Conditions: Macular Degeneration
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 225
Healthy volunteers: no

Brief summary:
This is a Phase II multicenter, dose-ranging, randomized, active treatment (monthly ITV injection)-controlled study to evaluate the efficacy, safety, and pharmacokinetics of ranibizumab delivered through the Implant using three ranibizumab formulation arms (10 mg/mL, 40 mg/mL, and 100 mg/mL) compared with the control arm (0.5-mg monthly ITV injections of 10-mg/mL formulation) in participants with subfoveal neovascular age-related macular degeneration (nAMD).

Detailed description:

Arms:
arm 1: Participants had the Implant (prefilled with approximately 20 μL of 10-mg/mL ,approximately 0.2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 10-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria. arm 2: Participants had the Implant (prefilled with approximately 20 μL of 40-mg/mL, approximately 0.8 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 40-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria. arm 3: Participants had the Implant (prefilled with approximately 20 μL of 100-mg/mL, approximately 2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 100-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria. arm 4: Participants received ranibizumab 0.5 mg monthly ITV injections of 10 mg/mL formulation at Day 1 and every month thereafter.

Interventions: intervention 1: Ranibizumab
Intervention descriptions: intervention 1: Ranibizumab will be administered at dose of 0.5 mg monthly ITV injections of 10-mg/mL formulation or delivered through the implant with three different formulations.

Protocol document:
Prot_000.pdf: 
 
Official Title: 
A Phase II, Multicenter, Randomized, Active Treatment-Controlled 
Study of the Efficacy and Safety of the Ranibizumab Port Delivery 
System for Sustained Delivery of Ranibizumab in Patients With 
Subfoveal Neovascular Age-Related Macular Degeneration 
NCT Number: 
NCT02510794 
Document Date: 
Protocol Version 8: 07-February-2018 
 
 


 
PROTOCOL AMENDMENT APPROVAL 
 
CONFIDENTIAL 
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an 
investigator, potential investigator, or consultant, for review by you, your staff, and an applicable 
Ethics Committee or Institutional Review Board.  It is understood that this information will not be 
disclosed to others without written authorization from Genentech except to the extent necessary 
to obtain informed consent from persons to whom the drug may be administered. 
 
Ranibizumab Port Delivery System—Genentech, Inc. 
Protocol GX28228, Version 8 
PROTOCOL  
TITLE: 
A PHASE II, MULTICENTER, RANDOMIZED, ACTIVE 
TREATMENT−CONTROLLED STUDY OF THE EFFICACY AND 
SAFETY OF THE RANIBIZUMAB PORT DELIVERY SYSTEM FOR 
SUSTAINED DELIVERY OF RANIBIZUMAB IN PATIENTS WITH 
SUBFOVEAL NEOVASCULAR AGE-RELATED MACULAR 
DEGENERATION 
PROTOCOL NUMBER: GX28228 
VERSION NUMBER: 
8 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
113,552 
TEST PRODUCT: 
Ranibizumab Port Delivery System for Sustained 
Delivery of Ranibizumab (RO4893594)  
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
Version 1:  02 January 2015 
DATES AMENDED: 
Version 2:  03 April 2015 
Version 3:  13 July 2015 
Version 4:  08 December 2015 
Version 5:  18 February 2016 
Version 6:  30 August 2016 
Version 7:  04 May 2017 
Version 8:  See electronic date stamp below. 
 
07-Feb-2018 05:07:28
Title
Approver's Name
Company Signatory
Date and Time (UTC)


 
Ranibizumab Port Delivery System—Genentech, Inc. 
2/Protocol GX28228, Version 8 
PROTOCOL AMENDMENT, VERSION 8: 
RATIONALE 
Protocol GX28228, Version 8 has been amended primarily to reflect the extension of 
study duration for patients in the intravitreal ranibizumab control arm.  Changes to the 
protocol, along with a rationale for each change, are summarized below. 
• 
Study duration for patients in the intravitreal ranibizumab control arm has been 
extended by approximately 4 months to align with the other treatment arms and to 
allow for continued monthly evaluation and study treatment until the Sponsor 
decides, based on the primary analysis results, to either terminate the study and 
discontinue study treatment, or offer patients entry into the Ranibizumab Port 
Delivery System (RPDS) Extension Study.  Primary analysis data is expected to be 
available approximately 4 months after the Month 9 visit of the last patient randomly 
assigned in the study.  The study duration extension for this control arm aligns the 
duration of patient participation for all study treatment arms at approximately 
13−38 months ,dependent on the date of the patient's randomization to the study 
(Sections 3.1 and 4.6.10.5, Figure 2, and Table 3). 
• 
"RPDS Extended Use Life Study" has been replaced with "RPDS Extension Study" 
(Sections 3.1, 3.2, 4.4.2, and 4.6.10.5, and Appendix 1). 
• 
The Secondary Medical Monitor information has been updated (Section 5.4.1). 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


 
Ranibizumab Port Delivery System—Genentech, Inc. 
3/Protocol GX28228, Version 8 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11 
PROTOCOL SYNOPSIS .................................................................................... 12 
1. 
BACKGROUND .......................................................................................... 23 
1.1 
Background on Age-Related Macular 
Degeneration ......................................................................... 23 
1.1.1 
Pathophysiology of Age-Related Macular 
Degeneration ......................................................................... 23 
1.1.2 
Treatment for Age-Related Macular 
Degeneration ......................................................................... 24 
1.2 
Background on Ranibizumab ................................................. 24 
1.3 
Background on the Ranibizumab Port 
Delivery System ..................................................................... 25 
1.4 
Study Rationale and Benefit-Risk Assessment ...................... 30 
2. 
STUDY OBJECTIVES ................................................................................. 31 
2.1 
Efficacy Objectives ................................................................ 31 
2.2 
Safety Objectives ................................................................... 32 
2.3 
Pharmacokinetic Objectives .................................................. 32 
2.4 
Exploratory Objectives ........................................................... 32 
3. 
STUDY DESIGN ......................................................................................... 33 
3.1 
Description of Study .............................................................. 33 
3.1.1 
Refill/Re-Treatment Criteria ................................................... 40 
3.1.2 
Pharmacokinetic Evaluation .................................................. 41 
3.1.3 
Planned Total Sample Size ................................................... 41 
3.1.4 
Internal Monitoring Committee ............................................... 42 
3.2 
Length of Study ..................................................................... 42 
3.3 
End of Study .......................................................................... 42 
3.4 
Rationale for Study Design .................................................... 42 
3.4.1 
Rationale for Ranibizumab Dose Selection ........................... 42 
3.4.2 
Rationale for Pharmacokinetic Evaluation 
Schedule ................................................................................ 43 
3.4.3 
Rationale for Patient Population ............................................ 43 
3.4.4 
Rationale for Control Group ................................................... 43 


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3.5 
Outcome Measures ............................................................... 43 
3.5.1 
Primary Efficacy Outcome Measure ...................................... 43 
3.5.2 
Secondary Efficacy Outcome Measures ................................ 44 
3.5.3 
Safety Outcome Measures .................................................... 44 
3.5.4 
Pharmacokinetic Outcome Measures .................................... 44 
3.5.5 
Exploratory Outcome Measures ............................................ 44 
4. 
MATERIALS AND METHODS .................................................................... 45 
4.1 
Patients .................................................................................. 45 
4.1.1 
Inclusion Criteria .................................................................... 46 
4.1.2 
Exclusion Criteria ................................................................... 49 
4.2 
Method of Treatment Assignment and Masking .................... 52 
4.2.1 
Randomization and Masking ................................................. 52 
4.2.2 
Unmasking Procedure ........................................................... 53 
4.3 
Study Treatment .................................................................... 53 
4.3.1 
Formulation, Packaging, and Handling .................................. 53 
4.3.1.1 
Ranibizumab Port Delivery System ....................................... 53 
4.3.1.2 
Formulation of Ranibizumab Used to Fill/Refill 
the Implant ............................................................................. 53 
4.3.1.3 
Formulation of Ranibizumab Used in ITV 
Injection Control Arm ............................................................. 54 
4.3.1.4 
Formulation of Open-Label Ranibizumab .............................. 54 
4.3.2 
Dosage, Administration, and Compliance .............................. 54 
4.3.2.1 
Implant ................................................................................... 54 
4.3.2.2 
Dosage .................................................................................. 54 
4.3.2.3 
Administration ........................................................................ 56 
4.3.2.4 
Storage .................................................................................. 57 
4.4 
Product Quality Assessments ................................................ 58 
4.4.1 
Ranibizumab in Contents Retrieval from Implant ................... 58 
4.4.1.1 
Explanted Implants with Contents ......................................... 58 
4.4.1.2 
Ancillary Devices ................................................................... 59 
4.4.2 
Continued Access to RPDS ................................................... 59 
4.5 
Concomitant Therapy ............................................................ 59 
4.5.1 
Permitted Therapy ................................................................. 59 


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4.5.2 
Prohibited Therapy ................................................................ 60 
4.6 
Study Assessments ............................................................... 61 
4.6.1 
Medical History, Concomitant Medication, and 
Demographic Data ................................................................. 61 
4.6.2 
Vital Signs .............................................................................. 61 
4.6.3 
Physical Examinations ........................................................... 61 
4.6.4 
Ocular Assessments .............................................................. 62 
4.6.5 
Ocular Imaging ...................................................................... 63 
4.6.6 
Laboratory Assessments ....................................................... 64 
4.6.7 
Patient-Reported Outcome .................................................... 66 
4.6.8 
Video Capturing of Implant Insertion, Refill, and 
Explantation Procedures ........................................................ 66 
4.6.9 
Exploratory Substudies .......................................................... 66 
4.6.10 
Timing of Study Assessments ............................................... 66 
4.6.10.1 
Screening and Pretreatment Assessments ............................ 66 
4.6.10.2 
Assessments during Treatment ............................................. 68 
4.6.10.3 
Assessments at Early Study Treatment 
Discontinuation ...................................................................... 68 
4.6.10.4 
Assessments at Early Study Discontinuation ......................... 69 
4.6.10.5 
Assessment at Study Completion .......................................... 69 
4.6.10.6 
Follow-Up Assessments ........................................................ 70 
4.6.10.7 
Assessments at Unscheduled Visits ...................................... 70 
4.6.11 
Refill Needle Sample Collection ............................................ 70 
4.6.12 
Samples for Roche Clinical Repository.................................. 70 
4.6.12.1 
Overview of the Roche Clinical Repository ............................ 70 
4.6.12.2 
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 70 
4.6.12.3 
Sample Collection .................................................................. 71 
4.6.12.4 
Confidentiality ........................................................................ 71 
4.6.12.5 
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 72 
4.6.12.6 
Withdrawal from the Roche Clinical Repository ..................... 72 
4.6.12.7 
Monitoring and Oversight ....................................................... 73 
4.7 
Patient, Treatment, Study, and Site 
Discontinuation ...................................................................... 73 


Ranibizumab Port Delivery System—Genentech, Inc. 
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4.7.1 
Patient Discontinuation .......................................................... 73 
4.7.2 
Early Study Treatment Discontinuation ................................. 73 
4.7.3 
Early Withdrawal from Study ................................................. 74 
4.7.4 
Study and Site Discontinuation .............................................. 75 
5. 
ASSESSMENT OF SAFETY ....................................................................... 75 
5.1 
Safety Plan ............................................................................ 75 
5.1.1 
Management of Specific Adverse Events .............................. 78 
5.1.1.1 
Dosing Interruption/Study Treatment or Study 
Discontinuation Criteria.......................................................... 78 
5.1.1.2 
Rescue Treatment with Open-Label Ranibizumab 
For Implant Patients .............................................................. 80 
5.1.1.3 
Management of Patients Who Meet Lack of 
Clinical Efficacy Criteria ......................................................... 80 
5.1.1.4 
Recommended Management of Cases of 
Vitreous Hemorrhage ............................................................ 82 
5.1.1.5 
Implant Clogging Assessment ............................................... 83 
5.2 
Safety Parameters and Definitions ........................................ 83 
5.2.1 
Adverse Events ..................................................................... 83 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ...................................................................... 84 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 85 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 86 
5.3.1 
Adverse Event Reporting Period ........................................... 86 
5.3.2 
Eliciting Adverse Event Information ....................................... 87 
5.3.3 
Assessment of Severity of Adverse Events ........................... 87 
5.3.4 
Assessment of Causality of Adverse Events ......................... 87 
5.3.5 
Procedures for Recording Adverse Events ............................ 88 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 89 
5.3.5.2 
Adverse Events That Are Secondary to Other 
Events .................................................................................... 89 
5.3.5.3 
Persistent or Recurrent Adverse Events ................................ 89 
5.3.5.4 
Abnormal Laboratory Values ................................................. 90 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 91 


Ranibizumab Port Delivery System—Genentech, Inc. 
7/Protocol GX28228, Version 8 
5.3.5.6 
Abnormal Liver Function Tests .............................................. 91 
5.3.5.7 
Deaths ................................................................................... 91 
5.3.5.8 
Preexisting Medical Conditions .............................................. 92 
5.3.5.9 
Worsening of Neovascular Age-Related Macular 
Degeneration in Study Eye .................................................... 92 
5.3.5.10 
Hospitalization or Prolonged Hospitalization .......................... 92 
5.3.5.11 
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 92 
5.3.5.12 
Patient-Reported Outcome Data ........................................... 93 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .......................................................... 93 
5.4.1 
Emergency Medical Contacts ................................................ 94 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious and Serious Adverse 
Events of Special Interest ...................................................... 94 
5.4.2.1 
Events That Occur Prior to Initiation of Study 
Drug (Day 1) .......................................................................... 94 
5.4.2.2 
Events That Occur After Study Drug Initiation ....................... 94 
5.4.3 
Reporting Requirements for Pregnancies .............................. 95 
5.4.3.1 
Pregnancies in Female Patients ............................................ 95 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................. 95 
5.4.3.3 
Abortions ............................................................................... 96 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 96 
5.4.4 
Reporting Requirements for Medical Device 
Complaints ............................................................................. 96 
5.4.4.1 
Device Defects or Deficiencies that Could Have 
Led to Medical Occurrence .................................................... 96 
5.5 
Follow-Up of Patients after Adverse Events .......................... 97 
5.5.1 
Investigator Follow-Up ........................................................... 97 
5.5.2 
Sponsor Follow-Up ................................................................ 97 
5.6 
Post-Study Adverse Events ................................................... 97 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ................................................................. 98 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 98 
6.1 
Determination of Sample Size ............................................... 98 


Ranibizumab Port Delivery System—Genentech, Inc. 
8/Protocol GX28228, Version 8 
6.2 
Summaries of Conduct of Study ............................................ 99 
6.3 
Summaries of Treatment Group Comparability ..................... 99 
6.4 
Efficacy Analyses .................................................................. 99 
6.4.1 
Primary Efficacy Analysis ...................................................... 99 
6.4.2 
Secondary Efficacy Analysis ................................................ 100 
6.5 
Safety Analyses ................................................................... 101 
6.5.1 
Adverse Events ................................................................... 101 
6.5.2 
Deaths ................................................................................. 102 
6.5.3 
Laboratory Tests .................................................................. 102 
6.5.4 
Vital Signs ............................................................................ 102 
6.5.5 
Ocular Assessments ............................................................ 102 
6.6 
Pharmacokinetic Analyses ................................................... 102 
6.7 
Patient-Reported Outcome Analyses .................................. 102 
6.8 
Exploratory Analyses ........................................................... 103 
6.8.1 
Time to Event Analysis with Data after Month 9 .................. 103 
6.8.2 
Analysis of Time to Subsequent Refills ............................... 103 
6.9 
Flexible Interim Analysis ...................................................... 103 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 103 
7.1 
Data Quality Assurance ....................................................... 103 
7.2 
Electronic Case Report Forms ............................................. 104 
7.3 
Patient-Reported Outcome Data ......................................... 104 
7.4 
Source Data Documentation ................................................ 104 
7.5 
Use of Computerized Systems ............................................ 105 
7.6 
Retention of Records ........................................................... 105 
8. 
ETHICAL CONSIDERATIONS .................................................................. 105 
8.1 
Compliance with Laws and Regulations .............................. 105 
8.2 
Informed Consent ................................................................ 105 
8.3 
Institutional Review Board or Ethics Committee .................. 107 
8.4 
Confidentiality ...................................................................... 107 
8.5 
Financial Disclosure ............................................................ 108 


Ranibizumab Port Delivery System—Genentech, Inc. 
9/Protocol GX28228, Version 8 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 108 
9.1 
Study Documentation .......................................................... 108 
9.2 
Protocol Deviations .............................................................. 108 
9.3 
Site Inspections ................................................................... 108 
9.4 
Administrative Structure ....................................................... 108 
9.5 
Publication of Data and Protection of 
Trade Secrets ...................................................................... 109 
9.6 
Protocol Amendments ......................................................... 110 
10.  REFERENCES ......................................................................................... 111 
 
 
LIST OF TABLES 
Table 1 
Components of the Ranibizumab Port Delivery System with 
Corresponding Terminology ........................................................ 27 
Table 2 
Dosing Guidelines Prior to Screening ......................................... 36 
Table 3 
Ranibizumab Dosing and Safety Assessment Schema .............. 37 
Table 4 
Definition of Terms Pertaining to AMD Inclusion Criteria ............ 47 
Table 5 
Imaging Requirements at Pre-Screening, Run-In, and 
Screening .................................................................................... 49 
Table 6 
Dose Interruption/Study Treatment or Study Discontinuation 
Criteria ........................................................................................ 79 
Table 7 
Lack of Clinical Efficacy Criteria .................................................. 81 
Table 8 
Management of Patients Who Meet Lack of Clinical Efficacy 
Criteria ........................................................................................ 81 
Table 9 
Recommended Management of Cases of Vitreous 
Hemorrhage ................................................................................ 82 
Table 10 
Adverse Event Severity Grading Scale ....................................... 87 
 
 
LIST OF FIGURES 
Figure 1 
RPDS Components ..................................................................... 26 
Figure 2 
Study Schema ............................................................................. 34 
 


Ranibizumab Port Delivery System—Genentech, Inc. 
10/Protocol GX28228, Version 8 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments for Implant Arms: Screening, 
Randomization, Day 1, Month 1 through Month 9, Month X, 
Safety Visits, and Final/Early Termination Visits ....................... 112 
Appendix 2 
Schedule of Assessments for ITV arm: Screening, 
Randomization/Day 1, Month 1 through Month 9, Month X, 
and Final/Early Termination Visits ............................................. 125 
Appendix 3 
Pre-Screening Visits (if Applicable) ........................................... 132 
Appendix 4 
Run-In Visit (if Applicable) ......................................................... 133 
Appendix 5 
Unscheduled Safety Assessment Visit ...................................... 134 
Appendix 6 
Implant Treatment Arms Procedures ........................................ 135 
Appendix 7 
Pre-Injection Procedures for ITV Treatment Arm ...................... 136 
Appendix 8 
Preparation and Administration of Ranibizumab ITV Injection .. 139 
Appendix 9 
Post-Injection Procedures for Patients in the ITV Injection 
Arm ........................................................................................... 141 
Appendix 10 
Best Corrected Visual Acuity Testing ........................................ 142 
Appendix 11 
Low Luminance Best Corrected Visual Acuity Testing .............. 143 
Appendix 12 
Grading Scales ......................................................................... 144 
Appendix 13 
Fundus Autofluorescence ......................................................... 146 
Appendix 14 
Color Fundus Photographs ....................................................... 147 
Appendix 15 
Fluorescein Angiography .......................................................... 148 
Appendix 16 
Spectral Domain Optical Coherence Tomography .................... 149 
Appendix 17 
External and Implant Photographs ............................................ 150 
Appendix 18 
Optical Coherence Tomography Angiography (at Selected 
Sites) ......................................................................................... 151 
Appendix 19 
Macular Degeneration Treatment Satisfaction Questionnaire ... 152 
Appendix 20 
Central Laboratory Sample Collection and Shipping ................. 182 
Appendix 21 
Ranibizumab Port Delivery System: Device Clinical 
Investigation Plan ...................................................................... 184 


Ranibizumab Port Delivery System—Genentech, Inc.
11/Protocol GX28228, Version 8
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE II, MULTICENTER, RANDOMIZED, 
ACTIVE TREATMENTCONTROLLED STUDY OF
THE EFFICACY AND SAFETY OF THE 
RANIBIZUMAB PORT DELIVERY SYSTEM FOR
SUSTAINED DELIVERY OF RANIBIZUMAB IN 
PATIENTS WITH SUBFOVEAL NEOVASCULAR 
AGE-RELATED MACULAR DEGENERATION
PROTOCOL NUMBER:
GX28228
VERSION NUMBER:
8
EUDRACT NUMBER:
Not applicable
IND NUMBER:
113,552
TEST PRODUCT:
Ranibizumab Port Delivery System for Sustained 
Delivery of Ranibizumab (RO4893594)
MEDICAL MONITOR:
, M.D.
SPONSOR:
Genentech, Inc.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
this form to your local study monitor. 


Ranibizumab Port Delivery System—Genentech, Inc.
12/Protocol GX28228, Version 8
PROTOCOL SYNOPSIS
TITLE:
A PHASE II, MULTICENTER, RANDOMIZED, ACTIVE 
TREATMENTCONTROLLED STUDY OF THE EFFICACY AND 
SAFETY OF THE RANIBIZUMAB PORT DELIVERY SYSTEM FOR 
SUSTAINED DELIVERY OF RANIBIZUMAB IN PATIENTS WITH 
SUBFOVEAL NEOVASCULAR AGE-RELATED MACULAR 
DEGENERATION
PROTOCOL NUMBER:
GX28228
VERSION NUMBER:
8
EUDRACT NUMBER:
Not applicable
IND NUMBER:
113,552
TEST PRODUCT:
Ranibizumab Port Delivery System for Sustained Delivery of 
Ranibizumab (RO4893594)
PHASE:
II
INDICATION:
Subfoveal neovascular age-related macular degeneration
SPONSOR:
Genentech, Inc.
Objectives
Efficacy Objectives
The primary efficacy objective for this study is as follows:

To evaluate the relative efficacy of 10-mg/mL, 40-mg/mL, and 100-mg/mL formulations of 
ranibizumab, delivered via the Implant, as measured by the time a patient first requires
Implant refill according to protocol-defined refill criteria
The secondary efficacy objectives for this study are as follows:

To evaluate and compare the relative efficacy of 10-mg/mL, 40-mg/mL, and 100-mg/mL 
formulations of ranibizumab, delivered via the Implant, to that of 10-mg/mL (0.5-mg dose) 
monthly ITV ranibizumab injections, as measured by the change in BCVA from baseline at 
Month 9

To evaluate the efficacy of 10-mg/mL, 40-mg/mL, and 100-mg/mL formulations of 
ranibizumab, delivered via the Implant, with that of 10-mg/mL (0.5-mg dose) monthly ITV 
ranibizumab injections over time, as measured by the change in BCVA from baseline over 
time

To evaluate the efficacy of 10-mg/mL, 40-mg/mL, and 100-mg/mL formulations of 
ranibizumab, delivered via the Implant, with that of 10-mg/mL (0.5-mg dose) monthly ITV 
ranibizumab injections over time, as measured by the change in central foveal thickness 
(CFT, defined as the retinal thickness in the center of the fovea) from baseline over time

To evaluate the functionality of the Implant by assessing that there is no evidence of 
Implant clogging in more than 10% of patients in the Implant arms at Month 9


Ranibizumab Port Delivery System—Genentech, Inc.
13/Protocol GX28228, Version 8
Safety Objectives
The safety objectives for this study are as follows:

To evaluate the safety of ranibizumab delivered via the Implant, compared with that of 
monthly ITV injection, as measured by ocular and non-ocular adverse events and serious 
adverse events

To evaluate the safety of the Ranibizumab Port Delivery System (RPDS), as measured by 
“Prespecified RPDS-associated adverse events”

To evaluate the proportion of patients with positive serum antibodies to ranibizumab
Pharmacokinetic Objectives
The pharmacokinetic (PK) objectives for this study are as follows:

To characterize the serum pharmacokinetics of ranibizumab in patients after the initial fill 
and subsequent refills in the Implant treatment arms
Exploratory Objectives
The exploratory objectives for this study are as follows:

To evaluate the development of macular atrophy in all three Implant treatment arms relative 
to one another and to the monthly ITV arm

To examine the impact of ranibizumab treatment on patient-reported treatment satisfaction 
as assessed by the Macular Degeneration Treatment Satisfaction Questionnaire (MacTSQ) 
at Months 1, 6, 9, and the final or early termination visit for patients who speak English or 
Spanish

To explore time to subsequent Implant refills according to protocol-defined refill criteria

To describe the number of times patients meet protocol-specified refill criteria

To evaluate the proportion of patients in each Implant arm who first meet the protocol-
defined refill criteria prior to and at Months 4, 5, and 6

To evaluate the proportion of patients with an improvement of 15 letters in BCVA from 
baseline 

To evaluate the proportion of patients with a loss of 15 letters in BCVA from baseline over 
time

To explore the utility of BCVA measured under low luminance as a predictor of treatment 
benefit over time

To evaluate the changes in total lesion area, area of CNV lesion, and CNV leakage over 
time, as assessed by fluorescein angiography

To explore the serum ranibizumab concentration data with a PK model in an attempt to infer 
the concentrationtime pattern in the vitreous or aqueous humor and, if possible, derive 
information on the rate of ranibizumab release from the Implant

To characterize ranibizumab aqueous humor concentration over time (optional)

To characterize ranibizumab vitreous or aqueous humor concentration after Implant 
explantation (if applicable)

To evaluate the potential association of circulating biomarkers with disease characteristics 
and response to ranibizumab (optional)

To evaluate the relationship of 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 (optional)

To evaluate the potential association of vitreous or aqueous humor biomarkers with disease 
characteristics and/or response to ranibizumab 

To evaluate the proportion of patients meeting lack of clinical efficacy criteria

To evaluate the proportion of patients requiring explantation

To evaluate the changes in CNV perfusion over time as assessed by OCT Angiography (at 
selected sites that have OCT angiography equipment)


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Study Design
Description of Study
Study GX28228 is a Phase II, multicenter, dose-ranging, randomized, active treatment (monthly 
ITV injection)-controlled study to evaluate the efficacy, safety, and pharmacokinetics of 
ranibizumab delivered through the Implant using three ranibizumab formulation arms (10 mg/mL, 
40 mg/mL, and 100 mg/mL) compared with the control arm (0.5-mg monthly ITV injections of 
10-mg/mL formulation) in patients with subfoveal neovascular age-related macular degeneration 
(nAMD).  The study will also evaluate the safety of the RPDS combination product.  The study 
will include pre-screening, screening, and randomization visits followed by a treatment period.  
Treatment and safety assessment schedules are set.
Number of Patients
Approximately 220 patients at up to 60 sites in the United States will be randomized in a 
3:3:3:2 ratio to four treatment arms (60 per each of three Implant treatment arms and 40 to the 
ITV injection arm) within an approximate 24-month period of time.
Target Population
Patients with subfoveal neovascularization secondary to age-related macular degeneration 
(AMD) diagnosed within 9 months and treated with ITV anti-VEGF agents will be enrolled in 
the study.
Inclusion Criteria
Patients must meet the following criteria for study entry:
General Inclusion Criteria

Age 50 years

Willingness and ability to provide signed informed consent and Health Insurance Portability 
and Accountability Act (HIPPA) authorization

Willingness and ability to undertake all scheduled visits and assessments

For sexually active women of childbearing potential, agreement to the use of an appropriate 
form of contraception (or abstinence) for the duration of the study.  A woman is considered 
not to be of childbearing potential if she is postmenopausal or has undergone hysterectomy 
and/or bilateral oophorectomy.  
For women who are not postmenopausal (12 months of non-therapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus):  agreement to 
remain abstinent or use single or combined contraceptive methods that result in a 
failure rate of 1% per year during the treatment period and for at least 30 days after 
the last dose of study treatment
Abstinence is only acceptable if it is in line with 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.

Sexually active men are recommended to use a barrier contraceptive method (condom), 
even if they have been surgically sterilized, for the duration of the treatment period and for 
at least 30 days after the last dose of study treatment.
Ocular Inclusion Criteria (Study Eye)

Newly diagnosed with nAMD within 9 months prior to screening visit

Patient must have received at least 2 prior anti-VEGF injections (including ranibizumab, 
bevacizumab, or aflibercept).  However, the most recent anti-VEGF injection must have 
been ranibizumab and must have occurred at least 7 days prior to the screening visit.

Demonstrated response to prior ITV anti-VEGF treatment, as evidenced by the following:
Decrease in CFT of 50 m since commencing ITV anti-VEGF treatment
OR
Stable or improved BCVA since commencing ITV anti-VEGF treatment

BCVA using ETDRS charts of 20/20-20/200 Snellen equivalent 


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
All subtypes of nAMD choroidal neovascularization (CNV) lesions are permissible 
(i.e., classic CNV, occult CNV, or with some classic CNV component, or retinal 
angiomatous proliferation lesions). 
Active primary CNV lesions at the time of diagnosis of nAMD must be subfoveal or 
juxtafoveal with a subfoveal component related to the CNV activity (such as subretinal 
hemorrhage, subretinal fluid, or retinal pigment epithelium [RPE] detachment)
Ocular Inclusion Criteria for Pre-Screening (Study Eye) (If Applicable)

Treatment naïve nAMD patients

BCVA using ETDRS charts of 20/20 to 20/200 Snellen equivalent

All subtypes of nAMD choroidal neovascularization (CNV) lesions are permissible 
(i.e., classic CNV, occult CNV, or with some classic CNV component, or retinal 
angiomatous proliferation lesions). 
Active primary CNV lesions must be subfoveal or juxtafoveal with a subfoveal 
component related to the CNV activity (such as subretinal hemorrhage, subretinal fluid, 
or RPE detachment)
Ocular Inclusion Criteria for Run-In (Study Eye) (If Applicable)

Previous treatment with a single anti-VEGF ITV injection or no more than eight anti-VEGF 
ITV injections, with aflibercept or bevacizumab being the most recent injection 

BCVA using ETDRS charts of 20/20 to 20/200 Snellen equivalent

All subtypes of nAMD CNV lesions are permissible (i.e., classic CNV, occult CNV, or with 
some classic CNV component or retinal angiomatous proliferation lesions) 
Active primary CNV lesions at the time of diagnosis of nAMD must be subfoveal or 
juxtafoveal with a subfoveal component related to the CNV activity (such as subretinal 
hemorrhage, subretinal fluid, or RPE detachment)
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
Prior Ocular Treatment

Treatment with ITV anti-VEGF agents other than ranibizumab within 1 month prior to the 
randomization visit in either eye

History of vitrectomy surgery, submacular surgery, or other surgical intervention for AMD in 
the study eye

Prior treatment with Visudyne®, external-beam radiation therapy, or transpupillary 
thermotherapy in the study eye

Previous treatment with ITV corticosteroid injection or device implantation in the study eye

Previous focal laser photocoagulation used for AMD treatment in the study eye

Prior participation in a clinical trial involving anti-angiogenic drugs, other than ranibizumab, 
in either eye within 2 months prior to the randomization visit

Treatment with Visudyne® in the fellow eye 7 days preceding screening visit
CNV Lesion Characteristics

Subretinal hemorrhage in the study eye that involves the center of the fovea, if the size of 
the hemorrhage is either 50% of the total area of the lesion or 1 disc area (2.54 mm2) in 
size at screening

Subfoveal fibrosis or atrophy in the study eye

CNV in either eye due to other causes, such as ocular histoplasmosis, trauma, or 
pathologic myopia
Concurrent Ocular Conditions

BCVA using ETDRS charts lower than 20/200 Snellen equivalent in the fellow eye

Retinal pigment epithelial tear involving the macula in the study eye


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
Any concurrent intraocular condition in the study eye (e.g., cataract, glaucoma, or diabetic 
retinopathy) that, in the opinion of the investigator, 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) in the study eye

History of vitreous hemorrhage in the study eye within 3 months prior to the randomization 
visit

History of rhegmatogenous retinal detachment or macular hole (Stage 3 or 4) in the study 
eye

History of idiopathic or autoimmune-associated uveitis in either eye

Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye

Aphakia or absence of the posterior capsule in the study eye
Previous violation of the posterior capsule break in the study eye is also excluded 
unless it occurred as a result of yttrium aluminium garnet laser posterior capsulotomy 
in association with prior, posterior chamber intraocular lens implantation.

Spherical equivalent of the refractive error in the study eye demonstrating more than 
8 diopters of myopia

For patients who have undergone prior refractive or cataract surgery in the study eye, the 
preoperative refractive error in the study eye does not exceed 8 diopters of myopia

Intraocular surgery (including cataract surgery) in the study eye within 3 months preceding 
the randomization visit

Uncontrolled ocular hypertension or glaucoma in the study eye (defined as intraocular 
pressure [IOP] 25 mmHg or a Cup to Disc ratio 0.8, despite treatment with anti-
glaucoma medication) and any such condition for which the investigator feels may require a 
glaucoma filtering surgery while in the study

History of glaucoma-filtering surgery in the study eye, tube shunts, or microinvasive 
glaucoma surgery in the study eye

History of corneal transplant in the study eye
Concurrent Systemic Conditions

Uncontrolled blood pressure (defined as systolic 155 mmHg and/or diastolic 95 mmHg, 
based on the average of 3 readings taken with the patient in a resting state [i.e., supine or
sitting, but consistent across readings] over a period of up to 15 minutes at screening)
If the average of 3 readings exceeds these values, patient’s blood pressure must to be 
controlled by antihypertensive medication.  The patient can become eligible for 
rescreening if medication is taken continuously for at least 30 days prior to the 
randomization visit.

Uncontrolled atrial fibrillation within 3 months of informed consent

History of stroke within the last 3 months prior to informed consent

History of myocardial infarction within the last 3 months prior to informed consent

History of other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of ranibizumab or placement of the Implant, that might affect interpretation of the 
results of the study or renders the patient at high risk of treatment complications

Current treatment for any active systemic infection

Use of any systemic anti-VEGF agents

Use of oral corticosteroids (prednisone 10mg/day or equivalent)


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
Use of anticoagulants, antiplatelets (other than aspirin), or medications known to exert 
similar effects at the time of study entry for a pre-existing condition.  Oral anticoagulants
include vitamin K antagonists (e.g. warfarin), direct factor Xa inhibitors (e.g., rivaroxaban, 
apixaban, edoxaban, fondaparinux) and direct thrombin inhibitors (e.g., dabigatran). 
Antiplatelet therapies include clopidogrel, prasugrel, dipyridamole, ticagrelor and ticlodipine.

Bleeding disorders, including platelet disorders, acquired or hereditary coagulations 
disorders, and acquired or hereditary vascular disorders.

Active malignancy 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.

History of allergy to fluorescein, not amenable to treatment

Inability to obtain fundus photographs, fluorescein angiograms, fundus autofluorescence, or 
spectral domain optical coherence tomography (SD-OCT) images of sufficient quality to be 
analyzed and graded by the central reading center 

Inability to comply with study or follow-up procedures

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 

Intolerance or hypersensitivity to topical anesthetics, mydriatic medications, any of the 
excipients in ranibizumab, fluorescein, or components of the Implant

Requirement for continuous use of any medications or treatments indicated in the 
“Prohibited Therapy” section.

Women who are pregnant or lactating or intending to become pregnant during the study

Women who are of childbearing potential, including those who have had tubal ligation, must 
have a negative serum pregnancy test result within 21 days prior to Day 1.  A woman is 
considered not to be of childbearing potential if she is postmenopausal or has undergone 
hysterectomy and/or bilateral oophorectomy.

No additional exclusions may be applied by the investigator, in order to ensure that the 
study population will be representative of all eligible patients
Length of Study
The estimated study duration is 38 months.
Patients randomized to the Implant treatment arms will have the Implant (pre-filled with 
ranibizumab) surgically inserted in the study eye at their Day 1 visit, after which they will be 
evaluated monthly for the need for an Implant refill, based upon protocol-specified refill criteria, 
until the Sponsor decides, based on the primary analysis results, to either terminate the study 
and discontinue study treatment, or offer patients entry into the RPDS Extension Study.  The 
duration of their participation in the study is expected to last approximately 1338 months
dependent on the date of their randomization to the study.
Patients randomized to the ITV injection treatment arm (control) will be treated monthly with ITV 
injections of ranibizumab until the Sponsor decides, based on the primary analysis results, to 
either terminate the study and discontinue study treatment, or offer patients entry into the 
RPDS Extension Study.  The duration of their participation in the study is expected to last 
approximately 1338 months dependent on the date of their randomization to the study.  
End of Study
The end of the study is defined as the date when the last patient, last study visit occurs.


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Outcome Measures
Efficacy Outcome Measures
The primary efficacy outcome measure for this study is the time until a patient first requires the 
Implant refill according to protocol-defined refill criteria.
The secondary efficacy outcome measures for this study are as follows:

Change in BCVA from baseline at Month 9

Average change in BCVA from baseline over time

Change in BCVA from baseline over time

Change in CFT over time, as assessed on SD-OCT by the Central Reading Center

Occurrence of implant clogging
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence of adverse events of Special Interest:  Adverse events associated with 
ranibizumab, the Implant, implant-associated procedures, and/or ancillary devices

Incidence of “Prespecified RPDS-associated adverse events” 

Incidence of ocular and non-ocular adverse events and serious adverse events

Incidence of positive serum antibodies to ranibizumab
Pharmacokinetic Outcome Measures
The PK outcome measures related to ranibizumab serum concentration-time data following the 
Implant insertion and refills are as follows:

Observed maximum serum concentrations (Cmax) and selected post dose serum 
concentrations after Implant insertion and all subsequent refills 

Additional estimated PK parameter values including AUC, tmax, and t1/2 after Implant 
insertion and all subsequent refills

Observed serum concentrations (Ct) over time from monthly serum sampling when no refills 
are administered

Observed trough serum concentrations (Ctrough) prior to refills
In addition, optional anterior chamber (aqueous humor) will be collected to assess ocular drug 
concentration.
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:

Treatment emergent macular atrophy in all treatment arms

The MacTSQ score at randomization and at Months 1, 6, 9, and the final or early 
termination visit for patients who speak English or Spanish

Time to subsequent Implant refills according to protocol-defined refill criteria

Number of times a patient meets protocol-specified refill criteria

Proportion of patients in each Implant arm who first meet the protocol-defined refill criteria 
prior to and at Months 4, 5,and 6

Proportion of patients with an improvement of BCVA from baseline of 15 letters over time

Proportion of patients losing 15 letters in BCVA from baseline over time

Change in BCVA from baseline over time measured under low luminance conditions


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
Changes from screening in total lesion area, area of CNV lesion, and CNV leakage over 
time, as assessed by fluorescein angiography  

Proportion of patients meeting lack of clinical efficacy criteria 

Proportion of patients requiring explantation

Changes in CNV perfusion over time, as assessed by OCT Angiography
In addition, vitreous samples from the Refill Needle (if applicable), optional aqueous humor 
samples, and optional serum and plasma samples may be collected to assess the relationship 
between biomarkers and the disease characteristics and/or response to treatment with 
ranibizumab.  Optional whole blood samples will be collected for DNA extraction (genetic 
analysis) to assess the relationship between genetic variants and the disease characteristics 
and/or response to treatment with ranibizumab.
In addition, vitreous or aqueous humor samples before Implant explantation, and optional 
aqueous humor samples prior to or immediately following one or more refills and at the Day 7 
safety visit post refill will be collected to characterize ranibizumab vitreous and aqueous humor
concentration.
Investigational Medicinal Products
Test Product (Investigational Drug)
The Implant initially filled and then refilled as per protocol specified refill criteria, with either 
10-mg/mL, 40-mg/mL, or 100-mg/mL ranibizumab formulations.
Non-Investigational Medicinal Products
Comparator
Ranibizumab 0.5-mg monthly intravitreal (ITV) injections of 10-mg/mL formulation
Statistical Methods
Detailed specifications of the statistical methods will be described in the statistical analysis plan 
(SAP).
Primary Analysis
The primary endpoint for this analysis will be time to first meeting refill criteria.  The primary 
analyses will be based on data as of 9 months after last patient’s entry into the study.  For 
patients without any refills prior to or on the cut-off date of 9 months after LPI, the time of refill 
will be censored. The censoring date will be defined as the date of a patient’s last visit before 
the cut-off date of 9 months after LPI, or the date when the patient discontinues from the study, 
whichever occurs first.
The primary analysis population for efficacy is the modified intent-to-treat population defined as 
all randomized patients who were randomly assigned to study treatment receive study 
treatment.  Patients will be summarized by treatment arm and analyzed according to the 
treatment actually received and not according to the treatment they were randomized to receive, 
in the event of a discrepancy.  
To support the dose level selection among the Implant groups, the primary analysis for TTFR 
will include the following pair-wise group comparisons, each with a stratified log-rank test at a 
one-sided significance level of 15%.  The stratification factors to be included are baseline BCVA 
score (65 letters vs. 66 letters) and number of anti-VEGF ITV injections (3 vs. 4).

Implant with 100 mg/mL versus Implant with 10 mg/mL

Implant with 100 mg/mL versus Implant with 40 mg/mL

Implant with 40 mg/mL versus Implant with 10 mg/mL
In addition, the HR for each pair-wise comparison of the treatment arms will be estimated using 
a Cox proportional hazards regression model stratified by baseline BCVA score (65 letters vs.
66 letters) and number of prior anti-VEGF ITV injections (3 vs. 4) with main effects for 
treatment.  Estimated HRs for each pair-wise comparison will be presented with the 
corresponding 80% CIs.  


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KaplanMeier plots will be provided showing TTFR by implant group.  Median time to first 
meeting refill criteria will be calculated for each treatment arm with the Kaplan Meier method, 
and the corresponding 80% confidence intervals will also be reported.

Moreover, for each treatment group, percentage of patients not meeting the protocol-
defined first refill criteria by Months 4, 5, 6, 7, 8, and 9, derived from Kaplan-Meier 
estimates will be provided.
Determination of Sample Size
This study is exploratory in nature and designed to estimate the time to first refill (TTFR) for 
each of the RPDS treatment arms (10 mg/mL, 40 mg/mL, and 100 mg/mL) enrolling 60 patients 
in each of the RPDS treatment arms.  The sample size of approximately 220 randomized 
patients will be adequate to evaluate the primary objective of the study.  PK/PD modeling and 
simulation was performed to inform key assumptions used in sample size calculation.  Given the 
simulation results, the HR for comparing the 100-mg/mL arm with the 10-mg/mL arm was 
estimated to be 0.66 for TTFR.  Assuming this HR, a total of at least 125 events from all three 
Implant groups is expected at the primary analysis time (approximately 85 events in the 
10-mg/mL group and a higher dose group).  With 85 events, this study will have approximately 
80% power to detect an HR0.66 between the two Implant arms using a log-rank test at a 
one-sided significance level of 15%.  No multiplicity adjustment is planned for this Phase II 
study.
Forty patients in the ITV arm are considered sufficient to compare each device arm versus the 
ITV arm in change in BCVA from baseline through Month 9 (assuming an estimated 
SD 10 letters, a two-sided 80% CI will extend approximately 2.62 letters from the observed 
mean). 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADE
adverse device effect
AE
adverse event
AESI
adverse event of special interest
AMD
age-related macular degeneration
ANCOVA
analysis of covariance
AREDS
Age-Related Eye Disease Study
ATE
arterial thromboembolic event
AUC
area under the concentration–time curve
BCVA
best corrected visual acuity
BLQ
below the lower limit of quantification
CFT
central foveal thickness
Cmax
maximum serum concentration
CNV
choroidal neovascularization
Ctrough
steady-state serum concentration at the end of a
dosing interval
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
ETDRS
Early Treatment Diabetic Retinopathy Study
FA
fluorescein angiogram
FAF
fundus autofluorescence
FDA
(U.S.) Food and Drug Administration
FSV4
ForSight VISION 4, Inc.
HA
health authority
HCl
hydrochloride
HIPAA
Health Insurance Portability and Accountability Act
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IFU
instruction for use
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IOP
intraocular pressure
IRB
Institutional Review Board


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Abbreviation
Definition
ITV
intravitreal
IxRS
interactive voice/Web response system
LPI
Last Patient In
MacTSQ
Macular Degeneration Treatment Satisfaction 
Questionnaire
MRI
magnetic resonance imaging
nAMD
neovascular age-related macular degeneration
PK
pharmacokinetic
PRO
patient-reported outcome
OCT
optical coherence tomography
RCE
release control element
RCR
Roche Clinical Repository
RPDS
Ranibizumab Port Delivery System
RPE
retinal pigment epithelium
SAP
Statistical Analysis Plan
SD-OCT
spectral domain optical coherence tomography
SOC
standard of care
t1/2
half-life
tmax
time to maximum concentration
TMP
Trial Monitoring Plan
ULN
upper limit of normal
VA
visual acuity
VEGF
vascular endothelial growth factor


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1.
BACKGROUND
1.1
BACKGROUND ON AGE-RELATED MACULAR DEGENERATION
Age-related macular degeneration (AMD) is one of the major causes of legal blindness 
in elderly persons in the developed world (Bressler et al. 2011).  Late stage AMD 
includes two morphological subtypes: neovascular AMD and geographic atrophy.  The 
prevalence of neovascular AMD increases exponentially with age, with prevalence 
estimates in the United States in 2011 ranging from 0.5% among those 65 to 69 years of 
age to 14.6% among those 90 years of age or greater (Rudnicka et al. 2012). In the 
next 40 years, the global population aged 60 years and older is projected to increase 
dramatically translating into an increase in the prevalence of neovascular AMD 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 two subtypes, dry and neovascular, based on clinical 
examination, ocular imaging, and pathologic findings.  In dry AMD, which represents 
approximately 80%90% of AMD cases, damage occurs at the level of the retinal 
pigment epithelium (RPE) and Bruch’s membrane, the basement membrane between 
the RPE and the underlying choriocapillaris.  The most notable early change in dry AMD 
is the accumulation of drusen within the macula and posterior pole of the retina.  Drusen 
are focal deposits of extracellular debris located between the basal lamina of the RPE 
and the inner collagenous layer of Bruch’s membrane. Drusen compositional studies 
have revealed carbohydrates, zinc, nearly 150 proteins, and numerous components of 
the complement system. The largest single component of drusen is lipid, thought to be 
derived from a large lipoprotein of intra-ocular origin (Spaide and Curcio 2010). Early 
dry AMD may not produce symptoms for many years.  However, as drusen continue to 
accumulate, the patient’s central vision can become impaired, sometimes significantly.  
At its most extreme, dry AMD results in widespread loss of the RPE, a condition called 
geographic atrophy that can cause severe central vision loss and legal blindness.
In approximately 10% of dry AMD cases, a conversion to neovascular AMD (nAMD)
occurs over time.  Although nAMD is comparatively rare, prior to the development of 
anti-VEGF therapy, it accounted for the majority of severe vision loss from AMD.  nAMD
is typically characterized by the development of choroidal neovascularization (CNV) 
beneath 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 
RPE and/or neurosensory retina.  This fluid and hemorrhage can cause acute and, 


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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 vascular endothelial growth 
factor (VEGF)-A in the pathogenesis of nAMD, as discussed in the Ranibizumab Port 
Delivery System (RPDS) Investigator’s Brochure (IB).
1.1.2
Treatment for Age-Related Macular Degeneration
No specific treatment yet exists for dry macular degeneration, although numerous 
therapies have and are being investigated.  The Age-Related Eye Disease Study 
(AREDS), conducted by the National Eye Institute, demonstrated that the rate of 
progression of dry AMD could be decreased by a specific vitamin and mineral 
supplement (AREDS Research Group 2001). 
The 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 
(Fab), which binds to all known isoforms of VEGF-A, was approved by the U.S. Food
and Drug Administration (FDA) for use in neovascular AMD, 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.  Both ranibizumab and 
aflibercept therapies require frequent intravitreal (ITV) injections and physician 
monitoring.
1.2
BACKGROUND ON RANIBIZUMAB
Ranibizumab is a recombinant humanized immunoglobulin (Ig) G1 kappa isotype 
monoclonal Fab developed by Genentech, Inc. as a therapeutic agent for treating ocular 
vascular diseases by ITV injection.  It binds to and inhibits the biologic activity of human 
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.
Monthly ITV injection of 0.5 mg of ranibizumab was approved for treatment of nAMD by 
the FDA on 30 June 2006. Current U.S. prescribing information also provides 
information on results that may be expected following less frequent than monthly dosing 
(after 3 to 4 monthly injections).  
See the RPDS Investigator Brochure (IB) for details on relevant nonclinical and clinical
ranibizumab information.


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1.3
BACKGROUND ON THE RANIBIZUMAB PORT 
DELIVERY SYSTEM
The RPDS is a drug delivery technology that allows physicians to use ranibizumab with 
a sustained drug delivery profile without altering its chemistry and consists of the port 
delivery implant (referred to as the Implant), ancillary devices (Insertion Tool, Initial Fill 
Needle, Refill Needle, and Explant Tool), and ranibizumab (see Figure 1).
The Implant is an intra-ocular refillable device that is surgically placed through the pars 
plana (similar to other surgically implanted ophthalmic devices such as Retisert [Bausch 
and Lomb, FDA approved in 2005]) to allow for a sustained delivery of ranibizumab into 
the vitreous. After insertion of the Implant, the proximal end of the Implant is
subconjunctival but external to the sclera, with the body of the Implant extending into the
vitreous.  The Implant is designed to be used in conjunction with ranibizumab to 
precisely control the rate and duration of drug delivery and is refillable through the 
Implant septum in situ.  
The following are the intended uses of the RPDS components:

Implant: The Implant is intended to be inserted through the pars plana of the eye to 
deliver ranibizumab in a controlled manner into the vitreous humor. The physician 
will initially fill the reservoir with the drug and will refill it in accordance with the 
instructions for use.  Contraindication:  the RPDS is contraindicated for use with 
medications other than ranibizumab.

Insertion Tool:  The Insertion Tool is a component designed to a) hold the Implant 
during sterilization and insertion, b) assist with filling of the Implant before insertion, 
and c) enable insertion of the Implant through a pars plana sclerotomy.

Initial Fill Needle: The Initial Fill Needle is a custom 33G Luer-Lock needle 
designed to perform the initial fill of the Implant while the Implant is held in the 
Insertion Tool.

Refill needles: The Refill Needle is a custom Luer-Lock needle designed to 
simultaneously exchange (in situ) any remaining old drug product in the Implant
reservoir with new drug product.

Explant Tool: The Explant Tool is a component designed to enable the removal of 
the Implant from the posterior segment of the eye after resection of the conjunctiva 
and removal of any scar tissue.
For additional RPDS details (e.g., fill, insertion, refill, and explantation of the Implant), 
consult the RPDS instructions for use (IFU) document and the RPDS IB.




