Clinical trial NCT03677934
Conditions: Neovascular Age-Related Macular Degeneration
Sponsor: Hoffmann-La Roche
Start date: 2018-09-12; Completion date: 2021-06-09
Enrollment: 415 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study GR40548 is a Phase III, randomized, multicenter, open-label (visual assessor \[VA\]-masked), active-comparator study designed to assess the efficacy, safety, and pharmacokinetics (PK) of 100mg/ml delivered via the Port Delivery System with ranibizumab (PDS) compared with ranibizumab intravitreal injections at 0.5 mg (10 mg/mL) in participants with neovascular age-related macular degeneration (nAMD).

Detailed description:

Arms: arm 1: Participants will receive ranibizumab delivered through the PDS implant with 100 mg/mL in the study eye on Day 1 and receive refill-exchanges at fixed 24-week intervals arm 2: Participants will receive ranibizumab 0.5 mg monthly intravitreal injections of 10 mg/mL formulation at Day 1 and every month thereafter.
Interventions: intervention 1: PDS Implant filled with 100 mg/mL Ranibizumab intervention 2: Intravitreal Injections of 10 mg/mL Ranibizumab
Intervention descriptions: intervention 1: Will be administered as per the schedule described in individual arm. intervention 2: Will be administered as per the schedule described in individual arm.

Protocol documents:
Prot_000.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
Protocol GR40548, Version 5
PROTOCOL
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, 
VISUAL ASSESSORMASKED, 
ACTIVE-COMPARATOR STUDY OF THE 
EFFICACY, SAFETY, AND PHARMACOKINETICS 
OF THE PORT DELIVERY SYSTEM WITH 
RANIBIZUMAB IN PATIENTS WITH 
NEOVASCULAR AGE-RELATED MACULAR 
DEGENERATION (ARCHWAY)
PROTOCOL NUMBER:
GR40548
VERSION NUMBER:
5
EUDRACT NUMBER:
Not applicable
IND NUMBER:
113,552
NCT NUMBER
NCT03677934
TEST PRODUCT:
Port Delivery System with ranibizumab
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd.
APPROVAL DATE:
See electronic date stamp below.
02-Feb-2021 17:50:26
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
2/Protocol GR40548, Version 5
PROTOCOL HISTORY
Protocol
Version
Date Final
4
16 June 2020
3
18 December 2019
2
29 July 2019
1
31 May 2018


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
3/Protocol GR40548, Version 5
PROTOCOL AMENDMENT, VERSION 5:
RATIONALE
Protocol GR40548 (Archway) has been amended to add “Device Dislocation” as an 
ocular Adverse Event of Special Interest (AESI).
Additional changes to the protocol, along with a rationale for each change, are 
summarized below:

Administration schedule for self-administered antimicrobial and/or anti-
inflammatory ophthalmic drops before and after the Port Delivery System with 
ranibizumab (PDS) procedures have been updated (Section 5.1.1 and Appendix 
17).

Section 5.1.2 (Risks associated with intravitreal ranibizumab injection) has been 
updated per the latest Investigator Brochure.

Device dislocation has been added to the list of anticipated risks associated with 
the PDS implant and/or implant insertion procedure (Section 5.1.3.7). In addition, 
language updates have been made to the other anticipated risks (vitreous 
hemorrhage, conjunctival bleb, conjunctival erosion, conjunctival retraction, 
rhegmatogenous retinal detachment, endophthalmitis) (Sections 5.1.3.1 
to 5.1.3.6)

Study treatment dose interruption criteria for local or systemic infection have 
been updated (Section 5.1.5.2, Table 2).

The statistical method to evaluate the secondary efficacy objective "proportion of 
patients who undergo supplemental treatment" was modified in order to more 
accurately reflect the number of patients receiving supplemental treatment 
among those able to be assessed for the need for supplemental treatment
(Section 6.4.2).

Instructions on the management of device dislocation have been added 
(Section 5.1.5.8, Table 7) and recommended management of patients with 
vitreous hemorrhage, conjunctival retraction or conjunctival erosion, conjunctival 
bleb, endophthalmitis instructions have been updated (Sections 5.1.5.4 
to 5.1.5.7).

The names and contact information of the primary and secondary Medical 
Monitors have been updated (Section 5.4.1).

Language has been added to clarify that adverse events associated with a 
special situation that also qualify as adverse events of special interest should be 
reported within 24 hours (Section 5.3.5.12).


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
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
Language has been added to indicate that the Informed Consent Form instructs
female patients to inform the investigator if they become pregnant (Section 
5.4.3.1).

The name of a Roche policy on data sharing has been corrected (Section 9.6).
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
5/Protocol GR40548, Version 5
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 13
PROTOCOL SYNOPSIS .................................................................................... 14
1.
BACKGROUND .......................................................................................... 26
1.1
Background on Age-Related Macular 
Degeneration......................................................................... 26
1.1.1
Pathophysiology of Age-Related Macular 
Degeneration......................................................................... 26
1.1.2
Treatment for Neovascular Age-Related Macular 
Degeneration......................................................................... 26
1.2
Background on Ranibizumab................................................. 27
1.3
Background on the Port Delivery System with 
Ranibizumab.......................................................................... 28
1.3.1
Phase I Port Delivery System with Ranibizumab 
Study:  FH-1.2 ....................................................................... 28
1.3.2
Phase II Port Delivery System with Ranibizumab:  
Study GX28228 (Ladder)....................................................... 29
1.4
Study Rationale and BenefitRisk Assessment..................... 30
2.
OBJECTIVES AND ENDPOINTS ............................................................... 31
3.
STUDY DESIGN......................................................................................... 35
3.1
Description of the Study......................................................... 35
3.2
Internal Safety Monitoring...................................................... 47
3.3
Independent Data Monitoring Committee .............................. 47
3.4
End of Study and Length of Study......................................... 47
3.5
Rationale for Study Design.................................................... 47
3.5.1
Rationale for Ranibizumab Dose and Schedule .................... 48
3.5.2
Rationale for Patient Population ............................................ 48
3.5.3
Rationale for Control Group................................................... 48
3.5.4
Rationale for Pharmacokinetic Sample Collection 
Schedule................................................................................ 49
3.5.5
Rationale for Immunogenicity Sample Collection .................. 49
3.5.6
Rationale for Biomarker Assessments................................... 49
4.
MATERIALS AND METHODS .................................................................... 50


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
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4.1
Patients.................................................................................. 50
4.1.1
Inclusion Criteria.................................................................... 50
4.1.1.1
General Inclusion Criteria ...................................................... 50
4.1.1.2
Ocular Inclusion Criteria ........................................................ 51
4.1.2
Exclusion Criteria................................................................... 51
4.1.2.1
Prior Ocular Treatment .......................................................... 51
4.1.2.2
CNV Lesion Characteristics................................................... 52
4.1.2.3
Concurrent Ocular Conditions ............................................... 52
4.1.2.4
Concurrent Systemic Conditions ........................................... 53
4.2
Method of Treatment Assignment and Masking .................... 54
4.2.1
Randomization and Masking ................................................. 54
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 55
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 55
4.3.1.1
Port Delivery System with Ranibizumab................................ 55
4.3.1.2
Formulation of Ranibizumab 100 mg/mL Used to 
Fill or Refill-Exchange the Implant......................................... 55
4.3.1.3
Formulation of Intravitreal Ranibizumab 10 
mg/mL.................................................................................... 56
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 56
4.3.2.1
Port Delivery System with Ranibizumab................................ 56
4.3.2.2
Ranibizumab Intravitreal Injection.......................................... 57
4.3.3
Investigational Medicinal Product Accountability ................... 57
4.3.4
Continued Access to Port Delivery System with 
Ranibizumab.......................................................................... 58
4.4
Concomitant Therapy ............................................................ 59
4.4.1
Permitted Therapy................................................................. 59
4.4.2
Prohibited Therapy ................................................................ 60
4.5
Study Assessments ............................................................... 61
4.5.1
Informed Consent Forms and Screening Log........................ 61
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 61
4.5.3
Height and Weight................................................................. 61


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4.5.4
Vital Signs.............................................................................. 61
4.5.5
Ocular Assessments.............................................................. 62
4.5.6
Ocular Imaging ...................................................................... 62
4.5.7
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 64
4.5.8
Patient Preference and Treatment Satisfaction ..................... 66
4.5.8.1
Port Delivery System Patient Preference 
Questionnaire ........................................................................ 66
4.5.8.2
Macular Degeneration Treatment Satisfaction 
Questionnaire ........................................................................ 66
4.5.9
Video Recording of Implant Insertion, Refill-
Exchange, and Explantation Procedures............................... 66
4.5.10
Optional Samples for Research Biosample 
Repository ............................................................................. 66
4.5.10.1
Overview of the Research Biosample Repository.................. 66
4.5.10.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 67
4.5.10.3
Sample Collection.................................................................. 67
4.5.10.4
Confidentiality........................................................................ 68
4.5.10.5
Consent to Participate in the Research 
Biosample Repository............................................................ 69
4.5.10.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 69
4.5.10.7
Monitoring and Oversight....................................................... 69
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 70
4.6.1
Study Treatment Discontinuation........................................... 70
4.6.2
Patient Discontinuation from Study........................................ 71
4.6.3
Study Discontinuation............................................................ 72
4.6.4
Site Discontinuation............................................................... 72
5.
ASSESSMENT OF SAFETY....................................................................... 72
5.1
Safety Plan ............................................................................ 72
5.1.1
Safety Assessments .............................................................. 73
5.1.2
Risks Associated with Intravitreal Ranibizumab 
Injection ................................................................................. 75
5.1.2.1
Increased Intraocular Pressure.............................................. 75




Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
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5.1.5.8
Recommended Management of Device 
Dislocation............................................................................. 86
5.2
Safety Parameters and Definitions ........................................ 87
5.2.1
Adverse Events ..................................................................... 87
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 87
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 88
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 89
5.3.1
Adverse Event Reporting Period ........................................... 90
5.3.2
Eliciting Adverse Event Information....................................... 90
5.3.3
Assessment of Severity of Adverse Events ........................... 90
5.3.4
Assessment of Causality of Adverse Events ......................... 90
5.3.5
Procedures for Recording Adverse Events............................ 92
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 93
5.3.5.2
Adverse Events That Are Secondary to Other 
Events.................................................................................... 93
5.3.5.3
Persistent or Recurrent Adverse Events................................ 93
5.3.5.4
Abnormal Laboratory Values ................................................. 94
5.3.5.5
Abnormal Vital Sign Values ................................................... 94
5.3.5.6
Abnormal Liver Function Tests.............................................. 95
5.3.5.7
Deaths ................................................................................... 95
5.3.5.8
Preexisting Medical Conditions.............................................. 96
5.3.5.9
Worsening of Neovascular Age-Related Macular 
Degeneration......................................................................... 96
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 96
5.3.5.11
Patient-Reported Questionnaire and Outcomes 
Data....................................................................................... 97
5.3.5.12
Reporting Requirements for Cases of Accidental 
Overdose or Medication Error................................................ 97
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 98
5.4.1
Emergency Medical Contacts................................................ 99
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 99


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
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5.4.2.1
Events That Occur Prior to Study Drug Initiation ................... 99
5.4.2.2
Events That Occur After Study Drug Initiation ....................... 99
5.4.3
Reporting Requirements for Pregnancies............................ 100
5.4.3.1
Pregnancies in Female Patients.......................................... 100
5.4.3.2
Abortions ............................................................................. 100
5.4.3.3
Congenital Anomalies/Birth Defects .................................... 101
5.4.4
Reporting Requirements for Medical Device 
Complaints........................................................................... 101
5.4.4.1
Device Defects or Deficiencies That Could Have 
Led to Medical Occurrence.................................................. 101
5.5
Follow-Up of Patients after Adverse Events ........................ 102
5.5.1
Investigator Follow-Up......................................................... 102
5.5.2
Sponsor Follow-Up .............................................................. 102
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 102
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 102
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 103
6.1
Determination of Sample Size ............................................. 103
6.2
Summaries of Conduct of Study.......................................... 104
6.3
Summaries of Demographic and Baseline 
Characteristics..................................................................... 104
6.4
Efficacy Analyses ................................................................ 104
6.4.1
Primary Efficacy Endpoint.................................................... 105
6.4.2
Secondary Efficacy Endpoints............................................. 108
6.4.3
Exploratory Endpoints.......................................................... 109
6.5
Safety Analyses................................................................... 109
6.5.1
Adverse Events ................................................................... 109
6.5.2
Ocular Assessments............................................................ 110
6.6
Pharmacokinetic Analyses................................................... 110
6.7
Immunogenicity Analyses.................................................... 111
6.8
Exploratory Biomarker Analyses.......................................... 111
7.
DATA COLLECTION AND MANAGEMENT ............................................. 112


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
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7.1
Data Quality Assurance....................................................... 112
7.2
Electronic Case Report Forms............................................. 112
7.3
Source Data Documentation................................................ 113
7.4
Use of Computerized Systems ............................................ 113
7.5
Retention of Records........................................................... 114
8.
ETHICAL CONSIDERATIONS.................................................................. 114
8.1
Compliance with Laws and Regulations .............................. 114
8.2
Informed Consent................................................................ 114
8.3
Institutional Review Board or Ethics Committee.................. 115
8.4
Confidentiality...................................................................... 116
8.5
Financial Disclosure ............................................................ 117
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 117
9.1
Study Documentation .......................................................... 117
9.2
Protocol Deviations.............................................................. 117
9.3
Management of Study Quality ............................................. 117
9.4
Site Inspections ................................................................... 118
9.5
Administrative Structure....................................................... 118
9.6
Dissemination of Data and Protection of 
Trade Secrets...................................................................... 118
9.7
Protocol Amendments ......................................................... 119
10. REFERENCES ......................................................................................... 120
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 31
Table 2
Dosing Guidelines during Run-in Period and at Screening 
Visit ............................................................................................. 40
Table 3
Scenarios for Archway Week 96 and Portal Enrollment Visits .... 44
Table 4
Dose Interruption, Study Treatment Discontinuation, or Study 
Discontinuation Criteria............................................................... 80
Table 5
Recommended Management of Cases of Vitreous 
Hemorrhage................................................................................ 82
Table 6
Recommended Management of Patients with Conjunctival 
Retraction or Conjunctival Erosion.............................................. 83


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Table 7
Recommended Management of Patients with Conjunctival 
Bleb............................................................................................. 84
Table 8
Recommended Management of Patients with 
Endophthalmitis .......................................................................... 85
Table 9
Recommended Management of Patients with Device 
Dislocation .................................................................................. 86
Table 10
Adverse Event Severity Grading Scale ....................................... 90
Table 11
Causal Attribution Guidance ....................................................... 92
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 36
LIST OF APPENDICES
Appendix 1 
Schedule of Activities: Implant Arm........................................... 123
Appendix 2
Schedule of Activities: Intravitreal Arm...................................... 137
Appendix 3 
Run-In Visits (If Applicable)....................................................... 147
Appendix 4
Unscheduled Safety Assessment Visits, Post-Study 
Treatment Discontinuation Visits, or Post-Explantation Safety 
Visits ......................................................................................... 149
Appendix 5
Additional Assessments if Supplemental  Treatment Criteria 
Are Met ..................................................................................... 150
Appendix 6
Best-Corrected Visual Acuity Testing........................................ 151
Appendix 7
Grading Scales for Anterior Chamber Flare or Cells and 
Vitreous Cells............................................................................ 152
Appendix 8
Grading Scales for Vitreous Hemorrhage ................................. 154
Appendix 9
Fundus Autofluorescence ......................................................... 155
Appendix 10
Fundus Photography................................................................. 156
Appendix 11
Fluorescein Angiography .......................................................... 157
Appendix 12
Spectral Domain Optical Coherence Tomography.................... 158
Appendix 13
Implant Photographs................................................................. 159
Appendix 14
Optical Coherence Tomography Angiography (at Selected 
Sites)......................................................................................... 160
Appendix 15
Sample Collection and Shipping ............................................... 161
Appendix 16
Port Delivery System with Ranibizumab ................................... 163
Appendix 17
Topical Antimicrobial and Anti-Inflammatory Ophthalmic 
Drops Administration Schedule................................................. 165


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
13/Protocol GR40548, Version 5
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, 
VISUAL ASSESSORMASKED, 
ACTIVE-COMPARATOR STUDY OF THE 
EFFICACY, SAFETY, AND PHARMACOKINETICS 
OF THE PORT DELIVERY SYSTEM WITH 
RANIBIZUMAB IN PATIENTS WITH 
NEOVASCULAR AGE-RELATED MACULAR 
DEGENERATION (ARCHWAY)
PROTOCOL NUMBER:
GR40548
VERSION NUMBER:
5
EUDRACT NUMBER:
Not applicable
IND NUMBER:
113,552
NCT NUMBER:
NCT03677934
TEST PRODUCT:
Port Delivery System with ranibizumab
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of the 
signed form to your local study monitor.


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
14/Protocol GR40548, Version 5
PROTOCOL SYNOPSIS
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, VISUAL 
ASSESSORMASKED, ACTIVE-COMPARATOR STUDY OF THE 
EFFICACY, SAFETY, AND PHARMACOKINETICS OF THE PORT 
DELIVERY SYSTEM WITH RANIBIZUMAB IN PATIENTS WITH 
NEOVASCULAR AGE-RELATED MACULAR DEGENERATION
(ARCHWAY)
PROTOCOL NUMBER:
GR40548
VERSION NUMBER:
5
EUDRACT NUMBER:
Not applicable
IND NUMBER:
113,552
NCT NUMBER:
NCT03677934
TEST PRODUCT:
Port Delivery System with ranibizumab 
PHASE:
Phase III 
INDICATION:
Neovascular age-related macular degeneration
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, and pharmacokinetics of ranibizumab delivered via
the Port Delivery System with ranibizumab (PDS) implant compared with ranibizumab 0.5 mg 
delivered as a monthly intravitreal injection in patients with neovascular age-related macular 
degeneration (nAMD).  Specific objectives and corresponding endpoints for the study are 
outlined below.
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the non-inferiority and 
equivalence in efficacy of ranibizumab 
delivered via the PDS Q24W with the 
100-mg/mL formulation compared with that 
of 10-mg/mL (0.5-mg dose) Q4W intravitreal
ranibizumab injections 
Change from baseline in BCVA score at the average of 
Week 36 and Week 40, as assessed using the ETDRS
visual acuity chart at a starting distance of 4 meters


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15/Protocol GR40548, Version 5
Secondary Efficacy Objectives
Corresponding Endpoints
To evaluate the relative efficacy of 
ranibizumab delivered via the PDS Q24W 
with the 100-mg/mL formulation compared 
with that of 10-mg/mL (0.5-mg dose) Q4W 
intravitreal ranibizumab injections, as 
assessed by visual acuity
Change from baseline in BCVA score averaged over Week 
60 and Week 64 
Change from baseline in BCVA score over time 
Proportion of patients with BCVA score of 38 letters (20/200 
approximate Snellen equivalent) or worse at the average 
over Week 36 and Week 40
Proportion of patients with BCVA score of 38 letters (20/200 
approximate Snellen equivalent) or worse over time
Proportion of patients with BCVA score of 69 letters (20/40 
approximate Snellen equivalent) or better at the average 
over Week 36 and Week 40
Proportion of patients with BCVA score of 69 letters (20/40 
approximate Snellen equivalent) or better over time
Proportion of patients who lose 10 or 5 letters in BCVA 
score from baseline to the average over Week 36 and 
Week 40
Proportion of patients who lose 10 or 5 letters in BCVA 
score from baseline over time
Proportion of patients who gain 0 letters in BCVA score 
from baseline to the average over Week 36 and Week 40
Proportion of patients who gain 0 letters in BCVA score 
from baseline over time
To evaluate the relative efficacy of 
ranibizumab delivered via the PDS Q24W 
with the 100-mg/mL formulation compared 
with that of 10-mg/mL (0.5-mg dose) Q4W 
intravitreal ranibizumab injections, as 
assessed by CPT on SD-OCT
Change from baseline in CPT at Week 36
Change from baseline in CPT over time
To evaluate the proportion of patients who 
undergo supplemental treatment with 
intravitreal ranibizumab 0.5 mg
Proportion of patients in the implant arm who undergo 
supplemental treatment with intravitreal ranibizumab 
0.5 mg before the first, second, third, and fourth fixed refill-
exchange intervals 
Proportion of patients in the implant arm that undergo a 
supplemental treatment that requires subsequent additional 
supplemental treatments during the study
Exploratory Efficacy Objectives
Corresponding Endpoints
To evaluate the impact of supplemental 
treatment with intravitreal ranibizumab 
0.5 mg
Endpoints will be results-dependent based on number of 
supplemental treatment


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
16/Protocol GR40548, Version 5
Exploratory Efficacy Objectives (cont.)
Corresponding Endpoints (cont.)
To evaluate the relative efficacy of 
ranibizumab delivered via the PDS Q24W 
with the 100-mg/mL formulation compared 
with that of 10-mg/mL (0.5-mg dose) Q4W 
intravitreal ranibizumab injections, as 
assessed by central subfield thickness on 
SD-OCT
Change from baseline in CST at Week 36
Change from baseline in CST over time
To assess clinically relevant features 
using advanced analytics tools 
(including artificial intelligence-based 
tools) on multimodal images and clinical 
data
Clinically relevant features over time
To evaluate the development of macular 
atrophy in patients treated with the PDS 
Q24W with the 100-mg/mL formulation 
compared with those with 10-mg/mL (0.5-
mg dose) Q4W intravitreal ranibizumab 
injections.
Proportion of patients with macular atrophy at baseline, 
Weeks 36, 48, and 96
Change from baseline in macular atrophy area at Weeks 36, 
48 and 96
To evaluate the relative efficacy of 
ranibizumab delivered via the PDS Q24W 
with the 100-mg/mL formulation compared 
with that of 10-mg/mL (0.5-mg dose) Q4W 
intravitreal ranibizumab injections, as 
assessed by visual acuity
Proportion of patients who gain 5 letters in BCVA score 
from baseline over time.
Safety Objective
Corresponding Endpoints
To evaluate the safety and tolerability of 
ranibizumab, delivered via the PDS Q24W 
with the 100-mg/mL formulation compared 
with that of 10-mg/mL (0.5-mg dose) Q4W 
intravitreal ranibizumab injections
Incidence and severity of ocular and systemic (non-ocular) 
AEs
Incidence, severity, and duration of AESIs, including 
PDS-associated AEs
Incidence, severity, and duration of ocular AESIs during the 
postoperative period (up to 37 days of initial implantation) 
and follow-up period (37 days after implantation surgery)
Pharmacokinetic Objective
Corresponding Endpoints
To characterize the serum pharmacokinetics 
of ranibizumab in patients after the initial fill 
and subsequent refill-exchanges in patients 
with the PDS
Observed serum ranibizumab concentrations at specified 
timepoints
Additional estimated PK parameter values, including 
AUC0-6M, Cmax, Cmin, and t1/2 after PDS implant insertion
Exploratory Pharmacokinetic Objectives
Corresponding Endpoints
To evaluate potential relationships between 
drug exposure and the efficacy of the PDS
Relationship between serum concentration or PK 
parameters for ranibizumab delivered via the PDS and 
efficacy endpoints
To characterize ranibizumab aqueous 
humor concentration over time
Observed aqueous humor ranibizumab concentrations over 
time


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Immunogenicity Objective
Corresponding Endpoint
To investigate the formation of serum anti-
ranibizumab antibodies
The incidence of ADAs during the study, grouped in the 
following manner:
Patients who were ADA negative at baseline and became 
positive only after dosing
Patients who were ADA positive at randomization and ADA 
titer increased after dosing
Patients who were ADA positive at randomization and ADA 
titer did not increase after dosing 
Exploratory Biomarker Objectives
Corresponding Endpoints
To explore relationships between aqueous 
humor free-VEGF concentrations over 
time and the efficacy of ranibizumab, 
delivered via the PDS Q24W with the 
100-mg/mL formulation 
Comparison of patients with and without aqueous humor 
free-VEGF present between refill-exchanges and needing 
supplemental treatment 
Comparison of patients with and without aqueous humor 
free-VEGF present between refill-exchanges and CST 
change from baseline over time 
Comparison of patients with and without aqueous humor 
free-VEGF present between refill-exchanges and BCVA 
score change from baseline over time
To identify biomarkers that are prognostic of 
response to ranibizumab, are associated 
with acquired resistance to ranibizumab, are 
associated with susceptibility to developing 
adverse events (i.e., safety biomarkers), can 
provide evidence of ranibizumab activity 
(i.e., pharmacodynamic biomarkers), or can 
increase the knowledge and understanding 
of AMD-related disease biology
Relationship between biomarkers in blood and aqueous 
humor with disease characteristics and response to 
ranibizumab
Relationship between genetic variants (such as AMD risk 
alleles, polymorphisms within the complement pathway, and 
polymorphisms within the VEGF-A genetic locus) with the 
disease characteristics and/or response to treatment with 
ranibizumab
Relationship between imaging features with disease 
characteristics and/or response to treatment with 
ranibizumab
Exploratory Patient Experience Objectives
Corresponding Endpoints
To evaluate the preference of patients for 
ranibizumab delivered via the PDS for 40 
weeks compared to intravitreal anti-VEGF 
treatment received in the 6 months prior to 
Day 1
Proportion of patients who report preferring ranibizumab 
treatment via the PDS compared with intravitreal anti-
VEGF treatment, as assessed by the PPPQ, at Week 40 
among patients in the implant arm
To evaluate patient-reported treatment 
satisfaction with ranibizumab delivered via 
the PDS for 40 weeks compared with that of 
Q4W intravitreal ranibizumab injections, as 
assessed by the MacTSQ
MacTSQ total score at Week 40


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ADA anti-drug antibody; AE adverse event; AESI adverse event of special interest; AMD age-related 
macular degeneration; AUC0-6M area under the concentrationtime curve from 0 to 6 months; 
BCVA best-corrected visual acuity; Cmax maximum serum concentration; Cmin minimum serum 
concentration; CPT center point thickness; CST central subfield thickness; ETDRS Early Treatment 
Diabetic Retinopathy Study; MacTSQ Macular Degeneration Treatment Satisfaction Questionnaire; 
PDS Port Delivery System with ranibizumab; PK pharmacokinetic; PPPQ PDS Patient Preference 
Questionnaire; Q4W every 4 weeks; Q24W every 24 weeks; SD-OCT spectral domain optical 
coherence tomography; t1/2 half-life; VEGF vascular endothelial growth factor.
Study Design
Description of Study
Study GR40548 (Archway) is a Phase III, randomized, multicenter, open-label (visual assessor 
[VA]masked), active-comparator study designed to assess the efficacy, safety, and 
pharmacokinetics of 100 mg/mL ranibizumab every 24 weeks (Q24W) delivered via the PDS 
compared with ranibizumab intravitreal injections every 4 weeks (Q4W) at 0.5 mg (10 mg/mL) in 
patients with nAMD.
Patients will be randomly allocated in a 3:2 ratio so that approximately 216 patients will receive 
the PDS implant filled with 100 mg/mL ranibizumab Q24W (implant arm) and approximately 
144 patients will receive monthly intravitreal injections of 10 mg/mL ranibizumab intravitreal 
injections Q4W (intravitreal arm). 
Patients who are randomly allocated to the implant arm will have the implant (pre-filled with 
ranibizumab 100 mg/mL) surgically inserted on Day 1, which must occur 17 days (inclusive) 
after randomization (i.e., randomization and Day 1 visit assessments cannot be performed on 
the same day) and no later than 28 days from the last intravitreal ranibizumab 0.5 mg injection.  
If the implant insertion surgery (Day 1) cannot be completed within the visit window after 
randomization, the randomization visit assessments may be repeated and an additional 
intravitreal ranibizumab 0.5 mg injection may be required after discussion with the Sponsor.  
After Day 1, patients in the implant arm will have scheduled safety visit assessments on Days 2 
and 7 (2 days) and will receive implant refill-exchanges with ranibizumab 100 mg/mL Q24W at 
Week 24 (7 days), Week 48 (7 days), and Week 72 (7 days). 
Patients who are randomly allocated to the intravitreal arm will receive intravitreal ranibizumab 
0.5 mg injections starting on Day 1, which is to be administered at the conclusion of the 
randomization visit (i.e., randomization and Day 1 visit assessments are performed on the same 
day).  Patients will receive ranibizumab 0.5 mg, injected intravitreally Q4W (7 days) from 
Day 1 until Week 92.
In order to provide flexibility due to extenuating circumstances, it is possible that patients may 
receive additional study treatments until they are able to enroll into the long-term safety study.
Study visits will occur according to the schedule of activities relative to Day 1 (first study 
treatment).  Study patients and all study site personnel with the exception of VA examiners will 
be unmasked to the study eye and study treatment assignment.  To minimize bias, VA 
examiners will only conduct refraction and VA assessments and will be masked as best as
possible to patient study eye assignment, study visit type, and patient treatment assignment.
Number of Patients
Approximately 360 patients were planned to be enrolled in this study; a total of 418 patients 
were ultimately recruited.
Target Population
Inclusion Criteria
General Inclusion Criteria
Patients must meet the following general inclusion criteria at screening and randomization for 
study entry:

Ability and willingness to provide signed informed consent
Additionally, patients must provide Health Insurance Portability and Accountability Act 
(HIPAA) authorization.

Age 50 years, at time of signing Informed Consent Form


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
Ability and willingness to undertake all scheduled visits and assessments 

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, 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 at least 28 days after the last 
intravitreal injection of ranibizumab or 1 year after the last implant refill-exchange of 
ranibizumab.
A woman is considered to be of childbearing potential if she is post-menarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements.
Examples of 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.
Ocular Inclusion Criteria
Patients must meet the following ocular inclusion criteria for the study eye for study entry:

Initial diagnosis of exudative nAMD within 9 months prior to the screening visit 

Previous treatment with at least three anti-vascular endothelial growth factor (VEGF)
intravitreal injections (e.g., ranibizumab, bevacizumab, or aflibercept) for nAMD per 
standard of care within 6 months prior to the screening visit
If a patient did not receive at least three anti-VEGF injections as described above but is 
otherwise eligible for the study, the patient can be treated in a run-in phase to meet this 
specific criterion.

Demonstrated response to prior anti-VEGF intravitreal treatment since diagnosis, as 
evidenced at screening by the following:
Overall decrease in nAMD disease activity detected on spectral-domain optical 
coherence tomography (SD-OCT), as assessed by the investigator and confirmed by the 
central reading center
and
Stable or improved best-corrected visual acuity (BCVA)

BCVA of 34 letters or better (20/200 or better approximate Snellen equivalent), using Early 
Treatment Diabetic Retinopathy Study (ETDRS) chart at a starting distance of 4 meters 
(see the BCVA manual for additional details) at screening and randomization visits

All subtypes of nAMD lesions are permissible (i.e., type I, type II, type III, or mixed forms 
per OCT classification)
nAMD lesions at the time of diagnosis must involve the macula (6-mm diameter centered 
at the fovea).

Sufficiently clear ocular media and adequate pupillary dilation to allow for analysis and 
grading by the central reading center of fundus photography FP, fluorescein angiography
FA, fundus autofluorescence FAF, and SD-OCT images
Exclusion Criteria
Prior Ocular Treatment
Patients who meet any of the following prior ocular treatment exclusion criteria will be excluded 
from study entry.


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Study Eye

History of vitrectomy surgery, submacular surgery, or other surgical intervention for 
age-related macular degeneration (AMD)

Prior treatment with Visudyne®, external-beam radiation therapy, or transpupillary 
thermotherapy

Previous treatment with corticosteroid intravitreal injection

Previous intraocular device implantation

Previous laser (any type) used for AMD treatment
Either Eye

Treatment with anti-VEGF agents other than ranibizumab within 1 month prior to the 
randomization visit

Prior participation in a clinical trial involving anti-VEGF drugs within 6 months prior to the 
randomization visit, other than ranibizumab
Choroidal Neovascularization (CNV) Lesion Characteristics
Patients who meet any of the following exclusion criteria related to CNV lesion characteristics 
will be excluded from study entry.
Study Eye

Subretinal hemorrhage that involves the center of the fovea, if the hemorrhage is greater 
than 0.5-disc area (1.27 mm2) in size at screening

Subfoveal fibrosis or subfoveal atrophy 
Either Eye

CNV due to other causes, such as ocular histoplasmosis, trauma, or pathologic myopia
Concurrent Ocular Conditions
Patients who meet any of the following exclusion criteria related to concurrent ocular conditions 
will be excluded from study entry.
Study Eye

Retinal pigment epithelial tear 

Any concurrent intraocular condition (e.g., cataract, glaucoma, diabetic retinopathy, or 
epiretinal membrane) that would either require surgical intervention during the study to 
prevent or treat visual loss that might result from that condition or affect interpretation of 
study results

Active intraocular inflammation (grade trace or above) 

History of vitreous hemorrhage

History of rhegmatogenous retinal detachment

History of rhegmatogenous retinal tears or peripheral retinal breaks within 3 months prior to 
the randomization visit

Aphakia or absence of the posterior capsule 
Previous violation of the posterior capsule is also an exclusion criterion unless it 
occurred as a result of yttrium-aluminum garnet (YAG) laser posterior capsulotomy in 
association with prior, posterior chamber intraocular lens implantation.

Spherical equivalent of the refractive error demonstrating more than 8 diopters of myopia

Preoperative refractive error that exceeds 8 diopters of myopia, for patients who have 
undergone prior refractive or cataract surgery in the study eye

Intraocular surgery (including cataract surgery) within 3 months preceding the 
randomization visit


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
Uncontrolled ocular hypertension or glaucoma (defined as intraocular pressure [IOP] 25 
mmHg or a cup to disc ratio 0.8, despite treatment with antiglaucoma medication) and any 
such condition the investigator determines may require a glaucoma-filtering surgery during 
a patient's participation in the study

History of glaucoma-filtering surgery, tube shunts, or microinvasive glaucoma surgery

History of corneal transplant

History of prior vitrectomy surgery and absence of posterior capsule
Either Eye

History of idiopathic or autoimmune-associated uveitis

Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis
Concurrent Systemic Conditions
Patients who meet any of the following exclusion criteria related to concurrent systemic 
conditions will be excluded from study entry:

Inability to comply with study schedule or procedures as described in the study protocol 

Uncontrolled blood pressure (defined as systolic blood pressure 180 mmHg and/or 
diastolic blood pressure 110 mmHg, while a patient is at rest)
If a patient's initial measurement exceeds these values, a second reading may be 
taken 30 or more minutes later.  If the patient's blood pressure must be controlled by 
antihypertensive medication, the patient may become eligible if medication is taken 
continuously for at least 30 days prior to Day 1.

History of stroke within the last 3 months prior to informed consent

Uncontrolled atrial fibrillation within 3 months of informed consent

History of myocardial infarction within the last 3 months prior to informed consent

History of other disease, metabolic dysfunction, or clinical laboratory finding giving 
reasonable suspicion of a disease or condition that contraindicates the use of ranibizumab 
or placement of the implant and that might affect interpretation of the results of the study or 
renders the patient at high risk of treatment complications in the opinion of the investigator

Current systemic treatment for a confirmed active systemic infection

Use of any systemic anti-VEGF agents

Chronic use of oral corticosteroids (10 mg/day of prednisone or equivalent)

Active cancer within 12 months of randomization except for appropriately treated carcinoma 
in situ of the cervix, non-melanoma skin carcinoma, and prostate cancer with a Gleason 
score of 6 and a stable prostate-specific antigen for 12 months

Previous participation in any non-ocular (systemic) disease studies of investigational drugs 
within 1 month preceding the informed consent (excluding vitamins and minerals)

Use of antimitotic or antimetabolite therapy within 30 days or 5 elimination half-lives of the 
randomization visit

Requirement for continuous use of any medications or treatments indicated in "Prohibited 
Therapy" 

Pregnant or breastfeeding, or intending to become pregnant during the treatment period 
and for at least 28 days after the last intravitreal injection of ranibizumab or 1 year after the 
last implant refill-exchange of ranibizumab
Women of childbearing potential, including those who have had tubal ligation, must 
have a urine pregnancy test at screening and at specified subsequent visits.  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
End of Study
The end of this study is defined as the date when the last patient, last visit occurs.  The end of 
study is expected to occur approximately 96 weeks after the last patient is enrolled.


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Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 34 months.
Investigational Medicinal Products
The investigational medicinal products (IMPs) for this study are the PDS with ranibizumab 
(100 mg/mL) and the monthly intravitreal ranibizumab 0.5 mg.
Test Product (Investigational Drug)
Patients will have the implant (filled prior to implantation with approximately 20 L of the 
100-mg/mL formulation of ranibizumab [approximately 2-mg dose of ranibizumab]) surgically 
inserted in the study eye at the Day 1 visit following their randomization visit.  After the initial fill 
of the implant with ranibizumab, patients will receive implant refill-exchanges at fixed 24-week 
intervals.
At each refill-exchange, a volume of approximately 100 L ranibizumab will be injected in situ 
into the implant through the septum to exchange the remaining contents of the implant with 
newly introduced ranibizumab.  The volume of newly introduced ranibizumab remaining in the 
implant after the refill-exchange procedure will be approximately 20 L.  Missed implant refill-
exchanges should be made up no later than the next scheduled study visit.  If at the next 
scheduled study visit the implant refill-exchange cannot be performed, the investigator must 
contact the Sponsor for further discussion prior to administering future implant refill-exchanges.  
Subsequent refill-exchanges will be administered according to the study treatment schedule 
relative to Day 1 until patients complete the study.
A representative from the Sponsor or an affiliate of the Sponsor may be present during the 
study-specific PDS surgeries or procedures (initial filling, insertion, refill-exchanging, and/or 
explantation) and/or other PDS-related surgeries or procedures to provide technical support to 
investigators during the use of the PDS and/or to observe the procedures related to the PDS.
Comparator
Ranibizumab (10 mg/mL) will be provided by the Sponsor and used in the study eye during the 
run-in period and at the screening visit for applicable patients; as study treatment for patients in 
the intravitreal arm; as supplemental treatment for the implant arm; if delaying surgery is 
required; as nAMD treatment in the fellow eye for patients, per investigator’s discretion; and if a 
patient in the PDS arm discontinues study treatment and starts receiving ranibizumab 
intravitreal injections in study eye, per investigator’s discretion.
Commercially available intravitreal ranibizumab 0.5 mg supply may be used only if an 
intravitreal ranibizumab injection is necessary per protocol and study supply is not available at 
the site.  Prior to administering commercial supply ranibizumab, the site will need to obtain 
Sponsor’s approval.
Patients in the intravitreal arm will receive their first intravitreal injection of 50 L of the 
ranibizumab10 mg/mL (0.5-mg dose) at the Day 1 visit, which will occur at the conclusion of the 
randomization visit.  Afterward, patients will receive intravitreal ranibizumab injections of 50 L 
of the 10-mg/mL formulation Q4W at each scheduled study visit until Week 92.  Missed 
treatments will not be made up.
Statistical Methods
Primary Analysis
The primary efficacy endpoint is the change in BCVA score from baseline averaged over 
Weeks 36 and 40 with BCVA assessed using the ETDRS chart at a distance of 4 meters.  The 
primary objective is to determine the non-inferiority (NI) and equivalence between the two 
treatment arms, as measured by the primary efficacy endpoint with an NI margin of 4.5 letters 
and equivalence margin of 4.5 letters.  To control the overall type I error, a fixed sequence 
testing procedure will be used.  If the implant arm is shown to be non-inferior to the intravitreal 
arm at the one-sided 0.025 level, then the clinical equivalence test will be conducted using two 
one-sided 0.025 tests.
The primary analysis will be performed using the mixed-effect model with repeated measures
(MMRM) based on all available data up to Week 40.  All observed measurements will be 


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included in the analysis regardless whether or not a patient has an intercurrent event. Missing 
data will be implicitly imputed by the MMRM model, assuming a missing at random mechanism.
The dependent variable in the MMRM model is the change from baseline in BCVA score at 
post-baseline visits, from 4 to 40 weeks, and the independent variables are the treatment group, 
time, treatment-by-time interaction, baseline BCVA score (continuous), and the randomization 
stratification factor of baseline BCVA (74 letters vs. 74 letters) as fixed effects.  The MMRM 
model will assume an unstructured covariance structure.  If there are convergence problems 
with the model, then a compound symmetry covariance or an AR(1) covariance structure will be 
used.  Comparisons between the two treatment arms will be made using a composite contrast 
over Weeks 36 and 40.
For the primary efficacy endpoint, if a lower bound of a two-sided 95.03% CI for the difference 
of two treatments is greater than 4.5 letters (the NI margin), then treatment via PDS is 
considered non-inferior to monthly intravitreal ranibizumab treatment.  If the two-sided 95% CI is 
within 4.5 letters and 4.5 letters, then the two treatment regimens are considered clinically 
equivalent.
As a sensitivity analysis, the per-protocol analysis will follow the same methods as the primary 
analysis except the Per-Protocol Population will be used.
Determination of Sample Size  
Patients will be randomly allocated in a 3:2 ratio to the implant arm or intravitreal arm. 
The primary endpoint is the change in BCVA score from baseline averaged over Weeks 36 and 
40.  The study is sized to achieve adequate power to show NI and equivalence of the implant 
arm to the intravitreal arm in the change in BCVA score from baseline averaged over Week 36 
and Week 40 using an NI margin of 4.5 letters and equivalence margins of 4.5 letters.
Assuming a standard deviation of 9.5 letters for the change from baseline in BCVA score 
averaged over 36 and 40 weeks, up to a true mean change from baseline in BCVA of 0.75 
letters worse for the implant arm, compared with the monthly intravitreal arm, 216 patients in the 
implant arm and 144 patients in the intravitreal arm will provide 90% power to demonstrate NI 
and equivalence between the two treatment groups.  Calculations were based on a one-sided t-
test at 0.025 level for the NI test and two one-sided t-tests at the 0.025 level for the 
equivalence test with the assumption of a 10% dropout rate by Week 40 and a 10% increase for 
the trimmed mean analysis.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody
AMD
age-related macular degeneration
ANCOVA
analysis of covariance 
ATE
arterial thromboembolic event
AUC
area under the concentration-time curve
BCVA
best-corrected visual acuity
CATT
the Comparison of Age-Related Macular Degeneration 
Treatment Trials
Cmax
maximum serum concentration
Cmin
minimum serum concentration
CNV
choroidal neovascularization
CPT
center point thickness
CST
central subfield thickness
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
ETDRS
Early Treatment Diabetic Retinopathy Study
FA
fluorescein angiography
FAF
fundus autofluorescence 
FDA
Food and Drug Administration
FP
fundus photography
FSV4
ForSight VISION4, Inc.
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Council for Harmonisation
iDMC
independent Data Monitoring Committee
IFU
instructions for use
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IOP
intraocular pressure
IRB
Institutional Review Board
IxRS
interactive voice or web-based response system
MacTSQ
Macular Degeneration Treatment Satisfaction 
Questionnaire
MMRM
mixed-effect model for repeated measures
MN
mobile nursing
MRI
magnetic resonance imaging


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Abbreviation
Definition
nAMD
neovascular AMD
NI
non-inferiority
NSAID
nonsteroidal anti-inflammatory drug
OCT
optical coherence tomography
PD
pharmacodynamics
PDS
Port Delivery System with ranibizumab
PK
Pharmacokinetic
PPPQ
PDS Patient Preference Questionnaire
PRO
patient-reported outcome
PVD
posterior vitreous detachment
Q4W
every 4 weeks
Q24W
every 24 weeks
RBR
Research Biosample Repository
RPE
retinal pigment epithelium 
SAP
Statistical Analysis Plan
SAR
specific absorption rate
SD-OCT
spectral-domain optical coherence tomography 
ULN
upper limit of normal
VA
visual acuity
VEGF (-A)
vascular endothelial growth factor (A)
WES
whole exome sequencing
WGS
whole genome sequencing 
YAG
yttrium-aluminum garnet


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1.
BACKGROUND
1.1
BACKGROUND ON AGE-RELATED MACULAR 
DEGENERATION 
Neovascular age-related macular degeneration (nAMD) (also known as choroidal 
neovascularization [CNV] secondary to age-related macular degeneration [AMD] is a 
form of advanced AMD that causes rapid and severe visual loss, and remains a leading 
cause of visual impairment in the elderly (Bourne et al. 2013; Wong et al. 2014).  The 
prevalence of nAMD increases exponentially with age, with estimates in the 
United States in 2011 ranging from 0.5% among people 6569 years old to 14.6% 
among those 90 years old or older (Rudnicka et al. 2012).  In the next 40 years, the 
global population aged 60 and older is projected to increase dramatically, translating into 
an increase in the prevalence of nAMD from 23 million in 2010 to 80 million by 2050 
(Smith 2010).  The precise causes of AMD remain unknown, although numerous risk 
factors have been identified, including genetic (e.g., complement factor H 
polymorphisms), demographic (e.g., ethnicity), nutritional (e.g., lack of antioxidant 
vitamins, dietary fats, or fish), lifestyle (e.g., smoking), medical (e.g., cardiovascular risk 
factors), environmental (e.g., sun exposure), and ocular factors (Chakravarthy et al. 
2010).
1.1.1
Pathophysiology of Age-Related Macular Degeneration
AMD is categorized into early, intermediate, and advanced forms, based on clinical 
examination, ocular imaging, and pathologic findings.  In approximately 10% of early or 
intermediate AMD cases, a conversion to nAMD occurs over time.  Although nAMD is 
comparatively uncommon, it accounted for the majority of severe vision loss from AMD 
prior to the development of anti-vascular endothelial growth factor (VEGF) therapy.  
nAMD is typically characterized by the development of CNV in the macula.  Abnormal 
capillary vessels and fibrovascular membranes proliferate in regions of Bruch’s 
membrane damage.  The new vessels are abnormally permeable and result in 
accumulation of exudative fluid and hemorrhage beneath the retinal pigment 
epithelium (RPE) and/or neurosensory retina.  The fluid and hemorrhage can cause 
acute and, historically, permanent loss of central vision.  At the end stage, fibrous 
metaplasia can occur, resulting in a chronic subretinal scar (disciform scar) (Jager et al. 
2008).
The stimuli that result in the development of CNV remain unclear.  However, there is 
significant experimental and clinical evidence implicating VEGF-A in the pathogenesis of 
nAMD, as discussed in the Port Delivery System with Ranibizumab (PDS) Investigator's 
Brochure.
1.1.2
Treatment for Neovascular Age-Related Macular Degeneration
Treatment of nAMD was significantly impacted by the introduction of anti-VEGF therapy.  
Prior to the availability of anti-VEGF therapy, vision loss could be slowed but not 
reversed.  Ranibizumab, a recombinant, humanized monoclonal antibody fragment, 


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which binds to all known isoforms of VEGF-A, was approved by the U.S. Food and Drug 
Administration (FDA) for use in nAMD, in June 2006.  In November 2011, a second 
anti-VEGF therapy, aflibercept, was approved for nAMD in the United States, with a 
similar safety and efficacy profile to ranibizumab.
A key challenge with currently available anti-VEGF treatments is the requirement for 
frequent and long-term administration to maintain vision gains (Heier et al. 2012; 
the Comparison of Age-Related Macular Degeneration Treatment Trials [CATT] 
Research Group 2016).  Real-world data suggest that many patients with nAMD do not 
receive treatment according to the approved prescribing information and this 
under-treatment in clinical practice is associated with lower visual acuity (VA) gains 
compared with those observed in controlled clinical trials (Cohen et al. 2013; 
Finger et al. 2013; Holz et al. 2015).  For example, a retrospective chart review of 
patients with newly diagnosed nAMD in multiple countries outside of the United States 
showed that patients received a mean of 5.0 and 2.2 injections in the first and second 
years, respectively and although an initial improvement in VA was observed, the gain 
was not maintained over time (mean change in VA score from baseline of only 2.4 and 
0.6 letters, respectively, at Years 1 and 2; Holz et al. 2015).
Under-treatment of nAMD in clinical practice reflects the burden of frequent therapy on 
patients, caregivers, and the healthcare system (Gohil et al. 2015; Prenner et al. 2015; 
Varano et al. 2015; CATT Research Group et al. 2016; Vukicevic et al. 2016).
This difference in outcomes between patients treated in the real-world setting and those 
treated in the controlled environment of a clinical trial demonstrates the clear clinical 
need for therapies with a more durable effect which would thus require less frequent 
dosing, while still being able to provide VA outcomes comparable to those observed in 
the pivotal clinical trials of licensed anti-VEGF monotherapies.
1.2
BACKGROUND ON RANIBIZUMAB 
Ranibizumab is a recombinant humanized IgG1 isotype monoclonal antibody fragment 
administered by intravitreal administration.  It binds to and inhibits the biologic activity of 
VEGF-A.  Ranibizumab is produced by standard recombinant technology methods in an 
Escherichia coli expression vector and bacterial fermentation.  Ranibizumab is not 
glycosylated and has a molecular mass of approximately 48,000 daltons.
Current U.S. prescribing information supports monthly intravitreal injection of 
ranibizumab 0.5 mg for treatment of nAMD and also provides information on results that 
may be expected following less frequent than monthly dosing after an initial loading 
phase.
Refer to the PDS Investigator's Brochure for details about nonclinical and clinical 
ranibizumab studies.


