment discontinuation criteria, and management of 
IOI.
5.1.5
Management Guidelines and Treatment Interruption and
Treatment Discontinuation Criteria
Treatment interruption and patient discontinuation from study treatment for adverse 
events will be determined on the basis of criteria listed in Table 1.  If treatment is 
interrupted, treatment will not be resumed earlier than the next scheduled study visit.  
The reason for study treatment interruption or discontinuation should be recorded on the 
appropriate eCRF and, if applicable, on the Adverse Event eCRF (see Section 5.2.1 for 
definition of an adverse event).  Adverse events should be reported to the Sponsor in 
accordance with instructions provided in Section 5.2 5.6.
In addition, for any patient who develops any of the exclusion criteria (see Section 4.1.2) 
after study onset, treatment may be interrupted or the patient may be discontinued from 
study treatment, after discussion with the Medical Monitor.
Additionally, patients who receive any of the prohibited therapies (Section 4.4.2) may 
have study treatment interrupted or discontinued and/or may be discontinued from the 
study.


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Table 1
Management Guidelines and Treatment Interruption and
Treatment Discontinuation Criteria


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Table 1
Management Guidelines and Treatment Interruption and 
Treatment Discontinuation Criteria (cont.)
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.


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Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.11 and 
5.3.5.12 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.13)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
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The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events; see Section 5.3.3); 
the event itself may be of relatively minor medical significance (such as severe 
headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.9)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

Adverse events resulting from medication error (see Section 5.3.5.14)
Examples of medication errors include, but are not limited to, overdose, 
incorrect dose, incorrect route, incorrect drug, incorrect administration, or 
incorrect kit.

Sight-threatening adverse events  
All sight-threatening adverse events listed below should be reported as serious 
adverse events, with the underlying cause of the event (if known) listed as the 
primary event term.
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 in BCVA of 30 letters, compared with the most 
recent prior BCVA assessment, that lasts more than 1 hour and is 
attributable to study drug.


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–
It requires surgical intervention (i.e., conventional surgery, vitreous tap, or 
biopsy with ITV injection of an anti-infective compound; or laser or retinal 
cryopexy with gas) to prevent permanent loss of sight.
–
It is associated with severe (Grade 4 ) IOI and/or IOI-associated retinal 
vasculitis as defined in Section 5.3.5.1 (see Section 5.1.1.1 for further 
details on potential ocular risks, Section 5.1.5, Table 1 for management 
guidelines and treatment interruption and treatment discontinuation
criteria, and Appendix 5 for IOI grading scales).
–
An additional serum ADA and PK sample should be collected as close 
as possible to the time of diagnosis (see Section 5.1.5 and Appendix 1
and Appendix 2).
–
In the opinion of the investigator, it may require medical intervention to 
prevent permanent loss of sight.
5.2.4
Selected Adverse Events
Additional data will be collected for the following selected adverse events:

CNV conversion requiring treatment for either the study eye or non-study eye

Any clinically significant ocular imaging finding 
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.4 5.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).  


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After initiation of study drug, all adverse events will be reported until 28 days after the 
final dose of study drug.  After the 28-day period, only serious adverse events (1) 
caused by a protocol-mandated intervention (e.g., invasive procedures such as 
aqueous humor sample), or (2) believed to be related to prior study drug treatment 
(see Section 5.6) should be reported (see Section 5.4.2 for instructions for reporting 
serious adverse events).
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The WHO toxicity grading scale (see Appendix 14) will be used for assessing adverse 
event severity.  Table 2 will be used for assessing severity for adverse events that are 
not specifically listed in the WHO toxicity grading scale.  
For adverse events of IOI, severity assessment ideally should be aligned with the 
grading scale for assessment of anterior chamber flare or cells and vitreous chamber 
(see Appendix 5).
Table 2
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in WHO Toxicity Grading Scale
Grade
Severity
1
Mild; transient or mild discomfort (48 hours); no medical intervention or 
therapy required
2
Moderate; mild to moderate limitation in activity; some assistance may be 
needed; no or minimal medical intervention or therapy required
3
Severe; marked limitation in activity; some assistance usually required; 
medical intervention or therapy required; hospitalization possible
4
Life-threatening; extreme limitation in activity; significant assistance required; 
significant medical intervention or therapy required, hospitalization or hospice 
care probable
Notes:  Developed by the Division of Microbiology and Infectious Diseases.
Regardless of severity, some events may also meet seriousness criteria.  Refer to definition of a 
serious adverse event (see Section 5.2.2).


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5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (see also 
Table 3):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
Table 3
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.


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5.3.5.1
Adverse Events of Ocular Infection and Inflammation
For the purposes of reporting events of ocular infection and inflammation, the following 
terms and definitions should be used:

Iritis:  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:  presence of inflammatory cells in both the aqueous and vitreous

Vitritis:  presence of active inflammation in the vitreous, demonstrated by the 
presence of inflammatory cells (trace or greater)
Active inflammation in the vitreous should be clinically differentiated from cellular 
debris from prior episodes of inflammation, hemorrhage, or other causes.

IOI-associated retinal vasculitis:  ocular inflammation and retinal vascular changes 
(i.e., perivascular sheathing and vascular leakage or occlusion on fluorescein 
angiogram), as defined by the Standardization of Uveitis Nomenclature Working 
Group (Jabs et al. 2005).
The presence of occlusive retinal vasculopathy, in the absence of visible 
inflammation, should not be considered IOI-associated retinal vasculitis. 

Endophthalmitis:  diffuse intraocular inflammation predominantly involving the 
vitreous cavity but also involving the anterior chamber, implying a suspected 
underlying infectious cause
A culture is required prior to initiating antibiotic treatment for presumed 
endophthalmitis.  Results of bacterial or fungal cultures, treatment given, and 
final ophthalmologic outcome must be provided in the details section of the 
Adverse Event eCRF.
Note:  Trace benign, aqueous pigmented cells visible on slit-lamp examination that are 
caused by the dilation process and are not RBCs, WBCs, or the result of any ocular 
disorder should not be recorded as an adverse event.
5.3.5.2
Increased Intraocular Pressure Values 
In general, the observation of elevated IOP values measured 3050 minutes 
post-injection should not be reported as an adverse event.  Elevated IOP values 
measured 3050 minutes post-injection should be reassessed at 6080 minutes 
post-injection prior to reporting as an adverse event.  Medical and scientific judgment 
should be exercised in deciding if an elevated IOP 3050 minutes post-injection that 
remains elevated at the follow-up 60- to 80-minute assessment is clinically significant 
and qualifies to be reported as an adverse event.


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5.3.5.3
Abnormal Findings on Ocular Imaging
Not every abnormal imaging finding on ocular imaging qualifies as an adverse event.  
An abnormal finding on ocular imaging must be reported as an adverse event if it meets 
any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment
It is the investigator’s responsibility to review all ocular images.  Medical and scientific 
judgment should be exercised in deciding whether an isolated imaging abnormality 
should be classified as an adverse event.
If a clinically significant abnormal image finding is a sign of a disease or syndrome 
(e.g., retinal edema), only the diagnosis (e.g., CNV) should be recorded on the Adverse 
Event eCRF.
Observations of the same clinically significant abnormal image finding from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.6 for 
details on recording persistent adverse events).
5.3.5.4
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.5
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.


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
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.6
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  Details regarding any increases in severity will be captured on the Adverse 
Event Intensity or Grade Changes eCRF.  If the event becomes serious, it should be 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning that the 
event became serious; see Section 5.4.2 for reporting instructions).  The Adverse Event 
eCRF should be updated by changing the event from "non-serious" to "serious," 
providing the date that the event became serious, and completing all data fields related 
to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.7
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.


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If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5ULN associated with cholestasis), only the diagnosis 
(e.g., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.6 for 
details on recording persistent adverse events).
5.3.5.8
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (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 5.3.5.6 for 
details on recording persistent adverse events).


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5.3.5.9
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.3) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.10
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.11
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening (Day 1) visit for 
this study.  Such conditions should be recorded on the General Medical History and 
Baseline Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").


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5.3.5.12
Worsening of Geographic Atrophy in Study Eye
Medical occurrences or symptoms of deterioration that are anticipated as part of the 
normal progression of GA secondary to AMD of the study eye should be recorded as an 
adverse event only if judged by the investigator to have unexpectedly worsened in 
severity or frequency or changed in nature at any time during the study.  When recording 
an unanticipated worsening of study eye GA secondary to AMD on the Adverse Event 
eCRF, it is important to convey the concept that the condition has changed by including 
applicable descriptors (e.g., “accelerated geographic atrophy”).  The expedited reporting 
requirements for sight-threatening events (listed in Section 5.2.3) apply to these 
unexpected changes in study eye GA secondary to AMD.
5.3.5.13
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.14
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 
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Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  For FHTR2163, adverse events associated with special 
situations should be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.
In addition, all special situations associated with FHTR2163, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF as described 
below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries.