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The Implant has been investigated in a prospective, Phase I, open-label study in patients 
with nAMD, conducted by the device developer, ForSight VISION 4, Inc. (FSV4), at a 
single site in Latvia.  The study investigated the safety, tolerability, and duration of 
ranibizumab exposure delivered with the Implant.  This Phase I Implant was composed 
of biocompatible materials (polymethyl methacrylate, silicone, 316L stainless steel, 
see Table 1).  For further Phase I study details, see Section 1.4 and the RPDS IB.
Table 1
Components of the Ranibizumab Port Delivery System with 
Corresponding Terminology
Terminology
Ranibizumab Port Delivery System 
Components
Ranibizumab port delivery system 
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 Implant
Port delivery Implant with Titanium RCE to be 
used in this Phase II study
Ancillary devices
Insertion Tool, Initial Fill Needle, Refill Needles, 
and Explant Tool
RCErelease control element.
The following RPDS components are manufactured by 
 
; see Figure 1):  Initial Fill Needle.
The following RPDS components are manufactured by 
 
; see Figure 1):  Implant, Insertion Tool, Refill Needles, and 
Explant Tool.
While the size and shape of the Implant is unchanged between the Phase I and II 
studies, material changes were made to improve functionality and reliability of the 
Phase II Implant.  These changes include the use of polysulfone for the Implant body 
and encapsulation of the subconjunctival Implant retention features with silicone.  
Changes to the release control element (RCE) porosity and tortuosity were made 
between the Phase I and Phase II Implant designs to enable the use of higher 
concentrations of ranibizumab during Phase II.  A change in material of the RCE from 
stainless steel to titanium was also implemented to take advantage of the superior 
physical and chemical properties of titanium.
Phase I RPDS Study
The safety, tolerability, and duration of ranibizumab exposure delivered through the 
Implant were investigated in a Phase I prospective, open-label study in a nAMD patient 
population by FSV4 at a single site in Latvia.  Patient enrollment was initiated in 
August 2010, and the study assessed the safety of the RPDS in 20 eyes through the 
collection and analysis of adverse events and complications, including procedure-related 


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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. 
At Month 12, 6 patients underwent per-protocol planned Implant removal and exited the 
study after completion of the 13-month visit.  The 14 remaining patients were eligible for 
an additional safety-monitoring phase of the protocol.  One patient was lost to follow-up 
after 12 months.  The remaining 13 patients continued in the safety-monitoring phase; 
one patient was subsequently lost to follow up after 21 months.  Follow up data up to 
36 months is available for the remaining 12 patients.
No patients were treated via the Implant after the first 12 months of the study, with the 
remaining 14 implanted patients returning for quarterly safety visits.
A total of 95 adverse events have been reported in this study as of 26 February 2015:  
87 during the 12-month treatment phase and 8 during the additional 2-year safety 
monitoring phase.  Of the 87 adverse events during the 12-month treatment phase, 
76 were considered related (possibly, probably, or definitely) to the Implant insertion
procedure, the refill procedure, the Implant removal procedure, or drug treatment.  
These 87 reported adverse events occurred in 20 out of 20 (100%) enrolled patients.
Among the 76 study related adverse events, the most frequent 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. The majority of these events 
(44/45, 98%) were considered mild and one was considered moderate. The average 
duration of these events was 8 days, with all resolving over a range of 3 to 48 days from 
onset.  This adverse event was observed typically following Implant insertion and 
Implant refill procedures.
Of the 76 study-related adverse events, 30 were considered by the Investigator to be 
possibly or definitely related to the Implant insertion procedure.  These adverse events 
occurred in 15 patients.  The most frequent adverse events related to the Implant 
insertion procedure were conjunctival hyperemia (55% of the patients), vitreous 
hemorrhage (25%), hyphema (15%), and VA decrease (15%).  Single adverse events 
were reported as related to the Implant insertion procedure:  endophthalmitis (5% of the 
patients) and traumatic cataract (5%). A single adverse event of retinal pigment epithelial 
tear (5%) was reported as possibly related to the Implant placement. The number of 
adverse events related to the Implant insertion procedure in the first 10 patients (Patient 
Group 1) was greater (63% versus 19%) than that observed in the second 10 patients 
(Patient Group 2), suggesting that refinements in surgical instrumentation, training, and
surgical experience that occurred during the trial may have in part mitigated the risk of 
the device placement procedure in Patient Group 2.


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A total of 96 Implant refill procedures were performed in the study. The most frequently 
reported adverse events considered to be related to Implant refill on a per-procedure 
basis by the investigator were conjunctival hyperemia (33%), eye dryness (2%), vitreous 
haze (2%), increased lacrimation (1%), and ocular discomfort (1%).The adverse event 
rate per Implant refill procedure was 38%.  These adverse events were mild in severity 
and the average duration to resolution was seven days.
Six patients underwent planned removal of the Implant at the 12-month visit as 
scheduled in the protocol.  All of these patients were in Group 1. Of these 6 patients, 
4 patients experienced 5 adverse events related to the Implant removal procedure:  two
incidents of conjunctival hyperemia (33%) and single incidences of hyphema (17%), VA 
decrease (17%), and conjunctival hemorrhage (17%).  All adverse events related to the 
implant removal procedure resolved within 7 days.
There were six reported serious adverse events during the treatment phase of the study.  
Four study-related serious adverse events were reported: two incidents of decreased 
VA consequent to adverse events of vitreous hemorrhage, one incident of 
endophthalmitis, and one incident of decreased VA consequent to the incident of 
endophthalmitis.  Two non-study-related serious adverse events were reported: gastric 
adenocarcinoma and rotavirus infection.  The two incidents of vitreous hemorrhage were 
likely caused by post-operative bleeding and were determined to be related to the 
Implant insertion procedure.  The single incident of endophthalmitis was observed at the 
2-week post-Implant insertion visit and was considered possibly related to the Implant 
insertion procedure.  The duration of this event was 14 days.
Of the 76 study-related adverse events, 7 were ongoing at the time of study exit.  These 
ongoing events were vitreous haze (3), and single incidents of vitreous hemorrhage, VA 
decrease, foreign body sensation in the eye, and retinal pigment epithelium tear.  
Thirteen patients entered the 24-month safety-monitoring phase (one patient was lost to 
follow-up after the 12-month follow-up); out of 13 patients, 12 completed the 
safety-monitoring phase and 1 was lost to follow-up after 21 months.  There were a total 
of eight reported adverse events during the safety-monitoring phase of the study.  Four 
adverse events were considered related (possibly, probably, or definitely) to the Implant 
insertion procedure, the refill procedure, or drug treatment.  These related adverse 
events were cataract progression (3) and a single incident of mild ocular discomfort.  
Two additional incidents of cataract progression, one incident of blurred vision, and one 
incident of leg edema were not considered study-related by the investigator.  No serious 
adverse events were reported during the safety-monitoring phase.


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There were no patient deaths during the 12-month treatment phase (the status of the 
2 patients lost to follow-up during the 24-month extended follow-up phase was not able 
to be confirmed), no adverse events led to patient withdrawal or dose reduction, and no 
adverse events represented a previously unsuspected important adverse effect of the 
device (implantation procedure or Implant).  
Refer to the RPDS IB for further details.
1.4
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
As a result of the chronic, progressive nature of nAMD, frequent ranibizumab ITV 
injections continue for extended periods for many patients.  Pivotal studies of 
ranibizumab in nAMD (Studies FVF2598g and FVF2587g) demonstrated significant and 
well-maintained visual acuity (VA) outcomes with monthly 0.5 mg ITV injections for 
2 years.  Trials that investigated less frequent than monthly dosing (Study FVF3192g 
and Lalwani et al. 2009) showed that visual outcomes were not as well maintained with 
more intermittent dosing schedules.  A recent trial that compared monthly to PRN 
ranibizumab ITV administration (Study FVF4579g) 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 
re-treatment and still required frequent ITV injections.  The mean number of ranibizumab 
ITV injections through month 24, with the 0.5-mg dose, was 21.4 for the monthly
treatment arm and 13.3 for the PRN treatment arm. In clinical practice, frequent office 
monitoring visits are required and regular injections are necessary to maintain optimal
vision gains.  Frequent office visits place a significant burden on patients and their 
caregivers, as well as treating physicians and the healthcare system. Sustained release 
of ranibizumab from the Implant is an alternate dosing method that may result in less 
frequent need of re-treatment than monthly dosing with ITV injections.  This decrease in 
treatment burden could possibly reduce the risk of ITV injectionrelated adverse events, 
increase compliance, and reduce the burden to patients, their caregivers, and the 
healthcare system, while maintaining optimum visual outcomes.
The safety, tolerability, and duration of ranibizumab exposure delivered through the 
Implant were investigated in a Phase I prospective, open-label study in a nAMD patient 
population by FSV4 at a single site in Latvia.  Patient enrollment was initiated in August 
2010 and the study was completed in July 2013. The study assessed the safety of the 
RPDS 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. Secondary endpoints of VA and optical coherence tomography (OCT)
change were also collected.
All 20 patients completed the 12-month treatment phase of the Phase I study. At 
month 12, 6 patients underwent per-protocol planned Implant removal and exited the 
study after completion of the 13-month visit.  Complete 13-month data are available for 


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these 6 explanted patients.  The 14 remaining patients completed an additional 2-year 
safety-monitoring phase, and follow-up data ranging from 27 to 36 months are available 
for 12 of these patients. The remaining 2 patients being monitored for ongoing safety 
were lost to follow-up at 12 and 21 months.
The overall safety profile of the combination product from the available study data is
generally consistent with the known safety profile of ranibizumab as administered by ITV 
injection (ranibizumab USPI) and similar surgical procedures involving intraocular 
implants (Vitrasert USPI, 2013; Retisert USPI, 2013; Dunn et al. 2004; Gedde et al. 2012; 
Buys 2013). Procedure-related adverse events for the 20 Implant placements were not 
unexpected.  In 96 Implant refill procedures, the refill procedure-related adverse events
were comparable to adverse events related to ITV injections (see Section 5.1 for further 
details).
The improvement in best corrected visual acuity (BCVA) appeared comparable to 
monthly injections with sustained reduction in macular thickness and area of CNV 
leakage. The Phase I study provided evidence of the safety and tolerability of the 
combination product and supports the evaluation of RPDS in a Phase II study. It is 
expected that in the Phase II study the drug efficacy of the Implant treatment arms will 
be similar to the control ITV monthly injection treatment arm.
2.
STUDY OBJECTIVES
2.1
EFFICACY OBJECTIVES
The primary efficacy objective for this study is as follows:

To evaluate the relative efficacy of 10-mg/mL, 40-mg/mL, and 100-mg/mL 
formulations of ranibizumab, delivered via the Implant, as measured by the time a 
patient first requires Implant refill according to protocol-defined refill criteria
The secondary efficacy objectives for this study are as follows:

To evaluate and compare the relative efficacy of 10-mg/mL, 40-mg/mL, and 
100-mg/mL formulations of ranibizumab, delivered via the Implant, to that of 
10-mg/mL (0.5-mg dose) monthly ITV ranibizumab injections, as measured by the 
change in BCVA from baseline at Month 9

To evaluate the efficacy of 10-mg/mL, 40-mg/mL, and 100-mg/mL formulations of 
ranibizumab, delivered via the Implant, with that of 10-mg/mL (0.5-mg dose) monthly 
ITV ranibizumab injections over time, as measured by the change in BCVA from 
baseline over time


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
To evaluate the efficacy of 10-mg/mL, 40-mg/mL, and 100-mg/mL formulations of 
ranibizumab, delivered via the Implant, with that of 10-mg/mL (0.5-mg dose) monthly 
ITV ranibizumab injections over time, as measured by the change in central foveal 
thickness (CFT, defined as the retinal thickness in the center of the fovea) from 
baseline over time

To evaluate the functionality of the Implant by assessing that there is no evidence of 
Implant clogging in more than 10% of patients in the Implant arms at Month 9
2.2
SAFETY OBJECTIVES
The safety objectives for this study are as follows:

To evaluate the safety of ranibizumab delivered via the Implant, compared with that 
of monthly ITV injection, as measured by ocular and non-ocular adverse events and 
serious adverse events

To evaluate the safety of the RPDS, as measured by “Prespecified 
RPDS-associated adverse events” (see Section 6.5.1)

To evaluate the proportion of patients with positive serum antibodies to ranibizumab
2.3
PHARMACOKINETIC OBJECTIVES
The pharmacokinetic (PK) objectives for this study are as follows:

To characterize the serum pharmacokinetics of ranibizumab in patients after the 
initial fill and subsequent refills in the Implant treatment arms
2.4
EXPLORATORY OBJECTIVES
The exploratory objectives for this study are as follows:

To evaluate the development of macular atrophy in all three Implant treatment arms 
relative to one another and to the monthly ITV arm

To examine the impact of ranibizumab treatment on patient-reported treatment 
satisfaction as assessed by the Macular Degeneration Treatment Satisfaction 
Questionnaire (MacTSQ) at Months 1, 6, 9, and the final or early termination visit for 
patients who speak English or Spanish (see Appendix 19)

To explore time to subsequent Implant refills according to protocol-defined refill 
criteria

To describe the number of times patients meet protocol-specified refill criteria

To evaluate the proportion of patients in each Implant arm who first meet the 
protocol-defined refill criteria prior to and at Months 4, 5, and 6

To evaluate the proportion of patients with an improvement of 15 letters in BCVA 
from baseline 

To evaluate the proportion of patients with a loss of 15 letters in BCVA from 
baseline over time

To explore the utility of BCVA measured under low luminance as a predictor of 
treatment benefit over time


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
To evaluate the changes in total lesion area, area of CNV lesion, and CNV leakage
over time, as assessed by fluorescein angiography

To explore the serum ranibizumab concentration data with a PK model in an attempt 
to infer the concentrationtime pattern in the vitreous or aqueous humor and, if 
possible, derive information on the rate of ranibizumab release from the Implant

To characterize ranibizumab aqueous humor concentration over time (optional)

To characterize ranibizumab vitreous or aqueous humor concentration after Implant 
explantation (if applicable)

To evaluate the potential association of circulating biomarkers with disease 
characteristics and response to ranibizumab (optional)

To evaluate the relationship of 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 (optional)

To evaluate the potential association of vitreous or aqueous humor biomarkers with 
disease characteristics and response to ranibizumab

To evaluate the proportion of patients meeting lack of clinical efficacy criteria
(see Section 5.1.1.3)

To evaluate the proportion of patients requiring explantation

To evaluate the changes in CNV perfusion over time as assessed by OCT 
Angiography (at selected sites that have OCT angiography equipment)
See the Device Clinical Investigation Plan (Appendix 21) for additional details of 
RPDS-specific data analyses to be conducted using the data generated during this study.
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
Study GX28228 is a Phase II, multicenter, dose-ranging, randomized, active treatment 
(monthly ITV injection)controlled study to evaluate the efficacy, safety, and 
pharmacokinetics of ranibizumab delivered through the Implant using three ranibizumab 
formulation arms (10 mg/mL, 40 mg/mL, and 100 mg/mL) compared with the control arm 
(0.5-mg monthly ITV injections of 10-mg/mL formulation) in patients with nAMD.  The 
study will also evaluate the safety of the RPDS combination product.  Approximately 
220 patients at up to 60 sites in the United States will be randomized in a 3:3:3:2 ratio to 
four treatment arms within an approximate 24-month period of time (see Figure 2).


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Figure 2
Study Schema
D1Day 1; ITVintravitreal; LPIlast patient in; M1Month 1; M9Month 9; PAprimary
analysis; PRNas needed (as per the refill criteria); RBZ PDranibizumab port delivery; 
RBZranibizumab; SOCstandard of care;
ranibizumab filled Implant inserted (Day 1).
Patients randomized to the Implant treatment arms will have the Implant (pre-filled with 
ranibizumab) surgically inserted in the study eye at their Day 1 visit, after which they will 
be evaluated monthly for the need for an Implant refill, based upon protocol-specified 
refill criteria (see Section 3.1.1), for the remainder of the study treatment duration
(see Section 3.2).  Patients randomized to the ITV injection treatment arm (control) will 
be treated monthly with ITV injections of ranibizumab, starting at their Day 1 visit and 
continuing for the remainder of the study treatment duration (see Section 3.2).  The 
monthly ITV treatment arm patients will also be evaluated monthly according to the 
protocol-specified refill criteria (see Section 3.1.1), but will be treated monthly regardless 
of whether they meet the refill criteria.  Study visits will be conducted every 307 days 
relative to the Day 1 visit.
Following implementation of Protocol GX28228, Version 5, if warranted, enrollment and 
implant insertion surgeries may be paused to enable real-time review of post-implant 
insertion safety data by the Internal Monitoring Committee (IMC). In the case of such a 
pause, dosing will continue as per the protocol for patients who have already received 
study drug (e.g., patients who have performed Day 1 visit), while patients who have not 
yet received study drug will stay in Pre-Screening, Run-In, Screening, or Randomization
period (as applicable) and receive monthly open-label ITV ranibizumab treatment until 
enrollment and implant insertion surgeries are restarted.  In addition, in the case of a
pause, patients who have been randomized but have not yet received the study drug 
must repeat the Randomization assessments after enrollment and implant insertion 
surgeries have recommenced and before receiving the study drug.  Patients who exceed 
nine total anti-VEGF doses before receiving the study drug will no longer be eligible for
the study.  
The study will include screening and randomization visits followed by a treatment period.  
Baseline measurements will be taken at the randomization visit.  On the day of patient


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randomization, BCVA will be measured based upon the Early Treatment Diabetic 
Retinopathy Study (ETDRS) chart assessment at a starting test distance of 4 meters.
The patients will then be randomized to a treatment arm using a stratified randomization:  
BCVA score (65 letters vs. 66 letters) and number of prior anti-VEGF ITV injections 
(3 vs. 4). Patients must satisfy all eligibility criteria at both the screening and the 
randomization visits, including receipt of all screening visit images by a central reading 
center.  Historical OCT images taken at the time of diagnosis of nAMD will also be 
evaluated by the reading center to determine patient’s eligibility.  If fluorescein 
angiograms were taken at the time of diagnosis of nAMD, they must be submitted to the 
reading center as well. If available, historical fluorescein angiograms will be evaluated 
by the reading center, but are not required to determine patient’s eligibility at the 
screening visit.  As part of the screening process, the central reading center will evaluate 
the patient’s FA, FP, and SD-OCT images taken both at the time of diagnosis of nAMD 
and at the screening visit to provide an objective, masked assessment of patient 
eligibility regarding lesion CNV, lesion classification, total lesion size, area of CNV lesion, 
and CNV leakage (see the Reading Center manual for details).  Macular atrophy will 
also be evaluated at screening, using fundus autofluorescence (FAF) and SD-OCT 
measurements (see the reading center manual for further details). After all eligibility 
requirements are confirmed, patients will be randomized through an interactive 
voice/Web response system (IxRS) in a 3:3:3:2 ratio so that approximately 60 patients 
will receive the Implant filled with 10-mg/mL ranibizumab formulation, 60 patients will 
receive the Implant filled with 40-mg/mL ranibizumab formulation, 60 patients will receive 
the Implant filled with 100-mg/mL ranibizumab formulation, and 40 patients will receive 
monthly ITV injections of 10-mg/mL ranibizumab formulation (50 L for the 0.5-mg dose; 
see Figure 2). 
There are 4 patient eligibility scenarios based on prior anti-VEGF treatment history:
1.
Newly diagnosed nAMD patients who are treatment naïve. These patients will 
undergo pre-screening if they satisfy eligibility criteria and sign informed consent
(Table 2).  During the pre-screening, patients will receive two ranibizumab ITV 
treatments to determine if they demonstrate response to ranibizumab treatment as 
outlined per the eligibility criteria (see Section 4.1.1). 
2.
Patients diagnosed with nAMD in the study eye within 9 months prior to 
screening who have been treated with a single anti-VEGF ITV injection. These 
patients may receive one “run-in” ITV ranibizumab treatment prior to screening if 
they satisfy eligibility criteria and sign the informed consent form (see Table 2). 
3.
Patients diagnosed with nAMD in the study eye within 9 months prior to 
screening who have been treated with no more than eight anti-VEGF ITV 
injections and with the most recent dose being aflibercept or bevacizumab.  
These patients may receive one “run-in” ITV ranibizumab treatment prior to 
screening if they satisfy eligibility criteria and sign the informed consent form 
(see Table 2). 


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4.
Patients diagnosed with nAMD in the study eye within 9 months prior to 
screening who have been treated with no more than nine anti-VEGF ITV 
injections and with the most recent dose being ranibizumab.  These patients
can proceed directly to screening (see Table 2). 
Table 2
Dosing Guidelines Prior to Screening
Historical anti-VEGF use in the 
study eye within the last 
9 months prior to screening
Open-label ranibizumab
dose(s) required prior to 
screening
Comments
Anti-VEGF treatment naive 
2
The Sponsor will provide 
2 ranibizumab doses prior to 
screeninga
Single previous anti-VEGF 
dose
1
The Sponsor will provide 
1 ranibizumab dose prior to 
screeninga
28 prior anti-VEGF dose AND 
most recent dose was 
aflibercept or bevacizumab
1
The Sponsor will provide 
1 ranibizumab dose prior to 
screeninga
29 prior anti-VEGF dose AND 
most recent dose was 
ranibizumab
0
Patients can proceed directly 
to screening
VEGFvascular endothelial growth factor.
a In the case of a pause of patient enrollment, additional ITV ranibizumab doses will be provided 
before receiving study drug, until enrollment and implant insertion surgeries recommence.  
Patients who exceed 9 total anti-VEGF doses before receiving the study drug will be excluded 
from the study.
A patient’s screening visit should occur no sooner than 7 days following administration of 
the last ITV ranibizumab treatment in the study eye.  All patients will be enrolled in the 
study on the day of their randomization visit and receive their Day 1 study treatment after 
conclusion of the Randomization visit.  If necessary, the Day 1 study treatment may be 
scheduled at a later date.  
Randomization visit cannot occur earlier than 28 days and no later than 37 days after the 
patient’s last ITV ranibizumab treatment.  
Day 1 study treatment visit cannot occur earlier than 28 days after and no later than 
37 days after the patient’s last ITV ranibizumab treatment, unless a patient randomized 
to the Implant arm needs more time to interrupt aspirin or NSAID usage 7 days before 
Day 1 (see Section 4.3.2.3).  For these patients, Day 1 study treatment visit must occur 
no later than 45 days after the patient’s last ITV ranibizumab treatment.
Patients who are randomized to the Implant treatment arms will have scheduled safety 
visit assessments on Day 2 (0), Day 7 (2 days), and Day 14 (2 days) after their 
Day 1 visit.  Starting at the Month 1 visit, the patients in the Implant treatment arms will 
be assessed monthly for the need for Implant refill with ranibizumab according to the


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protocol-specified refill criteria (see Section 3.1.1).  Their Implant will be refilled only if 
they meet re-treatment criteria.  The safety visits will be scheduled 7 (2) days after 
each refill (see Appendix 1).  After the Day 1 visit treatment, patients randomized to the
monthly ITV injection treatment arm will also be assessed monthly using the same 
re-treatment criteria as those for the Implant treatment arms (see Section 3.1.1) but will 
receive monthly ranibizumab injection treatment regardless of whether they meet the 
criteria (see Appendix 2 and Table 3).
Table 3
Ranibizumab Dosing and Safety Assessment Schema
Visit
Day
Month
Month 
X b
Final/
ET 
visit
1 a
2
7
14
1
2
3
4
5
6
7
8
9
Implant 
insertion/refill c
x
Refill Implant if refill criteria are met 
NA
Safety 
assessment 
visits d
x
x
x
7 Days after each Implant refill
NA
ITV injection e
x
x
x
x
x
X
x
x
x
x
x
NA
ET end of treatment; ITVintravitreal; NAnot applicable.
a The Day 1 treatment in all treatment arms (Implant and ITV injection) will occur on such date 
so that no fewer than 28 days and no more than 37 days have elapsed from patient’s last 
study eye ranibizumab ITV treatment.
b Month X visits: After completion of the Month 9 visit, the study patients in the Implant arms 
will continue monthly evaluation for refill according to the Month X schedule of assessments 
(see Appendix 1) until the Sponsor decides, based on the primary analysis results, to either 
terminate the study and discontinue study treatment or offer patients entry into the RPDS 
Extension Study. The ITV arm patients will continue to be treated monthly according to the 
Month X schedule of assessments (see Appendix 2) until the Sponsor decides, based on the 
primary analysis results, to either terminate the study and discontinue study treatment, or 
offer patients entry into the RPDS Extension Study.
c Starting at the Month 1 visit, Implant treatment arms will receive a refill with ranibizumab only 
if protocol refill criteria are met (see Section 3.1.1).
d There will be safety assessment visits on Days 2, 7, and 14 after the Implant insertion and 
then 7 days after each Implant refill.  These safety assessment visits are not applicable to the 
ITV injections treatment arm.
e ITV injection arm patients will be treated monthly regardless of meeting the re-treatment 
criteria.
Starting at the Day 1 visit (ITV treatment arm) or starting at the Month 1 visit (Implant
arms), all patients will be contacted by site personnel 3 (1) days after each ITV 
injection or Implant refill to elicit reports of decrease in vision, eye pain, unusual redness, 
or any other new ocular symptoms in the study eye. Patients in the Implant treatment 
arms will also be asked to verify whether they have taken the prescribed, 
self-administered, post-injection antimicrobial treatments.  The ITV arm patients’ 
self-administered antimicrobial treatments will be prescribed at the investigator’s 
discretion.


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Only one eye will be selected as the study eye during the screening period. If both eyes 
are eligible, the investigator will determine, during the screening, which eye will be 
selected for study treatment (study eye).  

Should a non-study (fellow) eye require treatment for nAMD after randomization, 
treatment with ranibizumab is not recommended within 7 days of the study eye 
scheduled visit.  For patients in the Implant arms, if the fellow eye will be treated 
7 days after study eye treatment, ranibizumab should be administered after serum 
PK sample collection.  

The drug for the fellow eye during the study will be open-label ranibizumab and will 
be supplied by Genentech (see Section 4.3.1.4 for the drug formulation for the 
non-study eye). If a change in therapy is clinically indicated for the fellow eye per 
investigator judgment, the change must be discussed and agreed by the Medical 
Monitor prior to being made.  
All study patients will have scheduled monthly visits during the study.  After the Day 1
visit, patients randomized to the Implant treatment arms will be evaluated for their 
Implant refill at each monthly visit. Patients randomized to the ITV injection arm will be 
treated at each monthly visit. Study visits will be scheduled to occur according to the
schedule of assessments in Appendix 1 and Appendix 2 and have to be relative to the 
Day 1 (first study treatment) visit date until the patient completes the study.
Each potential study patient can be randomized into the study only once.
Please see Section 5.1.1.1 for the criteria to be used for dose interruption and 
treatment/study discontinuation.  Missed ranibizumab doses will not be replaced.
The ITV treatment arm patients who are discontinued from study treatment prematurely 
will be asked to undergo the scheduled monthly assessments until Last Patient In (LPI)
Month 9 visit, after which they will be scheduled 30 (7) days later for their final study 
visit.  The patients who are discontinuing study treatment from the Implant treatment 
arms will be scheduled, within 7 days after the treatment discontinuation decision is 
made, for Implant explantation followed by safety visits 1 and 7 (2) days 
post-explantation. Afterwards, they will be followed in the study, attending their monthly 
scheduled visits, until LPI Month 9 visit, after which they will be scheduled for the early 
termination visit (see Appendix 1).  As per investigator judgement, these patients may 
start an approved anti-VEGF for their AMD once the need for Implant explantation is 
confirmed and, preferably, after explantation is completed. All explanted Implants with 
their remaining content will be returned to the designee of the Sponsor for storage and 
potential future exploratory analysis (see Section 4.4). A vitreous or aqueous humor
sample will be collected at the start of explantation for patients undergoing an 
explantation procedure (see Appendix 19).


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Patients who withdraw from the study prior to scheduled study completion will be asked 
to return for an early termination evaluation 30 (7) days following their last study 
treatment for monitoring of adverse events and early termination visit assessments if 
they are in the ITV treatment arm. The patients who are discontinuing the study from the 
Implant treatment arms will be scheduled for Implant explantation within 7 days of the 
treatment discontinuation decision, followed by Safety Visits 1, 7 (2), 30 (7), and 60 
(7) days post-explantation after which they will be scheduled for the early termination 
visit 30 (7) days later. As per investigator judgment, these patients may start an 
approved anti-VEGF treatment for their AMD once the need for Implant explantation is 
confirmed and, preferably, after explantation is completed. All explanted Implants with 
remaining content will be returned to the designee of the Sponsor for storage and 
potential future exploratory analysis (see Section 4.4). A vitreous or aqueous humor
sample will be collected at the start of explantation for patients undergoing an 
explantation procedure (see Appendix 19).
Patients in the ITV injection arm will be evaluated monthly and will receive monthly 
study treatments (Day 1, Month 1 through Month X visit, see Appendix 2) until the 
Sponsor decides, based on the primary analysis results, to either terminate the study 
and discontinue study treatment, or offer patients entry into the RPDS Extension 
Study.  Their participation (excluding screening period) in the study will last
approximately 1338 months dependent on the date of their randomization to the study.  
The patients in the Implant arms will be evaluated monthly for the Implant refill 
(see Appendix 1) until the Sponsor decides, based on the primary analysis results, to 
either terminate the study and discontinue study treatment, or offer patients entry into 
the RPDS Extension Study. If a patient requires refills outside of the protocol-defined
visits window, the Medical Monitor must be contacted by the investigator.  Study 
participation for patients in the Implant arms (excluding screening period) is expected to 
last approximately 1338 months dependent on the date of their randomization to the 
study.
Study investigators will be qualified ophthalmologists, trained in the management of 
retinal diseases and ocular surgery and will be certified by a Sponsor-selected vendor to 
perform initial Implant fill, insertion, refill, and explantation.  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 one investigator who evaluates and treats all 
patients with a backup investigator selected.  The site may opt to have two separate 
investigators 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 a 
patient throughout the trial.
Study patients and all study site personnel will be masked to the Implant treatment arms’ 
ranibizumab formulation assignment (10 mg/mL vs. 40 mg/mL vs. 100 mg/mL) until the 
study’s conclusion (see Section 5.1.1.3 for more details on formulation assignment for 


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patients who meet lack of clinical efficacy criteria).  The Sponsor’s personnel directly 
involved in the study conduct (except prespecified IMC members) will be masked to the 
Implant treatment arms’ ranibizumab formulation assignment (10 mg/mL vs. 40 mg/mL 
vs. 100 mg/mL) until the time of primary analyses (see Section 5.1.1.3 for more details
on formulation assignment for patients who meet lack of clinical efficacy criteria).  The
IMC will closely monitor patient safety throughout the study (see Section 3.1.4).
Clinical pharmacology and PK scientists may be unmasked early for the purposes of 
interpreting emerging safety and efficacy data; those staff will not be part of the study 
team or have any interactions with sites or investigators.
In addition, the VA examiner will only conduct refraction and VA assessments and will be 
masked to patient study eye assignment and patient treatment assignment.  The VA 
examiner will have no access to patient VA scores from previous visits, and will be only 
aware of the patient’s refraction data from previous visits.  The VA examiner may 
perform no other direct patient-care tasks.  Patients will be asked not to discuss their 
study eye assignment (right vs. left) with the VA examiner.  
3.1.1
Refill/Re-Treatment Criteria
Starting at the Month 1 visit, all randomized patients will be assessed monthly for the 
refill/re-treatment.  The patients randomized to the ITV injection arm will be treated 
monthly, regardless of whether they meet re-treatment criteria.  The patients randomized 
to the Implant treatment arms will have their Implant refilled only if any of the following 
criteria is met, as automatically determined by contacting IxRS:  

Increase in CFT of 75 µm on SD-OCT at the current visit compared with the 
average CFT over the last 2 available measurements, due to nAMD disease activity 
OR

Increase in CFT of 100 m from the lowest CFT measurement on study, due to 
nAMD disease activity 
OR

Decrease of 5 letters in BCVA at the current visit compared with the average 
BCVA over the last two available measurements, due to nAMD disease activity 
OR

Decrease of 10 letters from best recorded BCVA on study, due to nAMD disease 
activity 
OR

Presence of new macular hemorrhage, due to nAMD disease activity


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Note: To assess the need for refill at 1 month after initial fill, please utilize the following 
criteria:

Decrease of 10 letters in BCVA at the current visit compared with the baseline 
BCVA, due to nAMD disease activity
OR

Increase in CFT of 100 m at the current visit compared with the baseline CFT, 
due to nAMD disease activity
OR

Presence of new macular hemorrhage, due to nAMD disease activity
Patients assigned to the Implant treatment arms will be scheduled for a safety evaluation 
visit 7 (2) days after each refill.
The schedules of study assessments are provided in Appendix 1 and Appendix 2. 
3.1.2
Pharmacokinetic Evaluation
The objective of the PK analysis is to characterize the Implant sustained-delivery 
performance by characterizing the serum and optional aqueous humor concentrations 
(see Appendix 1 for details) of 10-mg/mL, 40-mg/mL, and 100-mg/mL formulations of 
ranibizumab delivered via the Implant.  PK parameters of interest will be estimated after 
implant and at subsequent refills using noncompartmental analysis (NCA) and/or a 
population PK model as appropriate; parameters will include area under the 
concentrationtime curve (AUC), maximum serum concentration (Cmax) observed, time to 
maximum concentration (tmax), steady-state serum concentration at the end of a dosing 
interval (Ctrough [predose]), and terminal half-life (t1/2).  
The population PK model couples the in-vitro release parameters of the Implant with the 
population pharmacokinetics of ranibizumab in AMD patients to describe the 
pharmacokinetics of ranibizumab in AMD patients receiving these Implants. Inter-patient 
variability will be assessed. Coefficient of variation (%CV) of serum concentration at 
each PK sampling time point will be reported.  The observed serum pharmacokinetics
will be compared to the expected PK profiles as predicted by a population PK model.
3.1.3
Planned Total Sample Size
The study will randomize approximately 220 patients, 60 per each of three Implant
treatment arms and 40 to the ITV injection arm (up to 60 sites). For further details 
see Section 6.1.


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3.1.4
Internal Monitoring Committee
Ongoing review of study data (including adverse events of special interest [AESIs], 
serious adverse events, adverse device effects [ADEs], and laboratory abnormalities) 
will be performed by the IMC. The IMC roles and responsibilities will be outlined in the 
IMC Agreement.
3.2
LENGTH OF STUDY
The completion of study treatment for all patients is defined as the date when the 
Sponsor makes the decision, based on the primary analysis results, to either terminate 
the study and discontinue study treatment, or offer patients entry into the RPDS 
Extension Study.  The primary analyses data is expected to be available approximately 
4 months after the Month 9 visit of the last patient randomized.
The length of the study is approximately 38 months.
3.3
END OF STUDY
The end of the study is defined as the date when the last patient, last study visit occurs.
3.4
RATIONALE FOR STUDY DESIGN
3.4.1
Rationale for Ranibizumab Dose Selection
Delivery of ranibizumab via the Implant was chosen to investigate an alternate dosing 
method.  Sustained release of ranibizumab from the Implant is an alternate dosing 
method that may result in less-frequent need of re-treatment than monthly dosing with 
ITV injections. It has the potential to reduce the number of patient visits, as well as the 
burden on patients, caregivers, and healthcare providers.  In addition, increased 
treatment compliance and optimum visual outcomes may result from the sustained 
delivery of ranibizumab through the Implant.
The three ranibizumab formulations administered via the Implant will be evaluated 
monthly to determine the efficacy and safety of each formulation.  Based on the fill 
volume of 20 L of the Implant, the maximum amount of ranibizumab with which the 
Implant can be initially filled and subsequently refilled is approximately 0.2 mg for the 
10-mg/mL formulation, 0.8 mg for the 40-mg/mL formulation, and 2 mg of ranibizumab 
for 100-mg/mL formulation.  The selection of the proposed Phase II doses was 
determined by several factors.  The selected doses are anticipated to maintain 
ranibizumab vitreous trough concentrations either below (10-mg/mL), at (40-mg/mL), or 
above (100-mg/mL) the vitreous drug levels estimated to be correlated with efficacy 
(12 g/mL), as assessed from pivotal studies that administered monthly 0.5-mg ITV 
injections.  Thus, the three dose levels may provide a range of exposures to assess the 
dose- and exposure-response relationships.  If the doses do not differentiate 
substantially on efficacy, as a result of potentially frequent refills for lower doses 
according to the “as needed” protocol defined refill criteria, then the treatment arms are 
expected to differentiate on the basis of time to first meeting refill criteria and number of 


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refills over the course of the study.  In addition, all doses were selected taking into 
account prior clinical experience to ensure patient safety.
3.4.2
Rationale for Pharmacokinetic Evaluation Schedule
The serum pharmacokinetics of ranibizumab following ITV administration have been well 
characterized, however the PK profile for sustained delivery is expected to be markedly 
different.  In order to characterize the PK profile and the in vivo sustained delivery of 
ranibizumab via the Implant, serum PK samples will be collected from patients in the 
Implant treatment arms at multiple timepoints (see Appendix 1) before and after refills.  
The sampling timepoints are expected to be sufficient to estimate key PK parameters of 
interest (see Section 3.1.2) following initial insertion of the ranibizumab-filled Implant and 
subsequent refills, and to demonstrate sustained exposure to ranibizumab.  An optional 
aqueous humor sample (collected prior to or immediately following Implant refills), and a 
vitreous or aqueous humor sample (collected at the start of explantation for patients 
undergoing an explantation procedure), will also be collected to further characterize 
Implant kinetics and relate serum to vitreous ranibizumab concentrations.  For additional 
details on ITV ranibizumab pharmacokinetics, refer to the RPDS IB.  
3.4.3
Rationale for Patient Population
Ranibizumab has been shown to be effective in preventing or reducing vision loss in 
patients with nAMD; therefore, this patient population was selected to be the first in 
which the RPDS would be evaluated. The goal is to demonstrate a treatment approach 
that maintains the efficacy seen with monthly ITV injections while reducing the number of 
ITV injections and monitoring visits. Other indications (diabetic macular edema, retinal 
vein occlusion) may also benefit but would be considered for investigation following the
Phase II study results in nAMD.
3.4.4
Rationale for Control Group
Ranibizumab is an approved treatment for nAMD in the European Union, United States,
and many other countries worldwide.  The monthly dosing of 0.5 mg (10-mg/mL) of ITV 
ranibizumab is the approved posology in the United States and was selected as the 
appropriate control group based on discussions with both the FDA and European 
Medicines Agency.  Therefore, patients in the control arm in the randomized phase of 
the study will be treated with monthly ITV injections of 0.5-mg dose of ranibizumab.
3.5
OUTCOME MEASURES 
The primary analysis of the study will take place after the LPI Month 9 visit has occurred. 
3.5.1
Primary Efficacy Outcome Measure
The primary efficacy outcome measure for this study is the time until a patient first
requires the Implant refill according to protocol-defined refill criteria. 


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3.5.2
Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures are as follows:

Change in BCVA from baseline at Month 9

Average change in BCVA from baseline over time

Change in BCVA from baseline over time

Change from baseline in CFT over time, as assessed on SD-OCT by the central 
reading center

Occurrence of Implant clogging (see Section 5.1.1.5 for details)
3.5.3
Safety Outcome Measures
The safety outcome measures are as follows:

Incidence of adverse events of special interest (see Section 5.2.3 for details):  
Adverse events associated with ranibizumab, the Implant, implant-associated 
procedures, and/or ancillary devices (see Table 1)

Incidence of “prespecified RPDS-associated adverse events” (see Section 6.5.1 for 
details)

Incidence of ocular and non-ocular adverse events and serious adverse events

Incidence of positive serum antibodies to ranibizumab
3.5.4
Pharmacokinetic Outcome Measures
The PK outcome measures related to ranibizumab serum concentration-time data 
following the Implant insertion and refills (see Appendix 1 for details):

Observed Cmax and selected post-dose serum concentrations after Implant insertion
and all subsequent refills 

Additional estimated PK parameter values including AUC, tmax, and t1/2 after Implant 
insertion and all subsequent refills

Observed serum concentrations (Ct) over time from monthly serum sampling when 
no refills are administered

Observed Ctrough prior to refills
In addition, optional anterior chamber (aqueous humor) will be collected to assess ocular 
drug concentration.  
3.5.5
Exploratory Outcome Measures
The exploratory outcome measures are as follows:

Treatment emergent macular atrophy in all treatment arms

The MacTSQ score at randomization and at Months 1, 6, 9, and the final or early 
termination visit for patients who speak English or Spanish (see Appendix 19)

Time to subsequent Implant refills according to protocol-defined refill criteria


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
Number of times a patient meets protocol-specified refill criteria

Proportion of patients in each Implant arm who first meet the protocol-defined refill 
criteria prior to and at Months 4, 5, and 6

Proportion of patients with an improvement of BCVA from baseline of 15 letters 
over time

Proportion of patients losing 15 letters in BCVA from baseline over time

Change in BCVA from baseline over time measured under low luminance conditions

Changes from screening in total lesion area, area of CNV lesion, and CNV leakage 
over time, as assessed by fluorescein angiography

Proportion of patients meeting lack of clinical efficacy criteria (see Section 5.1.1.3)

Proportion of patients requiring explantation

Changes in CNV perfusion over time, as assessed by OCT angiography
In addition, vitreous samples from the Refill Needle (if applicable), optional aqueous 
humor samples, and optional serum and plasma samples may be collected to assess 
the relationship between biomarkers and the disease characteristics and/or response to 
treatment with ranibizumab.  Optional whole blood samples will be collected for DNA 
extraction (genetic analysis) to assess the relationship between genetic variants and the 
disease characteristics and/or response to treatment with ranibizumab (see 
Section 4.6.12).
In addition, vitreous or aqueous humor samples before Implant explantation, and 
optional aqueous humor samples prior to or immediately following one or more refills 
and at the Day 7 safety visit post refill will be collected to characterize ranibizumab 
vitreous and aqueous humor concentration.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Patients with subfoveal neovascularization secondary to AMD diagnosed within 
9 months and treated with ITV anti-VEGF agents will be enrolled in the study.  Written 
informed consent will be obtained before initiation of any study-related procedures.  A 
patient’s screening visit should occur no sooner than 7 days following administration of 
the last ITV ranibizumab treatment to the study eye.  The screening visit will be followed 
by the randomization visit.  
The first study treatment (Day 1) may occur at the conclusion of the randomization visit 
for the ITV treatment arm; the Implant arm patients may have these two visits separated 
due to the systemic medication wash out period (see note below) and the surgery room 
availability.  Randomization visit and Day 1 study treatment visit must occur on a date 
such that no less than 28 days and no more than 37 days have elapsed from the
patient’s last study eye ITV ranibizumab treatment.


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There are 4 patient eligibility scenarios based on prior anti-VEGF treatment history.
1.
Newly diagnosed nAMD patients who are treatment naïve. These patients will 
undergo pre-screening if they satisfy eligibility criteria and sign informed consent
(Table 2). During the pre-screening, patients will receive two ranibizumab ITV 
treatments to determine if they demonstrate response to ranibizumab treatment as 
outlined per the eligibility criteria (see Section 4.1.1).  
2.
Patients diagnosed with nAMD in the study eye within 9 months prior to 
screening who have been treated with a single anti-VEGF ITV injection. These 
patients may receive one run-in ITV ranibizumab treatment prior to screening if they 
satisfy eligibility criteria and sign the informed consent form (see Table 2).
3.
Patients diagnosed with nAMD in the study eye within 9 months prior to 
screening who have been treated with no more than eight anti-VEGF ITV 
injections and with the most recent dose being aflibercept or bevacizumab.  
These patients may receive one run-in ITV ranibizumab treatment prior to screening 
if they satisfy eligibility criteria and sign the informed consent form (see Table 2).
4.
Patients diagnosed with nAMD in the study eye within 96 months prior to 
screening who have been treated with no more than nine anti-VEGF ITV 
injections and with the most recent dose being ranibizumab.  These patients
can proceed directly to screening (see Table 2).
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:  
General Inclusion Criteria

Age 50 years

Willingness and ability to provide signed informed consent and Health Insurance 
Portability and Accountability Act (HIPAA) authorization

Willingness and ability to undertake all scheduled visits and assessments

For sexually active women of childbearing potential, agreement to the use 
of an appropriate form of contraception (or abstinence) for the duration of the study.  
A woman is considered not to be of childbearing potential if she is postmenopausal 
or has undergone hysterectomy and/or bilateral oophorectomy.  
For women who are not postmenopausal (12 months of non-therapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus):  
agreement to remain abstinent or use single or combined contraceptive 
methods that result in a failure rate of 1% per year during the treatment period 
and for at least 30 days after the last dose of study treatment
Abstinence is only acceptable if it is in line with 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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
Sexually active men are recommended to use a barrier contraceptive method 
(condom), even if they have been surgically sterilized, for the duration of the 
treatment period and for at least 30 days after the last dose of study treatment.
Ocular Inclusion Criteria (Study Eye)

Newly diagnosed with nAMD within 9 months prior to screening visit

Patient must have received at least 2 prior anti-VEGF injections (including 
ranibizumab, bevacizumab, or aflibercept).  However, the most recent anti-VEGF 
injection must have been ranibizumab and must have occurred at least 7 days prior 
to the screening visit. 

Demonstrated response to prior ITV anti-VEGF treatment, as evidenced by the 
following:
Decrease in CFT of 50 m since commencing ITV anti-VEGF treatment
OR
Stable or improved BCVA since commencing ITV anti-VEGF treatment

BCVA using ETDRS charts of 20/2020/200 Snellen equivalent 

All subtypes of nAMD CNV lesions are permissible (i.e., classic CNV, occult CNV, or 
with some classic CNV component, or retinal angiomatous proliferation lesions). 
Active primary CNV lesions at the time of diagnosis of nAMD must be subfoveal 
or juxtafoveal with a subfoveal component (as defined in Table 4) related to the 
CNV activity (such as subretinal hemorrhage, subretinal fluid, or RPE 
detachment)
Note: Refer to Table 5 for further details on imaging requirements.
Table 4
Definition of Terms Pertaining to AMD Inclusion Criteria
Term
Definition
Primary
Newly diagnosed within 9 months of screening visit 
Subfoveal
Including the center of the fovea within the boundaries of the CNV
Juxtafoveal
Confined to an area up to 199 m from the geometric center of the fovea
Total area of
lesion
A contiguous area of abnormal tissue in the macula that encompasses 
angiographically documented CNV with possible additional components of 
subretinal hemorrhage, blocked fluorescence not from hemorrhage, 
serous detachment of the retinal pigment epithelium, and subretinal fibrosis
AMD
Clinical and/or angiographic signs consistent with AMD (e.g., drusen, 
retinal pigment epithelial changes, CNV) with no other likely etiologic 
explanations for the degenerative changes
AMD age-related macular degeneration; CNV choroidal neovascularization.


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Ocular Inclusion Criteria for Pre-Screening (Study Eye) (If Applicable)

Treatment naïve nAMD patients

BCVA using ETDRS charts of 20/20 to 20/200 Snellen equivalent

All subtypes of nAMD CNV lesions are permissible (i.e., classic CNV, occult CNV, or 
with some classic CNV component, or retinal angiomatous proliferation lesions). 
Active primary CNV lesions must be subfoveal or juxtafoveal with a subfoveal 
component (as defined in Table 4) related to the CNV activity (such as 
subretinal hemorrhage, subretinal fluid, or RPE detachment)
Note: Refer to Table 5 for further details on imaging requirements.  
Ocular Inclusion Criteria for Run-In (Study Eye) (If Applicable)

Previous treatment with a single anti-VEGF ITV injection or no more than eight
anti-VEGF ITV injections, with aflibercept or bevacizumab being the most recent 
injection 

BCVA using ETDRS charts of 20/20 to 20/200 Snellen equivalent

All subtypes of nAMD CNV lesions are permissible (i.e., classic CNV, occult CNV, or 
with some classic CNV component or retinal angiomatous proliferation lesions) 
Active primary CNV lesions at the time of diagnosis of nAMD must be subfoveal 
or juxtafoveal with a subfoveal component (as defined in Table 4) related to the 
CNV activity (such as subretinal hemorrhage, subretinal fluid, or RPE 
detachment)
Note: Refer to Table 5 for further details on imaging requirements.


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Table 5
Imaging Requirements at Pre-Screening, Run-In, and Screening
Visit
Applies to
Required Ocular 
Imaging at the 
Study Visit
Required 
Historical 
OCT a
Imaging 
Evaluation
Pre-screening
Treatment-naive patients
FA, SD-OCT b
NA b
Investigator (locally)
Run-in
Patients previously 
treated with anti-VEGF c
NA
Yes
Investigator (locally)
Screening
All patients
FA, FP, FAF, SD-
OCT, lens photo
Yes
Central reading 
center d
a Historical OCT taken at the time of diagnosis of nAMD is required to determine patient’s 
eligibility, and must be submitted to the reading center at the screening visit only.  If fluorescein 
angiograms were taken at the time of diagnosis of nAMD, they must be submitted to the 
reading center as well. If available, historical fluorescein angiograms will be evaluated by the 
reading center, but are not required to determine patient’s eligibility.  Refer to the Reading 
Center Manuals for details. 
b Fluorescein angiograms and SD-OCT will be required for entry to Pre-Screening, and must be 
taken following the instructions on the Reading Center Manual; these images will be used as 
historical images for patient’s eligibility at the screening visit.
c See Table 2 for details.
d The central reading center will evaluate fundus photography, fluorescein angiograms, and SD-
OCT for determination of a patient’s eligibility.  Historical OCT taken at the time of diagnosis of 
nAMD is also required to determine patient’s eligibility at the screening visit.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
Prior Ocular Treatment

Treatment with ITV anti-VEGF agents other than ranibizumab within 1 month prior to 
the randomization visit in either eye

History of vitrectomy surgery, submacular surgery, or other surgical intervention for 
AMD in the study eye

Prior treatment with Visudyne®, external-beam radiation therapy, or transpupillary 
thermotherapy in the study eye

Previous treatment with ITV corticosteroid injection or device implantation in the 
study eye

Previous focal laser photocoagulation used for AMD treatment in the study eye

Prior participation in a clinical trial involving anti-angiogenic drugs, other than 
ranibizumab, in either eye within 2 months prior to the randomization visit

Treatment with Visudyne® in the fellow eye 7 days preceding screening visit


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CNV Lesion Characteristics

Subretinal hemorrhage in the study eye that involves the center of the fovea, if the 
size of the hemorrhage is either 50% of the total area of the lesion or 1 disc area 
(2.54 mm2) in size at screening

Subfoveal fibrosis or atrophy in the study eye

CNV in either eye due to other causes, such as ocular histoplasmosis, trauma, or 
pathologic myopia
Note: Historical OCT taken at the time of diagnosis of nAMD will also be required to 
determine patient’s eligibility at the screening visit.  If fluorescein angiograms were taken 
at the time of diagnosis of nAMD, they must be submitted to the reading center as well. 
If available, historical fluorescein angiograms will be evaluated by the reading center, but
are not required to determine patient’s eligibility. If historical OCT images are not 
available or are not of sufficient quality to be evaluated by the Reading Center, patients
would not be eligible for enrollment in the study.
Concurrent Ocular Conditions

BCVA using ETDRS charts lower than 20/200 Snellen equivalent in the fellow eye

Retinal pigment epithelial tear involving the macula in the study eye

Any concurrent intraocular condition in the study eye (e.g., cataract, glaucoma, or 
diabetic retinopathy) that, in the opinion of the investigator, 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) in the study eye

History of vitreous hemorrhage in the study eye within 3 months prior to the
randomization visit

History of rhegmatogenous retinal detachment or macular hole (Stage 3 or 4) in the 
study eye

History of idiopathic or autoimmune-associated uveitis in either eye

Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye

Aphakia or absence of the posterior capsule in the study eye
Previous violation of the posterior capsule break in the study eye is also 
excluded unless it occurred as a result of yttrium aluminium garnet laser 
posterior capsulotomy in association with prior, posterior chamber intraocular 
lens implantation.

Spherical equivalent of the refractive error in the study eye demonstrating more than 
8 diopters of myopia

For patients who have undergone prior refractive or cataract surgery in the study 
eye, the preoperative refractive error in the study eye does not exceed 8 diopters of 
myopia


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
Intraocular surgery (including cataract surgery) in the study eye within 3 months 
preceding the randomization visit

Uncontrolled ocular hypertension or glaucoma in the study eye (defined as 
intraocular pressure [IOP] 25 mmHg or a Cup to Disc ratio 0.8, despite treatment 
with anti-glaucoma medication) and any such condition for which the investigator 
feels may require a glaucoma filtering surgery while in the study

History of glaucoma-filtering surgery, tube shunts, or microinvasive glaucoma 
surgery in the study eye

History of corneal transplant in the study eye
Concurrent Systemic Conditions

Uncontrolled blood pressure (defined as systolic 155 mmHg and/or diastolic 
95 mmHg, based on the average of 3 readings taken with the patient in a resting 
state [i.e., supine or sitting, but consistent across readings] over a period of up to 
15 minutes at screening)
If the average of 3 readings exceeds these values, patient’s blood pressure 
must be controlled by antihypertensive medication.  The patient can become 
eligible for rescreening if medication is taken continuously for at least 30 days 
prior to the randomization visit.