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1.3
BACKGROUND ON THE PORT DELIVERY SYSTEM WITH 
RANIBIZUMAB
The PDS is a drug delivery technology that allows physicians to use ranibizumab with a 
continuous drug delivery profile without altering its chemistry and consists of an 
intraocular implant (hereafter referred to as the implant), four ancillary devices (insertion 
tool, initial fill needle, refill needle, and explant tool), and a customized formulation of 
ranibizumab tailored for continuous delivery (see Appendix 16).
The implant is an intraocular refillable device that is surgically implanted through the 
pars plana to allow for a continuous delivery of ranibizumab into the vitreous.  After 
insertion of the implant, the proximal end of the implant (flange) sits on top of the sclera, 
under the conjunctiva and Tenon’s capsule, with the body of the implant extending into 
the vitreous.  The implant is used in conjunction with the customized formulation of
ranibizumab to precisely control the rate and duration of drug delivery and is refillable 
through the implant septum in situ.
For additional PDS details (e.g., fill, insertion, refill-exchange, and explantation of the 
implant), consult the PDS instructions for use (IFU) document and the PDS Investigator's 
Brochure.
Prior to this current study, the implant has been investigated in prospective Phase I and 
II studies.  A prospective Phase I, open-label study in patients with nAMD was 
conducted by the device developer, ForSight VISION4, Inc. (FSV4), at a single site in 
Latvia.  The study investigated the safety, tolerability, and duration of ranibizumab 
exposure delivered with the implant.  The implant used in Phase I was composed of 
biocompatible materials (polymethyl methacrylate, silicone, and 316L stainless steel; see 
Appendix 16).  
For additional details about the Phase I study, see Section 1.4 and the PDS 
Investigator's Brochure.  The implant evaluated in Phase II was composed of 
biocompatible materials (polysulfone, silicone, and titanium; see Appendix 16).
1.3.1
Phase I Port Delivery System with Ranibizumab Study:  FH-1.2
The safety, tolerability, and duration of ranibizumab (10 mg/mL) exposure delivered 
through the implant were investigated in a Phase I prospective, open-label study (FH-
1.2) in a patient population with nAMD and conducted by FSV4 at a single site in Latvia.  
Patient enrollment was initiated in August 2010, and the study assessed the safety of the 
PDS in 20 eyes through the collection and analysis of adverse events and complications, 
including procedure-related adverse events, device-related adverse events, 
ranibizumab-related adverse events, and all general health and patient-reported adverse 
events. 
All 20 patients completed the planned 12-month treatment phase of the Phase I study.  
No patients were treated via the implant after the first 12 months of the study.  At 


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Month 12, 6 patients underwent per-protocol planned implant removal and discontinued 
from the study after completion of the Month 13 visit.  Of the 14 remaining patients 
eligible for an additional 24-month safety-monitoring phase (quarterly safety visits),
1 patient was lost to follow-up after 12 months.  The remaining 13 patients continued in 
the safety-monitoring phase; and 1 of the 13 patients was subsequently lost to follow-up 
after 21 months.  Follow-up data out to 36 months are available for the remaining 
12 patients.
A total of 95 adverse events were reported in all 20 patients (100%) in this study:  
87 adverse events during the 12-month treatment phase and 8 adverse events during 
the safety-monitoring phase.  Of the 87 adverse events reported during treatment, 
76 events were considered by the investigator to be related (possibly, probably, or 
definitely) to the implant insertion procedure, the refill-exchange procedure, the implant
removal procedure, or study drug treatment. 
The most common study-related adverse events were conjunctival hyperemia (59%), 
vitreous hemorrhage (7%), hyphema (7%), VA decrease (5%), eye dryness (4%), and 
conjunctival edema (3%).  Conjunctival hyperemia occurred in 19 of 20 patients (95%), 
for a total of 45 events; 44 of those events (98%) were mild in severity and 1 event was 
of moderate severity.  Conjunctival hyperemia was typically observed following the 
implant insertion or refill-exchange procedures, and the average duration of these events 
was 8 days, with all resolving over a range from 3 to 48 days from onset.
A total of 96 implant refill-exchange procedures were performed in the study.  The most 
frequently reported adverse events considered by the investigator to be related to the 
implant refill-exchange on a per-procedure basis were conjunctival hyperemia (33%), 
eye dryness (2%), vitreous haze (2%), increased lacrimation (1%), and ocular discomfort 
(1%).  The adverse event rate per implant refill-exchange procedure was 38%.  The 
adverse events were of mild severity, and the average duration to resolution was 7 days.
Refer to the PDS Investigator's Brochure for further details.
1.3.2
Phase II Port Delivery System with Ranibizumab:  
Study GX28228 (Ladder)
Subsequent to Study FH-1.2, a Phase II, dose-ranging, randomized, active 
treatmentcontrolled, multicenter study (GX28228 [Ladder]) was initiated to evaluate the 
safety, efficacy, and pharmacokinetics of three different doses of ranibizumab 
(10 mg/mL, 40 mg/mL, and 100 mg/mL) delivered via the PDS versus monthly 
intravitreal ranibizumab 0.5 mg injections in patients with nAMD and a history of positive 
response to any anti-VEGF therapy.  The study, which was U.S. based, was 
approximately 43 months in duration. The last patient, last visit occurred on 
28 March 2019 and the final study analysis was then conducted (snapshot date of 2 May 
2019).


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The primary analysis, performed when all enrolled patients had been followed up for 
9 months, measured the time at which a patient first required an implant refill-exchange
according to protocol-defined refill-exchange criteria. In the PDS 100 mg/mL, PDS 
40 mg/mL, and PDS 10 mg/mL arms, the median time to first refill-exchange was 15.0, 
13.0, and 8.7 months, respectively. In addition, 79.8%, 71.3%, and 63.5% of patients 
went 6 months without requiring a refill-exchange in PDS 100 mg/mL, PDS 40 mg/mL, 
and PDS 10 mg/mL, respectively. Best-corrected visual acuity (BCVA) and anatomic 
outcomes were comparable between the PDS 100 mg/mL arm and the monthly 
intravitreal ranibizumab 0.5 mg arm. The overall safety profile from the primary analysis 
revealed a favorable benefitrisk assessment. The optimized implant insertion surgery 
and refill-exchange procedures were generally well tolerated.  Systemic safety profile of 
PDS treatment was well characterized and comparable with monthly intravitreal 
ranibizumab 0.5 mg treatment (Campochiaro et al. 2019). Results from the final analysis 
were consistent with the results from the primary analysis (Khanani et al. 2020).  Refer 
to the PDS Investigator's Brochure for further details.
Patients from Study GX28228 who completed the study and consented to the open-label 
extension study (GR40549 [Portal]) have now enrolled.
1.4
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
As a result of the chronic, progressive nature of nAMD, frequent intravitreal ranibizumab 
0.5 mg injections continue for extended periods for many patients.  The pivotal Phase III 
Studies MARINA (FVF2598g) and ANCHOR (FVF2587g) in nAMD demonstrated 
significant and well-maintained VA outcomes with monthly intravitreal ranibizumab 
0.5 mg injections for 2 years.
The Study HARBOR (FVF4579g), which compared monthly with as needed (PRN)
ranibizumab administration, showed comparable efficacy and maintenance of visual and 
anatomic improvements for 2 years between the two regimens.  However, all patients 
were evaluated monthly to determine the need for retreatment and still required frequent 
injections.  The mean number of intravitreal ranibizumab 0.5 mg injections through 
Month 24 was 21.4 injections for the monthly treatment arm and 13.3 injections for the 
PRN treatment arm.  In clinical practice, frequent office monitoring visits are required 
and regular injections are necessary to maintain optimal vision gains; however, this 
places a significant burden on patients and their caregivers, treating physicians, and the 
healthcare system. 
Such requirements present a substantial barrier to maintenance of desired efficacy 
outcomes.  Indeed, in clinical practice, many patients are treated less frequently than per 
the approved prescribing information and as a consequence experience suboptimal 
efficacy (Holz et al. 2015; Maguire et al. 2016; Egan et al. 2017; Rao et al. 2018).  As 
such, there remains a substantial unmet need for an optimized treatment and dosing 
regimen that could alleviate the current treatment burden on patients, caregivers, and 
healthcare providers and consequently improve vision outcomes in clinical practice.


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Continuous delivery of ranibizumab from the implant, with a prolonged fixed period 
between refill-exchanges, is a novel approach that may result in less-frequent need for 
retreatment than monthly dosing and patient monitoring.  The decrease in treatment 
burden may reduce the risk of intravitreal injectionrelated adverse events, increase 
compliance, and reduce the burden to patients, their caregivers, and the healthcare 
system, while maintaining optimal visual outcomes.
The primary analysis of the results of the Phase II GX28228 (Ladder) study revealed a 
favorable benefitrisk assessment for the PDS, which was well tolerated, with no 
evidence of dose dependency on the frequency or severity of the reported adverse 
events.  The overall safety profile of the PDS from available study data is generally 
consistent with the known safety profile of both ranibizumab administered by intravitreal 
injection (Lucentis® U.S. Package Insert [USPI]) and similar surgical procedures 
involving intraocular implants (Dunn et al. 2004; Gedde et al. 2012; Buys 2013; 
RetisertU.S. Package Insert; VitrasertImplant U.S. Package Insert).  See 
Section 5.1.3 for anticipated risks associated with the PDS or implant insertion 
procedure.  For a complete summary of safety information, refer to the PDS 
Investigator's Brochure.
The Phase I and II studies provide evidence of the safety and tolerability of the PDS and 
support the evaluation of the PDS in a Phase III study.  
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, and pharmacokinetics of ranibizumab 
delivered via the PDS implant compared with ranibizumab 0.5 mg delivered as a monthly 
intravitreal injection in patients with nAMD.  Specific objectives and corresponding 
endpoints for the study are outlined in Table 1.
Table 1
Objectives and Corresponding Endpoints
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the non-inferiority and 
equivalence in efficacy of ranibizumab 
delivered via the PDS Q24W with the 
100-mg/mL formulation compared with 
that of 10-mg/mL (0.5-mg dose) Q4W 
intravitreal ranibizumab injections 
Change from baseline in BCVA score at the average 
of Week 36 and Week 40, as assessed using the 
ETDRS visual acuity chart at a starting distance of 
4 meters


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Table 1
Objectives and Corresponding Endpoints (cont.)
Secondary Efficacy Objectives
Corresponding Endpoints
To evaluate the relative efficacy of 
ranibizumab delivered via the PDS 
Q24W with the 100-mg/mL formulation 
compared with that of 10-mg/mL (0.5-
mg dose) Q4W intravitreal ranibizumab 
injections, as assessed by visual acuity
Change from baseline in BCVA score averaged over 
Week 60 and Week 64
Change from baseline in BCVA score over time
Proportion of patients with BCVA score of 38 letters 
(20/200 approximate Snellen equivalent) or worse at 
the average over Week 36 and Week 40
Proportion of patients with BCVA score of 38 letters 
(20/200 approximate Snellen equivalent) or worse 
over time
Proportion of patients with BCVA score of 69 letters 
(20/40 approximate Snellen equivalent) or better at the 
average over Week 36 and Week 40
Proportion of patients with BCVA score of 69 letters 
(20/40 approximate Snellen equivalent) or better over 
time
Proportion of patients who lose 10 or 5 letters in 
BCVA score from baseline to the average over Week 
36 and Week 40
Proportion of patients who lose 10 or 5 letters in 
BCVA score from baseline over time
Proportion of patients who gain 0 letters in BCVA 
score from baseline to the average over Week 36 and 
Week 40
Proportion of patients who gain 0 letters in BCVA 
score from baseline over time
To evaluate the relative efficacy of 
ranibizumab delivered via the PDS
Q24W with the 100-mg/mL formulation 
compared with that of 10-mg/mL 
(0.5-mg dose) Q4W intravitreal
ranibizumab injections, as assessed by 
CPT on SD-OCT
Change from baseline in CPT at Week 36
Change from baseline in CPT over time
To evaluate the proportion of patients 
who undergo supplemental treatment 
with intravitreal ranibizumab 0.5 mg
Proportion of patients in the implant arm who undergo 
supplemental treatment with intravitreal ranibizumab 
0.5 mg before the first, second, third, and fourth fixed
refill-exchange intervals 
Proportion of patients in the implant arm that undergo 
a supplemental treatment that requires subsequent 
additional supplemental treatments during the study


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Table 1
Objectives and Corresponding Endpoints (cont.)
Exploratory Efficacy Objectives
Corresponding Endpoints
To evaluate the impact of supplemental 
treatment with intravitreal ranibizumab 
0.5 mg
Endpoints will be results-dependent based on 
number of supplemental treatments
To evaluate the relative efficacy of 
ranibizumab delivered via the PDS
Q24W with the 100-mg/mL formulation 
compared with that of 10-mg/mL (0.5-
mg dose) Q4W intravitreal ranibizumab 
injections, as assessed by central 
subfield thickness on SD-OCT
Change from baseline in CST at Week 36
Change from baseline in CST over time
To assess clinically relevant features 
using advanced analytics tools 
(including artificial intelligence-based 
tools) on multimodal images and 
clinical data
Clinically relevant features over time
To evaluate the development of 
macular atrophy in patients treated 
with the PDS Q24W with the 100-
mg/mL formulation compared with 
those with 10-mg/mL (0.5-mg dose) 
Q4W intravitreal ranibizumab 
injections.
Proportion of patients with macular atrophy at 
baseline, Weeks 36, 48, and 96
Change from baseline in macular atrophy area at 
Weeks 36, 48 and 96
To evaluate the relative efficacy of 
ranibizumab delivered via the PDS 
Q24W with the 100-mg/mL formulation 
compared with that of 10-mg/mL (0.5-
mg dose) Q4W intravitreal ranibizumab 
injections, as assessed by visual acuity
Proportion of patients who gain 5 letters in BCVA 
score from baseline over time.
Safety Objective
Corresponding Endpoints
To evaluate the safety and tolerability 
of ranibizumab, delivered via the PDS
Q24W with the 100-mg/mL 
formulation compared with that of 10-
mg/mL (0.5-mg dose) Q4W intravitreal
ranibizumab injections
Incidence and severity of ocular and systemic 
(non-ocular) AEs
Incidence, severity, and duration of AESIs
Incidence, severity, and duration of ocular AESIs 
during the postoperative period (up to 37 days of 
initial implantation) and follow-up period (37 days 
after implantation surgery)
Pharmacokinetic Objective
Corresponding Endpoints
To characterize the serum 
pharmacokinetics of ranibizumab in 
patients after the initial fill and 
subsequent refill-exchanges in 
patients with the PDS
Observed serum ranibizumab concentrations at 
specified timepoints
Additional estimated PK parameter values, including 
AUC0-6M, Cmax, Cmin, and t1/2 after PDS implant 
insertion


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Table 1
Objectives and Corresponding Endpoints (cont.)
Exploratory Pharmacokinetic 
Objectives
Corresponding Endpoints
To evaluate potential relationships 
between drug exposure and the 
efficacy of the PDS
Relationship between serum concentration or PK 
parameters for ranibizumab delivered via the PDS
and efficacy endpoints
To characterize ranibizumab aqueous 
humor concentration over time
Observed aqueous humor ranibizumab 
concentrations over time
Immunogenicity Objective
Corresponding Endpoint
To investigate the formation of serum 
anti-ranibizumab antibodies
The incidence of ADAs during the study, grouped in 
the following manner:
Patients who were ADA negative at baseline and 
became positive only after dosing
Patients who were ADA positive at randomization 
and ADA titer increased after dosing
Patients who were ADA positive at randomization 
and ADA titer did not increase after dosing 
Exploratory Biomarker Objectives
Corresponding Endpoints
To explore relationships between 
aqueous humor free-VEGF 
concentrations over time and the 
efficacy of ranibizumab, delivered via 
the PDS Q24W with the 100-mg/mL 
formulation
Comparison of patients with and without aqueous 
humor free-VEGF present between refill-exchanges 
and needing supplemental treatment 
Comparison of patients with and without aqueous 
humor free-VEGF present between refill-exchanges 
and CST change from baseline over time 
Comparison of patients with and without aqueous 
humor free-VEGF present between refill-exchanges 
and BCVA score change from baseline over time 
To identify biomarkers that are 
prognostic of response to 
ranibizumab, are associated with 
acquired resistance to ranibizumab, 
are associated with susceptibility to 
developing adverse events (i.e., 
safety biomarkers), can provide 
evidence of ranibizumab activity (i.e., 
pharmacodynamic biomarkers), or 
can increase the knowledge and 
understanding of AMD-related 
disease biology
Relationship between biomarkers in blood and 
aqueous humor with disease characteristics and 
response to ranibizumab
Relationship between genetic variants (such as AMD 
risk alleles, polymorphisms within the complement 
pathway, and polymorphisms within the VEGF-A 
genetic locus) with the disease characteristics and/or 
response to treatment with ranibizumab
Relationship between imaging features with disease 
characteristics and/or response to treatment with 
ranibizumab


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Table 1
Objectives and Corresponding Endpoints (cont.)
Exploratory Patient
Experience Objectives
Corresponding Endpoints
To evaluate the preference of patients 
for ranibizumab delivered via the PDS 
for 40 weeks compared to intravitreal
anti-VEGF treatment received in the 
6 months prior to Day 1
Proportion of patients who report preferring 
ranibizumab treatment via the PDS compared with 
intravitreal anti-VEGF treatment, as assessed by the 
PPPQ, at Week 40 among patients in the implant arm
To evaluate patient-reported treatment 
satisfaction with ranibizumab delivered 
via the PDS for 40 weeks compared 
with that of Q4W intravitreal 
ranibizumab injections, as assessed by 
the MacTSQ
MacTSQ total score at Week 40
ADAanti-drug antibody; AEadverse event; AESIadverse event of special interest; 
AMDage-related macular degeneration; AUC0-6Marea under the concentrationtime curve 
from 0 to 6 months; BCVA best-corrected visual acuity; Cmaxmaximum serum concentration; 
Cminminimum serum concentration; CPT center point thickness; CST central subfield 
thickness; ETDRSEarly Treatment Diabetic Retinopathy Study; MacTSQMacular 
Degeneration Treatment Satisfaction Questionnaire; PDSPort Delivery System with 
ranibizumab; PKpharmacokinetic; PPPQPDS Patient Preference Questionnaire;
Q4W every 4 weeks; Q24W every 24 weeks; SD-OCTspectral domain optical coherence 
tomography; t1/2half-life; VEGFvascular endothelial growth factor.
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
Study GR40548 (Archway) is a Phase III, randomized, multicenter, open-label 
(visual assessormasked), active-comparator study designed to assess the efficacy, 
safety, and pharmacokinetics of ranibizumab 100 mg/mL every 24 weeks (Q24W) 
delivered via the PDS compared with ranibizumab intravitreal 0.5 mg injections every 
4 weeks (Q4W) in patients with nAMD.  Approximately 360 patients were planned to be
enrolled at approximately 90 sites; a total of 418 were recruited. For the study schema, 
see Figure 1.


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Figure 1
Study Schema
Dday; Rdrandomization.
a Patients in the implant arm may be eligible for supplemental treatment with intravitreal ranibizumab 0.5 mg at Weeks 16, 20, 40, 44, 64, 68, 88, 
and 92.
b At Week 96, patients may consent to enter the open-label extension study GR40549 (Portal). In the event a patient is unable to complete 
Archway at Week 96 and enroll in Portal on the same day, follow the alternate scenarios presented in Table 3 and the schedules of activities in 
Appendix 1, Table 3 and Appendix 2, Table 3.


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Patients must satisfy all eligibility criteria at both the screening and the randomization 
visits, including receipt of all screening visit images by the central reading center.  
Historical optical coherence tomography (OCT) images taken around the time of 
diagnosis of nAMD will be evaluated by the central reading center to support 
determination of a patient's eligibility.
If available, fluorescein angiography (FA) images taken around the time of diagnosis of 
nAMD in the study eye should be submitted to the central reading center but will not be 
required to determine eligibility at the screening visit. 
As part of the screening process, the central reading center will evaluate the patient's 
FA, fundus photography (FP), fundus autofluorescence (FAF), and spectral-domain 
optical coherence tomography (SD-OCT) images obtained at the screening visit, as well 
as the patient's historical OCT (mandatory) and historical FA images (if available) taken 
around the time of nAMD diagnosis to provide an objective, masked assessment of 
patient eligibility regarding CNV lesion details (including macular atrophy).  Screening 
visit assessments may be performed on multiple days but must be completed within 7 
days of obtaining informed consent.
Patients who do not meet eligibility criteria (screen-failed patients) may be eligible to 
repeat screening up to two times if deemed appropriate by the investigator.  At 
rescreening, a new screening number will be assigned to the patient through an 
interactive voice or web-based response system (IxRS) and all screening visit 
assessments will be performed except for FA image collection if reading 
centeraccepted images were taken within 12 weeks from the rescreening visit. 
After all eligibility requirements are confirmed, patients will be randomly allocated in a 
3:2 ratio so that approximately 216 patients will receive the PDS implant filled with 
ranibizumab 100 mg/mL Q24W (implant arm) and approximately 144 patients will 
receive intravitreal injections of ranibizumab 10 mg/mL Q4W (intravitreal arm; see 
Figure 1).  On the day of a patient's randomization visit, BCVA will be measured based 
upon the Early Treatment Diabetic Retinopathy Study (ETDRS) chart assessment at a 
starting test distance of 4 meters, and randomization will be stratified by the BCVA score 
(74 letters vs. 74 letters).  Randomization will be performed by the IxRS.
Only one eye will be chosen as the study eye.  If both eyes are eligible, the investigator 
will determine which eye will be selected for study treatment. 


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There are five eligibility scenarios based on prior intravitreal anti-VEGF treatment history 
(see also Table 2):
1.
Patients newly diagnosed with nAMD who are anti-VEGF treatment-naive  
If patients in this group satisfy all other eligibility criteria (other than prior anti-VEGF 
treatment criteria in the study eye, see Section 4.1.1) and sign the Informed 
Consent Form, patients will:

Receive three monthly (28 [7] days) intravitreal ranibizumab 0.5 mg injections
in the run-in period to determine if they demonstrate response to anti-VEGF 
treatment as outlined per the eligibility criteria (see Appendix 3).

After the third run-in intravitreal ranibizumab 0.5 mg injection, patients will 
proceed to screening, scheduled 28 (7) days from the last administered 
intravitreal ranibizumab 0.5 mg injection, and will receive an additional 
intravitreal ranibizumab 0.5 mg injection at the end of the screening visit.

If all eligibility criteria are then met, patients will proceed to the randomization 
visit.
2.
Patients diagnosed with nAMD in the study eye within 9 months prior to 
screening who have been treated with one or two intravitreal anti-VEGF 
injections within the last 6 months
If patients in this group satisfy all other eligibility criteria (other than prior anti-VEGF 
treatment criteria in the study eye, see Section 4.1.1) and sign the Informed 
Consent Form, patients will:

Receive up to three intravitreal ranibizumab 0.5 mg injections in the run-in 
period to meet the required three anti-VEGF intravitreal injections within 6 
months prior to screening (see Appendix 3).  

After completing the required run-in treatments, patients will proceed to 
screening, scheduled 28 (7) days from the last administered intravitreal 
ranibizumab 0.5 mg injection, and will receive an additional intravitreal
ranibizumab 0.5 mg injection at the end of the screening visit. 

If all eligibility criteria are then met, patients will proceed to the randomization 
visit.
3.
Patients diagnosed with nAMD in the study eye within 9 months prior to 
screening who have been treated with three intravitreal anti-VEGF injections 
within 6 months prior to screening
If patients in this group satisfy all other eligibility criteria (see Section 4.1.1) and sign 
the Informed Consent Form, patients will: 

Proceed directly to screening, scheduled 21 days from the last intravitreal 
anti-VEGF injection administered per standard of care, and will receive an 
additional intravitreal ranibizumab 0.5 mg injection at the end of the screening 
visit.  


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
If all eligibility criteria are then met, patients will proceed to the randomization 
visit. 
4.
Patients diagnosed with nAMD in the study eye within 9 months prior to 
screening who have been treated with at least four intravitreal anti-VEGF 
injections within 6 months prior to screening and with the most recent dose 
being aflibercept or bevacizumab
If patients from this group satisfy all other eligibility criteria (see Section 4.1.1) and 
sign the Informed Consent Form, patients will:

Proceed directly to screening, scheduled 21 days from the last intravitreal 
anti-VEGF injection, and will receive an intravitreal ranibizumab 0.5 mg injection 
at the end of the screening visit.

If all eligibility criteria are then met, patients will proceed to the randomization 
visit. 
5.
Patients diagnosed with nAMD in the study eye within 9 months prior to 
screening who have been treated with at least four intravitreal anti-VEGF 
injections within 6 months prior to screening, with the most recent dose being 
ranibizumab
If patients from this group satisfy all other eligibility criteria (see Section 4.1.1) and 
sign the Informed Consent Form, patients will:

Proceed directly to the screening visit, which should be scheduled 7 days from 
the last administered ranibizumab dose, and will not receive another intravitreal 
ranibizumab 0.5 mg injection at the screening visit, provided that the 
randomization and Day 1 visits can be completed within 2128 days after the 
last ranibizumab dose administered in the study eye prior to screening.
If the randomization and Day 1 visit cannot be completed within the allotted 
time window, the patient should be scheduled for a screening visit at 
21 days from the last ranibizumab dose and will receive an additional 
intravitreal ranibizumab 0.5 mg injection at the end of the screening visit.  

If all eligibility criteria are then met, patients will proceed to the randomization 
visit. 
All patients must maintain the 9-month cap on the time from initial nAMD diagnosis to 
the screening visit and must meet the minimum number of required anti-VEGF 
treatments within the last 6 months prior to screening (see Section 4.1.1). 


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Table 2
Dosing Guidelines during Run-in Period and at Screening Visit
Eligibility
Scenario
Historical Anti-VEGF Use in the Study Eye 
within the Last 6 Months prior to Screening
Ranibizumab Dose(s) Required 
prior to Screening (Run-In 
Period)
Ranibizumab at Screening Visit
1
Anti-VEGF treatment-naive 
3 doses
Yes
2
12 previous anti-VEGF doses within the last 
6 months
Up to 3 doses
Yes
3
3 previous anti-VEGF doses within 6 months prior 
to screening
0
Yes
4
4 previous anti-VEGF doses within 6 months 
prior to screening and the most recent dose was 
aflibercept or bevacizumab
0
Yes
5
4 prior previous anti-VEGF doses within 
6 months prior to screening and the most recent 
dose was ranibizumab
0
No
(If randomization and Day 1 visits 
can be completed in required 
timeframe) a
Yes
(If randomization and Day 1 visits 
cannot be completed in required 
timeframe) a
Anti-VEGFantivascular endothelial growth factor.
a Randomization and the Day 1 visits should be completed within 2128 days (inclusive) after last ranibizumab dose in the study eye.


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All patients will return for a randomization visit and the Day 1 visit within 2128 days 
(inclusive) after their last ranibizumab dose.  
Patients who are randomly allocated to the implant arm will have the implant (pre-filled 
with ranibizumab 100 mg/mL) surgically inserted on Day 1, which must occur 17 days 
(inclusive) after randomization (i.e., randomization and Day 1 visit assessments cannot 
be performed on the same day) and no later than 28 days from the last intravitreal 
ranibizumab 0.5 mg injection.  If the implant insertion surgery (Day 1) cannot be 
completed within the visit window after randomization, the randomization visit 
assessments may be repeated and an additional intravitreal ranibizumab 0.5 mg
injection may be required after discussion with the Sponsor.  After Day 1, patients in the 
implant arm will have scheduled safety visit assessments on Days 2 and 7 (2 days) 
and will receive implant refill-exchanges with ranibizumab 100 mg/mL Q24W at Week 24 
(7 days), Week 48 (7 days), and Week 72 (7 days).
Patients who are randomly allocated to the intravitreal arm will receive intravitreal 
ranibizumab 0.5 mg injections starting on Day 1, which is to be administered at the 
conclusion of the randomization visit (i.e., randomization and Day 1 visit assessments 
are performed on the same day).  Patients will receive ranibizumab 0.5 mg, injected 
intravitreally Q4W (7 days) from Day 1 until Week 92.
Study visits will occur according to the schedule of activities in Appendix 1 and 
Appendix 2 relative to Day 1 (first study treatment) and will continue until the patient 
completes the study.  Patients are not expected to attend their scheduled visits if there 
are extenuating circumstances justifying their inability to come to the clinic.  Patients will 
be contacted by site personnel 3 (1) days after each intravitreal ranibizumab injection 
or implant refill-exchange procedure to elicit reports of eye pain, decrease in vision, 
unusual redness, or any other new ocular symptoms in the study eye.  Patients in the 
implant arm will also be asked to verify whether they have taken the prescribed, 
self-administered, post-treatment antimicrobial therapy.  Patients in the intravitreal arm 
will be prescribed self-administered antimicrobial treatments at the investigator’s 
discretion.
In the event a patient's non-study (fellow) eye requires treatment for nAMD, treatment 
with any FDA-approved intravitreal anti-VEGF treatment for nAMD may be administered.  
The Sponsor will provide intravitreal ranibizumab 0.5 mg starting from the screening 
visit, if the investigator chooses to treat the fellow eye with ranibizumab.  Study eye 
treatment and fellow eye treatment with anti-VEGF agents may be done at the same 
study visit; however, the study eye should receive study treatment per protocol prior to 
intravitreal anti-VEGF treatment in the fellow eye.


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Study investigators will be qualified ophthalmologists, trained in the management of 
retinal diseases and ocular surgery, and will be trained by the Sponsor to perform 
study-specific implant initial filling, insertion, refill-exchange, and explantation 
procedures.  The surgical procedures involved in the use of the investigational devices 
are also detailed in the IFU document.  It is strongly preferred that a site has at least one 
investigator who evaluates and treats all patients, with backup investigators selected.  
The site may opt to have more than one investigator, but to maintain consistency in the 
evaluation and treatment of patients, it is strongly suggested that the same physician 
conduct the evaluation and treatment of each individual patient throughout the trial.
Study patients and all study site personnel with the exception of VA examiners will be 
unmasked to the study eye and study treatment assignment.  
The Sponsor recognizes that it may be difficult to fully mask site staff in an open label 
surgical study.
The Sponsor will require that the following steps be implemented as a best attempt to 
mask VA examiners in order to minimize biases in VA assessments. 

The VA examiner will only conduct refraction and VA assessments and will be 
masked as best as possible to patient study eye assignment, study visit type, and 
patient treatment assignment. 

The VA examiner will have no access to a patient's BCVA scores from previous 
visits and will be aware only of the patient's refraction data from previous visits.

The VA examiner may provide no other direct or indirect patient care. 

Patients and unmasked site personnel will be asked not to discuss the study eye 
assignment, study visit type, and patient treatment assignment with the VA 
examiner.
At the Archway Week 96, eligible patients may consent to enter the open-label extension 
Study GR40549 (Portal), designed to evaluate the long-term safety and tolerability of 
PDS, and receive treatment according to the extension study protocol. The Portal 
enrollment visit will occur the same day as Archway Week 96 visit for both arms
(Table 3).  Eligible patients who do not consent to enter the Portal study should complete 
the Archway Week 96 procedures as described in Appendix 1 or Appendix 2, as 
applicable.  In the event that an eligible patient in the implant arm decides not to enter 
Portal, the patient will be instructed to contact their study physician or the Sponsor's 
adverse event reporting line if they experience an adverse event related to the implant.  
Patients must contact their study physician if they elect to remove the implant.


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In order to provide flexibility due to extenuating circumstances and assure appropriate 
patient care, if the patient is unable to complete Archway at Week 96 and enroll into
Portal during the same visit, several alternate final study visit scenarios are available
(Table 3). In general, Archway patients should be provided the opportunity to remain on 
study and receive treatment at regular intervals until consenting patients can enroll into
Portal per-protocol.


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Table 3
Scenarios for Archway Week 96 and Portal Enrollment Visits
IMPLANT ARM a
Scenario
Week 96 (± 7 days)
Monthly Week (X) (± 7 days)
Portal Enrollment Visit
Week 96 and Portal enrollment 
visits can be conducted within 
window.
Conduct the Week 96 visit.
Not Applicable
Conduct the Portal enrollment visit on 
the same day as the Week 96 visit.
Administer the PDS refill-exchange 
(per Portal protocol).
IMPLANT ARM / Alternate Scenarios b
1. Week 96 visit can be conducted 
within window; Portal enrollment 
can only be conducted 
21-28 days post-Week 96 visit.
Conduct the Week 96 visit; 
however do not administer 
a PDS-refill-exchange.
Conduct one Week (X) visit after
Week 96 (i.e., Week 100).
Conduct the Portal Enrollment visit on 
the same day as Week 100 visit.
Administer the PDS refill-exchange 
(per Portal protocol).
2. Week 96 visit can be conducted 
within window; Portal enrollment 
visit is NOT expected to be 
conducted 21-28 days post-
Week 96 visit.
Conduct the Week 96 visit 
and administer a PDS 
refill-exchange.
Conduct monthly Week (X) visits after 
Week 96 until the Portal Enrollment visit 
can be scheduled within the required 
window.
Conduct the Portal Enrollment on the 
same day as the final Week (X) visit.
Administer the PDS refill-exchange 
(per Portal protocol).
3. Week 96 visit is missed.
Not applicable
Conduct a Week (X) visit and 
administer a PDS refill-exchange c.
Conduct monthly Week (X) visits until 
the Portal Enrollment visit can be 
scheduled within the required window.
Conduct the Portal Enrollment visit on 
the same day as the final Week (X)
visit.
Administer the PDS refill-exchange 
(per Portal protocol).
PDSPort Delivery System
a See Appendix 1, Table 2 for Schedule of Activities.
b See Appendix 1, Table 3 for Schedule of Activities.
c If the first Week (X) is also missed, the investigator must contact the Sponsor for further discussion prior to scheduling the next visit.


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Table 3
Scenarios for Archway Week 96 and Portal Enrollment Visits (cont.)
INTRAVITREAL ARM a
Scenario
Week 96 (± 7 days)
Monthly Week (X) (± 7 days)
Portal Enrollment Visit
Week 96 visit and Portal 
enrollment visit can be 
conducted within window.
Conduct the Week 96 visit.
Not Applicable
Conduct the Portal enrollment visit 
on the same day as the Week 96 
visit.
Perform the implant surgery no 
later than 28 days after the last
intravitreal ranibizumab injection 
(per Portal protocol).
INTRAVITREAL ARM / Alternate Scenario b
1. Week 96 visit can be 
conducted within window; 
Portal enrollment can only be 
conducted 21-28 days post-
Week 96 visit.
Conduct the Week 96 visit and 
administer an intravitreal 
ranibizumab injection.
Conduct one Week (X) visit after 
Week 96 (i.e., Week 100); however,
do not administer an intravitreal 
ranibizumab injection.
Conduct the Portal Enrollment 
visit on the same day as the 
Week 100 visit.
Perform the implant surgery no 
later than 28 days after the last
intravitreal ranibizumab injection 
(per Portal protocol).
2. Week 96 visit can be 
conducted within window; 
Portal enrollment is NOT 
expected to be conducted 
21-28 days post-Week 96 
visit.
Conduct the Week 96 visit and 
administer an intravitreal 
ranibizumab injection.
Conduct monthly Week (X) visits 
after Week 96 and administer 
intravitreal ranibizumab injections
until the Portal Enrollment visit can 
be scheduled within the required 
window. At the final Week (X) visit, 
do not administer an intravitreal 
ranibizumab injection.
Conduct the Portal Enrollment 
visit on the same day as the final
Week (X) visit.
Perform the implant surgery no 
later than 28 days after the last 
intravitreal ranibizumab injection.
PDSPort Delivery System
a
See Appendix 1, Table 2 for Schedule of Activities.
b
See Appendix 1, Table 3 for Schedule of Activities.
c
If the first Week (X) is also missed, the investigator must contact the Sponsor for further discussion prior to scheduling the next visit.


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Table 3
Scenarios for Archway Week 96 and Portal Enrollment Visits (cont.)
INTRAVITREAL ARM / Alternate Scenario b (cont.)
3. Week 96 visit is missed.
Not applicable
Conduct monthly Week (X) visits c
and administer intravitreal 
ranibizumab injections until the 
Portal Enrollment visit can be 
scheduled within the required 
window.  At the final Week (X) visit, 
do not administer an intravitreal 
ranibizumab injection.
Conduct the Portal Enrollment 
visit on the same day as the final 
Week (X) visit.
Perform the implant surgery no 
later than 28 days after the last 
intravitreal ranibizumab injection.
PDSPort Delivery System
a See Appendix 2, Table 2 for Schedule of Activities.
b See Appendix 2, Table 3 for Schedule of Activities.
c If the first planned Week (X) is also missed, the investigator must contact the Sponsor for further discussion prior to scheduling the next visit.


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3.2
INTERNAL SAFETY MONITORING 
A safety team will closely monitor patient safety throughout the study to ensure early 
identification and corrective action of procedure- and operator-associated adverse 
events for individual patients.
Unmasked safety data will be reviewed on a routine basis by the Sponsor's safety team 
in order to expeditiously identify and manage risks.  The efficacy data will not be 
reviewed during internal safety monitoring.
3.3
INDEPENDENT DATA MONITORING COMMITTEE
An independent Data Monitoring Committee (iDMC) will monitor safety and study 
conduct on an ongoing basis.  Members of the iDMC will be external to the Sponsor and 
will follow a charter that outlines the iDMC's roles and responsibilities.  The iDMC will 
meet approximately every 6 months (frequency adjustable as required) to evaluate 
unmasked ocular and systemic (non-ocular) safety events both as summary statistics 
and individual patients.  After reviewing the data, the iDMC will provide a 
recommendation to the Sponsor as described in the iDMC Charter.  Final decisions will 
rest with the Sponsor.  Any outcomes of these data reviews that affect study conduct will 
be communicated in a timely manner to the investigators for notification of their 
respective Institutional Review Boards/Ethics Committees (IRBs/ECs).
3.4
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit occurs.  The 
end of study is expected to occur approximately 96 weeks after the last patient is 
enrolled.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 34 months.
3.5
RATIONALE FOR STUDY DESIGN
The PDS is being investigated as an alternate means of delivering ranibizumab in 
patients with nAMD.  Providing ranibizumab treatment through a device designed to 
provide continuous drug delivery for up to 6 months may reduce the number of required 
office visits and the frequency of drug administration necessary in clinical practice, while 
achieving efficacy similar to that observed in pivotal ranibizumab trials.  In addition, 
improved compliance that may result from such a regimen might lead to enhanced long-
term vision outcomes for patients.


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3.5.1
Rationale for Ranibizumab Dose and Schedule
The ranibizumab 100 mg/mL administered to patients via the PDS implant and the 
24-week refill-exchange interval were selected on the basis of:

Observed efficacy and safety data from Study GX28228 (Ladder), which evaluated 
a range of ranibizumab formulations (10 mg/mL, 40 mg/mL, and 100 mg/mL) and a 
refill-exchange dosing regimen based on pre-specified criteria

Pharmacokinetic (PK)-efficacy modeling and simulation for the 100-mg/mL 
formulation
Taken together, the above data and analyses support that ranibizumab 100 mg/mL will 
deliver pharmacologically efficacious concentrations of ranibizumab in the majority of 
patients over the entire dosing interval of 24 weeks.
Based on the implant fill volume of 20 L, the maximum amount of ranibizumab that can 
be initially filled and subsequently refilled is approximately 2 mg for the 100-mg/mL 
formulation.  Total local (i.e., vitreal) and systemic drug exposures with the 100-mg/mL 
formulation Q24W are estimated to be below the drug exposures from the intravitreal 
ranibizumab 0.5 mg injections and the highest ranibizumab dose tested (monthly 
intravitreal ranibizumab 2 mg injections).
3.5.2
Rationale for Patient Population 
Ranibizumab has been shown to be effective in improving and maintaining vision in 
patients with nAMD; therefore, this patient population was selected to evaluate the PDS 
with ranibizumab 100 mg/mL.  This study will enroll only patients with nAMD who have 
received multiple anti-VEGF treatments to control a recently active CNV lesion and who 
demonstrated a response to those injections.  This approach aims to limit the number of 
patients who would potentially not respond to continuous delivery of ranibizumab, thus 
minimizing the chance for an individual anti-VEGF non-responder to undergo surgery 
and receive the PDS implant.
The goal of exposing patients with nAMD to the PDS is to demonstrate a treatment 
approach that maintains the efficacy seen with monthly anti-VEGF intravitreal injections, 
while offering the potential for reduced monitoring, more sustained disease control, and 
better long-term visual outcomes than currently observed in clinical practice, in which 
many patients are treated less frequently than monthly and experience suboptimal 
efficacy as a consequence.
3.5.3 Rationale for Control Group
Ranibizumab administered via intravitreal injection is an approved, standard-of-care 
treatment for nAMD in the United States, the European Union, and many other countries 
worldwide.  The monthly dosing of intravitreal ranibizumab 0.5 mg is the most effective 
approved regimen based on United States product labeling for ranibizumab and was 
therefore selected as the most appropriate control group.


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3.5.4 Rationale for Pharmacokinetic Sample Collection Schedule
The objective of the serum PK sampling is to characterize the serum pharmacokinetics 
of ranibizumab delivered via the PDS in the implant arm and to assess the potential 
impact of immunogenicity on pharmacokinetics.  The serum pharmacokinetics of 
ranibizumab following intravitreal administration has been well characterized; however, 
the PK profile for continuous delivery is expected to be markedly different (by design).
In this study, PK serum samples will be collected from all patients at all sites at the 
randomization visit and at Weeks 4, 24, 36, and 96 to align with anti-drug antibody 
(ADA) sample collection timepoints.  At selected sites, additional PK samples will be 
collected from patients in the implant arm on Days 2 and 7 and Weeks 12, 48, and 72.  
The sampling timepoints through Week 24 are expected to be sufficient to estimate the 
half-life for ranibizumab delivery from the implant, and sampling timepoints at 
Weeks 3696 will be assessed to ensure consistent drug delivery over time.  Limited PK 
sampling will occur in the intravitreal arm (control) because the serum pharmacokinetics 
of ranibizumab following intravitreal administration has been well characterized, as 
presented in the PDS Investigator's Brochure. In addition, at selected sites, a PK sample 
will be collected in patients in the intravitreal arm 1 to 5 days after an intravitreal 
ranibizumab 0.5 mg injection in order to collect a sample near Cmax.
See Appendix 1 and Appendix 2 for sample collection timepoints.  
3.5.5
Rationale for Immunogenicity Sample Collection
The objective of serum sampling for ADA testing is to characterize the immunogenicity of 
ranibizumab delivered via the PDS in the implant arm compared with patients receiving 
ranibizumab by intravitreal administration.  The immunogenicity of ranibizumab following 
intravitreal administration has been well characterized, and the incidence of ADAs in the 
context of the delivery system is not expected to be markedly different.  The sampling 
timepoints for ADA assessment will ensure that the anti-ranibizumab immunogenicity 
profile of patients in the study is monitored throughout the study.
Serum ADA samples will be collected from all patients at the randomization visit and at 
Weeks 4, 24, 36, and 96 (see Appendix 1 and Appendix 2).
3.5.6
Rationale for Biomarker Assessments
Previous studies have demonstrated a broad range of treatment needs across patients 
(Ho et al. 2014); thus, some patients in the implant arm may require additional 
treatment(s) with ranibizumab outside of the fixed 24-week dosing interval.  To better 
understand the cause of their increased treatment needs, aqueous humor samples from 
patients who require supplemental treatment will be collected (just prior to the 
supplemental treatment and at the next subsequent visit) and analyzed for drug and/or 
free-VEGF concentrations and correlated with retreatment need.  In addition, aqueous 
humor, plasma, and serum samples will be collected from patients who terminate study 


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treatment early or who undergo explantation.  Information obtained from these analyses 
will be used in an effort to better understand variability in treatment need and to identify 
patients best suited for continuous delivery of ranibizumab.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 360 patients with CNV secondary to AMD, diagnosed within 9 months 
prior to screening and treated with at least three injections with any anti-VEGF agent 
within the last 6 months prior to screening, were planned to be enrolled in this study; a 
total of 418 patients were ultimately recruited.
4.1.1
Inclusion Criteria
4.1.1.1
General Inclusion Criteria
Patients must meet the following general inclusion criteria at screening and 
randomization for study entry:

Ability and willingness to provide signed informed consent
Additionally, patients must provide Health Insurance Portability and 
Accountability Act (HIPAA) authorization.

Age 50 years, at time of signing Informed Consent Form

Ability and willingness to undertake all scheduled visits and assessments

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, 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 at least 28 days after the last 
intravitreal injection of ranibizumab or 1 year after the last implant refill-exchange
of ranibizumab.
A woman is considered to be of childbearing potential if she is post-menarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).  The definition 
of childbearing potential may be adapted for alignment with local guidelines or 
requirements.
Examples of 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.


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4.1.1.2
Ocular Inclusion Criteria
Patients must meet the following ocular inclusion criteria for the study eye for study 
entry:

Initial diagnosis of exudative nAMD within 9 months prior to the screening visit 

Previous treatment with at least three anti-VEGF intravitreal injections 
(e.g., ranibizumab, bevacizumab, or aflibercept) for nAMD per standard of care 
within 6 months prior to the screening visit
If a patient did not receive at least three anti-VEGF injections as described 
above but is otherwise eligible for the study, the patient can be treated in a run-
in phase to meet this specific criterion.

Demonstrated response to prior anti-VEGF intravitreal treatment since diagnosis, as 
evidenced at screening by the following:
Overall decrease in nAMD disease activity detected on SD-OCT, as assessed 
by the investigator and confirmed by the central reading center
and
Stable or improved BCVA

BCVA of 34 letters or better (20/200 or better approximate Snellen equivalent), 
using ETDRS chart at a starting distance of 4 meters (see the BCVA manual for 
additional details) at screening and randomization visits

All subtypes of nAMD lesions are permissible (i.e., type I, type II, type III, or mixed 
forms per OCT classification)
nAMD lesions at the time of diagnosis must involve the macula (6-mm diameter 
centered at the fovea).

Sufficiently clear ocular media and adequate pupillary dilation to allow for analysis 
and grading by the central reading center of FP, FA, FAF, and SD-OCT images
4.1.2
Exclusion Criteria
4.1.2.1
Prior Ocular Treatment 
Patients who meet any of the following prior ocular treatment exclusion criteria will be 
excluded from study entry.
Study Eye

History of vitrectomy surgery, submacular surgery, or other surgical intervention for 
AMD

Prior treatment with Visudyne®, external-beam radiation therapy, or transpupillary 
thermotherapy

Previous treatment with corticosteroid intravitreal injection

Previous intraocular device implantation

Previous laser (any type) used for AMD treatment


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Either Eye

Treatment with anti-VEGF agents other than ranibizumab within 1 month prior to the 
randomization visit

Prior participation in a clinical trial involving anti-VEGF drugs within 6 months prior 
to the randomization visit, other than ranibizumab
4.1.2.2
CNV Lesion Characteristics
Patients who meet any of the following exclusion criteria related to CNV lesion 
characteristics will be excluded from study entry.
Study Eye

Subretinal hemorrhage that involves the center of the fovea, if the hemorrhage is 
greater than 0.5-disc area (1.27 mm2) in size at screening

Subfoveal fibrosis or subfoveal atrophy 
Either Eye

CNV due to other causes, such as ocular histoplasmosis, trauma, or pathologic 
myopia
4.1.2.3
Concurrent Ocular Conditions
Patients who meet any of the following exclusion criteria related to concurrent ocular 
conditions will be excluded from study entry.
Study Eye

Retinal pigment epithelial tear

Any concurrent intraocular condition (e.g., cataract, glaucoma, diabetic retinopathy, 
or epiretinal membrane) that would either require surgical intervention during the 
study to prevent or treat visual loss that might result from that condition or affect 
interpretation of study results

Active intraocular inflammation (grade trace or above)

History of vitreous hemorrhage

History of rhegmatogenous retinal detachment

History of rhegmatogenous retinal tears or peripheral retinal breaks within 3 months 
prior to the randomization visit

Aphakia or absence of the posterior capsule
Previous violation of the posterior capsule is also an exclusion criterion unless it 
occurred as a result of yttrium-aluminum garnet (YAG) laser posterior 
capsulotomy in association with prior, posterior chamber intraocular lens 
implantation.