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5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information
Genentech Medical Monitor contact information:
Medical Monitor:
, M.D., Ph.D. (Primary)
Telephone No.:
(mobile)
Email address: 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  


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These events should be reported to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the event) on the Adverse Event eCRF and submit 
the report via the electronic data capture (EDC) system.  A report will be generated and 
sent to Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest should be reported until 28 days after the final dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Safety 
Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur 28 days after the final dose 
of study drug are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 28 days after the final
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 


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Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  
5.4.3.2
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
5.4.3.3
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.


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5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
28 days after the final dose of study drug), if the event is believed to be related to prior 
study drug treatment or to a protocol-mandated intervention (see Section 5.3.1).  These 
events should be reported through use of the Adverse Event eCRF.  However, if the 
EDC system is not available, the investigator should report these events directly to the 
Sponsor or its designee, either by faxing or by scanning and emailing the paper Clinical 
Trial Serious Adverse Event/Adverse Event of Special Interest Reporting Form using the 
fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the document listed below:
Drug
Document
FHTR2163 
FHTR2163 Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.


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6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
Data collected from the Week 72 or Week 76 visit of the parent study or the Day 1 visit 
of the OLE study will serve as baseline data for the OLE study.
6.1
DETERMINATION OF SAMPLE SIZE
This study is open to all patients who completed FHTR2163 treatment and follow-up 
through the final (Week 76) visit of the parent study and meet the eligibility criteria 
outlined in Sections 4.1.1 and 4.1.2).  Accordingly, the sample size for this study is not 
based on a formal sample size calculation.
6.2
SUMMARIES OF CONDUCT OF STUDY
The clinical database will be used to assess study conduct. The numbers of patients 
who enroll, discontinue, or complete the study will be summarized.  Reasons for 
premature study treatment discontinuation and study discontinuation will be listed and 
summarized.  Patient exposure to study drug (number of study treatments and duration 
of treatment) will be summarized for all patients and by treatment group.  Eligibility 
criteria deviation and other major protocol deviations will be listed and evaluated for their 
potential effects on the interpretation of study results.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic data, OLE baseline safety data (e.g., vital signs and laboratory test 
results), and OLE baseline disease characteristics (e.g., GA area, BCVA, annualized GA 
growth rate) will be summarized for all patients and by treatment group through use of
descriptive statistics.
6.4
SAFETY ANALYSES
The safety analysis population will consist of all patients enrolled in this study who 
received at least one dose of study drug.  
Safety will be assessed through descriptive summaries of adverse events, ocular 
assessments (e.g., inflammation, IOP, BCVA), clinical laboratory evaluations, ocular 
imaging, and immunogenicity against FHTR2163.
Verbatim descriptions of adverse events will be summarized by mapped term, 
appropriate thesaurus level, and toxicity grade (severity) if applicable (see 
Section 5.3.3). 


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6.5
PHARMACOKINETIC ANALYSES
The PK analysis population will consist of all patients enrolled in this study who have at 
least one FHTR2163 serum or aqueous humor sample.  Serum and aqueous humor 
concentrations of FHTR2163 will be summarized descriptively by treatment arm (with 
patients grouped according to treatment actually received) and/or by treatment regimen 
(Q4W or Q8W).
Concentrations of FHTR2163 in serum and aqueous humor may be pooled and 
analyzed with data from other studies as appropriate.
6.6
IMMUNOGENICITY ANALYSES
The immunogenicity analysis population will consist of all patients enrolled in this study 
who have at least one serum ADA assessment.  The numbers and proportions of 
ADA-positive patients and ADA-negative patients at baseline (baseline prevalence) as 
well as after drug administration (postbaseline incidence) will be summarized by 
treatment arm (with patients grouped according to treatment actually received) and/or by 
treatment regimen (Q4W or Q8W).
The relationship between serum ADA status and safety and PK endpoints may be 
analyzed and reported via descriptive statistics.
6.7
BIOMARKER ANALYSES
Mean change in GA area from parent study baseline and OLE study baseline, as 
measured by FAF imaging and determined by a central reading center, will be 
summarized by descriptive statistics.  The relationship between change in GA area and 
HTRA1 risk-variant status (i.e., carriers versus non-carriers of the HTRA1 AMD risk 
variant, rs10490924) will be explored.  Biomarkers will be analyzed together with PK 
data to explore PK/PD relationships.  Additional analyses will be performed to identify 
biomarkers that are predictive of response to FHTR2163, are associated with rate of 
progression to a more severe disease state, are associated with susceptibility to 
developing adverse events, can provide evidence of FHTR2163 activity, or can increase 
the knowledge and understanding of disease biology and drug safety.
6.8
INTERIM ANALYSES
No formal interim analysis is planned since all patients will receive active FHTR2163
treatment. Exploratory safety analyses may be performed with interim data (e.g., to 
support regulatory submissions).
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 


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discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.  The designated Functional Service 
Provider will be responsible for discrepancy management.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and ocular 
imaging will be sent directly to the Sponsor, using the Sponsor’s standard procedures to 
handle and process the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
The Sponsor will supply eCRF specifications for this study.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.


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Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, images, Informed Consent Forms, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator for 15 years 
after completion or discontinuation of the study or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of 
time, the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer.


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8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC)
and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/ECapproved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
If the Consent Forms are revised (through an amendment or an addendum) while a 
patient is participating in the study, the patient or a legally authorized representative 


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must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB/EC policy.  For any updated or 
revised Consent Forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time.
Each Consent Form may also include patient authorization to allow use and disclosure 
of personal health information in compliance with the U.S. Health Insurance Portability 
and Accountability Act (HIPAA) of 1996.  If the site utilizes a separate Authorization 
Form for patient authorization for use and disclosure of personal health information 
under the HIPAA regulations, the review, approval, and other processes outlined above 
apply except that IRB review and approval may not be required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.


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Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data, which may include data on genomic variants, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study.  These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, redacted Clinical Study Reports 
and other summary reports will be provided upon request (see Section 9.5).
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.3).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.


FHTR2163—Genentech, Inc.
71/Protocol GR42558, Version 4
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by Genentech, Inc.  The Sponsor will maintain 
the medical, safety, data management, statistical programming, statistical analysis, and 
oversight of selected vendors during the study.  A contract research organization (CRO)
will manage the study, site monitoring, and selected vendors.  Genentech will oversee 
the CRO.
An IWRS will be used for patient enrollment and management of study drug requests 
and shipments.
A central laboratory will be used for most laboratory assessments and for storage of 
other laboratory samples prior to being shipped to Sponsor or its designee for analysis.  
Data will be recorded on eCRFs through use of an EDC system or will be forwarded to 
the Sponsor electronically (e.g., safety lab data).  A central reading center will conduct
independent analyses of ocular images (e.g., FAF, NI, CFP, OCT-A, and SD-OCT) as 
needed.
9.5
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 


FHTR2163—Genentech, Inc.
72/Protocol GR42558, Version 4
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Trials Data at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