Uncontrolled atrial fibrillation within 3 months of informed consent

History of stroke within the last 3 months prior to informed consent

History of myocardial infarction within the last 3 months prior to informed consent

History of other disease, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of ranibizumab or placement of the Implant, that might affect 
interpretation of the results of the study or renders the patient at high risk of 
treatment complications

Current treatment for any active systemic infection

Use of any systemic anti-VEGF agents

Use of oral corticosteroids (prednisone 10mg/day or equivalent)  

Use of anticoagulants, antiplatelets (other than aspirin), or medications known to 
exert similar effects at the time of study entry for a pre-existing condition.  Oral
anticoagulants include vitamin K antagonists (e.g., warfarin), direct factor Xa 
inhibitors (e.g., rivaroxaban, apixaban, edoxaban, fondaparinux) and direct thrombin 
inhibitors (e.g., dabigatran). Antiplatelet therapies include clopidogrel, prasugrel, 
dipyridamole, ticagrelor and ticlodipine (see Section 4.5.2).

Bleeding disorders, including platelet disorders, acquired or hereditary coagulations 
disorders, and acquired or hereditary vascular disorders.


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
Active malignancy 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.

History of allergy to fluorescein, not amenable to treatment

Inability to obtain fundus photographs, fluorescein angiograms, fundus 
autofluorescence, or SD-OCT images of sufficient quality to be analyzed and graded 
by the central reading center 

Inability to comply with study or follow-up procedures

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

Intolerance or hypersensitivity to topical anesthetics, mydriatic medications, any of 
the excipients in ranibizumab, fluorescein, or components of the Implant

Requirement for continuous use of any medications or treatments indicated in the 
“Prohibited Therapy” section (see Section 4.5.2)

Women who are pregnant or lactating or intending to become pregnant during the 
study

Women who are of childbearing potential, including those who have had tubal 
ligation, must have a negative serum pregnancy test result within 21 days prior to 
Day 1.  A woman is considered not to be of childbearing potential if she is 
postmenopausal or has undergone hysterectomy and/or bilateral oophorectomy.

No additional exclusions may be applied by the investigator, in order to ensure that 
the study population will be representative of all eligible patients.
4.2
METHOD OF TREATMENT ASSIGNMENT AND MASKING
4.2.1
Randomization and Masking
Patients will be randomized through an IxRS in a 3:3:3:2 ratio so that approximately 
60 patients will receive the Implant with 10-mg/mL ranibizumab formulation, 60 patients 
will receive the Implant with 40-mg/mL ranibizumab formulation, 60 patients will receive 
the Implant with 100-mg/mL ranibizumab formulation, and 40 patients will receive 
monthly ITV injections of 10-mg/mL ranibizumab formulation. On the day of patient 
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 (65 letters vs. 66 letters) and number of prior anti-VEGF injections (3 vs 4).
Study patients and all study site personnel will be masked to the Implant treatment arms’ 
ranibizumab formulation assignment (10 mg/mL vs. 40 mg/mL vs. 100 mg/mL) until the 
study’s conclusion (see Section 5.1.1.3 for more details on formulation assignment for 
patients who meet lack of clinical efficacy criteria).  The Sponsor’s personnel directly 


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involved in the study conduct (except prespecified IMC members) will also be masked to 
the Implant treatment arms’ ranibizumab formulation assignment (10 mg/mL vs. 
40 mg/mL vs. 100 mg/mL) until unblinding of treatment code after database lock
(see Section 5.1.1.3 for more details on formulation assignment for patients who meet 
lack of clinical efficacy criteria).  In addition, the VA examiner will conduct only refraction, 
BCVA assessment, BCVA assessment under low luminance conditions, and will be 
masked to patient study eye assignment and patient treatment assignment.  The VA 
examiner will have no access to the BCVA scores of a patient’s previous visits, and will 
be only aware of the patient’s refraction data from previous visits.  The VA examiner may 
provide no other direct patient care.  Patients will be asked not to discuss their study eye 
assignment with the VA examiner.
Patients and study site personnel will not be masked with regard to patient assignment 
to the ITV arm or an Implant arm because of the difficulties of maintaining masking 
following the surgical procedure, the additional safety visits applicable only to the Implant 
arms, and Implant visualization upon ophthalmic examination.
4.2.2
Unmasking Procedure
Treatment assignment should be unmasked for a patient in an Implant treatment arm in 
the event of a life-threatening medical emergency (if the investigator considers this 
necessary for treatment of the patient) that requires immediate unmasking or in the 
event of an unexpected serious adverse events judged by the investigator as related to 
study drug or RPDS, for FDA safety reporting.  In such cases, unmasking will be 
implemented following standard procedures.
4.3
STUDY TREATMENT 
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Ranibizumab Port Delivery System
For the list of the components of the RPDS, see Table 1.  For detailed information on the 
RPDS components, initial Implant fill, insertion, refill, as well as the explantation 
procedure consult the RPDS IFU and RPDS IB documents. 
Note:  Unless otherwise directed by the Sponsor, only ranibizumab will be injected into 
the Implant.
4.3.1.2
Formulation of Ranibizumab Used to Fill/Refill the Implant
Ranibizumab 10 mg/mL, 40 mg/mL, and 100 mg/mL
Ranibizumab is formulated as a sterile solution aseptically filled in a sterile 3-mL 
stoppered glass vial.  Each vial contains 0.5 mL of the 10-mg/mL, 40-mg/mL, or 
100-mg/mL formulations of ranibizumab aqueous humor solution (pH 5.5) with 10 mM 
histidine hydrochloride (HCI), 10% ,-trehalose dihydrate, and 0.01% polysorbate 20, 
pH 5.5.  Each vial contains no preservative and is suitable for single use only.  Vial
content should not be frozen or shaken and should be protected from direct light. 


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Ranibizumab vials must be refrigerated at 2C to 8C (36F to 46F) upon receipt until 
used. All vials will be labeled as required by the relevant regulatory agencies. 
4.3.1.3
Formulation of Ranibizumab Used in ITV Injection Control Arm 
Ranibizumab 10 mg/mL
Ranibizumab is formulated as a sterile solution aseptically filled in a sterile 2-mL 
stoppered glass vial.  Each vial contains 0.3 mL of the 10-mg/mL formulation of 
ranibizumab aqueous humor solution (pH 5.5) with 10 mM histidine HCI, 
10% ,-trehalose dihydrate, and 0.01% polysorbate 20, pH 5.5.  The vial contains no 
preservative and is suitable for single use only.  Vial contents should not be frozen or 
shaken and should be protected from direct light. Ranibizumab vials must be 
refrigerated at 2C to 8C (36F to 46F) upon receipt until used.  Each vial will be 
labeled as required by the relevant regulatory agencies.
For further details, see the RPDS IB.
4.3.1.4
Formulation of Open-Label Ranibizumab
Ranibizumab 10 mg/mL
Ranibizumab is formulated as a sterile solution aseptically filled in a sterile 2-mL 
stoppered glass vial.  Each vial contains 0.3 mL of the 10-mg/mL formulation of 
ranibizumab aqueous humor solution (pH 5.5) with 10 mM histidine HCI, 
10% ,-trehalose dihydrate, and 0.01% polysorbate 20, pH 5.5.  The vial contains no 
preservative and is suitable for single use only.  Vial contents should not be frozen or 
shaken and should be protected from direct light. Ranibizumab vials must be 
refrigerated at 2C to 8C (36F to 46F) upon receipt until used.  
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Implant
Please see the RPDS IFU document for a detailed description of the Implant initial fill, 
insertion, refill, and explantation procedures.
4.3.2.2
Dosage
Patients in the Implant Treatment Arms
Patients will have the Implant (prefilled with approximately 20 L of either the 10-mg/mL 
(approximately 0.2 mg dose), 40-mg/mL (approximately 0.8 mg dose), or 100-mg/mL 
formulation (approximately 2-mg dose) of ranibizumab) surgically inserted in the study 
eye at the Day 1 visit following their randomization visit.  Starting at the Month 1 visit, 
patients will be evaluated monthly for the need for Implant refill with the10-mg/mL, 
40-mg/mL, or 100-mg/mL formulations of ranibizumab according to their randomization
as per protocol-specified refill criteria (see Section 3.1.1).  If the criteria are not met, no
Implant refill will be given. At each refill, a volume of approximately 100 L of 
ranibizumab will be injected in situ into the Implant through the septum to exchange the
remaining contents of the Implant with newly introduced ranibizumab.  During the refill 
procedure, the contents of the Implant will be collected in the fluid collection reservoir of 


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the Refill Needle, if applicable (see the RPDS IFU for further details). The volume of 
newly introduced ranibizumab remaining in the Implant after the refill procedure will be 
approximately 20 L.  After the initial fill of the Implant with ranibizumab, patients will be 
evaluated for their Implant refill according to protocol-specified refill criteria 
(see Section 3.1.1) at each of their scheduled visits until the study treatment completion 
(see Section 3.2 for the definition).  Missed treatments will not be made up.
If a study patient meets criteria for lack of clinical efficacy, he or she will receive a rescue 
injection with open-label ranibizumab.  After that, he or she will receive the 100-mg/mL 
formulation for all future refills (see Section 5.1.1.3 for more details).
Study visits for the Implant treatment arms will be scheduled to occur according to the 
schedule in Appendix 1 and have to be relative to the Day 1 (the first study treatment) 
visit date until patients complete the study.
Patients in the ITV Injection Treatment (Control) Arm
Patients will receive their first ITV injection of 50 L of the 10-mg/mL ranibizumab 
(0.5 mg dose) formulation at the Day 1 visit, which may occur (if feasible) at the 
conclusion of the randomization visit.  Afterwards, patients will receive monthly ITV 
injections of 50 L of 10-mg/mL formulation.  Patients will be receiving the study 
treatment at each scheduled monthly visit until the study treatment completion (see
Section 3.2 for the definition).  Missed treatments will not be made up.
Study visits for the ITV treatment arm will be scheduled to occur according to the 
schedule in Appendix 2 and have to be relative to the Day 1 (the first study treatment) 
visit date until patients complete the study.
Ranibizumab dosing should not occur earlier than 22 days after the previous dosing.  
Guidelines for treatment interruption or discontinuation are provided in Section 5.1.1.1
and Table 6.
Pre-Screening
Pre-screening is available for newly diagnosed nAMD patients who are treatment naïve 
in the study eye.  Patients eligible for the pre-screening will receive their first ITV 
injection of 50 L of the 10-mg/mL ranibizumab (0.5 mg dose) formulation at the 
Pre-Screening visit 1, and their second injection 307 days later (Pre-Screening visit 2).  
A third pre-screening treatment may be allowed after consultation with the Medical 
Monitor.  Afterwards, patients will undergo the screening visit, which will occur at least 
7 days following administration of the last pre-screening ITV ranibizumab treatment to 
the study eye (see Appendix 3).


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Run-In
Run-in is available for patients diagnosed with nAMD in the study eye within 9 months 
prior to screening who have been treated with a single anti-VEGF ITV injection, or with 
no more than eight anti-VEGF ITV injections and with the most recent dose being 
aflibercept or bevacizumab.  Patients eligible for the run-in treatment will receive their 
single ITV injection of 50 L of the 10 mg/mL ranibizumab (0.5 mg dose) formulation in 
the study eye at the time of consent.  In exceptional cases, a second run-in treatment 
may be allowed after consultation with the Medical Monitor.  Afterwards, patients will 
undergo the screening visit, which will occur at least 7 days following administration of 
the run-in ITV ranibizumab treatment to the study eye (see Appendix 4).
4.3.2.3
Administration
Implant Treatment Arms
Prior to Implant insertion or explantation, patients will be required to verify that they have 
self-administered antimicrobial eye drops to the study eye 4 times within the previous 
24 hours.  As per investigator’s discretion, patients may also be required to have 
self-administered antimicrobial eye drops to the study eye 4 times within the 24 hours
prior to potential Implant refills.
All patients must be instructed to self-administer antimicrobial eye drops to the study eye 
4 times daily for 3 days following any refills.  Antimicrobial eye drops to the study eye will 
also be required 4 times daily for 7 days following Implant insertion and explantation.
All patients randomized to the Implant arm and receiving ongoing aspirin or NSAID 
treatment must interrupt aspirin or NSAID treatment 7 days prior to Implant insertion or 
explantation and until at least the Day 2 safety visit following the procedure.
Prior to and during the Implant insertion procedure, blood pressure must be controlled. 
Before surgery, blood pressure must be checked after the patient has been in a resting 
state (i.e., supine or sitting) for at least 15 minutes. If blood pressure exceeds the 
recommended levels (i.e., between 100/60 mmHg and 155/95 mmHg), the Implant 
insertion surgery must be rescheduled.
Patients in the Implant treatment arms will have the Implant, prefilled with ranibizumab,
surgically inserted into the study eye at the Day 1 visit and subsequently refilled at 
monthly visits only if the protocol-specified refill criteria are fulfilled (see Section 3.1.1).  
The insertion and explantation procedures must be performed in the surgery room while 
the refill procedure is permitted in the physician office setting.  For detailed instructions 
on the Implant initial fill, insertion, refill, and explantation procedures, refer to the 
RPDS IFU.


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ITV Injection Arm
Patients’ self-administered antimicrobial treatments will be prescribed at the 
investigator’s discretion. Prior to the monthly ITV injections, patients who are prescribed 
antimicrobials will be required to verify that they have self-administered their 
antimicrobials eye drops to the study eye pre- and post-injection. For detailed 
instructions on pre-injection preparation, administering the ITV injection, and post-ITV 
injection procedures for the study eye, consult Appendix 7 to Appendix 9.
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.
All Treatment Arms
Adverse events associated with an overdose or incorrect administration of ranibizumab
should be recorded on the Adverse Event electronic Case Report Form (eCRF).
ITV Injection of Open-Label Ranibizumab 
Patients’ self-administered antimicrobial treatments will be prescribed at the 
investigator’s discretion.
4.3.2.4
Storage
4.3.2.4.1
Ranibizumab Port Delivery System 
Ranibizumab.  Vials of ranibizumab are for single use only.  A vial used for one patient 
must not be used for any other patient. 
Upon receipt, study drug kits must be refrigerated at 2°C to 8°C (36°F to 46°F).  Sites 
must monitor and record refrigerator temperature at all times (24 hours per day, 7 days 
per week).  DO NOT FREEZE. Vial content should not be frozen or shaken and should 
be protected from direct light.  Store in original carton before and after use.
RPDS. Each Implant is held by an Insertion Tool and is packaged inside a sterile barrier 
system pouch.  The Initial Fill Needle and Explant Tool are each packaged separately in
a sterile barrier pouch system. The Refill Needles are packaged separately and 
individually in a tray. The Implant, Insertion Tool, Initial Fill Needle, Refill Needle, and 
Explant Tool should be maintained at a room temperature of 15C to 30C (59F to 
86F).  The storage location at the clinical site must have restricted access and be
available only to study personnel. The Implant, Initial Fill Needle, Insertion Tool, and 
Explant Tool are supplied sterilized by exposure to ethylene oxide. The Refill Needles 
are sterilized by e-beam.
DO NOT RESTERILIZE.
The RPDS components (see Table 1) must not be resterilized 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.


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DO NOT USE if the package is damaged, punctured, or broken as sterility may be 
compromised.  Do not use beyond the expiration date.
4.3.2.4.2
Investigational Medicinal Product and RPDS Accountability
All investigational medicinal products (IMPs) (ranibizumab) and RPDS required for 
completion of this study (including all the components of the RPDS, see Table 1) will be 
provided by the Sponsor.  The investigational site will acknowledge receipt of IMPs using 
the IxRS to confirm the shipment condition and content.  Any damaged shipments will be 
replaced.
RPDS (Initial Fill Needle, Refill Needle with its content, explanted Implant with its 
remaining content, Explant Tool, and Insertion Tool) must be returned to the Sponsor or 
Sponsor’s designee with the appropriate documentation.
In order to ensure traceability, each device component of the RPDS will be identified by 
a batch number.
Accurate records of all IMPs and RPDS received at, dispensed from, returned to, and
destroyed and/or disposed of by the study site should be recorded on the Drug and 
RPDS Inventory Logs.  See the Study Manual for further details.
IMPs (used, damaged drug kits) will either be disposed of at the study site according to 
the study site’s institutional standard operating procedure or returned to the Sponsor 
with the appropriate documentation.  The site’s method of IMP destruction must be 
agreed to by the Sponsor.  The site must obtain written authorization from the Sponsor 
before any IMP is destroyed.  IMP destruction must be documented on the appropriate 
form. See site Pharmacy binder for further details.
4.3.2.4.3
Ranibizumab (Non-Study Eye)
At the discretion of the evaluating investigator, study patients may receive ITV injection 
of ranibizumab for their fellow (non-study) eye.  The drug will be open-label ranibizumab 
and will be supplied by the Sponsor.  If a change in therapy is clinically indicated for the 
fellow eye per investigator judgment, the change must be discussed and agreed with the 
Medical Monitor prior to being made.  
4.3.2.4.4
Open-Label Ranibizumab
The drug will be open-label ranibizumab and will be supplied by the Sponsor.
4.4
PRODUCT QUALITY ASSESSMENTS
4.4.1
Ranibizumab in Contents Retrieval from Implant
4.4.1.1
Explanted Implants with Contents
Following explantation, the Implants containing a mixture of ranibizumab drug product 
(along with the vitreous components, which may have diffused into the Implant) will be 
preserved and forwarded by the site to the Sponsor or Sponsor selected designee for 


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potential future analysis.  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.
4.4.1.2
Ancillary Devices
The Initial Fill Needle, Insertion Tool, Refill Needle, and Explant Tool must be returned to 
the Sponsor or Sponsor’s designee for possible physical inspection and/or functional 
testing.
4.4.2
Continued Access to RPDS
Currently, the Sponsor does not plan to provide ranibizumab via Implant or via ITV 
injections or to provide other study interventions to patients after the conclusion of the 
study or following early patient withdrawal.  The Sponsor will evaluate the 
appropriateness of continuing to provide ranibizumab treatment to Implant treatment 
arms patients after evaluating RPDS efficacy, safety, and PK data gathered in the study.
Depending on the results of the study, the Sponsor may offer study patients in the 
Implant arms entry into a separate RPDS Extension Study to continue to provide 
ranibizumab via the Implant in an open-label manner.  If the results from this trial do not 
warrant further investigation of the RPDS, all patients in the Implant arms will have their 
Implants explanted.
4.5
CONCOMITANT THERAPY
4.5.1
Permitted Therapy 
Concomitant medications are any prescription drugs or over-the-counter preparations 
other than protocol-specified procedural medications (e.g., dilating drops, fluorescein 
dyes, cefazolin or vancomycin, or medications associated with Implant insertion, refill,
and extraction procedures) and pre- and poststudy treatment medications (e.g., 
proparacaine, antimicrobials, steroids) used by a patient within 7 days preceding the 
randomization visit until conclusion of the patient’s study participation or early 
termination visit.
Patients who use other maintenance therapy should continue its use unless prohibited 
as indicated in Section 4.5.2.  All concomitant medications should be reported to the 
investigator and recorded on the appropriate eCRF:

Following randomization, if a patient’s fellow eye requires treatment for nAMD, 
treatment with ITV ranibizumab injection may be administered at the discretion of 
the evaluating investigator. If a change in therapy is clinically indicated for the fellow 
eye per investigator judgment, the change must be discussed and agreed with the 
Medical Monitor prior to being made.  

All patients randomized to the Implant arm and receiving ongoing aspirin or NSAID 
treatment must interrupt aspirin or NSAID treatment 7 days prior to implant insertion 
or explantation. These medications can be restarted, if appropriate, after the Day 2
safety visit.


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
As per investigator discretion, the Implant arms patients who had the Implant 
explanted may receive ITV ranibizumab for their study eye treatment.

Cataract surgery in the study eye may be performed if clinically indicated and should 
occur 7 or more days after the last study treatment; the next study treatment will be 
held for 28 or more days following the surgery.  At least one study treatment 
(e.g., monthly ITV injection treatment arm) may be missed after cataract surgery is 
performed.

The onset of increased IOP and/or glaucoma in the study eye during a patient’s 
study participation should be treated as clinically indicated. 

Use of topical steroids post-implant insertion or post-explantation surgery in the 
study eye is permitted.

In a limited fashion, intra-articular or intramuscular corticosteroids may be allowed 
after consultation with the Medical Monitor.
4.5.2
Prohibited Therapy
At the discretion of their physician, patients may continue to receive all medications and 
standard treatments administered for other conditions except in the following instances:

Concurrent use of any systemic anti-VEGF agents

Concurrent use of oral corticosteroids (prednisone 10mg/day or equivalent)

Concurrent study eye treatment for nAMD with anti-VEGFs other than the study 
drug treatment

Concurrent fellow eye treatment for nAMD with anti-VEGFs other than ranibizumab.  
If a change in therapy is clinically indicated for the fellow eye per investigator 
judgment, the change must be discussed and agreed with the Medical Monitor prior 
to being made.

Concurrent treatment with focal laser photocoagulation for nAMD in the study eye

Concurrent treatment with Visudynefor nAMD in either eye

Concurrent use of ITV or subtenon corticosteroids in the study eye

Concurrent use of and participation in other experimental therapies (except those 
with minerals and vitamins) are not allowed.  
Note:  If patients receive the above listed treatments at any time during the study, the 
Sponsor will determine if discontinuation of the study treatment is required.

Concurrent use of anticoagulants, antiplatelets (other than aspirin), or medications 
known to exert similar effects are prohibited at study entry, but may be initiated after 
the Day 14 safety visit if medically necessary and in consultation with the Medical 
Monitor.  Oral anticoagulants include vitamin K antagonists (e.g., warfarin), direct 
factor Xa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, fondaparinux), and 
direct thrombin inhibitors (e.g., dabigatran).  Antiplatelet therapies include 
clopidogrel, prasugrel, dipyridamole, ticagrelor, and ticlodipine.


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
Concurrent use of aspirin or NSAID at both the time of Implant insertion and 
explantation procedure (see Section 4.5.1 and Section 4.3.2.3 for aspirin and 
NSAID interruption requirements)

Use of magnetic resonance imaging (MRI) scans for patients in the Implant
treatment arms is conditional.  Investigators should discuss with the Medical Monitor 
if MRI use is required prior to this procedure being performed.  For additional 
information refer to RPDS IFU.
4.6
STUDY ASSESSMENTS 
4.6.1
Medical History, Concomitant Medication, and Demographic 
Data
Medical history includes clinically significant diseases, surgeries, smoking history, and
use of alcohol.
All medications (e.g., prescription drugs, over-the-counter drugs, herbal/homeopathic 
remedies, nutritional supplements) other than protocol-specified procedural medications 
(e.g., dilating drops, fluorescein dyes, cefazolin or vancomycin, Implant insertion, refill 
and extraction procedures medications, and pre- and post-treatment medications 
[e.g., proparacaine, antimicrobials, steroids]) used by the patient within 7 days prior to 
the randomization visit until the study completion will be recorded on the eCRF 
concomitant medication log.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.6.2
Vital Signs
Vital signs will include measurements of pulse and systolic and diastolic blood pressure 
obtained with the patient in a seated position after resting for 5 minutes.  Height and 
weight will also be recorded at screening.  At visits when a patient receives study 
treatment, vital signs will be measured pre-treatment.
4.6.3
Physical Examinations
A targeted physical examination should include an evaluation of the head, eyes, ears, 
nose, throat, and cranial nerves.  A patient’s height and weight will be recorded as well. 
If any abnormalities are noted during the study, the patient may be referred to another 
doctor.
Changes from baseline abnormalities should be recorded in patient notes.  New or
worsened clinically significant abnormalities should be recorded as adverse events on 
the Adverse Event eCRF.


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4.6.4
Ocular Assessments
Except where noted, all ocular assessments should be performed for both eyes:

BCVA on ETDRS chart at a starting distance of 4 m (perform prior to dilating eyes; 
see Appendix 10)

BCVA on ETDRS chart under low luminance conditions at a starting distance of 4 m 
(perform prior to dilating eyes; see Appendix 11)

The following measurement will be performed in both eyes of the patients in the 
Implant treatment arms, from sites that have ultrasound or optical biometry, and will
be recorded on the appropriate eCRF: 
–
Axial length measurement (ultrasound or optical biometry)

IOP measurement
–
At each monthly visit, 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
–
Before Implant insertion or explantation surgery, the treating physician must 
check IOP for the study eye using Tono-Pen tonometry. 
–
Upon completion of the Implant insertion or explantation surgery, the treating 
physician must check IOP for the study eye only by digital palpation before 
patching the eye.  

Slit lamp examination (for grading scales for flare/cells and vitreal hemorrhage 
density; see Appendix 12)

Dilated binocular indirect high-magnification ophthalmoscopy
In addition, examinations will also be performed for patients in the Implant
treatment arms after Implant insertion in the study eye, and then on Days 2, 7 
(2 days), and 14 (2 days) after the Day 1 visit; afterward, dilated 
ophthalmoscopy examinations will be performed at each monthly visit to 
monitor the Implant placement, to evaluate visible clogging of the RCE tip, and 
to evaluate other Implant problems.

Finger counting test, followed by hand motion and light perception tests (as 
applicable) performed within 15 minutes following Implant refill or ITV ranibizumab
for the study eye only by the treating physician

After each treatment, the patients will remain in the office or in the surgical center
(as applicable) for approximately 40 minutes.  If there are no safety concerns 
40 (10) minutes following treatment, 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.


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
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.
4.6.5
Ocular Imaging
Note:  All ocular images will be forwarded to the central reading center for grading and/or 
storage, starting from the screening visit. See central reading center manual for details.
The following ocular images of both eyes with be collected from all study patients:

Fundus photographs (see Appendix 14) 

Lens photograph (fundus reflex photograph)

Fluorescein angiograms (to be performed after laboratory samples are obtained; 
see Appendix 15)

SD-OCT scans (Heidelberg; see Appendix 16)

Fundus autofluorescence (Heidelberg; see Appendix 13)
The following ocular images of both eyes will be collected only from patients in the 
Implant treatment arms from sites that have a Humphrey Visual Field machine and will 
be forwarded to the reading center for evaluation and/or storage:

Visual field testing (Humphrey Automated Visual Field testing using Swedish 
interactive threshold algorithm Fast 24-2 protocol)
The following ocular images will be collected only from the study eye of patients in the 
Implant treatment arms and forwarded to the reading center for evaluation and/or 
storage:

External photographs (high-magnification Implant and conjunctiva, scleral surface; 
see Appendix 17)

Implant photograph (high-magnification Implant in the eye, through dilated pupil; 
see Appendix 17)
The following ocular images of both eyes will be collected from all study patients at
selected sites that have OCT angiography equipment:

OCT angiography (Optovue; see Appendix 18)
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. 


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4.6.6
Laboratory Assessments
Laboratory samples for the following tests are to be performed by a central laboratory for 
all patients unless otherwise noted. Patients are not required to fast prior to the sample 
collection.

Hematology:  hemoglobin, hematocrit, quantitative platelet count, RBCs, WBCs, and 
differentials including neutrophils, bands, lymphocytes, basophils, eosinophils, and 
monocytes (absolute and percent)

Serum chemistry:  sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen, creatinine, calcium, phosphorus, total and direct bilirubin, total protein, 
albumin, AST, ALT, lactic dehydrogenase, alkaline phosphatase, 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 (-human chorionic gonadotropin) at screening for women of 
childbearing potential, including those who have had tubal ligation. If positive, study 
treatment will not be administered.

Urine pregnancy test at Day 1 and before each study treatment for women of 
childbearing potential, including those who have had tubal ligation. If urine 
pregnancy test is positive, a serum pregnancy sample will be collected and study 
treatment will not be performed until the final results are available. If the serum 
pregnancy test is positive, study treatment will not be administered (see 
Section 5.1.1).
Instructions for obtaining, processing, storing, and shipping of all specimens for central 
laboratory evaluations are provided in the Laboratory Manual. 
The following samples will be collected from patients who consent to the Roche Clinical 
Repository (RCR) sampling collection (see Section 4.6.12) and will be tested by the 
Sponsor or a selected designee:

Optional serum samples at the Randomization Visit and visits at Month 4 and 
Month 9, for the evaluation of circulating biomarkers.

Optional plasma samples at the Randomization Visit and Visits at Month 4 and 
Month 9, for the evaluation of circulating biomarkers.

Optional whole blood for DNA extraction (genetic analysis) at the Randomization
Visit


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The following samples will be collected from patients in the ITV arm and will be tested by 
the Sponsor or a selected designee:

Serum samples will be obtained for measurement of anti-therapeutic antibodies to 
ranibizumab (see Appendix 2). 

Serum samples will be obtained to measure ranibizumab concentrations (see 
Appendix 2).
The following samples will be collected from patients in the Implant treatment arms and 
will be tested by the Sponsor or a selected designee:

Serum samples will be obtained for measurement of anti-therapeutic antibodies to 
ranibizumab (see Appendix 1). 

Serum samples will be obtained to measure ranibizumab concentrations (see 
Appendix 1).
Note:  For patients who prefer not to visit the clinic for the sample collection 
1 day after each Implant refill, provision will be made for this timepoint sample 
collection to be collected at their home.  Training will be provided to site staff on 
how to perform this task.  The sample will be sent to a central laboratory.

Vitreous or aqueous humor samples will be obtained to measure ranibizumab 
concentrations at the start of explantation for patients undergoing an explantation 
procedure (see Appendix 1 and Appendix 21).

Optional anterior chamber (aqueous humor) samples will be collected prior to or 
immediately following one or more refills and at the Day 7 safety visit post refill for 
the exploratory analysis for VEGF, ranibizumab concentrations, anti-therapeutic 
antibodies to ranibizumab and other exploratory biomarkers (see Appendix 1 and 
Appendix 21).
The following samples will be obtained from patients in the Implant treatment arms 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) will be 
preserved for potential analysis upon explant procedure.

Residual content of the Implant present in the Refill Needle may be collected during
the refill procedure (if applicable) to evaluate the possible association of vitreous or 
aqueous humor biomarkers with disease characteristics and response to 
ranibizumab.  
Unless the patient gives specific consent for the leftover of their samples to be stored for 
optional exploratory research (see Section 4.6.12), biological samples will be destroyed 
when the final clinical study report has been completed, with the following exception{s}:

Aqueous humor, vitreous, serum PK and ATA samples for assay development, 
validation, or for additional characterization will be stored no longer than 5 years 
after the final Clinical Study Report has been completed.


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See Laboratory Manual for sample processing, storing, and shipping instructions.
4.6.7
Patient-Reported Outcome
The MacTSQ must be administered to patients by an interviewer (for patients who speak 
English or Spanish by site personnel other than the VA examiner), before the patient 
completes any other study visit procedures (see Appendix 19).
The MacTSQ is a 14-item questionnaire designed to assess treatment satisfaction in 
patients with AMD. Scoring of the MacTSQ results in two subscale scores (information 
provision and convenience; impact of treatment) and a total score.  Subscale scores 
range from 0 to 36 and total scores range from 0 to 72.  A higher score indicates greater 
satisfaction.
Two versions of the questionnaire will be used, differing only in recall period.  At 
randomization the questionnaire will refer to “since diagnosis”.  For interim assessments 
at Months 1, 6, and 9, and at the final/early termination visits, the questionnaire will refer 
to “since you enrolled in this study”.
4.6.8
Video Capturing of Implant Insertion, Refill, and Explantation 
Procedures
The Implant insertion and explantation procedures will be captured on video for 
Investigators training purposes unless the study center has policies in place that prohibit 
these procedures being video captured. The Implant refill procedure video capture is 
optional.
4.6.9
Exploratory Substudies
The Sponsor may propose exploratory substudies associated with the Study GX28228 
protocol.  Each substudy will be documented in a separate substudy protocol and 
associated ICF(s).
4.6.10
Timing of Study Assessments
4.6.10.1
Screening and Pretreatment Assessments
The study will randomize approximately 220 patients and will be performed at up to 
60 sites in the United States.  Written informed consent for participation in the study 
must be obtained before performing any study-specific screening tests or evaluations.  
Informed Consent Forms (ICFs) for all screened patients, including those who are not 
subsequently randomized, will be maintained at the study site.
Screening Visit
Screening visit assessments cannot be performed sooner than 7 days following 
administration of the last ITV ranibizumab treatment to the study eye. After a patient has 
signed the ICF, the site will contact IxRS for the patient’s screening number assignment.  
All screening visit evaluations must be completed and reviewed to confirm that patients 


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meet all eligibility criteria before they are scheduled for their randomization visit.
Screening visit assessments may be performed on multiple days. 
Note:  If a patient fails screening assessments, he or she may be re-screened once if 
deemed appropriate by the investigator.  A new screening number will be assigned to 
the patient through the IxRS. The investigator will maintain a screening log to record 
details of all patients screened and to confirm eligibility or record reasons for screening 
failure, as applicable.
For the schedule of screening assessments, refer to the schedule of assessments in
Appendix 1 and Appendix 2. 
Randomization Visit and Day 1 Treatment
The randomization visit and the Day 1 treatment can occur on the same day for ITV 
treatment arm patients; the Implant arm patients may have these two visits separated 
due to the medication washout period (see Section 4.1) and the surgery room availability.
However, for all study patients, the Randomization visit and Day 1 study treatment must 
occur between 28 days and 37 days after the patient’s last study eye ITV ranibizumab 
treatment.  Unless noted otherwise, all procedures and assessments should be 
performed prior to contacting IxRS for the patient’s randomization number assignment 
and prior to the first study treatment administration to confirm that the patient is still 
eligible to be randomized to the study.  All randomization study visit assessments must 
be performed on the same day.  A patient can only be randomized to the study once.
When a patient has satisfied all eligibility criteria at both the screening and the 
randomization visit, including the receipt and evaluation of historical and screening visit 
images by the central reading center, the patient will be assigned a randomization
number (a number different from the patient’s screening number) by the IxRS and will be 
randomized to one of the treatment arms.  It is recommended that the patients 
randomized to the ITV-injection arm receive their Day 1 study treatment on the day of 
randomization, while patients randomized to the Implant treatment arms may be 
scheduled for their Day 1, Implant surgical insertion visit later.  If the Day 1 study 
treatment for Implant arms cannot be completed within the visit window after 
randomization, an additional ITV ranibizumab treatment may be required.
Please see the schedule of assessments provided in Appendix 1 and Appendix 2 for the 
schedule of randomization and Day 1 visit assessments. 
Study visits will be scheduled to occur according to the schedule in Appendix 1 and 
Appendix 2 and have to be relative to the Day 1 (first study treatment) visit date until 
patients complete the study or the study is terminated early.


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Pre-Screening (if applicable)
Pre-screening is available for newly diagnosed nAMD patients who are treatment naïve 
in the study eye.  After a patient has signed the informed consent form, the site will 
contact IxRS for the patient’s pre-screening number assignment.  A patient may only 
participate once in the pre-screening.  For the schedule of assessments in the pre-
screening, refer to Appendix 3.
Run-In (if applicable)
“Run-in” is available for patients diagnosed with nAMD in the study eye within 9 months 
prior to screening who have been treated with a single anti-VEGF ITV injection, or with 
no more than eight anti-VEGF ITV injections and with the most recent dose being 
aflibercept or bevacizumab.  After a patient has signed the informed consent form, the 
site will contact IxRS for the patient’s number assignment.  A PK sample will be collected 
prior to receipt of the “run-in” ranibizumab ITV treatment.  For the schedule of 
assessments in the “run-in”, refer to Appendix 4.
4.6.10.2
Assessments during Treatment
All assessments must be performed on the day of the specified visit, unless a time 
window is specified in the schedule of assessments (see Appendix 1 and Appendix 2).  
Assessments scheduled on the day of study treatment administration should be 
performed prior to administration of study treatment, unless otherwise noted in the 
schedule of assessments.  The MacTSQ assessment should be administered prior to 
the completion of other study assessments.
Please see Appendix 1 and Appendix 2 for the schedule of assessments performed
during the treatment period.
Study visits will be scheduled according to the schedule in Appendix 1 and Appendix 2
and have to be relative to the Day 1 (first study treatment) visit date until patients 
complete or are early terminated from the study.  Ranibizumab dosing should occur no 
earlier than 22 days following the previous dosing.
4.6.10.3
Assessments at Early Study Treatment Discontinuation
The ITV treatment arm patients who are discontinued from study treatment prematurely 
will be asked to undergo the scheduled monthly visits until the LPI Month 9 visit, after 
which they will be scheduled for their final study visit 30 (7) days later.  The patients 
who are discontinuing study treatment from the Implant treatment arms will be scheduled, 
within 7 days after the treatment discontinuation decision is made, for Implant 
explantation followed by safety visits 1 and 7 (2) days post-explantation.  Afterwards 
they will be followed in the study, attending their monthly scheduled visits, until LPI
Month 9 visit, after which they will be scheduled for the early termination visit (see 
Appendix 1).  As per investigator judgement, these patients may start an approved 
anti-VEGF for their AMD once the need for Implant explantation is confirmed and, 
preferably, after explantation is completed.  All explanted Implants, with remaining 


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content, will be returned to the designee of the Sponsor for storage and potential future 
exploratory analysis (see Section 4.4).  A vitreous or aqueous humor sample will be 
collected at the start of explantation for patients undergoing an explantation procedure
(see Appendix 20).
4.6.10.4
Assessments at Early Study Discontinuation
Patients withdrawing from the study early should return for an early termination 
evaluation 30 (7) days following the last study drug treatment for monitoring of all 
adverse events (serious and non-serious), as well as for early termination assessments
if they are in the ITV treatment arm. The patients who are discontinuing the study from 
the Implant treatment arms will be scheduled for Implant explantation within 7 days of 
the study discontinuation decision.  This will be followed by Safety Visits 1, 7 (2), 
30 (7), and 60 (7) days post-explantation, after which they will be scheduled for the
early termination visit 30 (7) days later.  As per investigator judgment, these patients 
may start an approved anti-VEGF treatment for their AMD once the need for Implant 
explantation is confirmed and, preferably, after explantation is completed.  All explanted
Implants, with remaining content, will be returned to the designee of the Sponsor for 
storage and potential future exploratory analysis (see Section 4.4).  A vitreous or 
aqueous humor sample will be collected at the start of explantation for patients 
undergoing an explantation procedure (see Appendix 20).
4.6.10.5
Assessment at Study Completion
Study completion is defined as a patient completing the final study visit assessments.  
Please see Appendix 1 and Appendix 2 for the schedule of assessments performed at 
the final/early termination visit.
Patients in the ITV treatment arm will return for the final study visit evaluation 30 (7) 
days following the last study drug treatment for monitoring of all adverse events (serious 
and non-serious), as well as for final study visit assessments, unless they enter into the 
RPDS Extension Study (Section 4.4.2).
Patients in the Implant arms who complete the study will be scheduled for the Implant
explantation 30 (7) days following the last refill (if applicable), unless they enter into the 
RPDS Extension Study (Section 4.4.2). Explantation will be followed by Safety Visits 1, 
7 (2), 30 (7), and 60 (7) days post-explantation, after which patients will be 
scheduled for the final study visit 30 (7) days later. As per investigator judgment, these 
patients may start an approved anti-VEGF treatment for their AMD once the need for 
Implant explantation is confirmed and, preferably, after explantation is completed. All 
explanted Implants, with remaining content, will be returned to the designee of the 
Sponsor for storage and potential future exploratory analysis (see Section 4.4).  A 
vitreous or aqueous humor sample will be collected at the start of explantation for 
patients undergoing an explantation procedure (see Appendix 20).


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4.6.10.6
Follow-Up Assessments 
After the study completion/early termination visit, adverse events should be followed as 
outlined in Sections 5.5 and 5.6.
4.6.10.7
Assessments at Unscheduled Visits 
Refer to Appendix 5 for unscheduled safety assessments that can be utilized for all 
study patients.  All listed assessments are to be performed if determined to be 
necessary by the investigator.
4.6.11
Refill Needle Sample Collection
The following samples will be collected from patients in the Implant treatment arms and 
may be analyzed by the Sponsor or selected designee:

Residual content of the Implant present in the Refill Needle may be collected during 
refill procedure (if applicable) to evaluate the possible association of vitreous or 
aqueous humor biomarkers with disease characteristics and response to 
ranibizumab.  
4.6.12
Samples for Roche Clinical Repository
4.6.12.1
Overview of the Roche Clinical Repository
The Roche Clinical Repository (RCR) is a centrally administered group of facilities used 
for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection and 
analysis of RCR specimens will facilitate the rational design of new pharmaceutical 
agents and the development of diagnostic tests, which may allow for individualized drug 
therapy for patients in the future.
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  RCR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop, validate, and characterize biomarker, diagnostic, pharmacokinetic, or 
anti-therapeutic antibody assays and establish the performance characteristics of 
these assays
4.6.12.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site's Institutional Review Board or Ethics Committee (IRB/EC) 


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and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for RCR sampling, this section of the protocol (Section 4.6.12) will not be 
applicable at that site.
4.6.12.3
Sample Collection
The following RCR samples will be collected for research purposes, including but not 
limited to research on dynamic (non-inherited) biomarkers related to Ranibizumab mode 
of action, VEGF biology, AMD biology, and/or related diseases biology:

Serum samples at the Randomization Visit and Visits at Month 4 and Month 9, for 
the evaluation of circulating biomarkers.

Plasma samples at the Randomization Visit and Visits at Month 4 and Month 9, for 
the evaluation of circulating biomarkers.
The following RCR samples will be collected for research purposes, including but not 
limited to research on genetic (inherited) biomarkers related to Ranibizumab mode of 
action, VEGF biology, AMD biology and/or related diseases biology:

Whole blood for DNA extraction at the Randomization Visit
For all samples, dates of consent and specimen collection should be recorded on the 
associated RCR page of the eCRF.  For sampling procedures, storage conditions, and 
shipment instructions, see the laboratory manual.  
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below.  
4.6.12.4
Confidentiality
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable.


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Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate.
Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise.
4.6.12.5
Consent to Participate in the Roche Clinical Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens 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 RCR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate by completing the RCR Research Sample Informed Consent eCRF.
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research.
4.6.12.6
Withdrawal from the Roche Clinical Repository
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the RCR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RCR Research 
Sample Withdrawal of Informed Consent eCRF.  The patient will be provided with 
instructions on how to withdraw consent after the trial is closed.  A patient's withdrawal 
from Study GX28228 does not, by itself, constitute withdrawal of specimens from the 
RCR.  Likewise, a patient's withdrawal from the RCR does not constitute withdrawal from 
Study GX28228.


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4.6.12.7
Monitoring and Oversight
RCR specimens 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 specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  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 RCR samples.
4.7
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.7.1
Patient Discontinuation
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 at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance:  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.
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced.
See Appendix 1 and Appendix 2 for the assessments that are to be performed for 
patients who discontinue early from the study.  The reason for treatment discontinuation 
and early withdrawal from the study should be recorded on the appropriate eCRF.
Discontinued patients will not be allowed to re-enter the study.
4.7.2
Early Study Treatment Discontinuation
Patients must discontinue study treatment if they become pregnant.
The ITV treatment arm patients who are discontinued from study treatment prematurely 
will be asked to undergo the scheduled monthly visits until the LPI Month 9 visit, after 
which they will be scheduled for their final study visit 30 (7) days later.  The patients 
who are discontinuing study treatment from the Implant treatment arms will be scheduled, 
within 7 days after the treatment discontinuation decision is made, for Implant 


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explantation followed by safety visits 1 and 7 (2) days post-explantation.  Afterwards 
they will be followed in the study, attending their monthly scheduled visits, until LPI 
Month 9 visit, after which they will be scheduled for the early termination visit 
(see Appendix 1).  As per investigator discretion, explanted patients may start an 
approved anti-VEGF agent for their nAMD once the need for Implant explantation is 
confirmed and, preferably, after explantation is completed.  The sponsor will provide 
explanted patients with ranibizumab ITV treatment until the LPI Month 9 visit (if 
applicable).  All explanted Implants with remaining content will be returned to the
designee of the Sponsor for storage and potential future exploratory analysis (see 
Section 4.4).  A vitreous or aqueous humor sample will be collected at the start of 
explantation for patients undergoing an explantation procedure (see Appendix 19).
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
4.7.3
Early Withdrawal from Study 
Every effort should be made to obtain information on patients who are withdrawing from 
the study.  The primary reason for withdrawal from the study should be documented on 
the appropriate eCRF.
Patients withdrawing from the study early should return for an early termination 
evaluation 30 (7) days following the last study drug treatment for monitoring of all 
adverse events (serious and non-serious), as well as for early termination assessments
if they are in the ITV treatment arm. The patients who are discontinuing study from the 
Implant treatment arms will be scheduled for Implant explantation within 7 days of the 
treatment discontinuation decision, followed by Safety Visits 1, 7 (2), 30 (7), and 
60 (7) days post-explantation, after which they will be scheduled for the  early 
termination visit 30 (7) days later. As per investigator judgment, these patients may 
start an approved anti-VEGF treatment for their AMD once the need for Implant 
explantation is confirmed and, preferably, after explantation is completed. All explanted
Implants, with remaining content, will be returned to the designee of the Sponsor for 
storage and potential future exploratory analysis (see Section 4.4).  A vitreous or 
aqueous humor sample will be collected at the start of explantation for patients 
undergoing an explantation procedure (see Appendix 19).
The primary reason for premature study discontinuation (which may differ from study 
treatment discontinuation) should be documented on the appropriate eCRF.  Patients 
who discontinue from the study prematurely will not be replaced and cannot re-enter the 
study.


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4.7.4
Study and Site 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.
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 Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice

No study activity (i.e., all patients have completed and all obligations have been 
fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety and tolerability of ranibizumab ITV injections have been investigated in 
previous Phase I, I/II, III, and IIIb studies in patients with AMD.  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). Please see RPDS IB for 
further details.


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In this study, GX28228, the patients in the Implant treatment arms will return after 
Implant insertion for safety evaluation visits on Day 2 (0), Day 7 (2), and Day 14 (2); 
subsequently, the safety visit will be scheduled 7 (2) days postimplant refill with 
ranibizumab; and safety visits on 1 (0) and 7 (2) days post explantation of the Implant
for the patients who will continue to be followed up in the study; and for the patients who 
are exiting the study, safety visits on 1 (0), 7 (2), 30 (7), and 60 (7) days 
post-explantation of their Implant prior to being scheduled for the final/early termination 
visit 30 (7) days later.
All ranibizumab-treated patients will be contacted by study site personnel 3 (1) days 
after each treatment 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-injection antimicrobials (if 
applicable) for their study eye as directed by the investigator.
If warranted, patients will be asked to return to the clinic as soon as possible for an 
unscheduled safety assessment visit and will be instructed to contact the investigator at 
any time should they have any health-related concerns.
Upon completion of implant insertion or explantation procedure, patients will have 
indirect ophthalmoscopy performed to monitor the Implant placement and to evaluate 
any potential Implant problems.  The treating physician will check IOP for the study eye 
only digital palpation.  These assessments must be performed prior to placing a patch on 
the eye. The patients will remain at the surgical center for approximately 40 minutes.  If 
there are no safety concerns following treatment, patients will be allowed to leave the 
surgical center after 40 (10) minutes.  If any safety concerns or immediate toxicity is 
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 and treatment 
of adverse event (if applicable) will be reported on the appropriate eCRFs.
Following each treatment with ranibizumab, administered either intravitreally or as an 
Implant refill, patients will undergo a finger counting test, followed by hand motion and 
light perception tests (when necessary) performed within 15 minutes post-treatment for 
the study eye only by the designated physician; the patients in the Implant treatment 
arms will have indirect ophthalmoscopy performed after each implant refill to monitor the 
Implant and its RCE end for visible clogging and other Implant problems.  The patients
will remain at the clinic for approximately 40 minutes. If there are no safety concerns
following treatment, patients will be allowed to leave the clinic after 40 (10) minutes.  If 
any safety concerns or immediate toxicity is noted, the patient will remain at the clinic 
and will be treated according to the designated physician’s clinical judgment. If 
applicable, the adverse event and treatment of adverse event (if applicable) will be 
reported on the appropriate eCRFs. 


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Detailed ocular examinations, including indirect ophthalmoscopy and slit lamp 
examination, will be performed throughout the study.  For patients in the Implant
treatment arm, the monthly dilated binocular indirect high-magnification ophthalmoscopic
examination will include visual monitoring of the Implant placement, evaluation of visible 
clogging of the RCE tip, and evaluation of any other Implant-related problems, as well as 
data collection on the associated eCRF and/or Medical Device Complaint Form.  Routine 
hematologic, serum chemistry, coagulation, and urinalysis profiles will be obtained from 
all study patients at the screening visit.  Blood samples for assessing serum ranibizumab 
concentrations and antibodies to ranibizumab will be obtained from all study patients 
throughout the study.  In addition, optional aqueous humor samples will be obtained 
from patients in the Implant treatment arms only throughout the study.  The sample 
content retrieved during Implant refill (if applicable) and explant procedures will be 
collected and forwarded to the Sponsor designee and may be analyzed in the future.
Ranibizumab administration by ITV injection or Implant refill (if applicable) will be 
interrupted or discontinued as per the dose-interruption criteria listed in Table 6 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.  This decision will be at the investigator’s discretion and should be recorded on 
the eCRF.
The ITV treatment arm patients who are discontinued from the study treatment 
prematurely will be encouraged to undergo the scheduled monthly visits until the LPI
Month 9 visit, after which they will be scheduled for their final study visit 30 (7) days 
later.  The patients who are discontinuing study treatment from the Implant treatment 
arms will be scheduled, within 7 days after the treatment discontinuation decision is 
made, for Implant explantation followed by safety visits 1 and 7 (2) days 
post-explantation.  Afterwards they will be followed in the study, attending their monthly 
scheduled visits, until LPI Month 9 visit, after which they will be scheduled for the early 
termination visit (see Appendix 1).  As per investigator judgement, these patients may 
start an approved anti-VEGF for their AMD once the need for Implant explantation is 
confirmed and, preferably, after explantation is completed.  All explanted Implants, with 
remaining content, will be returned to the designee of the Sponsor for storage and 
potential future exploratory analysis (see Section 4.4).  A vitreous or aqueous humor
sample will be collected at the start of explantation for patients undergoing an 
explantation procedure (see Appendix 19).
Patients discontinuing the study early should return for an early termination evaluation 
30 (7) days following the last study drug treatment for monitoring of all adverse events
(serious and non-serious), as well as for early termination assessments if they are in the 


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ITV treatment arm.  The patients who are discontinuing the study from the Implant
treatment arms will be scheduled for Implant explantation within 7 days of the 
discontinuation decision.  This will be followed by safety visits 1, 7 (2), 30 (7), and 60 
(7) days post-explantation, after which they will be scheduled for the early termination 
visit 30 (7) days later. As per investigator judgment, these patients may start an 
approved anti-VEGF treatment for their AMD once the need for Implant explantation is 
confirmed and, preferably, after explantation is completed. All explanted Implants, with
remaining content, will be returned to the designee of the Sponsor for storage and 
potential future exploratory analysis (see Section 4.4).  A vitreous or aqueous humor
sample will be collected at the start of explantation for patients undergoing an 
explantation procedure (see Appendix 19).
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.
Ongoing review of safety data will be performed by Genentech IMC consisting of the 
Medical Monitor, Clinical Scientists, Drug Safety Scientist, and Biostatistician.  External 
experts may be consulted. Following implementation of Protocol GX28228, version 5, if 
warranted, enrollment and Implant insertion surgeries may be paused to enable 
real-time review of post-implant insertion safety data by the IMC. 
5.1.1
Management of Specific Adverse Events
5.1.1.1
Dosing Interruption/Study Treatment or Study Discontinuation 
Criteria
Study treatment dose interruption and/or study treatment or study discontinuation 
following an adverse event will be determined according to the criteria in Table 6.  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 6 Dose Interruption/Study Treatment 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 5.3.5 and Appendix 12) 
VA loss
Interrupt dose if there is a decrease in BCVA of 30 letters in 
the study eye compared with the last assessment of VA prior to 
the most recent treatment.
IOP
Interrupt dose if 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 
physician.
Sensory 
rhegmatogenous retinal 
break or detachment 
(including macular 
hole)
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 the study after 
consultation with the Medical Monitor.
Local or severe 
systemic infection
Interrupt dose if any of the following are present:  infectious 
conjunctivitis, infectious keratitis, infectious scleritis, or 
endophthalmitis in either eye, or if the patient is currently 
receiving treatment for a severe systemic infection.
Oral corticosteroids 
(prednisone10 mg/kg 
or equivalent)
Dose may be interrupted after consultation with the Medical 
Monitor if a patient needs to take oral corticosteroids 
(prednisone 10mg/day or equivalent).  Study treatment may 
be resumed when oral corticosteroids dosing is prednisone 
10 mg/day or equivalent.
IV corticosteroids
Dose may be interrupted after consultation with the Medical 
Monitor if patients need to take 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 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 will be explanted even if it did not cause any AE to the 
patient.  The patient will be discontinued from the study 
treatment.
Pregnancy
Explant the Implant and discontinue patient’s study treatment in 
the case of positive serum pregnancy test during the study.
Malignancy
At the discretion of the investigator and after consultation with 
the Medical Monitor, patients may discontinue from the study 
drug treatment.
AEadverse event; BCVAbest corrected visual acuity; CFT central foveal thickness; 
IOPintraocular pressure; VAvisual acuity.


