Clinical trial NCT03038880
Conditions: Neovascularization, Choroidal Macular Degeneration, Age-Related
Sponsor: Hoffmann-La Roche
Start date: 2017-01-27; Completion date: 2018-03-29
Enrollment: 76 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a Phase II, multicenter, randomized, active comparator-controlled, 52-week study to investigate the efficacy, safety and pharmacokinetics of faricimab (RO6867461; RG7716) administered with extended dosing regimens in treatment-naive participants with neovascular age related macular degeneration (nAMD). Only one eye was chosen as the study eye.

Detailed description:

Arms: arm 1: 6 mg faricimab was given by intravitreal (IVT) injection once every 4 weeks (Q4W) up to Week 12 (4 injections), followed by 6 mg faricimab IVT injection once every 12 weeks (Q12W) from Week 24 up to Week 48 (injections at Weeks 24, 36, and 48; 3 injections). arm 2: 6 mg faricimab was administered by IVT injection once every 4 weeks (Q4W) up to Week 12 (4 injections), followed by no doses up to Week 24 when a protocol-defined assessment of disease activity was performed. Participants with disease activity at Week 24 initiated 6 mg faricimab IVT Q12W dosing, and participants without disease activity at Week 24 initiated 6 mg faricimab IVT once every 16 weeks (Q16W) dosing for the remainder of the study. arm 3: 0.5 mg of ranibizumab was administered by IVT injection once every 4 weeks (Q4W) for 48 weeks (13 injections).
Interventions: intervention 1: Faricimab intervention 2: Ranibizumab intervention 3: Sham Procedure
Intervention descriptions: intervention 1: Faricimab was administered via IVT injections as specified during the treatment period. intervention 2: Ranibizumab was administered via IVT injections as specified during the treatment period. intervention 3: The sham was a procedure that mimicked an IVT injection and involved the blunt end of an empty syringe (without a needle) being pressed against the anesthetized eye. It was administered to participants in the faricimab treatments arms at applicable visits to maintain masking among treatment arms.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Official Title:  
 
STAIRWAY: SIMULTANEOUS BLOCKADE OF ANGIOPOIETIN-2 
AND VEGF-A WITH THE BISPECIFIC ANTIBODY RO6867461 
(RG7716) FOR EXTENDED DURABILITY IN THE TREATMENT OF 
NEOVASCULAR AGE-RELATED MACULAR DEGENERATION  
NCT Number: 
NCT03038880 
Document: 
Version & Date:  
PROTOCOL 
Version 2: 14-Feb-2017 
 


Title
14-Feb-2017 18:29:31
Date and Time (UTC)
Company Signatory
Approver's Name
PROTOCOL AMENDMENT APPROVAL 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
RO6867461—F. Hoffmann-La Roche Ltd 
Protocol CR39521, Version 2 
PROTOCOL 
TITLE: 
STAIRWAY:  SIMULTANEOUS BLOCKADE OF 
ANGIOPOIETIN-2 AND VEGF-A WITH THE 
BISPECIFIC ANTIBODY RO6867461 (RG7716) FOR 
EXTENDED DURABILITY IN THE TREATMENT OF 
NEOVASCULAR AGE-RELATED MACULAR 
DEGENERATION 
PROTOCOL NUMBER: CR39521 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
N/A 
IND NUMBER: 
119225 
TEST PRODUCT: 
RO6867461 (RG7716)  
MEDICAL MONITOR: 
, M.B.B.S. 
SPONSOR: 
F. Hoffmann-La Roche Ltd
DATE FINAL: 
Version 1:  7 November 2016
DATE AMENDED: 
Version 2:  See electronic date stamp below


 
PROTOCOL AMENDMENT, VERSION 2: 
RATIONALE 
Protocol CR39521 has been amended to provide further clarity on certain aspects of 
protocol execution.  Changes to the protocol, along with a rationale for each change, are 
summarized below. 
• 
For assessment of active disease using optical coherence tomography (OCT), 
measurement of central foveal thickness (CFT) has been replaced with 
measurement of central subfield thickness (CST), as CST can be calculated using 
an automated program within the Heidelberg Spectralis® OCT instrument and has 
lower risk of measurement error compared to manual calculation of CFT on the 
same device (Sections 3.1.1 and 4.5.5.4). 
• 
Language has been added to the study design (Section 3.1.1) to clarify that if the 
screening and Week 1/Day 1 visit occurs as a combined visit, informed consent 
must be documented before any study-specific screening procedure is performed, 
and may be obtained more than 28 days before initiation of study treatment.   
• 
The location of choroidal neovascularization (CNV) in the study eye has been 
further clarified in an inclusion criterion (Section 4.1.1). 
• 
To ensure consistency across study sites, specifications have been made for the 
timing for several of the inclusion/exclusion criteria (Sections 4.1.1 and 4.1.2). 
• 
Language has been added and revised to provide guidance and explanation of the 
masked and unmasked roles at the site and study levels, and for biosamples 
(Section 4.2.2).  
• 
Reimbursement by the Sponsor of commercial ranibizumab and other approved 
anti-VEGF treatments for the fellow eye has been clarified (Section 4.4.3). 
• 
It has been specified that adverse events of special interest (immediately reportable 
to the Sponsor) can be non-serious or serious (Section 5.2.3). 
• 
To adhere to current protocol template language for safety reporting, Section 5.3.5.7 
has been updated. 
• 
To provide sites the option to collect the whole blood DNA sample after the Week 1, 
Day 1 visit, language has been added to allow for this sample to be collected at any 
subsequent study visit where a blood draw is being performed (Appendix 1, 
footnote “n”).   
 
Additional minor changes have been made to improve clarity and consistency, and to 
adhere to current protocol template standards.  Substantive new information appears in 
italics.  This amendment represents cumulative changes to the original protocol. 
RO6867461—F. Hoffmann-La Roche Ltd 
2/Protocol CR39521, Version 2 


 
PROTOCOL AMENDMENT, VERSION 2: 
SUMMARY OF CHANGES 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 3.1.1:  Overview of the Study Design
Patients will undergo a screening examination within 4 weeks of study treatment 
administration.  The screening and Week 1/Day 1 (randomization) visit may occur as a 
combined visit if all assessments (with the exception of informed consent) are 
conducted completed within 48 hours.  Informed consent must be documented before any 
study-specific screening procedure is performed, and may be obtained more than 
28 days before initiation of study treatment.  Where screening and randomization are 
combined, assessments listed for both visits only need to be conducted once. … 
Determination of active disease will be made if any of the following criteria are met 
(also see Section 4.5.5.4): 
• 
Increase in central foveal subfield thickness (CFTCST of > 50 μm on Spectralis® 
OCT compared to average CFT CST over last 2 visits (Weeks 16 and 20) 
Or 
• 
Increase in CFT CST of ≥ 75 μm compared to lowest CFTCST recorded at either 
Week 16 or Week 20 … 
 
SECTION 4.1.1:  Inclusion Criteria
Patients must meet the following criteria for study entry: 
Ocular Criteria for Study Eye 
• 
Subfoveal CNV or CNV lesion component juxtafoveal CNV with a subfoveal 
component related to the CNV activity by FFA or SD-OCT (as evidenced by 
subretinal fluid, subretinal hyper-reflective material, evidence of leakage, or 
hemorrhage) 
 
General Criteria 
• 
Age  ≥ 50 years on Day 1 
 
SECTION 4.1.2:  Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry: 
Ocular Criteria for Study Eye 
• 
Cataract surgery within 3 months of baseline assessments (Day 1) 
 
Concurrent Ocular Conditions 
• 
Active intraocular inflammation (grade trace or above) in the study eye on Day 1 
(prior to randomization) 
RO6867461—F. Hoffmann-La Roche Ltd 
3/Protocol CR39521, Version 2 


 
• 
Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye on 
Day 1 (prior to randomization) 
 
SECTION 4.2.2:  Masking
This is a patient- and outcome assessor (BCVA and Central Reading Center)-masked 
study.  The intent of this design allows for a single investigator per site to be present at a 
given visit to fulfill the masking requirements of this study.   
At a site level: 
• 
Patients and BCVA examiners will be masked to treatment assignment.  BCVA 
examiners will also be masked to study eye (see Section 4.5.5.1).  All other site 
personnel that do not have a role in drug preparation and/or treatment delivery 
should be masked to study eye drug assignment.   
• 
The investigator administrating the patient’s treatment (RO6867461, comparator 
ranibizumab, or sham) and/or pharmacist/designated personnel responsible for 
drug preparation will be unmasked to treatment assignment.   
 
The number of unmasked study personnel should be limited to ensure the integrity of 
this masked study.  All roles for each study staff member should be clearly documented 
in the site delegation log.  The delegation log must be signed by the Principal 
Investigator.  Unmasked personnel cannot switch to a masked role, but masked 
personnel can switch to an unmasked role.  Any change should be documented in the 
delegation log. 
Patients, study site personnel (with the exception of the investigator, and/or 
pharmacist/designated personnel responsible for drug preparation), BCVA examiners, 
imaging technicians,  
At a study level: 
The Central Reading Center personnel, study vendors, Central Reading Center 
personnel, and the Sponsor (with the exception of a point person[s] to support 
unmasked site personnel and IMC members in the case of an optional interim analysis; 
Section 3.1.2 and Section 6.9) and its agents will be masked to study eye drug 
assignment. 
The number of unmasked study personnel should be limited to ensure the integrity of 
this masked study.  
To maintain the masked design of the study, blood samples collected at timepoints 
specified in the schedule of activities (Appendix 1) will also be taken from all patients 
receiving ranibizumab per the RO6867461 schedule.  The samples from these patients 
may or may not be analyzed. 
RO6867461—F. Hoffmann-La Roche Ltd 
4/Protocol CR39521, Version 2 


 
For biosamples: 
To maintain the masked design of the study, blood samples collected at timepoints 
specified in the schedule of activities (Appendix 1) will also be taken from all patients 
receiving ranibizumab per the RO6867461 schedule.  The samples from these patients 
may or may not be analyzed.  Unmasking for independent analysis of the relevant 
biosamples during the conduct of the study will be performed according the Sponsor’s 
internal standard procedures in place to ensure integrity of the data.  The number of 
Roche representative(s) and delegates unmasked will be kept to the minimum required 
to address the objective of the biosample analysis. 
Sponsor personnel responsible for performing PK assays will be unmasked to patients’ 
treatment assignments to identify appropriate PK samples to be analyzed.   
SECTION 4.4.3:  CNV Secondary to AMD in the Fellow Eye
When anti-VEGF therapy is recommended and ranibizumab warranted, every effort 
should be made to treat with ranibizumab.  This treatment will be provided by the 
Sponsor as long as the patient remains in the study.  When provided by the Sponsor, it 
will be in the commercial formulation for ranibizumab labelled for investigational use only 
(dispatched by IxRS).  Treatment with commercial supplies of ranibizumab may be 
reimbursed at the discretion and approval of the Sponsor. 
This treatment also Treatment with other approved anti-VEGF therapies may be 
provided by the site through commercial supplies.  However, commercial supplies of 
other approved anti-VEGF treatments will not be reimbursed by the Sponsor. 
SECTION 4.5.5.3:  Ocular Imaging 
For SD-OCT and optional OCT-A, images of the study eye and fellow eyes should only 
be captured and forwarded to the Central Reading Center at the screening, Week 24, 
Week 40, and Week 52 or early termination visits.  At all other visits, only the study eye 
images need to be acquired and forwarded to the Central Reading Center. 
SECTION 4.5.5.4:  Week 24 Assessment of Disease Activity 
Determination of active disease will be made if any of the following criteria are met: 
• 
Increase in CFT CST of > 50 μm on Spectralis OCT compared to average CFTCST 
over last 2 visits (Weeks 16 and 20) 
Or 
• 
Increase in CFTCST of ≥ 75 μm compared to lowest CFTCST recorded at either 
Week 16 or Week 20 … 
 
SECTION 5.2.3:  Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor)
Non-serious or serious Aadverse events of special interest are required to be reported 
by the investigator to the Sponsor immediately (i.e., no more than 24 hours after learning 
of the event; see Section 5.4.2 for reporting instructions). … 
RO6867461—F. Hoffmann-La Roche Ltd 
5/Protocol CR39521, Version 2 


 
• 
Sight-threatening adverse events 
An adverse event is considered to be sight threatening and should be reported 
by the investigator to the Sponsor immediately (i.e., no more than 24 hours 
after learning of the event; or reporting instructions) if it meets one or more of 
the following criteria: … 
 
SECTION 5.3.3:  Assessment of Severity of Adverse Events
The adverse event severity grading scale in Table 3 will be used provides guidance for 
assessing adverse event severity. 
SECTION 5.3.5.7:  Deaths 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour after the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable.  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"). 
SECTION 9.2:  PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
SECTION 9.5:  PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
… For more information, refer to the Roche Global Policy on Sharing of Clinical Trials 
Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.
pdf 
APPENDIX 1:  Schedule of Activities 
Appendix 1 has been revised to reflect changes to the protocol, and to add footnote “n” 
to the whole blood sample for DNA assessment. 
RO6867461—F. Hoffmann-La Roche Ltd 
6/Protocol CR39521, Version 2 