FHTR2163—Genentech, Inc.
73/Protocol GR42558, Version 4
10.
REFERENCES
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reducing the growth rate of geographic atrophy [resource on the Internet]. 2018 
[updated: 22 February 2018; cited 7 December 2018]. Available from: 
http://investors.apellis.com/news-releases/news-release-details/apellis-
pharmaceuticals-announces-18-month-results-phase-2-study.
Baumal CR, Spaide RF, Vajzovic L, et al. Retinal vasculitis and intraocular inflammation 
after intravitreal injection of brolucizumab. Ophthalmology 2020;127:134559.
Booler H, Kusi AM, Tassew N, et al. Functional and ultrastructural assessment of novel 
OCT findings in the cynomolgus monkey. Invest Ophthalmol Vis Sci 2019;60:186. 
Ciferri C, Lipari MT, Liang W-C, et al. The trimeric serine protease HtrA1 forms a 
cage-like inhibition complex with an anti-HtrA1 antibody. Biochem J 
2015;472:16981.
Clausen T, Southan C, Ehrmann M. The HtrA family of proteases: review implications for 
protein composition and cell fate. Mol Cell 2002;10:443–55.
DeWan A, Liu M, Hartman S, et al. HTRA1 promoter polymorphism in wet age-related 
macular degeneration. Science 2006;314:98992.
Friedman DS, O’Colmain BJ, Muñoz B, et al. Prevalence of age-related macular 
degeneration in the United States. Arch Ophthalmol 2004;122:56472.
Fritsche LG, Igl W, Bailey JN, et al. A large genome-wide association study of 
age-related macular degeneration highlights contributions of rare and common 
variants. Nat Genet 2016;48:13443.
Fukutake T. Cerebral autosomal recessive arteriopathy with subcortical infarcts and 
leukoencephalopathy (CARASIL): from discovery to gene identification. J Stroke 
and Cerebrovasc Dis 2011;20:8593.
Grau S, Richards PJ, Kerr B, et al. The role of human HtrA1 in arthritic disease. 
J Biol Chem 2006;281:61249.
Hara K, Shiga A, Fukutake T, et al. Association of HTRA1 mutations and familial 
ischemic cerebral small-vessel disease. N Engl J Med 2009;360:172939.
Holz FG, Sadda SR, Busbee B, et al. Efficacy and safety of lampalizumab for 
geographic atrophy due to age-related macular degeneration: Chroma and Spectri 
Phase 3 randomized clinical trials. JAMA Ophthalmol 2018;136:66677.
Jabs DA, Nussenblatt RB, Rosenbaum JT, et al. Standardization of uveitis nomenclature 
for reporting clinical data. Results of the First International Workshop. Am J 
Ophthalmol 2005;140:50916.


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Jaffe GJ, Westby K, Csaky KJ, et al. C5 inhibitor avacincaptad pegol for geographic 
atrophy due to age-related macular degeneration: a randomized pivotal Phase 2/3 
trial. Ophthalmology 2020;20:308459.
Jones A, Kumar S, Zhang N, et al. Increased expression of multifunctional serine 
protease, HTRA1, in retinal pigment epithelium induces polypoidal choroidal 
vasculopathy in mice. Proc Natl Acad Sci 2011;108:1457883.
Kersten E, Paun CC, Schellevis RL, et al. Systemic and ocular fluid compounds as 
potential biomarkers in age-related macular degeneration. Surv Ophthalmol 
2018;63:939.
Kitazawa K, Sotozono C, Koizumi N, et al. Safety of anterior chamber paracentesis 
using a 30-gauge needle integrated with a specially designed disposable pipette. 
Br J Ophthalmol 2017;101:54850. 
Kumar S, Berriochoa Z, Ambati BK, et al. Angiographic features of transgenic mice with 
increased expression of human serine protease HTRA1 in retinal pigment 
epithelium. Invest Ophthalmol Vis Sci 2014;55:384250.
Lindblad AS, Clemons TE. Responsiveness of the National Eye Institute Visual Function 
Questionnaire to progression to advanced age-related macular degeneration, 
vision loss, and lens opacity. AREDS report number 14. Arch Ophthalmol 
2005;123:120714.
Lindblad AS, Lloyd PC, Clemons TE, et al. Change in area of geographic atrophy in the 
Age-Related Eye Disease Study. AREDS report number 26. Arch Ophthalmol 
2009;127:116874.
Rudnicka AR, Jarrar Z, Wormald R, et al. Age and gender variations in age-related 
macular degeneration prevalence in populations of European ancestry: a 
meta-analysis. Ophthalmology 2012;119:57180. 
Sunness JS, Applegate CA, Haselwood D, et al. Fixation patterns and reading rates in 
eyes with central scotomas from advanced atrophic age-related macular 
degeneration and Stargardt disease. Ophthalmology 1996;103:145866.
Sunness JS, Bressler NM, Maguire MG. Scanning laser ophthalmoscopic analysis of the 
pattern of visual loss in age-related geographic atrophy of the macula. Am J 
Ophthalmol 1995;119:14351.
Sunness JS, Gonzalez-Baron J, Applegate CA, et al. Enlargement of atrophy and visual 
acuity loss in the geographic atrophy form of age-related macular degeneration. 
Ophthalmology 1999;106:176879.
Tom I, Pham VC, Katschke KJ, et al. Development of a therapeutic anti-HtrA1 antibody 
and the identification of DKK3 as a pharmacodynamic biomarker in geographic 
atrophy. Proc Natl Acad Sci U S A 2020;117;995263.
Trivedi D, Denniston AK, Murray PI. Safety profile of anterior chamber paracentesis 
performed at the slit lamp. Clin Exp Ophthal 2011;39:7258.


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Van der Lelij A, Rothova A. Diagnostic anterior chamber paracentesis in uveitis: a safe 
procedure. Br J Ophthalmol 1997;81:9769.
Vierkotten S, Muether PS, Fauser S. Overexpression of HTRA1 leads to ultrastructural 
changes in the elastic layer of Bruch's membrane via cleavage of extracellular 
matrix components. PloS One 2011;6:e22959.
Weeks DE, Conley YP, Tsai H-J, et al. Age-related maculopathy: an expanded 
genome-wide scan with evidence of susceptibility loci within the 1q31 and 17q25 
regions. Am J Ophthal 2001;132:68292.
Yang Z, Camp NJ, Sun H, et al. A variant of the HTRA1 gene increases susceptibility to 
age-related macular degeneration. Science 2006;314:9923.


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Appendix 1
Schedule of Activities for Q4W Arms
Day 1Week 96
Day 1 a
Week (5 days)
UV
ET c
PS b OLE
Treatment Period Visits
4
8
12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96
Written informed consent
x d
Review inclusion and 
exclusion criteria
x
Medical and surgical history, 
including tobacco history
Ex
Review medical and surgical 
history, including tobacco 
history
x
Demographic information
Ex
Physical examination e
x
x f
x
Vital signs g
x
x f
x
Hematology, coagulation, 
lipids, serum chemistry 
(central laboratory) h
Ex
x
x
x f
x
Urine pregnancy test i
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x f
Enrollment (IWRS)
x
Plasma sample for biomarkers
Ex
x
x
x f
x
Serum ADA sample j
Ex
x
x
x
x
x f, j
x
Serum PK sample for drug 
concentration j, n
Ex
x
x
x
x
x f, j
x
BCVA testing (starting at 
4 m) k
Ex
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


Appendix 1:
Schedule of Activities for Q4W Arms
Day 1Week 96
FHTR2163—Genentech, Inc.
77/Protocol GR42558, Version 4
Day 1 a
Week (5 days)
UV
ET c
PS b OLE
Treatment Period Visits
4
8
12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96
LL BCVA testing (starting at 
4 m) k
Ex
x
x
x
x
x f
x
IOP measurement k
Ex
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Slit-lamp examination l
Ex
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Aqueous humor sample m, n
Ex n
x
x
x
x
x f
Dilated binocular indirect 
ophthalmoscopy
Ex
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x f
x
FAF o
Ex
x
x
x
x
x f
x
SD-OCT o
x
x
x
x
x
x
x
x
x
x
x
x
x
x f, j
x
OCT-A o, p
Ex
x
x
x
x
x f
x
NI images o
Ex
x
x
x
x
x f
x
Color fundus photography o
Ex
x
x
x f, j
x
Administration of study drug 
to study eye q
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Post-treatment finger counting 
and IOP measurement r
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant medications s
Ex
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events t
Ex
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concurrent ocular 
procedures u
Ex
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Follow-up call v
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


Appendix 1:
Schedule of Activities for Q4W Arms
Day 1Week 96
FHTR2163—Genentech, Inc.
78/Protocol GR42558, Version 4
ADAanti-drug antibody; BCVAbest corrected visual acuity; CFPcolor fundus photograph; ET early termination; Ex extracted data (from 
PS); FAfluorescein angiography; FAFfundus autofluorescence; FUfollow-up; IOPintraocular pressure; IWRSinteractive web-based 
response system; LL BCVA low-luminance BCVA; NI near infrared; OCT-Aoptical coherence tomography angiography; OLEopen-label 
extension; PKpharmacokinetic; PSparent study; Q4W every 4 weeks; SD-OCTspectral domain optical coherence tomography; 
UVunscheduled visit.
Notes:  All ocular assessments are to be performed for both eyes unless noted otherwise.  
On treatment days, all assessments and sample collection should be completed prior to study drug administration, except for
post-treatment finger counting and IOP measurement.
Patients who discontinue study drug prematurely should be strongly encouraged to stay in the study and undergo as many scheduled 
visits as possible.
a The Day 1 visit for the OLE should be performed on the same day as the Week 76 visit for the PS, and all Week 76 assessments must be 
completed prior to conducting Day 1 assessments.  If all assessments for the Day 1 visit cannot be completed on the same day as the Week 76 
visit, patients may return to the clinic within 28 days to complete the Day 1 visit.  If a patient is not able to complete the Day 1 visit within 
28 days, the investigator must contact the Medical Monitor for further discussion prior to scheduling the Day 1 visit.
b Data from the PS will be extracted for use in the OLE study. 
c For patients who discontinue early from the study, early termination assessments will be performed after at least 30 days have lapsed following 
the final dose of study drug.
d Informed consent must be documented before any study-specific procedure is performed.
e Includes weight and an evaluation of the head, eyes, ears, nose, throat, and cranial nerves.
f
To be performed if clinically indicated.
g Vital signs consist of respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is in a seated position after resting 
for 5 minutes, and temperature.
h For a detailed description of sample collection, see the laboratory manual.
i
Collect and perform urine pregnancy test for women of childbearing potential, including those who have had tubal ligation, at each study 
treatment visit.  If positive, collect a serum pregnancy sample and forward it to central laboratory for testing; if the serum pregnancy test is 
positive, do not administer study drug.