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5.1.1.2
Rescue Treatment with Open-Label Ranibizumab For Implant 
Patients
Rescue treatment with open-label ranibizumab (0.5-mg ITV injections of 10-mg/mL 
formulation) for patients in the Implant arm is allowed only under the following 
circumstances:

Approximately 1 month and/or 2 months after occurrence of vitreous hemorrhage, if 
vitreous hemorrhage causes loss in BCVA, and neither assessment of the macula 
nor SD-OCT can be performed successfully (see Section 5.1.1.4)

At the time a patient meets criteria for lack of clinical efficacy (see Section 5.1.1.3)

In the case of progressive worsening of BCVA and/or CFT due to wet AMD activity 
across two consecutive scheduled visits, only if the patient does not meet refill 
criteria.  If a treatment is clinically necessary due to the progressive clinical 
worsening per the investigator’s judgment, rescue treatment must be discussed and 
agreed upon by the Medical Monitor prior to being introduced.  
5.1.1.3
Management of Patients Who Meet Lack of Clinical Efficacy
Criteria
Criteria for meeting lack clinical efficacy are shown in Table 7, and Table 8 describes 
how to manage patients who meet such criteria.  Patients who meet criteria for lack of 
clinical efficacy will receive rescue treatment with ITV injection of open-label ranibizumab 
as described in Section 5.1.1.2.  One month after meeting criteria for lack of clinical 
efficacy and receiving a rescue ITV ranibizumab injection, the patient will receive a 
mandatory refill with the 100-mg/mL ranibizumab formulation. At the next monthly visit 
and until the end of the study, the patient will receive a refill with the 100-mg/mL 
ranibizumab formulation if the patient meets protocol-defined refill criteria.
For information regarding patient discontinuation or early study treatment discontinuation 
refer to Section 4.7.


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Table 7 Lack of Clinical Efficacy Criteria 
Event
Lack of clinical efficacy
Loss in BCVA of 15 letters from the best recorded BCVA on 
study following two consecutive ranibizumab Implant refills (as 
per protocol-specified refill criteria) occurring 1 month apart due 
to nAMD disease activity and not attributable to a change in the 
ocular media (i.e., cornea, lens, aqueous or vitreous humor, 
epiretinal membrane development, etc.) unless there is at least 
a five-letter increase in BCVA, in which case a refill will occur.
and/or
Increase in CFT 150 m from the lowest CFT measurement 
on study following two consecutive ranibizumab Implant refills 
(as per protocol-specified refill criteria) occurring 1 month apart 
due to nAMD disease activity and not attributable to a change
in the ocular media (i.e., cornea, lens, aqueous or vitreous 
humor, epiretinal membrane development, etc.) unless there is 
a decrease in CFT 75 microns from the last refill, in which 
case a refill will occur.
Table 8
Management of Patients Who Meet Lack of Clinical Efficacy 
Criteria
Time of event
Treatment to be performed
At the time of meeting
lack of clinical efficacy criteria
Perform rescue treatment with intravitreal
injection of open-label ranibizumab
At the study visit one month after meeting
lack of clinical efficacy criteria
Perform a mandatory refill with the
100-mg/mL ranibizumab formulation
At subsequent study visits
(from Month 2 after meeting lack of clinical 
efficacy criteria and onwards)
Perform a refill with 100-mg/mL
ranibizumab formulation 
ONLY if refill criteria are met


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5.1.1.4
Recommended Management of Cases of Vitreous Hemorrhage 
Cases of vitreous hemorrhage secondary to Implant-related procedures throughout the 
study should be managed following the recommendations in Table 9.  
Table 9
Recommended Management of Cases of Vitreous Hemorrhage 
Timing 
Patient’s examination/management/determination of refill requirements
Day of vitreous 
hemorrhage 
diagnosis

If the diagnosis of vitreous hemorrhage is made during a 
scheduled visit, if possible perform ocular B-scan 
ultrasonography in addition to the assessments scheduled for 
that specific visit

If the diagnosis of vitreous hemorrhage is made during an 
unscheduled visit, if possible perform ocular ultrasonography in 
addition to the assessments listed in the Appendix 5

A safety assessment visit (scheduled or unscheduled) should 
be performed approximately 2 weeks after occurrence of 
vitreous hemorrhage (see Appendix 5 for unscheduled visit). If 
possible, perform ocular B-scan ultrasonography.
Approximately 
1 month after 
occurrence 
(scheduled 
visit)

If possible, perform ocular B-scan ultrasonography in addition to 
the assessments scheduled for that specific visit

If vitreous hemorrhage causes loss in BCVA, but assessment of 
the macula or SD-OCT can be performed successfully, 
determine if Implant refill is needed according to the protocol-
defined refill criteria (see Section 3.1.1)

If vitreous hemorrhage causes loss in BCVA, and neither 
assessment of the macula nor SD-OCT can be performed 
successfully, perform rescue treatment with ITV injection of 
open-label ranibizumab 

An unscheduled safety assessment visit should be performed 
between month 1 and month 2 after occurrence of vitreous 
hemorrhage (see Appendix 5).
Approximately 
2 months after 
occurrence 
(scheduled 
visit)

If possible, perform ocular B-scan ultrasonography

If vitreous hemorrhage causes loss in BCVA, but assessment of 
the macula or SD-OCT can be performed successfully, 
determine if Implant refill is needed according to the protocol-
defined refill criteria (see Section 3.1.1)

If vitreous hemorrhage causes loss in BCVA, and neither 
assessment of the macula nor SD-OCT can be performed 
successfully:
o
perform rescue treatment with ITV injection of open-label 
ranibizumab 
o
discuss a pars plana vitrectomy with the patient as a 
possibility to remove the vitreous hemorrhage.  Consultation 
with the Medical Monitor is required prior to perform pars 
plana vitrectomy.
BCVAbest corrected visual acuity; ITVintravitreal; SD-OCT spectral domain optical 
coherence tomography.


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5.1.1.5
Implant Clogging Assessment
If an Implant is explanted, it will be analyzed for possible clogging using the following
assessments:

Serum pharmacokinetics of ranibizumab will be used to help judge whether Implant
clogging may have occurred. Aqueous humor or vitreous PK samples will be 
collected at explantation and may be used to further assess possible Implant 
clogging.  For each individual patient, possible Implant clogging will be documented 
if at least one of the following conditions are met:
At Implant insertion and prior to the first refill: serum ranibizumab 
concentrations are below the lower limit of quantification (BLQ) or below the 
baseline serum ranibizumab concentration value at all time-points prior to refills, 
that is, Day 1 (within 60 min of insertion), Day 2, Day 7, Day 14, and all monthly 
time points after Implant insertion and prior to the first refill or to the end of the 
study visit for this patient if no refill occurs.
After the first refill: serum ranibizumab concentrations are BLQ or below the 
last pre-refill serum ranibizumab concentration value at all time-points post 
refills, that is, Day 7, and all monthly time points prior to the next refill for 
2 consecutive refills or to the end of the study visit for this patient if no further 
refill occurs.

Implants identified that meet PK criteria for possible clogging will then undergo 
further diagnostics if explanted.  The Implant “complete clogging” failure statistics 
will be summarized across all Implant patients based on the first 9 months of 
Implant insertion.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including
serious adverse events and AESIs; measurement of protocol-specified safety laboratory 
assessments; measurement of protocol-specified vital signs; and 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 and/or medical device 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 or 
device, whether or not considered related to the medicinal product or the device


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
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.9.

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., fluorescein 
angiography) 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)
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.10)

Results in persistent or significant disability/incapacity (i.e., the adverse event
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe; see Section 5.3.3); the event 
itself may be of relatively minor medical significance (such as severe headache without 
any further findings).
Severity and seriousness need to be independently assessed for each adverse event
recorded on the eCRF.


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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)
AESIs can be serious or non-serious and are required to be reported by the investigator 
to the Sponsor within 24 hours after learning of the event (see Section 5.4.2 for reporting 
instructions).  AESIs for this study include the following:
a) Adverse events resulting from medication errors
Examples of medication errors include, but are not limited to, overdose (see 
further details in the Section 5.3.5.11), incorrect dose, incorrect route, incorrect 
drug, incorrect administration, or incorrect kit.
If the medication error did result in an adverse event, the primary event term 
should reflect the adverse event that occurred as a result of the medication 
error.  The “Other” suspected causes of adverse event data field on the adverse 
event record should be reported as a medication error.
b) Sight-threatening adverse events
An adverse event is considered to be sight threatening and should be reported 
expeditiously if it meets one or more of the following criteria:

It causes a decrease of 30 letters in VA (compared with the last 
assessment of VA prior to the most recent assessment) lasting more than 
1 hour

It requires surgical intervention (i.e., conventional surgery, vitreous tap, or 
biopsy with ITV injection of anti-infective agents, or laser or retinal cryopexy 
with gas or explantation of Implant) to prevent permanent loss of sight

It is associated with severe intraocular inflammation (i.e., 4anterior 
chamber cell/flare or 4vitritis; see the definitions for intraocular 
inflammation, iritis, iridocyclitis, and vitritis in Section 5.3.5 and inflammation 
grading scales in Appendix 12).

In the opinion of the investigator, it may require medical intervention to 
prevent permanent loss of sight.
c) 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


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d) ADEs; that is, adverse events that are considered to be related to the RPDS and to 
the use of the RPDS.  They include, but are not limited to:

Adverse events resulting from insufficient or inadequate device RPDS IFU

Adverse events related to the Implant insertion procedure 

Adverse events related to the Implant refill procedure

Adverse events related to the Implant explantation procedure

Adverse events related to the presence of the Implant within the eye

Adverse events caused by any malfunction of the RPDS including any 
adverse events resulting from an excessive release of ranibizumab into the 
eye

Adverse events resulting from use error or from intentional misuse of the 
RPDS

A lack of efficacy of ranibizumab due to inadequate release of ranibizumab 
from the Implant
In addition, any adverse event considered causally related to the RPDS must also 
always be reported as a Medical Device Complaint (Section 5.4.4).
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), 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 to Section 5.6.  
In addition, the investigator is also responsible for reporting medical device complaints 
(see Section 5.4.4) associated with any of the components (see Table 1) of the RPDS.
For a device defect with an associated adverse event this means that the investigator 
must report both an adverse event and a Medical Device Complaint (see 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).
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the adverse event eCRF.


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After informed consent has been obtained but prior to initiation of study drug
(Day 1), only serious adverse events related to a protocol-mandated intervention 
(e.g., invasive procedures such as biopsies, discontinuation of medications, or ITV 
ranibizumab given as part of pre-screening) should be reported (see Section 5.4.2 for 
instructions for reporting serious adverse events).
After initiation of study drug, all adverse events, regardless of relationship to study 
drug, Implant, or ancillary devices, or study procedures, will be reported until the 
patient’s study completion or early termination from the study. After completion or early 
termination from the study, the investigator should report any serious adverse events
that are believed to be related to prior study treatment (study drug and/or RPDS, 
see 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.

Patients in the Implant arms:  The investigator will assess whether there is a 
potential association with each of the following “components” of the study 
intervention:  
–
Each component of the RPDS (i.e., a separate assessment for the Implant, the 
Initial Fill Needle, the Insertion Tool, the Refill Needle, and the Explant Tool)
–
The study procedures (including the procedures to insert, refill, or explant the 
Implant)
–
Ranibizumab (study drug)


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Investigators will assess any relationship between the adverse event and each 
component separately, indicating “yes” or “no” as applicable on Adverse Event eCRF.

Patients in the ITV arm:  The investigator will assess whether there is a potential 
association with each of the following “components” of the study intervention: 
–
The ITV 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, or explantation procedures or due to other RPDS components (see 
Table 1) or due to ITV 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 RPDS 
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
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:

Iritis:  the presence of inflammatory cells in the anterior chamber
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

Vitritis:  the presence of active inflammation in the vitreous, demonstrated by the 
presence of inflammatory cells (trace or greater)
Active inflammation in the vitreous should be clinically differentiated 
from cellular debris from prior episodes of inflammation, hemorrhage, or other 
causes.


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
Endophthalmitis:  diffuse intraocular inflammation predominantly involving the 
vitreous cavity but possibly also involving the anterior chamber, implying a 
suspected underlying infectious cause. A culture is required prior to initiating 
antibiotic treatment for presumed endophthalmitis.
Note:  Trace benign, aqueous humor pigmented cells visible on slitlamp examination that 
are caused by dilation and are not RBCs or WBCs or the result of any ocular disorder 
should not be recorded as an adverse event.
5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the adverse event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the adverse event
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.2
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event
that is separated in time from the initiating event should be recorded as an independent 
event on the adverse event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the adverse event eCRF if it is 
unclear as to whether the events are associated.
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) of the event will be recorded at the 


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time the event is first reported.  If a persistent adverse event becomes more severe, the 
most extreme severity should also be recorded on the adverse event eCRF.  If the event 
becomes serious, it should be reported to the Sponsor immediately (i.e., no more than 
24 hours after learning that the event became serious; see Section 5.4.2 for reporting 
instructions).  The adverse event eCRF should be updated by changing the event from 
"non-serious" to "serious," providing the date that the event became serious, and 
completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the adverse event eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5the 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 if 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 Ae.  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 event).


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5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the adverse event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the adverse event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3the ULN) in combination with either an 
elevated total bilirubin (2the 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 a serious adverse 
event the occurrence of either of the following:

Treatment-emergent ALT or AST 3the ULN in combination with total bilirubin 
2the ULN

Treatment-emergent ALT or AST 3the 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).
5.3.5.7
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the adverse 
event eCRF and immediately reported to the Sponsor (see Section 5.4.2).
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 


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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").
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 Medical History and Baseline Conditions 
eCRFs.
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
in Study Eye
Study eye medical occurrences or symptoms of deterioration that are anticipated as part 
of the nAMD disease state should only 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
study eye 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 
nAMD").
5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., in-patient 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.  
There are some hospitalization scenarios that do not require reporting as a serious 
adverse event when there is no occurrence of an adverse event.  These scenarios 
include a planned hospitalization or prolonged hospitalization to undergo a diagnostic or 
elective surgical procedure for a preexisting medical condition other than ocular that has 
not changed.
5.3.5.11
Adverse Events Associated with an Overdose or Error in 
Drug Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events


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associated with an overdose or incorrect administration of study drug should be 
recorded on the adverse event eCRF and should be reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2).
Defects in the device that are not associated with adverse events are captured 
according to Section 5.4.4.
5.3.5.12
Patient-Reported Outcome Data
Adverse event reports will not be derived from patient-reported outcome (PRO) data by 
the Sponsor, and safety analyses will not be performed using PRO data.  However, if 
any PRO responses suggestive of a possible adverse event are identified during site 
review of the PRO data, the investigator will determine whether the criteria for an 
adverse event have been met and, if so, will report the event on the adverse event eCRF.
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 (see Section 5.4.2 for further details)

AESI (see Section 5.4.2 for further details)

Pregnancies (see Section 5.4.3 for further details)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority (HA) and Institutional Review Board (IRB)/Ethics 
Committee (EC).


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5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for Sponsor’s Medical Responsible 
Contact
Medical Monitor:
, M.D. (primary)
Email:
Telephone No.:
Mobile Telephone No.:
Medical Monitor:
, M.D., PhD. (secondary)
Email:
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 
Monitor, 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 contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Non-Serious and Serious Adverse Events of Special Interest
5.4.2.1
Events That Occur Prior to Initiation of Study Drug (Day 1)
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events related to a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications, or ITV ranibizumab given 
as part of pre-screening) should be reported.  The 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 any AESI will be reported until 
30 (7) days after the last study drug administration for the ITV injection treatment arm 
and until 90 (7) days after the Implant explantation for the Implant treatment arms. 
However, if any patient continues to be followed in the study after an early 
discontinuation of the treatment, the adverse events will be reported until their study 
completion.  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 Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.  
Instructions for reporting post-study adverse events are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 30 days after the last 
dose of study drug.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  A pregnancy report will automatically be generated and sent to 
Roche Safety Risk Management.  Pregnancy should not be recorded on the adverse 
event eCRF.  The investigator should discontinue study drug and counsel the patient,
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the adverse event eCRF.
In the event that the EDC system is unavailable, the Clinical Trial Pregnancy 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 pregnancy), 
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.
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the ICF to immediately inform the investigator if 
their partner becomes pregnant during the study or within 30 days after the last dose of 
study drug.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  Attempts should be made to collect and report details of the course 
and outcome of any pregnancy in the partner of a male patient exposed to study drug.  
The pregnant partner will need to sign an Authorization for Use and Disclosure of 
Pregnancy Health Information to allow for follow-up on her pregnancy.  Once the 
authorization has been signed, the investigator will update the Pregnancy Report eCRF 
with additional information on the course and outcome of the pregnancy.  An investigator 
who is contacted by the male patient or his pregnant partner may provide information on 


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the risks of the pregnancy and the possible effects on the fetus, to support an informed 
decision in cooperation with the treating physician and/or obstetrician.
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1.
5.4.3.3
Abortions
Any abortion should be classified as a serious adverse events (as the Sponsor considers 
abortions to be medically significant), recorded on the adverse event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male 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
In this study, the Implant and the ancillary devices are considered medical devices.  The 
investigator must report all RPDS medical device complaints related to the Implant and 
ancillary devices (see Table 1) to the Sponsor.  
The investigator should provide as much information as possible to the personnel 
completing the IMP Deviation Form, including the product batch number.  The form will 
be forwarded to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event) (refer to the Study manual for further details).  
If the device complaint is also associated with an adverse event in a study participant, 
then the adverse event must additionally be reported on the adverse event eCRF
submitted through the EDC system.  If the event is serious or an AESI, 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 the medical device causes an adverse event to an individual other than the study 
patient (e.g., study site personnel), the event should be reported on the Medical Device 
Complaint form and the adverse event to Roche Safety Risk Management via telephone 
(see Study Manual for more details).
5.4.4.1
Device Defects or Deficiencies that Could Have Led to Medical 
Occurrence
Device deficiencies (inadequacy with respect to identity, quality, durability, reliability, 
safety or performance and including malfunctions, and inadequate labeling) that did not 
lead to an adverse event but could have led to a medical occurrence if suitable action 


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had not been taken, if intervention had not been made, or if circumstances had been 
less fortunate must be reported via the medical device complaints process immediately 
(i.e., no more than 24 hours after learning of the event) (refer to the Study manual for 
further details). 
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.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.
5.5.2
Sponsor Follow-Up
For serious adverse events, non-serious AESI, and pregnancies, the Sponsor or a 
designee may follow-up by telephone, fax, electronic mail, 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
POST-STUDY ADVERSE EVENTS
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 ITV treatment arm and 90 (7) days 
after the Implant explantation for patients in the Implant treatment arms), if the event is 
believed to be related to prior study drug treatment or due to the Implant.
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 Serious 
Adverse Event/Adverse Event of Special Interest Reporting Form using the fax number
or email address provided to investigators.


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5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and non-serious AESI 
against cumulative product experience to identify and expeditiously communicate 
possible new safety findings to investigators, IRBs, ECs, and applicable health 
authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

RPDS IB
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 analyses will take place after LPI has completed the Month 9 visit. Detailed 
specifications of the statistical methods will be described in the SAP.
6.1
DETERMINATION OF SAMPLE SIZE
This study is exploratory in nature and designed to estimate the time to first refill (TTFR) 
for each of the RPDS treatment arms (10 mg/mL, 40 mg/mL, and 100 mg/mL) enrolling 
60 patients in each of the RPDS treatment arms.  The sample size of approximately 
220 randomized patients will be adequate to evaluate the primary objective of the study. 
PK/PD modeling and simulation was performed to inform key assumptions used in 
sample size calculation. Given the simulation results, the HR for comparing the 
100-mg/mL arm with the 10-mg/mL arm was estimated to be 0.66 for TTFR. Assuming 
this HR, a total of at least 125 events from all three Implant groups is expected at the 
primary analysis time (approximately 85 events in the 10-mg/mL group and a higher 
dose group).  With 85 events, this study will have approximately 80% power to detect an
HR0.66 between the two Implant arms using a log-rank test at a one-sided significance 
level of 15%. No multiplicity adjustment is planned for this Phase II study.
Forty patients in the ITV arm are considered sufficient to compare each device arm 
versus the ITV arm in change in BCVA from baseline through Month 9 (assuming an 
estimated SD10 letters, a two-sided 80% CI will extend approximately 2.62 letters from 
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6.2
SUMMARIES OF CONDUCT OF STUDY
The demographic and baseline characteristics, such as age, sex, race/ethnicity, baseline 
VA, angiographic and clinical evaluation of CNV, time since diagnosis of nAMD, 
and stratification factors including baseline BCVA score and number of prior
anti-VEGF injections will be summarized by treatment group using descriptive statistics.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
The demographic and baseline characteristics, such as age, sex, race/ethnicity, baseline 
VA, angiographic and clinical evaluation of CNV, time since diagnosis of nAMD, baseline 
safety (patients outside the expected normal range for vital signs and laboratory test 
results), and baseline disease characteristics (i.e., BCVA and OCT parameters) will be 
summarized by treatment arm. 
6.4
EFFICACY ANALYSES
6.4.1
Primary Efficacy Analysis
The primary endpoint for this analysis will be time to first meeting refill criteria.  The 
primary analyses will be based on data as of 9 months after last patient’s entry into the 
study. For patients without any refills prior to or on the cut-off date of 9 months after LPI, 
the time of refill will be censored. The censoring date will be defined as the date of a 
patient’s last visit before the cut-off date of 9 months after LPI, or the date when the 
patient discontinues from the study, whichever occurs first.
The primary analysis population for efficacy is the modified intent-to-treat population 
defined as all randomized patients who were randomly assigned to study treatment 
receive study treatment.  Patients will be summarized by treatment arm and analyzed 
according to the treatment actually received and not according to the treatment they 
were randomized to receive, in the event of a discrepancy.  
To support the dose level selection among the Implant groups, the primary analysis for 
TTFR will include the following pair-wise group comparisons, each with a stratified log-
rank test at a one-sided significance level of 15%. The stratification factors to be 
included are baseline BCVA score (65 letters vs. 66 letters) and number of anti-VEGF 
ITV injections (3 vs.4).

Implant with 100 mg/mL versus Implant with 10 mg/mL

Implant with 100 mg/mL versus Implant with 40 mg/mL

Implant with 40 mg/mL versus Implant with 10 mg/mL
In addition, the HR for each pair-wise comparison of the treatment arms will be 
estimated using a Cox proportional hazards regression model stratified by baseline 
BCVA score (65 letters vs. 66 letters) and number of prior anti-VEGF ITV injections 
(3 vs. 4) with main effects for treatment.  Estimated HRs for each pair-wise 
comparison will be presented with the corresponding 80% CIs.  


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KaplanMeier plots will be provided showing TTFR by implant group. Median time to 
first meeting refill criteria will be calculated for each treatment arm with the Kaplan Meier 
method, and the corresponding 80% confidence intervals will also be reported.

Moreover, for each treatment group, percentage of patients not meeting the 
protocol-defined first refill criteria by Months 4, 5, 6, 7, 8, and 9, derived from 
Kaplan-Meier estimates will be provided.
6.4.2
Secondary Efficacy Analysis
A secondary efficacy outcome measure is the change in BCVA from baseline through 
Month 9 (by month). Missing BCVA data, prior to or at Month 9 for each patient, will be 
imputed using the last observation carry forward (LOCF).  Comparison of implant arms 
(10 mg/mL, 40 mg/mL, and 100 mg/mL) versus the monthly ITV arm will be assessed 
using an analysis of covariance (ANCOVA) model with an effect for treatment and with 
covariate adjustments for baseline stratification factors:  baseline BCVA score 
(65 letters vs. 66 letters) and number of anti-VEGF ITV injections (3 vs. 4).  
Separate models will be fit for each pairwise comparison and each study month.  The 
dependent variables will be change from baseline in BCVA at each of Months 19.  
Model-based (least squares) estimates of the pairwise treatment differences will be 
provided and 80% CIs.  Figures showing mean and median change in BCVA over time, 
by treatment group, will be provided.
The ANCOVA model above will be repeated using change from baseline in CFT from 
baseline through Month 9 (by month) as the outcome.  The stratification factors and 
baseline CFT will be included in the model as covariates.  Mean change from baseline in 
CFT from baseline through Month 9 (by month) will be compared between the implant 
arms and the monthly ITV arm.
In order to evaluate whether the Implant clogging rate exceeds 10% within the first 
9 months, the proportion of clogged Implants will be estimated and the 80% CI will be 
calculated based on the binomial distribution.  All clogging data from patients in the 
implant arms will be pooled for this analysis.
Additional statistical summaries will be reported for the secondary efficacy outcome 
measures as listed in Section 3.5.2. Detailed specifications of the statistical methods will 
be described in the SAP.


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6.5
SAFETY ANALYSES
All patients receiving at least one study treatment will be included in the safety analysis.  
Counts and incidence rates by treatment group for the following safety endpoints will be
provided:

Ocular and non-ocular adverse events and serious adverse events

"Prespecified RPDS-associated adverse events" (see Section 6.5.1)

Positive serum antibodies to ranibizumab
For "prespecified RPDS-associated adverse events”, the incidence in all implant arms 
patients will also be summarized.  
6.5.1
Adverse Events
Verbatim descriptions of treatment-emergent adverse events will be mapped to 
thesaurus terms.  Treatment-emergent adverse events will be defined as events 
beginning during or after surgical insertion/explantation of the Implant or the first 
ranibizumab ITV injection through the completion of the study or until a patient 
discontinues prematurely.  Adverse events will be tabulated by body system, high-level 
term, and preferred term.  Separate summaries will be prepared for non-ocular and 
ocular adverse events, with events in the study eye and fellow eye summarized 
separately.  Serious adverse events will be summarized similarly.  Adverse events
leading to discontinuation from the study or treatment will be listed and tabulated.
ADEs are adverse events that are considered to be related to the RPDS and to the use 
of the RPDS. Of particular interest are the following “Prespecified RPDSassociated 
adverse events”:  

Vitreous hemorrhage associated with a 30-letter decrease of BCVA on ETDRS 
chart compared with the last assessment of BCVA prior to the onset of vitreous 
hemorrhage lasting 1 month

Reduced VA (30 letters loss from previous scheduled visit)

Traumatic cataract

Endophthalmitis

Damage to sclera

Retinal detachment

Interference of the Implant with visual field
In addition to the “Prespecified RPDSassociated adverse events”, any other ocular 
adverse events and serious adverse events attributed by the investigator to the:  
1) Implant insertion procedure, 2) Implant refill procedure, 3) Implant explantation 
procedure, and 4) study drug, will be reported.


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6.5.2
Deaths
Patient deaths and primary cause of death will be summarized.
6.5.3
Laboratory Tests
Summary statistics for the proportion of patients with laboratory values above the ULN or 
below the lower limits of normal at the screening visit will be provided.
The number and percentage of patients with positive serum antibodies to ranibizumab at 
baseline and during the treatment period will be tabulated.
6.5.4
Vital Signs
Summary statistics for worst change from baseline in vital signs will be tabulated.  If an
imbalance between treatment groups is observed, the summaries of the corresponding 
vital signs over the course of the study will be provided.
6.5.5
Ocular Assessments
Results of the following ocular assessments will be summarized by timepoint and by eye 
(study vs. non-study) as applicable, using descriptive summaries:  IOP, fluorescein 
angiography, and fundus photography.  Changes from baseline for selected ocular 
assessments will be tabulated.  The presence of intraocular inflammation and vitreous 
hemorrhage, as determined from the slitlamp examination, will be tabulated by grade 
(according to grading scales for flare/cells and vitreal hemorrhage density in
Appendix 12).  The presence of retinal break or detachment as determined from 
ophthalmoscopy will be tabulated.
6.6
PHARMACOKINETIC ANALYSES
Individual and mean serum ranibizumab concentration over time will be tabulated and 
plotted by dose level and by refill number.  The serum pharmacokinetics of ranibizumab 
will be characterized by estimating AUC, Cmax, tmax, t1/2, and Ctrough between dose intervals.  
Estimates for these parameters will be tabulated and summarized by descriptive 
statistics.  Additional PK analyses may be conducted as appropriate.  More details are 
described in Section 3.5.4.
6.7
PATIENT-REPORTED OUTCOME ANALYSES
For each scheduled assessment, descriptive statistics will be computed for the total 
MacTSQ score and for the two subscales: 1) information provision and convenience 
and 2) impact of treatment.  The scoring algorithm and rules for handling missing data 
will be provided in the SAP.
PRO data will be presented separately from adverse events data.


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6.8
EXPLORATORY ANALYSES
Detailed specifications of the statistical methods for the exploratory analyses will be 
described in the SAP.
6.8.1
Time to Event Analysis with Data after Month 9
In case the required number of events (first refills) is not reached by Month 9, the 
primary analysis will be repeated as a follow-up analysis using all of the data collected 
up to the time when the required number of events is met. 
In addition, the primary efficacy analysis described in Section 6.4.1 will be repeated 
based on the full data collected during the entire study as an exploratory analysis. This 
analysis is considered supportive to the primary efficacy analysis.
6.8.2
Analysis of Time to Subsequent Refills
Time from last refill to subsequent refills will be analyzed for patients in the Implant arms 
as appropriate.  Details of the analysis will be described in the statistical analysis plan.
6.9
FLEXIBLE INTERIM ANALYSIS
Given the exploratory nature of this study, the Sponsor may choose to conduct up to two 
interim analyses.  The decision to conduct an optional interim analysis and the timing of 
the analysis will be documented in the Sponsor’s trial master file prior to the conduct of 
the interim analysis.  The interim analysis will be performed by members of the 
Sponsor’s unmasked study team and will be interpreted by the unmasked IMC and 
appropriate senior management personnel.  Access to treatment assignment information 
will follow the Sponsor’s standard procedures.  The details of the timing and scope of the 
interim analysis, if any, will be specified in the IMC Agreement.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for the data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC using 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 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. Data from PRO 


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questionnaires will be forwarded to the Sponsor electronically.  The Sponsor will supply 
eCRF specifications for this study.  For additional details of the data quality assurance
please see the Data Quality Review Plan.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed using a Sponsor-designated EDC system.  Sites will receive 
training and have access to Help Text within EDC for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
PATIENT-REPORTED OUTCOME DATA
Data from paper PRO questionnaires will be entered into the EDC system by site staff.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan (TMP).  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 7.6.


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To facilitate source data verification, 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. Please see TMP for additional details.
7.5
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 HA
requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data (if applicable), ICFs, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator for at least 
15 years after completion or discontinuation of the study, or for the length of time 
required by relevant national or local health authorities, whichever is longer.  After that 
period of time, the documents may be destroyed, subject to local regulations.
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
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 laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  It will also follow ISO 14155 for the RPDS Clinical 
Investigation Plan (see Appendix 21 for details).  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 FDA 
regulations and applicable local, state, and federal laws.
8.2
INFORMED CONSENT
The Sponsor’s sample ICF 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 ICFs or any alternate 


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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 HA submission purposes according to local requirements.
The benefit and risks associated with participation in this study is outlined and will be 
explained to the patient by the investigator. 
The ICF will contain a separate section that addresses the collection and use of the 
optional aqueous humor samples for optional exploratory research.  The investigator or 
authorized designee will explain to each patient the objectives of the exploratory 
research.  Patients will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the 15-year storage 
period.  A separate, specific signature will be required to document a patient's 
agreement to allow the optional aqueous humor sample to be collected and used for 
exploratory research.  Patients who decline to participate will check a “no” box in the 
appropriate section and will not provide a separate signature.
Patients’ compensation for costs resulting from participation in the study 
(e.g., transportation) may be provided if allowed by national regulations. Subject to 
national regulations, arrangement for additional healthcare for patients who suffer from 
an adverse event as a result of participation will be explained and documented in the
ICF.
The Consent Forms must be signed and dated by the patient before his or her 
participation in the study.  The case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC and HA (if applicable)-approved Consent Forms 
must be provided to the Sponsor for HA 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/HA policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient.  All signed and 
dated Consent Forms must remain in each patient’s study file or in the site file and must 
be available for verification by study monitors at any time.


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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 ICFs, any information to be given to the patient, and relevant 
supporting information must be submitted to the IRB/EC by the Principal Investigator and 
reviewed and approved by the IRB/EC before the study is initiated.  In addition, any 
patient recruitment materials must be approved by the IRB/EC.
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local HA 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 HA
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 ICF (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.
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other national and local health authorities, Sponsor
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.


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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 HAs.  Investigators are 
responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
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, ICFs, 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.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local HAs, Sponsor monitors, representatives, and collaborators, and 
the IRBs/ECs to inspect facilities and records relevant to this study.  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.
9.4
ADMINISTRATIVE STRUCTURE
This study is sponsored by Genentech, Inc.
Genentech 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).


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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.
An IxRS will be used for patient enrollment and for management of study drug/device
requests and shipments. Enrollment will be competitive.
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 Genentech or Genentech-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
(fluorescein angiography, fundus photography and SD-OCT). 
9.5
PUBLICATION OF DATA AND PROTECTION OF 
TRADE SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.


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Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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PrONTO Study. Am J Ophthalmol. 2009 Jul;148(1):43-58
Rudnicka AR, Jarrar Z, Wormald R, et al.  Age and gender variations in age-related 
macular degeneration prevalence in populations of European ancestry: a meta-
analysis.  Ophthalmology. 2012 Mar;119(3):571-80. 
Smith AF. The growing importance of pharmacoeconomics: the case of age-related 
macular degeneration.  Br J Ophthalmol. 2010 Sep;94(9):1116-7.
Spaide RF, Curcio CA. Drusen characterization with multimodal imaging.  Retina. 2010
Oct;30(9):1441–1454.


Ranibizumab Port Delivery System—Genentech, Inc.
112/Protocol GX28228, Version 8
Appendix 1
Schedule of Assessments for Implant Arms:  Screening, Randomization, Day 1, Month 1 through 
Month 9, Month X, Safety Visits, and Final/Early Termination Visits
Assessment
Screen a
7 days 
after 
RBZ tx
Rand b
28 and 
37 
days 
after 
RBZ tx
Day
Month
Month X 
Visit d
Safety 
Visit c
Final/
ETe
1 b
2 c
7 c
14 c
1
2
3
4
5
6
7
8
9
Window (Days)
0
2
2
7
7
7
7
7
7
7
7
7
7
See 
footnote c
See 
footnote e
Written informed 
consent
x
Review of 
inclusion and 
exclusion criteria
x
x
Medical and 
surgical history, 
tobacco and 
alcohol use
x
Demographic 
Information
x
Physical 
Examination 
x
x
x
MacTSQ f
x
x
x
x
x
Site to contact 
IxRS (as 
applicable) g
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


Appendix 1
Schedule of Assessments for Implant Arms:  Screening, Randomization, Day 1, Month 1 through 
Month 9, Month X, Safety Visits, and Final/Early Termination Visits (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
113/Protocol GX28228, Version 8
Assessment
Screen a
7 days 
after 
RBZ tx
Rand b
28 and 
37 
days 
after 
RBZ tx
Day
Month
Month X 
Visit d
Safety 
Visit c
Final/
ETe
1 b
2 c
7 c
14 c
1
2
3
4
5
6
7
8
9
Window (Days)
0
2
2
7
7
7
7
7
7
7
7
7
7
See 
footnote c
See 
footnote e
Vital signs h
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Central laboratory 
samples 
(hematology, 
coagulation, 
serum chemistry, 
and urinalysis) i
x
Serum pregnancy 
sample j
x
If urine pregnancy test is positive, collect serum pregnancy 
sample and do not perform study treatment until the final 
results are available.
x
Urine pregnancy 
test k
xl
If a patient meets criteria for Implant refill, collect urine 
pregnancy test prior to the refill. If urine pregnancy test is 
positive, collect serum pregnancy sample and do not 
perform study treatment until the final results are available.
Serum PK sample 
for ranibizumab 
concentration 
xm


Appendix 1
Schedule of Assessments for Implant Arms:  Screening, Randomization, Day 1, Month 1 through 
Month 9, Month X, Safety Visits, and Final/Early Termination Visits (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
114/Protocol GX28228, Version 8
Assessment
Screen a
7 days 
after 
RBZ tx
Rand b
28 and 
37 
days 
after 
RBZ tx
Day
Month
Month X 
Visit d
Safety 
Visit c
Final/
ETe
1 b
2 c
7 c
14 c
1
2
3
4
5
6
7
8
9
Window (Days)
0
2
2
7
7
7
7
7
7
7
7
7
7
See 
footnote c
See 
footnote e
Serum PK sample 
for ranibizumab 
concentration 
PRIOR to 
treatment n
x
Collect serum PK sample for ranibizumab concentration at 
each monthly visit PRIOR to the treatment, even if treatment is 
not subsequently given.
x
Serum PK sample 
for ranibizumab 
concentration 
POST treatment o
xp
x
x
x
If Implant refill is performed, collect PK sample 1 to 2 days 
after refill, and 7 days after refill
x
Serum anti-
ranibizumab 
antibody sample q
x
x
x
x
x
x
x
Optional whole 
blood for DNA 
(RCR Sample)
x
Optional serum 
sample for 
candidate 
biomarkers
x
x
x


Appendix 1
Schedule of Assessments for Implant Arms:  Screening, Randomization, Day 1, Month 1 through 
Month 9, Month X, Safety Visits, and Final/Early Termination Visits (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
115/Protocol GX28228, Version 8
Assessment
Screen a
7 days 
after 
RBZ tx
Rand b
28 and 
37 
days 
after 
RBZ tx
Day
Month
Month X 
Visit d
Safety 
Visit c
Final/
ETe
1 b
2 c
7 c
14 c
1
2
3
4
5
6
7
8
9
Window (Days)
0
2
2
7
7
7
7
7
7
7
7
7
7
See 
footnote c
See 
footnote e
Optional plasma 
(EDTA) sample 
for candidate 
biomarkers
x
x
x
Optional aqueous 
humor sample r
Obtain prior to or immediately following one or more refills and 
at the safety visit 7 days post refill
BCVA testing 
(starting at 4 m)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Low luminance 
BCVA testing s
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Visual Field 
testing 
(Humphrey 24-2)t
xu
x
x
Axial Length 
Measurement
(ultrasound or 
optical biometry)v
xu
Intraocular 
pressure (IOP) w
x
x
x x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


Appendix 1
Schedule of Assessments for Implant Arms:  Screening, Randomization, Day 1, Month 1 through 
Month 9, Month X, Safety Visits, and Final/Early Termination Visits (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
116/Protocol GX28228, Version 8
Assessment
Screen a
7 days 
after 
RBZ tx
Rand b
28 and 
37 
days 
after 
RBZ tx
Day
Month
Month X 
Visit d
Safety 
Visit c
Final/
ETe
1 b
2 c
7 c
14 c
1
2
3
4
5
6
7
8
9
Window (Days)
0
2
2
7
7
7
7
7
7
7
7
7
7
See 
footnote c
See 
footnote e
Slit-lamp 
examination
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Dilated binocular 
indirect 
ophthalmoscopy y
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Historical OCT
images 
collection z
x
SD-OCT w, aa
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Fundus 
photography w, aa
x
x
x
Fluorescein 
angiography w, aa
x
x
x
x
x
Fundus 
Autofluorescence
w, aa
x
x
x
x
OCT Angiography 
(at selected 
sites) ab
x
x
x
x
x
x
x
x
x
x
x
x
x
x


Appendix 1
Schedule of Assessments for Implant Arms:  Screening, Randomization, Day 1, Month 1 through 
Month 9, Month X, Safety Visits, and Final/Early Termination Visits (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
117/Protocol GX28228, Version 8
Assessment
Screen a
7 days 
after 
RBZ tx
Rand b
28 and 
37 
days 
after 
RBZ tx
Day
Month
Month X 
Visit d
Safety 
Visit c
Final/
ETe
1 b
2 c
7 c
14 c
1
2
3
4
5
6
7
8
9
Window (Days)
0
2
2
7
7
7
7
7
7
7
7
7
7
See 
footnote c
See 
footnote e
External Photo -
study eye only
(High 
magnification 
Implant and 
conjunctiva, 
scleral surface)
x
x
x
x
x
x
x
x
x
x
x
x
x
Lens Photo
(fundus reflex 
photo) 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Implant Photo -
study eye only 
(High 
magnification 
Implant in eye, 
through dilated 
pupil) ac
x
x
x
x
x
x
x
x
x
x
x
x
x
Pre-study 
treatment 
antimicrobials (as 
applicable) ad
x
x
x
x
x
x
x
x
x
x
x


Appendix 1
Schedule of Assessments for Implant Arms:  Screening, Randomization, Day 1, Month 1 through 
Month 9, Month X, Safety Visits, and Final/Early Termination Visits (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
118/Protocol GX28228, Version 8
Assessment
Screen a
7 days 
after 
RBZ tx
Rand b
28 and 
37 
days 
after 
RBZ tx
Day
Month
Month X 
Visit d
Safety 
Visit c
Final/
ETe
1 b
2 c
7 c
14 c
1
2
3
4
5
6
7
8
9
Window (Days)
0
2
2
7
7
7
7
7
7
7
7
7
7
See 
footnote c
See 
footnote e
Post-study 
treatment 
antimicrobials ad
x
x
x
x
x
x
x
x
x
x
x
Video of Implant 
insertion and 
explantation and, 
if feasible, video 
of refill ae
x
Video of Implant insertion and explantation and, if feasible, 
video of refill (if applicable)
Ranibizumab 
filled Implant 
insertion
x
Implant refill with 
ranibizumab af
Refill if refill criteria are met (see Section 3.1.1)
Post-treatment 
finger counting 
(as applicable) ag
As applicable per treatment
Post-treatment 
IOP measurement
xah


Appendix 1
Schedule of Assessments for Implant Arms:  Screening, Randomization, Day 1, Month 1 through 
Month 9, Month X, Safety Visits, and Final/Early Termination Visits (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
119/Protocol GX28228, Version 8
Assessment
Screen a
7 days 
after 
RBZ tx
Rand b
28 and 
37 
days 
after 
RBZ tx
Day
Month
Month X 
Visit d
Safety 
Visit c
Final/
ETe
1 b
2 c
7 c
14 c
1
2
3
4
5
6
7
8
9
Window (Days)
0
2
2
7
7
7
7
7
7
7
7
7
7
See 
footnote c
See 
footnote e
Refill Needle 
collection after 
Implant refill for 
vitreous 
biomarkers ai
Collect Refill Needle with its content if Implant refill is 
performed, if applicable
Implant insertion 
evaluation aj
x
Concomitant 
medications ak
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse event al
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concurrent ocular 
procedures or 
additional 
assessments am
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Follow-up call (if 
applicable) an
x
As applicable per treatment
x


Appendix 1
Schedule of Assessments for Implant Arms:  Screening, Randomization, Day 1, Month 1 through 
Month 9, Month X, Safety Visits, and Final/Early Termination Visits (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
120/Protocol GX28228, Version 8
Assessment
Screen a
7 days 
after 
RBZ tx
Rand b
28 and 
37 
days 
after 
RBZ tx
Day
Month
Month X 
Visit d
Safety 
Visit c
Final/
ETe
1 b
2 c
7 c
14 c
1
2
3
4
5
6
7
8
9
Window (Days)
0
2
2
7
7
7
7
7
7
7
7
7
7
See 
footnote c
See 
footnote e
Eye fluid sample 
collection ao
Collect vitreous or aqueous humor sample at the start of 
explantation for patients undergoing an explantation procedure
AMDage-related macular degeneration; AREDSAge-Related Eye Disease Study; BCVAbest corrected visual acuity; ET end of treatment; 
IOPintraocular pressure; ITVintravitreal; IxRSinteractive Voice/Web response system; MacTSQMacular Degeneration Treatment 
Satisfaction Questionnaire; NAnot applicable; PKpharmacokinetic; Randrandomization; RBZ ranibizumab; SAsafety visit; 
SD-OCT spectral domain optical coherence tomography; tx treatment.
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 Screening cannot occur earlier than 7 days after the last standard-of-care of ITV ranibizumab treatment in the study eye. 
b Patients randomized to Implant treatment arms will be scheduled at the conclusion of their randomization visit for their Implant insertion surgery 
(Day 1) on such a date that no less than 28 days and no more than 37 days have lapsed between the surgery and their the last standard-of-care
ITV ranibizumab treatment in the study eye, unless a patient needs more time to interrupt aspirin or NSAID usage 7 days before Day 1 (see 
Section 4.3.2.3).  For these patients, Day 1 study treatment visit must occur no later than 45 days after the patient’s last ITV ranibizumab 
treatment.  In the case of a pause of enrollment and implant insertion surgeries, patients who have been randomized but have not yet received 
the study drug must repeat all randomization assessments (except for the randomization transaction in IxRS) after enrollment and implant 
insertion surgeries recommence, before receiving the study drug.


Appendix 1
Schedule of Assessments for Implant Arms:  Screening, Randomization, Day 1, Month 1 through 
Month 9, Month X, Safety Visits, and Final/Early Termination Visits (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
121/Protocol GX28228, Version 8
c Implant treatment arms safety assessment visits will be scheduled on Days 2, 7 (2 days), and 14 (2 days) after Implant insertion; 7 (2) days 
after each Implant refill; 1 and 7 (2) days post-explantation if a patient is continuously followed in the study (prior to study Last Patient In 
Month 9 visit); and 1, 7(2), 30 (7), and 60 (7) days post-explantation if a patient is exiting the study, after which a patient will be scheduled 
for the early termination visit 30 (7) days later.
d After completion of the Month 9 visit, the Implant arms study patients will continue monthly study visits according to Month X (i.e., Month 10, 
Month 11, Month 12, etc.) schedule of assessments until the Sponsor decides, based on the primary analysis results, to either terminate the 
study and discontinue study treatment, or offer patients entry into the RPDS Extension Study.
e For patients who are completing the study or withdrawing early, perform 90 (7) days after the Implant explantation.
f
MacTSQ should be interviewer-administered by site personnel (other than VA examiner) prior to any other study procedures.
g Refer to the IxRS Manual for further details.
h Vital signs consist of blood pressure and pulse measurement.  Height and weight will also be performed at the screening visit.  On the visits 
when a patient receives treatment, including Day 1 visit, perform vital signs measurements pre-treatment.  On the day of implant insertion and 
explantation of procedure, blood pressure must also be recorded during surgery and upon completion of the surgery. 
i
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 4.6.6 or the separate laboratory manual.
j
Perform urine pregnancy test prior to fluorescein angiography (if applicable) 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 fluorescein angiography or study 
treatment until the final results are available. If the serum pregnancy test is positive, do not administer the study treatment.
k Collect and perform locally the urine pregnancy test prior to fluorescein angiography and/or study treatment (if applicable) for women of 
childbearing potential, including those who have had tubal ligation. If urine pregnancy test is positive, collect serum pregnancy sample and do not 
perform study treatment until the final results are available. If the serum pregnancy test is positive, do not administer the study treatment.
l
May be collected up to 1 day prior to day 1.
m Collect serum PK sample from Implant arms patients at each post explantation safety visit (see protocol Section 4.7.2 and Section 4.7.3).
n Collect serum PK sample for ranibizumab concentration from Implant treatment arms patients at the Randomization visit and then at each 
monthly visit PRIOR to the treatment, even if treatment is not subsequently given. 


Appendix 1
Schedule of Assessments for Implant Arms:  Screening, Randomization, Day 1, Month 1 through 
Month 9, Month X, Safety Visits, and Final/Early Termination Visits (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
122/Protocol GX28228, Version 8
o Collect serum PK sample for ranibizumab concentration from Implant treatment arms patients ≥ 60 minutes post treatment on Day 1 visit (if 
possible) and then on Days 2, 7(2 days), and 14 (2 days) after Day 1 visit; afterwards collect serum PK sample 1 and 7 (2) days after each 
refill.  Collect a serum PK sample at the early termination visit if applicable.  Note:  for patients who are unable to visit the clinic for the PK 
sample collection 1 day after each Implant refill, provision will be made for this timepoint sample collection to be collected at their home.  
Alternatively, the sample may be collected 2 days after the refill.  Training will be provided to site staff on how to perform this task.  The sample 
will be sent to a central laboratory.
p Perform only if possible.
q Obtain serum anti-ranibizumab antibody sample from the Implant treatment arms patients prior to the study treatment and prior to fluorescein 
angiography (if applicable) on the Randomization visit, Visits Day 14, Month 1, 3, 6, and 9 and at the early termination visit if applicable.
r
If a patient has consented to this optional sample collection, obtain the aqueous humor sample prior to or immediately following one or more 
refills and at the Day 7 safety visit post refill.
s Perform low luminance BCVA testing after standard BCVA testing.
t
Perform only if you have the Humphrey Visual Field machine at your site.  In addition to the listed timepoints, this testing will be performed any 
time the patient reports a new defect of the peripheral vision. 
u If it cannot be performed during Randomization, this testing must be performed on a subsequent day but before Day 1.
v Perform only if you have ultrasound or optical biometry capability at your site.
w Perform pre-treatment.
x Should be performed in the surgical center using Tono-Pen tomometry prior to the Implant insertion surgery.
y Dilated ophthalmoscopy examinations will be performed for patients in the Implant treatment arms after Implant insertion in the study eye at the 
Day 1 visit, and then on Days 2, 7 (2 days), and 14 (2 days) after the Day 1 visit; afterward, perform dilated ophthalmoscopy examinations at 
each monthly visit to monitor the Implant and its release control element for visible clogging and other Implant problems.
z Historical OCT taken at the time of diagnosis of nAMD will also be required to determine patient’s eligibility at the screening visit.  If fluorescein 
angiograms were taken at the time of diagnosis of nAMD, they must be submitted to the reading center as well. If available, historical fluorescein 
angiograms will be evaluated by the reading center, but are not required to determine patient’s eligibility.  Refer to the Reading Center Manuals 
for details.
aa The central reading center will evaluate fundus photography, fluorescein angiograms, and SD-OCT taken at the screening visit for determination 
of a patient’s eligibility, together with the historical OCT taken at the time of diagnosis of nAMD. Refer to the Reading Center Manual for details.
ab Only at selected sites. Perform pre-treatment.
ac In addition to the timepoints listed, the photo will also be taken at any visit if there are concerns with Implant function.