 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 13 
PROTOCOL SYNOPSIS .................................................................................... 14 
1. 
BACKGROUND .......................................................................................... 23 
1.1 
Background on Choroidal Neovascularization in 
Age-Related Macular Degeneration ...................................... 23 
1.2 
Background on RO6867461 .................................................. 24 
1.3 
Study Rationale and Benefit-Risk Assessment...................... 25 
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 28 
3. 
STUDY DESIGN ......................................................................................... 30 
3.1 
Description of the Study......................................................... 30 
3.1.1 
Overview of the Study Design ............................................... 30 
3.1.2 
Internal Monitoring Committee............................................... 34 
3.2 
End of Study and Length of Study......................................... 34 
3.3 
Rationale for Study Design.................................................... 34 
3.3.1 
Rationale for Dose and Schedule.......................................... 34 
3.3.2 
Rationale for Patient Population ............................................ 35 
3.3.3 
Rationale for Control Group................................................... 35 
3.3.4 
Rationale for Optional Aqueous Humor 
Assessments ......................................................................... 36 
4. 
MATERIALS AND METHODS .................................................................... 36 
4.1 
Patients.................................................................................. 36 
4.1.1 
Inclusion Criteria.................................................................... 36 
4.1.2 
Exclusion Criteria................................................................... 37 
4.2 
Method of Treatment Assignment and Masking .................... 39 
4.2.1 
Treatment Assignment........................................................... 39 
4.2.2 
Masking ................................................................................. 39 
4.3 
Study Treatment.................................................................... 40 
4.3.1 
Formulation, Packaging, and Handling.................................. 40 
4.3.1.1 
RO6867461 ........................................................................... 40 
4.3.1.2 
Ranibizumab.......................................................................... 41 
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4.3.1.3 
Sham ..................................................................................... 41 
4.3.2 
Dosage, Administration, and Compliance.............................. 42 
4.3.2.1 
RO6867461, Ranibizumab, and Sham .................................. 42 
4.3.3 
Investigational Medicinal Product Accountability ................... 43 
4.3.4 
Sham Boxes Accountability ................................................... 43 
4.3.5 
Post-Trial Access to RO6867461 .......................................... 43 
4.4 
Concomitant Therapy ............................................................ 44 
4.4.1 
Permitted Therapy ................................................................. 44 
4.4.2 
Prohibited Therapy ................................................................ 44 
4.4.3 
CNV Secondary to AMD in the Fellow Eye............................ 44 
4.5 
Study Assessments ............................................................... 45 
4.5.1 
Informed Consent Forms and Screening Log........................ 45 
4.5.2 
Medical History and Demographic Data ................................ 46 
4.5.3 
Physical Examinations........................................................... 46 
4.5.4 
Vital Signs.............................................................................. 46 
4.5.5 
Disease-Specific Assessments.............................................. 46 
4.5.5.1 
Best Corrected Visual Acuity ................................................. 46 
4.5.5.2 
Additional Ocular Assessments............................................. 47 
4.5.5.3 
Ocular Imaging ...................................................................... 47 
4.5.5.4 
Week 24 Assessment of Disease Activity.............................. 48 
4.5.6 
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 49 
4.5.7 
Optional Aqueous Humor Samples ....................................... 50 
4.5.8 
Optional Unscheduled Collection of Vitreous 
Humor Samples..................................................................... 51 
4.5.9 
Samples for Research Biosample Repository ....................... 51 
4.5.9.1 
Overview of the Research Biosample Repository.................. 51 
4.5.9.2 
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 52 
4.5.9.3 
Sample Collection.................................................................. 52 
4.5.9.4 
Confidentiality........................................................................ 52 
4.5.9.5 
Consent to Participate in the Research 
Biosample Repository............................................................ 53 
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4.5.9.6 
Withdrawal from the Research Biosample 
Repository ............................................................................. 53 
4.5.9.7 
Monitoring and Oversight....................................................... 54 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 54 
4.6.1 
Patient Discontinuation.......................................................... 54 
4.6.2 
Study Treatment Discontinuation........................................... 54 
4.6.3 
Study and Site Discontinuation.............................................. 55 
5. 
ASSESSMENT OF SAFETY....................................................................... 55 
5.1 
Safety Plan ............................................................................ 55 
5.1.1 
Risks Associated with RO6867461........................................ 56 
5.1.1.1 
Important Identified Risks ...................................................... 56 
5.1.1.2 
Potential Important Systemic Risks for anti-VEGF 
Agents ................................................................................... 56 
5.1.1.3 
Injection Procedure-Related Risks ........................................ 56 
5.1.1.4 
Risk of Increased Intraocular Pressure.................................. 57 
5.1.2 
Management of Patients Who Experience 
Specific Adverse Events........................................................ 57 
5.2 
Safety Parameters and Definitions ........................................ 57 
5.2.1 
Adverse Events ..................................................................... 58 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 58 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 59 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 60 
5.3.1 
Adverse Event Reporting Period ........................................... 60 
5.3.2 
Eliciting Adverse Event Information ....................................... 60 
5.3.3 
Assessment of Severity of Adverse Events ........................... 61 
5.3.4 
Assessment of Causality of Adverse Events ......................... 61 
5.3.5 
Procedures for Recording Adverse Events............................ 61 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 62 
5.3.5.2 
Adverse Events That Are Secondary to Other 
Events.................................................................................... 62 
5.3.5.3 
Persistent or Recurrent Adverse Events................................ 63 
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5.3.5.4 
Abnormal Laboratory Values ................................................. 63 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 64 
5.3.5.6 
Abnormal Liver Function Tests.............................................. 64 
5.3.5.7 
Deaths ................................................................................... 65 
5.3.5.8 
Preexisting Medical Conditions.............................................. 65 
5.3.5.9 
Lack of Efficacy or Worsening of Age-Related 
Macular Degeneration ........................................................... 65 
5.3.5.10 
Hospitalization or Prolonged Hospitalization.......................... 66 
5.3.5.11 
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 66 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 66 
5.4.1 
Emergency Medical Contacts................................................ 67 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 67 
5.4.2.1 
Events That Occur prior to Study Drug Initiation.................... 67 
5.4.2.2 
Events That Occur after Study Drug Initiation........................ 68 
5.4.3 
Reporting Requirements for Pregnancies.............................. 68 
5.4.3.1 
Pregnancies in Female Patients............................................ 68 
5.4.3.2 
Abortions ............................................................................... 68 
5.4.3.3 
Congenital Anomalies/Birth Defects ...................................... 69 
5.5 
Follow-Up of Patients after Adverse Events .......................... 69 
5.5.1 
Investigator Follow-Up........................................................... 69 
5.5.2 
Sponsor Follow-Up ................................................................ 69 
5.6 
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 69 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 70 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 70 
6.1 
Determination of Sample Size ............................................... 70 
6.2 
Summaries of Conduct of Study............................................ 70 
6.3 
Summaries of Treatment Group Comparability ..................... 70 
6.4 
Efficacy Analyses .................................................................. 71 
6.4.1 
Primary Efficacy Endpoint...................................................... 71 
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6.4.2 
Secondary Efficacy Endpoints............................................... 71 
6.4.3 
Exploratory Efficacy Endpoint................................................ 71 
6.5 
Pharmacodynamic Analysis................................................... 71 
6.6 
Safety Analyses..................................................................... 72 
6.7 
Pharmacokinetic Analyses..................................................... 72 
6.8 
Immunogenicity Analyses...................................................... 72 
6.9 
Optional Interim Analyses...................................................... 72 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 73 
7.1 
Data Quality Assurance......................................................... 73 
7.2 
Electronic Case Report Forms............................................... 73 
7.3 
Source Data Documentation.................................................. 73 
7.4 
Use of Computerized Systems .............................................. 74 
7.5 
Retention of Records............................................................. 74 
8. 
ETHICAL CONSIDERATIONS.................................................................... 74 
8.1 
Compliance with Laws and Regulations ................................ 74 
8.2 
Informed Consent .................................................................. 75 
8.3 
Institutional Review Board or Ethics Committee.................... 76 
8.4 
Confidentiality........................................................................ 76 
8.5 
Financial Disclosure .............................................................. 77 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 77 
9.1 
Study Documentation ............................................................ 77 
9.2 
Protocol Deviations................................................................ 77 
9.3 
Site Inspections ..................................................................... 77 
9.4 
Administrative Structure......................................................... 78 
9.5 
Publication of Data and Protection of Trade 
Secrets .................................................................................. 78 
9.6 
Protocol Amendments ........................................................... 79 
10. REFERENCES ........................................................................................... 80 
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LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints................................... 28 
Table 2 
Guidelines for Management of Patients Who Experience 
Specific Adverse Events ............................................................. 57 
Table 3 
Adverse Event Severity Grading Scale ....................................... 61 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema............................................................................. 33 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities.................................................................. 83 
Appendix 2 
Grading Scale for Assessment of Anterior Chamber Flare or 
Cells, Vitreal Hemorrhage Density, and Vitreous Cells ............... 87 
Appendix 3 
Study Treatment Administration Procedure ................................ 89 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
STAIRWAY:  SIMULTANEOUS BLOCKADE OF 
ANGIOPOIETIN-2 AND VEGF-A WITH THE 
BISPECIFIC ANTIBODY RO6867461 (RG7716) FOR 
EXTENDED DURABILITY IN THE TREATMENT OF 
NEOVASCULAR AGE-RELATED MACULAR 
DEGENERATION 
PROTOCOL NUMBER: CR39521 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
N/A 
IND NUMBER: 
119225 
TEST PRODUCT: 
RO6867461 (RG7716)  
MEDICAL MONITOR: 
, M.B.B.S. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy as 
instructed by the local study monitor. 
 
RO6867461—F. Hoffmann-La Roche Ltd 
13/Protocol CR39521, Version 2 


 
PROTOCOL SYNOPSIS 
TITLE: 
STAIRWAY:  SIMULTANEOUS BLOCKADE OF ANGIOPOIETIN-2 
AND VEGF-A WITH THE BISPECIFIC ANTIBODY RO6867461 
(RG7716) FOR EXTENDED DURABILITY IN THE TREATMENT OF 
NEOVASCULAR AGE-RELATED MACULAR DEGENERATION 
CR39521 
PROTOCOL NUMBER: 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
N/A 
IND NUMBER: 
119225 
TEST PRODUCT: 
RO6867461 (RG7716)  
PHASE: 
Phase II 
INDICATION: 
Choroidal neovascularization (CNV) secondary to age-related 
macular degeneration (AMD) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives and Endpoints 
This study will evaluate the efficacy, safety, and pharmacokinetics of RO6867461 administered 
at 12- and 16-week intervals in patients with neovascular age-related macular degeneration 
(nAMD).  Specific objectives and corresponding endpoints for the study are outlined below. 
Objectives and Corresponding Endpoints 
Primary Efficacy Objective 
Corresponding Endpoint 
• To evaluate the efficacy of RO6867461 
on visual acuity when administered at 
12- and 16-week intervals 
• Mean change from baseline BCVA at Week 40 using 
the ETDRS-like charts 
Secondary Efficacy Objectives 
Corresponding Endpoints 
• To evaluate the efficacy of RO6867461 
on additional visual acuity outcomes  
• Mean change from baseline BCVA over time using 
the ETDRS-like charts 
• Proportion of patients gaining ≥ 15, ≥ 10, ≥ 5, or 
≥ 0 letters from baseline BCVA over time 
• Proportion of patients avoiding loss of ≥ 15, ≥ 10, ≥ 5, 
or ≥ 0 letters from baseline BCVA over time 
• Proportion of patients with BCVA of 20/40 or better 
over time 
• Proportion of patients with BCVA of 20/200 or worse 
over time 
• To evaluate the efficacy of RO6867461 
on anatomic outcome measures using 
SD-OCT 
• Mean change from baseline in CFT over time 
• Mean change from baseline in mean CST (1 mm 
diameter) over time 
• Proportion of patients with intraretinal fluid, subretinal 
fluid, cysts, or pigment epithelial detachment 
over time 
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Secondary Efficacy Objectives (cont.)
Corresponding Endpoints (cont.) 
• To evaluate the efficacy of RO6867461  
on anatomic outcome measures 
using FFA 
• Mean change from baseline in total area of CNV at 
Week 40 and Week 52 
• Mean change from baseline in total area of CNV 
component at Week 40 and Week 52 
• Mean change from baseline in total area of leakage at 
Week 40 and Week 52 
Exploratory Efficacy Objective 
Corresponding Endpoints 
• To investigate the incidence of disease 
activity at Week 24 
• Proportion of patients with disease activity at 
Week 24 
Safety Objective 
Corresponding Endpoints 
• To evaluate the safety of multiple IVT 
doses of RO6867461 at 12- and 
16-week intervals 
• Incidence and severity of ocular adverse events 
• Incidence and severity of non-ocular adverse events 
• Other safety data, including but not limited to, 
reasons for withdrawal from study, laboratory data, 
concomitant medications, vital signs, and physical 
examination results will be listed and summarized 
descriptively 
Exploratory Pharmacokinetic/ 
Pharmacodynamic Objectives 
Corresponding Endpoints 
• To assess the systemic PK profile of 
RO6867461 
• Plasma concentration of RO6867461 at specified 
timepoints 
• To evaluate the RO6867461, 
ranibizumab, free VEGF-A, and Ang-2 
profile in aqueous humor 
• Relationship between aqueous humor RO6867461 
concentrations or PK parameters and free VEGF-A 
and Ang-2 concentrations 
• Relationship between aqueous humor ranibizumab 
concentrations or PK parameters and free VEGF-A 
and Ang-2 concentrations 
• Time course of free VEGF-A and Ang-2 
concentrations in aqueous humor 
Immunogenicity Objective 
Corresponding Endpoints 
• To investigate the formation of plasma 
anti-RO6867461 antibodies 
• Incidence of ADAs during the study  
Exploratory Biomarker Objective 
Corresponding Endpoints 
• To explore levels of potential 
biomarkers of angiogenesis and 
inflammation in aqueous humor at 
baseline and at additional timepoints 
to assess their response to 
RO6867461 
• Relationship between aqueous humor concentration 
of potential biomarkers with primary and secondary 
endpoints 
ADA = anti-drug antibody; Ang-2 = angiopoietin-2; BCVA = best corrected visual acuity; 
CFT = central foveal thickness; CNV = choroidal neovascularization; CST = central subfield 
thickness; ETDRS = Early Treatment Diabetic Retinopathy Study; FFA = fundus fluorescein 
angiography; IVT = intravitreal; PK = pharmacokinetic; SD-OCT = spectral domain optical 
coherence tomography; VEGF-A = vascular endothelial growth factor A. 
 