Appendix 1:
Schedule of Activities for Q4W Arms
Day 1Week 96
FHTR2163—Genentech, Inc.
79/Protocol GR42558, Version 4
j
In case of Grade 0 non-infectious intraocular inflammation, contact the Medical Monitor to discuss case. An additional serum ADA and PK 
sample should be collected as close as possible to the time of diagnosis. Consider performing CFP/FA (Appendix 12; widefield CFP/FA or 
standard CFP/FA with peripheral sweeps is preferred), SD-OCT, and uveitis lab workup as clinically indicated.  Additionally, consider treatment 
with corticosteroids if appropriate, based on the individual patient presentation and comorbidities (e.g., diabetes, systemic hypertension), and 
consider referring patient to a uveitis specialist and/or rheumatologist, per clinical judgment.
k Perform assessment prior to dilating the eyes.
l
Perform slit-lamp examination prior to dilating eyes; for grading scales for anterior chamber flare or cells and vitreous cells, see Appendix 5.
m Aqueous humor sample must be collected from the study eye after pretreatment IOP measurement, but prior to study drug administration.  For a 
detailed description of the anterior chamber paracentesis and aqueous humor sample collection procedures, see Appendix 13 and the 
laboratory manual.
n If the Day 1 visit for the OLE is not performed on the same day as the Week 76 visit for the parent study, and serum PK and aqueous humor 
samples were not collected on Week 76, these samples should be collected on Day 1 of OLE study.
o Both eyes will be dilated prior to ocular imaging. FAF, SD-OCT, OCT-A (as applicable), NI images, and color fundus photographs will be 
obtained from both eyes and will be forwarded to the central reading center.  If a patient misses a study visit where ocular images were 
scheduled to be obtained, the images should be obtained at the next scheduled visit.
p OCT-A is mandatory for sites that have the capability.
q All assessments (including a detailed examination to evaluate for signs of intraocular inflammation) and sample collection should be completed 
prior to study drug administration, except for post-treatment finger counting and IOP measurement.
r
After study drug administration in the study eye only, a finger-counting test, followed by hand motion and light perception tests when necessary, 
will be performed by the investigator within 15 minutes post-study drug injection, followed by an IOP measurement that will be obtained 
3050 minutes post-study drug injection.  If there are no safety concerns, the patient may be discharged from the clinic.  If the IOP is increased 
by 10 mmHg compared with the pre-injection measurement, the IOP will be measured again 6080 minutes post-study drug injection. If the 
IOP value remains a concern to the investigator, the patient will remain in the clinic and will be treated as necessary, in accordance with the 
investigator’s clinical judgment, prior to discharge. For guidance on adverse event reporting, see Section 5.3.5.2.
s Record any concomitant medications (e.g., prescription drugs, over-the-counter drugs) other than protocol-specified procedural medications 
(e.g., dilating drops, proparacaine) used by a patient in addition to protocol-mandated treatment.


Appendix 1:
Schedule of Activities for Q4W Arms
Day 1Week 96
FHTR2163—Genentech, Inc.
80/Protocol GR42558, Version 4
t
Any adverse events ongoing after the Week 76 visit from the PS has been completed should be transcribed to the OLE Adverse Event eCRF. 
After informed consent has been obtained for the OLE study but prior to initiation of study treatment, only serious adverse events caused by a 
protocol-mandated intervention should be reported. Adverse events will be recorded starting on Day 1 after study treatment until 28 days after 
the final dose of study drug.  After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse events
caused by a protocol-mandated intervention or believed to be related to prior study drug treatment (see Section 5.6) and should be reported 
(see Sections 5.3.1 and 5.4.2 for instructions for reporting serious adverse events).  Adverse events assessed by the investigator as related to 
study drug should be followed until the event resolves or the event is assessed as irreversible, chronic, or stable, even if patient’s participation 
in the study has ended.
u Record all concurrent ocular procedures performed on the study or non-study eye.
v After each study treatment visit, the site must contact the patient 14 (5) days after each treatment visit and query for adverse events; 
particularly any signs or symptoms of decreased visual acuity and/or inflammation (e.g., painful red eye, floaters, scotoma, pain); if the patient 
reports any concerning signs and/or symptoms, the patient must be evaluated by the investigator as soon as possible.


FHTR2163—Genentech, Inc.
81/Protocol GR42558, Version 4
Appendix 1 
Schedule of Activities for Q4W Arms
Weeks 100148
Week (5 days)
UV
ET a
Treatment Period Visits
FU 
Call
100
104
108
112
116
120
124
128
132
136
140
144
148
Physical examination b
x c
x
Vital signs d
x c
x
Hematology, coagulation, lipids, 
serum chemistry (central 
laboratory) e
x
x c
x
Urine pregnancy test f
x
x
x
x
x
x
x
x
x
x
x
x
x c
Plasma sample for biomarkers
x
x c
x
Serum ADA sample g
x
x c, g
x
Serum PK sample for drug 
concentration g
x
x c, g
x
BCVA testing (starting at 4 m) h
x
x
x
x
x
x
x
x
x
x
x
x
x
x
LL BCVA testing (starting at 4 m) h
x
x
x c
x
IOP measurement h
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Slit-lamp examination i
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Aqueous humor sample j
x
x c
Dilated binocular indirect 
ophthalmoscopy
x
x
x
x
x
x
x
x
x
x
x
x
x c
x
FAF k
x
x
x c
x
SD-OCT k
x
x
x
x
x
x
x c, g
x
OCT-A k, l
x
x
x c
x
NI images k
x
x
x c
x


Appendix 1:
Schedule of Activities for Q4W Arms
Weeks 100148
FHTR2163—Genentech, Inc.
82/Protocol GR42558, Version 4
Week (5 days)
UV
ET a
Treatment Period Visits
FU 
Call
100
104
108
112
116
120
124
128
132
136
140
144
148
Color fundus photography k
x
x c, g
x
Administration of study drug to 
study eye m
x
x
x
x
x
x
x
x
x
x
x
x
Post-treatment finger counting and 
IOP measurement n
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant medications o
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events p
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concurrent ocular procedures q
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Follow-up call r
x
x
x
x
x
x
x
x
x
x
x
x
ADAanti-drug antibody; BCVAbest corrected visual acuity; CFPcolor fundus photograph; ET early termination; 
FAfluorescein angiography; FAFfundus autofluorescence; FUfollow-up; IOP intraocular pressure; LL BCVAlow-luminance 
BCVA; NInear infrared; OCT-Aoptical coherence tomography angiography; OLEopen-label extension; PKpharmacokinetic; 
Q4W every 4 weeks; SD-OCTspectral domain optical coherence tomography; UVunscheduled visit.
Notes:  All ocular assessments are to be performed for both eyes unless noted otherwise.  
On treatment days, all assessments and sample collection should be completed prior to study drug administration, except 
for post-treatment finger counting and IOP measurement.
Patients who discontinue study drug prematurely should be strongly encouraged to stay in the study and undergo as 
many scheduled visits as possible.
a For patients who discontinue early from the study, early termination assessments will be performed after at least 30 days have 
lapsed following the final dose of study drug.
b Includes weight and an evaluation of the head, eyes, ears, nose, throat, and cranial nerves.
c To be performed if clinically indicated.