Appendix 1
Schedule of Assessments for Implant Arms:  Screening, Randomization, Day 1, Month 1 through 
Month 9, Month X, Safety Visits, and Final/Early Termination Visits (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
123/Protocol GX28228, Version 8
ad The pre-Implant insertion or explantation use of self-administered antimicrobials is required.  The pre-Implant refill use of self-administered 
antimicrobials is per the investigator’s discretion. The post-Implant insertion, explantation, or refill use of self-administered antimicrobials is 
required.
ae The video of the implant/explant procedure (if applicable) should be recorded. The video of the refill is optional.
af Initially fill the Implant with IxRS assigned kit of ranibizumab prior to its insertion into the study eye.  Afterwards, starting at Month 1 visit, if refill 
criteria are met (see Section 3.1.1), refill the Implant with IxRS assigned ranibizumab kit.
ag Following each Implant refill, patients will have a 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 patients will remain at the clinic for approximately 
40 minutes.  If there are no safety concerns 40 (10) minutes following treatment, the patient will be allowed to leave the clinic.  If any safety 
concerns or immediate toxicity is noted, the patient will remain at the clinic and will be treated according to the designated physician’s clinical 
judgment.  If applicable, the adverse event will be reported on the appropriate eCRF page.  
ah Upon completion of the Implant insertion or explantation procedure, patients will have indirect ophthalmoscopy performed to monitor the Implant 
placement and to evaluate any potential Implant problems.  Intraocular pressure will be checked for the study eye only by the treating physician 
by digital palpation.  These assessments must be performed prior to placing a patch on the eye.  If any safety concerns or immediate toxicity is 
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 on the appropriate eCRF page.
ai Follow Refill Needle return instructions from the laboratory manual if Implant refill has been performed (if applicable).
aj 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 on the appropriate eCRF page.
ak Record any concomitant medications (i.e., any prescription medications or over-the-counter preparations other than protocol-specified 
procedural medications, and pre-treatment and post-treatment medications, such as proparacaine, antimicrobials) 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.
al 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, medication wash-out, etc.) 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/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.
am 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.


Appendix 1
Schedule of Assessments for Implant Arms:  Screening, Randomization, Day 1, Month 1 through 
Month 9, Month X, Safety Visits, and Final/Early Termination Visits (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
124/Protocol GX28228, Version 8
an 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.
aoAqueous humor or vitreous sample collection must be performed at the start of explantation for all patients undergoing an explantation procedure.  
The choice between aqueous humor collection or vitreous collection is per investigator’s discretion (see Appendix 19).


Ranibizumab Port Delivery System—Genentech, Inc.
125/Protocol GX28228, Version 8
Appendix 2
Schedule of Assessments for ITV arm:  Screening, Randomization/Day 1, Month 1 through 
Month 9, Month X, and Final/Early Termination Visits
Assessment
Screen 
a
7 
days 
after 
RBZ tx
Rand/
Day 1 b
28 
and 
37 
days 
after 
RBZ tx
Month
Month 
X visit c
Final/
ET d
1
2
3
4
5
6
7
8
9
Window (Days)
7
7
7
7
7
7
7
7
7
7
7
Written informed consent
x
Review of inclusion and 
exclusion criteria
x
x
Medical and surgical 
history, tobacco and 
alcohol use
x
Demographic Information
x
Physical Examination 
x
x
x
MacTSQ e
x
x
x
x
x
Site to contact IxRS (as 
applicable) f
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital signs g
x
x
x
x
x
x
x
x
x
x
x
x
x
Central laboratory 
samples (hematology, 
coagulation, serum 
chemistry, and 
urinalysis) h
x


Appendix 2
Schedule of Assessments for ITV arm:  Screening, Randomization/Day 1, Month 1 through 
Month 9, Month X, and Final/Early Termination Visits (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
126/Protocol GX28228, Version 8
Assessment
Screen 
a
7 
days 
after 
RBZ tx
Rand/
Day 1 b
28 
and 
37 
days 
after 
RBZ tx
Month
Month 
X visit c
Final/
ET d
1
2
3
4
5
6
7
8
9
Window (Days)
7
7
7
7
7
7
7
7
7
7
7
Serum PK sample for 
ranibizumab i
x
x
x
x
x
x
Serum anti-ranibizumab 
antibody sample i
x
x
x
x
x
x
Serum pregnancy sample j
x
If urine pregnancy test is positive, collect serum pregnancy sample and do not perform study 
treatment until the final results are available
x
Urine pregnancy test k
x
Collect urine pregnancy test prior to treatment. If urine pregnancy test is positive, collect 
serum pregnancy sample and do not perform study treatment until the final results are 
available
BCVA testing (starting at 
4 m)
x
x
x
x
x
x
x
x
x
x
x
x
x
Low luminance BCVA 
testing l
x
x
x
x
x
x
x
x
x
x
x
x
x
Intraocular pressure
(IOP) m
x
x
x
x
x
x
x
x
x
x
x
x
x
Slit-lamp examination
x
x
x
x
x
x
x
x
x
x
x
x
x


Appendix 2
Schedule of Assessments for ITV arm:  Screening, Randomization/Day 1, Month 1 through 
Month 9, Month X, and Final/Early Termination Visits (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
127/Protocol GX28228, Version 8
Assessment
Screen 
a
7 
days 
after 
RBZ tx
Rand/
Day 1 b
28 
and 
37 
days 
after 
RBZ tx
Month
Month 
X visit c
Final/
ET d
1
2
3
4
5
6
7
8
9
Window (Days)
7
7
7
7
7
7
7
7
7
7
7
Dilated binocular indirect 
ophthalmoscopy
x
x
x
x
x
x
x
x
x
x
x
x
x
Historical fundus images 
collection n
x
SD-OCT m,o
x
x
x
x
x
x
x
x
x
x
x
x
x
Fundus photography m,o
x
x
x
Fluorescein 
angiography m,o
x
x
x
x
x
Fundus 
autofluorescence m,o
x
x
x
x
OCT Angiography p
x
x
x
x
x
x
x
x
x
x
x
x
Lens Photo
(fundus reflex photos)
x
x
x
x
Optional whole blood for 
DNA (RCR Sample)
x


Appendix 2
Schedule of Assessments for ITV arm:  Screening, Randomization/Day 1, Month 1 through 
Month 9, Month X, and Final/Early Termination Visits (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
128/Protocol GX28228, Version 8
Assessment
Screen 
a
7 
days 
after 
RBZ tx
Rand/
Day 1 b
28 
and 
37 
days 
after 
RBZ tx
Month
Month 
X visit c
Final/
ET d
1
2
3
4
5
6
7
8
9
Window (Days)
7
7
7
7
7
7
7
7
7
7
7
Optional serum sample for 
candidate biomarkers
x
x
x
Optional plasma (EDTA) 
sample for candidate 
biomarkers
x
x
x
Pre- and post- study 
treatment antimicrobials 
(as applicable) q
x
x
x
x
x
x
x
x
x
x
x
Administration of 
ranibizumab to ITV 
injection arm 
x
x
x
x
x
x
x
x
x
x
x
Post-treatment finger 
counting (as applicable) r
x
x 
x
x
x
x
x
x
x
x
x
Concomitant 
medications s
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse event t
x
x
x
x
x
x
x
x
x
x
x
x


Appendix 2
Schedule of Assessments for ITV arm:  Screening, Randomization/Day 1, Month 1 through 
Month 9, Month X, and Final/Early Termination Visits (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
129/Protocol GX28228, Version 8
Assessment
Screen 
a
7 
days 
after 
RBZ tx
Rand/
Day 1 b
28 
and 
37 
days 
after 
RBZ tx
Month
Month 
X visit c
Final/
ET d
1
2
3
4
5
6
7
8
9
Window (Days)
7
7
7
7
7
7
7
7
7
7
7
Concurrent ocular 
procedures u
x
x
x
x
x
x
x
x
x
x
x
x
Follow-up call (if 
applicable) v
x
x
x
x
x
x
x
x
x
x
x
AMDage-related macular degeneration; AREDSAge-Related Eye Disease Study; BCVAbest corrected visual acuity; ET end of treatment; 
IOPintraocular pressure; ITVintravitreal; IxRSinteractive Voice/Web response system; MacTSQMacular Degeneration Treatment 
Satisfaction Questionnaire; NAnot applicable; PKpharmacokinetic; Randrandomization; RBZ ranibizumab; SAsafety visit; 
SD-OCT spectral domain optical coherence tomography; tx treatment.
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 Screening cannot occur earlier than 7 days after the last standard-of-care of ITV ranibizumab treatment in the study eye. 
b Patients randomized to the ITV injection treatment arm may receive their first study treatment (Day 1) at the conclusion of the randomization visit 
or later; however no less than 28 days and no more than 37 days should have lapsed between the first study treatment and their last standard-
of-care ITV ranibizumab treatment in the study eye.
c After completion of the Month 9 visit, the ITV arm patients will continue monthly study visits according to Month X (i.e., Month 10, Month 11, 
Month 12, etc.) schedule of assessments until the Sponsor decides, based on the primary analysis results, to either terminate the study and 
discontinue study treatment, or offer patients entry into the RPDS Extension Study.
d Patients final study visit or early termination visit will be scheduled 30 (7) days following the last study treatment.  
e MacTSQ should be interviewer-administered by site personnel (other than VA examiner) prior to any other study procedures.


Appendix 2
Schedule of Assessments for ITV arm:  Screening, Randomization/Day 1, Month 1 through 
Month 9, Month X, and Final/Early Termination Visits (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
130/Protocol GX28228, Version 8
f
Refer to the IxRS Manual for details.
g Vital signs consist of blood pressure and pulse measurement.  Height and weight will also be performed at the screening visit.  On the visits 
when a patient receives treatment, perform vital signs measurements pre-treatment.
h Obtain from all study patients pre-treatment and prior to fluorescein angiography, if applicable, except early termination (no time requirement).  
For a description of the laboratory assessments to be performed, see Section 4.6.6 or the separate laboratory manual.
i
Obtain sample prior to the study treatment and prior to fluorescein angiography (if applicable).
j
Collect serum pregnancy sample prior to fluorescein angiography (if applicable) for women of childbearing potential, including those who have 
had tubal ligation. If the serum pregnancy test is positive, do not administer the study treatment.
k Collect and perform locally the urine pregnancy test prior to fluorescein angiography and study treatment for women of childbearing potential, 
including those who have had tubal ligation. If urine pregnancy test is positive, collect serum pregnancy sample and do not perform study 
treatment until the final results are available. If the serum pregnancy test is positive, do not administer the study treatment.
l
Perform low luminance BCVA testing after standard BCVA testing.
m Perform pre-treatment.
n Historical OCT taken at the time of diagnosis of nAMD will also be required to determine patient’s eligibility at the screening visit.  If fluorescein 
angiograms were taken at the time of diagnosis of nAMD, they must be submitted to the reading center as well. If available, historical fluorescein 
angiograms will be evaluated by the reading center, but are not required to determine patient’s eligibility.  Refer to the Reading Center Manuals 
for details.
o The central reading center will evaluate fundus photography, fluorescein angiograms, and SD-OCT taken at the screening visit for determination
of a patient’s eligibility, together with the historical OCT 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 The pre- and post-treatment use of self-administered antimicrobials for the ITV injection arm is per the investigator discretion.
r
Following each ITV treatment with ranibizumab, patients will have a 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 patients will remain at the clinic for 
approximately 40 minutes.  If there are no safety concerns 40 (10) minutes following treatment, the patient will be allowed to leave the clinic.  If 
any safety concerns or immediate toxicity is noted, the patient will remain at the clinic and will be treated according to the designated physician’s 
clinical judgment.  If applicable, the adverse event will be reported on the appropriate eCRF page.  
s Record any concomitant medications (i.e., any prescription medications or over-the-counter preparations other than protocol-specified 
procedural medications, and pre-treatment and post-treatment medications, such as proparacaine, antimicrobials) 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.


Appendix 2
Schedule of Assessments for ITV arm:  Screening, Randomization/Day 1, Month 1 through 
Month 9, Month X, and Final/Early Termination Visits (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
131/Protocol GX28228, Version 8
t
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 etc.) 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 ranibizumab and ITV 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.
u Record all concurrent ocular procedures performed on the study or fellow eye.
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 (if applicable).


Ranibizumab Port Delivery System—Genentech, Inc.
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Appendix 3
Pre-Screening Visits (if applicable)
Assessmentsa
Pre-Screening Visit 1 
(Month -2)
Pre-Screening Visit 2 
(Month -1)
Window (days)
+7
7
Written informed consent
X
Review of inclusion and exclusion 
criteriab
X
Fluorescein Angiographyc
X
SD-OCTc
X
Site to contact IxRS
X
X
Administration of ITV ranibizumab
X
X
Adverse eventsd
X
X
IxRSinteractive Voice/Web response system; PKpharmacokinetic; SD-OCT spectral 
domain optical coherence tomography 
a A pre-screening will be available for newly diagnosed nAMD patients who are treatment 
naïve.  Patients must satisfy pre-screening eligibility criteria and sign consent to study 
participation before entering the pre-screening.  
b Pre-screening evaluations for inclusion/exclusion criteria will only be performed and 
evaluated locally by the Investigator
c Must be taken following the instructions on the Reading Center Manual; these images will be 
used as historical images for patient’s eligibility at the screening visit.  
d During the pre-screening, only serious adverse events related to a protocol-mandated
intervention (e.g., ITV injection procedure, or ITV ranibizumab) should be reported. Adverse 
events assessed by the qualified ophthalmologist as related to ranibizumab and ITV 
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.


Ranibizumab Port Delivery System—Genentech, Inc.
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Appendix 4
Run-In Visit (if applicable)
Assessments a
Run-In Treatment 
(Month -1)
Window (days)
+7
Written informed consent
X
Review of inclusion and exclusion 
criteriab
X
Serum PK sample for ranibizumab 
concentration prior to treatment c
X
Site to contact IxRS
X
Administration of ITV ranibizumab
X
Adverse events d
X
IxRSinteractive Voice/Web response system.
a Run-In treatment will be available for patients who have been: 
o
diagnosed with nAMD in the study eye within 9months prior to screening and treated 
with a single anti-VEGF ITV injection, OR 
o
diagnosed with nAMD in the study eye within 9months prior to screening and treated 
with no more than eight anti-VEGF ITV injections, with aflibercept or bevacizumab
being the most recent injection.
Patients must satisfy run-in eligibility criteria and sign consent to study participation before 
completing any study procedures or receiving run-in treatment.
b Run-In evaluations for inclusion/exclusion criteria will only be performed and evaluated locally 
by the Investigator.
c Collect prior to administration of the run-in ITV ranibizumab treatment.
d Only serious adverse events related to a protocol-mandated intervention (e.g., ITV injection 
procedure, or ITV ranibizumab) should be reported.  Adverse events assessed by the 
qualified ophthalmologist as related to ranibizumab and ITV 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.


Ranibizumab Port Delivery System—Genentech, Inc.
134/Protocol GX28228, Version 8
Appendix 5
Unscheduled Safety Assessment Visit
Assessmentsa
Vital signs (blood pressure, respiration rate, pulse, and temperature)
x
Best corrected visual acuity (4-m starting distance)b
x
Slit-lamp examination
x
Dilated binocular indirect high-magnification ophthalmoscopy
x
Intraocular pressurec
x
SD-OCT
x
Adverse eventsd
x
Concurrent ocular procedures
x
Concomitant medications
x
IOPintraocular pressure; SD-OCT spectral domain optical coherence tomography.
a An unscheduled safety visit is applicable to any randomized study patients.  If determined to 
be necessary by the physician, perform the listed assessments.  All ocular assessments 
should be performed on both eyes.
b Perform finger-counting test followed by hand motion and light perception tests when 
necessary.
c The method used for the IOP measurement for a patient must remain consistent throughout 
the study.
d Adverse event causality to be evaluated by the qualified ophthalmologist.


Ranibizumab Port Delivery System—Genentech, Inc.
135/Protocol GX28228, Version 8
Appendix 6
Implant Treatment Arms Procedures
Please consult Instruction for Use (IFU) Manual for the Implant fill, insertion, refill, and 
explantation details as well as preparation of study drug (ranibizumab) for the Implant 
treatment arms.
Surgeons will be qualified ophthalmologists trained in the management of retinal 
diseases and retinal surgery who will be certified by a Roche-selected vendor prior to 
performing the Implant insertion, its fill, refill, and explantation.


Ranibizumab Port Delivery System—Genentech, Inc.
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Appendix 7
Pre-Injection Procedures for ITV Treatment Arm
The following procedures will be used to minimize the risk of potential adverse events 
associated with intravitreal (ITV) injections (e.g., endophthalmitis).  Aseptic technique will 
be observed by clinic staff involved in the injection tray assembly, anesthetic preparation, 
and study drug preparation and administration.  In addition to the procedures outlined 
below, any additional safety measures in adherence to specific institutional policies 
associated with ITV injections will be observed. Physician should wear surgical face 
mask and refrain from talking, coughing, or sneezing during the injection.
The following procedures (except where noted) will be conducted by the investigator 
performing the ITV injection of study drug.  
Patients self-administered antimicrobials will be prescribed for this treatment arm at the 
investigator’s discretion.  At the discretion of the investigator, sites may use either 
ophthalmic drops or lidocaine injection for study eye anesthesia.
PROCEDURE FOR PROPARACAINE OR TETRACAINE-BASED 
ANESTHESIA
Note: Topical anesthetic gels are prohibited.
If using proparacaine or tetracaine-based ophthalmic drops for anesthesia, the injecting 
physician or technician (if applicable) assembles the supplies and prepares a sterile field 
with supplies that include the following:

10% povidone iodine swabs, sterile surgical gloves

4 4 sterile pads

A pack of sterile cotton-tipped applicators

Eyelid speculum

Sterile ophthalmic drape, sterile 0.5% proparacaine hydrochloride or 0.5% 
tetracaine hydrochloride drops (topical ophthalmic gels for anesthesia are 
NOT permitted)

5% povidone iodine ophthalmic solution

Injection supplies
PROCEDURE

Instill two drops of proparacaine or tetracaine ophthalmic drops into the study eye.

Wait 5 minutes.

Instill two more drops of proparacaine or tetracaine ophthalmic drops into the study 
eye.


Appendix 7
Pre-Injection Procedures for ITV Treatment Arm (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
137/Protocol GX28228, Version 8

Disinfect the periocular skin and eyelid of the study eye in preparation for injection.  
Scrub the eyelid, lashes, and periorbital skin with 10% povidone iodine swabs, 
starting with the eyelid and lashes and continuing with the surrounding periocular 
skin.  Ensure that the eyelid margins and lashes are swabbed, and proceed in a 
systematic fashion, from medial to temporal aspects.

The physician will glove, place sterile ophthalmic drape to isolate the field, and place 
the speculum underneath the eyelid of the study eye.

Instill two drops of 5% povidone iodine ophthalmic solution in the study eye, 
ensuring that the drops cover the planned injection site on the conjunctiva.

Wait 90 seconds.

Saturate a sterile, cotton-tipped applicator with proparacaine or tetracaine 
ophthalmic drops and hold the swab against the planned intravitreal injection site for 
10 seconds.

Use a sterile 4 4 pad in a single wipe to absorb excess liquid and to dry the 
periocular skin.

Instruct the patient to direct gaze away from syringe prior to study drug injection.
PROCEDURE FOR LIDOCAINE-BASED ANESTHESIA

If using lidocaine injection for anesthesia, physician or technician (if applicable) 
assembles the supplies and prepares a sterile field with supplies that include the
following:

10% povidone iodine swabs, sterile surgical gloves

4 x 4 sterile pads

A pack of sterile cotton tipped applicators

Eyelid speculum

Sterile ophthalmic drape, sterile 0.5% proparacaine hydrochloride or 0.5% 
tetracaine hydrochloride 

5% povidone iodine ophthalmic solution

1% or 2% lidocaine for injection

Injection supplies
PROCEDURE

Instill two drops of proparacaine or tetracaine ophthalmic drops into the study eye.

Disinfect the periocular skin and eyelid of the study eye in preparation for injection.  
Scrub the eyelid, lashes, and periorbital skin with 10% povidone iodine swabs, 
starting with the eyelid and lashes and continuing with the surrounding periocular 
skin.  Ensure that the eyelid margins and lashes are swabbed, and proceed in a 
systematic fashion, from medial to temporal aspects.


Appendix 7
Pre-Injection Procedures for ITV Treatment Arm (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
138/Protocol GX28228, Version 8

The physician will glove, place sterile ophthalmic drape to isolate the field, and place 
the speculum underneath the eyelid of the study eye.

Instill two drops of 5% povidone iodine ophthalmic solution in the study eye, 
ensuring that the drops cover the planned injection site on the conjunctiva.

Wait 90 seconds.

Saturate a sterile, cotton-tipped applicator with 0.5% proparacaine hydrochloride 
drops and hold the swab against the planned intravitreal injection site for 
10 seconds in preparation for the subconjunctival injection of 1% or 2% lidocaine 
hydrochloride ophthalmic solution for injection (without epinephrine).

Inject 1% or 2% lidocaine (without epinephrine) subconjunctivally.

Use a sterile 4 x 4 pad in a single wipe to absorb excess liquid and to dry the 
periocular skin.

Instruct patient to direct gaze away from syringe prior to study drug injection.


Ranibizumab Port Delivery System—Genentech, Inc.
139/Protocol GX28228, Version 8
Appendix 8
Preparation and Administration of Ranibizumab ITV Injection
The physician will prepare the ranibizumab injection as outlined below.
Vials of ranibizumab in aqueous humor solution should remain refrigerated at 2C to 8C 
(36F to 46F) until just prior to use.  DO NOT FREEZE vials.  Protect from direct light.  
Do not use beyond the expiration date.  In order to minimize the risk of microbial growth, 
dose solutions should be prepared immediately before dosing.  Dose solutions are for 
single use only.
After preparing the study eye as outlined in Appendix 7, withdraw 0.2-mL ranibizumab 
dose solution through a 5-m filter needle.  Remove the filter needle, replace it with a 
30-gauge, 1/2-inch Precision Glideneedle, and expel excess ranibizumab so that the 
syringe contains 0.05 mL of solution.  Insert the syringe through an area 3.5 to 
4.0 mm posterior to the limbus, avoiding the horizontal meridian, and aiming toward the 
center of the globe.  The injection volume should be delivered slowly.  The needle 
should then be removed slowly to ensure that all drug solution is in the eye.  The scleral 
site for subsequent intravitreal injections should be rotated.  Refer to Appendix 9, 
for detailed post-injection procedures.
All injection materials (i.e., syringes, needles) will be discarded in a sharps container 
immediately following each ranibizumab injection.  
A patient’s study eye will be monitored with a finger count test within 15 minutes of the 
ranibizumab injection by the physician.  A measurement of IOP in the study eye will be 
obtained 40 (10) minutes post-injection. If there are no safety concerns, the patient will 
be allowed to leave the clinic.  If any safety concerns or immediate toxicity is noted, the 
patient will remain at the clinic and will be treated according to the designated 
physician’s clinical judgment.  The following table provides specific instructions for the 
preparation and administration of ranibizumab in aqueous humor solution.


Appendix 8
Preparation and Administration of Ranibizumab ITV Injection (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
140/Protocol GX28228, Version 8
Step
Procedures
Materials
Methods
1.
Filter study drug.
Withdraw 0.2-mL ranibizumab dose solution 
through a 5-m filter needle attached to 
provided 1mL syringe.
After withdrawing ranibizumab through the 
filter, remove filter needle, replace it with a 
30-gauge, ½-inch Precision Glideneedle, 
and expel excess ranibizumab so that the 
syringe contains 0.05-mL ranibizumab 
solution.
5-m filter needle (needle is 19-gauge, 1.5 
TW)
1-mL syringe
Ranibizumab dose solution in the 2-mL
ranibizumab vial
To minimize contamination from skin, 
sterile gloves should be used before 
handling the study drug vial and other 
supplies.
Use aseptic technique to maintain 
sterility of the surface of the rubber 
stopper.
2.
Administer ranibizumab.
Inject 0.05 mL ranibizumab into the eye 
3.5–4.0 mm posterior to the limbus.
30-gauge, 1/2-inch Precision Glideneedle
Ranibizumab dose solution in the syringe 
Avoid the horizontal meridian and aim 
toward the center of the globe.  Inject 
slowly.  Remove the needle slowly to 
ensure that all drug solution is in the eye.
3.
Discard the syringe and all needles on the 
sterile tray in the Sharps container 
immediately following each ranibizumab 
injection.
Sharps container 


Ranibizumab Port Delivery System—Genentech, Inc.
141/Protocol GX28228, Version 8
Appendix 9
Post-Injection Procedures for Patients in the ITV Injection Arm
INSTRUCTIONS
Immediately following the ranibizumab injection, discard all syringes and needles in the 
sharps container.
As per investigator’s discretion, instruct the patient to self-administer antimicrobial drops 
following each injection of study drug (ranibizumab).


Ranibizumab Port Delivery System—Genentech, Inc.
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Appendix 10
Best Corrected Visual Acuity Testing
SCOPE
Best corrected visual acuity (BCVA) will be measured by trained and certified personnel 
at the study sites.  The visual acuity (VA) examiner will be masked to the patient study 
eye assignment and patient treatment assignment.  The VA examiner will have no 
access to a patient’s previous visits’ VA scores; the VA examiner will only be aware of
the patient’s refraction data from previous visits.  The VA examiner is not permitted to 
perform any other tasks involving direct patient care except for VA refraction and VA 
examination.  VA will be measured at the intervals specified in the protocol (see 
Section 4.6 of the protocol and 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 Early 
Treatment Diabetic Retinopathy Study 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.


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Appendix 11
Low Luminance Best Corrected Visual Acuity Testing
There are the same requirements as the best corrected visual acuity described in 
Appendix 10; however, the low luminance visual acuity will be measured by placing a 
2.0-log-unit neutral density filter over the best correction for that eye and having the 
participant read the normally illuminated Early Treatment Diabetic Retinopathy Study 
chart.


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Appendix 12
Grading Scales
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 slit-lamp 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 slit-lamp 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 
slit-lamp 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 slit-lamp beam is swept across 
the anterior chamber.
Trace
Few (13) cells are observed when the slit-lamp 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 slit-lamp 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 slit-lamp beam is swept across the anterior chamber.  
When the instrument is held stationary, every optical section contains circulating cells.
3
2550 cells are seen when the slit-lamp 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 slit-lamp 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 MH, Kimura SJ, Thygeson P. Signs and symptoms of uveitis. I. Anterior 
uveitis. Am J Ophthalmol 1959;47(5, Part 2):155–70.


Appendix 12
Grading Scales (cont.)
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GRADING SCALE FOR VITREAL HEMORRHAGE DENSITY
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.
GRADING SCALE FOR VITREOUS CELLS
Cells in 
Retroilluminated 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. New York: Mosby, 1996, p. 64.


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Appendix 13
Fundus Autofluorescence
SCOPE
Fundus autofluorescence (FAF) will be performed at the study sites by trained personnel 
who are certified by the central reading center.  FAF imaging will be performed for each 
patient at the intervals specified in the protocol (see Appendix 1 and Appendix 2) and will 
be forwarded to the central reading center for analysis and/or storage.  Analysis (if 
applicable) of FAF images will be performed by the central reading center.  The list and 
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 14
Color Fundus Photographs
SCOPE
Color fundus photographs (CFP) will be taken by trained personnel at the study sites at 
the intervals specified in the protocol.
CFP imaging will be performed for each patient at the intervals specified in the protocol 
(see Appendix 1 and Appendix 2) and will be forwarded to the central reading center for 
analysis and/or storage. Analysis (if applicable) of fundus photographs will be performed 
by the central reading center.
The list and timepoints at which images will be analyzed are recorded in the reading 
center manual. 
EQUIPMENT
See the reading center manual.
PROCEDURE
The central reading center will provide a study manual and training materials.  
The photographer and equipment will be certified by the reading center before any study 
images are taken.


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Appendix 15
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 FAs will be obtained at the intervals 
specified in the protocol (see Section 4.6 of the protocol and Appendix 1 and Appendix 2)
and will be forwarded to the central reading center for analysis and/or storage.
The list and 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 materials.  
Photographers, systems, and software will be certified prior to obtaining patient 
angiograms.


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Appendix 16
Spectral Domain Optical Coherence Tomography
SCOPE
Spectral domain optical coherence tomography (SD-OCT) will be performed at the study 
sites by trained personnel who are certified by the central reading center.  SD-OCT 
imaging will be performed for each patient at the intervals specified in the protocol (see 
Section 4.6 and Appendix 1 and Appendix 2) and will be forwarded to the central reading 
center for analysis and/or storage.
The list and 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 17
External and Implant Photographs
SCOPE
External and 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 Appendix 1) 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 and timepoints at which images will be analyzed are recorded in the reading 
center manual.
EQUIPMENT
See the reading center manual.
PROCEDURE
The central reading center will provide a study manual and training materials.  The 
photographer and equipment will be certified by the reading center before any study 
images are taken.


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Appendix 18
Optical Coherence Tomography Angiography (at Selected Sites)
SCOPE
Optical coherence tomography (OCT) angiography will be performed 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 Appendix 1 and Appendix 2) and will 
be forwarded to the central reading center for analysis and/or storage.
The list and 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.  
OCT angiography will be performed using Optovue AngioVueTM Imaging System only
with the AngioVueTM software. 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 20
Central Laboratory Sample Collection and Shipping 
BIOLOGICAL SAMPLES
Serum for assessment of laboratory safety (hematology, serum chemistry, coagulation, 
pregnancy test) and urinalysis will be collected at screening visit.  Urine pregnancy test 
will be collected and performed at Day 1 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, residual content of the Implant from 
the Refill Needle (if applicable), and aqueous humor or vitreous samples (at the start of 
explantation for patients undergoing an explantation procedure) will be collected at the 
timepoints specified in Section 4.6.6 of the protocol and the schedule of assessments
(see Appendix 1 and Appendix 2).  The optional aqueous humor samples prior to one or 
more refills and at the Day 7 safety visit post refill will be collected as well.
All samples should be collected and shipped initially to the central laboratory.  The 
laboratory safety (hematology, serum chemistry, coagulation, and urinalysis) samples 
will be analyzed by the central laboratory.  The rest of the collected samples will be 
analyzed by Sponsor or selected designee. All necessary transfer tubes, labels, forms, 
and shipping supplies will be provided by the central laboratory.   
OPTIONAL ANTERIOR CHAMBER (AQUEOUS HUMOR) SAMPLE 
COLLECTION FROM IMPLANT TREATMENT ARMS
The optional aqueous humor paracentesis samples will be collected from patients who 
consent to the procedure and sample acquisition.  An aqueous humor sample will be 
collected prior to or immediately following the patient’s study eye treatment visits as 
indicated in Appendix 1.  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 study treatment to ITV arm patients following the collection of the 
aqueous humor sample, the subconjunctival lidocaine anesthetic must be injected into 
the eye prior to study treatment.


Appendix 20
Central Laboratory Sample Collection and Shipping (cont.)
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EYE FLUID SAMPLE COLLECTION FROM IMPLANT TREATMENT ARMS
Vitreous or aqueous humor sample collection must be performed at the start of 
explantation for all patients undergoing an explantation procedure.  The choice between 
vitreous collection or aqueous humor collection is per investigator’s discretion.  

The aqueous humor sample collection consists of an anterior chamber paracentesis 
(removing 0.050.1 mL of fluid from the anterior chamber of the eye).

The vitreous humor sample collection consists of a vitreous tap (removing 
0.050.1 mL of undiluted vitreous from the central vitreal cavity).
The vitreous humor sample collection will be performed by a qualified physician using
standard 23-gauge or 25-gauge vitrectomy procedures.  The infusion cannula will be 
inserted through a sclerotomy in the pars plana of the infero-temporal quadrant of the 
eye, without opening the infusion.  The vitreous humor tap will be performed by placing 
the vitrectome in the central vitreous through a second sclerotomy in the pars plana of 
the supero-nasal quadrant of the eye, and by aspirating 0.05 to 0.1 mL of undiluted 
vitreal sample with a 5-mL syringe while cutting vitreous actively.  After collecting 
enough vitreous humor sample, the aspiration will be stopped and the vitrectome will be 
carefully removed from the eye.  
After collecting the undiluted vitreous humor sample, the Implant will be removed from 
the eye and the scleral wound will be sutured as described in the RPDS IFU.  In case of 
hypotony, the infusion through the cannula will be opened to restore the normal 
intraocular pressure.  The physician will then perform a careful exploration of the retina, 
and a standard vitrectomy will be performed in the case of visible retinal detachment or 
other complications that require immediate surgical intervention.
Vitreous or aqueous humor samples will be collected with the kit provided by the central 
laboratory and shipped on dry ice to the central laboratory as soon as possible after the 
draw.  Please see the RPDS IFU for further details.
EXPLANTED IMPLANTS WITH CONTENTS
Explanted Implants containing ranibizumab drug product will be preserved for potential 
analysis upon explant 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.
Refer to the 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.


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Appendix 21
Ranibizumab Port Delivery System:  Device Clinical
Investigation Plan


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Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
 
 
TABLE OF CONTENTS 
1. 
GENERAL ................................................................................................. 195 
2. 
IDENTIFICATION AND DESCRIPTION OF THE 
INVESTIGATIONAL DEVICE .................................................................... 196 
2.1 
SUMMARY DESCRIPTION OF THE 
INVESTIGATIONAL DEVICE AND ITS 
INTENDED PURPOSE ........................................................ 197 
2.1.1 
Implant ................................................................................. 197 
2.1.2 
Initial Fill Needle .................................................................. 199 
2.1.3 
Insertion Tool ....................................................................... 200 
2.1.4 
Refill Needle ........................................................................ 201 
2.1.5 
Explant Tool ......................................................................... 202 
2.2 
DETAILS CONCERNING THE 
MANUFACTURER OF THE INVESTIGATIONAL 
DEVICE ............................................................................... 203 
2.3 
NAME OR NUMBER OF THE MODEL/TYPE TO 
PERMIT FULL IDENTIFICATION ........................................ 203 
2.4 
TRACEABILITY OF THE RPDS COMPONENTS 
AND INVESTIGATIONAL MEDICINAL 
PRODUCT ........................................................................... 203 
2.5 
INTENDED PURPOSE OF THE 
INVESTIGATIONAL DEVICE IN THE 
PROPOSED CLINICAL INVESTIGATION ........................... 204 
2.6 
THE POPULATIONS AND INDICATIONS FOR 
WHICH THE INVESTIGATIONAL DEVICE IS 
INTENDED .......................................................................... 204 
2.7 
DESCRIPTION OF THE INVESTIGATIONAL 
DEVICE INCLUDING ANY MATERIALS THAT 
WILL BE IN CONTACT WITH TISSUES OR 
BODY FLUIDS ..................................................................... 204 
2.7.1 
Implant ................................................................................. 205 
2.7.2 
Initial Fill Needle .................................................................. 205 
2.7.3 
Insertion Tool ....................................................................... 206 


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Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
 
2.7.4 
Refill Needle ........................................................................ 206 
2.7.5 
Explant Tool ......................................................................... 207 
2.8 
SUMMARY OF THE NECESSARY TRAINING 
AND EXPERIENCE NEEDED TO USE THE 
INVESTIGATIONAL DEVICE SYSTEM ............................... 208 
2.9 
DESCRIPTION OF THE SPECIFIC MEDICAL 
OR SURGICAL PROCEDURES INVOLVED IN 
THE USE OF THE INVESTIGATIONAL DEVICE ................ 208 
3. 
JUSTIFICATION FOR THE DESIGN OF THE CLINICAL 
INVESTIGATION ...................................................................................... 209 
3.1 
EVALUATION OF THE RESULTS OF THE 
RELEVANT PRECLINICAL 
TESTING/ASSESSMENT CARRIED OUT TO 
JUSTIFY THE USE OF THE INVESTIGATIONAL 
DEVICE IN HUMAN SUBJECTS ......................................... 212 
3.2 
EVALUATION OF CLINICAL DATA THAT ARE 
RELEVANT TO THE PROPOSED CLINICAL 
INVESTIGATION ................................................................. 213 
4. 
RISKS AND BENEFITS OF THE INVESTIGATIONAL DEVICE 
AND CLINICAL INVESTIGATION ............................................................. 213 
4.1 
ANTICIPATED CLINICAL BENEFITS ................................. 213 
4.2 
ANTICIPATED ADVERSE DEVICE EFFECTS ................... 214 
4.3 
RESIDUAL RISKS ASSOCIATED WITH THE 
INVESTIGATIONAL DEVICE, AS IDENTIFIED 
IN THE RISK ANALYSIS REPORT ..................................... 214 
4.4 
RISKS ASSOCIATED WITH PARTICIPATION IN 
THE CLINICAL INVESTIGATION ........................................ 214 
4.5 
POSSIBLE INTERACTIONS WITH 
CONCOMITANT MEDICAL TREATMENTS ........................ 215 
4.6 
STEPS THAT WILL BE TAKEN TO CONTROL 
OR MITIGATE THE RISKS ................................................. 215 
4.7 
RISK-TO-BENEFIT RATIONALE ........................................ 216 
5. 
OBJECTIVES AND HYPOTHESES OF THE CLINICAL 
INVESTIGATION ...................................................................................... 216 
5.1 
DEVICE OBJECTIVES ........................................................ 216 


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Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
 
5.2 
HYPOTHESES, IMPLANT FUNCTIONALITY TO 
BE ACCEPTED OR REJECTED BY 
STATISTICAL DATA FROM THE CLINICAL 
INVESTIGATION ................................................................. 216 
5.3 
CLAIMS AND INTENDED PERFORMANCE OF 
THE IMPLANT THAT ARE TO BE VERIFIED ..................... 217 
5.4 
RISKS AND ANTICIPATED ADVERSE DEVICE 
EFFECTS THAT ARE TO BE ASSESSED .......................... 218 
6. 
DESIGN OF THE CLINICAL INVESTIGATION ........................................ 218 
6.1 
GENERAL ........................................................................... 218 
6.1.1 
Type of Clinical Investigation and Rationale ........................ 218 
6.1.2 
Measures to Minimize or Avoid Bias .................................... 219 
6.1.3 
Device Endpoints, with Rationale for Their 
Selection and Measurement ................................................ 219 
6.1.4 
Methods and Timing for Assessing, Recording, 
and Analyzing Variables ...................................................... 220 
6.1.5 
Equipment to be Used for Assessing the Clinical 
Investigation Variables and Arrangements for 
Monitoring Maintenance and Calibration ............................. 220 
6.1.6 
Procedures for the Replacement of Subjects ...................... 220 
6.2 
INVESTIGATIONAL DEVICE(S) AND 
COMPARATOR(S) .............................................................. 220 
6.2.1 
Description of the Exposure to the Investigational 
Device(s) or Comparator(s), If Used .................................... 220 
Patients in the ITV Injection Treatment (Control) Arm ............................... 220 
6.2.2 
Justification of the Choice of Comparator(s) ........................ 220 
6.2.3 
List of Any Other Medical Device or Medication to 
be Used During the Clinical Investigation ............................ 220 
6.2.4 
Number of Investigational Devices to be Used .................... 220 
6.3 
SUBJECTS .......................................................................... 221 
6.3.1 
Inclusion Criteria for Subject Selection ................................ 221 
6.3.2 
Exclusion Criteria for Subject Selection ............................... 221 
6.3.3 
Criteria and Procedures for Subject Withdrawal 
or Discontinuation ................................................................ 221 


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6.3.4 
Point of Enrollment .............................................................. 221 
6.3.5 
Total Expected Duration of the Clinical 
Investigation ........................................................................ 221 
6.3.6 
Expected Duration of Each Subject's 
Participation ......................................................................... 221 
6.3.7 
Number of Subjects Required to be Included in 
the Clinical Investigation ...................................................... 222 
6.3.8 
Estimated Time Needed to Select this Number 
(i.e., Enrolment Period) ........................................................ 222 
6.4 
PROCEDURES ................................................................... 222 
6.4.1 
Description of All the Clinical-investigation-
related Procedures that Subjects Undergo During 
the Clinical Investigation ...................................................... 222 
6.4.2 
Description of Those Activities Performed by 
Sponsor Representatives (Excluding Monitoring) ................ 223 
6.4.3 
Any Known or Foreseeable Factors That May 
Compromise the Outcome of the Clinical 
Investigation or the Interpretation of Results ....................... 223 
6.4.4 
Monitoring Plan .................................................................... 223 
7. 
STATISTICAL CONSIDERATIONS .......................................................... 223 
7.1 
STATISTICAL DESIGN, METHOD AND 
ANALYTICAL PROCEDURES ............................................ 223 
7.2 
SAMPLE SIZE ..................................................................... 224 
7.3 
THE LEVEL OF SIGNIFICANCE AND THE 
POWER OF THE DEVICE CLINICAL 
INVESTIGATION ................................................................. 224 
7.4 
EXPECTED DROP-OUT RATES ........................................ 225 
7.5 
PASS/FAIL CRITERIA TO BE APPLIED TO THE 
RESULTS OF THE DEVICE CLINICAL 
INVESTIGATION ................................................................. 225 
7.6 
FLEXIBLE INTERIM ANALYSIS .......................................... 226 
7.7 
CRITERIA FOR THE TERMINATION OF THE 
CLINICAL INVESTIGATION ................................................ 226 
7.8 
SUBGROUPS ...................................................................... 226 


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7.9 
PROCEDURES THAT TAKE INTO ACCOUNT 
ALL DATA ............................................................................ 226 
7.10 
MISSING, UNUSED OR SPURIOUS DATA; 
EXCLUSION OF PARTICULAR INFORMATION ................ 226 
7.11 
NUMBER OF SUBJECTS TO BE INCLUDED 
FOR EACH CENTER .......................................................... 226 
8. 
DATA MANAGEMENT .............................................................................. 226 
8.1 
DATA REVIEW .................................................................... 226 
8.2 
VERIFICATION, VALIDATION AND SECURING 
OF ELECTRONIC CLINICAL DATA SYSTEMS .................. 227 
8.3 
DATA RETENTION AND SPECIFIED 
RETENTION PERIOD ......................................................... 227 
8.4 
OTHER ASPECTS OF CLINICAL QUALITY 
ASSURANCE ...................................................................... 227 
9. 
AMENDMENTS TO THE RPDS CIP ......................................................... 227 
10. DEVIATIONS FROM CLINICAL INVESTIGATION PLAN ......................... 227 
10.1 
RECORDING, REPORTING AND ANALYZING 
RPDS CIP DEVIATIONS ..................................................... 227 
10.2 
CORRECTIVE AND PREVENTIVE ACTIONS .................... 228 
11. DEVICE ACCOUNTABILITY ..................................................................... 228 
12. STATEMENTS OF COMPLIANCE ........................................................... 228 
13. INFORMED CONSENT PROCESS .......................................................... 229 
14. ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND 
DEVICE DEFICIENCIES ........................................................................... 229 
14.1 
DEFINITIONS OF ADVERSE EVENTS AND 
ADVERSE DEVICE EFFECTS ............................................ 229 
14.2 
DEFINITION OF DEVICE DEFICIENCIES .......................... 229 
14.3 
DEFINITIONS OF SERIOUS ADVERSE 
EVENTS AND SERIOUS ADVERSE DEVICE 
EFFECTS AND, WHERE APPROPRIATE, 
UNANTICIPATED SERIOUS ADVERSE DEVICE 
EFFECTS ............................................................................ 229 


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Ranibizumab Port Delivery System:  Device Clinical 
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14.4 
REPORTING OF ADVERSE EVENTS AND 
DEVICE DEFICIENCIES ..................................................... 229 
14.5 
PROCESS FOR REPORTING ADVERSE 
EVENTS .............................................................................. 230 
14.6 
PROCESS FOR REPORTING DEVICE 
DEFICIENCIES ................................................................... 230 
14.7 
FORESEEABLE ADVERSE EVENTS AND 
ANTICIPATED ADVERSE DEVICE EFFECTS ................... 230 
14.8 
EMERGENCY CONTACT DETAILS FOR 
REPORTING SERIOUS ADVERSE EVENTS 
AND SERIOUS ADVERSE DEVICE EFFECTS .................. 231 
14.9 
INFORMATION REGARDING THE SAFETY 
REVIEW COMMITTEE ........................................................ 231 
15. VULNERABLE POPULATION .................................................................. 231 
15.1 
SPECIFIC INFORMED CONSENT PROCESS ................... 231 
15.2 
ETHICS COMMITTEE'S SPECIFIC 
RESPONSIBILITY ............................................................... 231 
15.3 
MEDICAL CARE PROVIDED FOR SUBJECTS 
AFTER THE CLINICAL INVESTIGATION HAS 
BEEN COMPLETED ........................................................... 232 
16. SUSPENSION OR PREMATURE TERMINATION OF THE 
CLINICAL INVESTIGATION ..................................................................... 232 
16.1 
Requirements for Subject Follow-up .................................... 232 
17. PUBLICATION POLICY ............................................................................ 232 
18. BIBLIOGRAPHY ....................................................................................... 233 
 
 
LIST OF TABLES 
Table 1 
Material of Construction of Implant ........................................... 205 
Table 2 
Material of Construction of Initial Fill Needle ............................. 205 
Table 3 
Materials of Construction of Insertion Tool ................................ 206 
Table 4 
Materials of Construction of Refill Needle ................................. 207 
Table 5 
Materials of Construction of Explant Tool ................................. 208 
Table 6 
Operation States for the Implant ............................................... 210 


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Ranibizumab Port Delivery System:  Device Clinical 
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LIST OF FIGURES 
Figure 1 
Port Delivery Implant in the Eye ................................................ 197 
Figure 2 
Implant ...................................................................................... 198 
Figure 3 
Initial Fill Needle ........................................................................ 200 
Figure 4 
Insertion Tool ............................................................................ 201 
Figure 5 
Refill Needle .............................................................................. 202 
Figure 6 
Explant Tool .............................................................................. 203 


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Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADE 
adverse device effect 
AE 
adverse event 
AMD 
age-related macular degeneration 
BCVA 
best corrected visual acuity 
BLQ 
below the lower limit of quantification 
CIP 
Clinical Investigational Plan 
DME 
diabetic macular edema 
EC 
Ethics Committee 
eCRF 
electronic case report form 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FSV4 
Forsight Vision4 
GCP 
Good Clinical Practice 
HA 
Health Authority 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation of 
Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
ICF 
Informed Consent Form 
IFU 
instructions for use 
IMC 
Internal Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
ITV 
intravitreal 
PK 
pharmacokinetic 
RCE 
Release Control Element 
RPDS 
Ranibizumab Port Delivery System 
SAE 
serious adverse event 
VEGF 
vascular endothelial growth factor 
VA 
visual acuity 


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Ranibizumab Port Delivery System:  Device Clinical 
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GLOSSARY OF TERMS 
Assessment 
A procedure used to generate data required by the 
study 
Cohort 
A group of newly enrolled patients treated at a specific 
dose and regimen (i.e. treatment group) at the same time 
Control drug 
Any drug (an active drug or an inactive drug, such as a 
placebo) which is used as a comparator to the drug being 
tested in the trial 
Dose level 
The dose of drug given to the patient (total daily or 
weekly etc.) 
Enrollment 
Point/time of patient entry into the study at which informed 
consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol) 
Investigational drug 
The drug whose properties are being tested in the 
study; this definition is consistent with U.S. Code of 
Federal Regulations 21 Section 312.3 and is 
synonymous with “investigational new drug” or 
“investigational medicinal product.” 
Investigational treatment 
All investigational drug(s) whose properties are being 
tested in the study as well as their associated treatment 
controls. 
This includes any placebos, any active controls, as well as 
approved drugs used outside of their indication/approved 
dosage or tested in a fixed combination. 
Investigational treatment generally does not include 
protocol-specified concomitant background therapies 
when these are standard treatments in that indication 
Medication number 
A unique identifier on the label of each 
investigational/study drug package in studies that 
dispense medication using an Interactive Response 
Technology system 
Protocol 
A written account of all the procedures to be followed in a 
trial, which describes all the administrative, documentation, 
analytical and clinical processes used in the trial. 
Part 
A single component of a study which contains different 
objectives or populations within that single study. 
Common parts within a study are: a single dose part and a 
multiple dose part, or a part in patients with established 
disease and in those with newly-diagnosed disease. 
Period 
A subdivision of a cross-over study 


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Ranibizumab Port Delivery System:  Device Clinical 
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Premature subject/patient 
withdrawal 
Point/time when the patient exits from the study prior to the 
planned completion of all study treatment administration 
and/or assessments; at this time all study treatment 
administration is discontinued and no further assessments 
are planned, unless the patient will be followed for 
progression and/or survival 
Randomization number 
A unique identifier assigned to each randomized 
patient, corresponding to a specific treatment arm 
assignment 
Study drug/ treatment 
Any single drug or combination of drugs administered to 
the patient as part of the required study procedures; 
includes investigational drug (s), active drug run-ins or 
background therapy 
Study/investigational 
treatment discontinuation 
Point/time when patient permanently stops taking 
study/investigational treatment for any reason; may or 
may not also be the point/time of premature patient 
withdrawal 
Subject Number 
A number assigned to each patient who enrolls into the 
study 
Variable 
A measured value or assessed response that is 
determined in specific assessments and used in data 
analysis to evaluate the drug being tested in the study 


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Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
 
1. 
GENERAL 
The Ranibizumab Port Delivery System (RPDS) Device Clinical Investigational Plan (CIP) 
describes the data that will be extracted from the Phase II study (GX28228) that is being 
conducted with the RPDS in order to assess its safety and performance. This CIP also 
focuses on the endpoints and analyses that will demonstrate that the RPDS works as 
intended. The purpose of the CIP is to comply with the International Organization for 
Standardization (ISO) 14155 standard "Clinical investigation of medical devices for 
human subjects", to assess the Implant safety and performance. The CIP will also be 
used  to support obtaining a Conformité Européenne (CE; European Conformity) 
certificate, which is necessary for regulatory approval in the European Economic Area. 
This CIP is intended to complement the Phase II pivotal study, which will collect the 
clinical information needed to fulfill the Essential Requirements of the European Medical 
Device Directive. Data are collected as part of the Phase II protocol. This CIP is 
specifically designed to investigate the functionality of the Implant while the ancillary 
devices’ functionality will mainly be demonstrated as part of engineering/ design 
verification testing and human factor engineering studies. 
Age-related macular degeneration (AMD) is a chronic disorder of the macula and is the 
most common cause of irreversible vision loss in older Americans and Europeans. AMD 
is categorized into two subtypes, dry and wet, based on clinical examination, ocular 
imaging, and pathologic findings. Dry AMD represents approximately 80% to 90% of 
AMD cases. In approximately 10% of dry AMD cases, a conversion to wet, or 
neovascular, AMD occurs over time. Although wet AMD is comparatively rare, prior to 
the development of anti-vascular endothelial growth factor (anti-VEGF) therapy, it 
accounted for the majority of severe vision loss from AMD. Central vision loss is painless 
and emerges gradually or suddenly (Bressler 1995; Klein et al. 1997). 
Ranibizumab, a recombinant, humanized monoclonal antibody fragment (Fab), which 
binds to all known isoforms of VEGF-A, was first registered for use in neovascular wet 
AMD in the United States on 30 June 2006 and in the European Union on 22 January 
2007 and has a well-established efficacy and safety profile. 
Ranibizumab is approved for the treatment of wet AMD, macular edema secondary to 
retinal vein occlusion, diabetic macular edema (DME), and diabetic retinopathy in DME. 
In the European Union, ranibizumab is also approved for the treatment of choroidal 
neovascularization due to pathological myopia. The primary treatment modality is 
injection of ranibizumab into the vitreous humor of the patient’s eye. 