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Study Design 
Description of Study 
This is a Phase II, multicenter, randomized, active comparator-controlled, subject and outcome-
assessor masked, parallel group, 52-week study to investigate the efficacy, safety, and 
pharmacokinetics of RO6867461 administered at 12- and 16-week intervals in treatment-naive 
patients with nAMD.  Approximately 75 patients will be enrolled and randomized in a 2:2:1 ratio 
to one of three treatment arms:  
• 
Arm A (Q12W):  6 mg RO6867461 intravitreally (IVT) every 4 weeks up to Week 12 
(4 injections), followed by 6 mg RO6867461 IVT every 12 weeks up to Week 48 (injections 
at Weeks 24, 36, and 48; 3 injections) 
• 
Arm B (Q16W):  6 mg RO6867461 IVT every 4 weeks up to Week 12 (4 injections), 
followed by 6 mg RO6867461 IVT every 16 weeks up to Week 48 (injections at Weeks 28 
and 44; 2 injections) 
A protocol-defined assessment of disease activity at Week 24 requires Arm B patients 
with active disease (see criteria below) to switch to a 12-weekly dosing regimen of 
6 mg RO6867461 for the remainder of the study, with injections commencing at 
Week 24 and repeated at Weeks 36 and 48.  
• 
Arm C (comparator arm):  0.5 mg ranibizumab IVT every 4 weeks for 48 weeks 
(13 injections) 
Only one eye will be chosen as the study eye. 
The total duration of the study for each patient will be up to 56 weeks, divided as follows: 
• 
Screening:  up to 4 weeks prior to or on the same day as randomization 
• 
Randomization:  Day 1 
• 
Study Treatment Administration:  from Day 1 to Week 48 
• 
Final Visit:  Week 52 
Patients will undergo a screening examination within 4 weeks of study treatment administration.  
The screening and Week 1/Day 1 (randomization) visit may occur as a combined visit if all 
assessments (with the exception of informed consent) are completed within 48 hours.  
Informed consent must be documented before any study-specific screening procedure is 
performed, and may be obtained more than 28 days before initiation of study treatment.  
Where screening and randomization are combined, assessments listed for both visits only need 
to be conducted once.  During screening (or the combined screening/Day 1 visit), the patient’s 
eligibility will be assessed, including a central review of fundus photography (FP), spectral 
domain optical coherence tomography (SD-OCT), and fundus fluorescein angiography (FFA) to 
ensure that CNV secondary to AMD meets the predefined ocular criteria in the study. 
Patients who were deemed ineligible based on screening results for any of the following 
reasons will be allowed to be re-screened: 
• 
Uncontrolled blood pressure 
• 
Administrative reason (e.g., unable to schedule Day 1 within 28 days from the 
screening visit) 
• 
Not meeting eligibility criteria for the study eye (in the event the patient might be eligible to 
participate for the second eye after the initial screening period) 
At re-screening, all screening visit assessments will be performed (except for FFA imaging 
collection), provided the Central Reading Center-eligible FFA images were taken within 4 weeks 
before the new Day 1 visit (randomization). 
On Day 1, eligible patients will receive their first IVT administration of either RO6867461 or 
ranibizumab according to the randomization schedule described above and following 
established standard administration procedures.  Patients will return to the eye clinic 7 days 
after their first IVT administration and then every 4 weeks for study treatment administration and 
assessments as outlined in the schedule of activities in the protocol.  Sham IVT administration 
will be delivered to patients randomized to Arms A and B to maintain masking throughout the 
study period. 
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All patients will be assessed for disease activity at Week 24.  Patients randomized to Arm B 
who have active disease at Week 24 (see criteria below) will switch to the Q12W dosing 
regimen of 6 mg RO6867461 for the remainder of the study, with injections commencing at 
Week 24 and repeated at Weeks 36 and 48.  
Determination of active disease will be made if any of the following criteria are met: 
• 
Increase in central subfield thickness (CST of > 50 μm on Spectralis® OCT compared to 
average CST over last 2 visits (Weeks 16 and 20) 
Or 
• 
Increase in CST of ≥ 75 μm compared to lowest CST recorded at either Week 16 or 
Week 20  
Or 
• 
Decrease of at least 5 letters of best corrected visual acuity (BCVA) compared with average 
BCVA over last 2 visits (Weeks 16 and 20) due to nAMD disease activity  
Or 
• 
Decrease of ≥ 10 letters of BCVA compared to highest BCVA recorded at either Week 16 or 
Week 20 due to nAMD disease activity  
Or 
• 
Presence of new macular hemorrhage due to nAMD activity 
If, in the opinion of the investigator, there is significant nAMD disease activity at Week 24 that 
requires immediate treatment, but does not meet the above criteria, the Medical Monitor should 
be contacted.  In such cases, following approval by the Sponsor, patients randomized to Arm B 
will receive 6 mg RO6867461 at Week 24 and stay on repeated 12-weekly treatments at 
Weeks 36 and 48. 
Patients who are withdrawn from the study early but have not withdrawn consent should return 
for an early termination visit 28 (+ 7) days following the last study treatment for assessments as 
well as monitoring of all adverse events.   
Patients will return for a final visit at Week 52.  After the final visit, adverse events should be 
followed up as outlined in the protocol.  Assessments performed in case of an unscheduled 
visit(s) are at the discretion of the investigator. 
Number of Patients 
Approximately 75 treatment-naive patients with nAMD are expected to be enrolled and 
randomized in this study in the United States. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
Ocular Criteria for Study Eye 
• 
Treatment-naive CNV secondary to AMD (nAMD) 
• 
Subfoveal CNV or juxtafoveal CNV with a subfoveal component related to the CNV 
activity by FFA or SD-OCT (as evidenced by subretinal fluid, subretinal hyper-reflective 
material, evidence of leakage, or hemorrhage) 
• 
CNV lesion of all types (predominantly classic, minimally classic, or occult) with: 
Total lesion size (including blood, atrophy, fibrosis, and neovascularization) of ≤ 6 disc 
areas by FFA 
And  
CNV component area of ≥ 50% of total lesion size by FFA 
And 
Active CNV confirmed by FFA (evidence of leakage) 
And 
CNV exudation confirmed by SD-OCT (presence of fluid) 
• 
BCVA letter score of 73 to 24 letters (inclusive) on Early Treatment Diabetic Retinopathy 
Study (ETDRS)-like charts (20/40 to 20/320 Snellen equivalent) on Day 1  
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• 
Clear ocular media and adequate pupillary dilatation to allow acquisition of good quality 
retinal images to confirm diagnosis 
General Criteria 
• 
Signed Informed Consent Form 
• 
Age  ≥ 50 years on Day 1 
• 
Ability to comply with the study protocol, in the investigator’s judgment 
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a contraceptive method with a failure rate of < 1% per year 
during the treatment period and for at least 28 days after the last dose of study treatment 
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of < 1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception. 
• 
Patients must be willing not to participate in any other clinical trial including an 
investigational medicinal product (IMP) or device up to completion of the current study 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
Ocular Criteria for Study Eye 
• 
CNV due to causes other than AMD, such as ocular histoplasmosis, trauma, pathological 
myopia, angioid streaks, choroidal rupture, or uveitis  
• 
Central serous chorioretinopathy at screening 
• 
Retinal pigment epithelial tear involving the macula 
• 
On FFA  
Subretinal hemorrhage of > 50% of the total lesion area and/or that involves the fovea 
Fibrosis or atrophy of > 50% of the total lesion area and/or that involves the fovea 
• 
Any prior or concomitant treatment for CNV including (but not restricted to) IVT treatment 
(steroids, anti-vascular endothelial growth factor [VEGF], tissue plasminogen activator, 
ocriplasmin, C3F8 gas, air), periocular pharmacological intervention, argon LASER 
photocoagulation, verteporfin photodynamic therapy, diode laser, transpupillary 
thermotherapy, or surgical intervention  
• 
Cataract surgery within 3 months of baseline assessments (Day 1) 
• 
Any other intraocular surgery (pars plana vitrectomy, glaucoma surgery, corneal transplant, 
radiotherapy) 
• 
Prior IVT treatment (including anti-VEGF medication) except for management of cataract 
complication with steroid IVT treatment 
• 
Prior periocular pharmacological intervention for other retinal diseases 
Concurrent Ocular Conditions 
• 
Any concurrent intraocular condition in the study eye (e.g., amblyopia, aphakia, retinal 
detachment, cataract, diabetic retinopathy or maculopathy, or epiretinal membrane with 
traction) that, in the opinion of the investigator, could either reduce the potential for visual 
improvement or require medical or surgical intervention during the course of the study 
• 
Active intraocular inflammation (grade trace or above) in the study eye on Day 1 (prior to 
randomization) 
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• 
Current vitreous hemorrhage in the study eye 
• 
Uncontrolled glaucoma (e.g., progressive loss of visual fields or defined as intraocular 
pressure [IOP] ≥ 25 mmHg despite treatment with anti-glaucoma medication) in the 
study eye 
• 
Spherical equivalent of refractive error demonstrating more than 8 diopters of myopia in the 
study eye 
• 
History of idiopathic or autoimmune-associated uveitis in either eye 
• 
Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye on Day 1 
(prior to randomization) 
General Criteria 
• 
Any major illness or major surgical procedure within 1 month before screening  
• 
Uncontrolled blood pressure ([BP] defined as systolic > 180 mmHg and/or diastolic 
> 100 mmHg while patient at rest).  If a patient’s initial reading exceeds these values, 
a second reading may be taken later on the same day, or on another day during the 
screening period.  If the patient’s BP is controlled by antihypertensive medication, the 
patient should be taking the same medication continuously for at least 30 days prior to 
Day 1.  
• 
Stroke or myocardial infarction within 3 months prior to Day 1 
• 
History of other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory findings giving reasonable suspicion of a condition that contraindicated the use of 
the investigational drug or that might affect interpretation of the results of the study or 
renders the patient at high risk for treatment complications in the opinion of the investigator 
• 
Pregnant or breastfeeding, or intending to become pregnant during the study 
Women of childbearing potential must have a negative urine pregnancy test result 
within 28 days prior to initiation of study treatment.  If the urine pregnancy test is 
positive, it must be confirmed by a serum pregnancy test. 
• 
Known hypersensitivity to ranibizumab, fluorescein, any ingredients of the formulation used, 
dilating eye drops, or any of the anesthetic and antimicrobial drops used 
• 
Treatment with investigational therapy within 3 months prior to initiation of study treatment 
End of Study 
The end of the study is defined as the date when the last patient last visit (LPLV) occurs.  LPLV 
is expected to occur 52 weeks after the last patient is enrolled. 
Length of Study 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 18−19 months. 
Investigational Medicinal Products 
Test Product (Investigational Drug) 
RO6867461 Drug Product (120 mg/mL) will be provided as a sterile, colorless to brownish liquid 
and contains no preservatives.  Each single-use, 2-mL vial with a nominal 0.5-mL fill contains 
60 mg (nominal) of RO6867461 formulated as a 120-mg/mL in L-histidine/HCl buffer solution 
(approximately pH 6.0) containing sodium chloride, sucrose, and polysorbate 20. 
RO6867461 Drug Product required for completion of this study will be provided by the Sponsor.  
RO6867461 Drug Product packaging will be overseen by the Roche clinical trial supplies 
department and bear labels with the identification required by local law, the protocol number, 
drug identification, and strength. 
The packaging and labeling of RO6867461 Drug Product will be in accordance with Roche 
standard and local regulations. 
RO6867461 Drug Product must be stored according to the details on the product label and the 
information provided in the Pharmacy Manual. 
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Upon arrival of the masked investigational products at the site, site personnel should check 
them for damage and verify proper identity, quantity, integrity of seals and temperature 
conditions, and report any deviations or product complaints to the monitor upon discovery. 
For further details, see the RO6867461 Investigator’s Brochure. 
Comparator 
Ranibizumab (nominal content 0.5 mg/0.05 mL) required for completion of this study will be 
provided by the Sponsor as a solution formulated at 10 mg/mL, and supplied as a single-use 
2-mL vial.   
Ranibizumab packaging will be overseen by the Roche clinical trial supplies department and 
bear labels with the identification required by local law, the protocol number, drug identification, 
and strength. 
The packaging and labeling of ranibizumab will be in accordance with Roche standard and local 
regulations. 
Ranibizumab must be stored according to the details on the product label and the information 
provided in the Pharmacy Manual.  
Upon arrival of the masked investigational products at the site, site personnel should check 
them for damage and verify proper identity, quantity, integrity of seals, and temperature 
conditions, and report any deviations or product complaints to the monitor upon discovery. 
Sham Administration 
A sham administration is a procedure that mimics an IVT administration of study drug, except 
that the blunt end of an empty syringe is pressed against an anesthetized eye instead of a 
needle attached to a study drug-filled syringe.  Empty boxes identical to the other study 
treatment boxes will be supplied for sham administration. 
Upon arrival of the masked material at the site, site personnel should check sham boxes for 
damage and verify proper identity and quantity, and report any deviations or product complaints 
to the monitor upon discovery. 
Refer to the protocol for additional details on dosage, administration, and compliance for 
RO6867461, ranibizumab, and sham. 
Statistical Methods 
Primary Analysis 
The primary efficacy endpoint is BCVA change from baseline at Week 40.  The primary efficacy 
analysis will be performed using a Mixed Model for Repeated Measurement (MMRM) model.  
The model will include the categorical covariates of treatment group, visit, and visit by treatment 
group interaction and the continuous covariate of baseline BCVA.  An unstructured covariance 
will be used to account for within-patient correlation, but another variance-covariance structure, 
such as AR(1), may be selected in case of convergence issues.   
Means for RO6867461 and ranibizumab arms, difference of the means relative to ranibizumab, 
and the corresponding two-sided 80% confidence intervals will be computed.  There will not be 
formal correction for multiple testing. 
Determination of Sample Size   
The focus of this trial is estimation rather than hypothesis testing.  The sample size was 
determined largely based on logistical considerations.  Assuming a common standard deviation 
for BCVA change from baseline of 13.5 letters, the distance from the difference of the means 
between RO6867461 (n = 30) and ranibizumab (n = 15) to the 80% two-sided confidence interval 
bounds is estimated to be 5.5 letters. 
Optional Interim Analyses  
Given the hypothesis-generating 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 the Sponsor IMC and 
appropriate senior management personnel who will be unmasked at the treatment group level.  
Access to treatment assignment information will follow the Sponsor’s standard procedures. 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
ADA 
anti-drug antibody 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AMD 
age-related macular degeneration 
Ang-1 
angiopoietin-1 
Ang-2 
angiopoietin-2 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATE 
arterial thromboembolic event 
AUC 
area under the concentration−time curve 
BCVA 
best corrected visual acuity 
BP 
blood pressure 
CFT 
central foveal thickness 
Cmax
maximum concentration observed 
CNV 
choroidal neovascularization 
CRO 
contract research organization 
CST 
central subfield thickness 
DLE 
dose-limiting event 
DMC 
Data Monitoring Committee 
DME 
diabetic macular edema 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EDI 
enhanced depth imaging 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
FFA 
fundus fluorescein angiography 
FP 
fundus photography 
GLP 
Good Laboratory Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HCT 
hematocrit 
ICH 
International Council on Harmonisation 
IgG1 
immunoglobulin G1 
IMC 
Internal Monitoring Committee 
IMP 
investigational medicinal product 
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Abbreviation 
Definition 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IOP 
intraocular pressure 
IRB 
Institutional Review Board 
IVT 
intravitreal(ly) 
IxRS 
Interactive Voice and Web Response System 
LPLV 
last patient, last visit 
mAb 
monoclonal antibody 
MCH 
mean corpuscular hemoglobin 
MCV 
mean corpuscular volume 
MMRM 
Mixed Model for Repeated Measurement 
nAMD 
neovascular age-related macular degeneration 
NGS 
next-generation sequencing 
OCT 
optical coherence tomography 
OCT-A 
optical coherence tomography angiography 
PD 
pharmacodynamics 
PK 
pharmacokinetic 
PT 
prothrombin time 
Q4W 
every 4 weeks 
Q8W 
every 8 weeks 
Q12W 
every 12 weeks 
Q16W 
every 16 weeks 
RBR 
Research Biosample Repository 
SD-OCT 
spectral domain optical coherence tomography 
ULN 
upper limit of normal 
VA 
visual acuity 
VEGF 
vascular endothelial growth factor 
VEGF-A 
vascular endothelial growth factor A 
wAMD 
wet age-related macular degeneration 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON CHOROIDAL NEOVASCULARIZATION IN 
AGE-RELATED MACULAR DEGENERATION   
Choroidal neovascularization (CNV) secondary to age-related macular degeneration 
(AMD; also known as neovascular AMD [nAMD] or wet AMD [wAMD]) is a form of 
advanced AMD that can result in rapid and severe visual impairment, and remains a 
leading cause of vision loss and visual morbidity (Bourne et al. 2013; Wong et al. 2014).  
According to the National Eye Institute (2016), more than 2 million people in the United 
States had some form of advanced AMD in 2010, and this number is expected to grow 
to 2.95 million by 2020 and 3.6 million by 2030.  nAMD is characterized by the 
proliferation of abnormal choroidal vessels that penetrate Bruch’s membrane in the form 
of choroidal neovascular membranes leading to the exudation of fluid and blood into and 
underneath the retina.  This exudative process causes disruption to the normal retinal 
architecture and severe visual impairment. 
The treatment of nAMD was revolutionized by the introduction of biological molecules 
that targeted an important factor in pathological angiogenesis, vascular endothelial 
growth factor A (VEGF-A; Brown et al. 2006; Rosenfeld et al. 2006).  Although 
anti-VEGF therapies have set a new efficacy paradigm in terms of preventing further 
visual loss or blindness, some patients with nAMD do not gain vision or continue to lose 
vision despite anti-VEGF therapy (Brown et al. 2006; Rosenfeld et al. 2006; CATT 
Research Group 2016).  Even under trial conditions with regular monitoring visits and 
frequent injections, many eyes with nAMD fail to regain lost vision with approximately 
20% continuing to deteriorate and over 60% failing to achieve 20/40 vision 
(Schmidt-Erfurth et al. 2014; European Medicines Agency 2016; CATT Research Group 
2016).  Therefore, there is a need for more efficacious therapies that can increase vision 
gains and reduce the risk of further sight loss.  Neovascularization in AMD is a 
multifactorial process; therefore, targeting an additional soluble factor that is essential to 
angiogenesis, such as angiopoietin-2 (Ang-2), in addition to VEGF, may help to improve 
efficacy and treatment outcomes.  
To maintain vision gains, currently available anti-VEGF treatments require frequent and 
long-term administration (Heier et al. 2012; CATT Research Group 2016).  Real-world 
data suggest that many patients with nAMD do not receive optimal treatment 
frequency, and this under-treatment in clinical practice is associated with lower visual 
acuity gains compared with randomized in controlled clinical trials (Cohen et al. 2013; 
Finger et al. 2013; Holz et al. 2015).  Under-treatment in clinical practice reflects the 
burden of frequent therapy on patients, caregivers, and the healthcare system 
(Gohil et al. 2015; Prenner et al. 2015; Varano et al. 2015; CATT Research Group 2016; 
Vukicevic et al. 2016). 
Partly because some patients continue to lose vision despite regular treatment, and 
partly due to fewer injections being delivered in clinical practice than in clinical trials 
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(Holz et al. 2015), AMD remains a leading cause of blindness and visual morbidity 
despite the improved outcomes provided by anti-VEGF therapy (Bourne et al. 2014).  
The current treatment paradigm requires frequent administration for several years to 
maintain optimal results.  Clinical evaluation of alternative anti-angiogenic targets or 
mechanisms of action are warranted to improve upon the clinical benefit of approved 
anti-VEGF therapies and to reduce treatment burden. 
1.2 
BACKGROUND ON RO6867461  
RO6867461 (also known as RG7716) is a novel humanized bispecific immunoglobulin 
G1 (IgG1) monoclonal antibody (mAb) that selectively binds VEGF-A and Ang-2.  The 
VEGF-binding component binds all isoforms of VEGF-A with high affinity, and the 
Ang-2-binding component binds Ang-2, also with high affinity. 
VEGF-A is a signal protein produced by cells that stimulate vasculogenesis and 
angiogenesis.  Uncontrolled VEGF-A expression results in growth of new blood vessels, 
which fail to mature, and show a number of abnormalities including tortuosity and 
reduced number of pericytes.  These structural defects in the newly formed retinal 
vessels can result in fragility, hyperpermeability, and a propensity for exudation and 
bleeding, all of which are key features of pathological neovascularization, and can lead 
to photoreceptor damage and vision impairment. 
Angiopoietin-1 (Ang-1) and Ang-2 are of key importance in the homeostasis of the 
vascular compartment, functioning as ligands of the Tie-2 receptor tyrosine kinase that is 
expressed on endothelial cells (Davis et al. 1996; Maisonpierre et al. 1997; Fiedler et al. 
2003).  Ang-1 is a Tie-2 receptor agonist, and acts as a homeostatic factor that stabilizes 
the mature vasculature by promoting recruitment of pericytes and smooth muscle cells to 
the vessel wall.  In contrast, Ang-2 is an antagonist of Tie-2, and acts as a vascular 
destabilization factor by blocking Ang-1−dependent Tie-2 activation, which leads to 
dissociation of pericytes from existing vessels, thus increasing vessel plasticity, 
rendering vasculature amendable to endothelial barrier breakdown and sprouting of new 
vessels (Davis et al. 1996; Maisonpierre et al. 1997; Fiedler et al. 2003).  Ang-2 levels 
can be upregulated by other pro-angiogenic factors, including VEGF-A, and were shown 
to be increased during angiogenic stress triggered by hypoxia or hyperglycemia.  Ang-2 
also functions as a pro-inflammatory cytokine.  Since upregulation of Ang-2 is associated 
with the release of inflammatory cytokines, adhesion of leukocytes to endothelial cells, 
and migration of leukocytes into the retina, its inhibition may also have additional 
anti-inflammatory benefits. 
Nonclinical studies have shown that VEGF-A and Ang-2 act in concert to regulate the 
vasculature and cooperate to increase retinal endothelial cell permeability in vitro.  
Pharmacological evaluation in vivo demonstrated that simultaneous inhibition of VEGF 
and Ang-2 with the bispecific antibody RO6867461 led to a greater reduction in the size, 
number, and severity of CNV lesions in a laser-induced CNV model in non-human 
primates compared to ranibizumab (anti-VEGF-A) or anti-Ang-2 alone.  Earlier 
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experiments using a mouse model of spontaneous CNV showed that dual inhibition of 
VEGF-A and Ang-2 consistently outperformed monotherapeutic inhibition of either target 
alone in terms of reduction in vascular growth, leakage, edema, and photoreceptor loss 
(Regula et al. 2016).  
In addition, vitreous concentrations of both VEGF-A and Ang-2 were shown to be 
upregulated in diabetic retinopathy, retinal vein occlusion, and to a lesser extent, in 
patients with nAMD (Regula et al. 2016).  Therefore, simultaneous neutralization of both 
targets, VEGF-A and Ang-2, may further normalize the pathological ocular vasculature 
as compared to the current standard of care, anti-VEGF monotherapy. 
A multicenter, Phase I, open-label, single-ascending-dose (0.5, 1.5, 3, or 6 mg) and 
multiple-ascending-dose (3 or 6 mg) study to investigate the safety, tolerability, 
pharmacokinetics, and pharmacodynamics of RO6867461 administered intravitreally 
(IVT) in patients with nAMD has been completed (Study BP28936).  Patients recruited in 
the Phase I study had already received anti-VEGF treatment (≥ 3 IVT treatments in the 
preceding 6 months) but showed an insufficient response, as defined by best corrected 
visual acuity (BCVA) ≤ 20/40 and presence of fluid on optical coherence tomography 
(OCT).  While the primary focus of this study was safety and tolerability following a 
single dose and three sequential doses of RO6867461, 4 weeks apart, there were 
signals of activity in both visual acuity and anatomical endpoints.  
The current ongoing Phase II program includes two studies:  Study BP30099 
(BOULEVARD; ClinicalTrials.gov number NCT02699450) investigating RO6867461 in 
patients with diabetic macular edema (DME) and Study BP29647 (AVENUE; 
ClinicalTrials.gov number NCT02484690) in patients with nAMD. 
In Study BP30099, two dose levels (1.5 mg and 6 mg every 4 weeks [Q4W]) are being 
assessed over 36 weeks to evaluate the efficacy of RO6867461 compared to 0.3 mg 
ranibizumab monotherapy in treatment-naive patients with DME.  Study BP29647 is 
evaluating the efficacy of RO6867461 over 36 weeks at dose levels of 1.5 mg (Q4W) 
and 6 mg (Q4W and every 8 weeks [Q8W]) compared to 0.5 mg ranibizumab 
monotherapy in treatment-naive patients and anti-VEGF−incomplete responder patients 
with nAMD. 
Refer to the RO6867461 Investigator's Brochure for details on nonclinical and 
clinical studies. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
As a result of the chronic, progressive nature of nAMD, frequent injections of currently 
available therapies over extended periods (e.g., monthly or bimonthly injections) are 
recommended.  However, in routine clinical practice, such frequent office visits may not 
be practical or possible for all patients.  Real-world data suggest many patients are 
under-treated with current therapies, leading to suboptimal outcomes (Cohen et al. 2013; 
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Finger et al. 2013; Holz et al. 2015).  In addition, a significant burden is placed on 
patients and their caregivers, as well as treating physicians and the healthcare system.  
A less frequent treatment administration schedule (e.g., every 3 or 4 months) that would 
provide visual acuity outcomes comparable to clinical trial results with frequent 
anti-VEGF monotherapy would therefore represent an important advance on currently 
available therapies, and would address the high unmet medical need for a more feasible 
treatment approach in nAMD patients. 
RO6867461 binds to Ang-2, as well as to all isoforms of VEGF-A.  Nonclinical data 
suggest the potential of adjunctive Ang-2 inhibition for both additional efficacy and 
prolonged duration of anti-leakage action (Cheung et al. 2014; von Leithner et al. 2014; 
Heier 2016; Regula et al. 2016).  This study will assess whether RO6867461 has the 
potential for administration at 12-week or 16-week intervals in further, larger scale 
studies of treatment-naive patients with nAMD.  The study features four initial injections 
of the 6-mg dose followed by monthly assessment visits and fixed injections either every 
12 weeks (Q12W) or every 16 weeks (Q16W).  The extended initiation phase will allow 
patients to continue with frequent dosing during the “gain” phase of their treatment, 
aiming to maximize visual outcomes.  The less frequent dosing thereafter is expected to, 
on average, at least maintain these initial gains.  Only the 6-mg dose of RO6867461 will 
be utilized in this study to ensure sufficient VEGF-A and Ang-2 inhibition to permit less 
frequent dosing (Hutton-Smith et al. 2016).  Patients will undergo monthly assessments 
throughout the study, with those patients intended for Q16W dosing undergoing a 
disease activity assessment at Week 24.  Patients with anatomic or functional signs of 
disease activity at this timepoint will receive Q12W rather than Q16W dosing, in order to 
minimize the risk of under-treatment. 
There are limited clinical efficacy evaluations with anti-Ang-2 approaches in patients with 
retinal disease.  In the Phase I study (BP28936), RO6867461 was well tolerated up to 
the highest dose tested of 6 mg in previously treated patients with nAMD.  No dose-
limiting events (DLEs) or unexpected ocular adverse events were observed, and no 
systemic, drug-related serious adverse events or severe adverse events were reported.  
In addition, pharmacodynamic (PD) activity was observed both in terms of anatomical 
changes and improvements in visual acuity. 
Ongoing review of masked safety data from the two ongoing Phase II studies 
(Study BP29647 in nAMD and Study BP30099 in DME) indicates that the side effects 
are consistent with the safety profile observed in the Phase I study in nAMD, as well as 
the adverse events which are associated with an IVT procedure or natural progression of 
the respective diseases.  To date, no unexpected safety signals have been identified. 
Nonclinical toxicology studies did not reveal any adverse effects that require specific 
warnings and precautions that are different from those applicable to any anti-VEGF 
agents currently used in clinical practice for the treatment of nAMD. 
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This study is designed to evaluate the duration of efficacy response to 6 mg RO6867461 
administered at 12- or 16-week intervals as assessed by the mean change from baseline 
BCVA at Week 40 using Early Treatment Diabetic Retinopathy Study (ETDRS)-like 
charts in patients with nAMD.  Secondary endpoints will include further BCVA 
evaluations and anatomical PD imaging measures relevant to the mechanism of action 
of RO6867461.  In addition, safety and pharmacokinetics will be evaluated in patients 
receiving up to seven doses of RO6867461. 
Taken together, the nonclinical data, the results from the Phase I study in nAMD, and 
the ongoing masked safety assessment in the Phase II studies in nAMD and DME 
disease indications, as well as the unmet need for less frequent dosing, support initiation 
of this Phase II study assessing the duration of efficacy, safety, and PK response to 
RO6867461 in patients with nAMD.  
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2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, and pharmacokinetics of RO6867461 
administered at 12- and 16-week intervals in patients with nAMD.  Specific objectives 
and corresponding endpoints for the study are outlined below. 
Table 1 
Objectives and Corresponding Endpoints 
Primary Efficacy Objective 
Corresponding Endpoint 
• To evaluate the efficacy of RO6867461 
on visual acuity when administered at 
12- and 16-week intervals 
• Mean change from baseline BCVA at Week 40 using 
the ETDRS-like charts 
Secondary Efficacy Objectives 
Corresponding Endpoints 
• To evaluate the efficacy of RO6867461 
on additional visual acuity outcomes  
• Mean change from baseline BCVA over time using 
the ETDRS-like charts 
• Proportion of patients gaining ≥ 15, ≥ 10, ≥ 5, or 
≥ 0 letters from baseline BCVA over time 
• Proportion of patients avoiding loss of ≥ 15, ≥ 10, ≥ 5, 
or ≥ 0 letters from baseline BCVA over time 
• Proportion of patients with BCVA of 20/40 or better 
over time 
• Proportion of patients with BCVA of 20/200 or worse 
over time 
• To evaluate the efficacy of RO6867461 
on anatomic outcome measures using 
SD-OCT 
• Mean change from baseline in CFT over time 
• Mean change from baseline in mean CST (1 mm 
diameter) over time 
• Proportion of patients with intraretinal fluid, subretinal 
fluid, cysts, or pigment epithelial detachment 
over time 
• To evaluate the efficacy of RO6867461  
on anatomic outcome measures 
using FFA 
• Mean change from baseline in total area of CNV at 
Week 40 and Week 52 
• Mean change from baseline in total area of CNV 
component at Week 40 and Week 52 
• Mean change from baseline in total area of leakage at 
Week 40 and Week 52 
Exploratory Efficacy Objective 
Corresponding Endpoints 
• To investigate the incidence of disease 
activity at Week 24 
• Proportion of patients with disease activity at Week 24
Safety Objective 
Corresponding Endpoints 
• To evaluate the safety of multiple IVT 
doses of RO6867461 at 12- and 
16-week intervals 
• Incidence and severity of ocular adverse events 
• Incidence and severity of non-ocular adverse events 
• Other safety data, including but not limited to, 
reasons for withdrawal from study, laboratory data, 
concomitant medications, vital signs, and physical 
examination results will be listed and summarized 
descriptively 
 