Appendix 1:
Schedule of Activities for Q4W Arms
Weeks 100148
FHTR2163—Genentech, Inc.
83/Protocol GR42558, Version 4
d Vital signs consist of respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is in a seated 
position after resting for 5 minutes, and temperature.
e For a detailed description of sample collection, see the laboratory manual.
f
Collect and perform urine pregnancy test for women of childbearing potential, including those who have had tubal ligation, at
each study treatment visit.  If positive, collect a serum pregnancy sample and forward it to central laboratory for testing; if the 
serum pregnancy test is positive, do not administer study drug.
g In case of Grade 0 non-infectious intraocular inflammation, contact the Medical Monitor to discuss case. An additional serum 
ADA and PK sample should be collected as close as possible to the time of diagnosis. Consider performing CFP/FA
Appendix 12; widefield CFP/FA or standard CFP/FA with peripheral sweeps is preferred), SD-OCT, and uveitis lab workup as 
clinically indicated.  Additionally, consider treatment with corticosteroids if appropriate, based on the individual patient 
presentation and comorbidities (e.g., diabetes, systemic hypertension), and consider referring patient to a uveitis specialist 
and/or rheumatologist, per clinical judgment.
h Perform assessment prior to dilating the eyes.
i
Perform slit-lamp examination prior to dilating eyes; for grading scales for anterior chamber flare or cells and vitreous cells, see 
Appendix 5.
j
Aqueous humor sample must be collected from the study eye after pretreatment IOP measurement, but prior to study drug 
administration.  For a detailed description of the anterior chamber paracentesis and aqueous humor sample collection 
procedures, see Appendix 13 and the laboratory manual.
k Both eyes will be dilated prior to ocular imaging. FAF, SD-OCT, OCT-A (as applicable), NI images, and color fundus 
photographs will be obtained from both eyes and will be forwarded to the central reading center.  If a patient misses a study visit 
where ocular images were scheduled to be obtained, the images should be obtained at the next scheduled visit.
l
OCT-A is mandatory for sites that have the capability.
m All assessments (including a detailed examination to evaluate for signs of intraocular inflammation) and sample collection should 
be completed prior to study drug administration, except for post-treatment finger counting and IOP measurement.


Appendix 1:
Schedule of Activities for Q4W Arms
Weeks 100148
FHTR2163—Genentech, Inc.
84/Protocol GR42558, Version 4
n After study drug administration in the study eye only, a finger-counting test, followed by hand motion and light perception tests 
when necessary, will be performed by the investigator within 15 minutes post-study drug injection, followed by an IOP 
measurement that will be obtained 3050 minutes after study drug injection.  If there are no safety concerns, the patient may be 
discharged from the clinic.  If the IOP is increased by 10 mmHg compared with the pre-injection measurement, the IOP will be 
measured again 6080 minutes post-study drug injection. If the IOP value remains a concern to the investigator, the patient will 
remain in the clinic and will be treated as necessary, in accordance with the investigator’s clinical judgment, prior to discharge.
For guidance on adverse event reporting, see Section 5.3.5.2.
o Record any concomitant medications (e.g., prescription drugs, over-the-counter drugs) other than protocol-specified procedural 
medications (e.g., dilating drops, proparacaine) used by a patient in addition to protocol-mandated treatment.
p After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a 
protocol-mandated intervention should be reported. Adverse events will be recorded starting on Day 1 until 28 days after the 
final dose of study drug.  After this period, the Sponsor should be notified if the investigator becomes aware of any serious 
adverse events caused by a protocol-mandated intervention or believed to be related to prior study drug treatment 
(see Section 5.6) and should be reported (see Sections 5.3.1 and 5.4.2 for instructions for reporting serious adverse events).  
Adverse events assessed by the investigator as related to study drug should be followed until the event resolves or the event is 
assessed as irreversible, chronic, or stable, even if patient’s participation in the study has ended.
q Record all concurrent ocular procedures performed on the study or non-study eye.
r
After each study treatment visit, the site must contact the patient 14 (5) days after each treatment visit and query for adverse 
events; particularly any signs or symptoms of decreased visual acuity and/or inflammation (e.g., painful red eye, floaters, 
scotoma, pain); if the patient reports any concerning signs and/or symptoms, the patient must be evaluated by the investigator as 
soon as possible.


FHTR2163—Genentech, Inc.
85/Protocol GR42558, Version 4
Appendix 2
Schedule of Activities for Q8W Arms
Day 1 a
Week (5 days)
UV
ET c
PS b OLE
Treatment Period Visits
FU 
Call
8
16
24
32
40
48
56
64
72
80
88
96
104 112 120 128 136 144
148
Written informed consent
x d
Review inclusion and exclusion 
criteria
x
Medical and surgical history, 
including tobacco history
Ex
Review medical and surgical 
history including tobacco 
history
x
Demographic information
Ex
Physical examination e
x
x f
x
Vital signs g
x
x f
x
Hematology, coagulation, 
lipids, serum chemistry (central 
laboratory) h
Ex
x
x
x
x f
x
Urine pregnancy test i
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x f
Enrollment (IWRS)
x
Plasma sample for biomarkers
Ex
x
x
x
x f
x
Serum ADA sample j
Ex
x
x
x
x
x
x f, j
x
Serum PK sample for drug 
concentration j, n
Ex
x
x
x
x
x
x f, j
x
BCVA testing (starting at 4 m) k
Ex
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
LL BCVA testing (starting at 
4 m) k
Ex
x
x
x
x
x
x
x f
x


Appendix 2:
Schedule of Activities for Q8W Arms
FHTR2163—Genentech, Inc.
86/Protocol GR42558, Version 4
Day 1 a
Week (5 days)
UV
ET c
PS b OLE
Treatment Period Visits
FU 
Call
8
16
24
32
40
48
56
64
72
80
88
96
104 112 120 128 136 144
148
IOP measurement k
Ex
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Slit-lamp examination l
Ex
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Aqueous humor sample m, n
Ex n
x
x
x
x
x
x f
Dilated binocular indirect 
ophthalmoscopy
Ex
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x f
x
FAF o
Ex
x
x
x
x
x
x
x f
x
SD-OCT o
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x f, j
x
OCT-A o, p
Ex
x
x
x
x
x
x
x f
x
NI n
Ex
x
x
x
x
x
x
x f
x
Color fundus photography o
Ex
x
x
x
x f, j
x
Administration of study drug to 
study eye q
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Post-treatment finger counting 
and IOP measurement r
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant medications s
Ex
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events t
Ex
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concurrent ocular procedures u
Ex
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Follow-up call v
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ADAanti-drug antibody; BCVAbest corrected visual acuity; CFPcolor fundus photograph; ET early termination; Ex extracted data (from PS);
FAfluorescein angiography; FAFfundus autofluorescence; FUfollow-up; IOP intraocular pressure; IWRSinteractive web-based response system; 
LL BCVAlow-luminance BCVA; NInear infrared; OCT-Aoptical coherence tomography angiography; OLE open-label extension; 
PKpharmacokinetic; PSparent study; Q8W every 8 weeks; SD-OCT spectral domain optical coherence tomography; UVunscheduled visit.
Notes:  All ocular assessments are to be performed for both eyes unless noted otherwise.


Appendix 2:
Schedule of Activities for Q8W Arms
FHTR2163—Genentech, Inc.
87/Protocol GR42558, Version 4
On treatment days, all assessments and sample collection should be completed prior to study drug administration, except for post-treatment 
finger counting and IOP measurement.
Patients who discontinue study drug prematurely should be strongly encouraged to stay in the study and undergo as many scheduled visits 
as possible.
a The Day 1 visit for the OLE should be performed on the same day as the Week 76 visit for the PS, and all Week 76 assessments must be completed 
prior to conducting Day 1 assessments.  If all assessments for the Day 1 visit cannot be completed on the same day as the Week 76 visit, patients 
may return to the clinic within 28 days to complete the Day 1 visit.  If a patient is not able to complete the Day 1 visit within 28 days, the investigator 
must contact the Medical Monitor for further discussion prior to scheduling the Day 1 visit.
b Data from the PS will be extracted for use in the OLE study. 
c For patients who discontinue early from the study, early termination assessments will be performed after at least 30 days have lapsed following the 
final dose of study drug.
d Informed consent must be documented before any study-specific procedure is performed.
e Includes weight and an evaluation of the head, eyes, ears, nose, throat, and cranial nerves.
f
To be performed if clinically indicated.
g Vital signs consist of respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is in a seated position after resting for 
5 minutes, and temperature.
h For a detailed description of sample collection, see the laboratory manual.
i
Collect and perform urine pregnancy test for women of childbearing potential, including those who have had tubal ligation, at each study treatment 
visit.  If positive, collect a serum pregnancy sample and forward it to central laboratory for testing; if the serum pregnancy test is positive, do not 
administer study drug.
j
In case of Grade 0 non-infectious intraocular inflammation, contact the Medical Monitor to discuss case. An additional serum ADA and PK sample 
should be collected as close as possible to the time of diagnosis. Consider performing CFP/FA (Appendix 12; widefield CFP/FA or standard CFP/FA 
with peripheral sweeps is preferred), SD-OCT, and uveitis lab workup as clinically indicated.  Additionally, consider treatment with corticosteroids if 
appropriate, based on the individual patient presentation and comorbidities (e.g., diabetes, systemic hypertension), and consider referring patient to a 
uveitis specialist and/or rheumatologist, per clinical judgment.
k Perform assessment prior to dilating the eyes.
l
Perform slit-lamp examination prior to dilating eyes; for grading scales for anterior chamber flare or cells and vitreous cells, see Appendix 5.
m Aqueous humor sample must be collected from the study eye after pretreatment IOP measurement, but prior to study drug administration.  For a 
detailed description of the anterior chamber paracentesis and aqueous humor sample collection procedures, see Appendix 13 and the laboratory 
manual.