Spherical equivalent of the refractive error demonstrating more than 8 diopters of 
myopia


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
Preoperative refractive error that exceeds 8 diopters of myopia, for patients who 
have undergone prior refractive or cataract surgery in the study eye

Intraocular surgery (including cataract surgery) within 3 months preceding the 
randomization visit

Uncontrolled ocular hypertension or glaucoma (defined as intraocular pressure [IOP] 
25 mmHg or a cup to disc ratio 0.8, despite treatment with antiglaucoma 
medication) and any such condition the investigator determines may require a 
glaucoma-filtering surgery during a patient's participation in the study

History of glaucoma-filtering surgery, tube shunts, or microinvasive glaucoma 
surgery

History of corneal transplant

History of prior vitrectomy surgery and absence of posterior capsule
Either Eye

History of idiopathic or autoimmune-associated uveitis

Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis
4.1.2.4
Concurrent Systemic Conditions
Patients who meet any of the following exclusion criteria related to concurrent systemic 
conditions will be excluded from study entry:

Inability to comply with study schedule or procedures as described in the study 
protocol 

Uncontrolled blood pressure (defined as systolic blood pressure 180 mmHg and/or 
diastolic blood pressure 110 mmHg, while a patient is at rest)
If a patient's initial measurement exceeds these values, a second reading may be 
taken 30 or more minutes later.  If the patient's blood pressure must be controlled 
by antihypertensive medication, the patient may become eligible if medication is 
taken continuously for at least 30 days prior to Day 1.

History of stroke within the last 3 months prior to informed consent

Uncontrolled atrial fibrillation within 3 months of informed consent

History of myocardial infarction within the last 3 months prior to informed consent

History of other disease, metabolic dysfunction, or clinical laboratory finding giving 
reasonable suspicion of a disease or condition that contraindicates the use of 
ranibizumab or placement of the implant and that might affect interpretation of the 
results of the study or renders the patient at high risk of treatment complications in 
the opinion of the investigator

Current systemic treatment for a confirmed active systemic infection

Use of any systemic anti-VEGF agents

Chronic use of oral corticosteroids (10 mg/day of prednisone or equivalent)


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
Active cancer within 12 months of randomization except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, and prostate cancer 
with a Gleason score of 6 and a stable prostate-specific antigen for 12 months

Previous participation in any non-ocular (systemic) disease studies of investigational 
drugs within 1 month preceding the informed consent (excluding vitamins and 
minerals)

Use of antimitotic or antimetabolite therapy within 30 days or 5 elimination half-lives 
of the randomization visit

Requirement for continuous use of any medications or treatments indicated in 
Section 4.4.2, "Prohibited Therapy"

Pregnant or breastfeeding, or intending to become pregnant during the treatment 
period and for at least 28 days after the last intravitreal injection of ranibizumab or 
1 year after the last implant refill-exchange of ranibizumab
Women of childbearing potential, including those who have had tubal ligation, 
must have a urine pregnancy test at screening and at specified subsequent 
visits.  If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test.
4.2
METHOD OF TREATMENT ASSIGNMENT AND MASKING 
4.2.1
Randomization and Masking
Patients will be randomly allocated in a 3:2 ratio so that approximately 216 patients will 
receive the PDS implant with ranibizumab 100 mg/mL Q24W and approximately 
144 patients will receive Q4W intravitreal ranibizumab 0.5 mg injections.  On the day of a 
patient's randomization visit, BCVA will be measured based upon the ETDRS chart 
assessment at a starting test distance of 4 meters and randomization will be stratified by 
the BCVA score (74 letters vs. 74 letters).  Randomization will be performed through 
an IxRS. 
The Sponsor recognizes that it may be difficult to fully mask site staff in an open label 
surgical study.
The Sponsor will require that the following steps be implemented as a best attempt to 
mask VA examiners in order to minimize biases in VA assessments. 

The VA examiner will only conduct refraction and VA assessments and will be 
masked as best as possible to patient study eye assignment, study visit type, and 
patient treatment assignment. 

The VA examiner will have no access to a patient's BCVA scores from previous 
visits and will be aware only of the patient's refraction data from previous visits.

The VA examiner may provide no other direct or indirect patient care.

Patients and unmasked site personnel will be asked not to discuss the study eye 
assignment, study visit type, and patient treatment assignment with the VA 
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Patients and study site personnel (except VA examiner) will not be masked with regard 
to patient assignment to the intravitreal arm or the implant arm because of the difficulties 
of maintaining masking following the surgical procedure.  Additional safety visits will be 
applicable only to the implant arms, and implant visualization will occur during 
ophthalmic examinations.
Ocular images obtained from patients will be forwarded to the central reading center for 
masked analysis and/or storage.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are the PDS with 
ranibizumab (100 mg/mL) and the monthly intravitreal ranibizumab 0.5 mg.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Port Delivery System with Ranibizumab 
The PDS, described in Section 1.3 and Appendix 16, will be supplied by the Sponsor.  
For detailed information on the PDS components and the initial implant filling, insertion,
refill-exchange, and explantation procedures, as well as contraindicated uses, consult 
the PDS IFU and PDS Investigator's Brochure. 
The implant, insertion tool, initial fill needle, refill needle, and explant tool should be 
maintained at a room temperature below 25C (77F).  The storage location at the 
clinical site must have restricted access and be available only to study personnel.  The 
implant and insertion tool are supplied sterilized by exposure to ethylene oxide.  The 
initial fill needle, refill needle, and explant tool are sterilized by electron-beam 
processing. 
The PDS components must not be re-sterilized because of the possibility of damaging 
the mechanical integrity of the implant and ancillary devices.
The packages should be opened only immediately prior to use.
Do not use if the package is damaged, punctured, or broken as sterility may be 
compromised.  Do not use beyond the expiration date.
Note:  Unless otherwise directed by the Sponsor, only ranibizumab (100 mg/mL) will be 
injected into the implant.
4.3.1.2
Formulation of Ranibizumab 100 mg/mL Used to Fill or Refill-
Exchange the Implant
Ranibizumab 100 mg/mL for the PDS will be supplied by the Sponsor for the initial fill 
and refill-exchange of the implant.  


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Contents should not be frozen or shaken and should be protected from direct light.  
Ranibizumab must be refrigerated at 2°C8°C (36°F46°F) upon receipt until used.  
Sites must monitor and record refrigerator temperature at all times (24 hours per day, 
7 days per week).  Store in original carton before and after use.  Ranibizumab will be 
labeled as required by the relevant regulatory agencies.
For further details, see the pharmacy manual.
4.3.1.3
Formulation of Intravitreal Ranibizumab 10 mg/mL
Ranibizumab for intravitreal injection will be supplied by the Sponsor and is formulated 
as a sterile, colorless to pale yellow solution.  Ranibizumab is supplied as a 
preservative-free, sterile solution in a single-use container designed to deliver 0.05 mL of 
ranibizumab 10 mg/mL solution with 10 mM histidine hydrochloride, 10% ,-trehalose 
dihydrate, 0.01% polysorbate 20, pH 5.5.  Ranibizumab contents should not be frozen or 
shaken and should be protected from direct light.  Ranibizumab contents must be 
refrigerated at 2°C8°C (36°F46°F) upon receipt until used. 
For further details, see the pharmacy manual.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of accidental overdose or medication error, along 
with any associated adverse events, should be reported as described in
Section 5.3.5.12). 
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1.5.
4.3.2.1
Port Delivery System with Ranibizumab
Study investigators must adhere to study-specific implant initial filling, insertion, refill-
exchange, and explantation procedures as outlined in the PDS IFU document.
Patients will have the implant (filled prior to implantation with approximately 20 L of the 
100-mg/mL formulation of ranibizumab [approximately 2-mg dose of ranibizumab]) 
surgically inserted in the study eye at the Day 1 visit following their randomization visit.  
After the initial fill of the implant with ranibizumab, patients will receive implant refill-
exchanges at fixed 24-week intervals.  
At each refill-exchange, a volume of approximately 100 L ranibizumab will be injected 
in situ into the implant through the septum to exchange the remaining contents of the 
implant with newly introduced ranibizumab.  The volume of newly introduced 
ranibizumab remaining in the implant after the refill-exchange procedure will be 
approximately 20 L.  Missed implant refill-exchanges should be made up no later than 


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the next scheduled study visit.  If at the next scheduled study visit the implant refill-
exchange cannot be performed, the investigator must contact the Sponsor for further 
discussion prior to administering future implant refill-exchanges.  Subsequent refill-
exchanges will be administered according to the study treatment schedule relative to 
Day 1 as outlined in Appendix 1 until patients complete the study.
A representative from the Sponsor or an affiliate of the Sponsor may be present during 
the study-specific PDS surgeries or procedures (initial filling, insertion, refill-exchange, 
and/or explantation) and/or other PDS-related surgeries or procedures to provide 
technical support to investigators during the use of the PDS and/or to observe the 
procedures related to the PDS.
4.3.2.2
Ranibizumab Intravitreal Injection
Ranibizumab (10 mg/mL) will be provided by the Sponsor and used in the study eye 
during the run-in period and at the screening visit for applicable patients; as study 
treatment for patients in the intravitreal arm; as supplemental treatment for the implant 
arm; if delaying surgery is required; as nAMD treatment in the fellow eye for patients, per 
investigator’s discretion; and if a patient in the PDS arm discontinues study treatment 
and starts receiving ranibizumab intravitreal injections in study eye, per investigator’s 
discretion.
Commercially available intravitreal ranibizumab 0.5 mg supply may be used only if an 
intravitreal ranibizumab injection is necessary per protocol and study supply is not 
available at the site. Prior to administering commercial supply ranibizumab, the site will 
need to obtain Sponsor’s approval.
Patients in the intravitreal arm will receive their first intravitreal injection of 50 L of the 
ranibizumab 10 mg/mL (0.5-mg dose) at the Day 1 visit, which will occur at the 
conclusion of the randomization visit.  Afterward, patients will receive intravitreal 
ranibizumab injections of 50 L of the 10-mg/mL formulation Q4W at each scheduled 
study visit until Week 92 (see Appendix 2, Table 3 for guidance on additional intravitreal 
injections post-Week 92 due to extenuating circumstances).  Missed treatments will not 
be made up.  Study visits for the intravitreal arm will be scheduled to occur according to 
the schedule of activities in Appendix 2 and are relative to the Day 1 visit. 
Guidelines for treatment interruption or discontinuation are provided in Section 5.1.5.2
and Table 4. 
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (PDS with ranibizumab and intravitreal
ranibizumab) will be provided by the Sponsor where required by local health authority 
regulations.  The study site will acknowledge receipt of IMPs supplied by the Sponsor 
using the IxRS to confirm the shipment condition and content.  Any damaged shipments 
will be replaced.


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Prior to site closure, IMPs will either be disposed of at the study site according to the 
study site's institutional standard operating procedure or be returned to the Sponsor with 
the appropriate documentation, except all unused PDS components that should be 
returned to the Sponsor.  The site's method of destroying Sponsor-supplied IMPs must 
be agreed to by the Sponsor.  The site must obtain written authorization from the 
Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must be 
documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log and should provide a 
complete accounting of all IMPs provided by the Sponsor.
4.3.4
Continued Access to Port Delivery System with Ranibizumab
The Sponsor will offer continued access to Roche IMP (PDS with ranibizumab) free of 
charge to eligible patients in accordance with the Roche Global Policy on Continued 
Access to Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive Roche IMP (PDS with ranibizumab) after completing 
the study if all of the following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them.
A patient will not be eligible to receive Roche IMP (PDS with ranibizumab) after 
completing the study if any of the following conditions are met:

The Roche IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the IMP or data suggest that the IMP 
is not effective for nAMD

The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
nAMD

Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf


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Patients may be eligible to receive PDS with ranibizumab as part of an extension study, 
as described in Section 3.1.
4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medications (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient in addition to protocol-mandated treatment from 7 days prior to the 
randomization visit until conclusion of the patient's study participation or early 
termination visit.  All such medications should be reported to the investigator and 
recorded on the Concomitant Medications eCRF except for ranibizumab treatment of 
either eye (if applicable), which will be recorded on a separate eCRF log. 
4.4.1
Permitted Therapy 
Patients who use other maintenance therapy should continue its use unless prohibited 
as indicated in Section 4.4.2.  All concomitant medications should be reported to the 
investigator and recorded on the appropriate eCRF.  
Patients are permitted to use the following therapies during the study:

Intravitreal administration of FDA-approved anti-VEGF agents, including 
Sponsor-provided ranibizumab 0.5 mg, at the discretion of the evaluating investigator 
if a patient's fellow eye requires treatment for nAMD 
If the fellow eye is to receive an FDA-approved intravitreal anti-VEGF agent, 
treatment may be administered at the same visit as the study eye treatment.  All 
study assessments and study eye treatment per protocol should be completed 
prior to anti-VEGF administration in the fellow eye.  Individual trays and sterile 
preparation must be separately prepared for each eye treatment.

Continuous use of aspirin or nonsteroidal anti-inflammatory drug (NSAID) treatment, 
except as outlined below
All patients randomized to the implant arm and receiving ongoing aspirin or 
NSAID treatment must interrupt aspirin or NSAID treatment for 7 days prior to 
implant surgery.  Interruption of these medications must be pre-planned at the 
screening visit to avoid delay in implant surgery.  These medications can be 
restarted, if appropriate, after the Day 2 safety visit occurs.  One-time use of 
aspirin or NSAIDs for pain management after implantation is allowed.

Ongoing anticoagulant or antiplatelet therapy (other than aspirin or other NSAIDs), 
as outlined below 
Patients randomized to the implant arm who are receiving ongoing 
anticoagulant or antiplatelet therapy (other than aspirin or other NSAIDs) could 
be enrolled if they can safely and are willing to temporarily interrupt these 
medications prior to Day 1, after discussion with their prescribing physician.  
Oral anticoagulants include vitamin K antagonists (e.g., warfarin), direct factor 
Xa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, fondaparinux), and direct 


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thrombin inhibitors (e.g., dabigatran).  Antiplatelet therapies include clopidogrel, 
prasugrel, dipyridamole, ticagrelor, and ticlopidine.  The duration of the 
treatment interruption period should be deferred to the investigator in 
consultation with prescribing physician and should be made on the basis of the 
risks of oral anticoagulant or antiplatelet therapy weighed against potential 
benefits and in consideration of the medication’s prescribing information.  
Interruption of these medications must be pre-planned at the screening visit to 
avoid delay in implant surgery.  These medications can be restarted after the 
Day 2 safety visit occurs.

Cataract surgery in the study eye, if clinically indicated and occurring 7 or more days 
after the last study treatment, with the next study treatment held for 7 or more days 
following the surgery

Treatment, as clinically indicated, for the onset of increased IOP and/or glaucoma in 
the study eye during a patient’s study participation

Use of topical steroids post-implant insertion or post-explantation surgery in the 
study eye 

Conditional use of magnetic resonance imaging (MRI) scans for patients in the 
implant arm
Note that a patient with the PDS implant can be safely scanned in an MR 
system meeting the following conditions: 
–
Static magnetic field of 1.5-Tesla (1.5 T) or 3-Tesla (3 T) 
–
Maximum spatial field gradient of 3,000 G/cm (30 T/m) 
–
Maximum MR system reported, whole body averaged specific absorption 
rate (SAR) of 4.0 W/kg (First Level Controlled Operating Mode)
For additional information refer to the current PDS IFU document. 
4.4.2
Prohibited Therapy
Use of the following concomitant therapies is prohibited as described below:

Concurrent use of any systemic anti-VEGF agents 

Concurrent study eye treatment for nAMD with anti-VEGF agents other than the 
study-assigned treatment 

Concurrent fellow eye treatment for nAMD with unapproved anti-VEGF therapy 

Concurrent treatment with laser photocoagulation (any type) for nAMD in the study 
eye 

Concurrent treatment with Visudyne® for nAMD in study eye 

Concurrent use of intravitreal corticosteroids in the study eye 

Concurrent use of subtenon corticosteroids in the study eye (except at the 
conclusion of PDS implantation or explantation surgery)


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
Concurrent use of and participation in other experimental therapies (except those 
with minerals and vitamins)
Note:  If patients receive any of the above listed treatments at any time during the study, 
the Sponsor will determine if discontinuation of the study treatment is required. 
4.5
STUDY ASSESSMENTS
The schedule of activities to be performed during the study is provided in Appendix 1
and Appendix 2.  All activities should be performed and documented for each patient.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.
All screening and randomization visit evaluations must be completed and reviewed to 
confirm that patients meet all eligibility criteria.  The investigator will maintain a screening 
log to record details of all patients screened and to confirm eligibility or record reasons 
for screening failure.
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
and use of alcohol will be recorded at baseline.  In addition, all medications 
(e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic 
remedies, nutritional supplements) other than protocol-specified procedural medications 
(e.g., dilating drops, fluorescein dyes, cefazolin or vancomycin, implant insertion, 
refill-exchange and explantation procedures medications, and pre- and post-treatment 
medications [e.g., proparacaine, antimicrobials, steroids]) used by the patient within 
7 days prior to initiation of study treatment will be recorded.
All intravitreal anti-VEGF medications administered to the patient within 9 months prior to 
the screening visit will also be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Height and Weight
A patient's height and weight will be recorded. 
4.5.4
Vital Signs
Vital signs will include measurements of pulse and systolic and diastolic blood pressure 
while the patient in a seated position after resting for 5 minutes.


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4.5.5
Ocular Assessments
Except where noted, all of the following ocular assessments should be performed for 
both eyes:

BCVA, as assessed on an ETDRS chart at a starting distance of 4 meters 
(performed prior to dilating eyes)

IOP measurement
–
At each visit, perform IOP measurement prior to dilating eyes or refill-exchange
procedure; the method used for a patient must remain consistent throughout 
the study for visits in the office.
–
Before implant insertion or explantation surgery, the treating physician must 
check IOP for the study eye using indentation tonometry.
–
Upon completion of the implant insertion or explantation surgery, the treating 
physician will check IOP for the study eye only by digital palpation before 
patching the eye.

Slitlamp examination (for grading scales for anterior and vitreous flare/cells and 
vitreous hemorrhage density; see Appendix 7) 

Dilated binocular indirect high-magnification ophthalmoscopy 
In addition, examinations will be performed for patients in the implant arm after 
implant insertion in the study eye and on Days 2 and 7 (2 days); afterward, 
dilated ophthalmoscopy examinations will be performed at each visit to monitor 
the implant placement, and to evaluate other implant problems.

Finger-counting test, followed by hand motion and light perception tests 
(as applicable) performed by the treating physician within 15 minutes following 
implant refill-exchange or intravitreal ranibizumab treatment for the study eye only
Patients will remain at the surgical center after implant insertion and in the office after 
implant refill-exchange until the designated physician has assessed that there are no 
safety concerns following treatment, at which point the patient will be allowed to leave.  If 
any safety concerns or immediate toxicity is noted, the patient will remain and will be 
treated according to the designated physician’s clinical judgment.  If applicable, the 
adverse event and the adverse event treatment must be reported on the appropriate 
eCRF page.
Additional non-invasive ocular assessments may be performed by the investigator to 
explore patient factors related to the implant surgical procedures, regardless of whether 
a safety event occurred in a particular patient or not.  Results of the additional ocular 
assessments will be forwarded to the Sponsor for evaluation and/or storage. 
4.5.6
Ocular Imaging
The central reading center will provide a central reading center manual and training 
material to sites for specified study ocular images.  Before any study images are 
obtained, site personnel, test images, room, systems, and software (where applicable) 


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will be certified and validated by the reading center as specified in the central reading 
center manual.  All ocular imaging assessments will be obtained by trained site 
personnel at the study sites and forwarded to the central reading center for analysis 
and/or storage.  Ocular images obtained from patients will be retained by the reading 
center and will later be transferred to Roche. They may also be included in future 
exploratory analysis.
Note:  After randomization, if a patient misses a study visit when ocular images are 
scheduled (see Appendix 1 and Appendix 2), images should be obtained at the next 
scheduled visit the patient attends. 
The following ocular images of both eyes will be collected from all study patients:

Fundus photographs (see Appendix 10)

Lens photographs (fundus reflex photographs)

FA images (to be performed after laboratory samples are obtained; see 
Appendix 11)

Fundus autofluorescence images (Appendix 9)

SD-OCT scans (see Appendix 12)
Note: Center point thickness (CPT) is defined as the retinal thickness in the center 
point of the fovea measured between the internal limiting membrane and the inner 
third of the retinal pigment epithelium layer. Central subfield thickness (CST) is 
defined as the average thickness of the central 1 mm circle of the ETDRS grid 
centered on the fovea measured between the internal limiting membrane and the 
Bruch’s membrane (see central reading center manual).
The following ocular images will be collected only from the study eye of patients in the 
implant arm and forwarded to the reading center for evaluation and/or storage and will 
later be transferred to Roche: 

Implant photographs (high-magnification of the implant in the eye through dilated 
pupil and outside the eye; see Appendix 13) 
The following ocular images of both eyes will be collected from all study patients at 
selected sites that have OCT angiography equipment and forwarded to the reading 
center for evaluation and/or storage and will later be transferred to Roche: 

OCT-angiography images (see Appendix 10) 
Additional non-invasive ocular assessments (e.g., ocular B-scan ultrasonography or 
ultrasound biomicroscopy) may be performed by the investigator to explore patient 
factors related to the implant surgical procedures, regardless of whether a safety event 
occurred in a particular patient or not.
Ocular images collected from study patients may be evaluated using advanced analytics 
tools (e.g., artificial intelligence-based tools) to assess clinically relevant features.


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4.5.7
Laboratory, Biomarker, and Other Biological Samples
Samples for the laboratory tests listed below should be obtained prior to study eye 
treatment and FA (if applicable) for all study patients. Patients are not required to fast 
prior to sample collection.  Samples will be shipped to a central laboratory and/or the 
Sponsor or a selected designee for analysis and/or storage. All instructions for 
obtaining, processing, storing, and shipping specimens are provided in the laboratory 
manual. Laboratory supply kits will be provided to the sites by the central laboratory.  
Refer to Appendix 1, Appendix 2, and Appendix 5, for sample collection timepoints and 
Appendix 15 for biological sample collection and shipping instructions.
The following assessments will be performed:

Hematology: hemoglobin, hematocrit, quantitative platelet count, RBCs, WBCs, and 
differentials, including neutrophils, bands, lymphocytes, basophils, eosinophils, and 
monocytes (absolute and percent) 

Serum chemistry: bicarbonate or total carbon dioxide (if considered standard of care 
for the region), sodium, potassium, chloride, glucose, BUN, creatinine, calcium, 
phosphorus, total and direct bilirubin, total protein, albumin, AST, ALT, lactic 
dehydrogenase, ALP, and uric acid 

Urinalysis: specific gravity, pH, blood, protein, ketones, glucose, bilirubin, 
urobilinogen, and microscopic examination (if any of the preceding urinalysis tests, 
other than glucose and ketones, are abnormal)

Coagulation:  aPTT and PT 

Serum pregnancy test (if required)

Serum samples for measurement of ADAs

Serum samples for measurement of ranibizumab concentration

Aqueous humor, serum, and plasma samples (from supplemental treatment and the 
subsequent study visit, early termination, and implant explantation visits) for
exploratory biomarker research (including free-VEGF) and/or PK analysis

At selected sites, additional serum PK samples will be collected from the patients in 
the intravitreal arm 1-5 days after an intravitreal ranibizumab 0.5 mg injection (see 
Appendix 2).
Every attempt should be made to collect all samples prior to the primary analysis 
time point, which will occur when all patients have completed their Week 40 visit.
The sample collection may be performed at the study site or by a mobile nursing 
(MN) professional at the patient's home or another suitable location. The Sponsor 
will select a healthcare company that will be responsible for providing MN services 
for participating sites (the MN vendor).  The MN vendor is responsible for ensuring 
that all MN professionals are licensed, qualified, and in good standing, as per 
applicable regulations, and that appropriate background checks have been 
performed.


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Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Pregnancy test 
All women of childbearing potential, including those who have had tubal ligation, 
will have a urine pregnancy test at screening and at specified subsequent visits.  
If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy 
test, which will be sent to a central laboratory. 
The following samples will be obtained from patients in the implant arm only and may be 
analyzed in the future:

Explanted implant with contents (explanted implant containing a mixture of 
ranibizumab drug product and vitreal components diffused into the implant), 
preserved for potential analysis upon explantation procedure
Exploratory biomarker research may include, but will not be limited to, analysis of growth 
factors and cytokines associated with angiogenesis and genes associated with AMD 
risk.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.10), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions:

Serum 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.

Aqueous, plasma, and serum samples collected during supplemental treatment and 
the subsequent study visit, early termination, and implant explantation visits will be 
destroyed no later than 5 years after the final Clinical Study Report has been 
completed.
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 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.


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4.5.8
Patient Preference and Treatment Satisfaction
Patient preference and treatment satisfaction will be assessed using the PDS Patient 
Preference Questionnaire (PPPQ) and Macular Degeneration Treatment Satisfaction 
Questionnaire (MacTSQ).  Patient preference and treatment satisfaction questionnaires 
will be administered by an interviewer prior to any other visit assessments being 
performed.  Interviews will be conducted using versions of the questionnaire translated 
into the spoken language of the patient.  Patients may be excluded from completing 
these assessments if a translation is not available in their spoken language.
4.5.8.1
Port Delivery System Patient Preference Questionnaire
The PPPQ is a 3-item questionnaire that captures a patient's preference for treatment, 
the strength of their preference, and the reasons for their preference.  The PPPQ will be 
administered only to patients in the implant arm, who will have received intravitreal 
anti-VEGF treatment prior to Day 1.  The PPPQ was developed from patient preference 
questionnaires in the literature, modified for use with the PDS (Pivot et al. 2013; 
Rummel et al. 2017).
Refer to Patient Questionnaire Booklet for copy of the PPPQ.
4.5.8.2
Macular Degeneration Treatment Satisfaction Questionnaire
The MacTSQ is a 12-item questionnaire designed to assess treatment satisfaction in 
patients with macular degeneration.  Scoring of the MacTSQ results in two subscale 
scores:  1) convenience, information, and satisfaction; and 2) safety, efficacy, and 
discomfort.  A total score may also be computed.  Subscale scores range from 0 to 36, 
and the total score ranges from 0 to 72.  A higher score indicates greater satisfaction
(Mitchell and Bradley 2017).
Refer to Patient Questionnaire Booklet for copy of the MacTSQ.
4.5.9
Video Recording of Implant Insertion, Refill-Exchange, and 
Explantation Procedures
The implant insertion, explantation, refill-exchange, and any other ocular surgical 
procedures (e.g., conjunctival erosion or retinal detachment repair) performed in the 
study eye will be captured on video unless the study center has policies in place that 
prohibit these procedures from being video captured.  Recordings may be used for, but 
are not limited to, physician training or product characterization and may be forwarded to 
a central reading center for analysis and/or storage and will later be transferred to 
Roche.
4.5.10
Optional Samples for Research Biosample Repository
4.5.10.1
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 


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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 used to achieve the following 
objectives:

To study the association of biomarkers with efficacy or disease progression

To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation

To increase knowledge and understanding of disease biology and drug safety

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.10.2
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 4.5.10) 
will not be applicable at that site.
4.5.10.3
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 ranibizumab, AMD and 
other conditions, or drug safety:

Whole blood samples collected at randomization

Aqueous humor samples collected at randomization and at Weeks 24, 28, 48, 52, 
72, 76, 96, and X (for patients who follow an alternate final study visit scenario, as 
applicable)

Plasma and serum samples collected (if aqueous humor samples are collected) at 
randomization and at Weeks 24, 28, 48, 52, 72, 76, 96, and X (for patients who 
follow an alternate final study visit scenario, as applicable)

Leftover serum, plasma, and aqueous humor samples collected during 
supplemental treatment and at the subsequent study visit, early termination, and 
implant explantation visits

Leftover blood, serum, plasma, and aqueous humor samples, and any derivatives 
thereof (e.g., DNA, RNA, proteins, peptides), including leftover tissue samples from 
medically indicated procedures (e.g., bronchoscopy, esophagogastroduodenoscopy, 


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colonoscopy) performed at the investigator's discretion during the course of the 
study
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic mutations via whole genome sequencing (WGS), whole exome sequencing 
(WES), or other genomic analysis methods.
Genomics is increasingly informing researchers' 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 will 
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).
4.5.10.4
Confidentiality
RBR samples and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.


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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.
4.5.10.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research.
4.5.10.6
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 RBR Research Sample 
Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent to the 
testing of his or her RBR samples after closure of the site, the investigator must inform 
the Sponsor by emailing the study number and patient number to the following email 
address:
global_rcr-withdrawal@roche.com
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study.
4.5.10.7
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 


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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

Any treatment for nAMD not specified in the protocol 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
Upon study treatment discontinuation, patients in the implant arm will no longer receive 
implant refill-exchanges and patients in the intravitreal arm will no longer receive 
ranibizumab injections. 
All patients who discontinue study treatment will be strongly encouraged to attend as
many scheduled study visits as possible, with an emphasis on visits at Weeks 36, 40, 
and 96 (see Appendix 4 for the minimum required assessments to be performed).  Per 
investigator judgment, patients may start an FDA-approved intravitreal anti-VEGF 
treatment for nAMD in the study eye after the decision to discontinue study treatment is 
made.  Study-sponsored intravitreal ranibizumab 0.5 mg treatment will be provided for 
patients who discontinue from the implant arm only, if the anti-VEGF treatment chosen 
by the investigator is ranibizumab and until the patient completes the study.
The investigator must notify the Medical Monitor if the decision to perform explantation is 
made after study treatment discontinuation.  Explanted patients will return for safety 
assessments at 1, 7 (2), 30 (7), and 60 (7) days post-explantation (see Appendix 4). 
All patients will be strongly encouraged to remain in the study after their last post-
explantation safety visit.  They can return for as many scheduled study visits as possible
(with an emphasis on completing the Week 36, Week 40, and Week 96 visits).  Patients 
may start an FDA-approved intravitreal anti-VEGF treatment in the study eye, including 
Sponsor-provided intravitreal ranibizumab 0.5 mg if chosen by the investigator once the 
need for explantation is confirmed and preferably after explantation is completed.


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4.6.2
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent

Study termination or site closure

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues in the study

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
If a patient misses more than two consecutive monthly visits within any 6-month 
treatment period, the investigator and the Sponsor may consider withdrawing the 
patient from the study. 

Investigator or Sponsor determines it is in the best interest of the patient
Patients in the implant arm who withdraw from the study prematurely will be scheduled 
for an early termination evaluation visit 90 (7) days after the implant insertion 
procedure or 30 (7) days following the last implant refill-exchange for monitoring of all 
adverse events (serious and non-serious) (see Appendix 1).  
The investigator must notify the Medical Monitor if the decision to perform explantation is 
made. Explanted patients will return for safety assessments at 1, 7 (2), 30 (7), and 
60 (7) days post-explantation (see Appendix 4), and for an early termination visit 
90 (7) days post-explantation.  As per investigator judgment, patients may start an 
intravitreal FDA-approved anti-VEGF treatment for nAMD in the study eye once the need 
for explantation is confirmed, and preferably after explantation is completed if possible.
Patients may receive Sponsor-provided intravitreal ranibizumab 0.5 mg, if chosen by the 
investigator, until the early termination visit is completed and patients withdraw from the 
study.
Patients in the intravitreal arm who withdraw from the study prematurely should return 
for an early termination evaluation visit 30 (7) days following the last intravitreal 
ranibizumab 0.5 mg injection for monitoring of all adverse events (serious and non-
serious) and early termination assessments (see Appendix 2).
Every effort should be made to obtain information on patients who withdraw from the 
study but have not withdrawn consent.  The primary reason for withdrawal from the 
study should be documented on the appropriate eCRF.  Patients who withdraw from the 
study will not be replaced.


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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 study is placed on hold or if the Sponsor 
decides to discontinue the study.
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
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
The PDS is not approved for commercial distribution, and clinical development is 
ongoing.  The safety plan for patients in this study is based on clinical experience with 
the PDS in completed and ongoing studies.  Refer to the PDS Investigator's Brochure for 
a complete summary of safety information.
The safety and tolerability of intravitreal ranibizumab 0.5 mg injections have been 
investigated in previous Phase I, I/II, III, and IIIb studies in patients with nAMD.  Potential 
safety issues associated with the route of administration or the pharmacology of 
ranibizumab in the study population include VA reduction, intraocular inflammation, 
transient and/or sustained elevation of IOP, cataract development or progression, retinal 
hemorrhage, vitreous hemorrhage, macular edema, endophthalmitis, retinal tear or 
detachment, hypersensitivity reactions, and arterial thromboembolic events (ATEs).  
Adverse events that should be considered ATEs include, but are not limited to, 
myocardial infarction and cerebrovascular accident (ischemic and/or hemorrhagic).  See 
the PDS Investigator's Brochure for further details.


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5.1.1
Safety Assessments
Several measures will be taken to ensure the safety of patients participating in this 
study.  Eligibility criteria have been designed to exclude patients at higher risk for 
treatment-related complications.  Patients will undergo safety monitoring during the 
study, including assessment of the nature, frequency, and severity of adverse events.  In 
addition, guidelines for managing adverse events, including criteria for treatment 
interruption or discontinuation, are provided below.
If warranted, patients will be asked to return to the clinic as soon as possible for an 
unscheduled safety assessment visit (see Appendix 4) and will be instructed to contact 
the investigator at any time should they have any health-related concerns.
Upon completion of implant insertion procedure on Day 1, patients will have indirect 
ophthalmoscopy performed to monitor the implant placement and to evaluate any 
potential implant problems.  The treating physician will check IOP by digital palpation for 
the study eye only as clinically indicated.  These assessments must be performed prior 
to placing a patch on the eye after implant insertion.  Patients will remain in the surgical 
center until the designated physician has assessed that there are no safety concerns 
following treatment, at which point the patient will be allowed to leave.  If any safety 
concerns or immediate toxicity is noted, the patient will remain in the surgical center and 
will be treated according to the designated physician’s clinical judgment.  If applicable, 
the adverse event and treatment of adverse event will be reported on the appropriate 
eCRFs.
Patients in the implant arm will return after the implant insertion procedure for safety 
evaluation visits on Day 2, Day 7 (2), and at study visits every 4 weeks (7 days).  See 
Appendix 1 for assessments conducted at safety evaluation visits following implant 
insertion.
Following each implant refill-exchange, patients will undergo a finger-counting test, 
followed by hand motion and light perception tests (when necessary) performed by the 
designated physician within 15 minutes post-treatment for the study eye only; indirect 
ophthalmoscopy will be performed after each implant refill-exchange to monitor the 
implant.
The use of self-administered antimicrobial ophthalmic drops is required before and after
PDS implant insertion, and is optional per investigator’s discretion prior to the
implant refill-exchange procedure but required after the PDS implant refill-
exchange procedure. Anti-inflammatory (steroid) ophthalmic drops are required 
after implant insertion and explantation.  In addition, optional topical NSAID 
drops may be administered before and after implant insertion and after 
explantation per investigator’s discretion. Refer to Appendix 17 for 
administration schedule.


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For the study eye only, following each intravitreal ranibizumab 0.5 mg injection, patients 
will undergo a finger-counting test, followed by hand motion and light perception tests 
(when necessary), performed by the designated physician within 15 minutes post-
treatment.
All patients will remain at the office until the designated physician has assessed that
there are no safety concerns following treatment, at which point the patient will be 
allowed to leave.  If any safety concerns or immediate toxicity is noted, the patient will 
remain at the office and will be treated according to the designated physician’s clinical 
judgment.  If applicable, the adverse event and treatment of adverse event (if applicable) 
will be reported on the appropriate eCRFs. 
All patients will be contacted by study site personnel 3 (1) days after each treatment 
(implant refill-exchange or intravitreal injection) to elicit reports of any decrease in vision, 
eye pain, unusual redness, or any other new ocular symptoms in the study eye.  Patients 
will also be asked whether they have taken the prescribed, self-administered, post-
treatment antimicrobials (if applicable) for their study eye as directed by the investigator.
Detailed ocular examinations, including indirect ophthalmoscopy and slitlamp 
examination, will be performed throughout the study.  A careful examination of the 
implant using slit lamp should be performed at each study visit. All patients will 
undergo dilated binocular indirect high-magnification ophthalmoscopic examination at 
each visit, which will include visual monitoring of the implant placement and evaluation of 
any other implant-related problems, as well as data collection on the associated eCRF 
and/or Medical Device Complaint Form.  The sample content retrieved during 
explantation procedures will be collected and forwarded to the Sponsor's designee and 
may be analyzed in the future. 
Implant refill-exchange will be interrupted or discontinued as per the dose-interruption 
criteria listed in Table 4 and at the investigator's discretion if he or she suspects any 
safety or other treatment-related issues.  If the investigator decides to interrupt a dose, 
the reason will be recorded on the corresponding eCRF and, if appropriate, on the 
Adverse Event eCRF.  In the event a patient experiences an adverse event in the study 
eye that is considered by the investigator to be severe in intensity or serious in nature, 
consideration should be given to interrupting the treatment or discontinuing the patient 
from study drug treatment or the study.  The decision will be at the investigator's 
discretion and should be recorded on the eCRF.  See Section 4.3 for information of 
study drug and patient discontinuation.
The incidence of all adverse events (serious and non-serious) will be recorded on 
eCRFs for the duration of this study.  Serious adverse events will be collected and 
reported to the Sponsor in compliance with Good Clinical Practice guidelines. 


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5.1.2
Risks Associated with Intravitreal Ranibizumab Injection 
5.1.2.1
Increased Intraocular Pressure
Transient increases in IOP have been seen within 60 minutes of injection of 
ranibizumab.  Sustained IOP increases have also been reported.  Both IOP and 
perfusion of the optic nerve head must be monitored and managed appropriately.
5.1.2.2
Cataract
Cataract may be a clinically relevant event with possible outcome of visual loss.  
Patients receiving intravitreal injections are at risk for the development of traumatic 
cataract.  During the intravitreal injection, any direct trauma to the lens by the needle 
touching the lens could result in traumatic cataract.
5.1.2.3
Intraocular Inflammation
Intraocular inflammation can range from a mild to severe inflammation of the eye with
sequelae that may lead to vision loss.  Inflammation can occur due to potential 
immunogenicity, in reaction to the active substance or its excipients, or in response to 
the invasive nature of the procedure.  It is also hypothesized that intravitreal antibody 
formation may contribute to the development of intraocular inflammation; however, there 
is currently no evidence either from the published literature or from the postmarketing 
data to support this assertion. There is potential introduction of microorganisms during 
the injection procedure as described below in Section 5.1.2.5 (endophthalmitis).  
5.1.2.4
Retinal Detachment and Retinal Tear
Retinal detachment and retinal tear are considered clinically relevant events with a 
possible outcome of permanent vision loss.  A tear or hole in the retina, typically in the 
periphery, leads to fluid accumulation and separation of the neurosensory retina from the 
underlying RPE. Vitreoretinal traction is responsible for most of the rhegmatogenous 
retinal detachments. With age, the vitreous becomes more liquefied, and a posterior 
vitreous detachment (PVD) can occur. In some eyes, strong vitreoretinal adhesions are 
present and the occurrence of a PVD can lead to the formation of a retinal tear. The 
liquefied vitreous can then seep through the tear and under the retina, leading to a 
retinal detachment.
5.1.2.5
Endophthalmitis
Intravitreal injections, including those with ranibizumab, have been associated with 
endophthalmitis and retinal detachments.  Proper aseptic injection technique should 
always be used when administering ranibizumab.  In addition, patients should be 
monitored following the injection to permit early treatment should an infection occur.
Refer to the PDS Investigator's Brochure for further information.




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5.1.3.4
Conjunctival Retraction
The PDS implant and/or its procedures have been associated with conjunctival 
retraction (defined as a recession or opening of the limbal and/or radial peritomy).
These events may be clinically relevant especially if the implant becomes exposed, and 
could be associated with an increased risk of endophthalmitis. The tissue overlying the 
PDS implant flange should be monitored carefully following the implant insertion and 
refill-exchange procedures to identify early signs of retraction, and permit early 
medical or surgical intervention, if necessary.  After discussion with the Medical 
Monitor, surgical intervention (e.g., conjunctival/Tenon’s capsule repair) should be 
performed in case of conjunctival retraction with or without exposure of the implant 
flange.
Close adherence to the most up-to-date PDS IFU document (e.g., appropriate suturing 
of conjunctiva and Tenon’s capsule to the limbus, etc.) is required to minimize risks of 
conjunctival retraction.
5.1.3.5
Rhegmatogenous Retinal Detachment
The PDS implant and/or its procedures have been associated with rhegmatogenous
retinal detachment. These events are clinically relevant and may result in vision loss if 
not promptly treated with an intervention (e.g., pneumatic retinopexy, vitrectomy, or laser 
photocoagulation). Careful evaluation of the retinal periphery by scleral indentation 
should be performed, and any suspected areas of abnormal vitreo-retinal adhesion or 
retinal breaks should be treated before inserting the implant in the eye.
Close adherence to the most up-to-date PDS IFU document (e.g., appropriate 
management of vitreous prolapse after pars plana incision, etc.) is required to minimize 
risks of rhegmatogenous retinal detachment.
5.1.3.6
Endophthalmitis
The PDS implant and/or its procedures have been associated with endophthalmitis. 
These events are clinically relevant and require prompt treatment as per standard of 
care to reduce risk of vision loss and maximize recovery (e.g., intravitreal vancomycin 
and ceftazidime, as well as topical and/or oral antibiotics, for bacterial endophthalmitis). 
Saline flush of the implant content using the refill needle, followed by implant flush with 
100 l of vancomycin (1.0 mg/mL) may also be performed as additional treatment.
Close adherence to the most up-to date PDS IFU document (e.g., appropriate sterile 
controls during implant insertion or refill-exchange procedures) is required to 
minimize risks of endophthalmitis.
5.1.3.7
Device Dislocation 
The PDS implant and/or its procedures have been associated with device dislocation. 
The implant may dislocate or subluxate into the vitreous cavity, or may extend outside 
the vitreous cavity into or beyond the subconjunctival space.  These events are 


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clinically relevant and, in some cases, may require urgent surgical intervention to 
prevent vision loss.  After discussion with the Medical Monitor, urgent surgical 
intervention should be performed if device dislocation is associated with a positive 
Seidel test, retinal detachment, appositional choroidal detachment, dislocated implant 
resting on or near the macula, conjunctival opening with vitreous leak and implant 
expulsion (open globe).
Close adherence to the most up-to-date PDS IFU document (e.g., appropriate scleral 
incision length, appropriate targeting of the pars plana with during laser ablation) is 
required to minimize risks of device dislocation.
Refer to the PDS Investigator’s Brochure for further information.
5.1.4
Potential Risks Associated with Ranibizumab Administered as 
an Intravitreal Injection
5.1.4.1
Glaucoma
Sustained IOP increase can be associated with the development of glaucoma, which in 
turn can lead to permanent vision loss.  Although sustained increases in IOP have been 
reported following administration of VEGF inhibitors, there is no conclusive evidence to 
date that these IOP increases develop into glaucoma.
5.1.4.2
Venous Thromboembolic Events
Venous thromboembolic events are generally clinically relevant, ranging from superficial
phlebitis to a potentially fatal pulmonary embolism.  VEGF inhibition, especially 
systemically, could contribute to the development of this event.
5.1.4.3
Non-Myocardial Arterial Thromboembolic Events
ATEs may be associated with VEGF inhibition in the vascular system, as well as with 
underlying abnormal blood vessels due to medical conditions, such as hypertension, 
atherosclerosis, or diabetes.
5.1.4.4
Myocardial Infarction
Myocardial infarction is a clinically relevant event, ranging from an asymptomatic event 
to a fatal outcome.
5.1.4.5
Non-Ocular Hemorrhage
Non-ocular hemorrhage is a heterogeneous risk, ranging from events such as mild nose 
bleed to fatal gastrointestinal hemorrhage.  These events may be related to the systemic 
effects of anti-VEGF treatment.
5.1.4.6
Hypertension
Hypertension may be caused by VEGF inhibition, especially when anti-VEGF agents are 
used systemically.
Refer to the PDS Investigator's Brochure for further information.


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5.1.5
Management of Patients Who Experience Adverse Events
5.1.5.1
Dose Modifications
No dose modifications will be permitted in this study.
5.1.5.2
Treatment Interruption
Study treatment dose (refill-exchange or intravitreal ranibizumab injection) interruption 
and/or study treatment discontinuation or study discontinuation following an adverse 
event will be determined according to the criteria in Table 4.  The investigator should 
contact the Medical Monitor if the study treatment dose is interrupted and delay of 
treatment is to be considered for conditions outside of those specified in Table 4. 
The reason for interrupting the treatment should be recorded on the associated eCRF 
and, if applicable, on the Adverse Event eCRF.


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Table 4
Dose Interruption, Study Treatment Discontinuation, or Study 
Discontinuation Criteria
Event
Dose Interruption Criteria
Intraocular 
inflammation
Interrupt dose if intraocular inflammation is 2in the study eye 
(see the definitions of intraocular inflammation in Section 5.1.2.3). 
Study treatment may be delayed or the patient may be 
discontinued from study treatment after consultation with the 
Medical Monitor.
BCVA decrease
Interrupt dose if there is a study drugrelated decrease of 
30 letters in BCVA in the study eye compared with the last 
assessment of BCVA.
Elevated IOP
Interrupt ranibizumab study treatment via intravitreal injection if 
pre-treatment IOP in the study eye is 30 mmHg.  Treatment will 
be permitted when IOP has been lowered to 30 mmHg, either 
spontaneously or by treatment, as determined by the investigator. 
Note:  In the implant arm, if IOP in the study eye is 30 mmHg at 
an implant refill-exchange visit, study treatment may proceed if 
the implant is seated in correct position.
Rhegmatogenous 
retinal break or 
detachment and 
macular hole Stages 3 
or 4
Interrupt dose if a retinal break is present in the study eye.  
Treatment may be resumed 28 days after the retinal break has 
been successfully treated.  Patients with a rhegmatogenous 
retinal detachment or Stage 3 or 4 macular holes may require 
discontinuation from study treatment after consultation with the 
Medical Monitor.
Local or systemic 
infection
Interrupt dose if any of the following are present: infectious 
conjunctivitis, infectious keratitis, infectious scleritis, or 
endophthalmitis in either eye. Dose should be interrupted if the 
patient is currently under observation or receiving treatment for a 
suspected or confirmed severe systemic infection per clinical 
judgment (including COVID-19).
IV corticosteroids
Dose may be interrupted after consultation with the Medical 
Monitor if patients need to receive IV corticosteroids.  Study 
treatment may be resumed when the patient has finished IV 
corticosteroid course.
Intraocular surgery
Dose may be interrupted after consultation with the Medical 
Monitor if intraocular surgery (except cataract, see Section 4.4.1) 
has been performed in the study eye within the previous 28 days.
Observed damage to 
the implant
If damage to the implant is observed by the investigator, the 
implant may be explanted even if it did not cause any adverse 
event to the patient.  The patient may be discontinued from the 
study treatment.
Pregnancy
Discontinue patient's study treatment in the case of positive 
serum pregnancy test during the study.  For patients in the 
implant arm, a saline flush of implant content may be performed
to remove drug from the implant, after consultation with the 
Medical Monitor.
BCVAbest-corrected visual acuity; IOPintraocular pressure.


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5.1.5.3
Supplemental Treatment with Intravitreal Ranibizumab for 
Implant Patients 
Patients randomized to the implant arm will be eligible for supplemental treatment with 
ranibizumab (0.5 mg intravitreal injections of 10-mg/mL formulation) at Weeks 16 and 20 
(after implant insertion) and at Weeks 40, 44, 64, 68, 88, and 92 if any of the following 
criteria are met in the study eye:

Decrease of 15 letters from the best-recorded BCVA in the study, due to nAMD 
disease activity
OR

Increase of 150 m in central subfield thickness (CST) on SD-OCT from the lowest 
CST measurement in the study, due to nAMD disease activity
OR

Increase of 100 m in CST on SD-OCT from the lowest CST measurement in the 
study associated with a decrease of 10 letters from the best recorded BCVA 
during the study, due to nAMD disease activity
At each visit in which supplemental treatment is possible, the study eye BCVA score and 
CST value must be entered into IxRS to assess the need for supplemental treatment.  If 
any of the criteria above are met, the supplemental treatment must be administered at 
the end of the visit.  If treatment cannot be administered at the end of the visit, patients 
will be asked to return within 7 days to receive supplemental treatment.
Following supplemental treatment with intravitreal ranibizumab 0.5 mg, patients will 
continue with scheduled implant refill-exchanges at Weeks 24, 48, and 72 relative to the 
Day 1 visit. 
Note:  Supplemental treatment is allowed at Weeks 16 and 20 (after implant insertion) 
and at Weeks 40, 44, 64, 68, 88 and 92 only if any of the criteria listed above are met.  
Supplemental treatment is not allowed at any other study visits.  Patients with 
progressive worsening of nAMD disease activity (e.g., BCVA or CST worsening, new 
macular hemorrhage) who, in the investigator's judgment, require any treatment for 
nAMD in the study eye outside of protocol (e.g., ranibizumab intravitreal injection 
treatment at Week 8) will be discontinued from study treatment (i.e., no additional 
refill-exchanges) after discussion with the Medical Monitor.  Patients discontinuing study
treatment will be encouraged to attend as many scheduled study visits as possible, with 
an emphasis on completing the Week 36, Week 40, and Week 96 visits (see Appendix 4
for the minimum required assessments to be performed).