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Ranibizumab Port Delivery System:  Device Clinical 
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Ranibizumab is injected directly into the vitreous humor of the eye. Intravitreal (ITV) 
injections of ranibizumab have shown efficacy in treating these ocular diseases, however, 
a drug delivery system that could reduce the burden of regular, often monthly, injections 
while maintaining satisfactory clinical outcomes is desired. Ranibizumab has been 
studied extensively to date and treatment with ITV injection has been demonstrated to be 
effective in preventing vision loss associated with VEGF-related retinal disorders. For 
many patients with VEGF-driven ocular diseases, long-term managment involving 
frequent, repeated ranibizumab ITV injections and monitoring visits is required. 
Frequent clinic visits can place a significant burden on the patients and their caregivers 
as well as treating physicians and the healthcare system. 
Administration of ranibizumab through an intra-ocular implant with a drug reservoir and a 
controlled release element may enable sustained delivery over extended periods of time, 
to substantially reduce the number of ITV injections while achieving similar efficacy to 
monthly injections. This decrease in treatment burden could reduce the risk from ITV 
injection-related adverse events (AE), increase treatment compliance, and reduce the 
burden to patients, their caregivers, and the healthcare system while maintaining 
optimum visual outcomes. 
2. 
IDENTIFICATION AND DESCRIPTION OF THE 
INVESTIGATIONAL DEVICE 
The RPDS is a novel, investigational intraocular drug delivery system designed to be 
used specifically with ranibizumab. The system consists of an intraocular Implant along 
with four ancillary devices. 
The Implant is a refillable drug reservoir. It is filled with ranibizumab before it is inserted 
into the eye through the pars plana. The Implant is secured within the sclera, with an 
injection port that remains visible through the conjunctiva following insertion. Once filled 
with ranibizumab, the Implant is designed to provide sustained release of ranibizumab for 
the treatment of patients with neovascular wet AMD. The Implant can be refilled with 
ranibizumab in situ via an injection through the conjunctiva and Implant septum. 
The RPDS consists of five components: 
• 
Implant 
• 
Insertion Tool 
• 
Initial Fill Needle 
• 
Refill Needle 
• 
Explant Tool 


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Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
 
 
Each of these components is a novel, investigational device, specifically designed as part 
of the RPDS. 
Figure 1 Port Delivery Implant in the Eye 
 
 
 
2.1 
SUMMARY DESCRIPTION OF THE INVESTIGATIONAL DEVICE 
AND ITS INTENDED PURPOSE 
2.1.1 
Implant 
The Implant is designed to deliver ITV ranibizumab via sustained release over the course 
of at least 4 months and is intended to be refilled multiple times through a septum in the 
Implant. The primary mode of action of the combination product is provided by the drug, 
ranibizumab. 
The Implant is intended for surgical placement through the pars plana of the eye (see 
Figure 1). The distal end of the Implant extends into the vitreous humor with the proximal 
end accessible through the conjunctiva. When in place, an injection port is visible 
through the conjunctiva, and ranibizumab is refilled into the Implant through a septum that 
is in contact with the conjunctiva, thus not requiring repeat penetration of the sclera or 
choroid. The Implant is designed to contain approximately 20 µL of ranibizumab solution 
when filled. 
The rate of ranibizumab release from the Implant into the vitreous is controlled by 
passive, concentration gradient-driven molecular diffusion through the porous distal end 
of the Implant. This porous barrier, known as the Release Control Element (RCE), allows 


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Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
 
molecules to diffuse at a rate dependent on the diffusivity of the molecule and the 
concentration gradient across the RCE. 
The Implant is filled with ranibizumab solution with a custom Initial Fill Needle prior to 
insertion.  After placement of the Implant, subsequent injections are performed with a 
custom Refill Needle that allows for the exchange of the contents of the Implant (residual 
ranibizumab, vitreal components) with the new ranibizumab solution. 
The Implant is presented below in Figure 2. No material or design changes are expected 
after the clinical batch release of the Phase II Implant. 
Figure 2 Implant 
 
 
The Implant is a refillable reservoir designed for intravitreal insertion through the pars 
plana. The Implant consists of four primary components (Figure 2): 
• 
Extrascleral flange 
• 
Septum 
• 
Body 
• 
RCE 
 


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Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
 
Once inserted in the eye, the body and the release control element of the Implant extend 
into the vitreous cavity, while the flange anchors the Implant within the sclera. 
The extrascleral flange provides secure anchoring of the Implant within the sclera and is 
encased in silicone. 
The septum is a self-sealing interface through which ranibizumab is injected into the 
Implant both prior to insertion and during subsequent refills in situ. 
The body of the Implant contains the drug reservoir, which holds approximately 20 µL of 
drug. The Implant arrives with an empty reservoir. The reservoir is filled with ranibizumab 
by the surgeon immediately prior to insertion of the Implant into the eye. 
The RCE controls the rate of ranibizumab diffusion from the drug reservoir into the 
vitreous. 
The Implant is packaged in a sterile blister. 
2.1.2 
Initial Fill Needle 
The Initial Fill Needle is a needle designed to fill the Implant with ranibizumab prior to 
Implant insertion. The Initial Fill Needle consists of five primary components (Figure 3): 
• 
Needle (33-gauge) 
• 
Soft stop 
• 
External hub 
• 
Luer hub 
• 
Blue cap 
 
The needle contains a specialized external hub. This hub will be used to guide the 
syringe along the needle guide channel of the Insertion Tool so that the needle tip will be 
properly aligned with the Implant septum for Implant filling. 
The soft stop surrounds the needle at the junction of the needle and the external hub. 
The soft stop provides a seal with the septum during Implant filling. 
The Initial Fill Needle is packaged in a sterile pouch. 
 
 


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Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
 
 
Figure 3 Initial Fill Needle 
 
 
 
2.1.3 
Insertion Tool 
The Insertion Tool is a handheld ophthalmic instrument designed to facilitate handling of 
the Implant during the initial filling and insertion procedures. The Insertion Tool consists 
of four primary components (Figure 4): 
• 
Insertion Tool tips 
• 
Finger grips 
• 
Stainless steel shafts 
• 
Needle guide channel 
 
The Insertion Tool arrives preloaded with the Implant in a sterile plastic tray packaged in 
a sterile pouch. 
 


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Ranibizumab Port Delivery System:  Device Clinical 
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Figure 4 Insertion Tool 
 
 
 
2.1.4 
Refill Needle 
The Refill Needle is designed to simultaneously exchange the contents of the Implant 
reservoir with new ranibizumab in situ. The Refill Needle consists of five primary 
components (Figure 5): 
• 
Vented needle (34-gauge) 
• 
Soft stop 
• 
Fluid collection reservoir 
• 
Luer hub 
• 
Clear cap 
 
The vented needle and fluid collection reservoir enable exchange of ranibizumab 
between the Implant and the refill syringe. As fresh drug solution is injected into the 
Implant through the needle, fluid remaining in the Implant flows through openings in the 
vented needle and is collected into the fluid collection reservoir. 
The soft stop provides a non-traumatic contact surface between the conjunctiva and the 
Refill Needle during Implant refilling. 
The Refill Needle is packaged in a sterile blister. 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
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Figure 5 Refill Needle 
 
 
 
2.1.5 
Explant Tool 
The Explant Tool consists of a set of forceps with contoured tips. The contoured tips are 
designed to grasp underneath the Implant flange and securely pull the Implant for 
explantation (Figure 6). 
The Explant Tool is packaged in a sterile blister. 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
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Figure 6 Explant Tool 
 
 
 
2.2 
DETAILS CONCERNING THE MANUFACTURER OF THE 
INVESTIGATIONAL DEVICE 
The Sponsor (Genentech) is the manufacturer for the investigational device.   The 
Contract Manufacturing Organizations involved in the manufacture of the RPDS devices 
are a) 
) or b) 
 
).  
2.3 
NAME OR NUMBER OF THE MODEL/TYPE TO PERMIT FULL 
IDENTIFICATION 
Each RPDS device package is labeled with the name of the device as shown below.  
• 
Implant/Insertion Tool 
• 
Initial Fill Needle 
• 
Refill Needle 
• 
Explant Tool 
 
2.4 
TRACEABILITY OF THE RPDS COMPONENTS AND 
INVESTIGATIONAL MEDICINAL PRODUCT 
All investigational medicinal product (IMP; ranibizumab) and RPDS required for 
completion of this study (including all the components of the RPDS) will be provided by 
the Sponsor.  In order to ensure traceability, each RPDS device will be identified by a 
batch number.  


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
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2.5 
INTENDED PURPOSE OF THE INVESTIGATIONAL DEVICE IN 
THE PROPOSED CLINICAL INVESTIGATION 
The following are the intended use of the RPDS devices: 
• 
Implant: The Implant is intended to be inserted through the pars plana of the eye to 
deliver ranibizumab in a controlled manner into the vitreous humor. The physician 
will initially fill the reservoir with the drug and refill it in accordance with the 
instructions for use. The RPDS is contraindicated for use with medications other 
than ranibizumab. 
• 
Insertion Tool: The Insertion Tool is designed to a) hold the Implant during 
sterilization and insertion, b) assist with filling of the Implant before insertion, and c) 
enable insertion of the Implant through a pars plana sclerectomy. 
• 
Initial Fill Needle: The Initial Fill Needle is a 33-gauge Luer-Lock needle designed to 
perform the initial fill of the Implant while the Implant is held in the Insertion Tool. 
• 
Refill Needles: The Refill Needle is a Luer-Lock needle designed to simultaneously 
exchange (in situ) any remaining old drug product in the Implant reservoir with new 
drug product. 
• 
Explant Tool: The Explant Tool is designed to enable the removal of the Implant 
from the posterior segment of the eye after resection of the conjunctiva and removal 
of any scar tissue. 
 
For additional RPDS details (e.g., fill, insertion, refill, and explantation of the Implant), 
consult the RPDS instructions for use (IFU) document and RPDS Investigator’s Brochure 
(IB) Section 3. 
2.6 
THE POPULATIONS AND INDICATIONS FOR WHICH THE 
INVESTIGATIONAL DEVICE IS INTENDED 
The Implant is intended for intravitreal delivery of ranibizumab for the treatment of 
neovascular wet AMD. 
2.7 
DESCRIPTION OF THE INVESTIGATIONAL DEVICE INCLUDING 
ANY MATERIALS THAT WILL BE IN CONTACT WITH TISSUES 
OR BODY FLUIDS 
Chemical characterization, risk assessment, toxicology, and biocompatibility testing per 
ISO 10993-1 were performed on RPDS devices.  The comprehensive testing 
demonstrated that the RPDS direct and indirect contacting materials, manufacturing 
processes, and sterilization process resulted in biocompatible devices.  


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
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2.7.1 
Implant 
Table 1 
Material of Construction of Implant 
Component of Implant 
Raw Material and/or Trade 
Name, Vendor 
Patient/ User contact 
Silicone encasing 
Silicone, 
 
Patient: eye contact 
(conjunctiva, vitreous, sclera) 
User: N/A 
Distal/Proximal 
Body 
PSU, 
 
Patient: vitreous 
User: N/A 
Septum 
Silicone, 
 
Patient: eye contact (vitreous) 
User: N/A 
Adhesive bond 
Epoxy, 
 
 
Patient: vitreous 
User: N/A 
Release Control 
Element (RCE) 
Titanium, 
 
Patient: vitreous 
User: N/A 
N/A = not applicable; PSU = polysulfone. 
 
2.7.2 
Initial Fill Needle 
The Initial Fill Needle is used to perform the initial fill of the Implant while the Implant is 
held in the Insertion Tool.  The component materials listed in Table 2 below are in 
indirect contact with the patient’s eye.  Future material change information on the Initial 
Fill Needle may be provided to the clinical investigators according to the Sponsor’s 
internal procedure. 
Table 2 
Material of Construction of Initial Fill Needle 
Component of Initial Fill 
Needle 
Raw Material and/or Trade 
Name, Vendor 
Patient/ User contact 
Assembly 
Adhesive, 
 
 
 
 
Patient: N/A 
User: N/A 
 Primer 
(Manufacturing Material) 
Silicone Primer, 
 
 
Patient: N/A 
User: N/A 
 Silicone 
Silicone, 
 
 
Patient: N/A 
User: N/A 
Cannula, 33-1/2G Long, Sterile 
Needle 
Surgical Stainless Steel 
 
Patient: indirect contact 
through the drug 
User: N/A 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
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Component of Initial Fill 
Needle 
Raw Material and/or Trade 
Name, Vendor 
Patient/ User contact 
External hub 
Natural Polycarbonate, 
 
 
Patient: indirect contact 
through the drug 
User: N/A 
Hydrocarbon Solvent 
(Manufacturing Material) 
DCM 
 
Patient: indirect contact 
through the drug 
User: N/A 
Cap 
Polypropylene; 
 
 
Patient: N/A 
User: surgical gloves 
DCM = dichloromethane; N/A = not applicable; UV = ultraviolet. 
 
2.7.3 
Insertion Tool 
The Insertion Tool consists of polyether ether ketone (PEEK) plastic grippers holding the 
Implant. The grippers are attached with screws to a reverse-action forceps. 
If the Implant is repositioned during the insertion, the grippers listed in Table 3 will be in 
contact with the conjunctiva.  Future material change information on the Insertion Tool 
may be provided to the clinical investigators according to the Sponsor’s internal 
procedure.  
Table 3 
Materials of Construction of Insertion Tool 
Component of Insertion Tool Raw Material and/or Trade 
Name, Vendor 
Patient/ User contact 
Gripper Tips 
PEEK, 
 
PEEK 
 
Patient: conjunctiva 
User: N/A 
Tweezers 
Stainless steel, 
 
Patient: N/A 
User: surgical gloves 
Screws 
Stainless steel, 
 
 
Patient: N/A 
User: surgical gloves 
N/A = not applicable; PEEK = polyether ether ketone. 
 
2.7.4 
Refill Needle 
The component materials listed in Table 4 below are part of the Refill Needle that will 
have contact (direct contact or indirect contact) with the patient’s eye.  Future material 
change information on the Refill Needle may be provided to the clinical investigators 
according to the Sponsor’s internal procedure. 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
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Table 4 
Materials of Construction of Refill Needle 
Component of Refill Needle 
Raw Material and/or Trade 
Name, Vendor 
Patient/ User contact 
Gasket and soft stop 
 thermoplastic 
elastomer, 
 
 silicone, 
 
 
Patient: eye contact 
(conjunctiva) Indirect contact 
(drug contact) 
User: N/A 
Assembly 
Adhesive 
 
Patient: Indirect contact (drug 
contact) 
User: N/A 
Body 
Polycarbonate, 
 
 
Patient: Indirect contact (drug 
contact) 
User: gloves 
Outer cannula 
Polyimide, 
 
Patient: eye contact 
(conjunctiva) and indirect 
contact (drug contact) 
User: N/A 
Inner cannula 
Stainless steel 
Patient: eye contact 
(conjunctiva) and indirect 
contact (drug contact) 
User: N/A 
Bushing 
Stainless steel 
Patient: indirect (drug contact) 
User: N/A 
Needle Cap 
 
 
Patient: N/A 
User: surgical gloves 
LSR = liquid silicone rubber; N/A = not applicable; UV = ultraviolet. 
 
2.7.5 
Explant Tool 
The component materials listed in Table 5 below are part of the Explant Tool that will 
have contact direct contact or indirect contact with the patient’s eye.  Future material 
change information on the Explant Tool may be provided to the clinical investigators 
according to the Sponsor’s internal procedure.  


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
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Table 5 
Materials of Construction of Explant Tool 
Component of Explant Tool 
Raw Material and/or Trade 
Name, Vendor 
Patient/ User contact 
Contoured Tips  
Stainless steel, 
 
Patient: eye contact 
(conjunctiva) 
User: N/A 
Body 
Acrylonitrile butadiene styrene 
polymer, 
 
Patient: N/A 
User: surgical gloves 
N/A = not applicable. 
 
2.8 
SUMMARY OF THE NECESSARY TRAINING AND EXPERIENCE 
NEEDED TO USE THE INVESTIGATIONAL DEVICE SYSTEM 
The RPDS is intended for use by vitreoretinal surgeons, scrub nurses, other 
hospital/clinic staff, and patients. Study investigators will be qualified ophthalmologists 
trained in the management of retinal diseases and ocular surgery, and will be certified by 
a Sponsor-selected vendor to perform initial Implant fill, insertion, refill, and explantation. 
The surgical procedures involved in the use of the RPDS are detailed in the RPDS IFU. 
Scrub nurses will assist the surgeon in selected preparation tasks. Other hospital and 
clinic staff will perform routine tasks outside of the sterile field, such as receipt or storage 
of the product. Patients will retain the Implant for an extended period of time. 
2.9 
DESCRIPTION OF THE SPECIFIC MEDICAL OR SURGICAL 
PROCEDURES INVOLVED IN THE USE OF THE 
INVESTIGATIONAL DEVICE 
Patients in the Implant treatment arms will have the Implant, prefilled with ranibizumab, 
surgically inserted into the study eye at the Day 1 visit and subsequently refilled at 
monthly visits only if the protocol-specified refill criteria are fulfilled. The insertion and 
explantation procedures must be performed in the surgery room while the refill procedure 
is permitted in the physician office setting. 
The Implant is surgically placed through the pars plana to allow for a sustained delivery 
of ranibizumab into the vitreous. As the Implant insertion is a surgical procedure that is 
performed in an operating room, sterile controls must be in place to minimize the risk of 
ocular infection. The Implant is filled with approximately 20 µL of ranibizumab 
immediately prior to insertion of the Implant into the patient’s study eye. 
In addition to standard pre-operative instructions used in practice, patients will be 
instructed to apply topical antimicrobial ophthalmic drops to the ocular surface 4 times 
within 24 hours prior to the procedure. 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
209/Protocol GX28228, Version 8 
 
At each refill, a volume of approximately 100 µL of ranibizumab will be injected in situ into 
the Implant through the septum to exchange the remaining contents of the Implant with 
newly introduced ranibizumab.  During the refill procedure, the contents of the Implant 
will be collected in the fluid collection reservoir of the Refill Needle. The volume of newly 
introduced ranibizumab remaining in the Implant after the refill procedure will be 
approximately 20 µL 
The Implant has undergone design verification confirming Implant performance through 
the expected use life, including 93 punctures of the Implant septum for Implant refills. 
For detailed instructions on the Implant initial fill, insertion, refill, and explantation 
procedures, refer to the RPDS IFU. 
3. 
JUSTIFICATION FOR THE DESIGN OF THE CLINICAL 
INVESTIGATION 
The Phase II study is being conducted to determine the dose of ranibizumab that is both 
efficacious for patients and allows for a dosing schedule that is less frequent than 
monthly ITV injections. While the design and sample size of this clinical study is aiming 
at the determination of an appropriate dosing regimen for the drug ranibizumab delivered 
through the Implant, this study will also appropriately inform the safety and performance 
of the Implant in human subjects. 
This RPDS CIP will document whether the Implant and ancillary devices “work as 
intended.” 
The data extraction and analysis will allow documenting the following aspects: 
• 
Establish that there is no evidence of Implant clogging in more than 10% of patients 
in the Implant arms at Month 9 
• 
Demonstrate that the AE profile observed when using the Implant is clinically 
acceptable as compared with ranibizumab dosed using conventional ITV injection. In 
other words, any complications associated with Implant insertion, refill, or 
explantation, or associated with the long term presence of the Implant within the 
posterior chamber of the eye, are manageable and acceptable in an overall benefit-
risk assessment versus ITV dosing. 
 
This will include a characterization of the “Prespecified RPDS-associated AEs”, i.e., 
those adverse device effects (ADEs) that have been pre-specified as being most relevant 
for the risk assessment of the Implant and the procedures of Implant insertion, refill, and 
explantation. 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
210/Protocol GX28228, Version 8 
 
For each AE (including “Prespecified RPDS-associated AEs”) observed during the clinical 
study, the case report form (CRF) will collect a separate assessment of investigator 
causality for each “study intervention” element (i.e., investigator causality for “drug”, 
investigator causality for “procedures”, and investigator causality for Implant or ancillary 
devices). Investigators will be trained on the requirement to assess each AE for potential 
causal association to “drug”, “procedure”, Implant or ancillary devices – so that they may 
determine whether there is a causal association with one, more than one, or none of the 
“Study intervention” elements. 
• 
Particular focus will be paid to evaluate the safety of the RPDS, as measured by 
“Prespecified RPDS-associated AE” (see protocol Section 6.5.1) 
 
The RPDS CIP will evaluate whether the Implant is failing to operate as intended. As a 
passive diffusion device, the Implant can only operate in four different states as shown in 
Table 6. 
Table 6 
Operation States for the Implant 
Implant Operational States 
Ability to Detect State in Human Study 
Failure to Operate State 1: 
RCE is clogged and no drug 
diffuses from reservoir 
High detectability 
Will be apparent as deterioration in visual function and the 
development of further disease activity in a patient who had 
responded to ITV ranibizumab prior to the Implant insertion. 
The Implant will be assessed for possible clogging if the 
Implant is explanted. For a full description of the assessments 
refer to CIP section 5.3 
Failure to Operate State 2: 
RCE rapidly elutes drug from 
the reservoir 
Low detectability in humans 
The proportion of “failure to operate state 2” will be based upon 
bench testing with the Implant, as this is anticipated to be a 
very rare event with clinically implanted devices. 
It would be difficult to reliably observe a typical PK profile for 
this failure mode in a clinical study due to the potential high 
variability of the PK measurement. 
Clinically, the patient would be expected to require frequent 
refill. From previous high dose ITV studies, no safety signals 
have been identified that would be indicative of high ITV drug 
levels. 
Therefore, this failure mode is best evaluated as part of bench 
testing after explantation. 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
211/Protocol GX28228, Version 8 
 
Implant Operational States 
Ability to Detect State in Human Study 
Failure to Operate State 3: 
RCE elutes too slowly 
Low detectability in humans 
This will be based upon bench testing with the Implant. A 
target release rate of 4 µg/day and a vitreous concentration no 
lower than 12 µg/mL is currently established in the 
specifications. 
Implant Operational States 
Ability to Detect State in Human Study 
Successful Operation: 
Drug diffuses across RCE in a 
manner consistent with Fick’s 
Law of Diffusion as 
demonstrated in bench and 
animal studies. 
No direct detectability in humans of Implant functionality 
can be shown 
Implant functionality is demonstrated best in bench studies. It 
cannot be demonstrated in humans because there is no ethical 
method for directly measuring the flow of drug into the vitreous 
and serum pharmacokinetics is seen as too variable a 
measurement. 
CIP = Clinical Investigational Plan; ITV = intravitreal; PK = pharmacokinetic; RCE = release 
control element 
 
This RPDS CIP is not designed to determine a therapeutic dosing regimen for 
ranibizumab. It will determine whether the Implant meets an acceptable rate of failure to 
Operate State 1. 
The Implant is a passive diffusion device, so it cannot act outside of its native physics. It 
must diffuse the drug in accordance with Fick’s Law. Bench studies, in models of the 
ocular environment, are the most effective ways to document the rate of drug diffusion 
from the Implant. As a result, it is deemed unnecessary to directly measure the flow of 
ranibizumab from the Implant in humans. In addition, there is no appropriate method to 
directly measure the flow of ranibizumab from the Implant in humans. No direct 
monitoring of drug levels in the reservoir or vitreous would be ethical in humans as there 
is no benefit to an individual patient that would balance the risk of these repeated 
invasive collections of vitreous. There is no method for monitoring the drug levels in the 
Implant reservoir. 
Additionally, measurement of serum ranibizumab cannot provide quantitative data for the 
Implant diffusion. Serum ranibizumab concentration-time data are remote from the site of 
drug release (Implant vitreous  serum) and therefore are not a direct quantitative 
measurement of the drug release rate from the Implant. In addition, serum 
pharmacokinetics have high intersubject variability when administered by the ITV route; 
similar variability is expected by the Implant route. This may also confound the use of 
serum pharmacokinetics as a quantitative reflection of drug release from the Implant. 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
212/Protocol GX28228, Version 8 
 
This high variability was observed in the serum pharmacokinetic (PK) levels following 
refills in the Phase I human trial. Therefore, PK data will be collected in all patients in the 
Phase II study, but no clear conclusion on the Implant diffusion rate can be prespecified 
before results become available. 
It can be concluded that human studies will not provide better quantitative information 
about the diffusion rate of ranibizumab from the Implant than bench studies will. 
Adequate data have been generated in bench studies to demonstrate that the Implant will 
reliably diffuse ranibizumab in a controlled manner into the vitreous humor. 
3.1 
EVALUATION OF THE RESULTS OF THE RELEVANT 
PRECLINICAL TESTING/ASSESSMENT CARRIED OUT TO 
JUSTIFY THE USE OF THE INVESTIGATIONAL DEVICE IN 
HUMAN SUBJECTS 
The RPDS is a drug delivery system intended to release therapeutic levels of 
ranibizumab into the vitreous humor over an extended period of time. The RPDS 
includes three primary components: the drug (ranibizumab), the port delivery system 
permanent implant, and the ancillary devices. 
A comprehensive non clinical testing strategy was developed to support the clinical 
development (Phase II and Phase III) and registration of the Implant. The strategy 
included the assessment of the in vitro and in vivo functionality and biocompatibility of a 
prototype implant, Phase II Implant, and the ancillary devices. 
In vitro and in vivo biocompatibility studies were chosen based on direct and indirect 
interaction of the Implant and ancillary devices with ocular tissues and long-term ocular 
implantation, and are consistent with ISO 10993 (Biological evaluation of medical 
devices), ISO 11979-5 (Ophthalmic implants-intraocular lenses part 5: biocompatibility); 
and ANSI Z80.7 (Testing for intraocular lens devices). Biocompatibility testing is 
conducted with the finished Implant, and extracts from the Implant and ancillary devices. 
The nonclinical testing results are summarized in the RPDS IB Section 4. 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
213/Protocol GX28228, Version 8 
 
3.2 
EVALUATION OF CLINICAL DATA THAT ARE RELEVANT TO 
THE PROPOSED CLINICAL INVESTIGATION 
The Implant has been investigated in a prospective, Phase I, open-label study in patients 
with wet AMD, conducted by FSV4 at a single site in Latvia. The study investigated the 
safety, tolerability, and duration of ranibizumab exposure delivered with the Implant. 
This Phase I Implant was composed of biocompatible materials (polymethyl 
methacrylate, silicone, 316L stainless steel). 
For details of the design of the Phase I study as well as the results, refer to protocol 
Section 1.3 and to the RPDS IB Section 5. 
4. 
RISKS AND BENEFITS OF THE INVESTIGATIONAL DEVICE 
AND CLINICAL INVESTIGATION 
The general approach to identifying, planning, and execution of the risk management 
activities of the Phase II RPDS is in accordance with ISO 14971:2007/2012: Medical 
devices – application of risk management to medical devices. 
Risk management plans have been created to cover the following: 
• 
Implant, Insertion Tool, Initial Fill Needle, Refill Needle, and Explant Tool 
• 
Labeling 
• 
Packaging manufacturing of the combination product (assembly operations) 
• 
Shipping and storage (e.g., product shipping, handling and storage) 
• 
Clinical trial surveillance (e.g., product monitoring and complaints) 
• 
Components not off-the-shelf (e.g., molding assembly components) 
 
The results of risk/benefit assessment from the overall risk analysis are described in the 
RPDS IB Section 6. 
4.1 
ANTICIPATED CLINICAL BENEFITS 
As a result of the chronic, progressive nature of wet AMD, frequent ranibizumab ITV 
injections continue for extended periods for many patients. Pivotal studies of 
ranibizumab in wet AMD (FV2598g and FVF2587g) demonstrated significant and well-
maintained visual acuity (VA) outcomes with monthly ITV injections for 2 years. In these 
studies it was observed that the treatment effect reaches, on average, a plateau after 
three consecutive monthly injections. Subsequently, there have been several studies 
evaluating a PRN treatment regimen, with different re-treatment criteria also showing 
early response after start of treatment (Busbee et al 2013; CATT Research Group 2011). 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
214/Protocol GX28228, Version 8 
 
In clinical practice, frequent office monitoring visits are required and regular injections are 
necessary to maintain optimal vision gains. Sustained release of ranibizumab from the 
Implant is an alternate dosing method that may result in a less frequent need of 
retreatment than dosing with ITV injections. This decrease in treatment burden could 
possibly reduce the risk of ITV injection-related AEs, increase compliance, and reduce 
the burden to patients, their caregivers, and the healthcare system, while maintaining 
optimum visual outcomes. 
4.2 
ANTICIPATED ADVERSE DEVICE EFFECTS 
The safety of the RPDS, as assessed using the following “Prespecified RPDS-associated 
AEs” include, but is not limited to an evaluation of: 
• 
Vitreous hemorrhage associated with a >30-letter decrease in best corrected visual 
acuity (BCVA) on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart 
compared with the last assessment of BCVA prior to the onset of vitreous 
hemorrhage lasting >1 month 
• 
Reduced VA (>30-letter loss from previous scheduled visit) 
• 
Traumatic cataract 
• 
Endophthalmitis 
• 
Damage to sclera 
• 
Retinal detachment 
• 
Interference of the Implant with visual field 
 
Refer to protocol Section 6.5.1 and to the RPDS IB Section 6 for additional details. 
4.3 
RESIDUAL RISKS ASSOCIATED WITH THE INVESTIGATIONAL 
DEVICE, AS IDENTIFIED IN THE RISK ANALYSIS REPORT 
The details of the residual risks identified in the different risk analysis (e.g., failure mode 
and effects analysis) are described in the RPDS IB Section 6. 
4.4 
RISKS ASSOCIATED WITH PARTICIPATION IN THE CLINICAL 
INVESTIGATION 
The benefit and risks associated with participation in this study are outlined in the 
Informed Consent Form (ICF) and will be explained to the patient by the investigator. 
Ranibizumab has a well characterized safety profile, with clearly identified and potential 
risks associated with its use, which is described in the RPDS IB. The safety and 
tolerability of ranibizumab exposure delivered through the Implant were investigated in a 
Phase I prospective, open-label study in a wet AMD patient population by FSV4 at a 
single site in Latvia. The surgical procedure associated with Implant insertion could 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
215/Protocol GX28228, Version 8 
 
potentially lead to ocular AEs. These include, but are not limited to: ocular tissues 
inflammation or infection, conjunctival erosion, damage to the sclera, endophthalmitis, 
hypotony, suprachoroidal hemorrhage, and retinal detachment. The RPDS IFU 
describes all of the procedures necessary for successful insertion, refilling, and 
explantation of the Implant. It is imperative that specific surgical procedures are adhered 
to in order to minimize the risk of ocular AEs related to the procedure. 
4.5 
POSSIBLE INTERACTIONS WITH CONCOMITANT MEDICAL 
TREATMENTS 
At the discretion of their physician, patients may continue to receive all medications and 
standard treatments administered for other conditions with certain exceptions as detailed 
in the protocol Section 4.5.2. 
4.6 
STEPS THAT WILL BE TAKEN TO CONTROL OR MITIGATE 
THE RISKS 
Patients not considered suited for receiving the RPDS in this clinical investigation are 
excluded as outlined under exclusion criteria (see the protocol Section 4.1.2). 
Study investigators will be qualified ophthalmologists, trained in the management of 
retinal diseases and ocular surgery, and will be certified by a Sponsor-selected vendor to 
perform initial Implant fill, insertion, refill, and explantation. The surgical procedures 
involved in the use of the RPDS are also detailed in the RPDS IFU document. 
Patients must adhere to the instructions for prohibited therapy (see Section 4.5) and dose 
interruptions/study treatment or study discontinuation criteria (protocol Table 6). 
Prior to Implant insertion or explantation, patients will be required to verify that they have 
self-administered their antimicrobial eye drops to the study eye 4 times within the 
previous 24 hours. As per investigator’s discretion, patients may also be required to 
have self-administered antimicrobial eye drops to the study eye 4 times within the 24 
hours prior to Implant refills. It is required that all patients self-administer their 
antimicrobial drops again 4 times daily for 7 days following Implant insertion or 
explantation, and 4 times daily for 3 days following refills. Please see the protocol 
section 5.1 for additional details. 
The insertion procedure and, if applicable, the explantation procedure must be performed 
in the surgery room while the refill procedure is permitted in the physician office setting. 
The results of risk/benefit assessment from the overall risk analysis are described in the 
RPDS IB Section 6. 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
216/Protocol GX28228, Version 8 
 
4.7 
RISK-TO-BENEFIT RATIONALE 
The Phase I study provided preliminary evidence of a positive benefit−risk profile for the 
use of RPDS in patients with wet AMD and supports the evaluation of RPDS in a Phase II 
study. It is expected that in the Phase II study the drug efficacy of at least one Implant 
treatment arm will be similar to the control ITV monthly injection treatment arm. 
Further details are included in the protocol Section 1.4. 
5. 
OBJECTIVES AND HYPOTHESES OF THE CLINICAL 
INVESTIGATION 
The objectives of the Phase II study are described in the protocol section 2. This RPDS 
CIP provides an overview of the device objectives and focuses on the parameters used 
for the assessment of RPDS functionality and safety. 
5.1 
DEVICE OBJECTIVES 
• 
To evaluate the functionality of the Implant by assessing that there is no evidence of 
Implant clogging in more than 10% of patients in the Implant arms at Month 9 
• 
To explore the serum ranibizumab concentration data with a PK model in an attempt 
to infer the concentration−time pattern in the vitreous humor and, if possible, derive 
information on the rate of ranibizumab release from the Implant 
• 
To evaluate the safety of the RPDS, as measured by “Prespecified 
RPDS-associated AEs” (see protocol Section 6.5.1) 
 
5.2 
HYPOTHESES, IMPLANT FUNCTIONALITY TO BE ACCEPTED 
OR REJECTED BY STATISTICAL DATA FROM THE CLINICAL 
INVESTIGATION 
The hypothesis to be established is that the initial Implant clogging rate does not exceed 
10% of Implant arm patients at Month 9. In order to evaluate whether the Implant 
clogging rate exceeds 10% within the first 9 months, the proportion of clogged Implants 
will be estimated and the 90% confidence interval will be calculated. All clogging data 
from patients in the Implant arms will be pooled for this analysis. 
In the study, the Implant will be judged as “failed” if it is determined that the RCE is 
clogged and can no longer deliver the ranibizumab into the ocular space (see Table 6 
“Failure to Operate State 1” and description below). 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
217/Protocol GX28228, Version 8 
 
5.3 
CLAIMS AND INTENDED PERFORMANCE OF THE IMPLANT 
THAT ARE TO BE VERIFIED 
Intended performance of the Implant is demonstrated by successful operation of drug 
diffusing across the RCE in a manner consistent with Fick’s Law of Diffusion as 
demonstrated in bench and animal studies. Implant functionality is demonstrated best in 
bench studies since there is no direct detectability in humans of Implant functionality that 
can be shown. No ethical method exists for directly measuring the flow of drug into the 
vitreous. Additionally serum pharmacokinetics is seen as too variable a measurement. 
The clinical performance of the Implant will be demonstrated by measuring the rate of 
events related to the occurrence of Implant clogging. 
The Implant will be assessed for possible clogging if the Implant is explanted. The 
following assessments will be performed: 
• 
Serum pharmacokinetics of ranibizumab will be used to judge whether Implant 
clogging may have occurred.  Aqueous and vitreous humor PK samples will also be 
collected at explantation and may be used to further assess possible Implant 
clogging. For each individual patient, possible Implant clogging will be documented 
if at least one of the following conditions is met: 
– 
For 40-mg/mL or 100-mg/mL dose groups: At Implant insertion and prior to the 
first refill: serum ranibizumab concentrations are below the lower limit of 
quantification (BLQ) or below the baseline serum ranibizumab concentration 
value at all time-points prior to refills, that is, on Day 1 (within 60 min of 
insertion – only if possible to collect), Day 2, Day 7, Day 14, and all monthly 
time points after insertion and prior to the first refill or to the last study visit for 
the patient, if no refill occurs 
– 
For the 10-mg/mL dose group: At Implant insertion and prior to the first refill: 
serum ranibizumab concentrations are below the lower limit of quantification 
(BLQ) value at all time-points prior to refills, that is, on Day 1 (within 60 min of 
insertion – only if possible to collect), Day 2, Day 7, Day 14, and all monthly 
timepoints after insertion and prior to the first refill or to the last study visit for 
the patient, if no refill occurs 
OR 
– 
After the first refill: serum ranibizumab concentrations are BLQ or below the 
last pre-refill serum ranibizumab concentration value at all time-points post 
refills, that is, on Day 7, and all monthly time points prior to the next refill for 
two consecutive refills, or to the last study visit for the patient, if no further refill 
occurs 
 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
218/Protocol GX28228, Version 8 
 
The Implants meeting PK criteria for possible clogging will then undergo further 
diagnostics if explanted to confirm whether treatment failure was due to clogging. The 
“implant complete clogging” failure statistics will be summarized across all patients based 
on the first 9 months of Implant insertion. 
5.4 
RISKS AND ANTICIPATED ADVERSE DEVICE EFFECTS THAT 
ARE TO BE ASSESSED 
At the end of the study, the incidence of “Prespecified RPDS-associated AEs” will be 
compared between subjects receiving ranibizumab from the Implant and the control 
subjects receiving ranibizumab as ITV injections: 
• 
Vitreous hemorrhage associated with a > 30-letter decrease in BCVA on the ETDRS 
chart compared with the last assessment of BCVA prior to the onset of vitreous 
hemorrhage lasting >1 month 
• 
Reduced VA (>30-letter loss from previous scheduled visit) 
• 
Traumatic cataract 
• 
Endophthalmitis 
• 
Damage to sclera 
• 
Retinal detachment 
• 
Interference of the Implant with visual field 
 
In addition, ocular AEs and serious adverse events (SAEs) attributed by the investigator 
to: 1) the Implant insertion procedure, 2) the Implant refill procedure, 3) Implant 
explantation procedure, and 4) the Implant and other RPDS components, will be 
reported. 
Please also refer to the protocol Section 6.5.1. 
6. 
DESIGN OF THE CLINICAL INVESTIGATION 
6.1 
GENERAL 
6.1.1 
Type of Clinical Investigation and Rationale 
Study GX28228 is a Phase II, multicenter, randomized, active treatment (monthly ITV 
injection)−controlled study to evaluate ranibizumab delivered through the Implant using 
three ranibizumab formulation arms (10 mg/mL, 40 mg/mL, and 100 mg/mL) compared 
with the control arm (0.5-mg monthly ITV injections of 10-mg/mL formulation) in patients 
with subfoveal neovascular (wet) AMD. 
For details of the rationale for the design, refer to the Phase II protocol Section 3.4. 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
219/Protocol GX28228, Version 8 
 
6.1.2 
Measures to Minimize or Avoid Bias 
Patients will be randomized through an interactive voice/Web response system to one of 
four treatment arms. 
Study patients and all study site personnel will be masked to the Implant treatment arms’ 
ranibizumab formulation assignment (10 mg/mL vs. 40 mg/mL vs. 100 mg/mL) until the 
study conclusion. 
The Sponsor’s personnel directly involved in the study conduct (except the Internal 
Monitoring Committee [IMC] members) will be masked to the Implant treatment arms’ 
ranibizumab formulation assignment (10 mg/mL vs. 40 mg/mL vs. 100 mg/mL) until the 
time of primary analyses. The IMC will closely monitor patient safety throughout the 
study (see protocol Section 3.1.4). The IMC roles and responsibilities will be outlined in 
the IMC charter. 
Clinical pharmacology and PK scientists may be unmasked early for the purposes of 
interpreting emerging safety and efficacy data; those unmasked staff will not be part of 
the study team or have any interactions with sites or investigators. 
In addition, the VA examiner will only conduct refraction and VA assessments and will be 
masked to patient study eye assignment and patient treatment assignment. The VA 
examiner will have no access to patient VA scores from previous visits but will be only 
aware of the patient’s refraction data from previous visits. The VA examiner may perform 
no other direct patient-care tasks. Patients will be asked not to discuss their study       
eye assignment (right versus left) with the VA examiner. 
Patients and study site personnel will not be masked with regard to patient assignment to 
the ITV arm or an Implant arm because of the difficulties of maintaining masking following 
the surgical procedure, the additional safety visits applicable only to the Implant arms, 
and Implant visualization upon ophthalmic examination. 
6.1.3 
Device Endpoints, with Rationale for Their Selection and 
Measurement 
The Implant endpoint is the Implant status at the end of trial, which will be reported as 
either clogged or not clogged. The rationale for selecting Implant clogging as an 
endpoint is described in Section 3 of this RPDS CIP. 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
220/Protocol GX28228, Version 8 
 
6.1.4 
Methods and Timing for Assessing, Recording, and Analyzing 
Variables 
Details of the assessments to be performed during the study are provided in Appendix 1 
of the Phase II protocol. The Implant clogging rate at Month 9 will be determined 
(see Section 5.3). 
6.1.5 
Equipment to be Used for Assessing the Clinical Investigation 
Variables and Arrangements for Monitoring Maintenance and 
Calibration 
Not applicable. 
6.1.6 
Procedures for the Replacement of Subjects 
Patients who discontinue from the study will not be replaced. 
6.2 
INVESTIGATIONAL DEVICE(S) AND COMPARATOR(S) 
6.2.1 
Description of the Exposure to the Investigational Device(s) or 
Comparator(s), If Used 
Patients in the Implant Treatment Arms 
Patients will have the Implant (prefilled with approximately 20 µL of either the 10-mg/mL 
[approximately 0.2 mg dose], 40-mg/mL [approximately 0.8 mg dose], or 100-mg/mL 
formulation [approximately 2 mg dose] of ranibizumab) surgically inserted in the study 
eye at the Day 1 visit. For further details regarding exposure, refer to protocol 
Section 4.3.2.2. 
Patients in the ITV Injection Treatment (Control) Arm 
Patients will receive their first ITV injection of 50 µL of the 10-mg/mL ranibizumab (0.5 mg 
dose) formulation at the Day 1 visit. For further details regarding exposure, refer to 
protocol Section 4.3.2.2. 
6.2.2 
Justification of the Choice of Comparator(s) 
Refer to details in protocol Section 3.4.4. 
6.2.3 
List of Any Other Medical Device or Medication to be Used 
During the Clinical Investigation 
No medical devices other than the RPDS or medication for the treatment of neovascular 
AMD in the study eye will be used during the clinical investigation. 
6.2.4 
Number of Investigational Devices to be Used 
One Implant per study eye will be used during the clinical investigation in patients 
randomized to the RPDS treatment arms. 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
221/Protocol GX28228, Version 8 
 
6.3 
SUBJECTS 
6.3.1 
Inclusion Criteria for Subject Selection 
Patients with choroidal neovascularization secondary to AMD will be enrolled in the 
study. Written informed consent will be obtained before initiation of any study-related 
procedures. 
For the complete list of inclusion criteria, refer to protocol Section 4.1.1. 
6.3.2 
Exclusion Criteria for Subject Selection 
For the complete list of exclusion criteria, refer to protocol Section 4.1.2. 
No additional exclusions may be applied by the investigator, in order to ensure that the 
study population will be representative of all eligible patients. 
6.3.3 
Criteria and Procedures for Subject Withdrawal or 
Discontinuation 
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. 
For details, refer to protocol Section 4.7.1. 
Discontinued patients will not be allowed to re-enter the study. 
6.3.4 
Point of Enrollment 
The study will include pre-screening (if applicable), “run-in” (if applicable), screening, and 
randomization visits followed by a treatment period. Subjects will be enrolled into the 
study at the office of their vitreo-retinal specialist. Patients randomized to the Implant 
treatment arms will have the Implant (pre-filled with ranibizumab) surgically inserted in the 
study eye at their Day 1 visit. 
For additional details regarding description of study, refer to protocol Section 3.1. 
6.3.5 
Total Expected Duration of the Clinical Investigation  
Approximately 220 patients will be randomized within an approximate 24-month period 
of time. It is expected that the duration of the clinical investigation (length of study plus 
enrollment period) will be approximately 38 months. 
6.3.6 
Expected Duration of Each Subject's Participation 
Patients in the ITV injection arm will be evaluated monthly and will receive monthly 
study treatments (Day 1, Month 1 through Month X visit, see protocol Appendix 2) until 
the Sponsor decides, based on the primary analysis results, to either terminate the 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
222/Protocol GX28228, Version 8 
 
study and discontinue study treatment, or offer patients entry into the RPDS 
Extension Study.  Their participation (excluding screening period) in the study will last 
approximately 13−38 months dependent on the date of their randomization to the study.   
The patients in the Implant arms will continue to be evaluated monthly for the Implant 
refill (see protocol Appendix 1)until the Sponsor decides, based on the primary analysis 
results, to either terminate the study and discontinue study treatment,or offer patients 
entry into the RPDS Extension Study.  The Implant arms patients’ study participation 
(excluding screening period) is expected to last approximately 13 to 38 months 
dependent on the date of their randomization to the study. 
6.3.7 
Number of Subjects Required to be Included in the Clinical 
Investigation 
Approximately 220 patients up to 60 sites in the United States will be randomized in a 
3:3:3:2 ratio to four treatment arms: approximately 60 patients will receive the Implant 
filled with 10-mg/mL ranibizumab formulation, 60 patients will receive the Implant filled 
with 40-mg/mL ranibizumab formulation, 60 patients will receive the Implant filled with 
100-mg/mL ranibizumab formulation, and 40 patients will receive monthly ITV injections 
of 10-mg/mL ranibizumab formulation (50 µL for the 0.5-mg dose). 
6.3.8 
Estimated Time Needed to Select this Number (i.e., Enrolment 
Period) 
The enrolment period is expected to be approximately 24 months. 
6.4 
PROCEDURES 
For details regarding post-trial access to treatment, refer to protocol Section 4.4.2. 
6.4.1 
Description of All the Clinical-investigation-related Procedures 
that Subjects Undergo During the Clinical Investigation 
Medical history and demographic information will be collected. 
Medical history includes clinically significant diseases, surgeries, smoking history, and 
use of alcohol. 
All medications other than protocol-specified procedural medications used by the patient 
within 7 days prior to the randomization visit until the study completion will be recorded 
on the electronic case report form (eCRF) concomitant medication log. 
Demographic data will include age, sex, and self-reported race/ethnicity. 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
223/Protocol GX28228, Version 8 
 
The Implant insertion and explantation procedures will be captured on video for 
Investigators’ training purposes unless the study center has policies in place that prohibit 
these procedures being captured by video. The Implant refill procedure video capture is 
optional. 
For a complete list of study assessments, refer to protocol Section 4.6. 
Please see the schedule of assessments provided in protocol Appendix 1 and Appendix 
2 for the schedule of assessments to be performed at each study visit. 
6.4.2 
Description of Those Activities Performed by Sponsor 
Representatives (Excluding Monitoring) 
Genentech 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). 
For additional details regarding administrative structure, refer to protocol Section 9.4. 
6.4.3 
Any Known or Foreseeable Factors That May Compromise the 
Outcome of the Clinical Investigation or the Interpretation of 
Results 
Not applicable. 
6.4.4 
Monitoring Plan 
Study monitors will perform ongoing source data verification 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. Refer to protocol Section 7.4 
for additional details regarding source data documentation. 
7. 
STATISTICAL CONSIDERATIONS 
7.1 
STATISTICAL DESIGN, METHOD AND ANALYTICAL 
PROCEDURES 
One objective in the clinical study is to demonstrate that there is no evidence that the 
Implant clogging rate exceeds 10% of patients in the Implant arms at Month 9. 
Implant clogging data from all patients that receive the Implant will be pooled together for 
this analysis. If there are 22 or fewer clogged Implants, among 165 evaluable Implants, 
within 9 months since insertion, we can declare that there is no evidence for the initial 
Implant clogging rate exceeding 10%. This acceptance criterion will be adjusted based 
on the actual number of evaluable Implants at end of study. The proportion of Implants 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
224/Protocol GX28228, Version 8 
 
that clog within 9 months and its 90% confidence interval will be estimated based on the 
binomial distribution. 
In addition, the safety data from three Implant arms will be pooled and compared with 
monthly ITV injection arm. The summary statistics (frequency and percentage) will be 
provided by Implant arm and monthly ITV arm. The safety assessment will review the 
following: 
• 
AEs 
• 
SAEs 
• 
“Prespecified RPDS-associated AEs” (see protocol Section 6.5.1) 
 
7.2 
SAMPLE SIZE 
This study is exploratory in nature and designed to estimate the time to first refill (TTFR) 
for each of the RPDS treatment arms (10 mg/mL, 40 mg/mL, and 100 mg/mL) enrolling 
60 patients in each of the RPDS treatment arms.  The sample size of approximately 
220 randomized patients will be adequate to evaluate the primary objectiveof the study. 
Pharmacokinetic-Pharmacodynamic modeling and simulation was performed to inform 
key assumptions used in sample size calculation. Given the simulation results, the 
hazard ratio for comparing the 100-mg/mL arm to the 10-mg/mL arm was estimated to 
be 0.66 for TTFR.  Assuming this hazard ratio, a total of at least 125 events from all 
three Implant groups is expected at the primary analysis time (approximately 85 events 
in the 10-mg/mL group and a higher dose group).  With 85 events, this study will have 
approximately 80% power to detect a hazard ratio=0.66 between the two Implant arms 
using a log-rank test at a one-sided significance level of 15%.  No multiplicity adjustment 
is planned for this Phase II study. 
Forty patients in the ITV arm will be sufficient to compare each device arm versus the 
ITV arm in change in BCVA from baseline through Month 9 (assuming an estimated 
SD=10 letters, a two-sided 80% CI will extend approximately 2.62 letters from the 
observed mean). 
7.3 
THE LEVEL OF SIGNIFICANCE AND THE POWER OF THE 
DEVICE CLINICAL INVESTIGATION 
The significance level used for Implant clogging data analysis is 0.05 and a one-sided 
test will be performed. 80% statistical power was used in above sample size section. 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
225/Protocol GX28228, Version 8 
 
7.4 
EXPECTED DROP-OUT RATES 
Less than 8% dropout rate is expected based on the previous clinical trials for 
ranibizumab. Thus, an 8% dropout rate is assumed in the above sample size section for 
Implant clogging data analysis. 
7.5 
PASS/FAIL CRITERIA TO BE APPLIED TO THE RESULTS OF 
THE DEVICE CLINICAL INVESTIGATION 
The RPDS clinical investigation will be considered to successfully demonstrate Implant 
functionality if the following objective is met: 
• 
Establish that there is no evidence that the initial Implant clogging rate within 9 
months exceed 10% 
 
The RPDS clinical investigation will be considered to successfully demonstrate RPDS 
safety if the following objective is met: 
• 
Demonstrate that the AE profile observed when ranibizumab is administered using 
the Implant is clinically acceptable as compared with ranibizumab dosed using 
conventional ITV injection. In other words, any complications associated with 
Implant insertion, refill, or explantation, or associated with the long term presence of 
the Implant within the posterior chamber of the eye, are manageable and are 
acceptable in an overall benefit-risk assessment versus ITV dosing. 
 