Appendix 2:
Schedule of Activities for Q8W Arms
FHTR2163—Genentech, Inc.
88/Protocol GR42558, Version 4
n If the Day 1 visit for the OLE is not performed on the same day as the Week 76 visit for the parent study, and serum PK and aqueous humor 
samples were not collected on Week 76, these samples should be collected on Day 1 of OLE study.
o Both eyes will be dilated prior to ocular imaging. FAF, SD-OCT, OCT-A (as applicable), NI images, and color fundus photographs will be obtained 
from both eyes and will be forwarded to the central reading center.  If a patient misses a study visit where ocular images were scheduled to be 
obtained, the images should be obtained at the next scheduled visit.
p OCT-A is mandatory for sites that have the capability.
q All assessments (including a detailed examination to evaluate for signs of intraocular inflammation) and sample collection should be completed prior to 
study drug administration, except for post-treatment finger counting and IOP measurement.
r
In the study eye only, a finger-counting test, followed by hand motion and light perception tests when necessary, will be performed by the investigator 
within 15 minutes after study drug injection, followed by an IOP measurement 3050 minutes after study drug injection.  If there are no safety 
concerns, the patient may be discharged from the clinic.  If the IOP is increased by 10 mmHg compared with the pre-injection measurement, the IOP 
will be measured again 6080 minutes post-study drug injection. If the IOP value remains a concern to the investigator, the patient will remain in the 
clinic and will be treated as necessary, in accordance with the investigator’s clinical judgment, prior to discharge. For guidance on adverse event 
reporting, see Section 5.3.5.2.
s Record any concomitant medications (e.g., prescription drugs, over-the-counter drugs) other than protocol-specified procedural medications 
(e.g., dilating drops, proparacaine) used by a patient in addition to protocol-mandated treatment.
t
Any adverse events ongoing after the Week 76 visit from the PS has been completed should be transcribed to the OLE Adverse Event eCRF.  After 
informed consent has been obtained for the OLE study but prior to initiation of study treatment, only serious adverse events caused by a 
protocol-mandated intervention should be reported. Adverse events will be recorded starting on Day 1 until 28 days after the final dose of study drug.  
After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse events caused by a protocol-mandated 
intervention or believed to be related to prior study drug treatment (see Section 5.6) and should be reported (see Sections 5.3.1 and 5.4.2 for 
instructions for reporting serious adverse events).  Adverse events assessed by the investigator as related to study drug should be followed until the 
event resolves or the event is assessed as irreversible, chronic, or stable, even if patient’s participation in the study has ended.
u Record all concurrent ocular procedures performed on the study or non-study eye.
v After each study treatment visit, the site must contact the patient 14 (5) days after each treatment visit and query for adverse events; particularly any 
signs or symptoms of decreased visual acuity and/or inflammation (e.g., painful red eye, floaters, scotoma, pain); if the patient reports any concerning 
signs and/or symptoms, the patient must be evaluated by the investigator as soon as possible.


FHTR2163—Genentech, Inc.
89/Protocol GR42558, Version 4
Appendix 3
Best Corrected Visual Acuity Testing
SCOPE
Best corrected visual acuity (BCVA) assessment must be conducted before pupil 
dilation.  BCVA will be measured by trained and certified personnel at the study sites.  
The BCVA examiner must be masked to each patient’s study (treated) eye assignment.  
BCVA will be measured at the intervals specified in the protocol (see Appendix 1 and 
Appendix 2 of the protocol and the Clinical Edge Visual Acuity Certification Procedure 
Manual).
EQUIPMENT
The following are needed to conduct the examination:

Examination lane of adequate dimensions to allow testing at required distances

Standard chair with a firm back

Set of three Precision Visionor Lighthouse distance acuity charts (modified Early 
Treatment Diabetic Retinopathy Study Charts R, 1, and 2 in the United States)

Retro-illuminated box

Study frame

Study lens set
TRAINING AND CERTIFICATION
BCVA specifications document, procedure manual, and training materials will be 
provided to the investigational sites, and examiner certification will be obtained.  The 
BCVA examination room also must be certified before any BCVA examinations are 
performed.


FHTR2163—Genentech, Inc.
90/Protocol GR42558, Version 4
Appendix 4
Low-Luminance Best Corrected Visual Acuity Testing
These are the same requirements as the best corrected visual acuity described in 
Appendix 3; however, low-luminance visual acuity will be measured by placing a 
2.0log unit neutral density filter (Kodak Wratten 2.0 neutral density filter) over the best 
correction for the eye and having the participant read the standard illuminated Early 
Treatment Diabetic Retinopathy Study Chart.


FHTR2163—Genentech, Inc.
91/Protocol GR42558, Version 4
Appendix 5
Grading Scale for Assessment of Anterior Chamber Flare or 
Cells and Vitreous Cells
Table 1
Grading Scale for Anterior Chamber Flare or Cells
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)
Cells
Grade
Cells in field a
0
0
0.5
15
1
615
2
1625
3
2650
4
50
a Field size is a 1 mm by 1 mm slit beam.
Table 2
Grading Scale for Vitreous Cells
Grade
Number of Vitreous Cells 
0
0
0.5
110
1
1120
2
2130
3
31100
4
100
REFERENCES
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.  


FHTR2163—Genentech, Inc.
92/Protocol GR42558, Version 4
Appendix 6
Post-Injection Procedures for All Patients
In the study eye only, a finger-counting test, followed by hand motion and light
perception tests when necessary, will be performed by the investigator within 15 minutes 
after study drug injection.
In the study eye only, a measurement of intraocular pressure (IOP) will be obtained 
3050 minutes after study drug injection.  If there are no safety concerns, the patient 
may be discharged from the clinic.  If the IOP is increased by 10 mmHg compared with 
the pre-injection measurement or is of concern to the investigator, the IOP will be 
measured again 6080 minutes post-injection. If the IOP value remains a concern to the 
investigator, the patient will remain in the clinic and will be treated as necessary, in 
accordance with the investigator’s clinical judgment, prior to the patient’s discharge.
As per individual site investigator decision, the investigator may administer anti-microbial 
drops after study drug injection.  The individual site investigator may also instruct 
patients to self-administer anti-microbial drops before and after each injection.


FHTR2163—Genentech, Inc.
93/Protocol GR42558, Version 4
Appendix 7
Color Fundus Photography
SCOPE
Non-stereo color fundus photographs will be taken by trained personnel at the study 
sites.  Fundus photography will be performed at the intervals specified in the protocol 
(see Appendix 1 and Appendix 2).
EQUIPMENT
Equipment used during this study is described in the Central Reading Center Manual.
PROCEDURES AND CERTIFICATION
The central reading center will provide a study manual and training materials.  The 
fundus photographer and photography equipment will be certified by the reading center 
before any study images are taken.  See the Central Reading Center Manual for further 
details.


FHTR2163—Genentech, Inc.
94/Protocol GR42558, Version 4
Appendix 8
Fundus Autofluorescence
SCOPE
Fundus autofluorescence (FAF) will be performed at the study sites by trained personnel
who are certified by the central reading center.  FAF imaging will be performed for each 
patient at the intervals specified in the protocol (see Appendix 1 and Appendix 2) and will 
be forwarded to the central reading center.
EQUIPMENT
Equipment used during this study is described in the Central Reading Center Manual.  
The ability to transfer images to electronically exportable digital files is required (i.e., no 
printed FAF images will be sent to the central reading center).
PROCEDURES AND CERTIFICATION
The central reading center will provide a study manual and training materials.  
FAF operators, systems, and software will be certified prior to any evaluation of patients.  
See the Central Reading Center Manual for further details.