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5.1.5.4
Recommended Management of Cases of Vitreous Hemorrhage
The recommended management of patients with vitreous hemorrhage secondary to 
implant-related procedures throughout the study is presented in Table 5. 
Table 5
Recommended Management of Cases of Vitreous Hemorrhage
Timing
Patient's Examination and Management Guidelines
Day of vitreous 
hemorrhage 
diagnosis

If the diagnosis of vitreous hemorrhage is made during a scheduled 
visit and the view of the vitreous cavity is limited, perform ocular 
B-scan ultrasonography if possible in addition to the assessments 
scheduled for that specific visit.

If the diagnosis of vitreous hemorrhage is made during an 
unscheduled visit and the view of the vitreous cavity is limited, 
perform ocular B-scan ultrasonography if possible in addition to the 
assessments listed in Appendix 4.

A safety assessment visit (scheduled or unscheduled) should be 
performed approximately 2 weeks after occurrence of vitreous 
hemorrhage (see Appendix 4).  If possible, perform ocular B-scan 
ultrasonography if the view of the vitreous cavity is limited.
Approximately 
4 weeks after 
occurrence 
(scheduled 
visit)

If possible, perform ocular B-scan ultrasonography if the view of 
the vitreous cavity is limited, in addition to the assessments 
scheduled for that specific visit.

An unscheduled safety assessment visit should be performed 
between 4 and 8 weeks after occurrence of vitreous hemorrhage 
(Appendix 4).
Approximately 
8 weeks after 
occurrence 
(scheduled 
visit)

If possible, perform ocular B-scan ultrasonography if the view of 
the vitreous cavity is limited.

If vitreous hemorrhage causes loss in BCVA and neither 
assessment of the macula nor SD-OCT can be performed 
successfully: 

Discuss a pars plana vitrectomy with the patient as a possibility 
to remove the vitreous hemorrhage.  Consultation with the 
Medical Monitor is advised prior to performing pars plana 
vitrectomy.
BCVAbest-corrected visual acuity; SD-OCT spectral-domain optical coherence 
tomography.


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5.1.5.5
Recommended Management of Conjunctival Retraction or 
Conjunctival Erosion Cases
The recommended management of patients with conjunctival retraction or conjunctival 
erosion is presented in Table 6.
Table 6
Recommended Management of Patients with Conjunctival 
Retraction or Conjunctival Erosion
Event
Patient’s Examination and Management Guidelines
Conjunctival 
Retraction

Prescribe antibiotic drops as per standard of care.

Consult Medical Monitor for management.

Schedule for surgery as soon as possible.

Perform conjunctival flap revision with robust undermining of 
the surrounding conjunctiva and Tenon’s capsule and release 
of any traction from previous surgery before advancing healthy 
tissue to limbus.

Suture the flap with multiple interrupted sutures.

In case of recurrent conjunctival retraction, consider use of a split
thickness corneal graft placed underneath the conjunctiva and 
Tenon’s capsule (if corneal tissue is not available, consult Medical 
Monitor for advice on further management).
Conjunctival 
Erosion

In case of confirmed or suspected conjunctival erosion, Prescribe 
antibiotic drops as per standard of care.

For a suspected conjunctival erosion, consider application of 
topical fluorescein over conjunctiva to confirm erosion on slit 
lamp examination using cobalt blue light.

Consult the Medical Monitor for management.

Watch and wait in case of small localized erosion without flange 
exposure if the surrounding tissue is well adhered to sclera and 
there is no evidence of an active leak.

Schedule for surgery in case of full-thickness erosion (i.e., exposing 
the flange), or evidence of an active leak with Seidel positivity.

Perform conjunctival flap revision with robust undermining of 
the surrounding conjunctiva and Tenon’s capsule and release 
of any traction from previous surgery.

Suture the flap with multiple interrupted sutures.

In case of recurrent conjunctival erosion, consider use of a split
thickness corneal graft placed underneath the conjunctiva and 
Tenon’s capsule (if corneal tissue is not available, consult Medical 
Monitor for advice on further management).
5.1.5.6
Recommended Management of Conjunctival Bleb
The recommended management of patients with conjunctival bleb is presented in 
Table 7.


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Table 7
Recommended Management of Patients with Conjunctival Bleb
Timing of Occurrence
Patient’s Examination and Management Guidelines
Post implant insertion 
surgery

Perform Seidel test
–
If positive, discuss with the Medical Monitor 
about potential surgery to revise 
conjunctiva/Tenon’s capsule and sclerotomy.
–
If negative, continue with post-operative topical 
medications (Appendix 17), and follow regular 
visit schedule.
During a refill-exchange
attempt

If the implant septum is no longer visible, consider 
delaying the refill-exchange. Reattempt the 
refill-exchange after approximately 7 days once the 
bleb is resolved.
A month before a scheduled 
refill-exchange

If the bleb has not resolved and the implant septum is 
not fully visible, perform retroillumination by shining a 
light towards the implant body through the dilated 
pupil
–
If the implant septum becomes illuminated with 
clear margins to provide adequate visibility, 
consider observation.
–
If the implant septum does not illuminate or its 
margins do not appear sufficiently defined, 
discuss with the Medical Monitor about potential 
surgery to revise the conjunctiva and excise the 
bleb, potentially in conjunction with the refill-
exchange procedure.


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5.1.5.7
Recommended Management of Endophthalmitis
The recommended management of patients with endophthalmitis is presented in 
Table 8.
Table 8
Recommended Management of Patients with Endophthalmitis
Event
Patient’s Examination and Management Guidelines
Endophthalmitis 
(implant arm)

Perform vitreous tap and/or anterior chamber tap to obtain fluid 
specimen for culture.  Send aqueous humor sample to local 
laboratory for microbiology cultures.  

Treat with intravitreal vancomycin and ceftazidime or as per 
standard of care.

For patients with a PDS implant, perform a saline flush of implant 
contents using refill needle followed by a flush of the implant with
100 L of vancomycin (1.0 mg/mL) using the refill needle.

Start antibiotic drop coverage per standard of care. Oral antibiotics 
may also be considered.

In certain circumstances, a pars plana vitrectomy should be 
considered, after consultation with the Medical Monitor.

Perform a safety assessment visit (unscheduled; see Appendix 4) 
daily after occurrence of endophthalmitis until the posterior segment
of the eye improves with clearance of the vitreous debris.  If 
possible, perform ocular B-scan ultrasonography.

For patients with a PDS implant, perform a refill-exchange 
procedure (with ranibizumab 100 mg/mL) after endophthalmitis 
resolves as determined by the investigator and after discussion with 
Medical Monitor.
PDSport delivery system with ranibizumab


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5.1.5.8
Recommended Management of Device Dislocation 
The recommended management of patients with device dislocation is presented in
Table 9.
Table 9
Recommended Management of Patients with Device Dislocation
Type of 
dislocation
Patient’s Examination and Management Guidelines
Into the 
vitreous cavity
The implant may dislocate in the anterior vitreous behind the scleral 
wound, with secondary vitreous fluid leak underneath the Tenon’s 
capsule through the scleral wound. It is recommended to surgically 
remove the implant by performing a vitrectomy and implant removal 
procedure as soon as possible, after consultation with the Medical 
Monitor.
Urgent surgical intervention is recommended if device dislocation is 
associated with the following events: 

Positive Seidel test

Retinal detachment

Appositional choroidal detachments

Dislocated implant resting on or near the macula
Topical, intravitreal, and/or systemic treatment may also be needed 
per standard of care in case of ocular infections, intraocular 
inflammation, hypotony, or other associated events. Prophylactic 
treatment to limit the risk of ocular infections may be needed in some 
cases.
Outside the 
vitreous cavity
The implant may entirely dislocate or subluxate outside the vitreous 
cavity into or beyond the subconjunctival space. It is recommended to 
surgically intervene as soon as possible, after consultation with the 
Medical Monitor. 

If the implant is subluxated into the subconjunctival space without 
extrusion through the conjunctiva and part of the implant body is 
still in the scleral wound, the implant may be seated back into its 
original position. The oversized scleral wound should be sutured 
to reduce its length to 3.5 mm to provide tight fit of the implant.

If the implant is entirely dislocated into the subconjunctival space, 
removal of the implant is recommended followed by closure of the 
scleral wound with non-resorbable sutures.
Urgent surgical intervention is recommended if device dislocation is 
associated with the following events: 

Conjunctival opening with vitreous leak and implant expulsion 
(open globe)

Retinal detachment

Appositional choroidal detachments
Topical, intravitreal, and/or systemic treatment may also be needed 
per standard of care in case of ocular infections, intraocular 
inflammation, hypotony, or other associated events. Prophylactic 
treatment to limit the risk of ocular infections may be needed in some 
cases. 


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5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.8 and 
5.3.5.9 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.10)


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
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe according to the adverse 
event severity scale; see Section 5.3.3, Table 10); the event itself may be of relatively 
minor medical significance (such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.6)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

Sight-threatening adverse events:  an adverse event is considered to be sight 
threatening if it is a serious adverse event (as defined in Section 5.2.2) and it meets 
one or more of the following criteria:
– The adverse event causes a decrease of 30 letters in BCVA (compared with the 
last assessment of VA prior to the most recent treatment) lasting more than 
1 hour.


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–
The adverse event requires surgical intervention (i.e., conventional surgery, 
vitrectomy, vitreous tap, or biopsy with intravitreal injection of anti-infective 
medications, or laser or retinal cryopexy with gas) to prevent permanent loss of 
sight.
– The adverse event is associated with severe intraocular inflammation 
(e.g., endophthalmitis, 4anterior chamber cell/flare or 4cells in the vitreous; 
see Appendix 7 for intraocular inflammation grading scales).
Note: Adverse events should be reported, listing the underlying cause (if known) 
of the event as the primary event term (see Section 5.3.5.2).

Ocular adverse events of special interest, defined as any of the events listed below, 
regardless of whether they occur in the study eye or the fellow eye, in a patient 
randomized to the PDS arm or the intravitreal arm, or the AE causality:
– Vitreous hemorrhage
– Endophthalmitis
– Retinal detachment
– Conjunctival retraction
– Conjunctival erosion
– Conjunctival bleb or conjunctival filtering bleb leak
– Hyphema
– Cataract
– Device dislocation
Refer to the PDS Investigator's Brochure for further information.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events whether associated 
with the drug, with the implant or one of the ancillary devices, with any of the study 
procedures, and all adverse events not associated with any of these elements (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.
The investigator is also responsible for reporting medical device complaints (see 
Section 5.4.4) (see Appendix 16).  In the event of a device defect with an associated 
adverse event this means that the investigator must report both an adverse event and a 
Medical Device Complaint (Section 5.4.4).
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).


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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 treatment 
(Day 1), only serious adverse events caused by a protocol-mandated intervention 
(e.g., discontinuation of medications or intravitreal ranibizumab administered at 
screening or during run-in period) should be reported (see Section 5.4.2 for instructions 
for reporting serious adverse events).
After initiation of study treatment, all adverse events, regardless of relationship to study 
drug, implant, or ancillary devices, or study procedures, will be reported until the 
patient’s final study visit.  For patients who terminate study treatment and discontinue 
from the study prematurely, all adverse events will be reported up to the early 
termination visit.  For patients who discontinue study treatment early but continue to 
participate in the study, adverse events will be reported until their last or final study visit.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
Table 10 provides guidance for assessing adverse event severity.
Table 10 Adverse Event Severity Grading Scale
Severity
Description
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating with inability to work or to perform normal daily activity
Note:  Regardless of severity, some events may also meet seriousness criteria.  
Refer to definition of a serious adverse event (see Section 5.2.2).
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine causality of 
an adverse event.  Investigators will assess any relationship between the adverse event 


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and each component separately, indicating “yes” or “no” as applicable on Adverse Event 
eCRF.
Patients in the Implant Arm:  The investigator will assess whether there is a potential 
association with each of the following “components” of the study intervention:  

Implant, insertion tool, or implant procedure

Refill-exchange or refill needle

Explant or explant tool

Ranibizumab (study drug)
Patients in the Intravitreal Arm:  The investigator will assess whether there is a 
potential association with each of the following “components” of the study intervention: 

The intravitreal injection procedure 

Ranibizumab (study drug)
The following guidance should be taken into consideration when assessing causality:

Temporal relationship of event onset to the initiation of study drug, implant and its 
insertion, refill-exchange, or explantation procedures or due to other PDS 
components (see Table 11) or due to intravitreal injection procedure.  

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with study drug, implant or other PDS 
components/procedures, 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


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Table 11 Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
For the purposes of reporting events of infection and inflammation, the following terms 
and definitions should be used (see also Appendix 7 and Appendix 8):

Iritis:  the presence of inflammatory cells in the anterior chamber (trace or greater)
The presence of aqueous humor flare alone will not constitute iritis but should 
be documented as an anterior chamber flare for adverse event reporting 
purposes.

Iridocyclitis:  the presence of inflammatory cells in both the aqueous humor 
and vitreous (trace or greater)

Vitritis:  the presence of active inflammation in the vitreous, demonstrated by the 
presence of inflammatory cells (trace or greater)
Active inflammation in the vitreous should be clinically differentiated 
from cellular debris from prior episodes of inflammation, hemorrhage, or other 
causes.

Endophthalmitis:  diffuse intraocular inflammation predominantly involving the 
vitreous cavity but possibly also involving the anterior chamber, implying a 
suspected underlying infectious cause
A culture is required prior to initiating antibiotic treatment for presumed 
infectious endophthalmitis.


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5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases; record only endophthalmitis that 
resulted in 30 letters loss rather than the decrease of 30 letters in BCVA).  However, if 
a constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual event should be recorded 
on the Adverse Event eCRF.  If a diagnosis is subsequently established, all previously 
reported adverse events based on signs and symptoms should be nullified and replaced 
by one adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis.
5.3.5.2
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.


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A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5upper limit of normal [ULN] associated with cholestasis), only 
the diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 


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It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.7
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1 ), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of nAMD.
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").


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If the death is attributed to progression of nAMD, "neovascular age-related macular 
degeneration progression" should be recorded on the Adverse Event eCRF.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.9
Worsening of Neovascular Age-Related Macular Degeneration
Study eye medical occurrences or symptoms of deterioration in the study eye that are 
anticipated as part of nAMD should be recorded as an adverse event if judged by the 
investigator to have unexpectedly worsened in severity or frequency or changed in 
nature at any time during the study.  When recording an unanticipated worsening of 
nAMD on the Adverse Event eCRF, it is important to convey the concept that the 
condition has changed by including applicable descriptors (e.g., "accelerated worsening 
of neovascular age-related macular degeneration").
5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Planned hospitalization required by the protocol (e.g., for study drug 
administration or insertion of implant for study drug administration)

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


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An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.11
Patient-Reported Questionnaire and Outcomes Data
Adverse event reports will not be derived from patient-reported questionnaire data by the 
Sponsor, and safety analyses will not be performed using patient questionnaire data.  
Sites are not expected to review the patient questionnaire data for adverse events.
5.3.5.12
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
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 ranibizumab, 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.


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In addition, all special situations associated with ranibizumab, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event).  
Special situations should be recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries.
5.4
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)

Medical device complaints (see Section 5.4.4 for details on reporting requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results


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
Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for All Sites 
Medical Monitor:
, M.D. (Primary)
Mobile Telephone No.:
Medical Monitor:
, M.D. (Secondary) 
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur Prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur After Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until the final study visit.  For patients who terminate from study 
treatment and study early, all adverse events will be collected up to the early termination 
visit.  Investigators should record all case details that can be gathered immediately (i.e., 
within 24 hours after learning of the event) on the Adverse Event eCRF and submit the 
report via the electronic data capture (EDC) system.  A report will be generated and sent 
to Roche Safety Risk Management by the EDC system.


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In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting post-study serious adverse events are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed through the Informed 
Consent Form to immediately inform the investigator if they become pregnant during the 
study or within 28 days after the last intravitreal ranibizumab injection or 1 year after the 
last implant ranibizumab refill-exchange.  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.  If medically necessary, as per 
investigator’s judgment and after discussion with the Medical Monitor, a saline flush of 
implant content may be performed for patients in the implant arm.  Monitoring of the 
patient should continue until conclusion of the pregnancy.  Any serious adverse events 
associated with the pregnancy (e.g., an event in the fetus, an event in the mother during 
or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.  In addition, the investigator will submit a Clinical 
Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available.
5.4.3.2
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.


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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).
5.4.4
Reporting Requirements for Medical Device Complaints
The investigator must report all complaints associated with medical device and their 
packaging to the Sponsor no more than 24 hours after learning of the event.
In this study, the PDS implant, the PDS ancillary devices, and the intravitreal 
ranibizumab 0.5 mg single-use container are considered medical devices.
To report a medical device complaint, the investigator should follow the guidance 
outlined in the Device Complaints and Return Instructions for the Clinical Sites document 
and provide as much information as possible to the Sponsor, including the product batch 
number.
If the medical device results in an adverse event to the study patient, the event must be 
reported on the Adverse Event eCRF and submitted through the EDC system by the 
investigator.  If the event is serious, the Adverse Event eCRF must be completed 
immediately (i.e., no more than 24 hours after learning of the event), as outlined in 
Section 5.4.2.  If a medical device causes an adverse event to an individual other than 
the study patient (e.g., study site personnel), the event should be reported to the 
Sponsor (refer to the Device Complaints and Return Instructions for the Clinical Sites for 
further details).
For further information on returning the PDS implant and the ancillary devices 
associated with a complaint, refer to the Device Complaints and Return Instructions for 
the Clinical Sites document.
5.4.4.1
Device Defects or Deficiencies That Could Have Led to 
Medical Occurrence
Device deficiencies (inadequacy with respect to labeling, identity, quality, durability, 
reliability, safety, or performance, including malfunctions) that did not lead to an adverse 
event but could have led to a medical occurrence if suitable action had not been taken, 
must be reported immediately (i.e., no more than 24 hours after learning of the event). 
Refer to the Device Complaints and Return Instructions for the Clinical Sites for further 
details.


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5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
30 [7] days after the last dose of study drug for intravitreal arm; the final study visit for 
patients in the implant arm; and 90 [7] days after explantation for patients who undergo 
implant explantation), if the event is believed to be related to prior study drug treatment.  
These events should be reported through use of the Adverse Event eCRF.  However, if 
the EDC system is not available, the investigator should report these events directly to 
the Sponsor or its designee, either by faxing or by scanning and emailing the paper 
Clinical Trial Serious Adverse Event/Adverse Event of Special Interest Reporting Form 
using the fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.


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To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

PDS Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The primary analysis will be performed when all patients have completed the Week 40 
visit or have discontinued from the study prior to Week 40, all data collected through 
Week 40 are in the database, and the data have been cleaned and verified. At the time 
of the primary analysis, the study will be ongoing. An analysis of the available data post 
Week 40 (after Week 40 and up to a specified clinical cutoff date) will also be performed. 
Such results will be reported with, but separate from, the 40-week study results to 
provide additional information.
Additional analyses may be performed to support the requirements of health authorities
relative to marketing applications, as appropriate.
The final analysis will be performed after all patients have either completed the 2-year 
study treatment period including their final study visit, or discontinued early from the 
study, all data from the study are in the database, and the database is locked. 
The primary analysis, summarized by treatment group, may be reported to the public 
before completion of the study. 
Descriptive summaries will include the mean, standard deviation, median, and range for 
continuous variables, and counts and percentages for categorical variables. 
Detailed specifications of the statistical methods will be described in the Statistical 
Analysis Plan (SAP).
6.1
DETERMINATION OF SAMPLE SIZE
Patients will be randomly allocated in a 3:2 ratio to the implant arm or intravitreal arm. 
The primary endpoint is the change in BCVA score from baseline averaged over 
Weeks 36 and 40.  The study is sized to achieve adequate power to show 
non-inferiority (NI) and equivalence of the implant arm to the intravitreal arm in the 
change in BCVA score from baseline averaged over Week 36 and Week 40 using an 
NI margin of 4.5 letters and equivalence margins of 4.5 letters.


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Assuming a standard deviation of 9.5 letters for the change from baseline in BCVA score 
averaged over 36 and 40 weeks, up to a true mean change from baseline in BCVA of 
0.75 letters worse for the implant arm, compared with the monthly intravitreal arm, 
216 patients in the implant arm and 144 patients in the intravitreal arm will provide 90% 
power to demonstrate NI and equivalence between the two treatment groups.  
Calculations were based on a one-sided t-test at 0.025 level for the NI test and two 
one-sided t-tests at the 0.025 level for the equivalence test with the assumption of a 
10% dropout rate by Week 40 and a 10% increase for the trimmed mean analysis. 
An independent statistician was employed to conduct a masked evaluation of the 
variance of the primary efficacy endpoint, but not the proportion of patients who receive 
supplemental treatment during the study or the study dropout rate before the end of 
enrollment because the enrollment was too rapid for these evaluations to be of value. 
The variance comparison to the assumptions used in planning the study did not suggest 
the initial assumption for the variance of the primary efficacy endpoint was substantially 
lower. However, independent of this assessment, due to a high speed of enrollment 
combined with a lower screen failure rate than expected, the number of patients enrolled 
was unintentionally increased to 418.  Details of the masked assessment, findings, and 
actions will be documented in the SAP.
6.2
SUMMARIES OF CONDUCT OF STUDY
Patient disposition (the number of patients randomized, treated, and completing each 
study period) will be tabulated by treatment received.  Reasons for premature study 
treatment discontinuation and study discontinuation, any eligibility criteria deviation, and 
other major protocol deviations will also be tabulated.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics such as age, sex, race, baseline disease 
characteristics (such as baseline CPT, baseline BCVA), and number of prior anti-VEGF 
injections will be summarized in the efficacy population by treatment group using 
descriptive statistics.  Exposure to study treatment (number of study treatments and 
duration of treatment) will be summarized by treatment received.
6.4
EFFICACY ANALYSES
Efficacy data will be summarized on the efficacy population comprising all patients who 
are randomized and receive the study treatment, with patients grouped according to 
treatment actually received.  Patients who received the PDS implant will be included in 
the implant arm.
Unless otherwise noted, analyses of efficacy outcome measures will be stratified by 
baseline BCVA (74 letters vs. 74 letters). The stratification factor as recorded in IxRS 
will be used.  The estimates and confidence intervals (CIs) will be provided for the mean 


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(for continuous variables) or proportion (for binary variables) for each treatment group 
and the difference in means or proportions between two treatment groups.  All CIs will 
be two-sided and at the 95.03% level. Details of the calculation of the estimates and CIs 
will be provided in the SAP.
6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the change in BCVA score from baseline averaged over 
Weeks 36 and 40 with BCVA assessed using the ETDRS chart at a distance of 
4 meters. The primary estimand is defined as follows:

Population: Adult patients with nAMD diagnosed within 9 months and receiving at 
least four anti-VEGF intravitreal injections (with the last injection being ranibizumab), 
responsive to prior anti-VEGF treatment

Variable: Change in BCVA score from baseline averaged over Weeks 36 and 40

Intercurrent events: Regardless whether or not a patient has the following 
intercurrent event prior to Week 40: 
-Receives more than 1 supplemental treatment
-Receives any prohibited systemic treatment or prohibited therapy in the study eye 
(Section 4.4.2)
-Discontinues study treatment due to adverse events
-Discontinues study treatment due to lack of efficacy as per investigator’s clinical 
judgment

Population-level summary: Difference in adjusted mean between PDS 100 mg/mL 
and intravitreal groups.
Of note, lack of efficacy includes investigators choices for reason for discontinuation 
from treatment of lack of efficacy, progressive disease, disease relapse, and 
symptomatic deterioration.
The primary objective is to determine the NI and equivalence between the two treatment 
arms, as measured by the primary efficacy endpoint with an NI margin of 4.5 letters and 
equivalence margin of 4.5 letters.  To control the overall type I error, a fixed sequence 
testing procedure (Westfall and Krishen 2001) will be used.  If the implant arm is shown 
to be non-inferior to the intravitreal arm at the one-sided 0.02485 level, then the 
equivalence test will be conducted using two one-sided 0.02485 tests.
The primary analysis will be performed using the mixed-effect model with repeated 
measures (MMRM) based on all available data up to Week 40. All observed 
measurements will be included in the analysis regardless whether or not a patient has 
an intercurrent event. Missing data will be implicitly imputed by the MMRM model, 
assuming a missing at random mechanism.


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The dependent variable in the MMRM model is the change from baseline in BCVA score 
at post-baseline visits, from 4 to 40 weeks, and the independent variables are the 
treatment group, time, treatment-by-time interaction, baseline BCVA score (continuous), 
and the randomization stratification factor of baseline BCVA (74 letters vs. 74 letters)
as fixed effects.  The MMRM model will assume an unstructured covariance structure.  If 
there are convergence problems with the model, then a compound symmetry covariance
or an AR(1) covariance structure will be used.  Comparisons between the two treatment 
arms will be made using a composite contrast over Weeks 36 and 40.
For the primary efficacy endpoint, if a lower bound of a two-sided 95.03% CI for the 
difference of two treatments is greater than 4.5 letters (the NI margin), then treatment 
via PDS is considered non-inferior to monthly intravitreal ranibizumab treatment.  If the 
two-sided 95% CI is within 4.5 letters and 4.5 letters, then the two treatment regimens 
are considered clinically equivalent.  
As a sensitivity analysis, the per-protocol analysis will follow the same methods as the 
primary analysis except the Per-Protocol Population will be used.
Supplemental Analyses for the Primary Endpoint
The following supplemental analysis will be performed for the primary efficacy endpoint 
to evaluate the robustness of the primary analysis finding: 
Trimmed Mean Analysis: The analysis will be used to assess the difference in BVCA 
between two treatments using a truncated distribution, truncating patients with the worst 
outcome, with the assumption that patients have the worst outcome after intercurrent 
events.
The estimand is defined as follows:

Population: Adult patients with nAMD diagnosed within 9 months and receiving at 
least 4 anti-VEGF intravitreal injections (with the last injection being ranibizumab) 
responsive to prior anti-VEGF treatment

Variable: Change in BCVA score from baseline averaged over Weeks 36 and 40

Intercurrent events: Assume patients have the worst outcome after the following 
intercurrent events prior to Week 40:
-Receives more than 1 supplemental treatment
-Receives any prohibited systemic treatment or prohibited therapy in the 
Study eye (Section 4.4.2 of the Protocol)
-Discontinues study treatment due to adverse events
-Discontinues study treatment due to lack of efficacy as per investigator’s 
clinical judgment

Population-level summary: Difference in adjusted trimmed mean between PDS 
100 mg/mL and intravitreal groups.


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The trimmed mean analysis (Permutt and Li 2017) will be performed using an analysis of 
covariance (ANCOVA) model with adjustment for covariates.  The dependent variable in 
the ANOVA model is the average of non-missing values of Weeks 36 and 40 
assessments in change from baseline in BCVA score (if one of the two assessments is 
missing, the non-missing assessment will be used), and the independent variables are 
the treatment group, baseline BCVA score (continuous), and the randomization 
stratification factor of baseline (74 letters vs. 74 letters).
Patients will be considered to have the worst outcomes and will be trimmed from 
analysis if any of the following occurs:

They have an intercurrent event prior to Week 36.

They have a missing Week 36 assessment and have an intercurrent event at 
Week 36.

They have missing assessments at both Week 36 and Week 40, and have an 
intercurrent event in either of these two visits.
Such patients will be referred to as "must trimmed patients."  Of note, if a patient has a
non-missing Week 36 assessment and has an intercurrent event at Week 36, then the 
change in BCVA from baseline to Week 36 for this patient will be used for the analysis
and the Week 40 data would not be used.
For the remaining patients, if they have Week 36 and/or Week 40 BCVA assessments, 
they will be considered "completers"; if they have missing both Week 36 and Week 40 
assessments, the missing data will be considered missing at random and these patients 
will be removed from the analysis.
The inferential statistics (i.e., 95.03% CI) for the trimmed mean will be based on the 
permutation test.  The treatment assignments will be permuted in a sufficiently large 
random sample of possible ways (~30,000 random samples will be generated).
The method can be stated in the following four steps:
1. Remove patients whose missing BCVA assessments are considered missing at 
random (see definition above) from the analysis.
2. The percentage of patients to be trimmed will be based on a masked evaluation of 
percentage of patients meeting the trimming criteria by Week 36 and will be 
documented in the SAP.  The analysis will be used to assess the difference in 
BVCA between two treatments excluding the true or assumed worst outcomes. 
Order the data based on adjusted values from the ANCOVA model, and trim equal 
fractions (20.3% in the PDS 100 mg/mL arm and 20.2% in the intravitreal 
ranibizumab arm) from both treatment arms

The adjusted values are determined as follows.  An ANCOVA model as specified 
above will be fitted for all completers.  The estimated treatment effect will be 
discarded and the coefficients for the covariates will be kept to calculate the 
adjusted value Y - b' X for each patient, for which Y is the change in BCVA score 
averaged over 36 and 40 weeks, X is the matrix for the covariates—baseline BCVA 


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score (continuous) and the baseline BCVA category (74 letters vs. 74 letters), 
and b is the estimated coefficient matrix for the covariates.

These adjusted values will be used to rank the data within each treatment 
group. The “must trimmed patients” will always be ranked the lowest (regardless of 
whether their adjusted values are available) and trimmed from the analyses.  The 
best (1-trimming fraction) 100% in each group will be used for the analysis 
specified in Step 3. If multiple patients have the same adjusted values, they will be 
ranked randomly relative to each other prior to trimming.
3. Refit the ANCOVA model (as specified above) to the trimmed data set, and 
compute the difference in trimmed mean between two treatment groups.
4. Repeat Steps 2 and 3 30,000 times based on augmented datasets with the 
treatment assignment randomly permuted according to the original randomization 
procedures (blocked randomization stratified by baseline BCVA category).
When the proportion of the "must trimmed patients" in either treatment group in the 
permuted data exceeds the planned trimmed fraction, the trimming fraction will be 
chosen adaptively as the greater of the proportions of "must be trimmed patients" in the 
two treatment groups.
Other supportive analyses may be performed and details will be provided in the SAP.
6.4.2
Secondary Efficacy Endpoints
The continuous secondary endpoints will be summarized using descriptive statistics 
based on all observed data. These continuous endpoints will also be analyzed following
the same method as the analysis of the primary endpoint (see Section 6.4.1) with the 
independent variable, baseline BCVA score (continuous), in the model replaced with the 
baseline value of the corresponding endpoint (e.g., baseline CPT).  The intercurrent 
events and data handling rules for the primary endpoint will apply here.  Descriptive 
summaries will be provided for all secondary endpoints based on all observed data.  
Baseline is defined as the last available measurement prior to first treatment. 
Unless otherwise specified, for binary secondary endpoints, the proportion of patients in 
each treatment group and the overall difference in proportions between treatment groups 
will be estimated using the weighted average of the observed proportions and the 
differences in observed proportions over the strata defined by randomization 
stratification factor of baseline BCVA (74 letters vs. 74 letters) using the Cochran-
Mantel-Haenszel weights (Cochran 1954; Mantel and Haenszel 1959). All observed 
measurements will be included in the analysis regardless whether or not a patient has 
an intercurrent event. Confidence intervals of the proportion of patients in each 
treatment group and the overall difference in proportions between treatment groups will 
be calculated using the normal approximation to the weighted proportions (Mehrota and 
Railkar 2000).  If the response rate is low, an unstratified analysis may also be 
performed.


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The secondary efficacy endpoint, proportion of patients who undergo supplemental 
treatment, will be evaluated using only the patients who were able to be assessed for the 
need for supplemental treatment. The analysis will exclude any patients who 
discontinued treatment before the refill-exchange planned visit or who missed both 
refill-exchange visits, as these patients are not able to be assessed for the need for 
supplemental treatment.  The unadjusted proportion of patients who undergo 
supplemental treatment as well as of patients who do not undergo supplemental 
treatment will be reported.
In addition, the binary secondary endpoints through Week 40 will also be summarized 
using the same approach with missing assessments imputed with the last post-baseline 
observation carried forward (continuous BCVA values are carried forward and then the 
binary endpoint is derived). Different strata will be used for the 
CochranMantelHaenszel (CMH) analyses of the following binary endpoint: 
–
Proportion of subjects with a BCVA score of 69 letters (approximate 20/40 Snellen 
equivalent) or better at the average over Weeks 36 and 40: the difference between 
the two treatment groups will be estimated using the same approach stratified by 
baseline BCVA (Snellen equivalent of 20/40 or better vs. worse than 20/40).
6.4.3
Exploratory Endpoints
Details regarding the exploratory endpoints will be provided in the SAP.
6.5
SAFETY ANALYSES
Safety data will be summarized on the safety population comprising all patients who 
receive study treatment, with patients grouped according to treatment actually received 
(patients who receive PDS implant will be included in the implant arm).
Safety will be assessed through descriptive summaries of adverse events, ocular 
assessments, and ADAs to ranibizumab.  Clinically significant laboratory abnormalities 
and clinically significant vital sign abnormalities will be reported as adverse events and 
evaluated as part of the adverse event assessments.
At the time of the primary analysis, safety summaries will be summarized based on the 
complete Week 40 data in the safety population.  In addition, ongoing safety data (from 
first treatment up to a single specified clinical cutoff date) in the safety population will 
also be summarized.  At the time of the final analysis, safety summaries will be produced 
based on cumulative data in the safety population.
6.5.1
Adverse Events
All verbatim adverse event terms will be mapped to MedDRA thesaurus terms, and their 
incidence will be summarized by treatment arm.
Treatment-emergent adverse events will be defined as events beginning at the surgical 
insertion of the implant or at the first intravitreal ranibizumab 0.5 mg injection through the 


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completion of the study or until a patient discontinues prematurely.  Adverse events will 
be tabulated by body system and preferred term.  All adverse events, serious adverse 
events, deaths, adverse events leading to discontinuation of study treatment, adverse 
events of special interest, and adverse events judged to be related to study treatment or 
procedure will be summarized overall and by the adverse event onset day (37 days vs. 
37 days).  Separate summaries will be prepared for non-ocular and ocular adverse
events, with events in the study eye and fellow eye summarized separately.
6.5.2
Ocular Assessments
Results of the following ocular assessments will be summarized by treatment group, by 
timepoint and by eye (study vs. fellow) as applicable, using descriptive summaries:  IOP, 
slitlamp examination, and indirect ophthalmoscopy.  Changes from baseline for selected 
ocular assessments will be tabulated.  The presence of intraocular inflammation and 
vitreous hemorrhage, as determined on slitlamp examination, will be tabulated by grade 
(according to grading scales for flares and cells and vitreous hemorrhage grading scale 
and density in Appendix 7 and Appendix 8, respectively).  The presence of retinal break 
or detachment as determined from ophthalmoscopy will be tabulated.
6.6
PHARMACOKINETIC ANALYSES
The PK Population will consist of patients who receive study treatment grouped 
according to treatment received and have at least one post study treatment PK sample 
available and key parameters will be estimated (e.g., area under the concentrationtime 
curve [AUC], maximum serum concentration [Cmax], minimum serum concentration [Cmin], 
and half-life)  Sensitivity analysis may be performed with the PK-Evaluable Population: 
PK Population excluding patients receiving intravitreal injections of ranibizumab in the 
study eye post PDS implant (including supplemental treatment), patients with fellow eye 
ranibizumab or bevacizumab treatment, or prior bevacizumab treatment in either eye.
Individual and mean serum ranibizumab concentration versus time data will be tabulated 
and plotted by treatment arm for all patients in the PK Population and PK-Evaluable 
Population.  In a subset of patients in the implant arm with more intensive sampling (at 
selected sites), the serum pharmacokinetics of ranibizumab will be summarized by 
estimating total exposure (AUC), Cmax, and half-life of drug delivered from the implant 
after PDS implant insertion.  Estimates for these parameters will be tabulated and 
summarized (mean, standard deviation, coefficient of variation, median, and minimum 
and maximum).  Inter-patient variability will be evaluated.
Exploratory PK analyses to evaluate potential relationships between drug exposure and 
efficacy of the PDS will be performed.  Additional PK analyses will be conducted as 
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6.7
IMMUNOGENICITY ANALYSES
Because patients will have been exposed to ranibizumab prior to entry into study, the 
ADA status of patients at the randomization visit may not reflect pretreatment ADA 
prevalence in the study.  Thus, the ADA incidence will be analyzed as follows.
The immunogenicity analyses will group patients according to treatment received.  The 
analyses on incidence of immunogenicity will include all patients with at least one ADA 
sample collected at the randomization visit and at least one postdose ADA sample.  ADA 
samples will be collected prior to dosing during the randomization visit and at 
Weeks 4, 24, 36, and 96.  To account for pre-study exposure to ranibizumab, ADA 
incidence will be summarized as follows:

ADA incidence at the time of entry into the study (randomization visit)

ADA incidence at any time after randomization visit, grouped in the following 
manner:
a.
Patients who were ADA negative at randomization and became positive only 
after dosing, during the study.
b.
Patients who were ADA positive at randomization and ADA titer increased 
after dosing during the study; in this case, the titer of one or more samples 
collected after randomization must be at least 4-fold greater (i.e., 0.60 titer 
units) than the titer of the randomization visit sample.  These patients are 
considered to have treatment-enhanced ADA responses.
c.
Patients who were ADA positive at randomization and ADA titer did not 
increase after dosing during the study.
The combined rates described in (a) and (b) above will provide the incidence of 
treatment-emergent ADAs in the study.  Patients are considered to be negative for ADAs 
if they are ADA negative at all timepoints.  
The immunogenicity assessment will also include testing for the presence of neutralizing 
antibodies in samples confirmed to be positive for anti-ranibizumab antibodies.  The 
incidence of neutralizing antibodies will be grouped and reported in a similar fashion to 
that described above.
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported using descriptive statistics. 
6.8
EXPLORATORY BIOMARKER ANALYSES
The pharmacodynamic (PD) biomarker analysis population will consist of patients who 
are in the safety population and have sufficient data to enable assessment of potential 
changes in biomarkers in response to treatment during the conduct of this study. PD 
biomarker analyses will be focused primarily on, but not limited to, the change in 
free-VEGF or other angiogenesis-related biomarker concentrations (absolute or percent 
change as appropriate) over time.  The data will be analyzed in the context of 


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ranibizumab pharmacokinetics, using a longitudinal model approach, to gain an 
understanding of the relationship between ranibizumab concentrations and target 
modulation.  Results will be summarized descriptively. 
Additional analyses will be performed, as deemed appropriate, to explore biomarkers 
that are associated with progression to a more severe disease, are associated with 
acquired resistance to ranibizumab, are associated with susceptibility to developing 
adverse events, can provide evidence of ranibizumab activity, or can increase the 
knowledge and understanding of disease biology.  Prognostic biomarker analyses will 
include all patients for which biomarker assessments were made during randomization 
("baseline").  Baseline values will be used to evaluate prognostic biomarkers in the 
context of efficacy, PK, safety, and/or immunogenicity endpoints.  Results will be 
summarized descriptively. 
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and reading 
center data 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.  For additional details of the data quality assurance 
see the Data Quality Review Plan.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.


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At the end of the study, the investigator will receive patient data for his or her site in a 
readable format 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, images, laboratory notes, memoranda, patient-reported 
outcomes (PROs), questionnaires, treatment experience questionnaires, evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies of transcriptions that are certified after verification as being accurate and 
complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial -related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.


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7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO data (if applicable), Informed Consent 
Forms, laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 15 years after completion or discontinuation of the study or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final Clinical Study Report has been 
completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for 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 a Mobile Nursing Informed Consent Form, if applicable) will be provided 
to each site.  If applicable, it will be provided in a certified translation of the local 
language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  


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


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also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.7).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.6).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted clinical study reports and other summary reports will be provided upon 
request.


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8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.3).
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.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
MANAGEMENT OF STUDY QUALITY
The Sponsor has implemented a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  Prior 
to study initiation, the Sponsor identified potential risks associated with critical trial 
processes and data and implemented plans for evaluating and controlling these risks.  
Risk evaluation and control included the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation.  Detection of deviations 
from quality tolerance limits will trigger an evaluation to determine if action is needed.  
Details on the establishment and monitoring of quality tolerance limits are provided in a 
Quality Tolerance Limit Management Plan.


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9.4
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.5
ADMINISTRATIVE STRUCTURE
This study is sponsored by F. Hoffmann-La Roche Ltd.  
The Sponsor and/or its designee will perform study management, oversight of data 
management, statistical programming, project management, monitoring, vendor 
management, and data management (quality checking of the data).
Procedures used for data review, database cleaning, issuing and resolving data queries, 
verification and validation are detailed in the Data Management Plan and in the Internal 
Data Review Plan documents.
Approximately 90 sites will participate with original plans to enroll approximately 
360 patients; 418 patients were ultimately enrolled.  An IxRS will be used for patient 
enrollment and for management of study drug/device requests and shipments. 
A central laboratory will be used for most laboratory assessments (e.g., safety laboratory 
assessments) and for storage of other laboratory samples (e.g., serum samples for PK 
assessments) prior to being shipped to the Sponsor or a Sponsor-selected designee for 
analysis.
Data will be recorded by an EDC system using eCRFs (see Section 5.4.2).
A central reading center will be used for ocular imaging analyses and storage (e.g., FA, 
FP, and SD-OCT).
An iDMC will be employed to monitor and evaluate patient safety throughout the study.
9.6
DISSEMINATION OF DATA AND PROTECTION OF 
TRADE SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request. For more information, refer to the Roche Global Policy on Sharing of Clinical
Study Information at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf


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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.
9.7
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
120/Protocol GR40548, Version 5
10.
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Campochiaro PA, Marcus DM, Awh CC, et al. The port delivery system with ranibizumab 
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endothelial growth factor treatment of neovascular age-related macular 
degeneration: The Comparison of Age-Related Macular Degeneration Treatments 
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Chakravarthy U, Wong TY, Fletcher A, et al. Clinical risk factors for age-related macular 
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intravitreal injections of ranibizumab for diabetic macular oedema. Br J Ophthalmol 
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Finger RP, Wiedemann P, Blumhagen F, et al. Treatment patterns, visual acuity and 
quality-of-life outcomes of the WAVE studya noninterventional study of 
ranibizumab treatment for neovascular age-related macular degeneration in 
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2015;10:e0129361.


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Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet 
age-related macular degeneration. Ophthalmology 2012;119:253748.
Ho AC, Busbee BG, Regillio CD, et al., for the HARBOR Study Group. 
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Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
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Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd
123/Protocol GR40548, Version 5
Appendix 1
Schedule of Activities: Implant Arm
Table 1: Implant Arm, Year 1 
Assessment
Screening a
Rand. b
Week 1
Week Visit
D1 b, c
D2
D7
4
8
12
16
20
24
28
32
36
40
44
48
Visit window
(days)
21 days from prior 
ITV Anti-VEGF
2128 days from last 
ITV RBZ Tx
NA
2
7
Informed consent 
x d
Review of inclusion and 
exclusion criteria
x
x
Medical and surgical 
history
x
Demographic data
x
Height and Weight
x
Contact IxRS e
x
x
x
x
x
x
x
x
Vital signs f
x
x
x
Concomitant 
medications g
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events h
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concurrent ocular 
proceduresi
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
MacTSQ j
x
x
PPPQ j
x
Pregnancy test k
x
x
x
x
x
x
x
x
Urinalysis l
x
Hematology l
x


Appendix 1: Schedule of Activities: Implant Arm (cont.)
Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
124/Protocol GR40548, Version 5
Table 1: Implant Arm, Year 1 (cont.)
Assessment
Screening a
Rand. b
Week 1
Week Visit
D1 b, c
D2
D7
4
8
12
16
20
24
28
32
36
40
44
48
Visit window
(days)
21 days from prior 
ITV Anti-VEGF
2128 days from last 
ITV RBZ Tx
NA
2
7
Chemistry l
x
Coagulation l
x
Serum PK sample m
x
x
x
x
Serum PK sample (at 
selected sites) m
x
x
x
x
Serum ADA sample m
x
x
x
x
BCVA 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
IOP n
x
x
x o
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Slitlamp examination
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Dilated binocular indirect 
ophthalmoscopy p
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Historical images 
collection: OCT and FA q
x
SD-OCT r
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Fundus photography r
x
x
x
Fluorescein angiography r
x
x
x
Fundus autofluorescence r
x
x
x
Lens photo (fundus reflex 
photograph)
x
x
x
OCT-A (at selected sites) s
x
x
x
x
x
x
x
x


Appendix 1: Schedule of Activities: Implant Arm (cont.)
Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
125/Protocol GR40548, Version 5
Table 1: Implant Arm, Year 1 (cont.)
Assessment
Screening a
Rand. b
Week 1
Week Visit
D1 b, c
D2
D7
4
8
12
16
20
24
28
32
36
40
44
48
Visit window
(days)
21 days from prior 
ITV Anti-VEGF
2128 days from last 
ITV RBZ Tx
NA
2
7
Pre- and post-study 
treatment antimicrobials t
x
x
x
Intravitreal ranibizumab 
0.5 mg injection u
x
Ranibizumab filled implant 
insertion v
x
Implant insertion and refill-
exchange video w
x
x
x
Post-implantation IOP 
measurement x
x
Implant insertion 
evaluation y
x
Implant photographs z
x
x
x
x
x
x
x
x
x
Implant refill-exchange aa
x
x
Post-treatment finger-
counting test bb
x ii
x
x
Supplemental ranibizumab
(if supplemental treatment 
criteria are met) cc
x
x
x
x
Follow-up call dd
x ee
x
x
Whole blood sample 
for genotyping (optional) ff
x


Appendix 1: Schedule of Activities: Implant Arm (cont.)
Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
126/Protocol GR40548, Version 5
Table 1: Implant Arm, Year 1 (cont.)
Assessment
Screening a
Rand. b
Week 1
Week Visit
D1 b, c
D2
D7
4
8
12
16
20
24
28
32
36
40
44
48
Visit window
(days)
21 days from prior 
ITV Anti-VEGF
2128 days from last 
ITV RBZ Tx
NA
2
7
Aqueous humor sample 
for biomarkers and 
ranibizumab conc. 
(optional) gg
x
x
x
x
Serum and plasma 
samples for biomarkers (if 
aqueous humor sample 
collected) (optional) hh
x
x
x
x
Serum sample for PK (if 
aqueous humor sample 
collected) (optional) hh
x
x
ADAanti-drug antibody; anti-VEGFantivascular endothelial growth factor; BCVAbest-corrected visual acuity; conc. concentration; Dday; FAfluorescein 
angiography; FAFfundus autofluorescence; FPfundus photography; IOPintraocular pressure; ITVintravitreal; IxRSinteractive voice or web-based 
response system; MacTSQMacular Degeneration Treatment Satisfaction Questionnaire; NA not applicable; nAMDneovascular age-related macular 
degeneration; OCToptical coherence tomography; OCT-Aoptical coherence tomographyangiography; PDSPort Delivery System with ranibizumab; 
PKpharmacokinetics; PPPQPDS Patient Preference Questionnaire; Randrandomization; RBZranibizumab; SD-OCTspectral-domain optical coherence 
tomography; Txtreatment; VAvisual acuity. 
Notes:  All ocular assessments are to be performed for both eyes prior to study treatment unless noted otherwise.  All assessments for a visit are to be performed 
on the same day, except those at screening.
a Refer to Section 3.1 and Table 2 for patient eligibility scenario.
b
Randomization and implant insertion surgery (Day 1) should be scheduled 2128 days (inclusive) from the last intravitreal ranibizumab treatment in the study 
eye. 
c Implant insertion surgery (Day 1) should occur within 17 days from randomization and no later than 28 days from the last intravitreal ranibizumab treatment in 
the study eye. 
d
Patients who participate in the run-in must sign the Informed Consent Form prior to performing protocol-mandated assessments.
e
The IxRS will be contacted at Weeks 16, 20, 40, and 44 for supplemental treatment evaluation (for additional assessments if supplemental treatment criteria are 
met, see Appendix 5).