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Table 1 
Objectives and Corresponding Endpoints (cont.)  
Exploratory Pharmacokinetic/ 
Pharmacodynamic Objectives 
Corresponding Endpoints 
• To assess the systemic PK profile of 
RO6867461 
• Plasma concentration of RO6867461 at specified 
timepoints 
• To evaluate the RO6867461, 
ranibizumab, free VEGF-A, and Ang-2 
profile in aqueous humor 
• Relationship between aqueous humor RO6867461 
concentrations or PK parameters and free VEGF-A 
and Ang-2 concentrations 
• Relationship between aqueous humor ranibizumab 
concentrations or PK parameters and free VEGF-A 
and Ang-2 concentrations 
• Time course of free VEGF-A and Ang-2 
concentrations in aqueous humor 
Immunogenicity Objective 
Corresponding Endpoints 
• To investigate the formation of plasma 
anti-RO6867461 antibodies 
• Incidence of ADAs during the study  
Exploratory Biomarker Objective 
Corresponding Endpoints 
• To explore levels of potential 
biomarkers of angiogenesis and 
inflammation in aqueous humor at 
baseline and at additional timepoints 
to assess their response to 
RO6867461 
• Relationship between aqueous humor concentration 
of potential biomarkers with primary and secondary 
endpoints 
ADA = anti-drug antibody; Ang-2 = angiopoietin-2; BCVA = best corrected visual acuity; 
CFT = central foveal thickness; CNV = choroidal neovascularization; CST = central subfield 
thickness; ETDRS = Early Treatment Diabetic Retinopathy Study; FFA = fundus fluorescein 
angiography; IVT = intravitreal; PK = pharmacokinetic; SD-OCT = spectral domain optical 
coherence tomography; VEGF-A = vascular endothelial growth factor A. 
 
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3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of the Study Design 
This is a Phase II, multicenter, randomized, active comparator-controlled, subject and 
outcome-assessor masked, parallel group, 52-week study to investigate the efficacy, 
safety, and pharmacokinetics of RO6867461 administered at 12- and 16-week intervals  
in treatment-naive patients with nAMD.  Approximately 75 patients will be enrolled and 
randomized in a 2:2:1 ratio to one of three treatment arms:  
• 
Arm A (Q12W):  6 mg RO6867461 IVT every 4 weeks up to Week 12 (4 injections), 
followed by 6 mg RO6867461 IVT every 12 weeks up to Week 48 (injections at 
Weeks 24, 36, and 48; 3 injections) 
• 
Arm B (Q16W):  6 mg RO6867461 IVT every 4 weeks up to Week 12 (4 injections), 
followed by 6 mg RO6867461 IVT every 16 weeks up to Week 48 (injections at 
Weeks 28 and 44; 2 injections) 
A protocol-defined assessment of disease activity at Week 24 requires Arm B 
patients with active disease (see criteria below) to switch to a 12-weekly dosing 
regimen of 6 mg RO6867461 for the remainder of the study, with injections 
commencing at Week 24 and repeated at Weeks 36 and 48.  
• 
Arm C (comparator arm):  0.5 mg ranibizumab IVT every 4 weeks for 48 weeks 
(13 injections) 
 
Only one eye will be chosen as the study eye. 
The total duration of the study for each patient will be up to 56 weeks, divided as follows: 
• 
Screening:  up to 4 weeks prior to or on the same day as randomization 
• 
Randomization:  Day 1 
• 
Study Treatment Administration:  from Day 1 to Week 48 
• 
Final Visit:  Week 52 
 
Patients will undergo a screening examination within 4 weeks of study treatment 
administration.  The screening and Week 1/Day 1 (randomization) visit may occur as a 
combined visit if all assessments (with the exception of informed consent) are completed 
within 48 hours.  Informed consent must be documented before any study-specific 
screening procedure is performed, and may be obtained more than 28 days before 
initiation of study treatment.  Where screening and randomization are combined, 
assessments listed for both visits only need to be conducted once.  During screening (or 
the combined screening/Day 1 visit), the patient’s eligibility will be assessed, including a 
central review of fundus photography (FP), spectral domain optical coherence 
tomography (SD-OCT), and fundus fluorescein angiography (FFA) to ensure that CNV 
secondary to AMD meets the predefined ocular criteria in the study. 
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Patients who were deemed ineligible based on screening results for any of the following 
reasons will be allowed to be re-screened: 
• 
Uncontrolled blood pressure 
• 
Administrative reason (e.g., unable to schedule Day 1 within 28 days from the 
screening visit) 
• 
Not meeting eligibility criteria for the study eye (in the event the patient might be 
eligible to participate for the second eye after the initial screening period) 
 
At re-screening, all screening visit assessments will be performed (except for FFA 
imaging collection), provided the Central Reading Center-eligible FFA images were 
taken within 4 weeks before the new Day 1 visit (randomization). 
On Day 1, eligible patients will receive their first IVT administration of either RO6867461 
or ranibizumab according to the randomization schedule described above and following 
established standard administration procedures.  Patients will return to the eye clinic 
7 days after their first IVT administration and then every 4 weeks for study treatment 
administration and assessments as outlined in the schedule of activities (Appendix 1).  
Sham IVT administration will be delivered to patients randomized to Arms A and B to 
maintain masking throughout the study period. 
All patients will be assessed for disease activity at Week 24.  Patients randomized to 
Arm B who have active disease at Week 24 (see criteria below) will switch to the Q12W 
dosing regimen of 6 mg RO6867461 for the remainder of the study, with injections 
commencing at Week 24 and repeated at Weeks 36 and 48.  
Determination of active disease will be made if any of the following criteria are met 
(also see Section 4.5.5.4): 
• 
Increase in central subfield thickness (CST of > 50 μm on Spectralis® OCT 
compared to average CST over last 2 visits (Weeks 16 and 20) 
Or 
• 
Increase in CST of ≥ 75 μm compared to lowest CST recorded at either Week 16 or 
Week 20  
Or 
• 
Decrease of at least 5 letters of BCVA compared with average BCVA over last 
2 visits (Weeks 16 and 20) due to nAMD disease activity  
Or 
• 
Decrease of ≥ 10 letters of BCVA compared to highest BCVA recorded at either 
Week 16 or Week 20 due to nAMD disease activity  
Or 
• 
Presence of new macular hemorrhage due to nAMD activity 
 
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If, in the opinion of the investigator, there is significant nAMD disease activity at Week 24 
that requires immediate treatment, but does not meet the above criteria, the Medical 
Monitor should be contacted.  In such cases, following approval by the Sponsor, patients 
randomized to Arm B will receive 6 mg RO6867461 at Week 24 and stay on repeated 
12-weekly treatments at Weeks 36 and 48. 
Patients who are withdrawn from the study early but have not withdrawn consent should 
return for an early termination visit 28 (+ 7) days following the last study treatment for 
assessments as well as monitoring of all adverse events.   
Patients will return for a final visit at Week 52.  After the final visit, adverse events should 
be followed up as outlined in Section 5.6.  Assessments performed in case of an 
unscheduled visit(s) are at the discretion of the investigator. 
Figure 1 presents an overview of the study design.  A schedule of activities is provided in 
Appendix 1. 


 
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Figure 1 Study Schema 
Randomization
Screening
Study Treatment Administration
W48
W4
W8
W12
W16
W20
W24
W28
W44
W36
W32
W40
Day 1
W52
Final Visit
Day -28
Arm A:
RO6867461 Q12W
Arm C:
Ranibizumab Q4W
Arm B:
RO6867461 Q16W
6 mg RO6867461 IVT
Sham
0.5 mg Ranibizumab IVT
Active disease at Week 24 a:
Primary Endpoint
 
IVT = intravitreal; Q4W = every 4 weeks; Q12W = every 12 weeks; Q16W = every 16 weeks; W = week. 
a All patients will be assessed for disease activity at Week 24.  Patients in Arm B who are assessed with active disease at Week 24 will switch to 
RO6867461 Q12W dosing regimen for the remainder of the study.