FHTR2163—Genentech, Inc.
95/Protocol GR42558, Version 4
Appendix 9
Near Infrared Imaging
SCOPE
Near infrared (NI) imaging will be performed at the study sites by trained personnel who 
are certified by the central reading center.  NI imaging will be performed for each patient 
at the intervals specified in the protocol (see Appendix 1 and Appendix 2).
The NI images of both eyes will be obtained at protocol-specified visits and will be 
forwarded to the central reading center.
EQUIPMENT
Equipment used during this study is described in the Central Reading Center Manual.  
The ability to transfer images to electronically exportable digital files is required 
(i.e., no printed NI images will be sent to the central reading center).
PROCEDURES AND CERTIFICATION
The central reading center will provide the study manual and training materials.  
NI operators, systems, and software will be certified prior to any evaluation of patients.


FHTR2163—Genentech, Inc.
96/Protocol GR42558, Version 4
Appendix 10
Spectral Domain Optical Coherence Tomography
SCOPE
Spectral domain optical coherence tomography (SD-OCT) will be performed at the study 
sites by trained personnel who are certified by the central reading center.  SD-OCT 
imaging will be performed for each patient at the intervals specified in the protocol 
(see Appendix 1 and Appendix 2).
The SD-OCT images of both eyes will be obtained at protocol-specified visits and will be 
forwarded to the central reading center.
EQUIPMENT
Equipment used during this study is described in the Central Reading Center Manual.  
The SD-OCT equipment used for a patient must remain consistent throughout the study.  
The ability to transfer images to electronically exportable digital files is required 
(i.e., no printed SD-OCT images will be sent to the central reading center).
PROCEDURES AND CERTIFICATION
The central reading center will provide the study manual and training materials.  
SD-OCT operators, systems, and software will be certified prior to any evaluation 
of patients.


FHTR2163—Genentech, Inc.
97/Protocol GR42558, Version 4
Appendix 11
Optical Coherence Tomography Angiography
SCOPE
Optical coherence tomography angiography (OCT-A) will be performed at the study sites 
with this capability by trained personnel who are certified by the central reading center.  
OCT-A imaging will be performed for each patient at the intervals specified in the 
protocol (see Appendix 1 and Appendix 2).
The OCT-A images of both eyes will be obtained at protocol-specified visits and will be 
forwarded to the central reading center.
EQUIPMENT
Equipment used during this study is described in the Central Reading Center Manual.  
The ability to transfer images to electronically exportable digital files is required 
(i.e., no printed OCT-A images will be sent to the central reading center).
PROCEDURES AND CERTIFICATION
The central reading center will provide the study manual and training materials.  OCT-A 
operators, systems, and software will be certified prior to any evaluation of patients.


FHTR2163—Genentech, Inc.
98/Protocol GR42558, Version 4
Appendix 12
Fluorescein Angiography
SCOPE
Fluorescein angiography (FA) will be performed at the study sites by trained personnel, 
when non-infectious intraocular inflammation is suspected and investigator considers it 
as an important part of the diagnostic work-up.  Analysis (if applicable) will be performed 
by the central reading center.
EQUIPMENT AND DIGITAL IMAGING SYSTEMS
Digital angiograms must be used while conducting an angiographic evaluation for the 
study.  Widefield FA or standard FA with peripheral sweeps is preferred, if available.
Film-based angiography is not acceptable.
PROCEDURES
Refer to the Central Reading Center Manual for details.


FHTR2163—Genentech, Inc.
99/Protocol GR42558, Version 4
Appendix 13
Anterior Chamber Paracentesis and Aqueous Humor Sampling 
Procedures
An aqueous humor sample will be collected from the study eye after pretreatment 
intraocular pressure measurement, but prior to study drug administration, as indicated in
Appendix 1 and Appendix 2.  The anterior chamber paracentesis will be performed by a 
qualified physician by placing a drop of topical anesthetic on the cornea, passing a 
needle through the limbus into the anterior chamber, and removing approximately 
100 L of aqueous fluid and more volume, if possible without endangering patient safety
at applicable patient visits.  Samples will be collected with the kit provided by the central 
laboratory and shipped on dry ice to the central laboratory as soon as possible after the 
draw.
The following procedures will be used to minimize the risk of potential adverse events 
associated with aqueous humor sampling (e.g., endophthalmitis, corneal abscess, 
hyphema, cornea, lens, iris trauma).
Aseptic technique will be performed by clinic staff involved in the aqueous humor 
collection tray assembly, anesthetic preparation, and aqueous humor sample collection.  
In addition to the procedures outlined below, any additional safety measures in 
adherence to specific institutional policies associated with aqueous humor sample 
collection will be observed. 
As per individual site investigator decision, patients may self-administer anti-microbial 
drops prior to and after aqueous humor sample collection.
Prepare a sterile field that includes the following supplies:

10% povidone iodine swabs

Sterile surgical gloves

44 sterile pads

0.5% proparacaine hydrochloride

5% povidone iodine ophthalmic solution

1-cc syringe 

27- or 30-gauge needle, 0.5 inches in length

Sterile saline solution

Per individual investigator discretion:
Sterile cotton-tipped applicators
Eyelid speculum
Sterile ophthalmic drape
Surgical face mask


Appendix 13:
Anterior Chamber Paracentesis and Aqueous Humor 
Sampling Procedures
FHTR2163—Genentech, Inc.
100/Protocol GR42558, Version 4
Aqueous humor sampling should be performed using an aseptic procedure and sterile 
field as follows:

Instill two drops of 0.5% proparacaine hydrochloride into the study eye

Wait 90 seconds 

As per individual investigator discretion, instill two drops of anti-microbial drops

Wait 5 minutes (only if anti-microbial drops are used) 

Instill two drops of 5% povidone iodine ophthalmic solution in the study eye

Disinfect the peri-ocular skin and eyelid of the study eye 
Scrub the eyelid, lashes, and peri-orbital skin with 10% povidone-iodine 
swabs, starting with the eyelid and lashes and continuing with the 
surrounding peri-ocular skin.  Ensure that the eyelid margins and lashes are 
swabbed, and proceed in a systematic fashion from medial to temporal 
aspects.

Instill two additional drops of 5% povidone iodine ophthalmic solution in the 
study eye

After washing hands, put on sterile gloves

Per investigator discretion, the investigator may place sterile ophthalmic drape to 
isolate the field and place the speculum underneath the eyelid of the study eye

Collect the aqueous humor sample (approximately 100 L) using the 27- or 
30-gauge needle attached to the 1-cc syringe through a paracentesis inserted at the 
temporal paralimbal clear cornea on a horizontal angle in a plane above and parallel 
to the iris with the bevel of the needle facing away from the iris, paying strict 
attention to avoid contact with the patient’s eyelashes, lens, or iris.
NOTE:  The investigator and patient should refrain from talking, coughing, or 
sneezing during the aqueous sample collection.  A surgical face mask may 
be worn per investigator discretion.

Dispense collected aqueous humor into the appropriately labeled collection tube 
provided and store frozen until shipped as described in the laboratory manual

As per individual site investigator decision, patients may self-administer 
anti-microbial drops prior to and after aqueous humor sample collection