Appendix 1: Schedule of Activities: Implant Arm (cont.)
Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
127/Protocol GR40548, Version 5
Table 1: Implant Arm, Year 1, Footnotes (cont.)
f
Vital signs consist of blood pressure and pulse measurement while patient is in a seated position after resting for 5 minutes.  Vital signs will be measured pre-
treatment (as applicable).  On the day of implant insertion procedure (Day 1 visit), vital signs will be recorded before the surgery and only blood pressure will be 
recorded during surgery and after surgery.
g
Record any concomitant medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) other 
than protocol-specified procedural medications, and pretreatment and post-treatment medications (e.g., proparacaine, antimicrobials, steroids) used by the 
patient within 7 days preceding the randomization visit date and through the conclusion of the patient’s study participation or early termination visit.
h
After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events related to a protocol-mandated intervention (e.g., 
procedures such as fluorescein angiography or medication interruption) should be reported.  Adverse events will be recorded starting on Day 1 through the last 
study visit.  Adverse events assessed by the qualified ophthalmologist as related to implant insertion, refill-exchange, and explantation should be followed until 
the event resolves or the event is assessed as irreversible, chronic, or stable, even if the patient’s participation in the study is over.
i
Record all concurrent ocular procedures or additional assessments performed on the study or fellow eye.  Results of the additional ocular assessments must be 
forwarded to the Sponsor for evaluation and/or storage.
j
Must be interviewer-administered by site personnel (other than VA examiner) prior to any other study procedures.  
k
Urine pregnancy test will be performed locally prior to fluorescein angiography and study treatment (if applicable) at screening and subsequent specified visits.  
If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  Do not perform fluorescein angiography or administer study treatment until 
the final results are available.  If the serum pregnancy test is positive, do not administer the study treatment.
l
Obtain from all study patients pre-treatment and prior to fluorescein angiography, if applicable.  Hematology includes hemoglobin, hematocrit, quantitative 
platelet count, RBCs, WBCs, and differentials, including neutrophils, bands, lymphocytes, basophils, eosinophils, and monocytes (absolute and percent).  
Chemistry includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, potassium, chloride, glucose, BUN, creatinine, 
calcium, phosphorus, total and direct bilirubin, total protein, albumin, AST, ALT, lactic dehydrogenase, ALP, and uric acid.  Urinalysis includes specific gravity, 
pH, blood, protein, ketones, glucose, bilirubin, urobilinogen, and microscopic examination (if any of the preceding urinalysis tests, other than glucose and 
ketones, are abnormal).  Coagulation includes aPTT and PT.
m Collect prior to implant refill-exchange and prior to fluorescein angiography (if applicable).  
n
Perform IOP measurement prior to dilating eyes or procedure; the method used for a patient must remain consistent throughout the study for visits in the office. 
When performed at implant refill-exchange visit, IOP needs to be measured prior to implant refill-exchange.
o
Should be performed in the surgical center using indentation tonometry (e.g. Tono-Pen) for the study eye only prior to the implant insertion surgery.
p
Upon completion of the implant insertion surgery, patients will have dilated indirect ophthalmoscopy performed to monitor the implant placement and to evaluate 
any potential implant problems (capturing the results of the indirect ophthalmoscopy findings on EDC is not needed at Day 1).  Dilated ophthalmoscopy 
examinations will also be performed in the study eye at Day 2 and Day 7 (2 days); afterward, perform dilated ophthalmoscopy examinations at each visit to 
monitor the implant placement and to evaluate other implant problems.
q
Historical OCT images taken around the time of diagnosis of nAMD (and before the start of anti-VEGF treatment) will be required to determine patient’s eligibility 
at the screening visit. FAs if taken around the time of diagnosis of nAMD (and before the start of anti-VEGF treatment) must be submitted to the reading center 
as well and will be evaluated, but are not required to determine patient’s eligibility. Refer to the reading center manuals for details.


Appendix 1: Schedule of Activities: Implant Arm (cont.)
Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
128/Protocol GR40548, Version 5
Table 1: Implant Arm, Year 1, Footnotes (cont.)
r
The central reading center will evaluate FP, FA, FAF and SD-OCT images taken at the screening visit for determination of a patient’s eligibility, together with the 
historical OCT images taken at the time of diagnosis of nAMD. Refer to the reading center manual for details.
s
Only at selected sites.  Perform pre-treatment.
t
The pre-implant insertion use of self-administered antimicrobials is required.  The pre-implant refill-exchange use of self-administered antimicrobials is per the 
investigator’s discretion.  The post-implant insertion or refill-exchange use of self-administered antimicrobials is required.  Anti-inflammatory drops post-implant 
insertion may be administered as well, per standard of care.
u
As required, depending on patient eligibility category.  Refer to Section 3.1 and Table 2 for patient eligibility scenario.
v
Initially fill the implant with IxRS-assigned kit of ranibizumab 100 mg/mL prior to its insertion into the study eye. 
w At sites that permit video recording. 
x
IOP will be checked for the study eye only by the treating physician by digital palpation as clinically indicated.  These assessments must be performed prior to 
placing a patch on the eye.  Patients will be allowed to leave the surgical center after the designated physician has assessed that there are no safety concerns.  
If any safety concerns or immediate toxicity are noted, the patient will remain at the surgical center and will be treated according to the designated physician’s 
clinical judgment.  If applicable, the adverse event will be reported.
y
Upon completion of the implant insertion procedure, complete the implant insertion evaluation to indicate surgical details of the insertion procedure.  Information 
captured in the evaluation will be reported.
z
In addition to the timepoints listed, the photographs will also be taken at any visit if there are concerns with implant function.
aa Refill the implant with IxRS-assigned kit of ranibizumab 100 mg/mL. 
bb Finger-counting test, followed by hand motion and light perception tests (when necessary) performed by the physician within 15 minutes post-treatment for the 
study eye only.  The patient will be allowed to leave the office after the designated physician has assessed that there are no safety concerns.  If any safety 
concerns or immediate toxicity are noted, the patient will remain at the office and will be treated according to the designated physician’s clinical judgment.  If 
applicable, the adverse event will be reported.
cc Implant arm patients are eligible for supplemental treatment with intravitreal ranibizumab 0.5 mg if the supplemental treatment criteria are met (Section 5.1.5.3).  
Following supplemental treatment, patients will continue with implant refill-exchanges per protocol.
dd All study patients will be contacted 3 (1) days following study treatment to elicit reports of any decreases in vision, occurrence of eye pain, unusual redness, or 
any other new ocular symptoms.  Patients will also be asked whether they have taken the prescribed, self-administered, post-treatment antimicrobials.
ee If intravitreal ranibizumab 0.5 mg injection is given.
ff
If a patient has consented to this optional sample collection.
gg If a patient has consented to this optional sample collection. At implant refill-exchange visit, the aqueous humor sample should be obtained prior to or 
immediately after implant refill-exchange. 
hh If a patient has consented to this optional sample collection, obtain the sample prior to study treatment and prior to fluorescein angiography (if applicable).
ii
Only if patient receives intravitreal ranibizumab 0.5 mg injection.


Appendix 1: Schedule of Activities: Implant Arm (cont.)
Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
129/Protocol GR40548, Version 5
Table 2: Implant Arm, Year 2, Early Study Termination and Explantation Visits 
Assessment
Week Visit
Early Study 
Term. Visit y
Explant. 
Visit z
52
56
60
64
68
72
76
80
84
88
92
96 cc
Visit window (days)
7
Contact IxRS a
x
x
x
x
x
x
x
x
Vital signs b
x
x
x
Concomitant medications c
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events d
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concurrent ocular procedures e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
MacTSQ f
x
PPPQ f
x
Pregnancy test g
x
x
x
x
x
x
x
Serum PK sample h
x
x
Serum PK sample (at selected 
sites) h
x
Serum ADA sample h
x
x
BCVA
x
x
x
x
x
x
x
x
x
x
x
x
x
IOP i
x
x
x
x
x
x
x
x
x
x
x
x
x
x j
Slitlamp examination
x
x
x
x
x
x
x
x
x
x
x
x
x
Dilated binocular Indirect 
ophthalmoscopy k
x
x
x
x
x
x
x
x
x
x
x
x
x
x
SD-OCT l
x
x
x
x
x
x
x
x
x
x
x
x
x
Fundus photography l
x
x
Fluorescein angiography l
x
x
Fundus autofluorescence l
x
x


Appendix 1: Schedule of Activities: Implant Arm (cont.)
Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
130/Protocol GR40548, Version 5
Table 2: Implant Arm, Year 2, Early Study Termination and Explantation Visits (cont.)
Assessment
Week Visit
Early Study 
Term. Visit y
Explant. 
Visit z
52
56
60
64
68
72
76
80
84
88
92
96 cc
Visit window (days)
7
Lens photograph (fundus 
reflex photograph)
x
x
OCT-A (at selected sites) m
x
x
x
x
x
x
x
Pre-and post-study treatment 
antimicrobials n
x
x
Implant refill-exchange o
x
Post-treatment finger-counting 
test p
x
Implant explantation q
x
Implant refill-exchange and 
explantation video r
x
x
Implant photographs s
x
x
x
x
x
x
x
x aa
Supplemental ranibizumab (if 
supplemental treatment 
criteria are met) t
x
x
x
x
Aqueous humor sample for PD 
and ranibizumab conc. u
x
x bb
Plasma and serum samples 
for PD u
x
x bb
Follow-up call v
x
Aqueous humor sample for 
biomarkers and ranibizumab 
conc. (optional) w
x
x
x
x


Appendix 1: Schedule of Activities: Implant Arm (cont.)
Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
131/Protocol GR40548, Version 5
Table 2: Implant Arm, Year 2, Early Study Termination and Explantation Visits (cont.)
Assessment
Week Visit
Early Study 
Term. Visit y
Explant. 
Visit z
52
56
60
64
68
72
76
80
84
88
92
96 cc
Visit window (days)
7
Plasma and serum sample for 
biomarkers (if aqueous humor 
sample collected) (optional) x
x
x
x
x
Serum sample for PK (if 
aqueous humor sample 
collected) (optional) x
x
x
x
ADAanti-drug antibody; BCVAbest-corrected visual acuity; conc. concentration; Explant.explantation; IOPintraocular pressure; IxRSinteractive voice or 
web-based response system; MacTSQMacular Degeneration Treatment Satisfaction Questionnaire; OCT-Aoptical coherence tomographyangiography; 
PDpharmacodynamic; PKpharmacokinetics; PDSPort Delivery System with ranibizumab; PPPQPDS Patient Preference Questionnaire; SD-OCTspectral-
domain optical coherence tomography; Term. termination; VAvisual acuity.
Notes:  All ocular assessments are to be performed for both eyes prior to study treatment unless noted otherwise.  All assessments for a visit are to be performed 
on the same day, except those at screening.
a
The IxRS will be contacted at Weeks 64, 68, 88, and 92 for supplemental treatment evaluation (for additional assessments if supplemental treatment criteria are 
met, see Appendix 5).
b
Vital signs consist of blood pressure and pulse measurement while patient is in a seated position after resting for 5 minutes.  If implant explantation is required, 
vital signs will be recorded before the surgery and only blood pressure will be recorded during surgery and after surgery. 
c
Record any concomitant medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) other 
than protocol-specified procedural medications, and pretreatment and post-treatment medications (such as proparacaine, antimicrobials, steriods) used by the 
patient within 7 days preceding the randomization visit date and through the conclusion of the patient’s study participation or early termination visit.
d
Adverse events will be recorded starting on Day 1 through the last study visit.  Adverse events assessed by the qualified ophthalmologist as related to implant 
refill-exchange, and explantation should be followed until the event resolves or the event is assessed as irreversible, chronic, or stable, even if the patient’s 
participation in the study is over.
e
Record all concurrent ocular procedures or additional assessments performed on the study or fellow eye.  Results of the additional ocular assessments must be 
forwarded to the Sponsor for evaluation and/or storage.
f
Must be interviewer-administered by site personnel (other than VA examiner) prior to any other study procedures.  
g
Urine pregnancy test will be performed locally prior to fluorescein angiography and study treatment (if applicable) at specified subsequent visits.  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test.  Do not perform fluorescein angiography or administer the study treatment until the 
final results are available.  If the serum pregnancy test is positive, do not administer the study treatment.
h
Collect sample prior to implant refill-exchange, and/or fluorescein angiography (if applicable). 


Appendix 1: Schedule of Activities: Implant Arm (cont.)
Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
132/Protocol GR40548, Version 5
Table 2: Implant Arm, Year 2, Early Study Termination and Explantation Visits, Footnotes (cont.)
i
Perform IOP measurement prior to dilating eyes or procedure; the method used for a patient must remain consistent throughout the study for visits in the office. 
When performed at implant refill-exchange visit, IOP needs to be measured prior to implant refill-exchange.
j
Should be performed in the surgical center using indentation tonometry (e.g. Tono-Pen) prior to the implant explantation surgery.
k
Dilated ophthalmoscopy examinations will be performed at each visit to monitor the implant for any potential implant problems.  Upon completion of the 
explantation procedure, patients will also have indirect ophthalmoscopy of the study eye.
l
Refer to the reading center manual for details.
m Only at selected sites.  Perform pre-treatment.
n
The pre-implant refill-exchange use of self-administered antimicrobials is per the investigator's discretion.  The pre-explantation use of self-administered 
antimicrobials is required.  The post-implant refill-exchange or explantation use of self-administered antimicrobials is required.  Anti-inflammatory drops post-
implant explantation may administered as well, per standard of care.
o
Refill the implant with IxRS-assigned kit of ranibizumab 100 mg/mL.
p
Finger-counting test, followed by hand motion and light perception tests (when necessary) performed by the physician within 15 minutes post-treatment for the 
study eye only.  The patient will be allowed to leave the office after the designated physician has assessed that there are no safety concerns.  If any safety 
concerns or immediate toxicity are noted, the patient will remain at the office and will be treated according to the designated physician’s clinical judgment.  If 
applicable, the adverse event will be reported.
q
IOP will be checked after explantation for the study eye only by the treating physician by digital palpation as clinically indicated.  These assessments must be 
performed prior to placing a patch on the eye.  Patients will be allowed to leave the surgical center after the designated physician has assessed that there are no 
safety concerns.  If any safety concerns or immediate toxicity are noted, the patient will remain at the surgical center and will be treated according to the 
designated physician’s clinical judgment.  If applicable, the adverse event will be reported.
r
For sites that permit video recording.
s
In addition to the timepoints listed, the photograph will also be taken at any visit if there are concerns with Implant function.
t
Implant arm patients are eligible for supplemental treatment with intravitreal ranibizumab 0.5 mg if supplemental treatment criteria are met (see Section 5.1.5.3).  
Following supplemental treatment, patients will continue with implant refill-exchanges per protocol.
u
At the explantation visit, collect aqueous sample prior or immediately after explantation. At the early study termination visit, plasma/serum samples should be 
obtained prior to fluorescein angiography.  
v
All study patients will be contacted 3 (1) days following study treatment to elicit reports of any decreases in vision, occurrence of eye pain, unusual redness, or 
any other new ocular symptoms.  Patients will also be asked whether they have taken the prescribed, self-administered, post-treatment antimicrobials.
w If a patient has consented to this optional sample collection. At implant refill-exchange visit, the sample should be obtained prior to or immediately after implant 
refill-exchange. 
x
If a patient has consented to this optional sample collection, obtain the sample prior to study treatment and prior to fluorescein angiography (if applicable).
y
Patients will be scheduled for an early term evaluation visit 90 (7) days after the implant insertion procedure or 30 (7) days following the last implant refill-
exchange for monitoring of all adverse events.


Appendix 1: Schedule of Activities: Implant Arm (cont.)
Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
133/Protocol GR40548, Version 5
Table 2: Implant Arm, Year 2, Early Study Termination and Explantation Visits, Footnotes (cont.)
z
Patients will be scheduled for safety visits at 1, 7 (2), 30 (7), and 60 (7) days post-explantation (refer to Appendix 4 for visit assessments).
aa Implant photographs can be taken either the day of the explantation surgery (if possible) or within days leading to the explantation surgery.
bb Samples can be taken either the day of the explantation surgery (if possible) or within days leading to the explantation surgery.  Aqueous humor, plasma, and 
serum samples for biomarkers should all be taken at the same visit.
cc If a patient is unable to complete Archway at Week 96 and enroll in Portal on the same day, follow the alternate schedule of activities in Appendix 1, Table 3.


Appendix 1: Schedule of Activities: Implant Arm (cont.)
Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
134/Protocol GR40548, Version 5
Table 3: Alternate Scenarios for Implant Arm: Week 96 and Week (X)
(Q4W) 
Assessment
Visit
Week 96
Week (X) (Q4W)
Visit window (days)
7
Contact IxRS a
x
x
Vital signs b
x
x c
Concomitant medications d
x
x
Adverse events e
x
x
Concurrent ocular procedures f
x
x
Pregnancy test g
x
x
Serum PK sample h
x
x
Serum ADA sample h
x
x
BCVA
x
x
IOP i
x
x
Slitlamp examination
x
x
Dilated binocular Indirect ophthalmoscopy j
x
x
SD-OCT k
x
x
Fundus photography k
x
x l, m
Fluorescein angiograph k
x
x l, m
Fundus autofluorescence k
x
x l, m
Lens photograph (fundus reflex photograph) k
x
x l, m
OCT-A (at selected sites) n
x
x l, m
Implant refill-exchange and video
x o
x p
Pre-and post-study treatment antimicrobials q
x
x
Post-treatment finger-counting test r
x
x
Implant photographs s
x
x t
Supplemental ranibizumab (if supplemental 
treatment criteria are met)
x u
Follow-up call v
x
x
Aqueous humor sample for biomarkers and 
ranibizumab conc. (optional)
x w
x w, x
Plasma and serum sample for biomarkers (if 
aqueous humor sample collected) (optional)
x w
x w, x
ADAanti-drug antibody; BCVAbest-corrected visual acuity; conc. concentration; IOPintraocular 
pressure; IxRSinteractive voice or web-based response system; OCT-Aoptical coherence 
tomographyangiography; PKpharmacokinetics; PDSPort Delivery System with ranibizumab; 
(Q4W)optional every 4 weeks; SD-OCTspectral-domain optical coherence tomography; VAvisual 
acuity
Notes:  All ocular assessments are to be performed for both eyes prior to study treatment unless noted 
otherwise.


Appendix 1: Schedule of Activities: Implant Arm (cont.)
Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
135/Protocol GR40548, Version 5
Table 3:  Alternate Scenarios for Implant Arm: Week 96 and Week (X)
(Q4W), Footnotes (cont.) 
a
The IxRS will be contacted if visit is conducted and study treatment is required. 
b
Vital signs consist of blood pressure and pulse measurement while patient is in a seated position after 
resting for 5 minutes. 
c
Vital signs will be measured only at the last Week (X) of the study. 
d
Record any concomitant medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal 
or homeopathic remedies, nutritional supplements) other than protocol-specified procedural medications, 
and pretreatment and post-treatment medications (such as proparacaine, antimicrobials, steroids) used 
by the patient within 7 days preceding the randomization visit date and through the conclusion of the 
patient’s study participation or early termination visit.
e
Adverse events will be recorded starting on Day 1 through the last study visit.  Adverse events assessed 
by the qualified ophthalmologist as related to implant refill-exchange, and explantation should be followed 
until the event resolves or the event is assessed as irreversible, chronic, or stable, even if the patient’s 
participation in the study is over.
f
Record all concurrent ocular procedures or additional assessments performed on the study or fellow eye.  
Results of the additional ocular assessments must be forwarded to the Sponsor for evaluation and/or 
storage.
g
Urine pregnancy test will be performed locally prior to fluorescein angiography and study treatment (if 
applicable).  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  Do not 
perform fluorescein angiography or administer the study treatment until the final results are available.  If 
the serum pregnancy test is positive, do not administer the study treatment.
h
If implant refill-exchange is administered, collect sample, prior to implant refill-exchange, and/or 
fluorescein angiography (if applicable). If sample collection is missed, collect at the earliest visit 
scheduled after the refill-exchange is performed.
i
Perform IOP measurement prior to dilating eyes or procedure; the method used for a patient must remain 
consistent throughout the study for visits in the office.  When performed at implant refill-exchange visit, 
IOP needs to be measured prior to implant refill-exchange.
j
Dilated ophthalmoscopy examinations will be performed at each visit to monitor the implant for any 
potential implant problems. 
k
Refer to the reading center manual for details. 
l
If fundus photography, fluorescein angiography, fundus autofluorescence, lens photograph, OCT-A and 
implant photographs were missed at Week 96 visit or if Week 96 visit was not conducted (per scenario 3, 
Table 3), perform assessments at first conducted Week (X). 
m Fundus photography, fluorescein angiography, fundus autofluorescence, lens photograph, OCT-A, and 
implant photographs should be repeated if more than 3 months have passed since the last assessments 
were conducted. 
n
Only at selected sites.
o
If Week 96 visit is within window, but the patient will not be able to complete the Portal enrollment visit 
within 21-28 days post-Week 96, administer a refill-exchange at Week 96.  If Portal enrollment is 
expected to occur within 21-28 days after the Week 96 visit, do not administer a refill-exchange at Week 
96. For sites that permit video recording.
p
If Week 96 is missed, administer a refill-exchange at the first conducted Week (X) visit. If both Week 96 
and the first Week (X) are missed, the investigator must contact the Sponsor for further discussion prior 
to scheduling the next visit. For sites that permit video recording.
q
If Implant refill-exchange is administered. The pre-implant refill-exchange use of self-administered 
antimicrobials is per the investigator's discretion. The post-implant refill-exchange use of self-
administered antimicrobials is required.


Appendix 1: Schedule of Activities: Implant Arm (cont.)
Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
136/Protocol GR40548, Version 5
Table 3:  Alternate Scenarios for Implant Arm: Week 96 and Week (X)
(Q4W), Footnotes (cont.) 
r
If Implant refill-exchange is administered. Finger-counting test, followed by hand motion and light 
perception tests (when necessary) performed by the physician within 15 minutes post-treatment for the 
study eye only.  The patient will be allowed to leave the office after the designated physician has 
assessed that there are no safety concerns.  If any safety concerns or immediate toxicity are noted, the 
patient will remain at the office and will be treated according to the designated physician’s clinical 
judgment.  If applicable, the adverse event will be reported.
s
In addition to the timepoints listed, the photograph will also be taken at any visit if there are concerns with 
Implant function.
t
If Implant refill-exchange is administered and at the last Week (X) of the study.
u
Only for patients who will reach Week 112 and 116. For additional required assessments if supplemental 
treatment criteria are met see Appendix 5.
v
If study treatment is administered. All study patients will be contacted 3 (1) days following study 
treatment to elicit reports of any decreases in vision, occurrence of eye pain, unusual redness, or any 
other new ocular symptoms.  Patients will also be asked whether they have taken the prescribed, 
self-administered, post-treatment antimicrobials.
w If a patient has consented to this optional sample collection, collect if implant refill-exchange is performed 
at the visit (prior to or immediately after procedure, and prior to fluorescein angiography if applicable).
x
Collect at the last Week (X) of the study as required per scenarios 2 and 3, Table 3.


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd
137/Protocol GR40548, Version 5
Appendix 2 Schedule of Activities: Intravitreal Arm
Table 1:
Intravitreal Arm, Year 1
Assessment
Screening a
Rand. b
D1 c
Week Visit
4
8
12
16
20
24
28
32
36
40
44
48
Visit window (days)
21 days from prior 
ITV Anti-VEGF Tx
2127 days from 
last ITV RBZ Tx
NA
7
Informed consent
x d
Review of inclusion and 
exclusion criteria
x
Medical and surgical history
x
Demographic data
x
Height and Weight
x
Contact IxRS 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital signs e
x
x
Concomitant medications f
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse event g
x
x
x
x
x
x
x
x
x
x
x
x
x
Concurrent ocular procedures h
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
MacTSQ i
x
x
Pregnancy test j
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urinalysis k
x
Hematology k
x
Chemistry k
x
Coagulation k
x
Serum PK sample l
x
x
x
x


Appendix 2: Schedule of Activities: Intravitreal Arm (cont.)
Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
138/Protocol GR40548, Version 5
Table 1: 
Intravitreal Arm, Year 1 (cont.)
Assessment
Screening a
Rand. b
D1 c
Week Visit
4
8
12
16
20
24
28
32
36
40
44
48
Visit window (days)
21 days from 
prior ITV
Anti-VEGF Tx
2127 days from 
last ITV RBZ Tx
NA
7
Serum ADA sample l
x
x
x
x
BCVA
x
x
x
x
x
x
x
x
x
x
x
x
x
x
IOP m
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Slitlamp examination
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Dilated binocular Indirect 
ophthalmoscopy
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Historical images collection: OCT 
and FA n
x
SD-OCT o
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Fundus photography o
x
x
x
Fluorescein angiography o
x
x
x
Fundus autofluorescence o
x
x
x
Lens photograph (fundus reflex 
photograph)
x
x
x
OCT-A (at selected sites only) p
x
x
x
x
x
x
x
Optional pre- and post-study 
treatment antimicrobials
x
x
x
x
x
x
x
x
x
x
x
x
x
Administration of study treatment 
(0.5 mg intravitreal RBZ) 
x q
x
x
x
x
x
x
x
x
x
x
x
x
x
Post-treatment finger-counting 
test r
x s
x
x
x
x
x
x
x
x
x
x
x
x
x


Appendix 2: Schedule of Activities: Intravitreal Arm (cont.)
Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
139/Protocol GR40548, Version 5
Table 1: 
Intravitreal Arm, Year 1 (cont.)
Assessment
Screening a
Rand. b
D1 c
Week Visit
4
8
12
16
20
24
28
32
36
40
44
48
Visit window (days)
21 days from prior 
ITV Anti-VEGF Tx
2127 days from 
last ITV RBZ Tx
NA
7
Follow-up call t
x u
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum sample for PK  (at 
selected sites) v
Collect serum PK sample 1-5 days post intravitreal ranibizumab injection 
(collect only once per patient)
Whole blood sample for 
genotyping (optional) w
x
Aqueous humor sample for 
biomarkers and ranibizumab 
conc. (optional) w
x
x
x
x
Plasma and serum samples for 
biomarkers (if aqueous humor 
sample collected) (optional) x
x
x
x
x
Serum sample for PK (if 
aqueous humor sample 
collected) (optional) x
x
x
ADAanti-drug antibody; anti-VEGFantivascular endothelial growth factor; BCVAbest-corrected visual acuity; conc. concentration; Dday; FAfluorescein 
angiography; FAFfundus autofluorescence; FPfundus photography; IOPintraocular pressure; ITVintravitreal; IxRSinteractive voice or web-based 
response system; MacTSQMacular Degeneration Treatment Satisfaction Questionnaire; NA not applicable; nAMDneovascular age-related macular 
degeneration; OCToptical coherence tomography; OCT-Aoptical coherence tomographyangiography; PKpharmacokinetic; Rand.randomization; 
RBZranibizumab; SD-OCTspectral-domain optical coherence tomography; Txtreatment; VAvisual acuity.
Notes:  All ocular assessments are to be performed for both eyes prior to study treatment unless noted otherwise.  All assessments for a visit are to be performed 
on the same day, except those at screening.
a Refer to Section 3.1 and Table 2 for patient eligibility scenario.
b
Randomization should occur no later than 27 days from the last intravitreal ranibizumab treatment in the study eye. 
c
Day 1 study treatment visit should occur on the same day as randomization visit.
d
Patients who participate in the run-in must sign the Informed Consent Form prior to performing protocol-mandated assessments.


Appendix 2: Schedule of Activities: Intravitreal Arm (cont.)
Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
140/Protocol GR40548, Version 5
Table 1: 
Intravitreal Arm, Year 1, Footnotes (cont.)
e
Vital signs consist of blood pressure and pulse measurement while patient is in a seated position after resting for 5 minutes.  Vital signs will be measured pre-  
treatment (as applicable).  
f
Record any concomitant medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) other 
than protocol-specified procedural medications, and pre-treatment and post-treatment medications (such as proparacaine, antimicrobials, steroids) used by the 
patient within 7 days preceding the randomization visit date and through the conclusion of the patient’s study participation or early termination visit.
g
After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events related to a protocol-mandated intervention (e.g., 
procedures such as fluorescein angiography or medication interruption) should be reported.  Adverse events will be recorded starting on Day 1 through the last 
study visit.  
h
Record all concurrent ocular procedures or additional assessments performed on the study or fellow eye.  Results of the additional ocular assessments must be 
forwarded to the Sponsor for evaluation and/or storage.
i
Must be interviewer-administered by site personnel (other than VA examiner) prior to any other study procedures. 
j
Urine pregnancy test will be performed locally prior to fluorescein angiography and each study treatment (if applicable) at specified subsequent visits.  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test.  Do not perform fluorescein angiography or administer the study treatment until the 
final results are available.  If the serum pregnancy test is positive, do not administer the study treatment.
k
Obtain from all study patients pre-treatment and prior to fluorescein angiography, if applicable.  For a description of the laboratory assessments to be performed 
see Section 4.5.7 or the laboratory manual.
l
Collect prior to study treatment and prior to fluorescein angiography (if applicable).
m Perform IOP measurement prior to dilating eyes or study treatment; the method used for a patient must remain consistent throughout the study.
n
Historical OCT images taken around the time of diagnosis of nAMD (and before the start of anti-VEGF treatment) will be required to determine patient’s eligibility 
at the screening visit.  FAs if taken around the time of diagnosis of nAMD (and before the start of anti-VEGF treatment) must be submitted to the reading center 
as well and will be evaluated, but are not required to determine patient’s eligibility.  Refer to the reading center manuals for details.
o
The central reading center will evaluate FP, FA, FAF and SD-OCT images taken at the screening visit for determination of a patient’s eligibility, together with the 
historical OCT images taken at the time of diagnosis of nAMD.  Refer to the reading center manual for details.
p
Only at selected sites.  Perform pre-treatment. 
q
As required, depending on patient eligibility category.  Refer to Section 3.1 and Table 2 for patient eligibility scenario.
r
Finger-counting test, followed by hand motion and light perception tests (when necessary) performed by the physician within 15 minutes post-treatment for the 
study eye.  Patients will be allowed to leave the office after the designated physician has assessed that there are no safety concerns.  If any safety concerns or 
immediate toxicity are noted, the patient will remain at the office and will be treated according to the designated physician’s clinical judgment.  If applicable, the 
adverse event will be reported.
s
Only if patient receives intravitreal ranibizumab 0.5 mg injection.
t
All study patients will be contacted 3 (1) days following study treatment to elicit reports of any decreases in vision, occurrence of eye pain, unusual redness, or 
any other new ocular symptoms.
u
If treatment is given.


Appendix 2: Schedule of Activities: Intravitreal Arm (cont.)
Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
141/Protocol GR40548, Version 5
Table 1: 
Intravitreal Arm, Year 1, Footnotes (cont.)
v
One time serum PK collection only. Sample will be collected from patients in the intravitreal arm 1-5 days after an intravitreal ranibizumab 0.5 mg injection once 
per patient during the study (selected study visit will be at the discretion of the investigator and site). This sample collection may be performed at the study site or 
by a trained mobile nursing professional at the patient’s home or another suitable location.
w
If a patient has consented to this optional sample collection.
x
If a patient has consented to this optional sample collection, obtain the sample prior to study treatment and prior to fluorescein angiography (if applicable).


Appendix 2: Schedule of Activities: Intravitreal Arm (cont.)
Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
142/Protocol GR40548, Version 5
Table 2: Intravitreal Arm, Year 2 and Early Study Termination Visit 
Assessment
Week Visit
Early Study 
Term. Visit a
52
56
60
64
68
72
76
80
84
88
92
96 r
Visit window (days)
7
Contact IxRS 
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital signs b
x
x
Concomitant medications c
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events d
x
x
x
x
x
x
x
x
x
x
x
x
x
Concurrent ocular procedures e
x
x
x
x
x
x
x
x
x
x
x
x
x
MacTSQ f
x
Pregnancy test g
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum PK sample h
x
x
Serum ADA sample h
x
x
BCVA
x
x
x
x
x
x
x
x
x
x
x
x
x
IOP i
x
x
x
x
x
x
x
x
x
x
x
x
x
Slitlamp examination
x
x
x
x
x
x
x
x
x
x
x
x
x
Dilated binocular indirect 
ophthalmoscopy
x
x
x
x
x
x
x
x
x
x
x
x
x
SD-OCT j
x
x
x
x
x
x
x
x
x
x
x
x
x
Fundus photography j
x
x
Fluorescein angiography j
x
x
Fundus autofluorescence j
x
x
Lens photograph (fundus reflex 
photograph)
x
x
OCT-A (at selected sites) k
x
x
x
x
x
x
x


Appendix 2: Schedule of Activities: Intravitreal Arm (cont.)
Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
143/Protocol GR40548, Version 5
Table 2: Intravitreal Arm, Year 2 and Early Study Termination Visit (cont.)
Assessment
Week Visit
Early Study 
Term. Visit a
52
56
60
64
68
72
76
80
84
88
92
96 r
Visit window (days)
7
Optional pre- and post-study 
treatment antimicrobials
x
x
x
x
x
x
x
x
x
x
x
Administration of study 
treatment (intravitreal 
ranibizumab 0.5 mg)
x
x
x
x
x
x
x
x
x
x
x
Post-treatment finger-counting 
test l
x
x
x
x
x
x
x
x
x
x
x
Aqueous humor sample for 
biomarkers and ranibizumab 
concentration 
x
Plasma and serum samples for 
biomarkers m
x
Follow-up call n
x
x
x
x
x
x
x
x
x
x
x
Serum sample for PK  (at 
selected sites) o
Collect serum PK sample 1-5 days post intravitreal ranibizumab injection (collect only once 
per patient)
Aqueous humor sample for 
biomarkers and ranibizumab 
conc. (optional) p
x
x
x
x q
Plasma and serum samples for 
biomarkers (if aqueous humor 
sample collected) (optional) p
x
x
x
x q
Serum sample for PK (if 
aqueous humor sample 
collected) (optional) p
x
x
x


Appendix 2: Schedule of Activities: Intravitreal Arm (cont.)
Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
144/Protocol GR40548, Version 5
Table 2: Intravitreal Arm, Year 2 and Early Study Termination Visit, Footnotes
ADAanti-drug antibody; BCVAbest-corrected visual acuity; conc. concentration; IOPintraocular pressure; IxRSinteractive voice or web-based response 
system; MacTSQMacular Degeneration Treatment Satisfaction Questionnaire; OCT-Aoptical coherence tomographyangiography; PKpharmacokinetics; 
SD-OCT spectral-domain optical coherence tomography; Term.termination; VAvisual acuity.
Notes:  All ocular assessments are to be performed for both eyes prior to study treatment unless noted otherwise.  All assessments for a visit are to be performed 
on the same day, except those at screening.
a Patients will be scheduled for an early term evaluation 30 (7) days following the last study drug treatment for monitoring of all adverse events.  
b
Vital signs consist of blood pressure and pulse measurement while patient is in a seated position after resting for 5 minutes. 
c
Record any concomitant medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) other 
than protocol-specified procedural medications, and pre-treatment and post-treatment medications (such as proparacaine, antimicrobials, steroids) used by the 
patient within 7 days preceding the randomization visit date and through the conclusion of the patient’s study participation or early termination visit.
d
Adverse events will be recorded starting on Day 1 through the last study visit.
e
Record all concurrent ocular procedures or additional assessments performed on the study or fellow eye.  Results of the additional ocular assessments must be 
forwarded to the Sponsor for evaluation and/or storage.
f
Must be interviewer-administered by site personnel (other than VA examiner) prior to any other study procedures. 
g
Urine pregnancy test will be performed locally prior to fluorescein angiography and study treatment (if applicable) at specified subsequent visits.  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test.  Do not perform fluorescein angiography or administer the study treatment until the 
final results are available.  If the serum pregnancy test is positive, do not administer the study treatment.
h
Collect prior to study treatment and prior to fluorescein angiography (if applicable).
i
Perform IOP measurement prior to dilating eyes or study treatment; the method used for a patient must remain consistent throughout the study. 
j
Refer to the reading center manual for details.
k
Only at selected sites. Perform pre-treatment.
l
Finger-counting test, followed by hand motion and light perception tests (when necessary) should be performed by the physician within 15 minutes post-
treatment for the study eye only.  Patients will be allowed to leave the office after the designated physician has assessed that there are no safety concerns.  If 
any safety concerns or immediate toxicity are noted, the patient will remain at the office and will be treated according to the designated physician’s clinical 
judgment.  If applicable, the adverse event will be reported. 
m Samples should be obtained prior to fluorescein angiography.
n
All study patients will be contacted 3 (1) days following study treatment to elicit reports of any decreases in vision, occurrence of eye pain, unusual redness, or 
any other new ocular symptoms.
o
One time serum PK collection only. Sample will be collected from patients in the intravitreal arm 1-5 days after an intravitreal ranibizumab 0.5 mg injection once 
per patient during the study (selected study visit will be at the discretion of the investigator and site).  This sample collection may be performed at the study site 
or by a trained mobile nursing professional at the patient’s home or another suitable location.
p
If a patient has consented to this optional sample collection. For plasma/serum samples, obtain the sample prior to study treatment and prior to fluorescein 
angiography (if applicable).
q
Only collect if the patient is not enrolling in Portal.
r
If a patient is unable to complete Archway at Week 96 and enroll in Portal on the same day, follow the alternate schedule of activities in Appendix 2 Table 3.


Appendix 2: Schedule of Activities: Intravitreal Arm (cont.)
Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
145/Protocol GR40548, Version 5
Table 3:
Alternate Scenarios for Intravitreal Arm: Week 96 and Week (X)
(Q4W) 
Assessment
Week Visit
Week 96
Week (X)
(Q4W)
Visit window (days)
7
Contact IxRS a
x
x
Vital signs b
x
x c
Concomitant medications d
x
x
Adverse events e
x
x
Concurrent ocular procedures f
x
x
Pregnancy test g
x
x
Serum PK sample
x h
x i
Serum ADA sample
x h
x i
BCVA
x
x
IOP j
x
x
Slitlamp examination
x
x
Dilated binocular Indirect ophthalmoscopy k
x
x
SD-OCT l
x
x
Fundus photography l
x
x m, n
Fluorescein angiography l
x
x m, n
Fundus autofluorescence l
x
x m, n
Lens photograph (fundus reflex photograph) l
x
x m, n
OCT-A (at selected sites) o
x
x m, n
Optional pre-and post-study treatment 
antimicrobials
x
x
Administration of study treatment (intravitreal 
ranibizumab 0.5 mg)
x
x p
Post-treatment finger-counting test q
x
x
Follow-up call r
x
x
Aqueous humor sample for biomarkers and 
ranibizumab conc. (optional) s
x
x t
Plasma and serum sample for biomarkers (if 
aqueous humor sample collected) (optional) s
x
x t
ADAanti-drug antibody; BCVAbest-corrected visual acuity; conc. concentration; IOPintraocular 
pressure; IxRSinteractive voice or web-based response system; OCT-Aoptical coherence 
tomographyangiography; PKpharmacokinetics; PDSPort Delivery System with ranibizumab; 
(Q4W)optional every 4 weeks; SD-OCTspectral-domain optical coherence tomography; VAvisual 
acuity
Notes:  All ocular assessments are to be performed for both eyes prior to study treatment unless noted 
otherwise.


Appendix 2: Schedule of Activities: Intravitreal Arm (cont.)
Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
146/Protocol GR40548, Version 5
Table 3:
Alternate Scenarios for Intravitreal Arm: Week 96 and Week (X) 
(Q4W) Footnotes
a
The IxRS will be contacted if visit is conducted and study treatment is required.
b
Vital signs consist of blood pressure and pulse measurement while patient is in a seated position after 
resting for 5 minutes.
c
Vital signs will be measured only at the last Week (X) of the study.
d
Record any concomitant medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal 
or homeopathic remedies, nutritional supplements) other than protocol-specified procedural medications, 
and pretreatment and post-treatment medications (such as proparacaine, antimicrobials, steroids) used 
by the patient within 7 days preceding the randomization visit date and through the conclusion of the
patient’s study participation or early termination visit.
e
Adverse events will be recorded starting on Day 1 through the last study visit.
f
Record all concurrent ocular procedures or additional assessments performed on the study or fellow eye.  
Results of the additional ocular assessments must be forwarded to the Sponsor for evaluation and/or 
storage.
g
Urine pregnancy test will be performed locally prior to fluorescein angiography and study treatment (if 
applicable).  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  Do not 
perform fluorescein angiography or administer the study treatment until the final results are available.  If 
the serum pregnancy test is positive, do not administer the study treatment.
h
If intravitreal ranibizumab is administered, collect sample prior to study treatment and prior to fluorescein 
angiography (if applicable). If sample collection is missed, collect at the earliest visit scheduled after the 
treatment is administered.
i
If Week 96 visit is not conducted (per scenario 3, Table 3), collect sample prior to study treatment only at 
the first conducted Week (X) visit (and prior to fluorescein angiography if applicable). If sample collection 
is missed, it should be collected at the earliest visit scheduled after the treatment is administered.
j
Perform IOP measurement prior to dilating eyes or study treatment; the method used for a patient must 
remain consistent throughout the study for visits in the office. 
k
Dilated ophthalmoscopy examinations will be performed at each visit to monitor the implant for any 
potential implant problems.
l
Refer to the reading center manual for details.
m     If fundus photography, fluorescein angiography, fundus autofluorescence, lens photograph, OCT-A were 
missed at Week 96 visit or if Week 96 visit was not conducted (per scenario 3, Table 3), perform 
assessments at first conducted Week (X).
n   Fundus photography, fluorescein angiography, fundus autofluorescence, lens photograph and OCT-A 
should be repeated if more than 3 months have passed since the last assessments were conducted.
o
Only at selected sites.
p
If required, conduct monthly Week (X) visits and administer intravitreal ranibizumab injection until Portal 
enrollment visit can be scheduled within the required window; at the final planned Week (X), do not 
administer an intravitreal ranibizumab injection.
q
Finger-counting test, followed by hand motion and light perception tests (when necessary) performed by 
the physician within 15 minutes post-treatment for the study eye only.  The patient will be allowed to 
leave the office after the designated physician has assessed that there are no safety concerns.  If any 
safety concerns or immediate toxicity are noted, the patient will remain at the office and will be treated 
according to the designated physician’s clinical judgment.  If applicable, the adverse event will be 
reported
r
All study patients will be contacted 3 (1) days following study treatment to elicit reports of any 
decreases in vision, occurrence of eye pain, unusual redness, or any other new ocular symptoms.  
Patients will also be asked whether they have taken the prescribed, self-administered, post-treatment 
antimicrobials.
s
If a patient has consented to this optional sample collection, obtain the sample prior to study treatment 
and prior to fluorescein angiography (if applicable).
t
Only if Week 96 visit is not conducted (per scenario 3, Table 3), sample collection should be performed 
once at first conducted Week (X) when the study treatment is administered.


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
147/Protocol GR40548, Version 5
Appendix 3
Run-In Visits (If Applicable)
The following assessments will be performed on patients who enter the run-in period of 
the study. In the run-in period, after patients have reached the required number of 
anti-vascular endothelial growth factor (anti-VEGF) treatments prior to screening (see 
Section 4.1.1.2), they will be scheduled for screening 28 (7) days after the last run-in 
visit is completed. 
Assessments a
Run-In Visit 1
Run-In Visit 2
Run-In Visit 3
Window (days)
21 days from 
last intravitreal 
anti-VEGF
28 (7) days 
from Run-In 
Visit 1
28 (7) days 
from Run-In 
Visit 2
Informed consent
x b
x b
x b
Review of run-in inclusion and exclusion criteria c
x
Demographic data
x
BCVA (assessed on ETDRS chart at a 4-meter 
starting distance)
x
x
x
Pregnancy test d
x
x
x
FA e
x
SD-OCT e
x
x
x
Site to contact IxRS 
x
x
x
Optional pre and post-study treatment antimicrobials
x
x
x
Administration of intravitreal ranibizumab 0.5 mg
x
x
x
Post-treatment finger-counting test f
x
x
x
Adverse events g
x
x
x
Follow-up call h
x
x
x
BCVAbest-corrected visual acuity; ETDRSEarly Treatment Diabetic Retinopathy Study; 
FAfluorescein angiography; IxRS interactive voice/web-based response system; nAMDneovascular 
age-related macular degeneration; SD-OCT spectral-domain optical coherence tomography. 
a
A run-in period will be available for patients with newly diagnosed nAMD who are treatment naïve or who 
have had previous treatment with one or two intravitreal anti-VEGF injections within the previous 6 
months.  
b
Patients must satisfy all eligibility criteria and sign the Informed Consent Form only once, at their initial 
run-in visit.  
c
Run-in evaluations for inclusion/exclusion criteria will only be performed and evaluated locally by the 
investigator.
d
Perform locally the urine pregnancy test prior to FA (if applicable) and study treatment for women of 
childbearing potential, including those who have had tubal ligation.  If the urine pregnancy test is positive, 
collect serum pregnancy sample and do not perform FA or intravitreal ranibizumab treatment until the 
final results are available.  If the serum pregnancy test is positive, do not administer intravitreal 
ranibizumab treatment.


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
148/Protocol GR40548, Version 5
Appendix 3
Run-In Visits (If Applicable) (cont.)
e
Refer to the reading center manual for details.  These images, if taken around the time of diagnosis of 
nAMD, will be used as historical images for patient’s eligibility at the screening visit (both SD-OCT and 
FA images will be submitted to the reading center; only SD-OCT images are required for eligibility 
determination).  
f
Finger-counting test, followed by hand motion and light perception tests (when necessary) performed by 
the physician within 15 minutes post-treatment for the study eye only.  Patients will be allowed to leave 
the office after the designated physician has assessed that there are no safety concerns.  If any safety 
concerns or immediate toxicity are noted, the patient will remain at the office and will be treated according 
to the designated physician’s clinical judgment.  If applicable, the adverse event and treatment of adverse 
event (if applicable) will be reported.
g
During the run-in, only serious adverse events related to a protocol-mandated intervention (e.g., 
intravitreal injection procedure, or intravitreal ranibizumab) should be reported.  Adverse events assessed 
by the qualified ophthalmologist as related to ranibizumab and intravitreal injections should be followed 
until the event resolves or the event is assessed as irreversible, chronic, or stable, even if the patient’s 
participation in the study is over.
h
Patients will be contacted 3 (1) days following intravitreal ranibizumab treatment to elicit reports of any 
decreases in vision, occurrence of eye pain, unusual redness, or any other new ocular symptoms.  
Patients will also be asked whether they have taken the prescribed, self-administered, post-treatment 
antimicrobials.
ELIGIBILITY CRITERIA FOR RUN-IN (IF APPLICABLE)
Patients must meet the following ocular inclusion criteria in the study eye for entry in the 
run-in period in addition to the general inclusion criteria (Section 4.1.1.1) and exclusion 
criteria (Section 4.1.2):

Patients with neovascular age-related macular degeneration (nAMD) who are 
treatment-naive or who have had previous treatment with one or two intravitreal 
anti-VEGF injection within the previous 6 months

Best-corrected visual acuity (BCVA) of 34 letters or better (20/200 or better Snellen 
equivalent) using ETDRS chart at a starting distance of 4 meters (see the BCVA 
manual for additional details) 

All subtypes of nAMD lesions are permissible (i.e., type I, type II, type III, or mixed 
forms according to optical coherence tomography classification)

Active primary choroidal neovascularization lesions at the time of diagnosis of 
nAMD must involve the macula (6mm in diameter centered at the fovea)

Sufficiently clear ocular media and adequate pupillary dilation to allow for analysis 
and grading by the central reading center of fluorescein angiography and 
spectral-domain optical coherence tomography images


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
149/Protocol GR40548, Version 5
Appendix 4
Unscheduled Safety Assessment Visits, Post-Study Treatment 
Discontinuation Visits, or Post-Explantation Safety Visits
The assessments listed below will be performed at:

Unscheduled safety assessment visits

Study visits for patients who discontinued study treatment but remain in the 
study. Other assessments, listed in Appendix 1 and Appendix 2 for specific study 
visits, may be performed at discretion of the investigator.

Safety visits following explantation (at 1, 7 [2], 30 [7], and 60 [7] days post-
explantation).  
Assessments a,b
Vital signs (blood pressure and pulse)
x
BCVA (assessed on ETDRS chart at a 4-meter starting distance) c
x
Slitlamp examination
x
Dilated binocular indirect high-magnification ophthalmoscopy
x
IOP d
x
SD-OCT e
x
Adverse events f
x
Concurrent ocular procedures
x
Concomitant medications
x
BCVAbest-corrected visual acuity; ETDRSEarly Treatment Diabetic Retinopathy Study; 
IOP intraocular pressure; SD-OCT spectral-domain optical coherence tomography.
a
An unscheduled safety assessment visit is applicable to any randomized study patients.  If an 
unscheduled safety assessment visit is determined to be necessary by the physician, perform all listed 
assessments.  Ocular assessments may be performed on one eye only, except for BCVA that must be 
performed on both eyes. 
b
At a post-study treatment discontinuation visit or a post-explantation safety visit, perform all listed 
assessments. Ocular assessments may be performed on the study eye only, except for BCVA which 
must be performed on both eyes.
c
BCVA assessment must be performed in both eyes by masked visual acuity examiner. Perform finger-
counting test followed by hand motion and light perception tests when necessary.
d
The method used for the IOP measurement for a patient must remain consistent throughout the study.
e
Refer to the reading center manual for details.
f
Adverse event causality to be evaluated by the qualified ophthalmologist.