 
3.1.2 
Internal Monitoring Committee  
The unmasked Roche Internal Monitoring Committee (IMC) will be responsible for the 
review of interim data in the event of an interim analysis for efficacy and/or for safety 
(see Section 6.9).  The IMC will evaluate both safety and efficacy data in the instance 
where assessment of benefit-risk is warranted.  These analyses will take place at 
predefined timepoints or on an ad-hoc basis.  
The IMC consists of a selected subset of Roche representatives including a Statistician, 
Safety Science Representative, Clinical Science Representative, and Clinical 
Pharmacology Representatives.  The IMC members participating in a given interim 
analysis will be kept to the minimum required to address the objective of that interim 
analysis.  Additional Roche representatives may be involved to produce/process the 
unmasked listing/data to be analyzed by the IMC. 
Full details regarding the IMC will be provided separately in the IMC charter. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of the study is defined as the date when the last patient last visit (LPLV) occurs.  
LPLV is expected to occur 52 weeks after the last patient is enrolled. 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 18−19 months. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Dose and Schedule 
The RO6867461 dose (6 mg) selected for this study in patients with nAMD is based on 
both nonclinical and clinical studies.  The Phase I first-in-human study (BP28936) 
evaluated the safety and tolerability of single and multiple administrations of doses 
ranging from 0.5 mg to 6 mg RO6867461.  The selection of these doses was based on 
nonclinical findings and absolute IVT doses administered in the toxicology studies.  The 
nonclinical 6-month Good Laboratory Practice (GLP) toxicity study tested RO6867461 
up to the 3-mg dose level, seven times Q4W IVT.  Due to the approximately 2-fold lower 
vitreous humor volume in cynomolgus monkey as compared to humans, a 3-mg dose 
administered to monkeys achieves similar IVT initial concentrations to the 6-mg dose 
in humans.  
The dose of 6 mg RO6867461 was selected as the highest feasible dose of RO6867461 
in the Phase I study in nAMD, as well as in the two ongoing Phase II studies (one in 
nAMD and one in DME).  It represents an anti-VEGF dose equivalent to a 2-mg 
ranibizumab dose, which was shown to be safe in a large clinical trial (Busbee et al. 
2013).  The Phase I study did not reveal a safety signal following 3 monthly IVT doses of 
up to 6 mg RO6867461 (n = 6) in patients with nAMD.  RO6867461 was well tolerated in 
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23 patients up to 4 weeks after the last of 1−3 IVT administrations of up to the 6-mg 
dose level. 
The two ongoing Phase II studies are evaluating two dose levels (1.5 mg and 6 mg) of 
RO6867461 at different dosing schedules (Q4W for Study BP30099; Q4W and Q8W for 
Study BP29647) in nAMD and DME disease indications.  Of note, the Phase I study 
used a 60-mg/mL formulation as the highest concentration, translating to a 50- and 
100-μL injection volume for the 3 mg and 6 mg RO6867461 doses, 
respectively.  However, the formulation for the present study, similar to the ongoing 
Phase II studies, utilizes a 120-mg/mL concentration, which translates to a 50-μL 
injection volume for the 6-mg RO6867461 dose. 
Systemic exposure observed in patients following IVT administration is lower as 
compared to exposures observed in the cynomolgus monkey GLP toxicity study (refer to 
the RO6867461 Investigator's Brochure). 
The nonclinical and clinical data suggest that the 6-mg RO6867461 dose is safe and 
well tolerated.  The current study will assess the clinical outcomes of less frequent 
dosing following four initial monthly injections of RO6867461.  As the durability of effect 
is expected to increase with higher doses (Hutton-Smith et al. 2016), the 6-mg dose has 
been selected for this study.  RO6867461 will be delivered according to one of two 
dosing regimens following treatment initiation with four monthly injections.  Patients 
randomized to Arm A will then receive injections of RO6867461 Q12W, while patients in 
Arm B will receive injections of RO6867461 Q16W.  Based on a protocol-specified 
assessment of nAMD disease activity at Week 24 (see Section 4.5.5.4), patients in 
Arm B with active disease will receive an injection of RO6867461 at that visit, and then 
subsequently at 12-week intervals until end of study.  Patients in Arm B who do not 
exhibit active nAMD will receive 16-weekly injections until the end of the study.  
3.3.2 
Rationale for Patient Population 
This study will be conducted in patients with treatment-naive nAMD who meet all of the 
inclusion criteria and do not meet any of the exclusion criteria for this protocol 
(see Section 4.1.1 and Section 4.1.2). 
3.3.3 
Rationale for Control Group 
The proposed study includes an anti-VEGF arm instead of a placebo arm, as anti-VEGF 
therapy is a well-established standard of care in the target population and placebo is no 
longer an ethically acceptable comparator.  Ranibizumab was the first approved 
treatment demonstrating improvement of mean BCVA in patients with nAMD 
(Brown et al. 2006; Rosenfeld et al. 2006).  These data led to the U.S. approval of 
ranibizumab 0.5 mg monthly for the treatment of nAMD in 2006.  Since then, no 
approved treatment has demonstrated superiority over ranibizumab 0.5 mg monthly, and 
therefore it is an appropriate comparator for this study. 
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3.3.4 
Rationale for Optional Aqueous Humor Assessments 
nAMD is a heterogeneous disease, and VEGF-A and Ang-2 expression has been shown 
to vary among patients (Hera et al. 2005), as well as other mediators of angiogenesis 
and inflammation.  Levels of VEGF-A and Ang-2 in the aqueous humor are believed to 
resemble concentrations in vitreous humor and possibly in the retina.  The primary mode 
of action of RO6867461 is to decrease the free ocular concentrations of VEGF-A and 
Ang-2.  Thus, the assessment of free concentrations of VEGF-A and Ang-2 in aqueous 
humor provides information about the time course of VEGF-A and Ang-2 suppression, 
which is the basis for the duration of drug effect.  Moreover, aqueous humor contains 
several angiogenic and inflammatory factors that may be important for the disease 
progression or response to therapy (Muether et al. 2013; Rezar-Dreindl et al. 2016). 
Thus, assessment of these molecules that have potential to serve as biomarkers of 
angiogenesis and inflammation may help with understanding prognostic factors and 
predictors of response to treatment in nAMD. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 75 treatment-naive patients with nAMD are expected to be enrolled and 
randomized in this study in the United States. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
Ocular Criteria for Study Eye 
• 
Treatment-naive CNV secondary to AMD (nAMD) 
• 
Subfoveal CNV or juxtafoveal CNV with a subfoveal component related to the CNV 
activity by FFA or SD-OCT (as evidenced by subretinal fluid, subretinal hyper-
reflective material, evidence of leakage, or hemorrhage) 
• 
CNV lesion of all types (predominantly classic, minimally classic, or occult) with: 
Total lesion size (including blood, atrophy, fibrosis, and neovascularization) of 
≤ 6 disc areas by FFA 
And  
CNV component area of ≥ 50% of total lesion size by FFA 
And 
Active CNV confirmed by FFA (evidence of leakage) 
And 
CNV exudation confirmed by SD-OCT (presence of fluid) 
• 
BCVA letter score of 73 to 24 letters (inclusive) on ETDRS-like charts (20/40 to 
20/320 Snellen equivalent) on Day 1  
• 
Clear ocular media and adequate pupillary dilatation to allow acquisition of good 
quality retinal images to confirm diagnosis 
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General Criteria 
• 
Signed Informed Consent Form 
• 
Age  ≥ 50 years on Day 1 
• 
Ability to comply with the study protocol, in the investigator’s judgment 
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a contraceptive method with a failure rate of  < 1% 
per year during the treatment period and for at least 28 days after the last dose of 
study treatment 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (≥ 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of  < 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
• 
Patients must be willing not to participate in any other clinical trial including an 
investigational medicinal product (IMP) or device up to completion of the 
current study 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
Ocular Criteria for Study Eye 
• 
CNV due to causes other than AMD, such as ocular histoplasmosis, trauma, 
pathological myopia, angioid streaks, choroidal rupture, or uveitis  
• 
Central serous chorioretinopathy at screening 
• 
Retinal pigment epithelial tear involving the macula 
• 
On FFA  
Subretinal hemorrhage of  > 50% of the total lesion area and/or that involves 
the fovea 
Fibrosis or atrophy of  > 50% of the total lesion area and/or that involves 
the fovea 
• 
Any prior or concomitant treatment for CNV including (but not restricted to) IVT 
treatment (steroids, anti-VEGF, tissue plasminogen activator, ocriplasmin, C3F8 gas, 
air), periocular pharmacological intervention, argon LASER photocoagulation, 
verteporfin photodynamic therapy, diode laser, transpupillary thermotherapy, or 
surgical intervention  
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• 
Cataract surgery within 3 months of baseline assessments (Day 1) 
• 
Any other intraocular surgery (pars plana vitrectomy, glaucoma surgery, corneal 
transplant, radiotherapy) 
• 
Prior IVT treatment (including anti-VEGF medication) except for management of 
cataract complication with steroid IVT treatment 
• 
Prior periocular pharmacological intervention for other retinal diseases 
 
Concurrent Ocular Conditions 
• 
Any concurrent intraocular condition in the study eye (e.g., amblyopia, aphakia, 
retinal detachment, cataract, diabetic retinopathy or maculopathy, or epiretinal 
membrane with traction) that, in the opinion of the investigator, could either reduce 
the potential for visual improvement or require medical or surgical intervention 
during the course of the study 
• 
Active intraocular inflammation (grade trace or above) in the study eye on Day 1 
(prior to randomization) 
• 
Current vitreous hemorrhage in the study eye 
• 
Uncontrolled glaucoma (e.g., progressive loss of visual fields or defined as 
intraocular pressure [IOP]  ≥ 25 mmHg despite treatment with anti-glaucoma 
medication) in the study eye 
• 
Spherical equivalent of refractive error demonstrating more than 8 diopters of 
myopia in the study eye 
• 
History of idiopathic or autoimmune-associated uveitis in either eye 
• 
Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye on 
Day 1 (prior to randomization) 
 
General Criteria 
• 
Any major illness or major surgical procedure within 1 month before screening  
• 
Uncontrolled blood pressure ([BP] defined as systolic > 180 mmHg and/or diastolic 
> 100 mmHg while patient at rest).  If a patient’s initial reading exceeds these 
values, a second reading may be taken later on the same day, or on another day 
during the screening period.  If the patient’s BP is controlled by antihypertensive 
medication, the patient should be taking the same medication continuously for at 
least 30 days prior to Day 1.  
• 
Stroke or myocardial infarction within 3 months prior to Day 1 
• 
History of other disease, metabolic dysfunction, physical examination finding, or 
clinical laboratory findings giving reasonable suspicion of a condition that 
contraindicated the use of the investigational drug or that might affect interpretation 
of the results of the study or renders the patient at high risk for treatment 
complications in the opinion of the investigator 
• 
Pregnant or breastfeeding, or intending to become pregnant during the study 
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Women of childbearing potential must have a negative urine pregnancy test 
result within 28 days prior to initiation of study treatment.  If the urine pregnancy 
test is positive, it must be confirmed by a serum pregnancy test. 
• 
Known hypersensitivity to ranibizumab, fluorescein, any ingredients of the 
formulation used, dilating eye drops, or any of the anesthetic and antimicrobial 
drops used 
• 
Treatment with investigational therapy within 3 months prior to initiation of study 
treatment 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND MASKING  
4.2.1 
Treatment Assignment 
After written informed consent has been obtained, all patients will receive a screening 
number assigned through the Interactive Voice and Web Response System (IxRS).  
A patient must satisfy all eligibility criteria (see Section 4.1.1 and Section 4.1.2) prior to 
randomization.  
Patients will be randomized on the same day the study treatment is to be initiated (Day 1 
visit).  After randomization and at each visit with study treatment administration 
(i.e., including Day 1) the IxRS will assign the appropriate study treatment kit to be used. 
Randomization will be stratified for baseline BCVA ETDRS letter score assessed on 
Day 1 (55 letters or better vs. 54 letters or worse). 
Randomization with fixed permuted blocks will be used to obtain an approximate 2:2:1 
ratio between the different arms within each stratum. 
4.2.2 
Masking 
This is a patient- and outcome assessor (BCVA and Central Reading Center)-masked 
study.  The intent of this design allows for a single investigator per site to be present at a 
given visit to fulfill the masking requirements of this study.   
At a site level: 
• 
Patients and BCVA examiners will be masked to treatment assignment.  BCVA 
examiners will also be masked to study eye (see Section 4.5.5.1).  All other site 
personnel that do not have a role in drug preparation and/or treatment delivery 
should be masked to study eye drug assignment.   
• 
The investigator administrating the patient’s treatment (RO6867461, comparator 
ranibizumab, or sham) and/or pharmacist/designated personnel responsible for 
drug preparation will be unmasked to treatment assignment.   
 
The number of unmasked study personnel should be limited to ensure the integrity of 
this masked study.  All roles for each study staff member should be clearly documented 
in the site delegation log.  The delegation log must be signed by the Principal 
Investigator.  Unmasked personnel cannot switch to a masked role, but masked 
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personnel can switch to an unmasked role.  Any change should be documented in the 
delegation log. 
At a study level: 
The Central Reading Center personnel, study vendors, and the Sponsor (with the 
exception of a point person[s] to support unmasked site personnel and IMC members in 
the case of an optional interim analysis; Section 3.1.2 and Section 6.9) and its agents 
will be masked to study eye drug assignment. 
For biosamples: 
To maintain the masked design of the study, blood samples collected at timepoints 
specified in the schedule of activities (Appendix 1) will also be taken from all patients 
receiving ranibizumab per the RO6867461 schedule.  The samples from these patients 
may or may not be analyzed.  Unmasking for independent analysis of the relevant 
biosamples during the conduct of the study will be performed according the Sponsor’s 
internal standard procedures in place to ensure integrity of the data.  The number of 
Roche representative(s) and delegates unmasked will be kept to the minimum required 
to address the objective of the biosample analysis. 
4.3 
STUDY TREATMENT  
The investigational medicinal products (IMPs) for this study are RO6867461 and 
ranibizumab. 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
RO6867461  
RO6867461 Drug Product (120 mg/mL) will be provided as a sterile, colorless to 
brownish liquid and contains no preservatives.  Each single-use, 2-mL vial with a 
nominal 0.5-mL fill contains 60 mg (nominal) of RO6867461 formulated as a 120-mg/mL 
in L-histidine/HCl buffer solution (approximately pH 6.0) containing sodium chloride, 
sucrose, and polysorbate 20. 
RO6867461 Drug Product required for completion of this study will be provided by 
the Sponsor.  
RO6867461 Drug Product packaging will be overseen by the Roche clinical trial supplies 
department and bear labels with the identification required by local law, the protocol 
number, drug identification, and strength. 
The packaging and labeling of RO6867461 Drug Product will be in accordance with 
Roche standard and local regulations. 
RO6867461 Drug Product must be stored according to the details on the product label 
and the information provided in the Pharmacy Manual. 
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Upon arrival of the masked investigational products at the site, site personnel should 
check them for damage and verify proper identity, quantity, integrity of seals and 
temperature conditions, and report any deviations or product complaints to the monitor 
upon discovery. 
For further details, see the RO6867461 Investigator’s Brochure. 
4.3.1.2 
Ranibizumab 
Ranibizumab (nominal content 0.5 mg/0.05 mL) required for completion of this study will 
be provided by the Sponsor as a solution formulated at 10 mg/mL, and supplied as a 
single-use 2-mL vial.   
Ranibizumab packaging will be overseen by the Roche clinical trial supplies department 
and bear labels with the identification required by local law, the protocol number, drug 
identification, and strength. 
The packaging and labeling of ranibizumab will be in accordance with Roche standard 
and local regulations. 
Ranibizumab must be stored according to the details on the product label and the 
information provided in the Pharmacy Manual.  
Upon arrival of the masked investigational products at the site, site personnel should 
check them for damage and verify proper identity, quantity, integrity of seals, and 
temperature conditions, and report any deviations or product complaints to the monitor 
upon discovery. 
4.3.1.3 
Sham 
A sham administration is a procedure that mimics an IVT administration of study drug, 
except that the blunt end of an empty syringe is pressed against an anesthetized eye 
instead of a needle attached to a study drug-filled syringe (see Appendix 3).  Empty 
boxes identical to the other study treatment boxes will be supplied for sham 
administration. 
Upon arrival of the masked material at the site, site personnel should check sham boxes 
for damage and verify proper identity and quantity, and report any deviations or product 
complaints to the monitor upon discovery. 
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4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
RO6867461, Ranibizumab, and Sham 
Patients will be given a 50-μL IVT injection of RO6867461 or ranibizumab into the study 
eye, or a sham administration, according to the randomization schedule as described 
below (also see Section 3.1.1 and Figure 1). 
• 
Arm A (Q12W):  6 mg RO6867461 IVT every 4 weeks up to Week 12 (4 injections), 
followed by 6 mg RO6867461 IVT every 12 weeks up to Week 48 (injections at 
Weeks 24, 36, and 48; 3 injections) 
• 
Arm B (Q16W):  6 mg RO6867461 IVT every 4 weeks up to Week 12 (4 injections), 
followed by 6 mg RO6867461 IVT every 16 weeks up to Week 48 (injections at 
Weeks 28 and 44; 2 injections) 
• 
Arm C (comparator arm):  0.5 mg ranibizumab IVT every 4 weeks for 48 weeks 
(13 injections) 
 
Only one eye will be chosen as the study eye. 
A protocol-defined assessment of disease activity at Week 24 requires patients in Arm B 
with active disease (see criteria in Section 4.5.5.4) to switch to a 12-weekly dosing 
regimen of 6 mg RO6867461 for the remainder of the study, with injections commencing 
at Week 24 and repeated at Weeks 36 and 48. 
Sham IVT administration will be delivered to patients to maintain subject masking 
throughout the study period.  In Arm A, sham IVT administrations will occur at Weeks 16, 
20, 28, 32, 40, and 44.  In Arm B, sham IVT administrations will occur at Weeks 16, 20, 
24, 32, 36, 40, and 48, or at Weeks 16, 20, 28, 32, 40, and 44, the latter if the dosing 
regimen was switched to the 12-weekly schedule. 
The Pharmacist responsible for dispensing the study treatment, or designated personnel, 
will prepare the correct study treatment (RO6867461, ranibizumab, or sham) as 
assigned by the IxRS. 
Detailed stepwise instructions for the preparation of RO6867461, ranibizumab, or sham 
for administration, and mandatory materials to be used will be provided by the Sponsor, 
and are detailed in the Pharmacy Manual.  Pre- and post-treatment administration 
procedures as well as instructions for performing the IVT and sham administrations are 
provided in Appendix 3. 
A specified filter needle must be used for each dose preparation of RO6867461 or 
ranibizumab as per the instructions provided in the Pharmacy Manual.  All materials to 
prepare and administer study treatments will be provided by the Sponsor and no other 
material than provided should be used. 
Vials of RO6867461 Drug Product and vials of ranibizumab (active comparator) are for 
single-use only (one injection preparation per patient per eye).  Vials used for 1 patient 
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must not be used for any other patient.  Partially used vials, leftover RO6867461 Drug 
Product or ranibizumab vials, as well as administration material, must not be re-used.   
4.3.3 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (RO6867461 and ranibizumab) will be 
provided by the Sponsor where required by local health authority regulations.  The study 
site will acknowledge receipt of IMPs using the IxRS to confirm the shipment condition 
and content.  Any damaged shipments will be replaced. 
IMPs either will be disposed of at the study site according to the study site’s institutional 
standard operating procedure or at the central depot.  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, and IMP destruction must 
be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.4 
Sham Boxes Accountability 
Empty sham boxes will be provided by the Sponsor.  The investigational site will 
acknowledge receipt of the sham boxes to confirm the shipment condition.  Any damaged 
shipments will be replaced. 
The investigator is responsible for the control of all study treatments including sham.  
The same accountability requirements and activities apply for sham boxes as for IMPs 
(see Section 4.3.3). 
4.3.5 
Post-Trial Access to RO6867461 
Currently, the Sponsor does not have any plans to provide RO6867461 or any other 
study treatments or interventions to patients who have completed the study.  The 
Sponsor may evaluate whether to continue providing RO6867461 in accordance with the 
Roche Global Policy on Continued Access to Investigational Medicinal Product, available 
at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
 