FHTR2163—Genentech, Inc.
101/Protocol GR42558, Version 4
Appendix 14
WHO Toxicity Grading Scale for Determining the Severity of 
Adverse Events
ITEM
Grade 1 Toxicity Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
HEMATOLOGY
Hemoglobin
9.510.5 g/dL
8.09.4 g/dL
6.57.9 g/dL
6.5 g/dL
Absolute Neutrophil 
Count
10001500/mm3
750999/mm3
500749/mm3
500/mm3
Platelets
75,00099,000/mm3 50,00074,999/mm3
20,00049,000/mm3
20,000/mm3
Prothrombin Time 
(PT)
1.011.25ULN
1.261.5ULN
1.513.0ULN
3ULN
Activated Partial 
Thromboplastin 
(aPTT)
1.011.66ULN
1.672.33ULN
2.343ULN
3ULN
Fibrinogen
0.750.99LLN
0.500.74LLN
0.250.49LLN
0.25LLN
Fibrin Split Product
2040 g/mL
4150 g/mL
5160 g/mL
60 g/mL
Methemoglobin
5%9.9%
10.0%14.9%
15.0%19.9%
20%
LIVER ENZYMES
AST (SGOT)
1.252.5ULN
2.65ULN
5.110ULN
10ULN
ALT (SGPT)
1.252.5ULN
2.65ULN
5.110ULN
10ULN
GGT
1.252.5ULN
1.65ULN
5.110ULN
10ULN
Alkaline 
Phosphatase
1.252.5ULN
1.65ULN
5.110ULN
10ULN
Amylase
1.11.5ULN
1.62.0ULN
2.15.0ULN
5.1ULN
CHEMISTRIES
Hyponatremia
130135 mEq/L
123129 mEq/L
116122 mEq/L
116 or mental status 
changes or seizures
Hypernatremia
146150 mEq/L
151157 mEq/L
158165 mEq/L
165 mEq/L or mental 
status changes or 
seizures
Hypokalemia
3.03.4 mEq/L
2.52.9 mEq/L
2.02.4 mEq/L or 
intensive replacement 
Rx required or 
hospitalization 
required
2.0 mEq/L or paresis 
or ileus or 
life-threatening 
arrhythmia
Hyperkalemia
5.66.0 mEq/L
6.16.5 mEq/L
6.67.0 mEq/L
7.0 mEq/L or 
life-threatening 
arrhythmia
Hypoglycemia
5564 mg/dL
4054 mg/dL
3039 mg/dL
30 mg/dL or mental 
status changes or coma


Appendix 14:
WHO Toxicity Grading Scale for Determining the Severity of 
Adverse Events
FHTR2163—Genentech, Inc.
102/Protocol GR42558, Version 4
ITEM
Grade 1 Toxicity Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
CHEMISTRIES (cont.)
Hyperglycemia
(note if fasting)
116160 mg/dL
161250 mg/dL
251500 mg/dL
500 mg/dL or 
ketoacidosis or seizures
Hypocalcemia
(corrected for 
albumin)
8.47.8 mg/dL
7.77.0 mg/dL
6.96.1 mg/dL
6.1 mg/dL or 
life-threatening 
arrhythmia or tetany
Hypercalcemia
(corrected for 
albumin)
10.611.5 mg/dL
11.612.5 mg/dL
12.613.5 mg/dL
13.5 mg/dL or 
life-threatening 
arrhythmia
Hypomagnesemia
1.41.2 mEq/L
1.10.9 mEq/L
0.80.6 mEq/L
0.6 mEq/L or 
life-threatening 
arrhythmia
Hypophosphatemia
2.02.4 mg/dL
1.51.9 mg/dL or 
replacement Rx 
required
1.01.4 mg/dL 
intensive Rx or 
hospitalization 
required
1.0 mg/dL or 
life-threatening 
arrhythmia
Hyperbilirubinemia
1.11.5ULN
1.62.5ULN
2.65ULN
5ULN
BUN
1.252.5ULN
2.65ULN
5.110ULN
10ULN
Creatinine
1.11.5ULN
1.63.0ULN
3.16ULN
6ULN or required 
dialysis
URINALYSIS
Proteinuria
1or 0.3% or 
3 g/L or 
200 mg1 g
loss/day
23or 0.3%1.0% 
or 310 g/L or
12 g loss/day
4or 1.0% or 
10 g/L or
23.5 g loss/day
nephrotic syndrome or 
3.5 g loss/day
Hematuria
Microscopic only
Gross, no clots
Gross clots
Obstructive or required 
transfusion
CARDIAC DYSFUNCTION
Cardiac Rhythm
Asymptomatic, 
transient signs, no 
Rx required
Recurrent/persistent, 
no Rx required
Requires treatment
Hypertension
Transient increase,
20 mm, no Rx
Recurrent, chronic, 
20 mm,
Rx required
Requires acute Rx,
no hospitalization
Requires 
hospitalization
Hypotension
Transient 
orthostatic 
hypotension, no Rx
Symptoms 
correctable with 
oral fluids, Rx
Requires IV fluids,
no hospitalization 
required
Requires 
hospitalization
Pericarditis
Minimal effusion
Mild/moderate 
asymptomatic 
effusion, no Rx
Symptomatic effusion, 
pain, ECG changes
Tamponade, 
pericardiocentesis, or 
surgery required


Appendix 14:
WHO Toxicity Grading Scale for Determining the Severity of 
Adverse Events
FHTR2163—Genentech, Inc.
103/Protocol GR42558, Version 4
ITEM
Grade 1 Toxicity Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
CARDIAC DYSFUNCTION (cont.)
Hemorrhage, Blood 
Loss
Microscopic/occult
Mild, no transfusion
Gross blood loss,
12 units transfused
Massive blood loss,
3 units transfused
RESPIRATORY
Cough
Transient, no Rx
Treatment 
associated cough,
local Rx
Uncontrolled
Bronchospasm, 
Acute
Transient, no Rx
80%70% FEV1
(or peak flow)
Requires Rx, 
normalizes with 
bronchodilator,
FEV1 50%70% 
(or peak Flow)
No normalization 
with bronchodilator,
FEV1 25%50% 
(or peak flow 
retractions)
Cyanosis: FEV1 25%
(or peak flow) or 
intubated
GASTROINTESTINAL
Stomatitis
Mild discomfort, no 
limits on activity
Some limits on 
eating/drinking
Eating/talking very 
limited
Requires IV fluids
Nausea
Mild discomfort,
maintains 
reasonable intake
Moderate discomfort,
intake decreased 
significantly, some 
activity limited
Severe discomfort, 
no significant intake,
activities limited
Minimal fluid intake
Vomiting
Transient emesis
Occasional/moderate 
vomiting
Orthostatic 
hypotension or IV 
fluids required
Hypotensive shock or 
hospitalization required 
for IV fluid therapy
Constipation
Mild
Moderate
Severe
Distensions w/vomiting
Diarrhea
Transient, 34 
loose stools/day
57 loose
stools/day
Orthostatic 
hypotension or 
7 loose stools/day or 
IV fluids required
Hypotensive shock 
or hospitalization for 
IV fluid therapy
required
NEURO & NEUROMUSCULAR
Neuro-cerebellar
Slight 
incoordination,
dysdiadochokinesis
Intention tremor, 
dysmetria, slurred 
speech, nystagmus
Locomotor ataxia
Incapacitated
Mood
Mild anxiety or 
depression
Moderate anxiety or 
depression and 
therapy required
Severe anxiety or 
depression or mania,
needs assistance
Acute psychosis,
incapacitated, requires 
hospitalization
Neuro Control
Mild difficulty 
concentrating, no 
Rx, mild 
confusion/agitation,
ADLs unaffected
Moderate 
confusion/agitation,
some limitation of 
ADLs, minimal Rx
Severe 
confusion/agitation,
needs assistance 
for ADLs, therapy 
required
Toxic psychosis,
requires hospitalization


Appendix 14:
WHO Toxicity Grading Scale for Determining the Severity of 
Adverse Events
FHTR2163—Genentech, Inc.
104/Protocol GR42558, Version 4
ITEM
Grade 1 Toxicity Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
NEURO & NEUROMUSCULAR (cont.)
Muscle Strength
Subjective 
weakness, no 
objective 
symptoms/signs
Mild objective 
signs/symptoms,
no decrease in 
function
Objective weakness,
function limited
Paralysis
OTHER PARAMETERS
Fever: Oral, 
12 hours
37.7C38.5C or
100.0F101.5F
38.6C39.5C or
101.6F102.9F
39.6C40.5C or
103F105F
40.5C or
105F
Headache
Mild, 
no Rx therapy
Transient, 
moderate, 
Rx required
Severe,
responds to initial 
narcotic therapy
Intractable,
required repeated 
narcotic therapy
Fatigue
No decrease 
in ADLs
Normal activity 
decreased 
25%50%
Normal activity 
decreased 50%,
cannot work
Unable to care for self
Allergic Reaction
Pruritus without 
rash
Localized urticaria
Generalized urticaria,
angioedema
Anaphylaxis
Local Reaction
Tenderness or 
erythema
Induration 10 cm 
or phlebitis or 
inflammation
Induration 10 cm 
or ulceration
Necrosis
Mucocutaneous
Erythema, pruritus
Diffuse, 
maculopapular 
rash, dry 
desquamation
Vesiculation, moist 
desquamation, or 
ulceration
Exfoliative dermatitis, 
mucous membrane 
involvement or 
erythema, multiforme or 
suspected 
Stevens-Johnson or 
necrosis requiring 
surgery
ADLs activities of daily living; FEV1forced expiratory volume in 1 second; GGTgamma-glutamyl 
transferase; LLNlower limit of normal; Rx prescription; ULNupper limit of normal.