This will include a characterization of the “Prespecified RPDS-associated AEs”, that is, 
those ADEs that have been pre-specified as being most relevant for the risk assessment 
of the Implant and the procedures of insertion, refill, and explantation. 
For each AE (including “Prespecified RPDS-associated AEs”) observed during the clinical 
study, the CRF will collect a separate assessment of investigator causality for each 
“study intervention” element, that is, investigator causality for “study drug” (i.e., 
ranibizumab [for both Implant arms and ITV dosing arm]), investigator causality for 
“procedures” (for both Implant arms and ITV dosing arm), and investigator causality for 
each of the RPDS components (for Implant arms only – the Implant, the Initial Fill 
Needle, the Insertion Tool, the Refill Needle, and the Explant Tool). Investigators will be 
trained on the requirement to assess each AE for potential causal association to “drug”, 
“procedure” and each of the “RPDS” device components −so that they may 
determine whether there is a causal association with one, more than one, or none of the 
“Study intervention” elements. 
If these objectives are not met, further design changes will be mandated. 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
226/Protocol GX28228, Version 8 
 
7.6 
FLEXIBLE INTERIM ANALYSIS 
Given the exploratory nature of this study, the Sponsor may choose to conduct up to two 
interim efficacy analyses.  The decision to conduct an optional interim analysis and the 
timing of the analysis will be documented in the Sponsor’s trial master file prior to the 
conduct of the interim analysis.  The interim analysis will be performed by members of 
the Sponsor’s unmasked study team and will be interpreted by the unmasked IMC and 
appropriate senior management personnel.  Access to treatment assignment information 
will follow the Sponsor’s standard procedures.  The details of the timing and scope of the 
interim analysis, if any, will be specified in the IMC Agreement. 
7.7 
CRITERIA FOR THE TERMINATION OF THE CLINICAL 
INVESTIGATION 
The criteria for stopping the trial or a treatment arm will be outlined in the IMC charter. 
7.8 
SUBGROUPS 
Subgroup analysis will be performed if necessary. The subgroup variables should be 
pre-defined in the detailed statistical analysis plan before the clinical database lock. 
7.9 
PROCEDURES THAT TAKE INTO ACCOUNT ALL DATA 
All Implant clogging data up to Month 9 visit will be included for analysis. 
7.10 
MISSING, UNUSED OR SPURIOUS DATA; EXCLUSION OF 
PARTICULAR INFORMATION 
Missing data will not be imputed for Implant clogging assessment; however, all Implant 
data up to Month 9 visit will be included for Implant clogging data analysis. In case some 
patients discontinued from study prior to Month 9 visit, all data before last visit will still be 
used for data analysis. 
7.11 
NUMBER OF SUBJECTS TO BE INCLUDED FOR EACH 
CENTER 
It is expected that each site will enroll approximately of 3-5 patients. 
8. 
DATA MANAGEMENT 
8.1 
DATA REVIEW 
The Sponsor will be responsible for the data management of this study, including quality 
checking of the data. For additional details, refer to protocol Section 7.1. 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
227/Protocol GX28228, Version 8 
 
8.2 
VERIFICATION, VALIDATION AND SECURING OF 
ELECTRONIC CLINICAL DATA SYSTEMS 
The Sponsor will perform oversight of the data management of this study. For additional 
details, refer to protocol Section 7.1. 
8.3 
DATA RETENTION AND SPECIFIED RETENTION PERIOD 
For details, refer to protocol Section 7.6. 
8.4 
OTHER ASPECTS OF CLINICAL QUALITY ASSURANCE 
For details, refer to protocol Section 7.1. 
9. 
AMENDMENTS TO THE RPDS CIP 
Any amendments to the RPDS CIP will be prepared by the Sponsor. Protocol and RPDS 
CIP amendments will be submitted to the Institutional Review Board (IRB)/Ethics 
Committee (EC) and to regulatory authorities in accordance with local regulatory 
requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (according to local 
requirements) 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). 
10. 
DEVIATIONS FROM CLINICAL INVESTIGATION PLAN 
Investigators must follow instructions and procedures as described in the Phase II 
protocol. No deviations from the RPDS CIP or protocol are allowed except when 
necessary to protect the safety, rights, or welfare of patients. 
10.1 
RECORDING, REPORTING AND ANALYZING RPDS CIP 
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. 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
228/Protocol GX28228, Version 8 
 
10.2 
CORRECTIVE AND PREVENTIVE ACTIONS 
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 Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline for 
Good Clinical Practice (GCP) 
 
The Sponsor may also implement additional training for Investigators when warranted. 
11. 
DEVICE ACCOUNTABILITY 
All IMP (ranibizumab) and RPDS required for completion of this study (including all the 
components of the RPDS) will be provided by the Sponsor. For additional details 
regarding IMP and RPDS accountability, refer to protocol Section 4.3.2.4.2. 
12. 
STATEMENTS OF COMPLIANCE 
This study will be conducted in full conformance with the ICH E6 guideline for GCP and 
the principles of the Declaration of Helsinki, or the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the 
individual. It will also follow ISO 14155 for the Clinical Investigation Plan. 
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. Food and Drug Administration regulations and 
applicable local, state, and federal laws. 
This protocol, the ICFs, any information to be given to the patient, and relevant 
supporting information must be submitted to the IRB/EC by the Principal Investigator and 
reviewed and approved by the IRB/EC before the study is initiated. In addition, any 
patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC. Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments. 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
229/Protocol GX28228, Version 8 
 
In addition to the requirements for reporting all AEs to the Sponsor, investigators must 
comply with requirements for reporting SAEs to the local Health Authority (HA) 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 HA requirements and the policies 
and procedures established by their IRB/EC, and archived in the site’s study file. 
The statement for patient’s insurance due to injury in the RPDS Phase II clinical trial is 
available in the RPDS informed consent sample template. 
13. 
INFORMED CONSENT PROCESS 
The Sponsor’s sample ICF will be provided to each site. For additional details, refer to 
protocol Section 8.2. 
14. 
ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE 
DEFICIENCIES 
14.1 
DEFINITIONS OF ADVERSE EVENTS AND ADVERSE DEVICE 
EFFECTS 
Refer to protocol Section 5.2.1. 
14.2 
DEFINITION OF DEVICE DEFICIENCIES 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, 
safety or performance. 
14.3 
DEFINITIONS OF SERIOUS ADVERSE EVENTS AND SERIOUS 
ADVERSE DEVICE EFFECTS AND, WHERE APPROPRIATE, 
UNANTICIPATED SERIOUS ADVERSE DEVICE EFFECTS 
Refer to protocol Section 5.2.2. 
A serious ADE is an ADE that has resulted in any of the consequences characteristic of 
an SAE. 
14.4 
REPORTING OF ADVERSE EVENTS AND DEVICE 
DEFICIENCIES 
The investigator is responsible for ensuring that all AEs are recorded on the Adverse 
Event eCRF and reported to the Sponsor in accordance with instructions provided. The 
investigator is also responsible for reporting all complaints associated with any of the 
components of the RPDS. 
For additional details, refer to protocol Section 5.3.1. 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
230/Protocol GX28228, Version 8 
 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. For details, refer to protocol 
Section 5.4. 
14.5 
PROCESS FOR REPORTING ADVERSE EVENTS 
After informed consent has been obtained but prior to initiation of study drug (Day 1), 
only SAEs related to a protocol-mandated intervention will be reported (see protocol 
Section 5.4.2 for instructions for reporting SAEs). 
After initiation of study drug, all AEs, regardless of relationship to study drug, Implant, or 
ancillary devices, or study procedures, will be reported until the patient’s study 
completion or early termination from the study. All SAEs, (including serious adverse 
reactions and serious adverse device effects) will be collected and reported to the 
Sponsor in compliance with GCP guidelines. 
Investigators will seek information on AEs at each patient contact. All AEs, 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. 
The investigator is responsible for ensuring that all AEs are recorded on the Adverse 
Event eCRF and reported to the Sponsor in accordance with instructions provided. For 
each AE recorded on the Adverse Event eCRF, the investigator will make an assessment 
of seriousness, severity, and causality. 
14.6 
PROCESS FOR REPORTING DEVICE DEFICIENCIES 
The investigator must report all medical device complaints associated with any of the 
components of the RPDS to the Sponsor. 
For additional details, refer to protocol Section 5.4.4. 
14.7 
FORESEEABLE ADVERSE EVENTS AND ANTICIPATED 
ADVERSE DEVICE EFFECTS 
The following are “Prespecified RPDS-associated AEs”: 
• 
Vitreous hemorrhage associated with a > 30-letter decrease in BCVA on the ETDRS 
chart compared with the last assessment of BCVA prior to the onset of vitreous 
hemorrhage lasting >1 month 
• 
Reduced VA (>30-letter loss from previous scheduled visit) 
• 
Traumatic cataract 
• 
Endophthalmitis 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
231/Protocol GX28228, Version 8 
 
• 
Damage to sclera 
• 
Retinal detachment 
• 
Interference of the Implant with visual field 
 
In addition, ocular AEs and SAEs attributed by the investigator to: 1) the Implant 
insertion procedure, 2) the Implant refill procedure, 3) Implant explantation procedure, 
and 4) the Implant and other RPDS components, will be reported 
14.8 
EMERGENCY CONTACT DETAILS FOR REPORTING SERIOUS 
ADVERSE EVENTS AND SERIOUS ADVERSE DEVICE 
EFFECTS 
The Phase II study is being conducted in the United States only. 
Medical Monitor Contact Information for Sponsor’s Medical Responsible is provided in 
protocol Section 5.4.1. 
14.9 
INFORMATION REGARDING THE SAFETY REVIEW 
COMMITTEE 
Ongoing review of study data (including adverse events of special interest, SAEs, 
adverse device effects [ADEs], and laboratory abnormalities) will be performed by the 
IMC. The IMC roles and responsibilities will be outlined in the IMC charter. 
15. 
VULNERABLE POPULATION 
15.1 
SPECIFIC INFORMED CONSENT PROCESS 
This clinical investigation will only enroll patients who are able and willing to provide 
signed informed consent. 
15.2 
ETHICS COMMITTEE'S SPECIFIC RESPONSIBILITY 
This protocol, the ICFs, any information to be given to the patient, and relevant 
supporting information must be submitted to the IRB/EC by the Principal Investigator and 
reviewed and approved by the IRB/EC before the study is initiated. In addition, any 
patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC. Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments. 
In addition to the requirements for reporting all AEs to the Sponsor, investigators must 
comply with requirements for reporting SAEs to the local HA and IRB/EC. Investigators 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
232/Protocol GX28228, Version 8 
 
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 HA requirements and the policies and procedures 
established by their IRB/EC, and archived in the site’s study file. 
15.3 
MEDICAL CARE PROVIDED FOR SUBJECTS AFTER THE 
CLINICAL INVESTIGATION HAS BEEN COMPLETED 
Currently, the Sponsor doesn’t plan to provide ranibizumab via RPDS or via ITV 
injections or to provide other study interventions to patients after the conclusion of the 
study or following early patient withdrawal. The Sponsor will evaluate the 
appropriateness of continuing to provide ranibizumab treatment to RPDS treatment arms 
patients after evaluating RPDS efficacy, safety, and PK data gathered in the study. The 
Sponsor may offer study patients entry to a separate RPDS Extension Study to continue 
to provide ranibizumab to RPDS treatment arms patients via Implant in an open-label 
manner. 
For additional information, please refer to the ICF. 
16. 
SUSPENSION OR PREMATURE TERMINATION OF THE 
CLINICAL INVESTIGATION 
The Sponsor has the right to terminate this study or close a site at any time. For details, 
refer to protocol Section 4.7.4. 
16.1 
REQUIREMENTS FOR SUBJECT FOLLOW-UP 
For details refer to protocol Section 4.6.10.3. 
17. 
PUBLICATION POLICY 
For details regarding the publication policy, refer to protocol Section 9.5 and the Roche 
Global Policy on Sharing of Clinical Trials Data. 


Appendix 21  
Ranibizumab Port Delivery System:  Device Clinical 
Investigation Plan (cont.) 
Ranibizumab Port Delivery System—Genentech, Inc. 
233/Protocol GX28228, Version 8 
 
18. 
BIBLIOGRAPHY 
Bressler NM. Submacular surgery. Are randomized trials necessary? Arch 
Ophthalmol. 1995 Dec;113(12):1557-60. 
Busbee BG, Ho AC, Brown DM, et al. Twelve-month efficacy and safety of 
0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-
related macular degeneration. Ophthalmology; 2013 May;120(5):1046-56. 
CATT Research Group et al. Ranibizumab and bevacizumab for age-related 
macular degeneration (CATT study). N Engl J Med; 2011 May 
19;364(20):1897-908. 
ISO 14155:2011 Clinical investigation of medical devices for human subjects - 
Good Clinical Practice. 
Klein R, Klein BE, Jensen SC, et al. The five-year incidence and progression of 
age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology. 1997 
Jan;104(1):7-21. 

SAP_001.pdf: 
 
Official Title: 
A Phase II, Multicenter, Randomized, Active Treatment-Controlled 
Study of the Efficacy and Safety of the Ranibizumab Port Delivery 
System for Sustained Delivery of Ranibizumab in Patients With 
Subfoveal Neovascular Age-Related Macular Degeneration 
NCT Number: 
NCT02510794 
Document Date: 
SAP Version 2: 21-June-2018 
 
 


STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL 
 
CONFIDENTIAL 
 
This is Genentech, Inc. (or under its control) document that contains confidential information.  
Nothing herein is to be disclosed without written consent from Genentech, Inc. 
 
 
 
Ranibizumab Port Delivery System—Genentech, Inc. 
Statistical Analysis Plan GX28228 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A PHASE II, MULTICENTER, RANDOMIZED, ACTIVE 
TREATMENTCONTROLLED STUDY OF THE EFFICACY 
AND SAFETY OF THE RANIBIZUMAB PORT DELIVERY 
SYSTEM FOR SUSTAINED DELIVERY OF RANIBIZUMAB IN 
PATIENTS WITH SUBFOVEAL NEOVASCULAR 
AGE-RELATED MACULAR DEGENERATION 
PROTOCOL NUMBER: 
GX28228 
STUDY DRUG: 
Ranibizumab Port Delivery System for Sustained 
Delivery of Ranibizumab (RO4893594) 
VERSION NUMBER: 
2 
IND NUMBER: 
113,552 
EUDRACT NUMBER: 
Not applicable 
SPONSOR: 
Genentech, Inc. 
PLAN PREPARED BY: 
 Ph.D., Genentech 
 Ph.D., Novartis 
DATE FINAL: 
Version 1:  1 May 2017 
DATE(S) AMENDED: 
Version 2:  See electronic date stamp below. 
Name                                                             Reason for Signing                              Date and Time
(UTC)
21-Jun-2018 09:06:58
Company Signatory


Ranibizumab Port Delivery System—Genentech, Inc.
2/Statistical Analysis Plan GX28228
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE
The following changes to the Statistical Analysis Plan (SAP), Version 2, are being made 
subsequent to the end of Phase II meeting held with the U.S. Food and Drug 
Administration (FDA) on 23 March 2018.

Added details of two unplanned interim efficacy analyses conducted per allowance 
of the protocol:  the first interim was performed after ~50% of patients completed the 
6-month follow-up in October 2017, and the second interim was performed after ~70% 
of patients completed the 9-month follow-up in April 2018.

Added supportive preliminary assessments on the differences in best corrected 
visual acuity (BCVA) and anatomical outcomes between the Port Delivery System 
with ranibizumab (PDS) arms and ranibizumab monthly intravitreal injection arm.  
Statistical methods and the endpoints used for the preliminary assessments are 
provided. Formal hypothesis testing will not be performed because the study is not 
powered for such assessments.

Modified data handling rules for primary, secondary, and exploratory endpoints. 
The last observation carried forward approach will not be used as the primary 
method for imputation of missing data.

Updated the analysis population definitions with regard to the handling of sites with 
Good Clinical Practice (GCP) non-compliance issues.

Added additional safety analyses for comprehensive safety assessment.

Added information pertaining to the oral antithrombotic therapy (OAT) substudy.
Analysis plan for the OAT substudy is provided in the substudy protocol and is not 
repeated in this SAP.
Additional minor changes have been made to improve clarity and consistency.


Ranibizumab Port Delivery System—Genentech, Inc.
3/Statistical Analysis Plan GX28228
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE............................. 2
1.
BACKGROUND ............................................................................................ 5
2.
STUDY DESIGN........................................................................................... 5
2.1
Protocol Synopsis.................................................................... 8
2.2
Outcome Measures ................................................................. 8
2.2.1
Primary Efficacy Outcome Measure ........................................ 8
2.2.2
Secondary Efficacy Outcome Measures.................................. 8
2.2.3
Safety Outcome Measures ...................................................... 9
2.2.4
Pharmacokinetic Efficacy Outcome Measures ........................ 9
2.2.5
Exploratory Efficacy Outcome Measures................................. 9
2.3
Determination of Sample Size ............................................... 10
2.4
Analysis Timing ..................................................................... 10
3.
STUDY CONDUCT..................................................................................... 10
3.1
Randomization....................................................................... 10
3.2
Independent Image Review Facility....................................... 11
3.3
Data Monitoring ..................................................................... 11
4.
STATISTICAL METHODS .......................................................................... 11
4.1
Analysis Populations ............................................................. 11
4.1.1
Modified Intent-to-Treat Population ....................................... 12
4.1.2
Safety Population .................................................................. 12
4.1.3
Pharmacokinetic-Evaluable Population ................................. 12
4.2
Analysis of Study Conduct..................................................... 12
4.3
Analysis of Treatment Arm Comparability.............................. 12
4.4
Efficacy Analysis.................................................................... 12
4.4.1.1
Primary Efficacy Endpoint...................................................... 13
4.4.1.2
Additional Efficacy Analyses Focused on Refill 
Times..................................................................................... 14
4.4.2
Additional Efficacy Endpoints ................................................ 15
4.4.2.1
Visual Acuity.......................................................................... 15
4.4.2.2
Anatomical Outcomes............................................................ 19


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4.4.2.3
Patient-Reported Outcomes (MacTSQ)................................. 20
4.4.2.4
Other Exploratory Efficacy Endpoints .................................... 20
4.5
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 20
4.6
Safety Analyses..................................................................... 20
4.6.1
Exposure of Study Medication............................................... 22
4.6.2
Laboratory Data..................................................................... 22
4.6.3
Vital Signs.............................................................................. 22
4.6.4
Ocular Assessments.............................................................. 22
4.7
Missing Data.......................................................................... 22
4.8
Interim Analyses .................................................................... 23
5.
REFERENCES ........................................................................................... 24
LIST OF FIGURES
Figure 1
Study Schema............................................................................... 6
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 25
Appendix 2
Schedule of Assessments........................................................... 34


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1.
BACKGROUND
Age-related macular degeneration (AMD) is one of the major causes of legal blindness 
in elderly persons in the developed world (Bressler et al. 2011).  Advanced AMD 
includes two sub-types:  neovascular AMD (nAMD) and geographic atrophy (GA).  The 
prevalence of nAMD increases exponentially with age, with prevalence estimates in the 
United States in 2011 ranging from 0.5% among those 6569 years of age to 14.6% 
among those 90 years of age or greater (Rudnicka et al. 2012).
The treatment of nAMD was significantly impacted by the introduction of anti-vascular 
endothelial growth factor (VEGF) therapy because prior to the availability of anti-VEGF 
therapy, vision loss could be slowed but not reversed.  Ranibizumab, a recombinant, 
humanized monoclonal antibody fragment (Fab), 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.  Both ranibizumab and aflibercept therapies require frequent intravitreal 
injections and physician monitoring.
As a result of the chronic, progressive nature of nAMD, frequent ranibizumab intravitreal
injections continue for extended periods for many patients.  Pivotal studies of 
ranibizumab in nAMD (Studies FVF2598g and FVF2587g) demonstrated significant and 
well-maintained visual acuity (VA) outcomes with monthly 0.5-mg intravitreal injections 
for 2 years.  Trials that investigated less frequent than monthly dosing (Study FVF3192g 
and Lalwani et al. 2009) showed that visual outcomes were not as well maintained with 
more intermittent dosing schedules.
The Port Delivery System with ranibizumab (PDS), previously called ranibizumab Port 
Delivery System (RPDS), 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 port delivery implant (referred to as the Implant), ancillary devices 
(Insertion Tool, Initial Fill Needle, Refill Needle, and Explant Tool), and ranibizumab.  
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.
The analyses specified in this document supersede the analysis plan described in the 
Study GX28228 Protocol, Version 8.  Additional supportive analyses were added in this 
amendment to provide further evaluation of the treatment benefits.
2.
STUDY DESIGN
Study GX28228 is a Phase II, multicenter, dose-ranging, randomized, active treatment 
(monthly intravitreal injection)controlled study to evaluate the efficacy, safety, and 
pharmacokinetics (PK) of ranibizumab delivered through the Implant using three 
ranibizumab formulation arms (10 mg/mL, 40 mg/mL, and 100 mg/mL) compared with 


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the control arm (0.5-mg monthly intravitreal injections of 10 mg/mL formulation) in 
patients with nAMD.  Approximately 220 patients at up to 60 sites in the United States 
will be randomized in a 3:3:3:2 ratio to the PDS 10 mg/mL, PDS 40 mg/mL, 
PDS 100 mg/mL, and the control arms, respectively (Figure 1).
Figure 1
Study Schema
D1Day 1; ITVintravitreal; LPIlast patient in; M1Month 1; M9Month 9; PA primary 
analysis; PDranibizumab port delivery; PRN as needed (as per the refill criteria);
RBZranibizumab; SOC standard-of-care. 
Note:  Ranibizumab filled Implant inserted (Day 1).
The study will include screening and randomization visits followed by a treatment period.  
Baseline measurements will be taken at the randomization visit. The patients will then 
be randomized to a treatment arm using a permuted block randomization scheme 
stratifying by best corrected visual acuity (BCVA) score (65 letters vs. 66 letters) and 
number of prior anti-VEGF intravitreal injections (3 vs. 4).
Patients randomized to the Implant treatment arms will have the Implant (prefilled with 
ranibizumab) surgically inserted in the study eye at their Day 1 visit, after which they will 
be evaluated monthly for the need for an Implant refill based upon 
protocol-specified-refill criteria for the remainder of the study treatment duration. 
Patients randomized to the intravitreal injection treatment arm (control) will be treated 
monthly with intravitreal injections of ranibizumab, starting at their Day 1 visit and 
continuing for the remainder of the study treatment duration.


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The study had specific criteria for refill, rescue, and lack of clinical efficacy (LCE), which 
are provided below.
Refill Criteria:  The patients randomized to the Implant treatment arms will have their 
Implant refilled only if any of the following criteria is met, as automatically determined by 
contacting interactive voice/Web response system (IxRS): 

Increase in central foveal thickness (CFT) of 75 m on spectral domain optical 
coherence tomography (SD-OCT) at the current visit compared with the average 
CFT over the last 2 available measurements, due to nAMD disease activity 
OR

Increase in CFT of 100 m from the lowest CFT measurement on study, due to 
nAMD disease activity 
OR 

Decrease of 5 letters in BCVA at the current visit compared with the average 
BCVA over the last two available measurements, due to nAMD disease activity 
OR 

Decrease of 10 letters from best recorded BCVA on study, due to nAMD disease 
activity 
OR 

Presence of new macular hemorrhage, due to nAMD disease activity.
Rescue Criteria:  Rescue treatment with open-label ranibizumab (0.5 mg intravitreal
injections of 10 mg/mL formulation) for patients in the Implant arm is allowed only under 
the following circumstances: 

Approximately 1 month and/or 2 months after occurrence of vitreous hemorrhage, if 
vitreous hemorrhage causes loss in BCVA, and neither assessment of the macula 
nor SD-OCT can be performed successfully. 

At the time a patient meets criteria for LCE (see below).

In the case of progressive worsening of BCVA and/or CFT due to wet AMD activity 
across two consecutive scheduled visits, only if the patient does not meet refill 
criteria. If a treatment is clinically necessary due to the progressive clinical 
worsening per the investigator’s judgment, rescue treatment must be discussed and 
agreed upon by the Medical Monitor prior to being introduced.
Lack of Clinical Efficacy Criteria: If a study patient randomized to the Implant 
treatment arm meeting criteria for LCE, he or she will receive a rescue injection with 
open-label ranibizumab at the time of meeting LCE. In addition, he or she will receive a 
mandatory refill at the 100 mg/mL formulation one month after the rescue intravitreal 
injection. After that, the 100 mg/mL formulation will be used for all future refills, 
whenever the patient meets refill criteria. The LCE criteria are as follows:

Loss in BCVA of 15 letters from the best recorded BCVA on study following two 
consecutive ranibizumab Implant refills (as per protocol-specified refill criteria) 


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occurring 1 month apart due to nAMD disease activity and not attributable to a 
change in the ocular media (i.e., cornea, lens, aqueous or vitreous humor, epiretinal 
membrane development, etc.) unless there is at least a five-letter increase in BCVA, 
in which case a refill will occur.
and/or

Increase in CFT 150 m from the lowest CFT measurement on study following two 
consecutive ranibizumab Implant refills (as per protocol-specified refill criteria) 
occurring 1 month apart due to nAMD disease activity and not attributable to a 
change in the ocular media (i.e., cornea, lens, aqueous or vitreous humor, epiretinal 
membrane development, etc.) unless there is a decrease in CFT 75 microns from 
the last refill, in which case a refill will occur.
See the protocol synopsis (Appendix 1) for further study design features, including 
screening, inclusion details, and randomization.  The schedule of assessments is in 
Appendix 2.
An oral antithrombotic therapy (OAT) substudy is being conducted as a substudy of the 
main Study GX28228.  This substudy is a non-randomized, uncontrolled, open-label
study to evaluate the safety, efficacy, and PK of ranibizumab delivered through an 
implant using the 100-mg/mL formulation of ranibizumab in patients with nAMD who 
required ongoing OAT for a preexisting medical condition, and such subjects were not 
eligible to participate to the main study.  Subjects for the substudy are enrolled 
separately from the main study and the analyses for the substudy will also be conducted 
separately.  Please refer to Section 6 in the substudy protocol for details regarding 
statistical considerations and analysis plan.
2.1
PROTOCOL SYNOPSIS
The protocol synopsis is in Appendix 1.  The schedule of assessments is provided in 
Appendix 2. Of note, the analyses specified in this SAP supersede the analysis plan 
described in the Protocol.
2.2
OUTCOME MEASURES
2.2.1
Primary Efficacy Outcome Measure
The primary efficacy outcome measure for this study is the time until a patient first 
requires the Implant refill according to protocol-defined refill criteria.
2.2.2
Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures are as follows:

Change from baseline in BCVA at Month 9

Average change from baseline in BCVA over time

Change from baseline in BCVA over time


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
Change from baseline in CFT over time, as assessed on SD-OCT by the central 
reading center

Occurrence of Implant clogging
2.2.3
Safety Outcome Measures
The safety outcome measures are as follows:

Incidence of adverse events of special interest (AESIs): Adverse events (AEs) 
associated with ranibizumab, the Implant, Implant-associated procedures, and/or 
ancillary devices

Incidence of “pre-specified PDS-associated AEs”

Incidence of ocular and non-ocular AEs and serious adverse events (SAEs)

Incidence of positive serum antibodies to ranibizumab
2.2.4
Pharmacokinetic Efficacy Outcome Measures
The PK outcome measures related to ranibizumab serum concentration-time data 
following the Implant insertion and refills are as follows:

Observed maximum serum concentration (Cmax) and selected postdose-serum 
concentrations after Implant insertion and all subsequent refills

Additional estimated PK parameter values including area under the concentration
time curve (AUC), time to maximum concentration (tmax), and half-life (t1/2) after 
Implant insertion, and all subsequent refills

Observed serum concentrations (Ct) over time from monthly serum sampling when 
no refills are administered

Observed steady-state serum concentration (Ctrough) prior to refills
In addition, optional anterior chamber (aqueous humor) samples will be collected to 
assess ocular drug concentration.
2.2.5
Exploratory Efficacy Outcome Measures
The exploratory outcome measures are as follows: 

Treatment emergent macular atrophy in all treatment arms

The Macular Degeneration Treatment Satisfaction Questionnaire (MacTSQ) score 
at randomization and at Months 1, 6, 9, and the final or early termination visit for 
patients who speak English or Spanish

Time to subsequent Implant refills according to protocol-defined refill criteria

Number of times a patient meets protocol-specified refill criteria

Proportion of patients in each Implant arm who first meet the protocol-defined refill 
criteria prior to and at Months 4, 5, and 6

Proportion of patients with an improvement of BCVA from baseline of 15 letters 
over time


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
Proportion of patients losing 15 letters in BCVA from baseline over time

Change from baseline in BCVA over time measured under low luminance conditions

Changes from screening in total lesion area, area of choroidal neovascularization 
(CNV) lesion, and CNV leakage over time, as assessed by fluorescein angiography

Proportion of patients meeting LCE criteria

Proportion of patients requiring explantation

Changes in CNV perfusion over time, as assessed by optical coherence 
tomography (OCT) angiography
2.3
DETERMINATION OF SAMPLE SIZE
This study is exploratory in nature and designed to estimate the time to first refill (TTFR) 
for each of the PDS treatment arms (10 mg/mL, 40 mg/mL, and 100 mg/mL) enrolling 
60 patients in each of the PDS treatment arms.  The sample size of approximately 
220 randomized patients will be adequate to evaluate the primary objective of the study 
(see the protocol synopsis in Appendix 1).  Pharmacokinetic/pharmacodynamic (PK/PD) 
modeling and simulation were performed to inform key assumptions used in sample size 
calculation.  Given the simulation results, the hazard ratio (HR) for comparing the 
100 mg/mL arm with the 10 mg/mL arm was estimated to be 0.66 for TTFR.  Assuming 
this HR, a total of at least 125 events from all three Implant arms is expected at the 
primary analysis time (approximately 85 events in the 10 mg/mL arm and a higher dose 
arm).  With 85 events, this study will have approximately 80% power to detect an 
HR0.66 between the two Implant arms using a log-rank test at a one-sided significance 
level of 15%.  No multiplicity adjustment is planned for this Phase II study.
Forty patients in the intravitreal arm are considered sufficient to compare each device 
arm versus the intravitreal arm in change in BCVA from baseline through Month 9 
(assuming an estimated SD10 letters, a two-sided 80% CI will extend approximately 
2.62 letters from the observed mean).
2.4
ANALYSIS TIMING
The planned primary analysis will be conducted after the last patient’s Month 9 visit 
occurs.  The final analysis will be conducted following the conclusion of the study.  The 
analysis timing for interim analyses can be found in Section 4.8.
3.
STUDY CONDUCT
3.1
RANDOMIZATION
Stratified permutated block randomization was used to assign patients to one of the 
study treatment arms.  The randomization stratification factors are BCVA score
(65 letters vs. 66 letters) and number of prior anti-VEGF intravitreal injections 
(3 vs. 4).  Randomization was performed by the IxRS.  Outcomes of the stratification 
factors used in randomization and outcomes of stratification factors as recorded in Case 


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Report Forms (CRF) will be compared to examine whether there are mis-stratifications.  
For analyses, the stratification factors as recorded in IxRS will be used.
3.2
INDEPENDENT IMAGE REVIEW FACILITY
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 analyses and storage.
The staff at the central reading center is masked for the treatment assignment and the 
location (left vs. right) of the study eye.
3.3
DATA MONITORING
Ongoing review of aggregate safety (including AESIs, SAEs, and adverse device 
effects [ADEs]) along with key efficacy data (BCVA and refills for benefit-risk 
assessments) was performed by the Internal Monitoring Committee (IMC). The IMC is 
composed of two subcommittees:  a masked IMC that will meet regularly to review study 
safety data, study conduct, and operation and an unmasked IMC that will meet as 
needed to review unmasked safety and/or efficacy data and operational issues.  The 
masked IMC members were granted access to the unmasked interim efficacy analysis 
results for the purpose of planning future Phase III studies, and continued to review only 
the aggregate cumulative safety summary in an attempt to provide unbiased assessment.  
The IMC roles and responsibilities are outlined in the IMC Agreement.
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATIONS
Any site with serious Good Clinical Practice (GCP) non-compliance issues will impact 
the efficacy and safety assessments for this study.  In case of any data falsification or 
other deviations from GCP, data will be handled as follows:

Exclude data for summaries of patient disposition, summaries of demographic and
baseline characteristics, PK/PD analyses, and all efficacy analyses

Exclude data for all safety analyses for a clean overall summary

Additionally, include data for ocular adverse event summaries as sensitivity 
analyses

Provide a separate listing of all safety adverse events for non-compliance sites for 
full disclosure
A directed Roche Quality Assurance audit conducted in November 2017 confirmed 
serious GCP non-compliance involving fraudulent data collection on the part of multiple 
staff members (study coordinators) was established at Site
, and the FDA was 
notified of the alleged misconduct on 21 December 2017.  Due to the findings identified 
to date (data falsification), the data for this site will be handled as described above since 
the Sponsor concluded that the integrity of the data produced at this specific site did not 
meet requirements for GCP.


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4.1.1
Modified Intent-to-Treat Population
Efficacy analyses will be based on the modified intent-to-treat (ITT) population, which will 
comprise all patients who were randomly assigned to study treatment and receive at 
least one study treatment.  Patients will be summarized by treatment arm and analyzed 
according to the treatment actually received and not according to the treatment they 
were randomized to receive, in the event of a discrepancy. Patients who received an 
Implant will be considered a PDS patient.
4.1.2
Safety Population
The safety population will be composed of all patients who received at least one study 
treatment. Patients will be summarized by treatment arm and analyzed according to the 
treatment actually received and not according to the treatment they were randomized to 
receive, in the event of a discrepancy.  This population will be used for safety summaries 
and analyses.
4.1.3
Pharmacokinetic-Evaluable Population
Pharmacokinetic-evaluable patients will include randomized patients who have received 
at least one study drug administration and have provided at least one serum and/or 
aqueous PK sample for determination of ranibizumab concentration. Patients may be 
excluded from the PK analyses if they have AEs that will interfere with the interpretation 
of the results. Treatment arms for this population will be defined according to the actual 
treatment received.
4.2
ANALYSIS OF STUDY CONDUCT
A summary of patient disposition will be presented in the all randomized patient 
population excluding patients from site 
 and will include the number of patients 
randomized, and the number and percentage of patients who completed the study, who 
received study drug, who discontinued study drug, and who discontinued study 
participation.  The reasons for study/study drug discontinuation will also be summarized.  
A summary of the number and percentage of patient’s eligibility criteria deviations and 
other major protocol deviations will also be tabulated.  
4.3
ANALYSIS OF TREATMENT ARM COMPARABILITY
Demographic and baseline characteristics such as age, sex, race/ethnicity, and baseline 
disease characteristics (i.e., BCVA and OCT parameters) will be summarized by 
treatment arm in the modified ITT population using means, standard deviation, medians, 
and ranges for continuous variables, and counts and proportions for categorical 
variables, as appropriate. 
4.4
EFFICACY ANALYSIS
Efficacy analyses will be done using the modified ITT population.  Although this study is 
powered based on the log-rank test at a one-sided significance level of 15% for the 
primary outcome measure, there is no prespecified alpha level for other outcome 


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measures.  95% CIs will be reported for estimation purposes and for treatment arm 
differences unless stated otherwise.  No adjustments will be made for multiplicity.  
Except for the primary endpoint, no statistical tests will be conducted.  All analyses will 
be based on observed results unless imputation of missing data is specified.  For the 
analysis purpose, the stratification factors as recorded in IxRS will be used if there is a 
discrepancy between the CRF and the IxRS data.
Unless otherwise specified, continuous variables will be summaries using descriptive 
statistics including mean, standard deviation, median, and range.  Categorical variables 
will be summarized using counts and percentages.
4.4.1.1
Primary Efficacy Endpoint
The primary endpoint for this analysis is the time from the day of device implantation 
until a patient first requires the Implant refill according to protocol-defined refill 
criteria (TTFR).  For patients without any refills prior to or on the cutoff date, TTFR will 
be censored. The censoring date will be defined as the date of a patient’s last visit 
before the cutoff date or the date when the patient discontinues from the study, 
whichever occurs first.  Observed data will be used for these analyses.
Time to first refill will also be censored for the following patients:

At the time of an intravitreal anti-VEGF injection in the study eye if administered 
before the first refill

At the time the refill criteria cannot be assessed, which is defined as at least two 
refill variables (BCVA, CFT, or new macular hemorrhage) cannot be evaluated for 
any reason, or are affected by a clinical reason different from nAMD activity, before 
the first refill

At the time of explant
Kaplan-Meier plots will be provided by PDS treatment arm.  Median TTFR and 
corresponding 80% CIs will be calculated for each treatment arm using the Kaplan-Meier
method.
To support the dose level selection among the Implant groups, the primary analysis for 
TTFR will include the following pairwise group comparisons, each with a stratified 
log-rank test at a one-sided significance level of 15%.  The stratification factors to be 
included are baseline BCVA score (65 letters vs.66 letters) and number of 
anti-VEGF-intravitreal injections (3 vs.4).

Implant with 100 mg/mL versus Implant with 10 mg/mL

Implant with 100 mg/mL versus Implant with 40 mg/mL

Implant with 40 mg/mL versus Implant with 10 mg/mL
In addition, the HR for each pairwise comparison of the treatment arms will be estimated 
using a Cox proportional hazards regression model stratified by baseline BCVA score


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(65 letters vs. 66 letters) and number of prior anti-VEGF-intravitreal injections 
(3 vs. 4) with main effects for treatment.  Estimated HRs for each pairwise 
comparison will be presented with the corresponding 70% CIs.
Using the above methods, two sensitivity analyses will be performed. One sensitivity 
analysis will be done where TTFR will be additionally censored for patients with dosing 
errors. The other sensitivity analysis will be done where TTFR is defined as the time 
from day of device implantation until a patient actually received the first Implant refill, 
regardless whether there is an intravitreal anti-VEGF injection, a visit where refill criteria 
cannot be adequately assessed, or patients have dosing errors.  For patients without 
any refills prior to or on the cutoff date, TTFR will be censored on the date of a patient’s 
last visit before the cutoff date or the date when the patient discontinues from the study, 
whichever occurs first.
To assist in the interpretation of TTFR and change from baseline in BCVA, the following 
figures will be generated:

Swimmer plots by patient time from first dose of study treatment (ranibizumab filled 
Implant insertion) to the end of study with a mark for each refill time will be provided 
by Implant arm to explore the refill pattern.

Spaghetti plots of change in BCVA and change in CFT over time for each Implant 
arm showing refill times will be provided to explore the association of refill frequency 
with BCVA and CFT.
4.4.1.2
Additional Efficacy Analyses Focused on Refill Times
The following endpoints will be summarized using descriptive statistics and 80% CIs.  
These analyses will be done using the modified ITT population observed data.

Time to subsequent Implant refills according to protocol-defined refill criteria will be 
estimated using the Kaplan-Meier method.
Time from first refill to the second refill will be analyzed for patients who have 
undergone the first refill, do not receive an intravitreal anti-VEGF injection in the 
study eye prior to the first refill, and do not have visits prior to the first refill 
where refill criteria cannot be adequately assessed. 
Time from the first refill to the second refill is defined as time from the date of 
the first refill to the date of the second refill.  For patients who do not have the 
second refill prior to or on the cutoff date, time to second Implant refill will be 
censored on the date of a patient’s last visit before the cutoff date or the date 
when the patient discontinues from the study, whichever occurs first.
Time to second Implant refill will also be censored for the following patients:
–
At the time of an intravitreal anti-VEGF injection in the study eye if 
administered before the second refill
–
At the time the refill criteria cannot be adequately assessed, which is 
defined as at least two refill variables (BCVA, CFT, or new macular 


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hemorrhage) cannot be evaluated for any reason, or are affected by a 
clinical reason different from nAMD activity, before the second refill
–
At the time of explant
Similar approach will be used to define time from the second refill to the third 
refill, etc.

Total number of times a patient meets protocol-specified refill criteria and is refilled 
will be provided over the following time intervals first 5 months, from Month 6 to 
Month 10, greater than 10 months

Patient listing of dosing errors and refill time errors

Percentage of patients not meeting the protocol-defined first refill criteria over time, 
derived from Kaplan-Meier estimates
4.4.2
Additional Efficacy Endpoints
This section describes the analysis methods for the secondary and exploratory efficacy 
endpoints listed in Section 2.2.2 and Section 2.2.5.
Descriptive summaries will be provided for all secondary and exploratory endpoints for 
the 3 Implant arms (10 mg/mL, 40 mg/mL, and 10 mg/mL) and the monthly intravitreal
arm.  Figures based on the descriptive summaries over time may be provided when 
appropriate to support the interpretation of the study results.
Additional supportive analyses are provided for preliminary assessments of differences 
in visual acuity and anatomical outcomes between each of the Implant arms and the 
intravitreal arm. Descriptions of the statistical methods and the endpoints used for the 
preliminary assessments are grouped into the following subsections:  BCVA, anatomical 
outcomes, patient reported outcomes, and other exploratory efficacy endpoints. Formal 
hypothesis testing will not be performed because the study is not powered for such 
assessments. The difference in outcome measure between each of the Implant arms 
and the intravitreal arm will be provided along with a 95% CI.
4.4.2.1
Visual Acuity
Change in Best Corrected Visual Acuity (BCVA)
For change in BCVA from baseline, several supportive preliminary analyses will be 
performed as described below: 

Change from baseline in BCVA score averaged over Month 9 and Month 10 
analyzed with an mixed effects repeated measures (MMRM) model

Change from baseline in BCVA score averaged over Month 9 and Month 10 
analyzed with a trimmed mean approach

Change from baseline in BCVA score through Month 10 analyzed with an analysis 
of covariance (ANCOVA) model with missing data imputed by the last observation 
carry forward (LOCF) approach


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
Change from baseline in BCVA score over time through Month 10 for patients 
treated after surgical Instruction for Use Version 10 (IFU v10) analyzed with 
descriptive statistics
The details for these analyses are provided as follows:

Mixed effects with repeated measures (MMRM) analysis for change in BCVA score 
from baseline averaged over Month 9 and Month 10:
The change from baseline in BCVA score averaged over Month 9 and Month 10 will 
be compared between each PDS arm and the comparator intravitreal arm using a 
MMRM model. The model will include the change from baseline at Months 1 to 10 
as the response variables and will include the categorical covariates of treatment 
group, visit, visit-by-treatment group interaction, the continuous baseline value for 
the response variable (in this case, baseline BCVA), as well as randomization 
stratification factors as fixed effects. Comparisons between each PDS and the 
intravitreal arm will be made using a composite contrast over Months 9 and 10.  
The MMRM model will assume an unstructured covariance structure. If there are 
convergence problems with the model, then a heterogeneous compound symmetry 
or a first order autoregressive (AR [1]) covariance structure may be fitted.
Best corrected visual acuity (BCVA) assessments will be censored after the time of 
rescue intravitreal anti-VEGF injection in the study eye and after the time of explant.  
Missing data will be implicitly imputed by the MMRM model, assuming a missing at 
random missing data mechanism (i.e., missing data are dependent on other 
observed variables but not on the missing data).
An additional MMRM analysis will be performed including all observed 
measurements.  That is, all observed BCVA data will be included regardless of 
whether patients received rescue treatment or discontinued study treatment due to 
AE or LCE.  Best corrected visual acuity (BCVA) assessments at the time of explant 
will be censored.  This analysis evaluates the treatment policy of PDS with rescue 
therapy versus the monthly intravitreal ranibizumab.
From the recent end of Phase II meeting with the US FDA on 23 March 2018, the 
Agency agreed that the change in BCVA from baseline averaged over Month 9 and 
Month 10 is an appropriate primary endpoint for the Phase III study to assess the 
non-inferiority (NI) in visual acuity between the Implant and intravitreal arms with an 
NI margin of 4.5 letters. This NI margin will be used as a reference to assist data 
interpretation in this preliminary assessment.
To support the interpretation of BCVA change from baseline over time, figures for 
the adjusted mean change from baseline over time through Month 10 will be 
provided.

Trimmed mean analysis for change in BCVA score from baseline averaged over 
Month 9 and Month 10:
A trimmed mean analysis (Permutt and Li 2016) will be performed using an analysis 
of covariance (ANCOVA model) for adjustment for covariates.  The dependent 
variable in the ANCOVA model is the average of Month 9 and Month 10 


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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 (65 letters vs. 66 letters) and 
number of anti-VEGF-intravitreal injections (3 vs. 4).
Patients will be considered to have the worst outcomes and will be trimmed from 
analysis if any of the following occurs:
–
Patients in the PDS arm receive a rescue treatment (intravitreal injection) or 
undergo explantation prior to Month 9
–
Patients in all treatment arms discontinue study treatment due to LCE or AE 
prior to Month 9
–
Patients in all treatment arms have a missing Month 9 assessment and 
discontinue study treatment due to LCE or AE at Month 9
–
Patients in all treatment arms have missing Month 9 and Month 10 
assessments and discontinue study treatment due to LCE or AE at Month 10
Such patients will be referred to as "must be trimmed patients."  For the remaining
patients, if they have Month 9 and/or Month 10 BCVA assessments, they will be 
considered "completers"; if they have missing Month 9 and Month 10 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% 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 algorithm can be stated in the following four steps:
1.
Remove patients whose missing 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 (i.e., a pre-specified fraction for fixed trimming) 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 Month 9 and Month 10, X is the matrix for the covariates—
baseline BCVA score (continuous) and the baseline BCVA score (65 letters vs. 
66 letters) and number of anti-VEGF-intravitreal injections (3 vs.4), 
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 be trimmed” patients will always be ranked the lowest 
(regardless of whether their adjusted values are available) and trimmed from 


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the analyses. The best (1-trimming fraction)*100% in each group will be used 
for the analysis specified in Step 3.
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 on each permuted data to construct a reference 
distribution for confidence interval estimation for the difference in trimmed mean.
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.
The percentage of patients to be trimmed will be based on an evaluation of 
percentage of patients meeting the trimming criteria by Month 9 rounded up to 
the nearest 5% to avoid many permutation tests from reverting to an adaptive 
approach.  The analysis will be used to assess the difference in BCVA between 
two treatments excluding the true or assumed worst outcomes.  Sensitivity 
analyses with different choices of trimming percentage may also be conducted.

Change from baseline in BCVA score through Month 10 analyzed with an ANCOVA 
model:  
The ANCOVA model will include the categorical covariates of treatment group,
baseline BCVA score (continuous), and the randomization stratification factors as 
fixed effects.  Separate models will be fit for each pairwise comparison and each 
study visit.  Missing BCVA data, prior to or at Month 10 for each patient, will be 
imputed using the LOCF approach.
BCVA assessments will be censored after the time of rescue intravitreal anti-VEGF 
injection in the study eye and after the time of explant.  These assessments after 
initiation of rescue treatment will be imputed using the LOCF approach.

Descriptive summaries and figures will be provided for change from baseline in 
BCVA over time through Month 10 for patients treated after IFU Version 10.  
Observed data will be used.  BCVA assessments will be censored after the time of 
rescue intravitreal anti-VEGF injection in the study eye and after the time of explant.
In addition, a descriptive summary for change from baseline in BCVA over time through 
the end of the study will be provided. This summary will include all observed data
without censoring observations after use of rescue treatment or after explant.
Proportion of Patients Who Lose <15 Letters in BCVA score from Baseline
For proportion of patients who lose 15 letters in BCVA score from baseline to the 
average over Month 9 and Month 10, the proportion of patients in each treatment group 
and the overall difference in proportions between treatment groups will be estimated 
using the weighted average of the observed proportions and the differences in observed 
proportions over the strata defined by randomization factors using the 
Cochran-Mantel-Haenszel weights (Cochran 1954; Mantel and Haenszel 1959).  
Confidence intervals of the proportion of patients in each treatment group and the 


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overall difference in proportions between treatment groups will be calculated using the 
normal approximation to the weighted proportions (Mehrotra and Railkar 2000).  Data 
for patients who receive rescue treatment or undergo explantation prior to Month 9 will 
be censored for binary endpoints.  For all other patients, the analysis will be based on 
the available data at each visit, with no imputation for missing data.
In addition, figures for proportion of patients who lose 15 letters in BCVA score from 
baseline over time will be provided.
Additional Efficacy Analyses Focused on BCVA Parameters

The mean average change from baseline through Month 9 (AUC-like endpoint) in 
BCVA and 95% CIs will be generated for each treatment arm.

Summary statistics and figures by treatment arm showing the proportion of patients 
losing 15 letters, 10 letters, 5 letters, and 0 letters over time through Month 10 
will be provided.

Change from baseline in BCVA over time through Month 10 measured under low 
luminance conditions will be summarized by treatment arm using descriptive 
statistics.
Data for patients who receive rescue treatment or undergo explantation prior to Month 9 
will be censored. Missing data will not be imputed.
4.4.2.2
Anatomical Outcomes
The change in CFT (with and without inclusion of pigment epithelium thickness and its 
elevation in the foveal center, as assessed by the Reading Center) from baseline at 
Month 9 will be compared between each PDS arm and the intravitreal arm using the 
same analysis method (MMRM) and data handling rules that are used for the change 
from baseline in BCVA score at the average of Month 9 and Month 10. Comparisons
between the Implant arms and the intravitreal arm will be made using a contrast at 
Month 9.  Figures for adjusted mean change from baseline in CFT over time through 
Month 9 will be provided. Descriptive summaries for change from baseline in CFT 
through Month 9 will also be provided. Data for patients who receive rescue treatment 
or undergo explantation prior to Month 9 will be censored.
In addition, a descriptive summary for change from baseline in CFT over time through 
the end of the study will be provided. This summary will include all observed data 
without censoring observations after use of rescue treatment or after explant.
Changes from screening in total lesion area, area of CNV lesion, and CNV leakage over 
time through Month 9, as assessed by fluorescein angiography, as well as changes in 
CNV perfusion over time through Month 9, as assessed by OCT angiography will be 
summarized using descriptive statistics. Data for patients who receive rescue treatment 
or undergo explantation prior to Month 9 will be censored. Missing data will not be 
imputed.


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4.4.2.3
Patient-Reported Outcomes (MacTSQ)
The MacTSQ was developed to provide a means of evaluating satisfaction with 
therapies for macular disease.  The MacTSQ provides 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 descriptive statistics based on the observed data.  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 items in the subscale is missing.

Subscale 2 (impact of treatment score): Set the subscale 2 value to missing if two 
or more 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 
items are missing. If three or less items are missing, impute the missing item values 
based on the average of the other available items.
Data for patients who receive rescue treatment or undergo explantation prior to Month 9 
will be censored. 
4.4.2.4
Other Exploratory Efficacy Endpoints 
Other exploratory efficacy endpoints listed in Section 2.2.5 will be summarized using 
descriptive statistics.  Observed data will be used.
4.5
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
Analyses were performed using a PK-PD model, and this model was used to run clinical 
trial simulations to inform Phase III clinical study design
(RPDS EOP2 PMP, February 2018).
Individual and mean serum ranibizumab concentrations over time will be tabulated and 
plotted by refill number.  The serum PK of ranibizumab will be characterized by 
estimating the AUC, Cmax, tmax, t1/2, and Ctrough between dose intervals.  Estimates for 
these parameters will be tabulated and summarized by descriptive statistics.  Additional 
PK analyses may be conducted as appropriate.
4.6
SAFETY ANALYSES
The safety analyses will use the safety population as described in Section 4.1 and 4.1.2. 
Missing data will not be imputed.
Adverse events (AEs) are coded using the current MedDRA version.  Rates will be 
provided for intravitreal patients and PDS patients by dose arm and pooled across PDS 
arms.


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For safety analyses, unless otherwise specified, AEs after the start of study treatment 
(intravitreal injection or Implant) will be included in the analyses; AEs from patients who 
are explanted will be included up to a follow-up period of 90 days after explant; the 
post-explant ocular AEs considered related to PDS will also be included in the analyses 
regardless of the timing of the AE onset.  To fully characterize these patients’ safety, a 
listing will be provided for ocular AEs that occurred 90 days after explant.
Frequency tables including patient incidence rates will be provided for the following:

Ocular AEs and SAEs (study and fellow eye) 

Non-ocular AEs and SAEs (study and fellow eye)

Adverse events of special interest (study and fellow eye)
–
AEs resulting from medication errors
–
An AE considered to be sight threatening
–
Suspected transmission of an infectious agent by the study drug
–
AEs resulting from use error or from intentional misuse of the PDS
–
ADEs, that is, AEs that are considered to be related to the PDS and to the use 
of the PDS

Adverse events potentially related to the PDS Implant or Implant procedures:
–
Vitreous hemorrhage
–
Endophthalmitis
–
Retinal detachment
–
Conjunctival retraction
–
Conjunctival erosion
–
Conjunctival bleb
–
Conjunctival filtering bleb leak
–
Hyphema
–
Cataract
For AEs potentially related to the PDS Implant or Implant procedures in the study eye, 
incidence tables will be generated using the following time windows relative to first dose 
or implant surgery: 

1 month (up to the end of Month 1 visit window, 37 days) 

1 month

during the entire study
In addition, ocular AEs and SAEs will be provided by causality as determined by the 
investigator.