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4.4 
CONCOMITANT THERAPY 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) other than 
protocol-specified procedural medications and pre- and post-treatment administration 
medications used by a patient from 7 days prior to initiation of study drug to the final 
study visit/early termination visit.  All such medications should be reported to the 
investigator and recorded on the Concomitant Medications electronic Case Report 
Form (eCRF).  
4.4.1 
Permitted Therapy  
Patients who use maintenance therapy other than those required to treat nAMD should 
continue their use (see Section 4.4.3 regarding treatment of nAMD in the fellow eye). 
The decision to administer antimicrobial drops before and after the IVT administration is 
at the discretion of the investigator.  Where antimicrobials are administered, it must be 
recorded on the concomitant medication forms of the eCRF. 
4.4.2 
Prohibited Therapy 
At the discretion of the investigator, patients may continue to receive all medications and 
standard treatments administered for other conditions except in the following instances: 
• 
Concurrent use of systemic anti-VEGF agents 
• 
Concurrent use of IVT or subtenon corticosteroids in the study eye, except as 
required to treat adverse events 
• 
Concurrent use of photocoagulation or photodynamic therapy with verteporfin in the 
study eye 
 
4.4.3 
CNV Secondary to AMD in the Fellow Eye 
Should nAMD emerge or recur and require treatment in the fellow eye during the study 
period, the patient may receive approved anti-VEGF standard of care treatment. 
When treatment in the fellow eye is scheduled on the same day as a study visit, all study 
assessments should be completed before treating the fellow eye. 
When anti-VEGF therapy is recommended and ranibizumab warranted, every effort 
should be made to treat with ranibizumab.  This treatment will be provided by the 
Sponsor as long as the patient remains in the study.  When provided by the Sponsor, it 
will be in the commercial formulation for ranibizumab labelled for investigational use only 
(dispatched by IxRS).  Treatment with commercial supplies of ranibizumab may be 
reimbursed at the discretion and approval of the Sponsor. 
Treatment with other approved anti-VEGF therapies may be provided by the site.  
However, commercial supplies of other approved anti-VEGF treatments will not be 
reimbursed by the Sponsor. 
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Standard of care treatment after the early termination visit or final visit will not be 
supplied by the Sponsor. 
4.5 
STUDY ASSESSMENTS  
Please see Appendix 1 for the schedule of activities to be performed during the study. 
At timepoints when several assessments coincide, the following sequence is suggested, 
at the discretion of the investigator.  The order can be adjusted to optimize site 
personnel and patient’s time management, except where explicitly stated as mandatory 
(i.e., text in italics): 
• 
Vital signs 
• 
Blood sampling:  At visits where FFA is performed, blood sampling and angiography 
can be performed from the same venous cannula.  Blood samples must be collected 
before angiography. 
• 
Ocular assessments and imaging 
BCVA:  BCVA must be conducted before pupil dilation.  At screening and Day 1 
visits, BCVA can be performed before vital signs and blood sampling to avoid 
unnecessary investigations in those patients who may be a screen failure as a 
result of BCVA letter score. 
Slitlamp examination 
Pupil dilation 
SD-OCT  
FP (+ infrared reflectance) 
FFA 
Dilated binocular indirect high-magnification ophthalmoscopy 
IOP:  mandatory to be performed after all imaging assessments, and the same 
method should be used throughout the study period 
• 
Aqueous humor sampling (optional) 
 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures.  Informed Consent Forms for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site. 
All screening evaluations and pretreatment assessments must be completed and 
reviewed to confirm that patients meet all eligibility criteria, including Central Reading 
Center confirmation of eligibility for a predefined set of imaging criteria.  The investigator 
will maintain a screening log to record details of all patients screened and to confirm 
eligibility or record reasons for screening failure, as applicable. 
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An Eligibility Screening Form documenting the investigator’s assessment of each 
screened patient with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the investigator and kept at the investigational site. 
4.5.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
use of alcohol, and drugs of abuse.  In addition, all medications (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by the patient within 7 days prior to the screening visit and within the 
screening period (other than reported to treat an adverse event as defined in 
Section 5.3.1) will be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Physical Examinations 
A physical examination will include body weight and height at screening, and should 
cover head and neck including lymph nodes, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, neurological systems, and others as 
applicable. 
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient’s notes.  New or worsened clinically significant abnormalities should 
be recorded as adverse events on the Adverse Event eCRF. 
4.5.4 
Vital Signs 
Vital signs will include measurements of pulse rate and systolic and diastolic blood 
pressure while the patient is in a seated position, and temperature. 
4.5.5 
Disease-Specific Assessments 
Unless otherwise noted in schedule of activities (Appendix 1), all ocular assessments 
should be performed for both eyes. 
4.5.5.1 
Best Corrected Visual Acuity 
BCVA at a starting test distance of 4 meters will be measured prior to dilating eyes by a 
trained and certified visual acuity (VA) examiner masked to study eye treatment 
assignment.   
BCVA will be measured using the set of three Precision VisionTM or Lighthouse distance 
acuity charts (modified ETDRS Charts 1, 2, and R).  A VA Procedure Manual will be 
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provided to the investigators.  VA examiner and VA examination room certifications will 
be obtained before any VA examinations are performed. 
The BCVA examiner will be masked to the study eye and treatment assignment and will 
perform the refraction and BCVA assessments (e.g., VA Specification Manual).  The 
BCVA examiner will also be masked to the BCVA letter scores of a patient’s previous 
visits and may only know patient refraction data from previous visits. 
4.5.5.2 
Additional Ocular Assessments 
Additional ocular assessments to be performed during the study include the following: 
• 
Slitlamp examination (scales for grading flare/cells and vitreous hemorrhage density 
are detailed in Appendix 2) 
• 
Dilated binocular indirect high-magnification ophthalmoscopy 
• 
IOP  
The method of IOP measurement used for a patient must remain consistent 
throughout the study.  IOP measurement of both eyes is to be performed after 
all imaging.  
At study treatment visits, IOP pressure is to be conducted prior to study 
treatment administration and 30 (± 15) minutes post-treatment administration 
in the study eye, and if IOP ≥ 30 mmHg, IOP should be re-assessed 
30 (± 15) minutes later.  If IOP continues to be elevated, treatment should be 
undertaken at the discretion of the investigator. 
• 
Finger count vision assessment 
In the study eye, a post-treatment optic nerve head perfusion will be assessed 
for each patient immediately after study treatment administration (maximum 
within 15 minutes after treatment administration) by testing finger count vision, 
hand motion, or light perception as appropriate. 
 
4.5.5.3 
Ocular Imaging  
The Central Reading Center will provide sites with the Central Reading Center Manual 
and training materials for study-mandated ocular imaging.  Before study images are 
obtained, site personnel and imaging systems (where applicable) will be certified by the 
reading center as specified in the Central Reading Center Manual.  All study subject 
ocular images will be obtained only by trained and Central Reading Center certified 
personnel on certified/registered equipment at the study sites.  A copy of all study 
subject ocular images will be transferred to the central reading center for storage and for 
independent analysis, including for confirmation of eligibility of defined image-related 
criteria. 
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Ocular images to be obtained and a copy transferred to the Central Reading Center, 
according to specifications provided in the Central Reading Center Manual, include 
the following: 
• 
Fundus photography (FP) 
• 
Fundus fluorescein angiography (FFA) 
• 
Spectral domain optical coherence tomography (SD-OCT) 
• 
Optional optical coherence tomography angiography (OCT-A; to be conducted at 
sites with OCT-A capability) 
 
For FFA and FP, images of both eyes should be acquired and forwarded to the Central 
Reading Center. 
For SD-OCT and optional OCT-A, images of the study eye and fellow eyes should be 
captured and forwarded to the Central Reading Center at the screening, Week 24, Week 
40, and Week 52 or early termination visits.  At all other visits, only the study eye images 
need to be acquired and forwarded to the Central Reading Center. 
At visits where FFA is performed, blood sampling and angiography can be performed 
from the same venous cannula.  Blood samples must be collected before angiography. 
SD-OCT will be performed at the study sites by trained and Central Reading 
Center-certified personnel on a Spectralis instrument (Heidelberg Engineering, 
Heidelberg, Germany), equipped with TrueTrack™ Active Eye Tracking, AutoRescan™, 
and enhanced depth imaging (EDI).  All devices used in the study will be registered with 
the Central Reading Center.  Scans will be acquired and a copy transferred to the 
Central Reading Center according specifications provided in the separate Central 
Reading Center Manual.  The Heidelberg Eye Explorer (HEYEX) software will be used to 
review the images at the study site. 
4.5.5.4 
Week 24 Assessment of Disease Activity 
All patients will be assessed for disease activity at Week 24.  Patients randomized to 
Arm B who have active disease at Week 24 (see criteria below) will switch to the Q12W 
dosing regimen of 6 mg RO6867461 for the remainder of the study, with injections 
commencing at Week 24 and repeated at Weeks 36 and 48.   
Determination of active disease will be made if any of the following criteria are met: 
• 
Increase in CST of > 50 μm on Spectralis OCT compared to average CST over last 
2 visits (Weeks 16 and 20) 
Or 
• 
Increase in CST of ≥ 75 μm compared to lowest CST recorded at either Week 16 or 
Week 20  
Or 
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• 
Decrease of at least 5 letters of BCVA compared with average BCVA over last 
2 visits (Weeks 16 and 20), due to nAMD disease activity  
Or 
• 
Decrease of ≥ 10 letters of BCVA compared to highest BCVA recorded at either 
Week 16 or Week 20 due to nAMD disease activity 
Or 
• 
Presence of new macular hemorrhage due to nAMD activity 
 
If, in the opinion of the investigator, there is significant nAMD disease activity at Week 24 
that requires immediate treatment, but does not meet the above criteria, the Medical 
Monitor should be contacted.  In such cases, following approval by the Sponsor, patients 
randomized to Arm B will receive 6 mg RO6867461 at Week 24 and stay on repeated 
12-weekly treatments at Weeks 36 and 48. 
4.5.6 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis: 
• 
Hematology:  hemoglobin, hematocrit (HCT), RBC count, mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), platelet count, total and differential 
white blood cell count (neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils in absolute numbers) 
• 
Chemistry panel (serum or plasma):  sodium, potassium, bicarbonate, phosphate, 
chloride, calcium, urea, creatinine, total bilirubin, alkaline phosphatase (ALP), 
aspartate aminotransferase (AST), alanine aminotransferase (ALT)  
• 
Coagulation:  activated partial thromboplastin time (aPTT) and prothrombin 
time/international normalized ratio (PT/INR) 
• 
Pregnancy test 
All women of childbearing potential will have a urine pregnancy test within 
28 days prior to initiation of study treatment.  If the urine pregnancy test is 
positive, it must be confirmed by a serum pregnancy test. 
• 
Plasma samples for assessment of ADAs to RO6867461 through use of a 
validated method 
Samples may or may not be analyzed for ranibizumab.  Samples must be taken 
prior to administration of study drug at visits where study drug is administered. 
• 
Plasma samples for RO6867461 PK analysis through use of a validated method 
Samples may or may not be analyzed for ranibizumab.  Samples must be taken 
prior to administration of study drug at visits where study drug is administered. 
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• 
Whole blood sample for DNA extraction 
The sample may be used to study genes related to AMD (e.g., AMRS2. HTRA1, 
CFH, C3) and angiogenesis pathways (e.g., VEGF-A, VEGFR2, Ang-2, Tie-2), 
and the effect on the PK/PD/efficacy/safety of RO6867461.   
 
Any residual material from PK and ADA samples may be used for additional exploratory 
biomarker profiling, identification, assay development purposes, and assay validation 
during the development of the study or compound-related assays after the mentioned 
intended uses.  Exploratory biomarker profiling may include, but will not be limited to, 
analysis of biomarkers of angiogenesis (including, but not limited to, Ang-1, Tie-2, 
VEGFR, PDGF) and inflammation (including, but not limited to, IL-1b, IL-6, autotaxin). 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.9), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions: 
• 
Plasma samples collected for PK analysis and immunogenicity analysis may be 
needed for additional immunogenicity characterization and PK and immunogenicity 
assay development and validation; therefore, these samples will be destroyed no 
later than 5 years after the final Clinical Study Report has been completed. 
• 
The whole blood samples for DNA extraction will be destroyed no later than 5 years 
after the final Clinical Study Report has been completed. 
 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples. 
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4. 
4.5.7 
Optional Aqueous Humor Samples 
Aqueous humor samples will be collected from all patients who provide additional 
consent to participate.  Where the patient consents to aqueous humor sampling, all 
efforts should be made to collect a baseline aqueous humor sample on Day 1 (predose).  
The schedule of activities (Appendix 1) provides guidance on recommended visits at 
which aqueous humor samples should be taken; however, (unscheduled) sampling 
could be performed at other or additional planned visits at the discretion of the 
investigator in agreement with the participating patient.  
The aqueous humor sample (0.1 mL) should be collected by a qualified physician after 
all predose assessments have been completed, using an aseptic procedure and sterile 
field and according to local guidelines. 
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Aqueous humor samples will be analyzed primarily for RO6867461 concentrations and 
may also be analyzed for ranibizumab concentrations.  Remaining samples may be 
analyzed for VEGF and Ang-2 concentrations, and possibly other biomarkers of 
angiogenesis (including, but not limited to, Ang-1, Tie-2, VEGFR, PDGF) and 
inflammation (including, but not limited to, IL-1b, IL-6, autotaxin).  Unless the patient 
gives specific consent for his or her leftover samples to be stored for optional exploratory 
research (see Section 4.5.9), biological samples will be destroyed no later than 5 years 
after the final Clinical Study Report has been completed. 
4.5.8 
Optional Unscheduled Collection of Vitreous Humor Samples 
Elective vitrectomy surgery is not allowed in the study eye during study participation; 
however, if the surgery is medically necessary and the patient consents, a vitreous 
sample can be obtained from the study eye.  Approximately 0.5 mL of undiluted vitreous 
humor should be collected using an aseptic procedure and sterile field and according to 
local guidelines and shipped to the Sponsor.  A PK blood sample (for plasma 
preparation) should also be collected and shipped to the Sponsor. 
Vitreous humor samples will be analyzed primarily for RO6867461 concentrations and 
may also be analyzed for ranibizumab concentrations.  The remaining samples may be 
analyzed for VEGF and Ang-2 concentrations, and possibly other biomarkers. 
The Sponsor should be contacted prior to performing any vitrectomy surgeries in the 
study eye.  Unless the patient gives specific consent for his or her leftover samples to be 
stored for optional exploratory research (see Section 4.5.9), biological samples will be 
destroyed no later than 5 years after the final Clinical Study Report has been completed. 
4.5.9 
Samples for Research Biosample Repository  
4.5.9.1 
Overview of the Research Biosample Repository 
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR 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 RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR 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 
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• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.9.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's Institutional Review Board or Ethics Committee (IRB/EC) 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for RBR sampling, this section of the protocol will not be applicable at that site. 
4.5.9.3 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to RO6867461 or diseases: 
• 
Leftover whole blood samples (see Section 4.5.6)  
• 
Leftover optional aqueous humor samples (see Section 4.5.7) 
• 
Leftover optional vitreous humor samples (see Section 4.5.8)  
 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic mutations via whole genome sequencing (WGS), whole exome sequencing 
(WES), next-generation sequencing (NGS), or other genomic analysis methods.   
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches.  Data will be analyzed in the 
context of this study but will also be explored in aggregate with data from other studies.  
The availability of a larger dataset will assist in identification of important pathways, 
guiding the development of new targeted agents. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.9.4 
Confidentiality 
Specimens and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
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authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses, data derived from RBR 
specimens will generally not be provided to study investigators or patients unless 
required by law.  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication. 
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.9.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their 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 RBR 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 and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research. 
4.5.9.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR specimens have the right to withdraw their 
specimens from the RBR 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 appropriate RBR Subject 
Withdrawal Form and, if the trial is ongoing, must enter the date of withdrawal on the 
RBR 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 CR39521 does not, by itself, constitute withdrawal of 
specimens from the RBR.  Likewise, a patient's withdrawal from the RBR does not 
constitute withdrawal from Study CR39521. 
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4.5.9.7 
Monitoring and Oversight 
RBR 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.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
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 
 