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
150/Protocol GR40548, Version 5
Appendix 5
Additional Assessments if Supplemental
Treatment Criteria Are Met
If a patient in the implant arm meets the supplemental treatment criteria (see 
Section 5.1.5.3 at any of the following weeks (Weeks 16, 20, 40, 44, 64, 68, 88, and 92
and Weeks 112 and 116 for patients who follow an alternate final study visit scenario), 
the following assessments must be performed in addition to assessments listed in 
Appendix 1.
Assessments
Pregnancy test a
x
Serum PK sample b
x c
Aqueous humor PD sample b
x c
Plasma and serum PD sample
x c
Optional pre- and post-study treatment antimicrobials
x
Supplemental intravitreal ranibizumab 0.5 mg
x
Post-treatment finger-counting test d
x
Follow-up call e
x
IxRS interactive voice or web-based response system; PD pharmacodynamic; PK pharmacokinetic.
a
For women of childbearing potential, including those who have had tubal ligation, urine pregnancy test 
will be performed locally prior to supplemental treatment.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test.  Do not administer the supplemental treatment until the final results 
are available.  If the serum pregnancy test is positive, do not administer the supplemental treatment. 
b
Collect sample prior to supplemental intravitreal injection.
c
Sample should be collected at the supplemental treatment visit and at the subsequent study visit.
d
Finger-counting test, followed by hand motion and light perception tests (when necessary) performed by 
the physician within 15 minutes post-treatment for the study eye only.  Patients will be allowed to leave 
the office after the designated physician has assessed that there are no safety concerns.  If any safety 
concerns or immediate toxicity are noted, the patient will remain at the office and will be treated according 
to the designated physician’s clinical judgment.  If applicable, the adverse event and treatment of adverse 
event (if applicable) will be reported.
e
Patients will be contacted 3 (1) days following supplemental treatment to elicit reports of any decreases 
in vision, occurrence of eye pain, unusual redness, or any other new ocular symptoms.  Patients will also 
be asked whether they have taken the prescribed, self-administered, post-treatment antimicrobials.


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd
151/Protocol GR40548, Version 5
Appendix 6
Best-Corrected Visual Acuity Testing
SCOPE
Best-corrected visual acuity (BCVA) will be measured by trained and certified personnel at 
the study sites.  
The Sponsor recognizes that it may be difficult to fully mask site staff in an open label 
surgical study.
The Sponsor will require that the following steps be implemented as a best attempt to mask 
VA examiners in order to minimize biases in VA assessments. 

The VA examiner will only conduct refraction and VA assessments and will be masked 
as best as possible to patient study eye assignment, study visit type, and patient 
treatment assignment. 

The VA examiner will have no access to a patient's BCVA scores from previous visits 
and will be aware only of the patient's refraction data from previous visits.

The VA examiner may provide no other direct or indirect patient care. 

Patients and unmasked site personnel will be asked not to discuss the study eye 
assignment, study visit type, and patient treatment assignment with the VA examiner.
VA will be measured at the intervals specified in the protocol (see Section 4.5.5, Appendix 1, 
and Appendix 2).  
EQUIPMENT
The following is needed at minimum 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 ETDRS
Charts 1, 2, and R)

Retro-illuminated box

Trial frame

Trial lens set
TRAINING AND CERTIFICATION
A VA specifications document, procedure manual, and training materials will be provided to 
the investigational sites, and VA examiner certification will be obtained.  The VA examination 
room also must be certified before any VA examinations are performed.  If new VA personnel 
or VA rooms are added to the study, certification must be obtained prior to performing study 
assessments.


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd
152/Protocol GR40548, Version 5
Appendix 7
Grading Scales for Anterior Chamber Flare or Cells and Vitreous 
Cells
GRADING SCALE FOR ANTERIOR CHAMBER FLARE OR CELLS
Flare
0
No protein is visible in the anterior chamber when viewed by an experienced 
observer using slitlamp biomicroscopy; a small, bright, focal slit-beam of white 
light; and high magnification.
Trace
Trace amount of protein is detectable in the anterior chamber:  This protein is 
visible only with careful scrutiny by an experienced observer using slitlamp 
biomicroscopy; a small, bright, focal slit-beam of white light; and high 
magnification.
1
Slight amount of protein is detectable in the anterior chamber:  The presence of 
protein in the anterior chamber is immediately apparent to an experienced 
observer using slitlamp biomicroscopy and high magnification, but such protein is 
detected only with careful observation with the naked eye and a small, bright, 
focal slit-beam of white light.
23
Moderate amount of protein is detectable in the anterior chamber.  These grades 
are similar to 1but the opacity would be readily visible to the naked eye of an 
observer using any source of a focused beam of white light.  This is a continuum 
of moderate opacification, with 2being less apparent than 3.
4
A large amount of protein is detectable in the anterior chamber.  This grade is 
similar to 3, but the density of the protein approaches that of the lens.  
Additionally, frank fibrin deposition is frequently seen in acute circumstances.  
It should be noted that because fibrin may persist for a period of time after partial 
or complete restoration of the bloodaqueous humor barrier, it is possible to 
have resorbing fibrin present with lower numeric assignations for flare 
(e.g., 1flare with fibrin).
Cells
0
No cells are seen in any optical section when a large slitlamp beam is swept 
across the anterior chamber.
Trace
Few (13) cells are observed when the slitlamp beam is swept across the 
anterior chamber.  When the instrument is held stationary, not every optical 
section contains circulating cells.
1
310 cells/optical section are seen when the slitlamp beam is swept across the 
anterior chamber.  When the instrument is held stationary, every optical section 
contains circulating cells.
2
1025 cells are seen when the slitlamp beam is swept across the anterior 
chamber.  When the instrument is held stationary, every optical section contains 
circulating cells.
Modified from:  Hogan MJ, Kimura SJ, Thygeson P. Signs and symptoms of uveitis. I. 
Anterior uveitis. Am J Ophthalmol 1959;47(Part 2):15570.


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd.
153/Protocol GR40548, Version 5
Appendix 7
Grading Scales for Anterior Chamber Flare or Cells and Vitreous 
Cells (cont.)
GRADING SCALE FOR ANTERIOR CHAMBER FLARE OR CELLS
Cells (cont.)
3
2550 cells are seen when the slitlamp beam is swept across the anterior 
chamber.  When the instrument is held stationary, every optical section contains 
circulating cells.  Keratic precipitates or cellular deposits on the anterior lens 
capsule may be present.
4
More than 50 cells are seen when the slitlamp beam is swept across the anterior 
chamber.  When the instrument is held stationary, every optical section contains 
cells, or hypopyon is noted.  As for fibrin deposition, hypopyon may persist for 
some period of time after the active exudation of cells into the anterior chamber 
has diminished or ceased entirely, making it possible to have 1circulating cells 
in the anterior chamber with a resolving hypopyon.
Modified from:  Hogan MJ, Kimura SJ, Thygeson P. Signs and symptoms of uveitis. I. 
Anterior uveitis. Am J Ophthalmol 1959;47(Part 2):15570.
GRADING SCALE FOR VITREOUS CELLS
Number of Cells in Retro 
Illuminated Field
Description
Grade
0
Clear
0
120
Few opacities
Trace
2150
Scattered opacities
1
51100
Moderate opacities
2
101250
Many opacities
3
251
Dense opacities
4
Modified from:  Nussenblatt RB, Whitcup SM, Palestine AG. Uveitis: fundamentals and 
clinical practice. 2nd rev. ed. St. Louis: Mosby, 1996, p. 64.


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd
154/Protocol GR40548, Version 5
Appendix 8
Grading Scales for Vitreous Hemorrhage
GRADING SCALE FOR VITREOUS HEMORRHAGE DENSITY
Grade
Description
None (0)
Retina is visible.
Trace
Retina is visible and red blood cells are visible only on slitlamp 
examination.
1
Retinal detail is visible; some hemorrhage is visible by ophthalmoscopy.
2
Large retinal vessels are visible, but central retinal detail is not visible by 
ophthalmoscopy.
3
Red reflex is visible, but no central retinal detail is seen posterior to the 
equator by ophthalmoscopy.
4
No red reflex by ophthalmoscopy.
VITREOUS HEMORRHAGE FUNCTIONAL GRADING SCALE 
Grade
Description
1
15 letter BCVA loss from the previous visit
2
1630 letter BCVA loss from the previous visit
3
30 letter BCVA loss from the previous visit to hand motion
4
Light Perception or worse


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd
155/Protocol GR40548, Version 5
Appendix 9
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 Section 4.5.6, Appendix 1, and 
Appendix 2) and will be forwarded to the central reading center for analysis and/or 
storage.  Analysis (if applicable) of FAF images will be performed by the central reading 
center.  The list of timepoints at which images will be analyzed are recorded in the 
reading center manual.
EQUIPMENT
Equipment utilized during this trial is described in the central reading center manual.  
The ability to transfer images to electronically export 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 the study manual and training materials.  FAF 
operators, systems, and software will be certified prior to any evaluation of patients.


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Appendix 10
Fundus Photography
SCOPE
Fundus photography (FP) will be taken by trained personnel at the study sites at 
the intervals specified in the protocol.
FP imaging will be performed for each patient at the intervals specified in the protocol 
(see Section 4.5.6, Appendix 1, and Appendix 2) and will be forwarded to the central 
reading center for analysis and/or storage.  Analysis (if applicable) of fundus 
photographs will be performed by the central reading center.
The list of timepoints at which images will be analyzed are recorded in the reading 
center manual. 
EQUIPMENT
See the central reading center manual.
PROCEDURE
The central reading center will provide a study manual and training material.  
The photographer and equipment will be certified by the reading center before any study 
images are taken.


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Appendix 11
Fluorescein Angiography
SCOPE
Fluorescein angiography (FA) will be performed at the study sites by trained personnel 
who are certified by the central reading center.  The FA images will be obtained at the 
intervals specified in the protocol (see Section 4.5.5, Appendix 1, and Appendix 2) and 
will be forwarded to the central reading center for analysis and/or storage.
The list of timepoints at which images will be analyzed are recorded in the reading 
center manual. 
EQUIPMENT
Digitally based angiograms must be used while conducting an angiographic evaluation 
for the study.
FILM-BASED ANGIOGRAPHY AND CERTIFICATION
Film-based angiography is not acceptable. 
DIGITAL IMAGING SYSTEMS AND CERTIFICATION
Digital imaging systems are required.  The system and software at the site will be 
certified by the central reading center prior to obtaining any study angiograms.  This 
certification and validation process will ensure that the central reading center will be able 
to correctly calculate the required measurements.
PROCEDURES
The central reading center will provide a study manual and training material.  
Photographers, systems, and software will be certified prior to obtaining patient 
angiograms.


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Appendix 12
Spectral Domain Optical Coherence Tomography
SCOPE
Spectral-domain optical coherence tomography (SD-OCT) will be performed on both 
eyes 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 Section 4.5.6, Appendix 1, and Appendix 2) and will be forwarded to 
the central reading center for analysis and/or storage.
The list of timepoints at which images will be analyzed are recorded in the reading 
center manual. 
EQUIPMENT
Equipment utilized during this trial is described in the central reading center manual.  
The ability to transfer images to electronically export digital files is required 
(i.e., no printed SD-OCT images will be sent to the central reading center).
PROCEDURES AND CERTIFICATION
The central reading center will provide the study manual and training materials.  
SD-OCT operators, systems, and software will be certified prior to any evaluation of 
patients.


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Appendix 13
Implant Photographs
SCOPE
Implant photographs will be taken by trained personnel at the study sites at the intervals 
specified in the protocol.
Implant imaging will be performed for implant patients only at Day 2 after Day 1 visit and 
at each study visit as specified in the protocol (see Section 4.5.6 and Appendix 1) and 
will be forwarded to the central reading center for analysis and/or storage.  Analysis (if 
applicable) of implant photographs will be performed by the central reading center.
The list of timepoints at which images will be analyzed are recorded in the reading 
center manual.
EQUIPMENT
See the central reading center manual.
PROCEDURE
The central reading center will provide a study manual and training material.  The 
photographer and equipment will be certified by the reading center before any study 
images are taken.


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Appendix 14
Optical Coherence Tomography Angiography (at Selected Sites)
SCOPE
Optical coherence tomography (OCT) angiography will be performed on both eyes only 
at selected study sites that have OCT angiography equipment by trained personnel who 
are certified by the central reading center.  OCT angiography imaging will be performed 
for each patient at the intervals specified in the protocol (see Section 4.5.6, Appendix 1, 
and Appendix 2) and will be forwarded to the central reading center for analysis and/or 
storage.
The list of timepoints at which images will be analyzed are recorded in the central 
reading center manual. 
EQUIPMENT
Equipment utilized during this trial is described in the central reading center manual.  
The ability to transfer images to electronically export digital files is required (i.e., no 
printed OCT angiography 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 
angiography operators, systems, and software will be certified prior to any evaluation of 
patients.


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Appendix 15
Sample Collection and Shipping 
Refer to the laboratory study manual for detailed sample collection, storage, and 
shipping instructions.  All necessary transfer tubes, Vacutainers, labels, shipping 
boxes, and forms will be provided by the central laboratory, except when indicated.
BIOLOGICAL SAMPLES
Samples for assessment of laboratory safety (hematology, serum chemistry, 
coagulation) and urinalysis will be collected at screening visit. 
Urine pregnancy test will be collected and performed prior to each treatment for women 
of childbearing potential, including those who have had tubal ligation.  If positive, serum 
pregnancy test will be performed.  If the serum pregnancy test is positive, the study 
treatment will be discontinued.  
Serum for assessment of ranibizumab concentrations (pharmacokinetics) and 
anti-ranibizumab antibodies will be collected at the timepoints specified in Section 4.5.7
of the protocol and the schedule of activities (see Appendix 1and Appendix 2).  
Aqueous humor (see below for sample collection), plasma, and serum PD samples will 
be collected if patient requires a supplemental treatment and at the subsequent study 
visit, terminates early, or undergoes an explantation. 
In addition, optional aqueous humor, plasma, and serum samples prior to refill-
exchanges and at the subsequent scheduled study visit post-refill-exchange will be 
collected in the implant arm (see Appendix 1).  Sampling in the intravitreal arm will also 
be performed following the same schedule (see Appendix 2).
The laboratory safety (hematology, serum chemistry, coagulation, and urinalysis) and 
serum pregnancy (as required) will be shipped and analyzed by the central laboratory.
The rest of the collected samples will be shipped to the central laboratory and analyzed
by Sponsor or selected designee, except for the urine pregnancy test which will be 
analyzed at study site's local laboratory.  All necessary transfer tubes, labels, forms, and 
shipping supplies will be provided by the central laboratory.   
ANTERIOR CHAMBER (AQUEOUS HUMOR) SAMPLE COLLECTION
Aqueous humor samples will be required to be collected if a patient in the implant arm 
receives a supplemental intravitreal injection and at the subsequent study visit, 
terminates early, or undergoes an explantation.  A patient, in either study arm, may also 
consent to optional aqueous humor sampling, which would occur at the timepoints listed 
in Appendix 1.  Unscheduled sampling may be performed at other or additional planned 
visits at the discretion of the investigator in agreement with the participating patient.


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Appendix 15
Sample Collection and Shipping (cont.)
The optional aqueous humor paracentesis samples will be collected from patients who 
consent to the procedure and sample acquisition.  The aqueous humor sample collection 
consists of an anterior chamber paracentesis (removing 0.05 to 0.1 mL of fluid from the 
anterior chamber of the eye).
The anterior chamber paracentesis will be performed by a qualified physician by placing 
a drop of topical anesthetic on the cornea, passing a 30-gauge needle through the 
limbus into the anterior chamber and removing 0.05 to 0.1 mL of aqueous humor fluid.  
Samples will be collected with the kit provided by central laboratory and shipped on dry 
ice to the central laboratory as soon as possible after the draw.
For administration of intravitreal injection (intravitreal arm or supplemental treatment in 
the implant arm) following the collection of the aqueous humor sample, if the investigator 
chooses to use subconjunctival lidocaine anesthetic, it must be injected 
subconjunctivally prior to study treatment.
EXPLANTED IMPLANTS WITH CONTENTS
Explanted implants containing ranibizumab drug product will be preserved for potential 
analysis upon explantation procedure.  A method to retrieve the contents from explanted 
implants is in place and protocols to characterize drug product are under development.  
In addition, the explanted implants may undergo physical inspection and/or functional 
testing.  All necessary materials to return explanted implants will be provided to each 
site. Refer to the Device Complaints and Return Instructions for the Clinical Sites 
document.


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Appendix 16
Port Delivery System with Ranibizumab
Figure 1
Port Delivery System Components
The following are the intended uses of the Port Delivery System (PDS) components:

Implant:  The implant is designed to be inserted through the pars plana of the eye to 
deliver ranibizumab in a controlled and continuous manner into the vitreous humor.  
The physician will both initially fill and subsequently refill-exchange the reservoir 
with the ranibizumab and will refill-exchange it in accordance with the instructions 
for use.  

Insertion tool:  The insertion tool is a component designed to a) hold the implant, 
b) assist with filling of the implant before insertion, and c) enable insertion of the 
implant through a sclera-pars plana incision.


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164/Protocol GR40548, Version 5
Appendix 16
Port Delivery System with Ranibizumab (cont.)

Initial fill needle:  The initial fill needle is a 34G Luer-Lock needle designed to 
perform the initial fill of the implant while the implant is held in the insertion tool.

Refill needle:  The refill needle is a 34G Luer-Lock needle designed to 
simultaneously exchange (in situ) the fluid in the implant reservoir, including any 
remaining ranibizumab, with new ranibizumab.

Explant tool:  The explant tool is a component designed to enable the removal of the 
implant from the eye after resection of the conjunctiva and removal of any scar 
tissue. 
The implant used in a Phase I study conducted by the device developer, ForSight 
VISION4, was composed of biocompatible materials (polymethyl methacrylate, silicone, 
316L stainless steel).  The implant in the Phase II (GX28228/Ladder) study conducted 
by Roche was composed of biocompatible materials (polysulfone, silicone, titanium).  
The implant in this Phase III study conducted by Roche is composed of the identical 
biocompatible materials (polysulfone, silicone, titanium) as in the Phase II study.  The 
implant remains unchanged in its exterior shape and size between the Phase II and 
Phase III designs; however, some processing changes were made to improve the overall 
manufacturability of the Phase III implant.  These changes include the semi-automation 
of critical alignments and bonds.  The Phase III release control element is identical to the 
Phase II titanium design.  Details and terminology are shown in the table below.
Table 1
Components of the Port Delivery System with 
Corresponding Terminology
Terminology
PDS Components
PDS with ranibizumab
Ranibizumab, implant, and ancillary devices
Implant
Port delivery implant 
Phase I implant
Port delivery implant with stainless steel RCE 
used in Phase I FSV4 (FH-1.2) study
Phase II and III implant
Port delivery implant with titanium RCE used in 
the Phase II and to be used in the Phase III 
studies
Ancillary devices
Insertion tool, initial fill needle, refill needle, and 
explant tool
FSV4ForSight VISION4; PDSPort Delivery System with ranibizumab; RCErelease control 
element.
The PDS (implant and ancillary components) is manufactured by Phillips Medisize 
(Hudson, WI).


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Appendix 17
Topical Antimicrobial and Anti-Inflammatory Ophthalmic Drops 
Administration Schedule
Prior to Procedure
After Procedure
Implant 
Insertion
Antimicrobial 
ophthalmic drops a
Required – 4 times 
within 24 hours (every 
6 hours) prior to Implant 
insertion
Required – dosing per 
standard of care
Anti-inflammatory 
ophthalmic drops b
Optional topical 
NSAID-dosing per 
standard of care 
Required topical 
steroid-dosing per 
standard of care
Optional topical 
NSAID-dosing per 
standard of care 
Refill-
exchange 
procedure
Antimicrobial 
ophthalmic drops a
Optional – 4 times within 
24 hours (every 6 hours) 
prior to Implant 
refill-exchange 
procedure
Required – dosing per 
standard of care
Explantation
Antimicrobial 
ophthalmic drops a
Required – 4 times 
within 24 hours (every 
6 hours) prior to 
explantation
Required – dosing per 
standard of care
Anti-inflammatory 
ophthalmic drops b
Not required
Required topical 
steroid-dosing per 
standard of care
Optional topical 
NSAID-dosing per 
standard of care
Intravitreal 
Injection 
Antimicrobial 
ophthalmic drops a
Optional – dosing per 
standard of care
Optional – dosing per 
standard of care
NSAID = nonsteroidal anti-inflammatory drug
a Suggested topical broad spectrum antimicrobial ophthalmic drops:  ofloxacin ophthalmic 
solution (Ocuflox®), gatifloxacin ophthalmic solution (Zymar®), moxifloxacin ophthalmic 
solution (Vigamox®), or trimethoprim-polymyxin B ophthalmic solution [Polytrim®]).
b Topical anti-inflammatory ophthalmic drops:  Per investigator’s discretion.

SAP_001.pdf: 
Official Title: 
A Phase Ill, Multicenter, Randomized, Visual Assessor-Masked, 
Active-Comparator Study of the Efficacy, Safety, and 
Pharmacokinetics of the Port Delivery System With Ranibizumab in 
Patients With Neovascular Age-Related Macular Degeneration 
(Archway) 
NCT Number: 
NCT03677934 
Document Date: 
SAP Version 3: 09 April 2021 


TITLE: 
STATISTICAL ANALYSIS PLAN 
A PHASE Ill, MUL TICENTER, RANDOMIZED, VISUAL 
ASSESSOR-MASKED, ACTIVE-COMPARATOR STUDY OF THE 
EFFICACY, SAFETY, AND PHARMACOKINETICS OF THE PORT 
DELIVERY SYSTEM WITH RANIBIZUMAB IN PATIENTS WITH 
NEOVASCULAR AGE-RELATED MACULAR DEGENERATION 
(ARCHWAY) 
PROTOCOL NUMBER: 
GR40548 
STUDY DRUG: 
VERSION NUMBER: 
IND NUMBER: 
EUDRACT NUMBER: 
SPONSOR: 
PLAN PREPARED BY: 
DATE FINAL: 
DATE AMENDED: 
Port Delivery System with Ranibizumab 
3 
113,552 
Not applicable 
F. Hoffmann-La Roche Ltd
, Ph.D. 
Ph.D. 
, Ph.D. 
Version 1: 29 March 2019 
Version 2: 21 April 2020 
See electronic date stamp below,. 
09-Apr-2021 17:44:46 
Company Signatory 
CONFIDENTIAL 
This is F. Hoffmann-La Roche Ltd document that contains confidential information. Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
Port Delivery System with Ranibizumab-F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GR40548 


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan GR40548
STATISTICAL ANALYSIS PLAN AMENDMENT
RATIONALE OF CHANGES
Changes from Statistical Analysis Plan (SAP) Version 2 to SAP Version 3 have been 
made in preparation for the Final CSR analysis. At the time of amendment, the Primary 
CSR and Update CSR have been completed, and the following changes to the SAP are 
focused on analyses of data after Study Week 48. Changes include the following:
Changes to add additional analysis to assess the impact of COVID-19

Changes to Section 4.4.2.2 to specify additional supplemental analyses 
incorporating COVID-19 related intercurrent events.

Changes to Section 4.7.2 to specify additional safety analyses performed for 
COVID-19.
Changes to add additional details of secondary efficacy endpoints

Changes to Section 4.4.2 to modify the definition of the proportion used to measure 
the secondary efficacy objectives on supplemental treatment.

Changes to Section 4.4.2.1 to add an additional sensitivity analysis of the per 
protocol complete cases population.
Additional changes include:

Changes to Section 4.4.3 to add the Exploratory Efficacy Endpoint assessed at 
Weeks 88 and 92 of the proportion of patients who gain or lose 15 letters from 
baseline.

Changes to Section 4.7.1 with the addition of the new Ocular AESI term “Device 
Dislocation”.

Changes to Appendix 1, Appendix 2, and Appendix 3 to align with the current 
version of the Protocol (version 5).


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3/Statistical Analysis Plan GR40548
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE OF 
CHANGES .................................................................................................... 2
1.
BACKGROUND ............................................................................................ 6
2.
STUDY DESIGN........................................................................................... 7
2.1
Protocol Synopsis.................................................................... 9
2.2
Determination of Sample Size ................................................. 9
2.3
Analysis Timing ..................................................................... 10
3.
STUDY CONDUCT..................................................................................... 10
3.1
Randomization....................................................................... 10
3.2
Independent Image Reading Center...................................... 10
3.3
Data Monitoring ..................................................................... 10
4.
STATISTICAL METHODS .......................................................................... 11
4.1
Analysis Populations ............................................................. 11
4.1.1
Efficacy Population................................................................ 11
4.1.2
Per-Protocol Population......................................................... 11
4.1.3
Pharmacokinetic Population .................................................. 11
4.1.4
Pharmacokinetic-Evaluable Population ................................. 11
4.1.5
Aqueous Humor Pharmacokinetic-Evaluable 
Population.............................................................................. 11
4.1.6
Safety Population .................................................................. 12
4.1.7
Biomarker Analysis Population.............................................. 12
4.2
Analysis of Study Conduct..................................................... 12
4.3
Analysis of Treatment Group Comparability .......................... 13
4.4
Efficacy Analysis.................................................................... 13
4.4.1
Primary Efficacy Endpoint...................................................... 14
4.4.1.1
Supplemental Analyses ......................................................... 15
4.4.2
Secondary Efficacy Endpoints............................................... 18
4.4.2.1
Key Secondary Endpoints for EMA ....................................... 20
4.4.2.2
Supplemental Analysis to Assess COVID-19 
Impact.................................................................................... 21
4.4.3
Exploratory Efficacy Endpoints.............................................. 22


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4/Statistical Analysis Plan GR40548
4.4.4
Patient-Reported Experiences............................................... 23
4.4.5
Subgroup Analyses ............................................................... 24
4.5
Pharmacokinetic Analyses..................................................... 24
4.6
Exploratory Biomarker Analyses............................................ 25
4.7
Safety Analyses..................................................................... 25
4.7.1
Adverse Events ..................................................................... 25
4.7.2
Additional Safety Analyses Performed for 
COVID-19.............................................................................. 28
4.7.3
Laboratory Data..................................................................... 30
4.7.4
Vital Signs.............................................................................. 30
4.7.5
Ocular Assessments.............................................................. 30
4.7.6
Immunogenicity Analyses...................................................... 30
4.8
Missing Data.......................................................................... 31
4.9
Interim Analyses .................................................................... 31
5.
REFERENCES ........................................................................................... 32
LIST OF TABLES
Table 1
Roche COVID-19 SMQ (narrow) Preferred Terms for all 
Cases (Confirmed and Suspected)............................................. 29
Table 2
Roche COVID-19 SMQ (narrow) Preferred Terms for 
Confirmed Cases ........................................................................ 30
LIST OF FIGURES
Figure 1
Study Schema............................................................................... 7
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 33
Appendix 2
Schedule of Activities: Implant Arm, Year 1 and Year 2.............. 44
Appendix 3
Schedule of Activities: Intravitreal Arm........................................ 54
Appendix 4
Memorandum on the Variability In Change From Baseline 
Best-Corrected Visual Acuity Through Week 16 In Pooled 
Treatment Arms .......................................................................... 61


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5/Statistical Analysis Plan GR40548
GLOSSARY OF ABBREVIATIONS
ADA
anti-drug antibody
AE
adverse event
AESI
adverse event of special interest
AMD
age-related macular degeneration
ANCOVA
analysis of covariance
AUC
area under the concentration-time curve
BCVA
best-corrected visual acuity
CI
confidence interval
Cmax
maximum serum concentration
CMH
Cochran-Mantel-Haenszel
COVID-19
coronavirus disease 2019
CPT
center point thickness
CST
central subfield thickness
CSR
Clinical Study Report
EMA
European Medicines Agency
ETDRS
Early Treatment Diabetic Retinopathy Study
FDA
Food and Drug Administration
iDCC
independent Data Coordinating Center
iDMC
independent Data Monitoring Committee
ILM
inner limiting membrane
IOP
intraocular pressure
IxRS
interactive voice/web based response system
MacTSQ
Macular Disease Treatment Satisfaction Questionnaire
MMRM
mixed-effect model with repeated measures
nAMD
neovascular age-related macular degeneration
NI
non-inferiority
PD
pharmacodynamic
PDS
Port Delivery System
PK
Pharmacokinetics
PPPQ
PDS Patient Preference Questionnaire
Q24W
every 24 weeks
Q4W
every 4 weeks
RPE
retinal pigment epithelium
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD-OCT
spectral domain optical coherence tomography
SMQ
Standardized MedDRA Query
t1/2
half-life
VA
visual acuity
VEGF
vascular endothelial growth factor


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6/Statistical Analysis Plan GR40548
1.
BACKGROUND
Neovascular age-related macular degeneration (nAMD) is a form of advanced 
age-related macular edema (AMD) that causes rapid and severe visual loss, and 
remains a leading cause of visual impairment in the elderly.  The prevalence of nAMD 
increases exponentially with age, with onset typically after 50 years of age (National 
Institutes of Health 2014).  Prevalence of nAMD is also found to increase with age, 
based on a meta-analysis of 31 population-based studies of persons with European 
ancestry (Rudnicka et al. 2012; Owen et al. 2012).  In the next 30 years, the global 
population aged 60 years and older is projected to increase dramatically, translating into 
an increase in the prevalence of nAMD from 23 million in 2010 to 80 million by 2050 
(Smith AF 2010).
Ranibizumab, a recombinant, humanized monoclonal antibody fragment, which binds to 
all known isoforms of vascular endothelial growth factor (VEGF)-A, was approved by the 
US Food and Drug Administration (FDA) for use in nAMD, in June 2006 and by the 
European Medicine Agency (EMA) in January 2007.  As a result of the chronic, 
progressive nature of nAMD, frequent ranibizumab intravitreal injections continue for 
extended periods for many patients.  Pivotal studies of intravitreal ranibizumab in nAMD 
(Studies MARINA [FVF2598g] and ANCHOR [FVF2587g]) demonstrated significant and 
well-maintained visual acuity (VA) outcomes with monthly 0.5 mg intravitreal injections 
for 2 years.
Real-world data suggest that many patients with nAMD do not receive treatment 
according to the approved prescribing information and this under-treatment in clinical 
practice is associated with lower visual acuity gains compared with those observed in 
controlled clinical trials.  Under-treatment of nAMD in clinical practice reflects the burden 
of frequent therapy on patients, caregivers, and the healthcare system.
The Port Delivery System with ranibizumab (PDS) is a drug delivery technology that 
allows physicians to use ranibizumab with a continuous drug delivery mechanism 
without altering its chemistry.  It consists of the PDS implant (referred to as the implant), 
4 ancillary devices (insertion tool, initial fill needle, refill needle, and explant tool), and a 
customized formulation of ranibizumab 100 mg/mL tailored for continuous delivery.  The 
implant is an intra-ocular refillable device that is surgically placed through the pars plana 
to allow for continuous delivery of ranibizumab into the vitreous.
Continuous delivery of ranibizumab from the implant, with a prolonged fixed period 
between refill-exchange intervals, is a novel approach that may result in less-frequent 
need for treatment than monthly dosing and patient monitoring, while maintaining 
optimal visual outcomes. The Phases I and II PDS studies provided evidence of the 
safety and tolerability of the PDS and support the evaluation of the PDS in a Phase III 
study.


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7/Statistical Analysis Plan GR40548
The purpose of this document is to provide details of the planned analyses for 
Study GR40548 (Archway). The analyses and endpoints specified in this document 
supersede the analysis plan described in the study protocol and the previous version of 
the Statistical Analysis Plan (SAP).
2.
STUDY DESIGN
Study GR40548 is a Phase III, randomized, multicenter, open-label (visual 
assessor-masked), active-comparator study, designed to assess the efficacy, safety, 
and pharmacokinetics (PK) of PDS with ranibizumab 100 mg/mL every 24 weeks (Q24W) 
compared with ranibizumab intravitreal injections every 4 weeks (Q4W) at 0.5 mg (10 
mg/mL) in patients with nAMD.  Approximately 360 patients will be enrolled at 
approximately 90 sites.  For the study schema, see Figure 1.  
Figure 1
Study Schema
Dday; Rdrandomization.
a Patients in the implant arm may be eligible for supplemental treatment with intravitreal 
ranibizumab 0.5mg at Weeks 16, 20, 40, 44, 64, 68, 88, and 92.
Patients must satisfy all eligibility criteria at both the screening and the randomization 
visits, including receipt of all screening visit images by the central reading center. 
Patients who do not meet eligibility criteria (screen-failed patients) may be eligible to 
repeat screening up to two times if deemed appropriate by the investigator.
After all eligibility requirements are confirmed, patients are to be randomly allocated in a 
3:2 ratio so that approximately 216 patients receive the PDS implant filled with 
100 mg/mL ranibizumab Q24W (implant arm) and approximately 144 patients will 
receive monthly intravitreal ranibizumab 0.5 mg injections Q4W (intravitreal arm).  On 
the day of a patient's randomization visit, best-corrected visual acuity (BCVA) is
measured based upon the Early Treatment Diabetic Retinopathy Study (ETDRS) chart 
assessment at a starting test distance of 4 meters, and randomization is stratified by the 


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8/Statistical Analysis Plan GR40548
BCVA score (74 letters vs.74 letters).  Randomization will be performed by the 
interactive voice/web based response system (IxRS).
Only one eye will be chosen as the study eye.  If both eyes are eligible, the investigator 
will determine which eye will be selected for study treatment.
Patients who are randomly allocated to the PDS 100 mg/ml arm will have the implant 
(pre-filled with 100 mg/mL ranibizumab) surgically inserted on Day 1, which must occur 
1-7 days (inclusive) after randomization (i.e., randomization and Day 1 visit assessments 
cannot be performed on the same day) and no later than 28 days from the last 
intravitreal ranibizumab injection.  After Day 1, patients in the implant arm will have 
scheduled safety visit assessments on Days 2 and 7 (2 days) and will receive implant 
refill-exchanges with 100 mg/mL ranibizumab Q24W at Week 24 (7 days), Week 48 
(7 days), and Week 72 (7 days).
Patients who are randomly allocated to the intravitreal arm will receive 0.5 mg of 
ranibizumab intravitreal injections starting on Day 1, which is to be administered at the 
conclusion of the randomization visit (i.e., randomization and Day 1 visit assessments 
are performed on the same day).  Patients will receive 0.5 mg ranibizumab, injected 
intravitreally Q4W (7 days) from Day 1 until Week 92.
Patients randomized to the implant arm will be eligible for supplemental treatment with 
intravitreal ranibizumab (0.5 mg intravitreal injections of 10 mg/mL formulation) at 
Weeks 16 and 20 (after implant insertion) and at Weeks 40, 44, 64, 68, 88, and 92 if any 
of the following criteria are met in the study eye:

Decrease of 15 letters from the best-recorded BCVA in the study, due to nAMD 
disease activity.
OR

Increase of 150 m in central subfield thickness (CST) on spectral domain optical 
coherence tomography (SD-OCT) from the lowest CST measurement in the study, 
due to nAMD disease activity.
OR

Increase of 100 µm in CST on SD-OCT from the lowest CST measurement in the 
study associated with a decrease of 10 letters from the best recorded BCVA during 
the study, due to nAMD disease activity.
Note: CST is assessed by central reading center with boundaries of the inner limiting 
membrane (ILM) to Bruch’s Membrane, which includes the pigment epithelial 
detachment (PED) thickness.
In the event a patient's non-study (fellow) eye requires treatment for nAMD after 
randomization, treatment with any FDA-approved intravitreal anti-VEGF treatment for 
nAMD may be administered. The Sponsor will provide intravitreal ranibizumab 0.5 mg 


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9/Statistical Analysis Plan GR40548
starting from the screening visit, if the Investigator chooses to treat the fellow eye with 
ranibizumab.
All study assessments and study eye treatment should be completed per protocol prior 
to anti-VEGF administration in the fellow eye. 
Refer to Section 3 of the Study GR40548 Protocol for the further details of the study 
design and Appendix 2 and Appendix 3 for the Schedule of Activities.
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1.
2.2
DETERMINATION OF SAMPLE SIZE
Patients will be randomly allocated in a 3:2 ratio to the implant arm or intravitreal arm.
The primary endpoint is the change in BCVA score from baseline averaged over 
Weeks 36 and 40.  The study is sized to achieve adequate power to show non-inferiority 
(NI) and equivalence of the implant arm to the intravitreal arm in the change in BCVA 
score from baseline averaged over Week 36 and Week 40 using an NI margin of 
4.5 letters and equivalence margins of4.5 letters.
Assuming a standard deviation of 9.5 letters for the change from baseline in BCVA score 
averaged over 36 and 40 weeks, up to a true mean change from baseline in BCVA of 
0.75 letters worse for the PDS 100 mg/ml arm, compared with the monthly intravitreal 
arm, 216 patients in the implant arm and 144 patients in the intravitreal arm will provide
at least 90% power to demonstrate NI and equivalence between the two treatment 
groups.  Calculations were based on a one-sided t-test at 0.025 level for the NI test 
and two one-sided t-tests at the 0.025 level for the equivalence test with the 
assumption of a 10% dropout rate by Week 40 and a 10% increase for the trimmed 
mean analysis.  Note, the original sample size did not account for the type I error
adjustment specified in Section 3.2, however the study will still have at least 90% power 
with this adjustment.
An independent statistician from the Independent Data Coordinating Center (iDCC) was 
employed to conduct a masked evaluation of the variance of the primary efficacy 
endpoint, but not the proportion of patients who receive supplemental treatment during 
the study or the study dropout rate before the end of enrollment because the enrollment 
was too rapid for these evaluations to be of value. The variance comparison to the 
assumptions used in planning the study did not suggest the initial assumption for the 
variance of the primary efficacy endpoint was substantially lower. Therefore, no change 
to the planned sample size was required. However, independent of this assessment, 
due to a high speed of enrollment combined with a lower screen failure rate than 
expected, there were a total of 418 patients enrolled. Details of the masked assessment 
and findings are provided in the memorandum from the iDCC in Appendix 4.


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2.3
ANALYSIS TIMING
The primary analysis will be performed when all patients have completed the Week 40 
visit or have discontinued from the study prior to Week 40, all data collected through 
Week 40 are in the database, and the data have been cleaned and verified.  At the time 
of the primary analysis, the study will be ongoing.  An analysis of the available data post 
Week 40 (after Week 40 and up to a specified clinical cutoff date) will also be performed.  
Such results will be reported with, but separate from, the 40-week study results to 
provide additional information.
Additional analyses may be performed to support the requirements of health authorities
relative to marketing applications, as appropriate.
The final analysis will be performed when all patients have either completed the 2-year 
study period (i.e., Week 96) or discontinued early from the study, all data from the study 
are in the database, and the database is locked.
3.
STUDY CONDUCT
3.1
RANDOMIZATION
Patients will be randomly allocated in a 3:2 ratio so that approximately 216 patients will 
receive the PDS implant with 100 mg/mL ranibizumab Q24W and approximately 
144 patients will receive Q4W intravitreal injections of 10 mg/mL ranibizumab.  On the 
day of a patient's randomization visit, BCVA will be measured based upon the ETDRS 
chart assessment at a starting test distance of 4 meters and randomization will be 
stratified by the BCVA score (74 letters vs.74 letters).  Randomization will be 
performed through an IxRS. 
3.2
INDEPENDENT IMAGE READING CENTER
All ocular images will be obtained by trained and certified site personnel at the study 
sites and forwarded to the central reading center for independent, masked, analyses and 
storage.
3.3
DATA MONITORING
An independent Data Monitoring Committee (iDMC) will monitor safety and study 
conduct on an ongoing basis.  Members of the iDMC will be external to the Sponsor and 
will follow a charter that outlines the iDMC's roles and responsibilities.  The iDMC will 
meet approximately every 6 months (frequency adjustable as required) to evaluate 
unmasked ocular and systemic (non-ocular) safety events.  After reviewing the data, the 
iDMC will provide a recommendation to the Sponsor as described in the iDMC Charter.  
Final decisions will rest with the Sponsor.  Any outcomes of these data reviews that 
affect study conduct will be communicated in a timely manner to the investigators for 
notification of their respective Institutional Review Boards (IRBs).


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A nominal type I error penalty of 0.0001 will be taken for each time the iDMC reviews 
unmasked data prior to the formal analysis of the primary efficacy endpoint. At the time 
of the primary analysis, it is estimated that 3 interim data reviews will have been 
conducted by the iDMC; therefore, efficacy analyses will be performed with a family-wise 
significance level of 0.0497.
4.
STATISTICAL METHODS
Descriptive summaries will include the mean, standard deviation, median, and range for 
continuous variables, and counts and percentages for categorical variables.
4.1
ANALYSIS POPULATIONS
4.1.1
Efficacy Population
Efficacy data will be summarized for the Efficacy Population comprising all patients who 
are randomized and receive the study treatment, with patients grouped according to 
treatment actually received (patients who receive PDS implant will be included in the 
PDS 100 mg/ml group).
4.1.2
Per-Protocol Population
A per protocol analysis is planned as a sensitivity analysis for the primary endpoint and 
the key secondary endpoint. Prior to study unblinding, protocol deviations will be 
reviewed and a determination of the definition of the population for per protocol analysis 
will be made.
The Per-Protocol Population is defined as all patients in the Efficacy Population who do 
not have a major protocol deviation that impact the efficacy evaluation. For analyses 
based on this patient population, patients will be grouped according to the treatment 
actually received.
4.1.3
Pharmacokinetic Population
The PK population will be based on the subset of patients in the Safety Population with
at least one post study treatment PK sample available.
4.1.4
Pharmacokinetic-Evaluable Population
The PK-Evaluable Population will consist of patients in the PK Population excluding 
patients receiving intravitreal injections of ranibizumab in the study eye post PDS implant
(including supplemental treatment), patients with fellow eye ranibizumab or bevacizumab 
treatment, or prior bevacizumab treatment in either eye.
4.1.5
Aqueous Humor Pharmacokinetic-Evaluable Population
The Aqueous Humor PK-Evaluable Population is the subset of patients in the 
PK-Evaluable Population with at least one optional aqueous-humor sample.


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4.1.6
Safety Population
Safety data will be summarized on the Safety Population comprising all patients who 
receive the study treatment, with patients grouped according to treatment actually 
received.
4.1.7
Biomarker Analysis Population
The Biomarker Analysis Population will consist of patients who are in the Safety 
Population and have sufficient data to enable assessment of potential changes in 
biomarkers in response to treatment during the conduct of this study. The analysis will 
group patients according to treatment actually received.
4.2
ANALYSIS OF STUDY CONDUCT
Patient disposition (the number of patients randomized, treated, and completing each 
study period) will be tabulated by treatment actually received in Efficacy Population. 
Reasons for premature study treatment discontinuation and study discontinuation will be 
tabulated and a listing will be provided. Detailed, free text reasons are collected for 
discontinuations due to physician decision and ‘other’ reasons. This information will be 
included in the listing.
Eligibility criteria deviation and other major protocol deviations will be tabulated and a 
listing will be provided. 
Exposure to study treatment (number of study treatments [PDS refill-exchanges, 
intravitreal ranibizumab injection, supplemental intravitreal ranibizumab injection] and 
duration of treatment) will be summarized by treatment group for the study eye in the 
Safety Population. 
Duration of treatment is the time from first study treatment (implant or intravitreal 
ranibizumab injection) to the earlier of:

The date of treatment discontinuation or date of study completion

The analysis cutoff date 
Pre-treatment and concomitant systemic medications, ocular medications for the fellow 
eye and, ocular medications for the study eye will be summarized separately by 
treatment group. Measures were implemented to mitigate the risk to data integrity posed 
by coronavirus disease 2019 (COVID-19). The impact of COVID-19 will be assessed in 
the COVID-19 Clinical Study Report (CSR) Annex in terms of the following criteria: 

Early study treatment discontinuation due to COVID-19

Missed treatments due to COVID-19 or related precautions

Use of prohibited therapy due to COVID-19

Missing BCVA or BCVA not performed per protocol due to COVID-19 or related 
precautions


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
Major protocol deviations associated with COVID-19 directly or indirectly

Missed visits reported as due to COVID-19 or related precautions

Early study discontinuation due to COVID-19

Death due to COVID-19

Confirmed or suspected cases of COVID-19 and adverse events (AEs) associated 
with COVID-19
Additional details on the analysis to address the impact of COVID-19 are provided in 
Section 4.4. The impact of COVID-19 on safety analysis is expected to be low since 
physicians will retrospectively collect safety events following missed visits; hence, the 
safety analysis plan is not amended except that additional summaries/listings will be 
provided for confirmed or suspected COVID-19 infection and AEs associated with 
COVID-19, as described in Section 4.7.2.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics, such as age, sex, race, baseline disease 
characteristics (such as baseline center point thickness [CPT], and baseline BCVA), and 
number of prior anti-VEGF injections, will be summarized in the Efficacy Population by 
treatment group using descriptive statistics.
Baseline is defined as the last available measurement prior to first study treatment (PDS 
implant or post-randomization intravitreal injection).  
4.4
EFFICACY ANALYSIS
The efficacy analyses will be based on the Efficacy Population.
Patients in the PDS 100 mg/mL arm can receive intravitreal ranibizumab injection as 
supplemental treatment if they meet the criteria described in Section 2.
Unless otherwise noted, analyses of efficacy outcome measures will be stratified by 
baseline BCVA (74 letters vs.74 letters). The stratification factor as recorded in IxRS 
will be used.  The estimates and confidence intervals (CIs) will be provided for the mean 
(for continuous variables) or proportion (for binary variables) for each treatment group 
and the difference in means or proportions between two treatment groups. All CIs will 
be two-sided and at the 95.03% level (see Section 3.3).


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4.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the change in BCVA score from baseline averaged over 
Weeks 36 and 40 with BCVA assessed using the ETDRS chart at a starting distance of 
4 meters. The primary estimand is defined as follows:
–
Population: Adult patients with nAMD diagnosed within 9 months and receiving at 
least 4 anti-VEGF intravitreal injections (with the last injection being ranibizumab), 
responsive to prior anti-VEGF treatment
–
Variable: Change in BCVA score from baseline averaged over Weeks 36 and 40
–
Intercurrent events: Regardless whether or not a patient has the following 
intercurrent event prior to Week 40:
-Receives more than 1 supplemental treatment
-Receives any prohibited systemic treatment or prohibited therapy in the 
Study eye (Section 4.4.2 of the Protocol)
-Discontinues study treatment due to AEs
-Discontinues study treatment due to lack of efficacy as per investigator’s 
clinical judgment
–
Population-level summary: Difference in adjusted mean between PDS 100 mg/mL 
and intravitreal groups
Of note, lack of efficacy includes investigators choices for reason for discontinuation 
from treatment of lack of efficacy, progressive disease, disease relapse, and 
symptomatic deterioration.
The primary objectives are to determine the NI and equivalence between the two 
treatment groups, as measured by the primary efficacy endpoint with a NI margin of 
4.5 letters and equivalence margins of4.5 letters.  To control the overall type I error, a 
fixed sequence testing procedure (Westfall and Krishen 2001) will be used.  If the PDS 
100 mg/mL arm is shown to be non-inferior to the intravitreal arm at the one-sided 
0.02485 level, then the equivalence test will be conducted using two one-sided 0.02485 
tests.
The primary analysis will be performed using the mixed-effect model with repeated 
measures (MMRM) based on all available data up to Week 40.  All observed 
measurements will be included in the analysis regardless whether or not a patient has 
an intercurrent event. Missing data will be implicitly imputed by the MMRM model, 
assuming a missing at random mechanism.
The dependent variable in the MMRM model is the change from baseline in BCVA score 
at post-baseline visits, up to 40 weeks, and the independent variables are the treatment 
group, time, treatment-by-time interaction, baseline BCVA score (continuous), and the 
randomization stratification factor of baseline BCVA (74 letters vs.74 letters) as fixed 


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effects.  The MMRM model will assume an unstructured covariance structure.  If there 
are convergence problems with the model, then a compound symmetry covariance or a 
first order autoregressive order (AR [1]) covariance structure will be used.  Comparisons 
between the two treatment groups will be made using a composite contrast over 
Weeks 36 and 40.
For the primary efficacy endpoint, if a lower bound of a two-sided 95.03% CI for the 
difference of two treatments is greater than 4.5 letters (the NI margin), then treatment 
via PDS is considered non-inferior to monthly intravitreal ranibizumab treatment.  If the 
two-sided 95.03% CI is within 4.5L and 4.5L, then the two treatment regimens are 
considered clinically equivalent.
As a sensitivity analysis the per-protocol analysis will follow the same methods as the 
primary analysis except the Per-Protocol Population will be used.
4.4.1.1
Supplemental Analyses
The following supplemental analyses will be performed for the primary efficacy endpoint 
to evaluate the robustness of the primary analysis finding:
a)
Trimmed Mean Analysis: The analysis will be used to assess the difference in BVCA 
between two treatments using a truncated distribution, truncating patients with the 
worst outcome, with the assumption that patients have the worst outcome after 
intercurrent events.
The estimand is defined as follows:
–
Population: Adult patients with nAMD diagnosed within 9 months and receiving at 
least 4 anti-VEGF intravitreal injections (with the last injection being ranibizumab) 
responsive to prior anti-VEGF treatment
–
Variable: Change in BCVA score from baseline averaged over Weeks 36 and 40
–
Intercurrent events: Assume patients have the worst outcome after the following 
intercurrent events prior to Week 40:
-Receives more than 1 supplemental treatment
-Receives any prohibited systemic treatment or prohibited therapy in the 
Study eye (Section 4.4.2 of the Protocol)
-Discontinues study treatment due to AEs
-Discontinues study treatment due to lack of efficacy as per investigator’s 
clinical judgment
–
Population-level summary: Difference in adjusted trimmed mean between PDS 
100 mg/mL and intravitreal groups
The trimmed mean analysis (Permutt and Li 2017) will be performed using an analysis of 
covariance (ANCOVA) model with adjustment for covariates. The dependent variable in 
the ANCOVA model is the average of non-missing values of Weeks 36 and 40 


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assessments in change from baseline in BCVA score (if one of the two assessments is 
missing, the non-missing assessment will be used), and the independent variables are 
the treatment group, baseline BCVA score (continuous), and the randomization 
stratification factor of baseline BCVA (74 letters vs.74 letters).
Patients will be considered to have the worst outcomes and will be trimmed from 
analysis if any of the following occurs:
–
They have an intercurrent event prior to Week 36.
–
They have a missing Week 36 assessment and have an intercurrent event at 
Week 36.
–
They have missing assessments at both Week 36 and Week 40, and have an 
intercurrent event in either of these two visits.
Such patients will be referred to as "must be trimmed patients”. Of note, if a patient has 
a non-missing Week 36 assessment and has an intercurrent event at Week 36, then the 
change in BCVA from baseline to Week 36 for this patient will be used for the analysis, 
the Week 40 data would not be used.
For the remaining patients, if they have Week 36 and/or Week 40 BCVA assessments, 
they will be considered "completers"; if they have missing assessments at both Week 36 
and Week 40, the missing data will be considered missing at random and these patients 
will be removed from the analysis.
The inferential statistics (i.e., 95.03% CI) for the trimmed mean will be based on the 
permutation test. The treatment assignments will be permuted in a sufficiently large 
random sample of possible ways (~30,000 random samples will be generated).
The method can be stated in the following four steps:
1.
Remove patients whose missing BCVA assessments are considered missing at 
random (see definition above) from the analysis.
2.
Order the data based on adjusted values from the ANCOVA model, and trim equal 
fractions (approximately 20%, the trimming fraction will be finalized based on a 
masked assessment prior to the primary analysis) from both treatment groups.