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Adverse events (AEs) potentially related to the PDS Implant or Implant procedures will 
be summarized separately for two subgroups of patients based on the IFU version in use 
at the time of their randomization (before IFU 10 vs. IFU 10 forward).  There was a study 
pause to evaluate post-implantation vitreous hemorrhage and modifications were made 
beginning with Version 10 with the aim to reduce the risk of vitreous hemorrhages.
Non-ocular AEs and SAEs will be tabulated using the following time windows relative to 
first ranibizumab injection or device implant following randomization:

Cumulative rates through 10-month follow-up for each patient

Cumulative rates for through the end of the study (expected Month 38)
A listing of patients who died during the study will be provided.
The number and percentage of patients with positive serum anti-drug antibodies (ADA)
at baseline and post-baseline during the study period will be tabulated. Impact of 
positive serum ADA on efficacy and safety will be explored. A listing of patients with 
positive serum antibodies to ranibizumab will be provided.
4.6.1
Exposure of Study Medication
Patient exposure to ranibizumab will be summarized in the intravitreal arm and the PDS 
arms for the study eye.
4.6.2
Laboratory Data
Laboratory data will be collected at baseline only (see Section 4.3). This data can be 
used for interpretation of some adverse events, no general summary is planned.
4.6.3
Vital Signs
Summary statistics for worst change from baseline in vital signs will be tabulated.  If an
imbalance between treatment arms is observed, the summaries of the corresponding 
vital signs over the course of the study will be provided.
4.6.4
Ocular Assessments
Results of the following ocular assessments will be summarized by timepoint and by eye 
(study vs. fellow), as applicable, using descriptive summaries:  intra-ocular pressure, 
fluorescein angiography, and fundus photography.  Changes from baseline for selected 
ocular assessments will be tabulated.  The presence of intra-ocular inflammation and 
vitreous hemorrhage, as determined from the slit-lamp examination, will be tabulated by 
grade (according to grading scales for flare/cells and vitreous hemorrhage density in the 
appendix of the study protocol).  The presence of retinal break or detachment as 
determined from ophthalmoscopy will be tabulated.
4.7
MISSING DATA
Refer to the relevant sections above for further details.


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4.8
INTERIM ANALYSES
Given the exploratory nature of this study, the Sponsor decided to conduct two interim
efficacy analyses per allowance of the protocol:  the first interim was performed after ~50% 
of patients completed the 6-month follow-up in October 2017 and the second interim was 
performed after ~70% of patients completed the 9-month follow-up in April 2018. The 
decision to conduct an optional interim analysis and the timing of the analysis was
documented in the IMC Agreement prior to the conduct of the interim analysis.
The interim efficacy analyses were performed by members of the Sponsor’s unmasked 
study team and were interpreted by the unmasked IMC and senior management 
personnel from the Sponsor. The details of the timing and scope of the interim analyses
and the communication of the interim results were specified in the IMC Agreement, data 
analysis plan, and a statistical note to file (in the Sponsor’s trial master file).


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5.
REFERENCES
Bressler NM, Doan QV, Varma R, et al. Estimated cases of legal blindness and visual 
impairment avoided using ranibizumab for choroidal neovascularization: 
non-Hispanic white population in the United States with age-related macular 
degeneration. Arch Ophthalmol 2011;129:70917.
Cochran WG. Some methods for strengthening the common X2 tests. Biometrics 1954; 
10:417-451.
Lalwani GA, Rosenfeld PJ, Fung AE, et al.  A variable-dosing regimen with intravitreal 
ranibizumab for neovascular age-related macular degeneration: year 2 of the 
PrONTO Study. Am J Ophthalmol 2009;148:4358.
Mantel N and Haenszel W. Statistcial aspects of the analysis of data from retrospective 
studies of disease. Journal of the National Cancer Institute 1959; 22(4):719-48.
Mehrotra DV and Railkar R. Minimum risk weights for comparing treatments in stratified 
binomial trials. Statistics in Medicine 2000; 19, 811-825.
Rudnicka AR, Jarrar Z, Wormald R, et al. Age and gender variations in age-related 
macular degeneration prevalence in populations of European ancestry: a 
meta-analysis. Ophthalmology 2012;119:57180.
Permutt T, Li F. Trimmed means for symptom trials with dropouts. Pharm Stat 2017; 
16(1):20-28.
Pre-meeting Package (RO4893594)Type B (End of Phase II) MeetingRanibizumab 
port delivery system (implant, ancillary devices, and ranibizumab). February 2018.


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Appendix 1
Protocol Synopsis
PROTOCOL SYNOPSIS
TITLE:
A PHASE II, MULTICENTER, RANDOMIZED, ACTIVE 
TREATMENTCONTROLLED STUDY OF THE EFFICACY AND 
SAFETY OF THE RANIBIZUMAB PORT DELIVERY SYSTEM FOR 
SUSTAINED DELIVERY OF RANIBIZUMAB IN PATIENTS WITH 
SUBFOVEAL NEOVASCULAR AGE-RELATED MACULAR 
DEGENERATION
PROTOCOL NUMBER:
GX28228
VERSION NUMBER:
8
EUDRACT NUMBER:
Not applicable
IND NUMBER:
113,552
TEST PRODUCT:
Ranibizumab Port Delivery System for Sustained Delivery of 
Ranibizumab (RO4893594)
PHASE:
II
INDICATION:
Subfoveal neovascular age-related macular degeneration
SPONSOR:
Genentech, Inc.
Objectives
Efficacy Objectives
The primary efficacy objective for this study is as follows:

To evaluate the relative efficacy of 10-mg/mL, 40-mg/mL, and 100-mg/mL formulations of 
ranibizumab, delivered via the Implant, as measured by the time a patient first requires
Implant refill according to protocol-defined refill criteria
The secondary efficacy objectives for this study are as follows:

To evaluate and compare the relative efficacy of 10-mg/mL, 40-mg/mL, and 100-mg/mL 
formulations of ranibizumab, delivered via the Implant, to that of 10-mg/mL (0.5-mg dose) 
monthly ITV ranibizumab injections, as measured by the change in BCVA from baseline at 
Month 9

To evaluate the efficacy of 10-mg/mL, 40-mg/mL, and 100-mg/mL formulations of 
ranibizumab, delivered via the Implant, with that of 10-mg/mL (0.5-mg dose) monthly ITV 
ranibizumab injections over time, as measured by the change in BCVA from baseline over 
time

To evaluate the efficacy of 10-mg/mL, 40-mg/mL, and 100-mg/mL formulations of 
ranibizumab, delivered via the Implant, with that of 10-mg/mL (0.5-mg dose) monthly ITV 
ranibizumab injections over time, as measured by the change in central foveal thickness 
(CFT, defined as the retinal thickness in the center of the fovea) from baseline over time


Appendix 1
Protocol Synopsis (cont.)
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
To evaluate the functionality of the Implant by assessing that there is no evidence of 
Implant clogging in more than 10% of patients in the Implant arms at Month 9.
Safety Objectives
The safety objectives for this study are as follows:

To evaluate the safety of ranibizumab delivered via the Implant, compared with that of 
monthly ITV injection, as measured by ocular and non-ocular adverse events and serious 
adverse events

To evaluate the safety of the Ranibizumab Port Delivery System (RPDS), as measured by 
“Prespecified RPDS-associated adverse events”

To evaluate the proportion of patients with positive serum antibodies to ranibizumab
Pharmacokinetic Objectives
The pharmacokinetic (PK) objectives for this study are as follows:

To characterize the serum pharmacokinetics of ranibizumab in patients after the initial fill 
and subsequent refills in the Implant treatment arms
Exploratory Objectives
The exploratory objectives for this study are as follows:

To evaluate the development of macular atrophy in all three Implant treatment arms relative 
to one another and to the monthly ITV arm

To examine the impact of ranibizumab treatment on patient-reported treatment satisfaction 
as assessed by the Macular Degeneration Treatment Satisfaction Questionnaire (MacTSQ) 
at Months 1, 6, 9, and the final or early termination visit for patients who speak English or 
Spanish

To explore time to subsequent Implant refills according to protocol-defined refill criteria

To describe the number of times patients meet protocol-specified refill criteria

To evaluate the proportion of patients in each Implant arm who first meet the protocol-
defined refill criteria prior to and at Months 4, 5, and 6

To evaluate the proportion of patients with an improvement of 15 letters in BCVA from 
baseline 

To evaluate the proportion of patients with a loss of 15 letters in BCVA from baseline over 
time

To explore the utility of BCVA measured under low luminance as a predictor of treatment 
benefit over time

To evaluate the changes in total lesion area, area of CNV lesion, and CNV leakage over 
time, as assessed by fluorescein angiography

To explore the serum ranibizumab concentration data with a PK model in an attempt to infer 
the concentrationtime pattern in the vitreous or aqueous humor and, if possible, derive 
information on the rate of ranibizumab release from the Implant

To characterize ranibizumab aqueous humor concentration over time (optional)

To characterize ranibizumab vitreous or aqueous humor concentration after Implant 
explantation (if applicable)

To evaluate the potential association of circulating biomarkers with disease characteristics 
and response to ranibizumab (optional)

To evaluate the relationship of 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 (optional)

To evaluate the potential association of vitreous or aqueous humor biomarkers with disease 
characteristics and/or response to ranibizumab 

To evaluate the proportion of patients meeting lack of clinical efficacy criteria


Appendix 1
Protocol Synopsis (cont.)
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
To evaluate the proportion of patients requiring explantation

To evaluate the changes in CNV perfusion over time as assessed by OCT Angiography (at 
selected sites that have OCT angiography equipment)
Study Design
Description of Study
Study GX28228 is a Phase II, multicenter, dose-ranging, randomized, active treatment (monthly 
ITV injection)-controlled study to evaluate the efficacy, safety, and pharmacokinetics of 
ranibizumab delivered through the Implant using three ranibizumab formulation arms (10 mg/mL, 
40 mg/mL, and 100 mg/mL) compared with the control arm (0.5-mg monthly ITV injections of 
10-mg/mL formulation) in patients with subfoveal neovascular age-related macular degeneration 
(nAMD).  The study will also evaluate the safety of the RPDS combination product.  The study 
will include pre-screening, screening, and randomization visits followed by a treatment period. 
Treatment and safety assessment schedules are set.
Number of Patients
Approximately 220 patients at up to 60 sites in the United States will be randomized in a 
3:3:3:2 ratio to four treatment arms (60 per each of three Implant treatment arms and 40 to the
ITV injection arm) within an approximate 24-month period of time.
Target Population
Patients with subfoveal neovascularization secondary to age-related macular degeneration 
(AMD) diagnosed within 9 months and treated with ITV anti-VEGF agents will be enrolled in 
the study.
Inclusion Criteria
Patients must meet the following criteria for study entry:
General Inclusion Criteria

Age 50 years

Willingness and ability to provide signed informed consent and Health Insurance Portability 
and Accountability Act (HIPPA) authorization

Willingness and ability to undertake all scheduled visits and assessments

For sexually active women of childbearing potential, agreement to the use of an appropriate 
form of contraception (or abstinence) for the duration of the study.  A woman is considered 
not to be of childbearing potential if she is postmenopausal or has undergone hysterectomy 
and/or bilateral oophorectomy.  
For women who are not postmenopausal (12 months of non-therapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus):  agreement to 
remain abstinent or use single or combined contraceptive methods that result in a 
failure rate of 1% per year during the treatment period and for at least 30 days after 
the last dose of study treatment
Abstinence is only acceptable if it is in line with 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.

Sexually active men are recommended to use a barrier contraceptive method (condom), 
even if they have been surgically sterilized, for the duration of the treatment period and for 
at least 30 days after the last dose of study treatment.


Appendix 1
Protocol Synopsis (cont.)
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Ocular Inclusion Criteria (Study Eye)

Newly diagnosed with nAMD within 9 months prior to screening visit

Patient must have received at least 2 prior anti-VEGF injections (including ranibizumab, 
bevacizumab, or aflibercept).  However, the most recent anti-VEGF injection must have 
been ranibizumab and must have occurred at least 7 days prior to the screening visit.

Demonstrated response to prior ITV anti-VEGF treatment, as evidenced by the following:
Decrease in CFT of 50 m since commencing ITV anti-VEGF treatment
OR
Stable or improved BCVA since commencing ITV anti-VEGF treatment

BCVA using ETDRS charts of 20/20-20/200 Snellen equivalent 

All subtypes of nAMD choroidal neovascularization (CNV) lesions are permissible 
(i.e., classic CNV, occult CNV, or with some classic CNV component, or retinal 
angiomatous proliferation lesions). 
Active primary CNV lesions at the time of diagnosis of nAMD must be subfoveal or 
juxtafoveal with a subfoveal component related to the CNV activity (such as subretinal 
hemorrhage, subretinal fluid, or retinal pigment epithelium [RPE] detachment)
Ocular Inclusion Criteria for Pre-Screening (Study Eye) (If Applicable)

Treatment naïve nAMD patients

BCVA using ETDRS charts of 20/20 to 20/200 Snellen equivalent

All subtypes of nAMD choroidal neovascularization (CNV) lesions are permissible 
(i.e., classic CNV, occult CNV, or with some classic CNV component, or retinal 
angiomatous proliferation lesions). 
Active primary CNV lesions must be subfoveal or juxtafoveal with a subfoveal 
component related to the CNV activity (such as subretinal hemorrhage, subretinal fluid, 
or RPE detachment)
Ocular Inclusion Criteria for Run-In (Study Eye) (If Applicable)

Previous treatment with a single anti-VEGF ITV injection or no more than eight anti-VEGF 
ITV injections, with aflibercept or bevacizumab being the most recent injection 

BCVA using ETDRS charts of 20/20 to 20/200 Snellen equivalent

All subtypes of nAMD CNV lesions are permissible (i.e., classic CNV, occult CNV, or with 
some classic CNV component or retinal angiomatous proliferation lesions) 
Active primary CNV lesions at the time of diagnosis of nAMD must be subfoveal or 
juxtafoveal with a subfoveal component related to the CNV activity (such as subretinal 
hemorrhage, subretinal fluid, or RPE detachment)
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
Prior Ocular Treatment

Treatment with ITV anti-VEGF agents other than ranibizumab within 1 month prior to the 
randomization visit in either eye

History of vitrectomy surgery, submacular surgery, or other surgical intervention for AMD in 
the study eye

Prior treatment with Visudyne®, external-beam radiation therapy, or transpupillary 
thermotherapy in the study eye

Previous treatment with ITV corticosteroid injection or device implantation in the study eye

Previous focal laser photocoagulation used for AMD treatment in the study eye


Appendix 1
Protocol Synopsis (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
29/Statistical Analysis Plan GX28228

Prior participation in a clinical trial involving anti-angiogenic drugs, other than ranibizumab, 
in either eye within 2 months prior to the randomization visit

Treatment with Visudyne® in the fellow eye 7 days preceding screening visit
CNV Lesion Characteristics

Subretinal hemorrhage in the study eye that involves the center of the fovea, if the size of 
the hemorrhage is either 50% of the total area of the lesion or 1 disc area (2.54 mm2) in 
size at screening

Subfoveal fibrosis or atrophy in the study eye

CNV in either eye due to other causes, such as ocular histoplasmosis, trauma, or 
pathologic myopia
Concurrent Ocular Conditions

BCVA using ETDRS charts lower than 20/200 Snellen equivalent in the fellow eye

Retinal pigment epithelial tear involving the macula in the study eye

Any concurrent intraocular condition in the study eye (e.g., cataract, glaucoma, or diabetic 
retinopathy) that, in the opinion of the investigator, 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) in the study eye

History of vitreous hemorrhage in the study eye within 3 months prior to the randomization 
visit

History of rhegmatogenous retinal detachment or macular hole (Stage 3 or 4) in the study 
eye

History of idiopathic or autoimmune-associated uveitis in either eye

Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye

Aphakia or absence of the posterior capsule in the study eye
Previous violation of the posterior capsule break in the study eye is also excluded 
unless it occurred as a result of yttrium aluminium garnet laser posterior capsulotomy 
in association with prior, posterior chamber intraocular lens implantation.

Spherical equivalent of the refractive error in the study eye demonstrating more than 
8 diopters of myopia

For patients who have undergone prior refractive or cataract surgery in the study eye, the 
preoperative refractive error in the study eye does not exceed 8 diopters of myopia

Intraocular surgery (including cataract surgery) in the study eye within 3 months preceding 
the randomization visit

Uncontrolled ocular hypertension or glaucoma in the study eye (defined as intraocular 
pressure [IOP] 25 mmHg or a Cup to Disc ratio 0.8, despite treatment with anti-
glaucoma medication) and any such condition for which the investigator feels may require a 
glaucoma filtering surgery while in the study

History of glaucoma-filtering surgery in the study eye, tube shunts, or microinvasive 
glaucoma surgery in the study eye

History of corneal transplant in the study eye
Concurrent Systemic Conditions

Uncontrolled blood pressure (defined as systolic 155 mmHg and/or diastolic 95 mmHg, 
based on the average of 3 readings taken with the patient in a resting state [i.e., supine or
sitting, but consistent across readings] over a period of up to 15 minutes at screening)


Appendix 1
Protocol Synopsis (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
30/Statistical Analysis Plan GX28228
If the average of 3 readings exceeds these values, patient’s blood pressure must to be 
controlled by antihypertensive medication.  The patient can become eligible for 
rescreening if medication is taken continuously for at least 30 days prior to the 
randomization visit.

Uncontrolled atrial fibrillation within 3 months of informed consent

History of stroke within the last 3 months prior to informed consent

History of myocardial infarction within the last 3 months prior to informed consent

History of other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of ranibizumab or placement of the Implant, that might affect interpretation of the 
results of the study or renders the patient at high risk of treatment complications

Current treatment for any active systemic infection

Use of any systemic anti-VEGF agents

Use of oral corticosteroids (prednisone 10mg/day or equivalent)

Use of anticoagulants, antiplatelets (other than aspirin), or medications known to exert 
similar effects at the time of study entry for a pre-existing condition.  Oral anticoagulants
include vitamin K antagonists (e.g. warfarin), direct factor Xa inhibitors (e.g., rivaroxaban, 
apixaban, edoxaban, fondaparinux) and direct thrombin inhibitors (e.g., dabigatran). 
Antiplatelet therapies include clopidogrel, prasugrel, dipyridamole, ticagrelor and ticlodipine.

Bleeding disorders, including platelet disorders, acquired or hereditary coagulations 
disorders, and acquired or hereditary vascular disorders.

Active malignancy 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.

History of allergy to fluorescein, not amenable to treatment

Inability to obtain fundus photographs, fluorescein angiograms, fundus autofluorescence, or 
spectral domain optical coherence tomography (SD-OCT) images of sufficient quality to be 
analyzed and graded by the central reading center 

Inability to comply with study or follow-up procedures

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 

Intolerance or hypersensitivity to topical anesthetics, mydriatic medications, any of the 
excipients in ranibizumab, fluorescein, or components of the Implant

Requirement for continuous use of any medications or treatments indicated in the 
“Prohibited Therapy” section.

Women who are pregnant or lactating or intending to become pregnant during the study

Women who are of childbearing potential, including those who have had tubal ligation, must 
have a negative serum pregnancy test result within 21 days prior to Day 1.  A woman is 
considered not to be of childbearing potential if she is postmenopausal or has undergone 
hysterectomy and/or bilateral oophorectomy.

No additional exclusions may be applied by the investigator, in order to ensure that the 
study population will be representative of all eligible patients
Length of Study
The estimated study duration is 38 months.


Appendix 1
Protocol Synopsis (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
31/Statistical Analysis Plan GX28228
Patients randomized to the Implant treatment arms will have the Implant (pre-filled with 
ranibizumab) surgically inserted in the study eye at their Day 1 visit, after which they will be 
evaluated monthly for the need for an Implant refill, based upon protocol-specified refill criteria, 
until the Sponsor decides, based on the primary analysis results, to either terminate the study 
and discontinue study treatment, or offer patients entry into the RPDS Extension Study.  The 
duration of their participation in the study is expected to last approximately 1338 months
dependent on the date of their randomization to the study.
Patients randomized to the ITV injection treatment arm (control) will be treated monthly with ITV 
injections of ranibizumab until the Sponsor decides, based on the primary analysis results, to 
either terminate the study and discontinue study treatment, or offer patients entry into the 
RPDS Extension Study.  The duration of their participation in the study is expected to last 
approximately 1338 months dependent on the date of their randomization to the study.  
End of Study
The end of the study is defined as the date when the last patient, last study visit occurs.
Outcome Measures
Efficacy Outcome Measures
The primary efficacy outcome measure for this study is the time until a patient first requires the 
Implant refill according to protocol-defined refill criteria.
The secondary efficacy outcome measures for this study are as follows:

Change in BCVA from baseline at Month 9

Average change in BCVA from baseline over time

Change in BCVA from baseline over time

Change in CFT over time, as assessed on SD-OCT by the Central Reading Center

Occurrence of implant clogging
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence of adverse events of Special Interest:  Adverse events associated with 
ranibizumab, the Implant, implant-associated procedures, and/or ancillary devices

Incidence of “Prespecified RPDS-associated adverse events” 

Incidence of ocular and non-ocular adverse events and serious adverse events

Incidence of positive serum antibodies to ranibizumab
Pharmacokinetic Outcome Measures
The PK outcome measures related to ranibizumab serum concentration-time data following the 
Implant insertion and refills are as follows:

Observed maximum serum concentrations (Cmax) and selected post dose serum 
concentrations after Implant insertion and all subsequent refills 

Additional estimated PK parameter values including AUC, tmax, and t1/2 after Implant 
insertion and all subsequent refills

Observed serum concentrations (Ct) over time from monthly serum sampling when no refills 
are administered

Observed trough serum concentrations (Ctrough) prior to refills
In addition, optional anterior chamber (aqueous humor) will be collected to assess ocular drug 
concentration.
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:


Appendix 1
Protocol Synopsis (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
32/Statistical Analysis Plan GX28228

Treatment emergent macular atrophy in all treatment arms

The MacTSQ score at randomization and at Months 1, 6, 9, and the final or early 
termination visit for patients who speak English or Spanish

Time to subsequent Implant refills according to protocol-defined refill criteria

Number of times a patient meets protocol-specified refill criteria

Proportion of patients in each Implant arm who first meet the protocol-defined refill criteria 
prior to and at Months 4, 5,and 6

Proportion of patients with an improvement of BCVA from baseline of 15 letters over time

Proportion of patients losing 15 letters in BCVA from baseline over time

Change in BCVA from baseline over time measured under low luminance conditions

Changes from screening in total lesion area, area of CNV lesion, and CNV leakage over 
time, as assessed by fluorescein angiography  

Proportion of patients meeting lack of clinical efficacy criteria 

Proportion of patients requiring explantation

Changes in CNV perfusion over time, as assessed by OCT Angiography
In addition, vitreous samples from the Refill Needle (if applicable), optional aqueous humor 
samples, and optional serum and plasma samples may be collected to assess the relationship 
between biomarkers and the disease characteristics and/or response to treatment with 
ranibizumab.  Optional whole blood samples will be collected for DNA extraction (genetic 
analysis) to assess the relationship between genetic variants and the disease characteristics 
and/or response to treatment with ranibizumab.
In addition, vitreous or aqueous humor samples before Implant explantation, and optional 
aqueous humor samples prior to or immediately following one or more refills and at the Day 7 
safety visit post refill will be collected to characterize ranibizumab vitreous and aqueous humor
concentration.
Investigational Medicinal Products
Test Product (Investigational Drug)
The Implant initially filled and then refilled as per protocol specified refill criteria, with either 
10-mg/mL, 40-mg/mL, or 100-mg/mL ranibizumab formulations.
Non-Investigational Medicinal Products
Comparator
Ranibizumab 0.5-mg monthly intravitreal (ITV) injections of 10-mg/mL formulation 
Statistical Methods
Detailed specifications of the statistical methods will be described in the statistical analysis plan 
(SAP).
Primary Analysis
The primary endpoint for this analysis will be time to first meeting refill criteria.  The primary 
analyses will be based on data as of 9 months after last patient’s entry into the study.  For 
patients without any refills prior to or on the cut-off date of 9 months after LPI, the time of refill 
will be censored. The censoring date will be defined as the date of a patient’s last visit before 
the cut-off date of 9 months after LPI, or the date when the patient discontinues from the study, 
whichever occurs first.
The primary analysis population for efficacy is the modified intent-to-treat population defined as 
all randomized patients who were randomly assigned to study treatment receive study 
treatment.  Patients will be summarized by treatment arm and analyzed according to the 
treatment actually received and not according to the treatment they were randomized to receive, 
in the event of a discrepancy.  


Appendix 1
Protocol Synopsis (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
33/Statistical Analysis Plan GX28228
To support the dose level selection among the Implant groups, the primary analysis for TTFR 
will include the following pair-wise group comparisons, each with a stratified log-rank test at a 
one-sided significance level of 15%.  The stratification factors to be included are baseline BCVA 
score (65 letters vs. 66 letters) and number of anti-VEGF ITV injections (3 vs. 4).

Implant with 100 mg/mL versus Implant with 10 mg/mL

Implant with 100 mg/mL versus Implant with 40 mg/mL

Implant with 40 mg/mL versus Implant with 10 mg/mL
In addition, the HR for each pair-wise comparison of the treatment arms will be estimated using 
a Cox proportional hazards regression model stratified by baseline BCVA score (65 letters vs.
66 letters) and number of prior anti-VEGF ITV injections (3 vs. 4) with main effects for 
treatment.  Estimated HRs for each pair-wise comparison will be presented with the 
corresponding 80% CIs.  
KaplanMeier plots will be provided showing TTFR by implant group.  Median time to first 
meeting refill criteria will be calculated for each treatment arm with the Kaplan Meier method, 
and the corresponding 80% confidence intervals will also be reported.

Moreover, for each treatment group, percentage of patients not meeting the protocol-
defined first refill criteria by Months 4, 5, 6, 7, 8, and 9, derived from Kaplan-Meier 
estimates will be provided.
Determination of Sample Size
This study is exploratory in nature and designed to estimate the time to first refill (TTFR) for 
each of the RPDS treatment arms (10 mg/mL, 40 mg/mL, and 100 mg/mL) enrolling 60 patients 
in each of the RPDS treatment arms.  The sample size of approximately 220 randomized 
patients will be adequate to evaluate the primary objective of the study.  PK/PD modeling and 
simulation was performed to inform key assumptions used in sample size calculation.  Given the 
simulation results, the HR for comparing the 100-mg/mL arm with the 10-mg/mL arm was 
estimated to be 0.66 for TTFR.  Assuming this HR, a total of at least 125 events from all three 
Implant groups is expected at the primary analysis time (approximately 85 events in the 
10-mg/mL group and a higher dose group).  With 85 events, this study will have approximately 
80% power to detect an HR0.66 between the two Implant arms using a log-rank test at a 
one-sided significance level of 15%.  No multiplicity adjustment is planned for this Phase II 
study.
Forty patients in the ITV arm are considered sufficient to compare each device arm versus the 
ITV arm in change in BCVA from baseline through Month 9 (assuming an estimated 
SD10 letters, a two-sided 80% CI will extend approximately 2.62 letters from the observed 
mean).


Ranibizumab Port Delivery System—Genentech, Inc.
34/Statistical Analysis Plan GX28228
Appendix 2
Schedule of Assessments
Schedule of Assessments for Implant Arms:  Screening, Randomization, Day 1, Month 1 through Month 9, Month X, 
Safety Visits, and Final/Early Termination Visits
Assessment
Screen a
7 days 
after 
RBZ tx
Rand b
28 and 
37 
days 
after 
RBZ tx
Day
Month
Month X 
Visit d
Safety 
Visit c
Final/
ETe
1 b
2 c
7 c
14 c
1
2
3
4
5
6
7
8
9
Window (Days)
0
2
2
7
7
7
7
7
7
7
7
7
7
See 
footnote c
See 
footnote e
Written informed 
consent
x
Review of 
inclusion and 
exclusion criteria
x
x
Medical and 
surgical history, 
tobacco and 
alcohol use
x
Demographic 
Information
x
Physical 
Examination 
x
x
x
MacTSQ f
x
x
x
x
x


Appendix 2
Schedule of Assessments (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
35/Statistical Analysis Plan GX28228
Assessment
Screen a
7 days 
after 
RBZ tx
Rand b
28 and 
37 
days 
after 
RBZ tx
Day
Month
Month X 
Visit d
Safety 
Visit c
Final/
ETe
1 b
2 c
7 c
14 c
1
2
3
4
5
6
7
8
9
Window (Days)
0
2
2
7
7
7
7
7
7
7
7
7
7
See 
footnote c
See 
footnote e
Site to contact 
IxRS (as 
applicable) g
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital signs h
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Central laboratory 
samples 
(hematology, 
coagulation, 
serum chemistry, 
and urinalysis) i
x
Serum pregnancy 
sample j
x
If urine pregnancy test is positive, collect serum pregnancy 
sample and do not perform study treatment until the final 
results are available.
x
Urine pregnancy 
test k
xl
If a patient meets criteria for Implant refill, collect urine 
pregnancy test prior to the refill. If urine pregnancy test is 
positive, collect serum pregnancy sample and do not 
perform study treatment until the final results are available.
Serum PK sample 
for ranibizumab 
concentration 
xm


Appendix 2
Schedule of Assessments (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
36/Statistical Analysis Plan GX28228
Assessment
Screen a
7 days 
after 
RBZ tx
Rand b
28 and 
37 
days 
after 
RBZ tx
Day
Month
Month X 
Visit d
Safety 
Visit c
Final/
ETe
1 b
2 c
7 c
14 c
1
2
3
4
5
6
7
8
9
Window (Days)
0
2
2
7
7
7
7
7
7
7
7
7
7
See 
footnote c
See 
footnote e
Serum PK sample 
for ranibizumab 
concentration 
PRIOR to 
treatment n
x
Collect serum PK sample for ranibizumab concentration at 
each monthly visit PRIOR to the treatment, even if treatment is 
not subsequently given.
x
Serum PK sample 
for ranibizumab 
concentration 
POST treatment o
xp
x
x
x
If Implant refill is performed, collect PK sample 1 to 2 days
after refill, and 7 days after refill
x
Serum anti-
ranibizumab 
antibody sample q
x
x
x
x
x
x
x
Optional whole 
blood for DNA 
(RCR Sample)
x
Optional serum 
sample for 
candidate 
biomarkers
x
x
x


Appendix 2
Schedule of Assessments (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
37/Statistical Analysis Plan GX28228
Assessment
Screen a
7 days 
after 
RBZ tx
Rand b
28 and 
37 
days 
after 
RBZ tx
Day
Month
Month X 
Visit d
Safety 
Visit c
Final/
ETe
1 b
2 c
7 c
14 c
1
2
3
4
5
6
7
8
9
Window (Days)
0
2
2
7
7
7
7
7
7
7
7
7
7
See 
footnote c
See 
footnote e
Optional plasma
(EDTA) sample 
for candidate 
biomarkers
x
x
x
Optional aqueous 
humor sample r
Obtain prior to or immediately following one or more refills and 
at the safety visit 7 days post refill
BCVA testing 
(starting at 4 m)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Low luminance 
BCVA testing s
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Visual Field 
testing 
(Humphrey 24-2)t
xu
x
x
Axial Length 
Measurement
(ultrasound or 
optical biometry)v
xu
Intraocular 
pressure (IOP) w
x
x
x x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Slit-lamp 
examination
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


Appendix 2
Schedule of Assessments (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
38/Statistical Analysis Plan GX28228
Assessment
Screen a
7 days 
after 
RBZ tx
Rand b
28 and 
37 
days 
after 
RBZ tx
Day
Month
Month X 
Visit d
Safety 
Visit c
Final/
ETe
1 b
2 c
7 c
14 c
1
2
3
4
5
6
7
8
9
Window (Days)
0
2
2
7
7
7
7
7
7
7
7
7
7
See 
footnote c
See 
footnote e
Dilated binocular 
indirect 
ophthalmoscopy y
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Historical OCT 
images 
collection z
x
SD-OCT w, aa
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Fundus 
photography w, aa
x
x
x
Fluorescein 
angiography w, aa
x
x
x
x
x
Fundus 
Autofluorescence
w, aa
x
x
x
x
OCT Angiography 
(at selected 
sites) ab
x
x
x
x
x
x
x
x
x
x
x
x
x
x


Appendix 2
Schedule of Assessments (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
39/Statistical Analysis Plan GX28228
Assessment
Screen a
7 days 
after 
RBZ tx
Rand b
28 and 
37 
days 
after 
RBZ tx
Day
Month
Month X 
Visit d
Safety 
Visit c
Final/
ETe
1 b
2 c
7 c
14 c
1
2
3
4
5
6
7
8
9
Window (Days)
0
2
2
7
7
7
7
7
7
7
7
7
7
See 
footnote c
See 
footnote e
External Photo -
study eye only 
(High 
magnification 
Implant and 
conjunctiva, 
scleral surface)
x
x
x
x
x
x
x
x
x
x
x
x
x
Lens Photo
(fundus reflex 
photo) 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Implant Photo -
study eye only 
(High 
magnification 
Implant in eye, 
through dilated 
pupil) ac
x
x
x
x
x
x
x
x
x
x
x
x
x
Pre-study 
treatment 
antimicrobials (as 
applicable) ad
x
x
x
x
x
x
x
x
x
x
x


Appendix 2
Schedule of Assessments (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
40/Statistical Analysis Plan GX28228
Assessment
Screen a
7 days 
after 
RBZ tx
Rand b
28 and 
37 
days 
after 
RBZ tx
Day
Month
Month X 
Visit d
Safety 
Visit c
Final/
ETe
1 b
2 c
7 c
14 c
1
2
3
4
5
6
7
8
9
Window (Days)
0
2
2
7
7
7
7
7
7
7
7
7
7
See 
footnote c
See 
footnote e
Post-study 
treatment 
antimicrobials ad
x
x
x
x
x
x
x
x
x
x
x
Video of Implant 
insertion and 
explantation and, 
if feasible, video 
of refill ae
x
Video of Implant insertion and explantation and, if feasible, 
video of refill (if applicable)
Ranibizumab 
filled Implant 
insertion
x
Implant refill with 
ranibizumab af
Refill if refill criteria are met (see Section 3.1.1)
Post-treatment 
finger counting 
(as applicable) ag
As applicable per treatment
Post-treatment 
IOP measurement
xah


Appendix 2
Schedule of Assessments (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
41/Statistical Analysis Plan GX28228
Assessment
Screen a
7 days 
after 
RBZ tx
Rand b
28 and 
37 
days 
after 
RBZ tx
Day
Month
Month X 
Visit d
Safety 
Visit c
Final/
ETe
1 b
2 c
7 c
14 c
1
2
3
4
5
6
7
8
9
Window (Days)
0
2
2
7
7
7
7
7
7
7
7
7
7
See 
footnote c
See 
footnote e
Refill Needle 
collection after 
Implant refill for 
vitreous 
biomarkers ai
Collect Refill Needle with its content if Implant refill is 
performed, if applicable
Implant insertion 
evaluation aj
x
Concomitant 
medications ak
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse event al
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concurrent ocular 
procedures or 
additional 
assessments am
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Follow-up call (if 
applicable) an
x
As applicable per treatment
x
Eye fluid sample 
collection ao
Collect vitreous or aqueous humor sample at the start of 
explantation for patients undergoing an explantation procedure


Appendix 2
Schedule of Assessments (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
42/Statistical Analysis Plan GX28228
AMDage-related macular degeneration; AREDSAge-Related Eye Disease Study; BCVAbest corrected visual acuity; ET end of treatment; 
IOPintraocular pressure; ITVintravitreal; IxRSinteractive Voice/Web response system; MacTSQMacular Degeneration Treatment 
Satisfaction Questionnaire; NAnot applicable; PKpharmacokinetic; Randrandomization; RBZ ranibizumab; SAsafety visit; 
SD-OCT spectral domain optical coherence tomography; tx treatment.
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 Screening cannot occur earlier than 7 days after the last standard-of-care of ITV ranibizumab treatment in the study eye. 
b Patients randomized to Implant treatment arms will be scheduled at the conclusion of their randomization visit for their Implant insertion surgery 
(Day 1) on such a date that no less than 28 days and no more than 37 days have lapsed between the surgery and their the last standard-of-care 
ITV ranibizumab treatment in the study eye, unless a patient needs more time to interrupt aspirin or NSAID usage 7 days before Day 1 (see 
Section 4.3.2.3).  For these patients, Day 1 study treatment visit must occur no later than 45 days after the patient’s last ITV ranibizumab
treatment.  In the case of a pause of enrollment and implant insertion surgeries, patients who have been randomized but have not yet received 
the study drug must repeat all randomization assessments (except for the randomization transaction in IxRS) after enrollment and implant 
insertion surgeries recommence, before receiving the study drug. 
c Implant treatment arms safety assessment visits will be scheduled on Days 2, 7 (2 days), and 14 (2 days) after Implant insertion; 7 (2) days 
after each Implant refill; 1 and 7 (2) days post-explantation if a patient is continuously followed in the study (prior to study Last Patient In 
Month 9 visit); and 1, 7(2), 30 (7), and 60 (7) days post-explantation if a patient is exiting the study, after which a patient will be scheduled 
for the early termination visit 30 (7) days later.
d After completion of the Month 9 visit, the Implant arms study patients will continue monthly study visits according to Month X (i.e., Month 10, 
Month 11, Month 12, etc.) schedule of assessments until the Sponsor decides, based on the primary analysis results, to either terminate the 
study and discontinue study treatment, or offer patients entry into the RPDS Extension Study.
e For patients who are completing the study or withdrawing early, perform 90 (7) days after the Implant explantation.
f
MacTSQ should be interviewer-administered by site personnel (other than VA examiner) prior to any other study procedures.
g Refer to the IxRS Manual for further details.
h Vital signs consist of blood pressure and pulse measurement.  Height and weight will also be performed at the screening visit.  On the visits 
when a patient receives treatment, including Day 1 visit, perform vital signs measurements pre-treatment.  On the day of implant insertion and 
explantation of procedure, blood pressure must also be recorded during surgery and upon completion of the surgery. 
i
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 4.6.6 or the separate laboratory manual.


Appendix 2
Schedule of Assessments (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
43/Statistical Analysis Plan GX28228
j
Perform urine pregnancy test prior to fluorescein angiography (if applicable) 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 fluorescein angiography or study 
treatment until the final results are available. If the serum pregnancy test is positive, do not administer the study treatment.
k Collect and perform locally the urine pregnancy test prior to fluorescein angiography and/or study treatment (if applicable) for women of 
childbearing potential, including those who have had tubal ligation. If urine pregnancy test is positive, collect serum pregnancy sample and do not 
perform study treatment until the final results are available. If the serum pregnancy test is positive, do not administer the study treatment.
l
May be collected up to 1 day prior to day 1.
m Collect serum PK sample from Implant arms patients at each post explantation safety visit (see protocol Section 4.7.2 and Section 4.7.3).
n Collect serum PK sample for ranibizumab concentration from Implant treatment arms patients at the Randomization visit and then at each 
monthly visit PRIOR to the treatment, even if treatment is not subsequently given. 
o Collect serum PK sample for ranibizumab concentration from Implant treatment arms patients ≥ 60 minutes post treatment on Day 1 visit (if 
possible) and then on Days 2, 7(2 days), and 14 (2 days) after Day 1 visit; afterwards collect serum PK sample 1 and 7 (2) days after each 
refill.  Collect a serum PK sample at the early termination visit if applicable.  Note:  for patients who are unable to visit the clinic for the PK 
sample collection 1 day after each Implant refill, provision will be made for this timepoint sample collection to be collected at their home.  
Alternatively, the sample may be collected 2 days after the refill.  Training will be provided to site staff on how to perform this task.  The sample 
will be sent to a central laboratory.
p Perform only if possible.
q Obtain serum anti-ranibizumab antibody sample from the Implant treatment arms patients prior to the study treatment and prior to fluorescein 
angiography (if applicable) on the Randomization visit, Visits Day 14, Month 1, 3, 6, and 9 and at the early termination visit if applicable.
r
If a patient has consented to this optional sample collection, obtain the aqueous humor sample prior to or immediately following one or more 
refills and at the Day 7 safety visit post refill.
s Perform low luminance BCVA testing after standard BCVA testing.
t
Perform only if you have the Humphrey Visual Field machine at your site.  In addition to the listed timepoints, this testing will be performed any 
time the patient reports a new defect of the peripheral vision. 
u If it cannot be performed during Randomization, this testing must be performed on a subsequent day but before Day 1.
v Perform only if you have ultrasound or optical biometry capability at your site.
w Perform pre-treatment.
x Should be performed in the surgical center using Tono-Pen tomometry prior to the Implant insertion surgery.
y Dilated ophthalmoscopy examinations will be performed for patients in the Implant treatment arms after Implant insertion in the study eye at the 
Day 1 visit, and then on Days 2, 7 (2 days), and 14 (2 days) after the Day 1 visit; afterward, perform dilated ophthalmoscopy examinations at 
each monthly visit to monitor the Implant and its release control element for visible clogging and other Implant problems.


Appendix 2
Schedule of Assessments (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
44/Statistical Analysis Plan GX28228
z Historical OCT taken at the time of diagnosis of nAMD will also be required to determine patient’s eligibility at the screening visit.  If fluorescein 
angiograms were taken at the time of diagnosis of nAMD, they must be submitted to the reading center as well.  If available, historical fluorescein 
angiograms will be evaluated by the reading center, but are not required to determine patient’s eligibility.  Refer to the Reading Center Manuals 
for details.
aa The central reading center will evaluate fundus photography, fluorescein angiograms, and SD-OCT taken at the screening visit for determination 
of a patient’s eligibility, together with the historical OCT taken at the time of diagnosis of nAMD. Refer to the Reading Center Manual for details.
ab Only at selected sites. Perform pre-treatment.
ac In addition to the timepoints listed, the photo will also be taken at any visit if there are concerns with Implant function.
ad The pre-Implant insertion or explantation use of self-administered antimicrobials is required.  The pre-Implant refill use of self-administered 
antimicrobials is per the investigator’s discretion. The post-Implant insertion, explantation, or refill use of self-administered antimicrobials is 
required.
ae The video of the implant/explant procedure (if applicable) should be recorded. The video of the refill is optional.
af Initially fill the Implant with IxRS assigned kit of ranibizumab prior to its insertion into the study eye.  Afterwards, starting at Month 1 visit, if refill 
criteria are met (see Section 3.1.1), refill the Implant with IxRS assigned ranibizumab kit.
ag Following each Implant refill, patients will have a 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 patients will remain at the clinic for approximately 
40 minutes.  If there are no safety concerns 40 (10) minutes following treatment, the patient will be allowed to leave the clinic.  If any safety 
concerns or immediate toxicity is noted, the patient will remain at the clinic and will be treated according to the designated physician’s clinical 
judgment.  If applicable, the adverse event will be reported on the appropriate eCRF page.  
ah Upon completion of the Implant insertion or explantation procedure, patients will have indirect ophthalmoscopy performed to monitor the Implant 
placement and to evaluate any potential Implant problems.  Intraocular pressure will be checked for the study eye only by the treating physician 
by digital palpation.  These assessments must be performed prior to placing a patch on the eye.  If any safety concerns or immediate toxicity is 
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 on the appropriate eCRF page.
ai Follow Refill Needle return instructions from the laboratory manual if Implant refill has been performed (if applicable).
aj 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 on the appropriate eCRF page.
ak Record any concomitant medications (i.e., any prescription medications or over-the-counter preparations other than protocol-specified 
procedural medications, and pre-treatment and post-treatment medications, such as proparacaine, antimicrobials) 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.


Appendix 2
Schedule of Assessments (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
45/Statistical Analysis Plan GX28228
al 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, medication wash-out, etc.) 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/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.
am 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.
an 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.
aoAqueous humor or vitreous sample collection must be performed at the start of explantation for all patients undergoing an explantation procedure.  
The choice between aqueous humor collection or vitreous collection is per investigator’s discretion (see Appendix 19).


Appendix 2
Schedule of Assessments (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
46/Statistical Analysis Plan GX28228
Schedule of Assessments for ITV Arm:  Screening, Randomization/Day 1, Month 1 through Month 9, Month X, and 
Final/Early Termination Visits
Assessment
Screen 
a
7 
days 
after 
RBZ tx
Rand/
Day 1 b
28 
and 
37 
days 
after 
RBZ tx
Month
Month 
X visit c
Final/
ET d
1
2
3
4
5
6
7
8
9
Window (Days)
7
7
7
7
7
7
7
7
7
7
7
Written informed consent
x
Review of inclusion and 
exclusion criteria
x
x
Medical and surgical 
history, tobacco and 
alcohol use
x
Demographic Information
x
Physical Examination 
x
x
x
MacTSQ e
x
x
x
x
x
Site to contact IxRS (as 
applicable) f
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital signs g
x
x
x
x
x
x
x
x
x
x
x
x
x


Appendix 2
Schedule of Assessments (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
47/Statistical Analysis Plan GX28228
Assessment
Screen 
a
7 
days 
after 
RBZ tx
Rand/
Day 1 b
28 
and 
37 
days 
after 
RBZ tx
Month
Month 
X visit c
Final/
ET d
1
2
3
4
5
6
7
8
9
Window (Days)
7
7
7
7
7
7
7
7
7
7
7
Central laboratory 
samples (hematology, 
coagulation, serum 
chemistry, and 
urinalysis) h
x
Serum PK sample for 
ranibizumab i
x
x
x
x
x
x
Serum anti-ranibizumab 
antibody sample i
x
x
x
x
x
x
Serum pregnancy sample j
x
If urine pregnancy test is positive, collect serum pregnancy sample and do not perform study 
treatment until the final results are available
x
Urine pregnancy test k
x
Collect urine pregnancy test prior to treatment. If urine pregnancy test is positive, collect 
serum pregnancy sample and do not perform study treatment until the final results are 
available
BCVA testing (starting at 
4 m)
x
x
x
x
x
x
x
x
x
x
x
x
x
Low luminance BCVA 
testing l
x
x
x
x
x
x
x
x
x
x
x
x
x


Appendix 2
Schedule of Assessments (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
48/Statistical Analysis Plan GX28228
Assessment
Screen 
a
7 
days 
after 
RBZ tx
Rand/
Day 1 b
28 
and 
37 
days 
after 
RBZ tx
Month
Month 
X visit c
Final/
ET d
1
2
3
4
5
6
7
8
9
Window (Days)
7
7
7
7
7
7
7
7
7
7
7
Intraocular pressure
(IOP) m
x
x
x
x
x
x
x
x
x
x
x
x
x
Slit-lamp 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
Historical fundus images 
collection n
x
SD-OCT m,o
x
x
x
x
x
x
x
x
x
x
x
x
x
Fundus photography m,o
x
x
x
Fluorescein 
angiography m,o
x
x
x
x
x
Fundus 
autofluorescence m,o
x
x
x
x
OCT Angiography p
x
x
x
x
x
x
x
x
x
x
x
x
Lens Photo
(fundus reflex photos)
x
x
x
x
Optional whole blood for 
DNA (RCR Sample)
x


Appendix 2
Schedule of Assessments (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
49/Statistical Analysis Plan GX28228
Assessment
Screen 
a
7 
days 
after 
RBZ tx
Rand/
Day 1 b
28 
and 
37 
days 
after 
RBZ tx
Month
Month 
X visit c
Final/
ET d
1
2
3
4
5
6
7
8
9
Window (Days)
7
7
7
7
7
7
7
7
7
7
7
Optional serum sample for 
candidate biomarkers
x
x
x
Optional plasma (EDTA) 
sample for candidate 
biomarkers
x
x
x
Pre- and post- study 
treatment antimicrobials 
(as applicable) q
x
x
x
x
x
x
x
x
x
x
x
Administration of 
ranibizumab to ITV 
injection arm 
x
x
x
x
x
x
x
x
x
x
x
Post-treatment finger 
counting (as applicable) r
x
x 
x
x
x
x
x
x
x
x
x
Concomitant 
medications s
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse event t
x
x
x
x
x
x
x
x
x
x
x
x
Concurrent ocular 
procedures u
x
x
x
x
x
x
x
x
x
x
x
x


Appendix 2
Schedule of Assessments (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
50/Statistical Analysis Plan GX28228
Assessment
Screen 
a
7 
days 
after 
RBZ tx
Rand/
Day 1 b
28 
and 
37 
days 
after 
RBZ tx
Month
Month 
X visit c
Final/
ET d
1
2
3
4
5
6
7
8
9
Window (Days)
7
7
7
7
7
7
7
7
7
7
7
Follow-up call (if 
applicable) v
x
x
x
x
x
x
x
x
x
x
x
AMDage-related macular degeneration; AREDSAge-Related Eye Disease Study; BCVAbest corrected visual acuity; ET end of treatment; 
IOPintraocular pressure; ITVintravitreal; IxRSinteractive Voice/Web response system; MacTSQMacular Degeneration Treatment 
Satisfaction Questionnaire; NAnot applicable; PKpharmacokinetic; Randrandomization; RBZ ranibizumab; SAsafety visit; 
SD-OCT spectral domain optical coherence tomography; tx treatment.
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 Screening cannot occur earlier than 7 days after the last standard-of-care of ITV ranibizumab treatment in the study eye. 
b Patients randomized to the ITV injection treatment arm may receive their first study treatment (Day 1) at the conclusion of the randomization visit 
or later; however no less than 28 days and no more than 37 days should have lapsed between the first study treatment and their last standard-
of-care ITV ranibizumab treatment in the study eye.
c After completion of the Month 9 visit, the ITV arm patients will continue monthly study visits according to Month X (i.e., Month 10, Month 11, 
Month 12, etc.) schedule of assessments until the Sponsor decides, based on the primary analysis results, to either terminate the study and 
discontinue study treatment, or offer patients entry into the RPDS Extension Study.
d Patients final study visit or early termination visit will be scheduled 30 (7) days following the last study treatment.  
e MacTSQ should be interviewer-administered by site personnel (other than VA examiner) prior to any other study procedures.
f
Refer to the IxRS Manual for details.
g Vital signs consist of blood pressure and pulse measurement.  Height and weight will also be performed at the screening visit.  On the visits 
when a patient receives treatment, perform vital signs measurements pre-treatment.


Appendix 2
Schedule of Assessments (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
51/Statistical Analysis Plan GX28228
h Obtain from all study patients pre-treatment and prior to fluorescein angiography, if applicable, except early termination (no time requirement).  
For a description of the laboratory assessments to be performed, see Section 4.6.6 or the separate laboratory manual.
i
Obtain sample prior to the study treatment and prior to fluorescein angiography (if applicable).
j
Collect serum pregnancy sample prior to fluorescein angiography (if applicable) for women of childbearing potential, including those who have 
had tubal ligation. If the serum pregnancy test is positive, do not administer the study treatment.
k Collect and perform locally the urine pregnancy test prior to fluorescein angiography and study treatment for women of childbearing potential, 
including those who have had tubal ligation. If urine pregnancy test is positive, collect serum pregnancy sample and do not perform study 
treatment until the final results are available. If the serum pregnancy test is positive, do not administer the study treatment.
l
Perform low luminance BCVA testing after standard BCVA testing.
m Perform pre-treatment.
n Historical OCT taken at the time of diagnosis of nAMD will also be required to determine patient’s eligibility at the screening visit.  If fluorescein 
angiograms were taken at the time of diagnosis of nAMD, they must be submitted to the reading center as well.  If available, historical fluorescein 
angiograms will be evaluated by the reading center, but are not required to determine patient’s eligibility.  Refer to the Reading Center Manuals 
for details.
o The central reading center will evaluate fundus photography, fluorescein angiograms, and SD-OCT taken at the screening visit for determination
of a patient’s eligibility, together with the historical OCT 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 The pre- and post-treatment use of self-administered antimicrobials for the ITV injection arm is per the investigator discretion.
r
Following each ITV treatment with ranibizumab, patients will have a 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 patients will remain at the clinic for 
approximately 40 minutes.  If there are no safety concerns 40 (10) minutes following treatment, the patient will be allowed to leave the clinic.  If 
any safety concerns or immediate toxicity is noted, the patient will remain at the clinic and will be treated according to the designated physician’s
clinical judgment.  If applicable, the adverse event will be reported on the appropriate eCRF page.  
s Record any concomitant medications (i.e., any prescription medications or over-the-counter preparations other than protocol-specified 
procedural medications, and pre-treatment and post-treatment medications, such as proparacaine, antimicrobials) 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.


Appendix 2
Schedule of Assessments (cont.)
Ranibizumab Port Delivery System—Genentech, Inc.
52/Statistical Analysis Plan GX28228
t
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 etc.) 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 ranibizumab and ITV 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.
u Record all concurrent ocular procedures performed on the study or fellow eye.
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 (if applicable).