Patients who are withdrawn from the study early but have not withdrawn consent should 
return for an early termination visit 28 (+ 7) days following the last study treatment.  
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. 
4.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
• 
Pregnancy 
• 
Drop in BCVA by ≥ 30 letters if considered to be adverse and related to study  
treatment in the study eye (compared with the last assessment of visual acuity prior 
to the most recent treatment) and lasting for more than 1 hour 
• 
Endophthalmitis in the study eye 
• 
Severe intraocular inflammation (i.e., 4 + anterior chamber cell/flare or 4 + vitritis; 
see the definition of intraocular inflammation in Section 5.3.5 and grading scales for 
assessment in Appendix 2) 
• 
Retinal detachment in the study eye 
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• 
Vitreous hemorrhage that will preclude examination of macula and retinal imaging in 
the study eye 
• 
Surgical intervention (i.e., conventional surgery, vitreous tap, or biopsy with IVT 
injection of anti-infectives or laser or retinal cryopexy with gas) to prevent permanent 
loss of sight 
 
Patients who discontinue study treatment prematurely will be asked to return to the clinic 
for an early termination visit as outlined in the schedule of activities (Appendix 1).  The 
primary reason for premature study treatment discontinuation should be documented on 
the appropriate eCRF. 
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. 
Patients will not be followed up as part of the study for any reason after consent has 
been withdrawn. 
4.6.3 
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 
 
The Sponsor will notify the investigator 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 Council on Harmonisation (ICH) guideline for 
Good Clinical Practice 
• 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
RO6867461 is not approved, and clinical development is ongoing.  The safety plan for 
patients in this study is based on clinical experience with RO6867461 in completed and 
ongoing studies.   
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In the BP28936 first-in-human study, no safety signals for the drug RO6867461 were 
observed for up to 3 monthly administrations of the highest dose tested in this study 
(cutoff:  ≥ 4 weeks after last patient last dose of the multiple-dose part).  The majority of 
adverse events were of mild and moderate intensity.  No deaths occurred during the 
study period and no premature withdrawals from the study as a result of serious adverse 
events were reported. 
To date, no identified important safety risks for the drug RO6867461 have been 
observed in the development program of RO6867461.  Although there was a low rate of 
arterial thromboembolic events (ATEs) observed in clinical trials with anti-VEGF agents 
administered IVT, there is a potential risk of ATEs following IVT use of VEGF inhibitors, 
including RO6867461.  IVT injections have also been associated with serious adverse 
reactions related to the injection procedure, including endophthalmitis, rhegmatogenous 
retinal detachments, and iatrogenic traumatic cataracts.  For additional details on the 
risks associated with RO6867461, see Section 5.1.1 and refer to the RO6867461 
Investigator's Brochure for a complete summary of safety information.  
Several measures will be taken to ensure the safety of patients participating in this study.   
Patients will undergo safety monitoring, including adverse event monitoring and regular 
ophthalmological monitoring (ocular safety panel and SD-OCT assessments) during 
the study, and the nature, frequency, and severity of adverse events will be assessed.  
In addition, guidelines for managing adverse events, including criteria for dosage 
modification and treatment interruption or discontinuation, are provided below. 
5.1.1 
Risks Associated with RO6867461 
5.1.1.1 
Important Identified Risks 
To date, no identified risks for RO6867461 have been observed. 
5.1.1.2 
Potential Important Systemic Risks for anti-VEGF Agents 
Results from nonclinical studies did not reveal any adverse effects that require specific 
warnings and precautions that are different from those applicable to any anti-VEGF 
agents currently used in clinical practice for the treatment of nAMD.  Based on previous 
experience with ranibizumab, important potential risks of RO6867461 include ATEs and 
immunogenicity to RO6867461. 
5.1.1.3 
Injection Procedure-Related Risks 
IVT injections have been associated with serious adverse reactions related to the 
injection procedure, including endophthalmitis, rhegmatogenous retinal detachments, 
and iatrogenic traumatic cataracts.  Serious adverse reactions related to the injection 
procedure have occurred in < 0.1% of IVT injections of ranibizumab (Lucentis  U.S. 
Package Insert
®
). 
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Proper aseptic injection technique should always be used when administering 
RO6867461.  In addition, patients should be monitored following the injection to permit 
early treatment should an infection occur. 
5.1.1.4 
Risk of Increased Intraocular Pressure 
Increases in IOP have been noted while being treated with repeated IVT injections of 
anti-VEGF agents, both immediately post-injection (within 60 minutes), as well as 
pre-injection IOP increases during the duration of studies with monthly treatment 
administration.  Monitoring of IOP prior to and following IVT injection with RO6867461 
will be implemented in the Phase II studies.  Appropriate management of IOP increases 
should be initiated as necessary. 
5.1.2 
Management of Patients Who Experience Specific Adverse 
Events 
Guidelines for management of specific adverse events are outlined in Table 2.   
Table 2 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events 
Event 
Action to Be Taken 
Endophthalmitis or severe ocular inflammation 
(endophthalmitis, 4 + anterior chamber cell/flare or 4 + 
vitritis; see Section 5.3.5 and Appendix 2 for intraocular 
inflammation grading scales) 
• Discontinue study treatment. 
 
 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events (systemic and ocular) and adverse events of special interest; 
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 (i.e., regular ophthalmological monitoring and 
SD-OCT assessments). 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.  
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5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), 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., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death) 
• 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.10) 
• 
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 
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itself may be of relatively minor medical significance (such as severe headache without 
any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).  
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Non-serious or serious adverse events of special interest are required to be reported by 
the investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2 for reporting instructions).  Adverse events of special 
interest for this study include the following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s law (see Section 5.3.5.6) 
• 
Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
• 
Sight-threatening adverse events 
An adverse event is considered to be sight threatening and should be reported 
by the investigator to the Sponsor immediately (i.e., no more than 24 hours 
after learning of the event; or reporting instructions) if it meets one or more of 
the following criteria: 
− 
It causes a decrease of ≥ 30 letters in BCVA (compared with the last 
assessment of  VA prior to the most recent treatment) lasting more than 
1 hour 
− 
It requires surgical intervention (i.e., conventional surgery, vitreous tap, or 
biopsy with IVT injection of anti-infectives, or laser or retinal cryopexy with 
gas) to prevent permanent loss of sight 
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− 
It is associated with severe intraocular inflammation (i.e., 4 + anterior 
chamber cell/flare or 4 + vitritis; see the definitions of intraocular 
inflammation in Section 5.3.5 and grading scales for assessment in 
Appendix 2) 
− 
In the opinion of the investigator, it may require medical intervention to 
prevent permanent loss of sight 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.4, Section 5.5, and 
Section 5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will 
make an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study treatment, 
only serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as angiographies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported until 28 days after the 
last dose of study treatment. 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
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5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale in Table 3 will be used for assessing adverse 
event severity. 
Table 3 
Adverse Event Severity Grading Scale 
Severity 
Description 
Mild 
Discomfort noticed, but no disruption of normal daily activity 
Moderate 
Discomfort sufficient to reduce or affect normal daily activity 
Severe 
Incapacitating with inability to work or to perform normal daily activity 
Note:  Regardless of severity, some events may also meet seriousness criteria.  
Refer to definition of a serious adverse event (see Section 5.2.2). 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
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. 
For the purposes of reporting events of infection and inflammation of the eye, the 
following terms and definitions should be used. 
• 
Iritis:  the presence of inflammatory cells in the anterior chamber 
The presence of aqueous flare alone will not constitute iritis but should be 
documented as an anterior chamber flare for adverse event reporting purposes. 
• 
Iridocyclitis:  the presence of inflammatory cells in both the aqueous and vitreous 
• 
Vitritis:  the presence of active inflammation in the vitreous, demonstrated by the 
presence of inflammatory cells (trace or greater) 
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Active inflammation in the vitreous should be clinically differentiated from 
cellular debris from prior episodes of inflammation, hemorrhage, or other 
causes. 
• 
Endophthalmitis:  diffuse intraocular inflammation predominantly involving the 
vitreous cavity but also involving the anterior chamber, implying a suspected 
underlying infectious cause 
Note:  Trace benign, aqueous 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. 
Only one adverse event term should be recorded in the event field on the Adverse 
Event eCRF. 
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. 
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5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 
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 whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
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Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events). 
5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × ULN) in combination with either an elevated 
total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), as a serious adverse event or an adverse event of special interest not 
considered serious (see Section 5.4.2). 
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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 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.8 
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 
Lack of Efficacy or Worsening of Age-Related Macular 
Degeneration 
Medical occurrences or symptoms of deterioration that are anticipated as part of AMD 
should be recorded as an adverse event if judged by the investigator to have 
unexpectedly worsened in severity or frequency or changed in nature at any time during 
the study.  When recording an unanticipated worsening of AMD on the Adverse Event 
eCRF, it is important to convey the concept that the condition has changed by including 
applicable descriptors (e.g., "accelerated AMD"). 
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5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious 
adverse event (per the definition of serious adverse event in Section 5.2.2), except 
as outlined below. 
• 
Hospitalization for a preexisting condition, provided that the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease. 
The patient has not experienced an adverse event. 
 
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.   
Any study drug overdose or incorrect administration of study treatment should be noted 
on the study drug administration form (eCRF). 
All adverse events associated with an overdose or incorrect administration of study drug 
should be recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2). 
No safety data related to overdosing of RO6867461 are available. 
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) 
• 
Adverse events of special interest (see Section 5.4.2 for further details) 
• 
Pregnancies (see Section 5.4.3 for further details) 
 
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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 and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information for All Sites  
Medical Monitor 
, M.B.B.S.  
Mobile Telephone No. (primary): 
Telephone No.: 
 
Alternate Medical Monitor Contact Information for All Sites 
Medical Monitor: 
, M.D.  
Telephone No.: 
Mobile Telephone No.: 
 
  
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators.  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The 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. 
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5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 28 days after the last dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system. 
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 serious adverse events that occur > 28 days after the last dose 
of study treatment are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 28 days after the last 
dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Pregnancy should not be 
recorded on the Adverse Event eCRF.  The investigator should 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 addition, the investigator will submit a Clinical 
Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available.  
5.4.3.2 
Abortions 
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).   
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5.4.3.3 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest immediately reportable to 
the Sponsor, 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 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
28 days after the last dose of study treatment), if the event is believed to be related to 
prior study drug treatment.  These events should be reported through use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the investigator should report 
these events directly to the Sponsor or its designee, either by faxing or by scanning and 
emailing the 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 adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents: 
• 
RO6867461 Investigator's Brochure 
• 
Ranibizumab U.S. Prescribing Information 
 
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. 
The IMC will monitor the incidence of these expected events during the study.  An 
aggregate report of any clinically relevant imbalances that do not favor RO6867461 will 
be submitted to health authorities.  
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
6.1 
DETERMINATION OF SAMPLE SIZE 
The focus of this trial is estimation rather than hypothesis testing.  The sample size was 
determined largely based on logistical considerations.  Assuming a common standard 
deviation for BCVA change from baseline of 13.5 letters, the distance from the difference 
of the means between RO6867461 (n = 30) and ranibizumab (n = 15) to the 80% two-
sided confidence interval bounds is estimated to be 5.5 letters. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The number of patients who are enrolled, discontinued, and completed the study will be 
summarized as well as the major protocol violations.  Demographic and other baseline 
characteristics will be summarized with descriptive statistics. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographics, baseline characteristics (including ocular assessments, patient 
disposition, and medical history), and all baseline laboratory values will be summarized 
descriptively by treatment group using frequency tables and summary statistics providing 
means, medians, standard deviations, first and third quartiles, and extreme values. 
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6.4 
EFFICACY ANALYSES 
The primary, secondary, and exploratory efficacy analyses will be carried out in the 
intent-to-treat population (defined as all randomized patients), with patients grouped 
according to their assigned treatment.     
The baseline measurement is defined as the latest non-missing observation before the 
first dose of study medication. 
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is BCVA change from baseline at Week 40.  The primary 
efficacy analysis will be performed using a Mixed Model for Repeated Measurement 
(MMRM) model.  The model will include the categorical covariates of treatment group, 
visit, and visit by treatment group interaction and the continuous covariate of baseline 
BCVA.  An unstructured covariance will be used to account for within-patient correlation, 
but another variance-covariance structure, such as AR(1), may be selected in case of 
convergence issues.   
Means for RO6867461 and ranibizumab arms, difference of the means relative to 
ranibizumab, and the corresponding two-sided 80% confidence intervals will be 
computed.  There will not be formal correction for multiple testing. 
6.4.2 
Secondary Efficacy Endpoints 
Mean change from baseline BCVA over time using the ETDRS-like charts will be 
analyzed using the MMRM model described in Section 6.4.1. 
Categorical outcomes measured repeatedly will be analyzed using Generalized 
Estimating Equations with a binomial distribution, logit link function, and unstructured 
covariance.  In case of convergence issues, AR(1) covariance structure will be used.  
The model will include the categorical covariates of treatment group, visit, and visit by 
treatment group interaction.  Least squares means with the corresponding two-sided 
80% confidence intervals and odds ratios will be computed. 
6.4.3 
Exploratory Efficacy Endpoint 
The proportion of patients with disease activity at Week 24 will be reported with the 
corresponding 80% Wilson score confidence intervals by study arm. 
6.5 
PHARMACODYNAMIC ANALYSIS 
An empirical drug-disease model of longitudinal BCVA previously developed on the 
ranibizumab database will be used to analyze the effect of RO6867461 on BCVA by 
using a meta-analysis approach. 
A similar modeling approach will be used to analyze the relationship between 
RO6867461 exposure and BCVA.  The influence of various baseline covariates on 
model parameters will be investigated.  The PK/PD or dose/PD relationship will be 
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characterized.  The results will be reported in a separate document from the Clinical 
Study Report. 
6.6 
SAFETY ANALYSES 
The safety analyses will include all randomized patients who received at least one dose 
of the study treatment, whether prematurely withdrawn from the study or not, with 
patients grouped according to treatment received. 
The original terms recorded on the eCRF by the investigators for adverse events will be 
standardized by the Sponsor.  Adverse events will be summarized by mapped term and 
appropriate thesaurus level. 
Separate summaries will be prepared for systemic and ocular adverse events, with 
events in the study eye and non-study eye summarized separately.  Serious adverse 
events will be summarized similarly.  Adverse events leading to discontinuation from the 
study will be listed and tabulated. 
6.7 
PHARMACOKINETIC ANALYSES 
A non-linear mixed effects modeling approach (with NONMEM® software [Beal and 
Sheiner 1998]) will be used to analyze the concentration-time data of RO6867461.  
Population and individual primary PK parameters (i.e., clearances and volumes) will be 
estimated, and the influence of various covariates (e.g., gender, body weight) on these 
parameters will be investigated.  The data collected in this study may be pooled with 
data collected in the previous studies, as appropriate, to build a PK model.  Secondary 
PK parameters such as area under the concentration−time curve (AUC) and maximum 
concentration observed (Cmax) will be derived from the individual post-hoc predictions.  
The result of this analysis will be reported in a separate document from the Clinical 
Study Report. 
Additional PK analyses will be conducted as appropriate. 
6.8 
IMMUNOGENICITY ANALYSES 
The immunogenicity analyses will include patients with at least one predose and one 
postdose ADA assessment, with patients grouped according to treatment received. 
6.9 
OPTIONAL INTERIM ANALYSES 
Given the hypothesis-generating 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 
the Sponsor IMC (see Section 3.1.2) and appropriate senior management personnel 
who will be unmasked at the treatment group level.  Access to treatment assignment 
information will follow the Sponsor’s standard procedures. 
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7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data Central 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. 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
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, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
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Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, Informed Consent Forms, 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.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
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Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/EC−approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
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each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
Each Consent Form may also include patient authorization to allow use and disclosure 
of personal health information in compliance with the U.S. Health Insurance Portability 
and Accountability Act (HIPAA) of 1996.  If the site utilizes a separate Authorization 
Form for patient authorization for use and disclosure of personal health information 
under the HIPAA regulations, the review, approval, and other processes outlined above 
apply except that IRB review and approval may not be required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Given the complexity and exploratory nature of the analyses, data derived from 
exploratory biomarker specimens will generally not be provided to study investigators or 
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patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes 
to data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, subjects’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
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9.4 
ADMINISTRATIVE STRUCTURE 
This research study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland and may be implemented in individual countries by Roche’s local affiliates.  
The Sponsor will perform project management, study management, monitoring, vendor 
management, and statistical programming.  An IxRS will be used for patient screening 
and randomization and for management of study drug requests and shipments.  A 
central laboratory will be used for most laboratory assessments and for storage of other 
laboratory samples (i.e., anti-RO6867461 antibody samples) prior to being shipped to 
Sponsor or its designee for analysis.  Data will be recorded by an EDC system using 
eCRFs (Section 7.2) or forwarded to Sponsor electronically (e.g., PK data).  A Central 
Reading Center will be used for ocular imaging analyses (FP, FFA, and SD-OCT), which 
will be forwarded to Sponsor electronically. 
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: 
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.
pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
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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). 
RO6867461—F. Hoffmann-La Roche Ltd 
79/Protocol CR39521, Version 2 