The adjusted values are determined as follows. An ANCOVA model as 
specified above will be fitted for all completers. The estimated treatment effect 
will be discarded and the coefficients for the covariates will be kept to calculate 
the adjusted value Y ' X for each patient, for which Y is the change in BCVA 
score averaged over 36 and 40 weeks, X is the matrix for the 
covariates-baseline BCVA score (continuous) and the baseline BCVA category 
(74 letters vs. 74 letters), and is the estimated coefficient matrix for the 
covariates.

These adjusted values will be used to rank the data within each treatment 
group.  The “must be trimmed” patients will always be ranked the lowest 


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(regardless of whether their adjusted values are available) and trimmed from 
the analyses.  The best (10.2) 100 (80%) in each group will be used for the 
analysis specified in Step 3. If multiple patients have the same adjusted values, 
they will be ranked randomly relative to each other prior to trimming.
3.
Refit the ANCOVA model (as specified above) to the trimmed data set, and compute 
the difference in trimmed mean between two treatment groups.
4.
Repeat steps 2 and 3 30,000 times based on augmented datasets with the 
treatment assignment randomly permuted according to the original randomization 
procedures (blocked randomization stratified by baseline BCVA category).
When the proportion of the "must be trimmed patients" in either treatment group in the 
permuted data exceeds the planned trimmed fraction, the trimming fraction will be 
chosen adaptively as the greater of the proportions of the "must be trimmed patients" in 
the two treatment groups.
b)
Analyses using different handling rules for intercurrent event
The estimand is defined as follows:
–
Population: Adult patients with nAMD diagnosed within 9 months and receiving at 
least 4 anti-VEGF intravitreal injections (with the last injection being ranibizumab), 
responsive to prior anti-VEGF treatment
–
Variable: Change in BCVA score from baseline averaged over Weeks 36 and 40
–
Intercurrent events prior to Week 40:
- Had more than 1 supplemental treatment not been made available
- Had any prohibited systemic treatment or prohibited therapy in the Study 
eye (Section 4.4.2 of the Protocol) not been made available
- Regardless whether a patient discontinues study treatment due to AEs
- Regardless whether a patient discontinues study treatment due to lack of 
efficacy as per investigator’s clinical judgment
–
Population-level summary: Difference in adjusted mean between PDS 100 mg/ml
and intravitreal groups
Two analyses will be performed using the same analysis method as the primary 
endpoint with the exception that data handling methods for intercurrent events and 
missing data: 
–
Method 1: Assessments at any timepoint after 2 or more supplemental treatments or 
after prohibited treatments in the study eye will be imputed using the last 
post-baseline observation prior to such intercurrent event. This means for example
that if a patient has their first intercurrent event at Week 36 or between the Week 36 
and Week 40, the Week 36 assessment will be used for Week 40 (BCVA 
assessment will be performed before any treatment).  Other missing assessments


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not preceded by an intercurrent event will be imputed using the last post-baseline 
observation carried forward method. 
–
Method 2: Assessments after 2 or more supplemental treatments or after prohibited 
treatment will be excluded. All missing data will be implicitly imputed by the MMRM 
model, assuming a missing at random mechanism.
4.4.2
Secondary Efficacy Endpoints
Descriptive summaries will be provided for all secondary endpoints based on all 
observed data. The secondary endpoints are:
1. Change from baseline in BCVA score averaged over Week 60 and Week 64.
2. Change from baseline in BCVA score over time.
3. Proportion of patients with BCVA score of 38 letters (20/200 approximate Snellen 
equivalent) or worse at the average over Week 36 and Week 40.
4. Proportion of patients with BCVA score of 38 letters (20/200 approximate Snellen 
equivalent) or worse over time.
5. Proportion of patients with BCVA score of 69 letters (20/40 approximate Snellen 
equivalent) or better at the average over Week 36 and Week 40.
6. Proportion of patients with BCVA score of 69 letters (20/40 approximate Snellen 
equivalent) or better over time.
7. Proportion of patients who lose < 10 or < 5 letters in BCVA score from baseline 
to the average over Week 36 and Week 40.
8. Proportion of patients who lose < 10 or < 5 letters in BCVA score from baseline 
over time.
9. Proportion of patients who gain 0 letters in BCVA score from baseline to the 
average over Week 36 and Week 40.
10. Proportion of patients who gain 0 letters in BCVA score from baseline over time.
11. Change from baseline in CPT assessed by central imaging vendor with 
boundaries ILM to inner third of the retinal pigment epithelium (RPE) at Week 36.
12. Change from baseline in CPT assessed by central imaging vendor with 
boundaries ILM to inner third of the RPE over time.
13. Proportion of patients in the PDS 100 mg/ml group who undergo supplemental 
treatment of intravitreal ranibizumab before the first, second, third, and fourth 
fixed refill-exchange intervals.
14. Proportion of patients in the PDS 100 mg/ml group that undergo a supplemental 
treatment that requires at least one additional supplemental treatments during 
the study.


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The estimand for the binary secondary endpoints are defined as follows:
–
Population: Adult patients with nAMD diagnosed within 9 months and receiving at 
least 4 anti-VEGF intravitreal injections (with the last injection being ranibizumab), 
responsive to prior anti-VEGF treatment.
–
Variable: Proportion of patients for event of interest
–
Intercurrent events: Regardless whether or not a patient has the following 
intercurrent event prior to visit for endpoint:
- Receives more than 1 supplemental treatments
- Receives any prohibited systemic treatment or prohibited therapy in the 
Study eye (Section 4.4.2 of the Protocol) 
- Discontinuation study treatment due to AEs
- Discontinuation study treatment due to lack of efficacy as per investigator’s 
clinical judgment.
–
Population-level summary: Difference in proportions between PDS 100 mg/ml and 
intravitreal groups
The proportion of patients in each treatment group and the overall difference in 
proportions between treatment groups will be estimated using the weighted average of 
the observed proportions and the differences in observed proportions over the strata 
defined by randomization stratification factor of baseline BCVA (74 letters 
vs.74 letters) using the Cochran-Mantel-Haenszel (CMH) weights (Cochran 1954; 
Mantel and Haenszel 1959).  All observed measurements will be included in the analysis 
regardless whether or not a patient has an intercurrent event. Confidence intervals of 
the proportion of patients in each treatment group and the overall difference in 
proportions between treatment groups will be calculated using the normal approximation 
to the weighted proportions (Mehrotra and Railkar 2000).  If the response rate is low, an 
unstratified analysis may also be performed.
In addition, the binary secondary endpoints through Week 40 will also be summarized 
using the same approach with missing assessments imputed with the last post-baseline 
observation carried forward (continuous BCVA values are carried forward and then the 
binary endpoint is derived).
Different strata will be used for the CMH analyses of the following binary endpoint: 
–
Proportion of subjects with a BCVA score of 69 letters (approximate 20/40 Snellen 
equivalent) or better at the average over Weeks 36 and 40: the difference between 
the two treatment groups will be estimated using the same approach stratified by 
baseline BCVA (Snellen equivalent of 20/40 or better vs. worse than 20/40).
The continuous secondary endpoints will be summarized using descriptive statistics 
based on all observed data. These continuous endpoints will also be analyzed following 


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the same method as the analysis of the primary endpoint (see Section 4.4.1) with the 
independent variable, baseline BCVA score (continuous), in the model replaced with the 
baseline value of the corresponding endpoint (e.g., baseline CPT).  The intercurrent 
events and data handling rules for the primary endpoint will apply here.
The proportion of patients in the PDS 100 mg/ml group who undergo supplemental 
treatment of intravitreal ranibizumab and who do not undergo supplemental treatment
will be summarized descriptively during the entire study period and between each refill-
exchange. The proportion of patients in the PDS 100 mg/ml group who undergo a 
supplemental treatment and require subsequent additional supplemental treatments 
during the study will also be summarized descriptively. The proportion of patients who 
undergo supplemental treatment will be evaluated using only the patients who were able 
to be assessed for the need for supplemental treatment. This is the subset of patients 
who were assessed for supplemental treatment at least once at eligible weeks within a 
given interval (at 4 and 8 weeks prior to the scheduled refill visit), which does not include 
those who missed both visits within a given interval or discontinued the study prior to 
these 2 visits within a given interval, as these patients are not able to be assessed for 
the need for supplemental treatment. The proportion of patients who undergo 
supplemental treatment during the entire study period will be evaluated using the subset 
of patients who were assessed for supplemental treatment at least once during the 
entire study period. 
For the Final CSR analysis, the following secondary efficacy endpoints occurring after 
Week 48 will be analyzed using the same MMRM model as specified in Section 4.1.1, 
with the dependent variables of changes in BCVA at Weeks 4-96: change in BCVA 
averaged over Week 60 and Week 64, change in BCVA averaged over Week 88 and 
Week 92, and change in BCVA over time through Week 96.  Composite contrasts will be 
used to estimate each endpoint. These endpoints will also be analyzed on the Per 
Protocol Population using the same MMRM approach. No data collected after Week 96 
will be used to evaluate these efficacy endpoints. In addition, a small number of BCVA 
assessments were not assessed per protocol (e.g., completed by uncertified staff or by 
unmasked staff), and these records will be removed from the efficacy analyses, as these 
records may not be reliable assessments of BCVA.
4.4.2.1
Key Secondary Endpoints for EMA
The following endpoints are considered key secondary endpoints for purpose of the
marketing authorization application for EMA:
–
Change from baseline in BCVA score averaged over Week 36 and Week 40
–
Change from baseline in BCVA score averaged over Week 44 and Week 48
–
Change from baseline in BCVA score averaged over Week 88 and Week 92
The hypothesis testing for these endpoint will be gated on achieving NI for the primary 
endpoint test at a 4.5 letter margin as per Section 4.4.1. A fixed sequence testing 


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procedure will be used to control the type I error rate.  The NI tests for the key secondary 
endpoints will be performed in the order shown above with a NI margin of 3.9 letters, 
proceeding sequentially and testing each after achieving NI on the previous endpoint.  
Analysis of these key secondary endpoints will follow the same method as the analysis 
of the primary endpoint (see Section 4.4.1) in all respects except for the NI margin and 
timepoints included in the analysis. The two supplementary analyses for using different 
handling rules for intercurrent events (Section 4.4.1.1) and the per protocol sensitivity 
analysis (Section 4.4.1) used in the analysis of the primary endpoint will also be 
conducted for the key secondary endpoints.
Additionally, to address feedback from the EMA, sensitivity analyses will be conducted 
for each of the above 3 endpoints based on the complete cases in the Per Protocol 
Population.  These analyses include only patients in the Per Protocol Population with 
BCVA assessments available at both study visits for a particular endpoint (e.g., patients 
needed to have BCVA assessments at both Weeks 36 and 40 for change in BCVA 
averaged over Weeks 36 and 40).  The analyses will be conducted using the MMRM 
model as specified in Section 4.4.1, , and using the ANCOVA models with adjustment of 
treatment group, baseline BCVA score (continuous), and the randomization stratification 
factor of baseline BCVA (< 74 letters vs. 74 letters).
4.4.2.2
Supplemental Analysis to Assess COVID-19 Impact
Additional supplemental analyses incorporating intercurrent events related to COVID-19 
will be used to assess the impact of COVID-19. Previous assessments of the impact of 
COVID-19 in the Primary and Update CSRs concluded that the impact of COVID-19 on 
the efficacy findings through Week 48 was minimal; therefore, the additional analyses 
will only be performed on the following endpoints after Week 48: change in BCVA 
averaged over Week 60 and Week 64, change in BCVA averaged over Week 88 and 
Week 92, and change in BCVA over time through Week 96.
The estimand for the additional supplemental analyses is defined as follows:
–
Population: Adult patients with nAMD diagnosed within 9 months and receiving at 
least 4 anti-VEGF intravitreal injections (with the last injection being ranibizumab), 
responsive to prior anti-VEGF treatment
–
Variable: Change in BCVA score from baseline averaged over Week 60 and Week 
64, Change in BCVA averaged over Week 88 and Week 92, and Change in BCVA 
over time through Week 96
–
Intercurrent events: 

Discontinuation of study treatment due to adverse events (AEs) or lack of 
efficacy not due to COVID-19: A treatment policy strategy will be applied where 
all observed values will be used regardless of the occurrence of the intercurrent 
event

Use of any prohibited systemic treatment or prohibited therapy in the study eye 
(Section 4.4.2 of Protocol) not due to COVID-19: A treatment policy strategy will 


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be applied where all observed values will be used regardless of the occurrence 
of the intercurrent event

Discontinuation of study treatment due to COVID-19: A hypothetical strategy 
will be applied where all values will be censored after the intercurrent event

Use of any prohibited systemic treatment or prohibited therapy in the study eye 
due to COVID-19: A hypothetical strategy will be applied where all values will 
be censored after the intercurrent event

Missed dose(s) with potentially major impact on efficacy due to COVID-19, 
defined according to the treatment arm: 
–
Intravitreal arm: two or more consecutive missed visits due to COVID-19 
(reported as an intercurrent event at the second consecutive missed visit), 
or three or more total missed visits due to COVID-19 (reported as an 
intercurrent event at the third missed visit)
–
PDS arm: any missed refill-exchange due to COVID-19 (reported as an 
intercurrent event at the missed refill-exchange visit), or missed both 
supplemental treatment evaluation visits during the refill-exchange interval 
due to COVID-19
A hypothetical strategy will be applied where all values will be censored 
after the intercurrent event 
–
COVID-19 death: A hypothetical strategy will be applied 
–
Population-level summary: Difference in adjusted mean between PDS 100 mg/mL 
and intravitreal groups
The analyses will be performed using the same analysis method as the primary endpoint 
(see Section 4.4.1 ). 
In addition, the COVID-19 related intercurrent events will be summarized by treatment 
arm.
4.4.3
Exploratory Efficacy Endpoints
Exploratory endpoints are:
–
BCVA and CST results over time relative to supplemental treatment
–
Change from baseline in CST at Week 36
–
Change from baseline in CST over time
–
Proportion of patients with macular atrophy at baseline, Weeks 36, 48, and 96 
–
Change from baseline in macular atrophy area at Weeks 36, 48 and 96
–
Proportion of patients who gain 5 letters in BCVA score from baseline over time.
–
Proportion of patients who lose < 15 letters in BCVA score from baseline to the 
average over Week 88 and Week 92


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–
Proportion of patients who gain > 15 letters in BCVA score from baseline to the 
average over Week 88 and Week 92 
To evaluate the impact of supplemental treatment with intravitreal ranibizumab on 
efficacy endpoints for the PDS 100 mg/ml group patients receiving supplemental 
treatment, graphs by patient showing BCVA and CST over time and indicating times of 
refill-exchange or supplemental treatments will be provided.
Change from baseline in CST at Week 36 and over time will be analyzed using the same 
analysis method and data handling rules as the primary endpoint.
Proportion of patients with macular atrophy and macular atrophy area will be analyzed
by descriptive summaries including confidence intervals at each timepoint.
The other binary endpoints will be analyzed using the same method as the binary 
secondary endpoints (see Section 4.4.2).
4.4.4
Patient-Reported Experiences 
Patient preference will be assessed using the PDS Patient Preference Questionnaire 
(PPPQ).  The PPPQ is a 3-item questionnaire that captures a patient's preference for 
treatment, the strength of their preference, and the reasons for their preference.  The 
PPPQ will be administered only to patients in the PDS 100 mg/ml arm, who received 
intravitreal anti-VEGF treatment prior to Day 1.  The PPPQ specifically assesses patient 
preference for treatment and could demonstrate a benefit of PDS over monthly 
intravitreal ranibizumab 0.5 mg due to less frequent treatments and the advantage of a 
refill-exchange over injection. However, due to the nature of the clinical trial, monthly 
visits are required so study participants will not experience the advantage of less 
frequent visits.  The strength of preference and reasons for preference will be 
summarized descriptively.
The Macular Disease Treatment Satisfaction Questionnaire (MacTSQ) was developed to 
provide a means of evaluating satisfaction with therapies for macular disease.  The 
MacTSQ provides a total score and two subscale scores: impact of treatment, and 
information provision and convenience.  Higher scores for the total scale and the 
subscales represent increased satisfaction with treatment.
The MacTSQ score, including both total score and subscale scores at scheduled visits,
will be summarized using appropriate descriptive statistics based on the observed data. 
The MacTSQ will be scored per the instructions in the “Summary of the MacTSQ 
rev11.8.15.” Subscale 1 (Information provision and convenience) contains six items 
(1, 9, 10 to 13). Item scores are summed to give a subscale score between 0 and 36. 
Subscale 2 (Impact of treatment) contains six items (items 2 to 6, 8). After recoding item 
2 and 3 per the instructions, item scores are summed to create a subscale score 


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between 0 and 36. The total score is calculated by combining the 12 items from the two 
subscales, and ranges from 0 to 72.
Data will be specifically imputed using the rules as follows:
–
Subscale 1 (information provision and convenience): Set the subscale 1 value to 
missing if any of the 6 items in the subscale are missing.
–
Subscale 2 (impact of treatment score): Set the subscale 2 value to missing if two or 
more of the 6 items in the subscale 2 are missing. If only one item is missing, 
impute the item value based on the average of the other five items.
–
Single scale (overall score): Set the single scale value to missing if four or more of 
the 12 items are missing. If three or less items are missing, impute the missing item 
values based on the average of the other available items.
4.4.5
Subgroup Analyses
Subgroup analyses will be provided in forest plots for the following endpoints:
–
Change from baseline in BCVA score averaged over Week 36 and Week 40
–
Change from baseline in CPT at Week 36
Subgroups will be Age (< 65 years, 65 to <75 years, 75 years) and Sex (male, 
female). In addition subgroups may be analyzed according to number of anti-VEGF 
injections performed before randomization (<5, 5), baseline BCVA (74 letters vs. 74 
letters). The analyses will follow the same methods (except in the case of baseline 
BCVA subgroup the baseline covariate consisting of the BCVA stratification factor will be 
removed) as for these endpoints in the overall analysis but will be done for each 
subgroup separately.
4.5
PHARMACOKINETIC ANALYSES
Individual and mean serum ranibizumab concentration versus time data will be tabulated 
and plotted by treatment group for all patients in the Pharmacokinetic Population and 
Pharmacokinetic-Evaluable Population.  In a subset of patients in the PDS 100 mg/mL
group with more intensive sampling (at selected sites), the serum pharmacokinetics of 
ranibizumab will be summarized by estimating total exposure (area under the 
concentration-time curve [AUC]), maximum serum concentration (Cmax), and half-life (t1/2)
of drug delivered from the implant after PDS implant insertion.  Estimates for these 
parameters will be tabulated and summarized (mean, standard deviation, coefficient of 
variation, median, and minimum and maximum).  Inter-patient variability will be 
evaluated.
Exploratory PK analyses to evaluate potential relationships between drug exposure and 
efficacy of the PDS will be performed. Additional PK analyses will be conducted as 
appropriate.


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4.6
EXPLORATORY BIOMARKER ANALYSES
Pharmacodynamic (PD) biomarker analyses will be focused primarily on, but not limited 
to, the change in free-VEGF or other angiogenesis-related biomarker concentrations 
(absolute or percent change as appropriate) over time and analyzed based on the 
Biomarker Analysis Population.  The data will be analyzed in the context of ranibizumab 
pharmacokinetics, using a longitudinal model approach, to gain an understanding of the 
relationship between ranibizumab concentrations and target modulation.  Results will be 
summarized descriptively.
Additional analyses will be performed, as deemed appropriate, to explore biomarkers 
that are associated with progression to a more severe disease, acquired resistance to 
ranibizumab, and susceptibility to developing AEs, can provide evidence of ranibizumab 
activity, or can increase the knowledge and understanding of disease biology.  
Prognostic biomarker analyses will include all patients for which biomarker assessments 
were made during randomization (“baseline”).  Baseline values will be used to evaluate 
prognostic biomarkers in the context of efficacy, PK, safety, and/or immunogenicity 
endpoints.  Results will be summarized descriptively.
4.7
SAFETY ANALYSES
The safety analyses will be performed on the Safety Population (described in 
Section 4.1.6).
Safety will mainly be assessed through descriptive summaries of AEs, ocular 
assessments, and anti-drug antibodies (ADAs) to ranibizumab.  Clinically significant 
laboratory abnormalities and clinically significant vital sign abnormalities will be reported 
as AEs and evaluated as part of the AE assessments.
At the time of the primary analysis, safety data will be summarized based on the 
complete Week 40 data in the Safety Population.  In addition, ongoing safety data (from 
first treatment up to a single specified clinical cutoff date) in the Safety Population will 
also be summarized.  Such results will be reported with, but separate from, the 40-week 
study results to provide additional safety information.
At the time of the final analysis, safety summaries will be produced based on cumulative 
Week 96 data in the Safety Population. Due to the addition of several final study visit 
scenarios specified in the Protocol Version 4 in order to provide flexibility and assure 
appropriate patient care in response to the COVID-19 public health emergency, safety 
data will be available for some patients beyond Week 96. Post-Week 96 data will not be 
included in the safety summaries and will be provided separately in a listing.  
4.7.1
Adverse Events
All verbatim AE terms will be coded using the latest version of Medical Dictionary for 
Regulatory Activities (MedDRA).


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For safety analyses, unless otherwise specified, only treatment-emergent AEs will be 
included in the analyses. Treatment-emergent AEs will be defined as any new AEs 
reported or any worsening of an existing condition on or after the surgical insertion of the 
implant or the first intravitreal ranibizumab injection post randomization through the 
completion of the study or until a patient discontinues prematurely. Adverse events with 
missing onset date will be considered to be treatment emergent. Adverse events with 
partially missing onset date will also be included as treatment emergent when the month 
(if it was recorded) and the year occur on or later than the month and year of the study 
treatment start date.
Frequency tables, including patient incidence rates by treatment group, will be provided 
for the events listed below. For ocular AEs, events in the study eye and fellow eye will 
be summarized separately.

Ocular AEs and serious adverse events (SAEs)

Non-ocular AEs and SAEs 

Adverse events of special interest (AESI) defined as follows:
– An AE considered to be sight threatening (see Section 5.2.3 of the Protocol) 
– Cases of potential drug-induced liver injury that include elevated alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) in combination with 
either an elevated bilirubin or clinical jaundice, as defined by Hy's Law (see 
Section 5.3.5.6 of the Protocol)
– Suspected transmission of an infectious agent by the study drug
– Ocular AESIs (formerly adverse events potentially related to PDS) defined as:
o
Vitreous hemorrhage
o
Endophthalmitis
o
Retinal detachment
o
Conjunctival retraction
o
Conjunctival erosion
o
Conjunctival bleb or conjunctival filtering bleb leak
o
Hyphema
o
Cataract (includes Preferred Terms cataract, cataract nuclear, cataract 
cortical, and cataract subcapsular)
o
Device dislocation (added in Protocol v 5)

AEs leading to discontinuation of study treatment

Treatment related Ocular AEs and SAEs as determined by the Investigator

Anti-Platelet Trialists Collaboration Events (APTCs) defined as:
–
non-fatal stroke AEs defined by terms from the conditions associated with central 
nervous system haemorrhages and cerebrovascular accidents Standardized 


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MedDRA Query (SMQ) (Narrow), ischaemic cerebrovascular conditions SMQ 
(Narrow), and haemorrhagic cerebrovascular conditions SMQ (Narrow) or 
–
non-fatal myocardial infarction AEs defined by terms from the myocardial infarction 
SMQ (Narrow) or 
–
vascular death (including deaths of unknown cause)
Of note, vitreous hemorrhage data will be presented by the functional grading scale for 
vitreous hemorrhage (see Study GR40458 Study Protocol Appendix 8) which 
incorporates impact of vitreous hemorrhage on patient’s BCVA.  All vitreous hemorrhage 
data will be presented however for key analyses the focus will be on Grades 3 and 4 as 
these are clinically relevant when discussing vitreous hemorrhage.
A subgroup analysis of cataract incidence will be performed by baseline lens status 
subgroup (phakic vs pseudophakic), as in the Primary CSR Section 3.11.8. 
In addition, the rates of intraocular inflammation AEs will be analyzed as in the Primary 
CSR Section 6.3.5.2.1, based on selected PTs according to the Standardization of 
Uveitis Nomenclature (SUN) (Jabs et al. 2005). Intraocular inflammation will be defined 
as anterior uveitis (included iritis, iridocycltis, anterior cyclytis, anterior channel cell, flare, 
and inflammation); intermediate uveitis (included pars planitis, posterior cyclitis, hyalitis, 
vitritis, and vitreous haze); posterior uveitis (included choroiditis, chorioretinitis, 
retinochoroiditis, retinitis, neuroretinitis, and retinal vasculitis); and events which were 
not otherwise specified (included eye inflammation, uveitis, post procedural inflammation, 
incision site inflammation, inflammation of wound, and ocular vasculitis). Endophthalmitis, 
while included in the SUN criteria for intraocular inflammation, will be analyzed 
separately as an AESI. 
Adverse events (AEs) of endophthalmitis will additionally be summarized as incidence
rates by treatment group on a per study treatment intervention basis (total number of 
endophthalmitis AEs divided by the total number of interventions in the study eye.  
Interventions in the intravitreal group include intravitreal ranibizumab injections.  
Interventions in the PDS 100 mg/ml group include implantation, PDS refill-exchange 
procedure, and supplementary ranibizumab treatment in the study eye. 
Frequency tables including patient incidence rates will also be generated by treatment 
group and by onset of events using the following time windows relative to first dose or 
implant surgery:
–
Week 4 (up to the end of Week 4 visit window, 37 days) (post-operative period)
–
Week 4 (37 days) (follow-up period)
for the following AEs:
–
Ocular AEs and SAEs in the study eye 
–
Ocular AESIs.


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A listing of patients who died during the study will be provided.
4.7.2
Additional Safety Analyses Performed for COVID-19
Based on the first reports of COVID-19 infection globally, the Sponsor determined that 
the window for all analyses of COVID-19 associated events would start from 01 
December 2019, until CCOD for the study. At the time of the Update CSR, the Sponsor 
developed a narrow search strategy to identify AEs of confirmed or suspected COVID-19 
infection, a Roche Adverse Event Grouped Term (AEGT) that included 19 terms 
identified by Maintenance and Support Services Organization (MSSO) as relevant to the 
COVID-19 infection. These AEGT terms were used to assess the impact of COVID-19 in 
the Update CSR. 
Following the MedDRA 23.1 release, a COVID-19 SMQ (narrow) is now available. This 
SMQ includes 18 terms relevant to COVID-19 infection (see Table 1), and these terms 
will be used to assess the impact of COVID-19 in the Final CSR. Patients with AEs from 
this COVID-19 SMQ (narrow) will be considered to have a confirmed or suspected 
COVID-19 infection.
A listing or table of confirmed and suspected COVID-19 AEs will be produced from the 
patients identified from the search as having confirmed or suspected COVID-19 infection
(Table 1).


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Table 1
Roche COVID-19 SMQ (narrow) Preferred Terms for all Cases 
(Confirmed and Suspected)
Asymptomatic COVID-19
Coronavirus infection
Coronavirus test positive
COVID-19
COVID-19 immunisation
COVID-19 pneumonia
COVID-19 prophylaxis
COVID-19 treatment
Exposure to SARS-CoV-2
Multisystem inflammatory syndrome in children
Occupational exposure to SARS-CoV-2
SARS-CoV-2 antibody test positive
SARS-CoV-2 carrier
SARS-CoV-2 sepsis
SARS-CoV-2 test false negative
SARS-CoV-2 test positive
SARS-CoV-2 viraemia
Suspected COVID-19
In addition to presenting the suspected/confirmed COVID-19 infections, the Sponsor 
developed a broad search strategy for AEs associated with COVID-19 infection to further 
evaluate the confirmed events of COVID-19 and reported AEs that could be considered 
complications of the disease. This search strategy includes both the AEs of a confirmed 
or suspected COVID-19 infection (PTs in Table 1) and any AEs considered associated 
with COVID-19 (temporally reported around PTs in Table 2). As causality to COVID-19 
was not collected on the standard eCRF, the Sponsor identified associated AEs as those 
reported 7 days before and 30 days after any reported AE suggesting a confirmed 
COVID-19 infection (PTs listed in Table 2). The COVID-19 associated AEs for patients 
with confirmed COVID-19 infection will be provided in a summary table or a listing.


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Table 2
Roche COVID-19 SMQ (narrow) Preferred Terms for Confirmed Cases
Coronavirus Infection 
Coronavirus Test Positive 
COVID-19 
COVID -19 Pneumonia
Sars-Cov-2 Test Positive
SARS-CoV-2 sepsis
SARS-CoV-2 viraemia
COVID-19 Treatment
Multisystem Inflammatory Syndrome in Children
4.7.3
Laboratory Data
Laboratory data will be collected at baseline only (see Study GR40548 Protocol 
Section 4.5.7). These data can be used for interpretation of some AEs, no general 
summary is planned.
4.7.4
Vital Signs
Vital signs will be collected at screening, randomization and Week 96 or early 
termination visit only. These data can be used for interpretation of some AEs, no 
general summary is planned.
4.7.5
Ocular Assessments
Results of the following ocular assessments will be summarized by treatment group, by 
timepoint and by eye (study vs. non-study) as applicable, using descriptive summaries:

intraocular pressure (IOP)

slit lamp examination

indirect ophthalmoscopy
Changes from baseline for IOP assessments will be tabulated.  The presence of 
intraocular inflammation and vitreous hemorrhage, as determined on slit lamp 
examination, will be tabulated by grade (according to grading scales for flares and cells 
in Study GR40548 Protocol Appendix 7, and vitreous hemorrhage density and functional 
scales in Study GR40548 Protocol Appendix 8).  The presence of retinal break or 
detachment as determined from ophthalmoscopy will be tabulated.
4.7.6
Immunogenicity Analyses
Because patients will have been exposed to ranibizumab prior to entry into study, the 
ADA status of patients at the randomization visit may not reflect pretreatment ADA 
prevalence in the study. Thus, the ADA incidence will be analyzed.
The immunogenicity analyses will group patients according to treatment received.  
Anti-drug antibody samples will be collected prior to dosing during the randomization 


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visit and at Weeks 4, 24, 36, and 96.  To account for pre-study exposure to ranibizumab, 
ADA incidence (number and percentage) will be summarized as follows:
–
ADA incidence at the time of entry into the study (randomization visit) based on the 
Safety Population
–
ADA incidence at any time after randomization visit, grouped in the following
manner, based on patients in the Safety Population who have ADA samples at 
randomization and after dosing:
a)
Patients who were ADA negative at randomization and became positive 
only after dosing, during the study.
b)
Patients who were ADA positive at randomization and ADA titer increased 
after dosing during the study; in this case, the titer of one or more samples 
collected after randomization must be at least 4-fold greater (i.e.,0.60 titer 
units) than the titer of the randomization visit sample. These patients are 
considered to have treatment-enhanced ADA responses.
c)
Patients who were ADA positive at randomization and ADA titer did not
increase after dosing during the study.
The combined rates described in (a) and (b) above will provide the incidence of 
treatment-emergent ADAs in the study.  Patients are considered to be negative for ADAs 
if they are ADA negative at all timepoints. Patients are also considered to be negative 
for ADAs if they are ADA positive at randomization and ADA negative at all 
post-randomization timepoints. A listing of patients with positive serum antibodies to 
ranibizumab will be provided.
The immunogenicity assessment will also include testing for the presence of neutralizing 
antibodies in samples confirmed to be positive for anti-ranibizumab antibodies.  The 
incidence of neutralizing antibodies will be grouped and reported in a similar fashion to 
that described above.
In addition, subgroup analyses will be performed summarizing ADA and neutralizing 
antibody incidences based on pre-screening anti-VEGF intravitreal treatment.
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
may be explored.
4.8
MISSING DATA
In efficacy analyses, the handling of missing data is specified for analysis in the efficacy 
analysis section.
4.9
INTERIM ANALYSES
No interim efficacy or futility analyses are planned. The iDMC will review the interim 
safety analyses approximately every 6 months


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5.
REFERENCES
Cochran WG. Some methods for strengthening the common χ 2 tests. Biometrics, Vol. 
10, No. 4. (December 1954), pp. 417-451.
Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of Uveitis Nomenclature 
(SUN) Working Group. Standardization of uveitis nomenclature for reporting 
clinical data. Results of the First International Workshop. Am J Ophthalmol. 
2005;140:509-516
Mantel N and Haenszel W. Statistical aspects of the analysis of data from retrospective 
studies of disease. J Natl Cancer I, 1959;22(4):719-748.
Mehrotra DV, Railkar R. Minimum risk weights for comparing treatments in stratified 
binomial trials. Stat Med. 2000;19:811-25.
Owen CG, Jarrar Z, Wormald R, et al. The estimated prevalence and incidence of late 
stage age related macular degeneration in the UK. Br J Ophthalmol 2012;96:752-6.
Permutt T and Li F. Trimmed means for symptom trials with dropouts. Pharm Stat 
2017;16:208.
Rudnicka AR, Jarrar Z, Wormald R, et al. Age and gender variations in age-related 
macular degeneration prevalence in populations of European ancestry: a 
metaanalysis. Ophthalmology 2012;119:57180.
Smith AF. The growing importance of pharmacoeconomics: the case of age-related 
macular degeneration. Br J Ophthalmol 2010;94(9):11161117.
Westfall PH, Krishen A. Optimally weighted, fixed sequence and gatekeeper multiple 
testing procedures. J Stat Plan Infer 2001;99:2540.


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Appendix 1
Protocol Synopsis
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, VISUAL 
ASSESSORMASKED, ACTIVE-COMPARATOR STUDY OFTHE 
EFFICACY, SAFETY, AND PHARMACOKINETICS OF THE PORT 
DELIVERY SYSTEM WITH RANIBIZUMAB IN PATIENTS WITH 
NEOVASCULAR AGE-RELATED MACULAR DEGENERATION 
(ARCHWAY)
PROTOCOL NUMBER:
GR40548
VERSION NUMBER:
5
EUDRACT NUMBER:
Not applicable
IND NUMBER:
113,552
NCT NUMBER:
NCT03677934
TEST PRODUCT:
Port Delivery System with ranibizumab
PHASE:
Phase III
INDICATION:
Neovascular age-related macular degeneration
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, and pharmacokinetics of ranibizumab delivered via 
the Port Delivery System with ranibizumab (PDS) implant compared with ranibizumab 0.5 mg 
delivered as a monthly intravitreal injection in patients with neovascular age-related macular 
degeneration (nAMD). Specific objectives and corresponding endpoints for the study are 
outlined below.
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the non-inferiority and 
equivalence in efficacy of ranibizumab 
delivered via the PDS Q24W with the
100-mg/mL formulation compared with that 
of 10-mg/mL (0.5-mg dose) Q4W intravitreal 
ranibizumab injections
Change from baseline in BCVA score at the average of 
Week 36 and Week 40, as assessed using the ETDRS 
visual acuity chart at a starting distance of 4 meters


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Secondary Efficacy Objectives
Corresponding Endpoints
To evaluate the relative efficacy of 
ranibizumab delivered via the PDS Q24W 
with the 100-mg/mL formulation compared 
with that of 10-mg/mL (0.5-mg dose) Q4W 
intravitreal ranibizumab injections, as 
assessed by visual acuity
Change from baseline in BCVA score averaged over Week 
60 and Week 64
Change from baseline in BCVA score over time
Proportion of patients with BCVA score of 38 letters (20/200 
approximate Snellen equivalent) or worse at the average 
over Week 36 and Week 40
Proportion of patients with BCVA score of 38 letters (20/200 
approximate Snellen equivalent) or worse over time
Proportion of patients with BCVA score of 69 letters (20/40 
approximate Snellen equivalent) or better at the average 
over Week 36 and Week 40
Proportion of patients with BCVA score of 69 letters (20/40 
approximate Snellen equivalent) or better over time
Proportion of patients who lose 10 or 5 letters in BCVA 
score from baseline to the average over Week 36 and 
Week 40
Proportion of patients who lose 10 or 5 letters in BCVA 
score from baseline over time
Proportion of patients who gain 0 letters in BCVA score 
from baseline to the average over Week 36 and Week40
Proportion of patients who gain 0 letters in BCVA score 
from baseline over time
To evaluate the relative efficacy of 
ranibizumab delivered via the PDS Q24W 
with the 100-mg/mL formulation compared 
with that of 10-mg/mL (0.5-mg dose) Q4W 
intravitreal ranibizumab injections, as 
assessed by CPT on SD-OCT
Change from baseline in CPT at Week 36
Change from baseline in CPT over time
To evaluate the proportion of patients who 
undergo supplemental treatment with 
intravitreal ranibizumab 0.5 mg
Proportion of patients in the implant arm who undergo 
supplemental treatment with intravitreal ranibizumab
0.5 mg before the first, second, third, and fourth fixed refill-
exchange intervals
Proportion of patients in the implant arm that undergo a 
supplemental treatment that requires subsequent additional 
supplemental treatments during the study
Exploratory Efficacy Objectives
Corresponding Endpoints
To evaluate the impact of supplemental 
treatment with intravitreal ranibizumab
0.5 mg
Endpoints will be results-dependent based on number of 
supplemental treatment


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Exploratory Efficacy Objectives (cont.)
Corresponding Endpoints (cont.)
To evaluate the relative efficacy of 
ranibizumab delivered via the PDS Q24W 
with the 100-mg/mL formulation compared 
with that of 10-mg/mL (0.5-mg dose) Q4W 
intravitreal ranibizumab injections, as 
assessed by central subfield thickness on 
SD-OCT
Change from baseline in CST at Week 36
Change from baseline in CST over time
To assess clinically relevant features 
using advanced analytics tools 
(including artificial intelligence-based 
tools) on multimodal images and clinical 
data
Clinically relevant features over time
To evaluate the development of macular 
atrophy in patients treated with the PDS 
Q24W with the 100-mg/mL formulation 
compared with those with 10-mg/mL (0.5-
mg dose) Q4W intravitreal ranibizumab 
injections.
Proportion of patients with macular atrophy at baseline, 
Weeks 36, 48, and 96
Change from baseline in macular atrophy area at Weeks 36, 
48 and 96
To evaluate the relative efficacy of 
ranibizumab delivered via the PDS Q24W 
with the 100-mg/mL formulation compared 
with that of 10-mg/mL (0.5-mg dose) Q4W 
intravitreal ranibizumab injections, as 
assessed by visual acuity
Proportion of patients who gain 5 letters in BCVA score 
from baseline over time.
Safety Objective
Corresponding Endpoints
To evaluate the safety and tolerability of 
ranibizumab, delivered via the PDS Q24W 
with the 100-mg/mL formulation compared 
with that of 10-mg/mL (0.5-mg dose) Q4W 
intravitreal ranibizumab injections
Incidence and severity of ocular and systemic (non-ocular) 
AEs
Incidence, severity, and duration of AESIs, including 
PDS-associated AEs
Incidence, severity, and duration of ocular AESIs during the 
postoperative period (up to 37 days of initial implantation) 
and follow-up period (37 days after implantation surgery)
Pharmacokinetic Objective
Corresponding Endpoints
To characterize the serum pharmacokinetics 
of ranibizumab in patients after the initial fill 
and subsequent refill-exchanges in patients 
with the PDS
Observed serum ranibizumab concentrations at specified 
timepoints
Additional estimated PK parameter values, including
AUC0-6M, Cmax, Cmin, and t1/2 after PDS implant insertion
Exploratory Pharmacokinetic Objectives
Corresponding Endpoints
To evaluate potential relationships between 
drug exposure and the efficacy of the PDS
Relationship between serum concentration or PK 
parameters for ranibizumab delivered via the PDS and 
efficacy endpoints
To characterize ranibizumab aqueous 
humor concentration over time
Observed aqueous humor ranibizumab concentrations over 
time


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36/Statistical Analysis Plan GR40548
Immunogenicity Objective
Corresponding Endpoint
To investigate the formation of serum anti-
ranibizumab antibodies
The incidence of ADAs during the study, grouped in the 
following manner:
Patients who were ADA negative at baseline and became 
positive only after dosing
Patients who were ADA positive at randomization and ADA 
titer increased after dosing
Patients who were ADA positive at randomization and ADA 
titer did not increase after dosing
Exploratory Biomarker Objectives
Corresponding Endpoints
To explore relationships between aqueous 
humor free-VEGF concentrations over 
time and the efficacy of ranibizumab, 
delivered via the PDS Q24W with the
100-mg/mL formulation
Comparison of patients with and without aqueous humor 
free-VEGF present between refill-exchanges and needing 
supplemental treatment
Comparison of patients with and without aqueous humor 
free-VEGF present between refill-exchanges and CST 
change from baseline over time
Comparison of patients with and without aqueous humor 
free-VEGF present between refill-exchanges and BCVA 
score change from baseline over time
To identify biomarkers that are prognostic of 
response to ranibizumab, are associated 
with acquired resistance to ranibizumab, are 
associated with susceptibility to developing 
adverse events (i.e., safety biomarkers), can 
provide evidence of ranibizumab activity 
(i.e., pharmacodynamic biomarkers), or can 
increase the knowledge and understanding 
of AMD-related disease biology
Relationship between biomarkers in blood and aqueous 
humor with disease characteristics and response to 
ranibizumab
Relationship between genetic variants (such as AMD risk 
alleles, polymorphisms within the complement pathway, and 
polymorphisms within the VEGF-A genetic locus) with the 
disease characteristics and/or response to treatment with 
ranibizumab
Relationship between imaging features with disease 
characteristics and/or response to treatment with 
ranibizumab
Exploratory Patient Experience Objectives
Corresponding Endpoints
To evaluate the preference of patients for 
ranibizumab delivered via the PDS for 40 
weeks compared to intravitreal anti-VEGF 
treatment received in the 6 months prior to 
Day 1
Proportion of patients who report preferring ranibizumab 
treatment via the PDS compared with intravitreal anti-
VEGF treatment, as assessed by the PPPQ, at Week 40 
among patients in the implant arm
To evaluate patient-reported treatment 
satisfaction with ranibizumab delivered via 
the PDS for 40 weeks compared with that of 
Q4W intravitreal ranibizumab injections, as 
assessed by the MacTSQ
MacTSQ total score at Week 40


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37/Statistical Analysis Plan GR40548
ADA anti-drug antibody; AE adverse event; AESI adverse event of special interest; 
AMD age-related macular degeneration; AUC0-6M area under the concentrationtime 
curve from 0 to 6 months;
BCVA best-corrected visual acuity; Cmax maximum serum concentration; Cmin 
minimum serum concentration; CPT center point thickness; CST central subfield 
thickness; ETDRS Early Treatment Diabetic Retinopathy Study; MacTSQ Macular 
Degeneration Treatment Satisfaction Questionnaire; PDS Port Delivery System with 
ranibizumab; PK pharmacokinetic; PPPQ PDS Patient Preference Questionnaire; 
Q4W every 4 weeks; Q24W every 24 weeks; SD-OCT spectral domain optical 
coherence tomography; t1/2 half-life; VEGF vascular endothelial growth factor.
Study Design 
Description of Study
Study GR40548 (Archway) is a Phase III, randomized, multicenter, open-label (visual 
assessor
[VA]masked), active-comparator study designed to assess the efficacy, 
safety, and pharmacokinetics of 100 mg/mL ranibizumab every 24 weeks 
(Q24W) delivered via the PDS compared with ranibizumab intravitreal 
injections every 4 weeks (Q4W) at 0.5 mg (10 mg/mL) in patients with nAMD.
Patients will be randomly allocated in a 3:2 ratio so that approximately 216 
patients will receive the PDS implant filled with 100 mg/mL ranibizumab 
Q24W (implant arm) and approximately 144 patients will receive monthly 
intravitreal injections of 10 mg/mL ranibizumab intravitreal injections Q4W 
(intravitreal arm).
Patients who are randomly allocated to the implant arm will have the implant 
(pre-filled with ranibizumab 100 mg/mL) surgically inserted on Day 1, which 
must occur 17 days (inclusive) after randomization (i.e., randomization and 
Day 1 visit assessments cannot be performed on the same day) and no later 
than 28 days from the last intravitreal ranibizumab 0.5 mg injection. If the 
implant insertion surgery (Day 1) cannot be completed within the visit window 
after randomization, the randomization visit assessments may be repeated 
and an additional intravitreal ranibizumab 0.5 mg injection may be required 
after discussion with the Sponsor.
After Day 1, patients in the implant arm will have scheduled safety visit 
assessments on Days 2 and 7 (2 days) and will receive implant refill-
exchanges with ranibizumab 100 mg/mL Q24W at Week 24 (7 days), Week
48 (7 days), and Week 72 (7 days).
Patients who are randomly allocated to the intravitreal arm will receive intravitreal 
ranibizumab
0.5 mg injections starting on Day 1, which is to be administered at the 
conclusion of the randomization visit (i.e., randomization and Day 1 visit 
assessments are performed on the same day). Patients will receive 
ranibizumab 0.5 mg, injected intravitreally Q4W (7 days) from
Day 1 until Week 92.
In order to provide flexibility due to extenuating circumstances, it is possible 
that patients may receive additional study treatments until they are able to 
enroll into the long-term safety study.
Study visits will occur according to the schedule of activities relative to Day 1 
(first study treatment). Study patients and all study site personnel with the 
exception of VA examiners will be unmasked to the study eye and study 
treatment assignment. To minimize bias, VA examiners will only conduct 
refraction and VA assessments and will be masked as best as possible to 
patient study eye assignment, study visit type, and patient treatment 
assignment.


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38/Statistical Analysis Plan GR40548
Number of Patients
Approximately 360 patients were planned to be enrolled in this study; a total 
of 418patients were ultimately recruited.
Target Population
Inclusion on Criteria
General Inclusion Criteria
Patients must meet the following general inclusion criteria at screening and 
randomization for study entry:

Ability and willingness to provide signed informed consent
Additionally, patients must provide Health Insurance Portability and 
Accountability Act (HIPAA) authorization.

Age 50 years, at time of signing Informed Consent Form

Ability and willingness to undertake all scheduled visits and assessments

For women of childbearing potential: agreement to remain 
abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, 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 at least 28 days 
after the last intravitreal injection of ranibizumab or 1 year after 
the last implant refill-exchange of ranibizumab.
A woman is considered to be of childbearing potential if she is post-
menarcheal, has not reached a postmenopausal state (12 continuous 
months of amenorrhea with no identified cause other than menopause), 
and has not undergone surgical sterilization (removal of ovaries and/or 
uterus). The definition of childbearing potential may be adapted for 
alignment with local guidelines or requirements.
Examples of 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 withdrawalare not 
acceptable methods of contraception.
Ocular Inclusion Criteria
Patients must meet the following ocular inclusion criteria for the study eye for study 
entry:

Initial diagnosis of exudative nAMD within 9 months prior to the screening visit

Previous treatment with at least three anti-vascular endothelial 
growth factor (VEGF) intravitreal injections (e.g., ranibizumab,
bevacizumab, or aflibercept) for nAMD per standard of care within 6 
months prior to the screening visit
If a patient did not receive at least three anti-VEGF injections as 
described above but is otherwise eligible for the study, the patient can 
be treated in a run-in phase to meet this specific criterion.

Demonstrated response to prior anti-VEGF intravitreal treatment 
since diagnosis, as evidenced at screening by the following:
Overall decrease in nAMD disease activity detected on spectral-domain 
optical coherence tomography (SD-OCT), as assessed by the 
investigator and confirmed by the central reading center


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd
39/Statistical Analysis Plan GR40548
and
Stable or improved best-corrected visual acuity (BCVA)

BCVA of 34 letters or better (20/200 or better approximate Snellen 
equivalent), using Early Treatment Diabetic Retinopathy Study (ETDRS) 
chart at a starting distance of 4 meters (see the BCVA manual for 
additional details) at screening and randomization visits

All subtypes of nAMD lesions are permissible (i.e., type I, type II, type 
III, or mixed forms per OCT classification)
nAMD lesions at the time of diagnosis must involve the macula (6-mm 
diameter centered at the fovea).

Sufficiently clear ocular media and adequate pupillary dilation to allow 
for analysis and grading by the central reading center of fundus 
photography FP, fluorescein angiography FA, fundus autofluorescence 
FAF, and SD-OCT images
Exclusion Criteria
Prior Ocular Treatment
Patients who meet any of the following prior ocular treatment exclusion 
criteria will be excluded from study entry.
Study Eye

History of vitrectomy surgery, submacular surgery, or other surgical intervention
for
age-related macular degeneration (AMD)

Prior treatment with Visudyne®, external-beam radiation therapy, 
or transpupillary thermotherapy

Previous treatment with corticosteroid intravitreal injection

Previous intraocular device implantation

Previous laser (any type) used for AMD treatment
Either Eye

Treatment with anti-VEGF agents other than ranibizumab within 1 
month prior tothe randomization visit

Prior participation in a clinical trial involving anti-VEGF drugs within 6 
months prior to the randomization visit, other than ranibizumab
Choroidal Neovascularization (CNV) Lesion Characteristics
Patients who meet any of the following exclusion criteria related to CNV 
lesion characteristics will be excluded from study entry.
Study Eye

Subretinal hemorrhage that involves the center of the fovea, if the 
hemorrhage is greater than 0.5-disc area (1.27 mm2) in size at
screening

Subfoveal fibrosis or subfoveal atrophy
Either Eye

CNV due to other causes, such as ocular histoplasmosis, trauma, or pathologic
myopia
Concurrent Ocular Conditions
Patients who meet any of the following exclusion criteria related to concurrent 
ocular conditions will be excluded from study entry.


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40/Statistical Analysis Plan GR40548
Study Eye

Retinal pigment epithelial tear

Any concurrent intraocular condition (e.g., cataract, glaucoma, 
diabetic retinopathy, or epiretinal membrane) that would either require 
surgical intervention during the study to prevent or treat visual loss 
that might result from that condition or affect interpretation of study
results

Active intraocular inflammation (grade trace or above)

History of vitreous hemorrhage

History of rhegmatogenous retinal detachment

History of rhegmatogenous retinal tears or peripheral retinal breaks within 
3 months prior to the randomization visit

Aphakia or absence of the posterior capsule
Previous violation of the posterior capsule is also an exclusion 
criterion unless it occurred as a result of yttrium-aluminum garnet 
(YAG) laser posterior capsulotomy in association with prior, 
posterior chamber intraocular lens implantation.

Spherical equivalent of the refractive error demonstrating more than 8 diopters of
myopia

Preoperative refractive error that exceeds 8 diopters of myopia, for 
patients whohave undergone prior refractive or cataract surgery in 
the study eye

Intraocular surgery (including cataract surgery) within 3 months preceding
the randomization visitUncontrolled ocular hypertension or glaucoma 
(defined as intraocular pressure [IOP] 25 mmHg or a cup to disc ratio
0.8, despite treatment with antiglaucoma medication) and any such 
condition the investigator determines may require a glaucoma-filtering 
surgery during a patient's participation in the study

History of glaucoma-filtering surgery, tube shunts, or microinvasive glaucoma
surgery

History of corneal transplant

History of prior vitrectomy surgery and absence of posterior capsule
Either Eye

History of idiopathic or autoimmune-associated uveitis

Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis
Concurrent Systemic Conditions
Patients who meet any of the following exclusion criteria related to 
concurrent systemic conditions will be excluded from study entry:

Inability to comply with study schedule or procedures as described in the study
protocol

Uncontrolled blood pressure (defined as systolic blood pressure
180 mmHg and/or diastolic blood pressure 110 mmHg, while a 
patient is atrest)
If a patient's initial measurement exceeds these values, a second 
reading may be taken 30 or more minutes later. If the patient's blood 
pressure must be controlled by antihypertensive medication, the 
patient may become eligible if medication is taken continuously for at 
least 30 days prior to Day 1.

History of stroke within the last 3 months prior to informed consent

Uncontrolled atrial fibrillation within 3 months of informed consent


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41/Statistical Analysis Plan GR40548

History of myocardial infarction within the last 3 months prior to informed consent

History of other disease, metabolic dysfunction, or clinical laboratory 
finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of ranibizumab or placement of the implant and 
that might affect interpretation of the results of the studyor renders the 
patient at high risk of treatment complications in the opinion of the
investigator

Current systemic treatment for a confirmed active systemic infection

Use of any systemic anti-VEGF agents

Chronic use of oral corticosteroids (10 mg/day of prednisone or equivalent)

Active cancer within 12 months of randomization except for appropriately 
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, 
and prostate cancer with a Gleason score of 6 and a stable prostate-
specific antigen for 12 months

Previous participation in any non-ocular (systemic) disease studies of 
investigationaldrugs within 1 month preceding the informed consent 
(excluding vitamins and minerals)

Use of antimitotic or antimetabolite therapy within 30 days or 5 
elimination half-lives of the randomization visit

Requirement for continuous use of any medications or treatments 
indicated in"Prohibited Therapy"

Pregnant or breastfeeding, or intending to become pregnant during the 
treatment period and for at least 28 days after the last intravitreal 
injection of ranibizumab or 1 year afterthe last implant refill-exchange of
ranibizumab
Women of childbearing potential, including those who have had 
tubal ligation, must have a urine pregnancy test at screening and at 
specified subsequent visits. If a urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test.
End of Study
The end of this study is defined as the date when the last patient, last visit 
occurs. The end of study is expected to occur approximately 96 weeks after 
the last patient is enrolled.
Length of Study
The total length of the study, from screening of the first patient to the 
end of the study, is expected to be approximately 34 months.
Investigational Medicinal Products
The investigational medicinal products (IMPs) for this study are the PDS 
with ranibizumab (100 mg/mL) and the monthly intravitreal ranibizumab 
0.5 mg.
Test Product (Investigational Drug)
Patients will have the implant (filled prior to implantation with approximately 20 L of 
the
100-mg/mL formulation of ranibizumab [approximately 2-mg dose of 
ranibizumab]) surgically inserted in the study eye at the Day 1 visit following 
their randomization visit. After the initial fill of the implant with ranibizumab, 
patients will receive implant refill-exchanges at fixed 24-week intervals.
At each refill-exchange, a volume of approximately 100 L ranibizumab will 
be injected in situ into the implant through the septum to exchange the 
remaining contents of the implant with newly introduced ranibizumab. The 
volume of newly introduced ranibizumab remaining in the implant after the 
refill-exchange procedure will be approximately 20 L. Missed implant refill-


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42/Statistical Analysis Plan GR40548
exchanges should be made up no later than the next scheduled study visit. If 
at the next scheduled study visit the implant refill-exchange cannot be 
performed, the investigator must contact the Sponsor for further discussion 
prior to administering future implant refill-exchanges. Subsequent refill-
exchanges will be administered according to the study treatment schedule 
relative to Day 1 until patients complete the study.
A representative from the Sponsor or an affiliate of the Sponsor may be 
present during the study-specific PDS surgeries or procedures (initial filling, 
insertion, refill-exchanging, and/or explantation) and/or other PDS-related 
surgeries or procedures to provide technical support to investigators during 
the use of the PDS and/or to observe the procedures related to the PDS.
Comparator
Ranibizumab (10 mg/mL) will be provided by the Sponsor and used in the 
study eye during the run-in period and at the screening visit for applicable 
patients; as study treatment for patients in the intravitreal arm; as 
supplemental treatment for the implant arm; if delaying surgery is required; as 
nAMD treatment in the fellow eye for patients, per investigator’s discretion; 
and if a patient in the PDS arm discontinues study treatment and starts 
receiving ranibizumab intravitreal injections in study eye, per investigator’s 
discretion.
Commercially available intravitreal ranibizumab 0.5 mg supply may be used 
only if an intravitreal ranibizumab injection is necessary per protocol and 
study supply is not available at the site. Prior to administering commercial 
supply ranibizumab, the site will need to obtain Sponsor’s approval.
Patients in the intravitreal arm will receive their first intravitreal injection of 50 
L of the ranibizumab10 mg/mL (0.5-mg dose) at the Day 1 visit, which will 
occur at the conclusion of the randomization visit. Afterward, patients will 
receive intravitreal ranibizumab injections of 50 L of the 10-mg/mL 
formulation Q4W at each scheduled study visit until Week 92. Missed 
treatments will not be made up.
Statistical Methods 
Primary Analysis
The primary efficacy endpoint is the change in BCVA score from baseline averaged 
over
Weeks 36 and 40 with BCVA assessed using the ETDRS chart at a distance 
of 4 meters. The primary objective is to determine the non-inferiority (NI) and 
equivalence between the two treatment arms, as measured by the primary 
efficacy endpoint with an NI margin of 4.5 letters and equivalence margin of 
4.5 letters. To control the overall type I error, a fixed sequence testing 
procedure will be used. If the implant arm is shown to be non-inferior to the 
intravitreal arm at the one-sided 0.025 level, then the clinical equivalence 
test will be conducted using two one-sided 0.025 tests.
The primary analysis will be performed using the mixed-effect model with 
repeated measures (MMRM) based on all available data up to Week 40. All 
observed measurements will be included in the analysis regardless whether 
or not a patient has an intercurrent event. Missing data will be implicitly 
imputed by the MMRM model, assuming a missing at random mechanism.
The dependent variable in the MMRM model is the change from baseline in BCVA 
score at
post-baseline visits, from 4 to 40 weeks, and the independent variables are the 
treatmentgroup, time, treatment-by-time interaction, baseline BCVA score 
(continuous), and the randomization stratification factor of baseline BCVA (74 
letters vs. 74 letters) as fixed effects. The MMRM model will assume an 
unstructured covariance structure. If there are convergence problems with the 
model, then a compound symmetry covariance or an AR(1) covariance structure 
will be used. Comparisons between the two treatment arms will be made using a 
composite contrast over Weeks 36 and 40.


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43/Statistical Analysis Plan GR40548
For the primary efficacy endpoint, if a lower bound of a two-sided 95.03% CI for 
the difference of two treatments is greater than 4.5 letters (the NI margin), then 
treatment via PDS is considered non-inferior to monthly intravitreal ranibizumab 
treatment. If the two-sided 95% CI is within 4.5 letters and 4.5 letters, then the 
two treatment regimens are considered clinically equivalent.
As a sensitivity analysis, the per-protocol analysis will follow the same methods 
as the primary analysis except the Per-Protocol Population will be used.
Determination of Sample Size
Patients will be randomly allocated in a 3:2 ratio to the implant arm or intravitreal arm.
The primary endpoint is the change in BCVA score from baseline averaged over Weeks 
36 and
40. The study is sized to achieve adequate power to show NI and equivalence 
of the implant arm to the intravitreal arm in the change in BCVA score from 
baseline averaged over Week 36 and Week 40 using an NI margin of 4.5 letters 
and equivalence margins of 4.5 letters.
Assuming a standard deviation of 9.5 letters for the change from baseline in 
BCVA score averaged over 36 and 40 weeks, up to a true mean change from 
baseline in BCVA of 0.75 letters worse for the implant arm, compared with the 
monthly intravitreal arm, 216 patients in the implant arm and 144 patients in the 
intravitreal arm will provide 90% power to demonstrate NI and equivalence 
between the two treatment groups. Calculations were based on a one-sided t-
test at 0.025 level for the NI test and two one-sided t-tests at the 0.025 
level for the equivalence test with the assumption of a 10% dropout rate by Week 
40 and a 10% increase for the trimmed mean analysis.
.


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44/Statistical Analysis Plan GR40548
Appendix 2
Schedule of Activities: Implant Arm, Year 1 and Year 2
Table 1: Schedule of Activities: Implant Arm, Year 1 
Assessment
Screening a
Rand. b
Week 1
Week Visit
D1 b, c
D2
D7
4
8
12
16
20
24
28
32
36
40
44
48
Visit window
(days)
21 days from prior 
ITV Anti-VEGF
2128 days from last 
ITV RBZ Tx
NA
2
7
Informed consent
x d
Review of inclusion and 
exclusion criteria
x
x
Medical and surgical
history
x
Demographic data
x
Height and Weight
x
Contact IxRS e
x
x
x
x
x
x
x
x
Vital signs f
x
x
x
Concomitant 
medications g
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events h
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concurrent ocular
proceduresi
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
MacTSQ j
x
x
PPPQ j
x
Pregnancy test k
x
x
x
x
x
x
x
x
Urinalysis l
x
Hematology l
x


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Appendix 2
Schedule of Activities: Implant Arm, Year 1 and Year 2 (cont.)
Table 1: Schedule of Activities: Implant Arm, Year 1 (cont.)
Assessment
Screening a
Rand. b
Week 1
Week 
Visit
D1 b, c D2
D7
4
8
12
16
20
24
28
32
36
40
44
48
Visit window (days)
21 days from 
prior ITV Anti-
VEGF
2128 days from 
last ITV RBZ 
Tx
NA
2
7
Chemistry l
x
Coagulation l
x
Serum PK sample m
x
x
x
x
Serum PK sample (at selected 
sites) m
x
x
x
x
Serum ADA sample m
x
x
x
x
BCVA
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
IOP n
x
x
x o
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Slitlamp examination
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Dilated binocular indirect 
ophthalmoscopy p
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Historical images collection: OCT 
and FA q
x
SD-OCT r
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Fundus photography r
x
x
x
Fluorescein angiography r
x
x
x
Fundus autofluorescence r
x
x
x
Lens photo (fundus reflex 
photograph)
x
x
x
OCT-A (at selected sites) s
x
x
x
x
x
x
x
x


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46/Statistical Analysis Plan GR40548
Appendix 2
Schedule of Activities: Implant Arm, Year 1 and Year 2 (cont.)
Table 1: Schedule of Activities: Implant Arm, Year 1 (cont.)
Assessment
Screening a
Rand. b
Week 1
Week Visit
D1 b, c
D2
D7
4
8
12
16
20
24
28
32
36
40
44
48
Visit window 
(days)
21 days from prior 
ITV Anti-VEGF
2128 days from last 
ITV RBZ Tx
NA
2
7
Pre- and post-study 
treatment antimicrobials t
x
x
x
Intravitreal ranibizumab
0.5 mg injection u
x
Ranibizumab filled implant 
insertion v
x
Implant insertion and refill-
exchange video w
x
x
x
Post-implantation IOP 
measurement x
x
Implant insertion 
evaluation y
x
Implant photographs z
x
x
x
x
x
x
x
x
x
Implant refill-exchange aa
x
x
Post-treatment finger-
counting test bb
x ii
x
x
Supplemental ranibizumab 
(if supplemental treatment 
criteria are met) cc
x
x
x
x
Follow-up call dd
x ee
x
x
Whole blood sample
for genotyping (optional) ff
x


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd
47/Statistical Analysis Plan GR40548
Appendix 2
Schedule of Activities: Implant Arm, Year 1 and Year 2 (cont.)
Table 1: Schedule of Activities: Implant Arm, Year 1 (cont.)
Assessment
Screening a
Rand. b
Week 1
Week Visit
D1 b, c D2
D7
4
8
12
16
20
24
28
32
36
40
44
48
Visit window 
(days)
21 days from prior 
ITV Anti-VEGF
2128 days from last 
ITV RBZ Tx
NA
2
7
Aqueous humor sample 
for biomarkers and 
ranibizumab conc. 
(optional) gg
x
x
x
x
Serum and plasma 
samples for biomarkers (if 
aqueous humor sample 
collected) (optional) hh
x
x
x
x
Serum sample for PK (if 
aqueous humor sample 
collected) (optional) hh
x
x
ADAanti-drug antibody; anti-VEGFantivascular endothelial growth factor; BCVAbest-corrected visual acuity; conc. concentration; Dday; FAfluorescein 
angiography; FAFfundus autofluorescence; FPfundus photography; IOPintraocular pressure; ITVintravitreal; IxRSinteractive voice or web-based 
response system; MacTSQMacular Degeneration Treatment Satisfaction Questionnaire; NA not applicable; nAMDneovascular age-related macular 
degeneration; OCToptical coherence tomography; OCT-Aoptical coherence tomographyangiography; PDSPort Delivery System with ranibizumab; 
PKpharmacokinetics; PPPQPDS Patient Preference Questionnaire; Randrandomization; RBZranibizumab; SD-OCTspectral-domain optical coherence 
tomography; Txtreatment; VAvisual acuity. 
Notes:  All ocular assessments are to be performed for both eyes prior to study treatment unless noted otherwise.  All assessments for a visit are to be performed 
on the same day, except those at screening.
a Refer to Section 3.1 and Table 2 (Protocol v3) for patient eligibility scenario.
b Randomization and implant insertion surgery (Day 1) should be scheduled 2128 days (inclusive) from the last intravitreal ranibizumab treatment in the study eye. 
c Implant insertion surgery (Day 1) should occur within 17 days from randomization and no later than 28 days from the last intravitreal ranibizumab treatment in 
the study eye. 
d
Patients who participate in the run-in must sign the Informed Consent Form prior to performing protocol-mandated assessments.


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd
48/Statistical Analysis Plan GR40548
Appendix 2
Schedule of Activities: Implant Arm, Year 1 and Year 2 (cont.)
e
The IxRS will be contacted at Weeks 16, 20, 40, and 44 for supplemental treatment evaluation (for additional assessments if supplemental treatment criteria are 
met, see Appendix 5 of Protocol v3). 
f
Vital signs consist of blood pressure and pulse measurement while patient is in a seated position after resting for 5 minutes.  Vital signs will be measured pre-
treatment (as applicable).  On the day of implant insertion procedure (Day 1 visit), vital signs will be recorded before the surgery and only blood pressure will be 
recorded during surgery and after surgery.  
g
Record any concomitant medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) other 
than protocol-specified procedural medications, and pretreatment and post-treatment medications (e.g., proparacaine, antimicrobials, steroids) used by the 
patient within 7 days preceding the randomization visit date and through the conclusion of the patient’s study participation or early termination visit.
h
After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events related to a protocol-mandated intervention (e.g., 
procedures such as fluorescein angiography or medication interruption) should be reported.  Adverse events will be recorded starting on Day 1 through the last 
study visit.  Adverse events assessed by the qualified ophthalmologist as related to implant insertion, refill-exchange, and explantation should be followed until 
the event resolves or the event is assessed as irreversible, chronic, or stable, even if the patient’s participation in the study is over.
i
Record all concurrent ocular procedures or additional assessments performed on the study or fellow eye.  Results of the additional ocular assessments must be 
forwarded to the Sponsor for evaluation and/or storage.
j
Must be interviewer-administered by site personnel (other than VA examiner) prior to any other study procedures.  
k
Urine pregnancy test will be performed locally prior to fluorescein angiography and study treatment (if applicable) at screening and subsequent specified visits.  
If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  Do not perform fluorescein angiography or administer study treatment until 
the final results are available.  If the serum pregnancy test is positive, do not administer the study treatment.
l
Obtain from all study patients pre-treatment and prior to fluorescein angiography, if applicable.  Hematology includes hemoglobin, hematocrit, quantitative 
platelet count, RBCs, WBCs, and differentials, including neutrophils, bands, lymphocytes, basophils, eosinophils, and monocytes (absolute and percent).  
Chemistry includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, potassium, chloride, glucose, BUN, creatinine, 
calcium, phosphorus, total and direct bilirubin, total protein, albumin, AST, ALT, lactic dehydrogenase, ALP, and uric acid. Urinalysis includes specific gravity, 
pH, blood, protein, ketones, glucose, bilirubin, urobilinogen, and microscopic examination (if any of the preceding urinalysis tests, other than glucose and 
ketones, are abnormal).  Coagulation includes aPTT and PT. 
m Collect prior to implant refill-exchange and prior to fluorescein angiography (if applicable).  
n
Perform IOP measurement prior to dilating eyes or procedure; the method used for a patient must remain consistent throughout the study for visits in the office. 
When performed at implant refill-exchange visit, IOP needs to be measured prior to implant refill-exchange.
o
Should be performed in the surgical center using indentation tonometry (e.g. Tono-Pen) for the study eye only prior to the implant insertion surgery.
p
Upon completion of the implant insertion surgery, patients will have dilated indirect ophthalmoscopy performed to monitor the implant placement and to evaluate 
any potential implant problems (capturing the results of the indirect ophthalmoscopy findings on EDC is not needed at Day 1).  Dilated ophthalmoscopy 
examinations will also be performed in the study eye at Day 2 and Day 7 (2 days); afterward, perform dilated ophthalmoscopy examinations at each visit to 
monitor the implant placement and to evaluate other implant problems.
q
Historical OCT images taken around the time of diagnosis of nAMD (and before the start of anti-VEGF treatment) will be required to determine patient’s eligibility 
at the screening visit. FAs if taken around the time of diagnosis of nAMD (and before the start of anti-VEGF treatment) must be submitted to the reading center 
as well and will be evaluated, but are not required to determine patient’s eligibility. Refer to the reading center manuals for details.


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd
49/Statistical Analysis Plan GR40548
Appendix 2
Schedule of Activities: Implant Arm, Year 1 and Year 2 (cont.)
r
The central reading center will evaluate FP, FA, FAF and SD-OCT images taken at the screening visit for determination of a patient’s eligibility, together with the 
historical OCT images taken at the time of diagnosis of nAMD. Refer to the reading center manual for details.
s
Only at selected sites.  Perform pre-treatment.
t
The pre-implant insertion use of self-administered antimicrobials is required.  The pre-implant refill-exchange use of self-administered antimicrobials is per the 
investigator’s discretion.  The post-implant insertion or refill-exchange use of self-administered antimicrobials is required.  Anti-inflammatory drops post-implant 
insertion may be administered as well, per standard of care.
u
As required, depending on patient eligibility category.  Refer to Section 3.1 and Table 2 (Protocol v3) for patient eligibility scenario.
v
Initially fill the implant with IxRS-assigned kit of ranibizumab 100 mg/mL prior to its insertion into the study eye. 
w At sites that permit video recording. 
x
IOP will be checked for the study eye only by the treating physician by digital palpation as clinically indicated.  These assessments must be performed prior to 
placing a patch on the eye.  Patients will be allowed to leave the surgical center after the designated physician has assessed that there are no safety concerns.  
If any safety concerns or immediate toxicity are noted, the patient will remain at the surgical center and will be treated according to the designated physician’s 
clinical judgment.  If applicable, the adverse event will be reported.
y
Upon completion of the implant insertion procedure, complete the implant insertion evaluation to indicate surgical details of the insertion procedure.  Information 
captured in the evaluation will be reported.
z
In addition to the timepoints listed, the photographs will also be taken at any visit if there are concerns with implant function.
aa Refill the implant with IxRS-assigned kit of ranibizumab 100 mg/mL. 
bb Finger-counting test, followed by hand motion and light perception tests (when necessary) performed by the physician within 15 minutes post-treatment for the 
study eye only.  The patient will be allowed to leave the office after the designated physician has assessed that there are no safety concerns.  If any safety 
concerns or immediate toxicity are noted, the patient will remain at the office and will be treated according to the designated physician’s clinical judgment.  If 
applicable, the adverse event will be reported.
cc Implant arm patients are eligible for supplemental treatment with intravitreal ranibizumab 0.5 mg if the supplemental treatment criteria are met (Section 5.1.5.3 of 
Protocol v3).  Following supplemental treatment, patients will continue with implant refill-exchanges per protocol.
dd All study patients will be contacted 3 (1) days following study treatment to elicit reports of any decreases in vision, occurrence of eye pain, unusual redness, or 
any other new ocular symptoms.  Patients will also be asked whether they have taken the prescribed, self-administered, post-treatment antimicrobials.
ee If intravitreal ranibizumab 0.5 mg injection is given.
ff
If a patient has consented to this optional sample collection.
gg If a patient has consented to this optional sample collection. At implant refill-exchange visit, the aqueous humor sample should be obtained prior to or 
immediately after implant refill-exchange. 
hh If a patient has consented to this optional sample collection, obtain the sample prior to study treatment and prior to fluorescein angiography (if applicable).
ii
Only if patient receives intravitreal ranibizumab 0.5 mg injection.


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd
50/Statistical Analysis Plan GR40548
Appendix 2
Schedule of Activities: Implant Arm, Year 1 and Year 2 (cont.)
Table 2: Schedule of Activities:  Implant Arm, Year 2, Early Study Termination and Explantation Visits 
Assessment
Week Visit
Early Study 
Term. Visit y
Explant. 
Visit z
52
56
60
64
68
72
76
80
84
88
92
96 cc
Visit window (days)
7
Contact IxRS a
x
x
x
x
x
x
x
x
Vital signs b
x
x
x
Concomitant medications c
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events d
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concurrent ocular procedures e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
MacTSQ f
x
PPPQ f
x
Pregnancy test g
x
x
x
x
x
x
x
Serum PK sample h
x
x
Serum PK sample (at selected 
sites) h
x
Serum ADA sample h
x
x
BCVA
x
x
x
x
x
x
x
x
x
x
x
x
x
IOP i
x
x
x
x
x
x
x
x
x
x
x
x
x
x j
Slitlamp examination
x
x
x
x
x
x
x
x
x
x
x
x
x
Dilated binocular Indirect 
ophthalmoscopy k
x
x
x
x
x
x
x
x
x
x
x
x
x
x
SD-OCT l
x
x
x
x
x
x
x
x
x
x
x
x
x
Fundus photography l
x
x
Fluorescein angiography l
x
x
Fundus autofluorescence l
x
x


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd
51/Statistical Analysis Plan GR40548
Appendix 2
Schedule of Activities: Implant Arm, Year 1 and Year 2 (cont.)
Table 2: Schedule of Activities:  Implant Arm, Year 2, Early Study Termination and Explantation Visits (cont.)
Assessment
Week Visit
Early Study 
Term. Visit y
Explant. 
Visit z
52
56
60
64
68
72
76
80
84
88
92
96 cc
Visit window (days)
7
Lens photograph (fundus reflex 
photograph)
x
x
OCT-A (at selected sites) m
x
x
x
x
x
x
x
Pre-and post-study treatment 
antimicrobials n
x
x
Implant refill-exchange o
x
Post-treatment finger-counting test p
x
Implant explantation q
x
Implant refill-exchange and 
explantation video r
x
x
Implant photographs s
x
x
x
x
x
x
x
x aa
Supplemental ranibizumab (if 
supplemental treatment criteria are 
met) t
x
x
x
x
Aqueous humor sample for PD and 
ranibizumab conc. u
x
x bb
Plasma and serum samples for 
PD u
x
x bb
Follow-up call v
x
Aqueous humor sample for 
biomarkers and ranibizumab conc. 
(optional) w
x
x
x
x


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd
52/Statistical Analysis Plan GR40548
Appendix 2
Schedule of Activities: Implant Arm, Year 1 and Year 2 (cont.)
Table 2: Schedule of Activities:  Implant Arm, Year 2, Early Study Termination and Explantation Visits (cont.)
Assessment
Week Visit
Early Study 
Term. Visit y
Explant. 
Visit z
52
56
60
64
68
72
76
80
84
88
92
96 cc
Visit window (days)
7
Plasma and serum sample for 
biomarkers (if aqueous humor 
sample collected) (optional) x
x
x
x
x
Serum sample for PK (if 
aqueous humor sample 
collected) (optional) x
x
x
x
ADAanti-drug antibody; BCVAbest-corrected visual acuity; conc. concentration; Explant.explantation; IOPintraocular pressure; IxRSinteractive voice or 
web-based response system; MacTSQMacular Degeneration Treatment Satisfaction Questionnaire; OCT-Aoptical coherence tomographyangiography; 
PDpharmacodynamic; PKpharmacokinetics; PDSPort Delivery System with ranibizumab; PPPQPDS Patient Preference Questionnaire; SD-OCTspectral-
domain optical coherence tomography; Term. termination; VAvisual acuity.
Notes:  All ocular assessments are to be performed for both eyes prior to study treatment unless noted otherwise.  All assessments for a visit are to be performed 
on the same day, except those at screening.
a
The IxRS will be contacted at Weeks 64, 68, 88, and 92 for supplemental treatment evaluation (for additional assessments if supplemental treatment criteria are 
met, see Appendix 5 of Protocol v3).
b
Vital signs consist of blood pressure and pulse measurement while patient is in a seated position after resting for 5 minutes.  If implant explantation is required, 
vital signs will be recorded before the surgery and only blood pressure will be recorded during surgery and after surgery. 
c
Record any concomitant medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) other 
than protocol-specified procedural medications, and pretreatment and post-treatment medications (such as proparacaine, antimicrobials, steriods) used by the 
patient within 7 days preceding the randomization visit date and through the conclusion of the patient’s study participation or early termination visit.
d
Adverse events will be recorded starting on Day 1 through the last study visit.  Adverse events assessed by the qualified ophthalmologist as related to implant 
refill-exchange, and explantation should be followed until the event resolves or the event is assessed as irreversible, chronic, or stable, even if the patient’s 
participation in the study is over.
e
Record all concurrent ocular procedures or additional assessments performed on the study or fellow eye.  Results of the additional ocular assessments must be 
forwarded to the Sponsor for evaluation and/or storage.
f
Must be interviewer-administered by site personnel (other than VA examiner) prior to any other study procedures.  
g
Urine pregnancy test will be performed locally prior to fluorescein angiography and study treatment (if applicable) at specified subsequent visits.  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test.  Do not perform fluorescein angiography or administer the study treatment until the 
final results are available.  If the serum pregnancy test is positive, do not administer the study treatment.
h
Collect sample prior to implant refill-exchange, and/or fluorescein angiography (if applicable). 


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd
53/Statistical Analysis Plan GR40548
Appendix 2
Schedule of Activities: Implant Arm, Year 1 and Year 2(cont.)
i
Perform IOP measurement prior to dilating eyes or procedure; the method used for a patient must remain consistent throughout the study for visits in the office. 
When performed at implant refill-exchange visit, IOP needs to be measured prior to implant refill-exchange.
j
Should be performed in the surgical center using indentation tonometry (e.g. Tono-Pen) prior to the implant explantation surgery.
k
Dilated ophthalmoscopy examinations will be performed at each visit to monitor the implant for any potential implant problems.  Upon completion of the 
explantation procedure, patients will also have indirect ophthalmoscopy of the study eye.
l
Refer to the reading center manual for details.
m Only at selected sites.  Perform pre-treatment.
n
The pre-implant refill-exchange use of self-administered antimicrobials is per the investigator's discretion.  The pre-explantation use of self-administered 
antimicrobials is required.  The post-implant refill-exchange or explantation use of self-administered antimicrobials is required.  Anti-inflammatory drops post-
implant explantation may administered as well, per standard of care.
o
Refill the implant with IxRS-assigned kit of ranibizumab 100 mg/mL.
p
Finger-counting test, followed by hand motion and light perception tests (when necessary) performed by the physician within 15 minutes post-treatment for the 
study eye only.  The patient will be allowed to leave the office after the designated physician has assessed that there are no safety concerns.  If any safety 
concerns or immediate toxicity are noted, the patient will remain at the office and will be treated according to the designated physician’s clinical judgment.  If 
applicable, the adverse event will be reported.
q
IOP will be checked after explantation for the study eye only by the treating physician by digital palpation as clinically indicated.  These assessments must be 
performed prior to placing a patch on the eye.  Patients will be allowed to leave the surgical center after the designated physician has assessed that there are no 
safety concerns.  If any safety concerns or immediate toxicity are noted, the patient will remain at the surgical center and will be treated according to the 
designated physician’s clinical judgment.  If applicable, the adverse event will be reported.
r
For sites that permit video recording.
s
In addition to the timepoints listed, the photograph will also be taken at any visit if there are concerns with Implant function.
t
Implant arm patients are eligible for supplemental treatment with intravitreal ranibizumab 0.5 mg if supplemental treatment criteria are met (see Section 5.1.5.3 of 
Protocol v3).  Following supplemental treatment, patients will continue with implant refill-exchanges per protocol.
u
At the explantation visit, collect aqueous sample prior or immediately after explantation. At the early study termination visit, plasma/serum samples should be 
obtained prior to fluorescein angiography.  
v
All study patients will be contacted 3 (1) days following study treatment to elicit reports of any decreases in vision, occurrence of eye pain, unusual redness, or 
any other new ocular symptoms.  Patients will also be asked whether they have taken the prescribed, self-administered, post-treatment antimicrobials.
w If a patient has consented to this optional sample collection. At implant refill-exchange visit, the sample should be obtained prior to or immediately after implant 
refill-exchange. 
x
If a patient has consented to this optional sample collection, obtain the sample prior to study treatment and prior to fluorescein angiography (if applicable).
y
Patients will be scheduled for an early termination evaluation visit 90 (7) days after the implant insertion procedure or 30 (7) days following the last implant 
refill-exchange for monitoring of all adverse events (serious and non-serious).
z
Patients will be scheduled for safety visits at 1, 7 (2), 30 (7), and 60 (7) days post-explantation (refer to Appendix 4 [Protocol v3] for visit assessments).
aa Implant photographs can be taken either the day of the explantation surgery (if possible) or within days leading to the explantation surgery.
bb Samples can be taken either the day of the explantation surgery (if possible) or within days leading to the explantation surgery. Aqueous humor, 
plasma, and serum samples for biomarkers should all be taken at the same visit.
cc If a patient is unable to complete Archway at Week 96 and enroll in Portal on the same day, follow the alternate schedule of activities in Protocol 
Appendix 1, Table 3.


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd
54/Statistical Analysis Plan GR40548
Appendix 3
Schedule of Activities: Intravitreal Arm
Table 1: Schedule of Activities: Intravitreal Arm, Year 1
Assessment
Screening a
Rand. b
D1 c
Week Visit
4
8
12
16
20
24
28
32
36
40
44
48
Visit window (days)
21 days from prior 
ITV Anti-VEGF Tx
2127 days from 
last ITV RBZ Tx
NA
7
Informed consent
x d
Review of inclusion and 
exclusion criteria
x
Medical and surgical history
x
Demographic data
x
Height and Weight
x
Contact IxRS
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital signs e
x
x
Concomitant medications f
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse event g
x
x
x
x
x
x
x
x
x
x
x
x
x
Concurrent ocular procedures h
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
MacTSQ i
x
x
Pregnancy test j
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urinalysis k
x
Hematology k
x
Chemistry k
x
Coagulation k
x
Serum PK sample l
x
x
x
x


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd
55/Statistical Analysis Plan GR40548
Appendix 3
Schedule of Activities: Intravitreal Arm (cont.)
Table 1: Schedule of Activities: Intravitreal Arm, Year 1 (cont.)
Assessment
Screening a
Rand. b
D1 c
Week Visit
4
8
12
16
20
24
28
32
36
40
44
48
Visit window (days)
21 days from 
prior ITV
Anti-VEGF Tx
2127 days from 
last ITV RBZ Tx
NA
7
Serum ADA sample l
x
x
x
x
BCVA
x
x
x
x
x
x
x
x
x
x
x
x
x
x
IOP m
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Slitlamp examination
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Dilated binocular Indirect 
ophthalmoscopy
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Historical images collection: OCT 
and FA n
x
SD-OCT o
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Fundus photography o
x
x
x
Fluorescein angiography o
x
x
x
Fundus autofluorescence o
x
x
x
Lens photograph (fundus reflex 
photograph)
x
x
x
OCT-A (at selected sites only) p
x
x
x
x
x
x
x
Optional pre- and post-study 
treatment antimicrobials
x
x
x
x
x
x
x
x
x
x
x
x
x
Administration of study treatment 
(0.5 mg intravitreal RBZ)
x q
x
x
x
x
x
x
x
x
x
x
x
x
x


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd
56/Statistical Analysis Plan GR40548
Appendix 3
Schedule of Activities: Intravitreal Arm (cont.)
Table 1: Schedule of Activities: Intravitreal Arm, Year 1 (cont.)
Assessment
Screening a
Rand. b
D1 c
Week Visit
4
8
12
16
20
24
28
32
36
40
44
48
Visit window (days)
21 days from prior 
ITV Anti-VEGF Tx
2127 days from 
last ITV RBZ Tx
NA
7
Post-treatment finger-counting 
test r
x s
x
x
x
x
x
x
x
x
x
x
x
x
x
Follow-up call t
x u
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum sample for PK (at 
selected sites) v
Collect serum PK sample 1-5 days post intravitreal ranibizumab injection 
(collect only once per patient)
Whole blood sample for 
genotyping (optional) w
x
Aqueous humor sample for 
biomarkers and ranibizumab 
conc. (optional) w
x
x
x
x
Plasma and serum samples for 
biomarkers (if aqueous humor 
sample collected) (optional) x
x
x
x
x
Serum sample for PK (if 
aqueous humor sample 
collected) (optional) x
x
x
ADAanti-drug antibody; anti-VEGFantivascular endothelial growth factor; BCVAbest-corrected visual acuity; conc. concentration; Dday; FAfluorescein 
angiography; FAFfundus autofluorescence; FPfundus photography; IOPintraocular pressure; ITVintravitreal; IxRSinteractive voice or web-based 
response system; MacTSQMacular Degeneration Treatment Satisfaction Questionnaire; NA not applicable; nAMDneovascular age-related macular 
degeneration; OCToptical coherence tomography; OCT-Aoptical coherence tomographyangiography; PKpharmacokinetic; Rand.randomization; 
RBZranibizumab; SD-OCTspectral-domain optical coherence tomography; Txtreatment; VAvisual acuity.
Notes:  All ocular assessments are to be performed for both eyes prior to study treatment unless noted otherwise.  All assessments for a visit are to be performed 
on the same day, except those at screening.
a Refer to Section 3.1 and Table 2 (see Protocol v3) for patient eligibility scenario.
b
Randomization should occur no later than 27 days from the last intravitreal ranibizumab treatment in the study eye. 


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd
57/Statistical Analysis Plan GR40548
Appendix 3
Schedule of Activities: Intravitreal Arm (cont.)
c
Day 1 study treatment visit should occur on the same day as randomization visit.
d
Patients who participate in the run-in must sign the Informed Consent Form prior to performing protocol-mandated assessments.
e
Vital signs consist of blood pressure and pulse measurement while patient is in a seated position after resting for 5 minutes.  Vital signs will be measured pre-
treatment (as applicable).
f
Record any concomitant medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) other 
than protocol-specified procedural medications, and pre-treatment and post-treatment medications (such as proparacaine, antimicrobials, steroids) used by the 
patient within 7 days preceding the randomization visit date and through the conclusion of the patient’s study participation or early termination visit.
g
After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events related to a protocol-mandated intervention (e.g., 
procedures such as fluorescein angiography or medication interruption) should be reported.  Adverse events will be recorded starting on Day 1 through the last 
study visit.  
h
Record all concurrent ocular procedures or additional assessments performed on the study or fellow eye.  Results of the additional ocular assessments must be 
forwarded to the Sponsor for evaluation and/or storage.
i
Must be interviewer-administered by site personnel (other than VA examiner) prior to any other study procedures. 
j
Urine pregnancy test will be performed locally prior to fluorescein angiography and each study treatment (if applicable) at specified subsequent visits.  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test.  Do not perform fluorescein angiography or administer the study treatment until the 
final results are available.  If the serum pregnancy test is positive, do not administer the study treatment.
k
Obtain from all study patients pre-treatment and prior to fluorescein angiography, if applicable.  For a description of the laboratory assessments to be performed 
see Section 4.5.7 (see Protocol v3) or the laboratory manual.
l
Collect prior to study treatment and prior to fluorescein angiography (if applicable).
m Perform IOP measurement prior to dilating eyes or study treatment; the method used for a patient must remain consistent throughout the study.
n
Historical OCT images taken around the time of diagnosis of nAMD (and before the start of anti-VEGF treatment) will be required to determine patient’s eligibility 
at the screening visit.  FAs if taken around the time of diagnosis of nAMD (and before the start of anti-VEGF treatment) must be submitted to the reading center 
as well and will be evaluated, but are not required to determine patient’s eligibility.  Refer to the reading center manuals for details.
o
The central reading center will evaluate FP, FA, FAF and SD-OCT images taken at the screening visit for determination of a patient’s eligibility, together with the 
historical OCT images taken at the time of diagnosis of nAMD.  Refer to the reading center manual for details.
p
Only at selected sites.  Perform pre-treatment. 
q
As required, depending on patient eligibility category.  Refer to Section 3.1 and Table 2 (see Protocol v3) for patient eligibility scenario.
r
Finger-counting test, followed by hand motion and light perception tests (when necessary) performed by the physician within 15 minutes post-treatment for the 
study eye.  Patients will be allowed to leave the office after the designated physician has assessed that there are no safety concerns.  If any safety concerns or 
immediate toxicity are noted, the patient will remain at the office and will be treated according to the designated physician’s clinical judgment.  If applicable, the 
adverse event will be reported.
s
Only if patient receives intravitreal ranibizumab 0.5 mg injection.
t
All study patients will be contacted 3 (1) days following study treatment to elicit reports of any decreases in vision, occurrence of eye pain, unusual redness, or 
any other new ocular symptoms.
u
If treatment is given.
v
One time serum PK collection only. Sample will be collected from patients in the intravitreal arm 1-5 days after an intravitreal ranibizumab 0.5 mg 
injection once per patient during the study (selected study visit will be at the discretion of the investigator and site). This sample collection may be 
performed at the study site or by a trained mobile nursing professional at the patient’s home or another suitable location.
w
If a patient has consented to this optional sample collection.
x
If a patient has consented to this optional sample collection, obtain the sample prior to study treatment and prior to fluorescein angiography (if applicable).


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd
58/Statistical Analysis Plan GR40548
Appendix 3
Schedule of Activities: Intravitreal Arm (cont.)
Table 2: Schedule of Activities: Intravitreal Arm, Year 2 and Early Study Termination Visit 
Assessment
Week Visit
Early Study 
Term Visit
a
52
56
60
64
68
72
76
80
84
88
92
96 r
Visit window (days)
7
Contact IxRS
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital signs 
b
x
x
Concomitant medications 
c
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events 
d
x
x
x
x
x
x
x
x
x
x
x
x
x
Concurrent ocular procedures 
e
x
x
x
x
x
x
x
x
x
x
x
x
x
MacTSQ 
f
x
Pregnancy test 
g
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum PK sample 
h
x
x
Serum ADA sample 
h
x
x
BCVA
x
x
x
x
x
x
x
x
x
x
x
x
x
IOP 
i
x
x
x
x
x
x
x
x
x
x
x
x
x
Slitlamp examination
x
x
x
x
x
x
x
x
x
x
x
x
x
Dilated binocular indirect ophthalm
oscopy
x
x
x
x
x
x
x
x
x
x
x
x
x
SD-OCT 
j
x
x
x
x
x
x
x
x
x
x
x
x
x
Fundus photography 
j
x
x
Fluorescein angiography 
j
x
x
Fundus autofluorescence 
j
x
x
Lens 
photograph (fundus reflex photograph)
x
x
OCT-A (at selected sites) 
k
x
x
x
x
x
x
x


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd
59/Statistical Analysis Plan GR40548
Appendix 3
Schedule of Activities: Intravitreal Arm (cont.)
Table 2: Schedule of Activities: Intravitreal Arm, Year 2 and Early Study Termination Visit (cont.)
Assessment
Week Visit
Early Study 
Term Visit a
52
56
60
64
68
72
76
80
84
88
92
96 r
Visit window (days)
7
Optional pre- and post-study 
treatment antimicrobials
x
x
x
x
x
x
x
x
x
x
x
Administration of study 
treatment (intravitreal 
ranibizumab 0.5 mg)
x
x
x
x
x
x
x
x
x
x
x
Post-treatment finger-counting 
test l
x
x
x
x
x
x
x
x
x
x
x
Aqueous humor sample for 
biomarkers and ranibizumab 
concentration
x
Plasma and serum samples for 
biomarkers m
x
Follow-up call n
x
x
x
x
x
x
x
x
x
x
x
Serum sample for PK (at 
selected sites) o
Collect serum PK sample 1-5 days post intravitreal ranibizumab injection (collect only once 
per patient)
Aqueous humor sample for 
biomarkers and ranibizumab 
conc. (optional) p
x
x
x
x q
Plasma and serum samples for 
biomarkers (if aqueous humor 
sample collected) (optional) p
x
x
x
x q
Serum sample for PK (if 
aqueous humor sample 
collected) (optional) p
x
x
x


Port Delivery System with Ranibizumab—F. Hoffmann-La Roche Ltd
60/Statistical Analysis Plan GR40548
Appendix 3
Schedule of Activities: Intravitreal Arm (cont.)
ADAanti-drug antibody; BCVAbest-corrected visual acuity; conc. concentration; IOPintraocular pressure; IxRSinteractive voice or web-based response 
system; MacTSQMacular Degeneration Treatment Satisfaction Questionnaire; OCT-Aoptical coherence tomographyangiography; PKpharmacokinetics; 
SD-OCT spectral-domain optical coherence tomography; Term.termination; VAvisual acuity.
Notes:  All ocular assessments are to be performed for both eyes prior to study treatment unless noted otherwise.  All assessments for a visit are to be performed 
on the same day, except those at screening.
a Patients will be scheduled for an early termination evaluation 30 (7) days following the last study drug treatment for monitoring of all adverse events (serious 
and non-serious). 
b
Vital signs consist of blood pressure and pulse measurement while patient is in a seated position after resting for 5 minutes. 
c
Record any concomitant medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) other 
than protocol-specified procedural medications, and pre-treatment and post-treatment medications (such as proparacaine, antimicrobials, steroids) used by the 
patient within 7 days preceding the randomization visit date and through the conclusion of the patient’s study participation or early termination visit.
d
Adverse events will be recorded starting on Day 1 through the last study visit.
e
Record all concurrent ocular procedures or additional assessments performed on the study or fellow eye.  Results of the additional ocular assessments must be 
forwarded to the Sponsor for evaluation and/or storage.
f
Must be interviewer-administered by site personnel (other than VA examiner) prior to any other study procedures. 
g
Urine pregnancy test will be performed locally prior to fluorescein angiography and study treatment (if applicable) at specified subsequent visits.  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test.  Do not perform fluorescein angiography or administer the study treatment until the 
final results are available.  If the serum pregnancy test is positive, do not administer the study treatment.
h
Collect prior to study treatment and prior to fluorescein angiography (if applicable).
i
Perform IOP measurement prior to dilating eyes or study treatment; the method used for a patient must remain consistent throughout the study. 
j
Refer to the reading center manual for details.
k
Only at selected sites. Perform pre-treatment.
l
Finger-counting test, followed by hand motion and light perception tests (when necessary) should be performed by the physician within 15 minutes post-
treatment for the study eye only.  Patients will be allowed to leave the office after the designated physician has assessed that there are no safety concerns.  If 
any safety concerns or immediate toxicity are noted, the patient will remain at the office and will be treated according to the designated physician’s clinical 
judgment.  If applicable, the adverse event will be reported. 
m Samples should be obtained prior to fluorescein angiography.
n
All study patients will be contacted 3 (1) days following study treatment to elicit reports of any decreases in vision, occurrence of eye pain, unusual redness, or 
any other new ocular symptoms.
o
One time serum PK collection only. Sample will be collected from patients in the intravitreal arm 1-5 days after an intravitreal ranibizumab 0.5 mg 
injection once per patient during the study (selected study visit will be at the discretion of the investigator and site).This sample collection may be 
performed at the study site or by a trained mobile nursing professional at the patient’s home or another suitable location.
p If a patient has consented to this optional sample collection. For plasma/serum samples, obtain the sample prior to study treatment and prior to 
fluorescein angiography (if applicable).
q Only collect if the patient is not enrolling in Portal.
r If a patient is unable to complete Archway at Week 96 and enroll in Portal on the same day, follow the alternate schedule of activities in Protocol Appendix 2 
Table 3.