 
10. 
REFERENCES 
Beal S and Sheiner L (Eds.). NONMEM users guides, NONMEM projects group. 
University of California, San Francisco. 1998. 
Bourne RR, Jonas JB, Flaxman SR, et al. Prevalence and causes of vision loss in high-
income countries and in Eastern and Central Europe: 1990-2010. Br J Ophthalmol 
2014;98:629−38.   
Bourne RR, Stevens GA, White RA, et al. Causes of vision loss worldwide, 1990−2010: 
a systematic analysis. Lancet Glob Health 2013;1:e339−49. 
Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular 
age-related macular degeneration. N Engl J Med 2006;355:1432−44.   
Busbee BG, Ho AC, Brown DM, et al. Twelve-month efficacy and safety of 0.5 mg or 
2 mg ranibizumab in patients with subfoveal neovascular age-related macular 
degeneration. Ophthalmol 2013;120:1046−56. 
Cheung GCM, Barathi VA, Tun BB, et al. Dual inhibition of angiopoietin-2 and vascular 
endothelial growth factor-A with Crossmab RG7716 suppressed laser-induced 
choroidal neovascularization in a non-human primate model. Investigative 
Ophthalmology & Visual Science April 2014;55:1174. 
Cohen SY, Mimoun G, Oubraham H, et al. Changes in visual acuity in patients with wet 
age-related macular degeneration treated with intravitreal ranibizumab in daily 
clinical practice: the LUMIERE study. Retina 2013;33:474−81. 
Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research 
Group, Maguire MG, Martin DF, et al. Five-year outcomes with anti-vascular 
endothelial growth factor treatment of neovascular age-related macular 
degeneration: The Comparison of Age-Related Macular Degeneration Treatments 
Trials. Ophthalmology 2016;123:1751−61. 
Davis S, Aldrich TH, Jones PF, et al. Isolation of angiopoietin-1, a ligand for the TIE2 
receptor, by secretion-trap expression cloning. Cell 1996;87:1161−9. 
European Medicines Agency.  Eylea European Assessment Report Product Information. 
Available at: http://www.ema.europa.eu. Last updated 24 August 2016. Accessed 
4 October 2016.  
Fiedler U, Krissl T, Koidl S, et al. Angiopoietin-1 and angipoietin-2 share the same 
binding domains in the Tie-2 receptor involving the first Ig like loop and the 
epidermal growth factor-like repeats. J Biol Chem 2003;278:1721−7. 
Finger RP, Wiedemann P, Blumhagen F, et al. Treatment patterns, visual acuity and 
quality-of-life outcomes of the WAVE study − a noninterventional study of 
ranibizumab treatment for neovascular age-related macular degeneration in 
Germany. Acta Ophthalmol 2013;91:540−6. 
RO6867461—F. Hoffmann-La Roche Ltd 
80/Protocol CR39521, Version 2 


 
Gohil R, Crosby-Nwaobi R, Forbes A, et al. Caregiver burden in patients receiving 
ranibizumab therapy for neovascular age related macular degeneration. PLoS One 
2015;10:e0129361. 
Heier JS. Aflibercept combination therapies: aflibercept/anti-ANG 2 and aflibercept/anti-
PDGF. Preseneted at Angiogenesis, Exudation, and Degeneration 2016. 
6 February 2016. 
Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-
related macular degeneration. Ophthalmology 2012;119:2537−48. 
Hera R, Keramidas M, Peoc'h M, et al. Expression of VEGF and angiopoietins in 
subfoveal membranes from patients with age-related macular degeneration. Am J 
Ophthalmol. 2005;139:589−96. 
Holz FG, Tadayoni R, Beatty S, et al. Multi-country real-life experience of anti-vascular 
endothelial growth factor therapy for wet age-related macular degeneration. Br J 
Ophthalmol 2015;99:220−6. 
Hutton-Smith LA, Gaffney EA, Byrne HM, et al. A mechanistic model of the intravitreal 
pharmacokinetics of large molecules and the pharmacodynamic suppression of 
ocular vascular endothelial growth factor levels by ranibizumab in patients with 
neovascular age-related macular degeneration. Mol Pharm 2016;13:2941−50. 
Lucentis (ranibizumab injection) U.S. Package Insert. Genentech, Inc., A Member of the 
Roche Group. February 2015 [cited 10 October 2016]. Available at: 
https://www.gene.com/download/pdf/lucentis_prescribing.pdf. 
Maisonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural antagonist for Tie2 
that disrupts in vivo angiogenesis. Science 1997;277:55−60. 
Muether PS, Neuhann I, Buhl C, et al. Intraocular growth factors and cytokines in 
patients with dry and neovascular age-related macular degeneration. Retina 
2013;33:1809−14. 
National Eye Institute (NEI). Age-Related Macular Degeneration (AMD). Projections for 
AMD (2010-2030-2050) [resource on the Internet]. Available at: 
https://nei.nih.gov/eyedata/amd#5. Accessed 4 October 2016. 
Prenner JL, Halperin LS, Rycroft C, et al. Disease burden in the treatment of age-related 
macular degeneration: findings from a time-and-motion study. Am J Ophthalmol 
2015;160:725−31. 
Regula JT, Lundh von Leithner P, Foxton R, et al. Targeting key angiogenic pathways 
with a bispecific CrossMAb optimized for neovascular eye diseases. EMBO Mol 
Med 2016; pii: e201505889. doi: 10.15252/emmm.201505889. [Epub ahead of 
print]. 
Resnikoff S, Pascolini D, Etya'ale D, et al. Global data on visual impairment in the year 
2002. Bull World Health Organ 2004;82:844−51. 
RO6867461—F. Hoffmann-La Roche Ltd 
81/Protocol CR39521, Version 2 


 
RO6
82/Proto
867461—F. Hoffmann-La Roche Ltd 
col CR39521, Version 2 
Rezar-Dreindl S, Sacu S, Eibenberger K, et al. The intraocular cytokine profile and 
therapeutic response in persistent neovascular age-related macular degeneration. 
Invest Ophthalmol Vis Sci. 2016;57:4144−50. 
Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related 
macular degeneration. N Engl J Med 2006;355:1419−31. 
Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept injection for 
neovascular age-related macular degeneration: ninety-six-week results of the 
VIEW studies. Ophthalmology 2014;121:193−201. 
Varano M, Eter N, Winyard S, et al. Current barriers to treatment for wet age-related 
macular degeneration (wAMD): findings from the wAMD patient and caregiver 
survey. Clin Ophthalmol 2015;9:2243−50. 
von Leithner PL, Iwata D, Ng Y, et al. Bispecific anti-VEGF/ANG2 antibody exhibits 
superior efficacy to VEGF monotherapy in a model of spontaneous CNV. 
Investigative Ophthalmology & Visual Science 2014;55:2356. 
Vukicevic M, Heraghty J, Cummins R, et al. Caregiver perceptions about the impact of 
caring for patients with wet age-related macular degeneration. Eye (Lond). 
2016;30(3):413−21. 
Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and 
disease burden projection for 2020 and 2040: a systematic review and meta-
analysis. Lancet Glob Health 2014;2:e106−16.  


 
Appendix 1  
Schedule of Activities 
Week Screening 
Wk 
1 
Wk
4 
Wk
8 
Wk
12 
Wk
16 
Wk
20 
Wk
24 
Wk
28 
Wk 
32 
Wk
36 
Wk
40 
Wk
44 
Wk
48 
Wk
52 
Day 
(Visit window) 
–28 to 1 a  1 a
7 
(± 3)
28
(± 7)
56
(± 7)
84
(± 7)
112
(± 7)
140
(± 7)
168
(± 7)
196 
(± 7)
224 
(± 7) 
252
(± 7)
280
(± 7)
308
(± 7)
336
(± 7)
364
(± 7)
Early 
Termination b Unscheduled 
Visit c
Informed consent 
x d
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical histo
 
ry
x
x
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination e
x
x
x
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight and height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs f
x
x
x
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BCVA g
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Slitlamp 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Indirect ophthalmoscopy 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SD-OCT h
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Optional OCT-A h, i
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
FFA h
x
x
x
x
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fundus photography h
x
x
x
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional aqueous humour 
sample j  
 
x 
 
 
 
 
 
 
x 
x 
x 
x 
 
 
 
x 
 
x 
Optional vitreous humor 
sample k  
 
If elective vitrectomy surgery is performed k
 
 
Plasma PK sample j
 
x 
 
 
 
 
x 
 
x 
x 
 
 
 
x 
 
x 
x 
 
RO6867461—F. Hoffmann-La Roche Ltd 
83/Protocol CR39521, Version 2 


Appendix 1  
Schedule of Activities (cont.) 
RO6867461—F. Hoffmann-La Roche Ltd 
84/Protocol CR39521, Version 2 
Week Screening 
Wk 
1 
Wk
4 
Wk
8 
Wk
12 
Wk
16 
Wk
20 
Wk
24 
Wk
28 
Wk 
32 
Wk
36 
Wk
40 
Wk
44 
Wk
48 
Wk
52 
Day 
(Visit window) 
–28 to 1 a  1 a
7 
(± 3)
28
(± 7)
56
(± 7)
84
(± 7)
112
(± 7)
140
(± 7)
168
(± 7)
196 
(± 7)
224 
(± 7) 
252
(± 7)
280
(± 7)
308
(± 7)
336
(± 7)
364
(± 7)
Early 
Termination b Unscheduled 
Visit c
Plasma sample for ADAs j  
 
x 
 
 
 
 
x 
 
x 
x 
 
 
 
x 
 
x 
x 
 
Blood hematology/ 
chemistry l, m
x m
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x
x
x
 
 
 
Coagulation m
x m
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Whole blood sample 
for DNA 
 
x n
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test o
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of disease 
activity p
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
IOP (post-imaging) q
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
IOP (pre- and post-study 
treatment) r
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Administration of study 
treatment s
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Finger count vision 
assessment t
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Adverse events u
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 


Appendix 1  
Schedule of Activities (cont.) 
RO6867461—F. Hoffmann-La Roche Ltd 
85/Protocol CR39521, Version 2 
ADA = anti-drug antibody; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BCVA = best corrected visual 
acuity; FFA = fundus fluorescein angiography; HCT = hematocrit; IOP = intraocular pressure; IVT = intravitreal; MCH = mean corpuscular hemoglobin; 
MCV = mean corpuscular volume; OCT-A = optical coherence tomography  angiography; PK = pharmacokinetic; SD-OCT = spectral domain optical coherence 
tomography; Wk = week.  
Notes:  There must be a minimum of 21 days between all study visits occurring from Week 4 through Week 52.  Standard of care treatment for nAMD in the 
fellow eye may be provided by the Sponsor as long as the patient remains in the study (see Section 4.4.3).  Standard of care treatment after the early 
termination visit or final visit will not be supplied by the Sponsor.  
a The screening and Week 1/Day 1 (randomization) visit may occur as a combined visit if all assessments (with the exception of informed consent) are 
completed within 48 hours.  Where screening and randomization are combined, assessments listed for both visits only need to be conducted once.   
b Patients who are withdrawn from the study early but have not withdrawn consent should return for an early termination visit 28 (+ 7) days following the last 
study treatment.   
c Assessments performed in case of an unscheduled visit(s) are at the discretion of the investigator. 
d Informed consent must be documented before any study-specific screening procedure is performed, and may be obtained more than 28 days before 
initiation of study treatment.  
e A physical examination should cover head and neck including lymph nodes, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, neurological systems, and others as applicable.  Any abnormality identified at baseline should be recorded on the General Medical History 
and Baseline Conditions eCRF.  At subsequent visits (or as clinically indicated), limited, symptom-directed physical examinations should be performed. 
Changes from baseline abnormalities should be recorded in patient’s notes. New or worsened clinically significant abnormalities should be recorded as 
adverse events on the Adverse Event eCRF. 
f Vital signs include measurements of pulse rate and systolic and diastolic blood pressure while the patient is in a seated position, and temperature.   
g To be performed prior to other ocular assessments. 
h The Central Reading Center will review these assessments at screening for determination of patient eligibility.  At all subsequent visits, outputs from these 
assessments will be sent to the Central Reading Center.  For SD-OCT and OCT-A, images of the study eye and fellow eyes should be captured and 
forwarded to the Central Reading Center at the screening, Week 24, Week 40, and Week 52 or early termination visits.  At all other visits, only the study 
eye images need to be acquired and forwarded to the Central Reading Center. 
i To be conducted at sites with OCT-A capability.   
j Sample must be taken prior administration of study drug at visits where study drug is administered.  
k If elective vitrectomy surgery is medically necessary and the patient consents, a vitreous sample can be obtained from the study eye.  A PK blood sample 
(for plasma preparation) should also be collected and shipped to the Sponsor.  Vitreous humor samples will be analyzed primarily for RO6867461 
concentrations and may also be analyzed for ranibizumab concentrations.  The remaining samples may be analyzed for VEGF and Ang-2 concentrations, 
and possibly other biomarkers. 


Appendix 1  
Schedule of Activities (cont.) 
RO6867461—F. Hoffmann-La Roche Ltd 
86/Protocol CR39521, Version 2 
l Hematology includes hemoglobin, HCT, RBC count, MCV, MCH, platelet count, and total and differential white blood cell count (neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils in absolute numbers).  Chemistry panel includes sodium, potassium, bicarbonate, phosphate, chloride, calcium, 
urea, creatinine, total bilirubin, ALP, AST, and ALT. 
m Results from the screening samples are not required for randomization.  
n If whole blood sample for DNA is not taken at the assigned visit (Week 1, Day 1), this sample may be collected at any subsequent study visit where a 
blood draw is being performed for other purposes as specified in the schedule of activities (e.g., PK, ADA, and/or blood hematology/chemistry). 
o All women of childbearing potential will have a urine pregnancy test within 28 days prior to initiation of study treatment.  If the urine pregnancy test is 
positive, it must be confirmed by a serum pregnancy test. 
p Assessment of disease activity conducted per specified criteria outlined in Section 4.5.5.4.   
q Assessment to be performed after all imaging assessments, and the same method should be used throughout the study period. 
r IOP pressure is to be conducted prior to study treatment administration and 30 (±15) minutes post-treatment administration in the study eye, and if IOP 
≥ 30 mmHg, IOP should be re-assessed 30 (± 15) minutes later.  If IOP continues to be elevated, treatment should be undertaken at the discretion of the 
investigator. 
s Sham IVT administration will be delivered to patients to maintain subject masking throughout the study period.  In Arm A, sham IVT administrations will 
occur at Weeks 16, 20, 28, 32, 40, and 44.  In Arm B, sham IVT administrations will occur at Weeks 16, 20, 24, 32, 36, 40, and 48, or at Weeks 16, 20, 28, 
32, 40 and 44, the latter if the dosing regimen was switched to the 12-weekly schedule. 
t Finger count vision assessment should be conducted within 15 minutes of study treatment administration for the study eye only. 
u After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated intervention 
should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the last dose of study treatment.  After this period, 
the Sponsor should be notified if the investigator becomes aware of any serious adverse event that are believed to be related to prior  study drug 
treatment (see Section 5.6).  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. 


 
Appendix 2  
Grading Scale for Assessment of Anterior Chamber Flare or 
Cells, Vitreal Hemorrhage Density, and Vitreous Cells 
GRADING SCALE FOR ANTERIOR CHAMBER FLARE OR CELLS 
 
Flare 
No protein is visible in the anterior chamber when viewed by an experienced observer 
using slitlamp biomicroscopy; a small, bright, focal slit-beam of white light; and high 
magnification. 
0 
Trace amount of protein is detectable in the anterior chamber:  This protein is visible only 
with careful scrutiny by an experienced observer using slitlamp biomicroscopy; a small, 
bright, focal slit-beam of white light; and high magnification. 
Trace 
Slight amount of protein is detectable in the anterior chamber:  the presence of protein in 
the anterior chamber is immediately apparent to an experienced observer using slitlamp 
biomicroscopy and high magnification, but such protein is detected only with careful 
observation with the naked eye and a small, bright, focal slit-beam of white light. 
1 +  
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 + . 
2-3 +  
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 barrier, it is possible to have resorbing fibrin present with lower numeric 
assignations for flare (e.g., 1 + flare with fibrin). 
4 +  
Cells 
No cells are seen in any optical section when a large slitlamp beam is swept across the 
anterior chamber. 
0 
Few (1−3) cells are observed when the slitlamp beam is swept across the anterior 
chamber.  When the instrument is held stationary, not every optical section contains 
circulating cells. 
Trace 
 3−10 cells/optical section are seen when the slitlamp beam is swept across the anterior 
chamber.  When the instrument is held stationary, every optical section contains 
circulating cells. 
1 +  
2 +  
10−25 cells are seen when the slitlamp beam is swept across the anterior chamber. 
When the instrument is held stationary, every optical section contains circulating cells. 
25−50 cells are seen when the slitlamp beam is swept across the anterior chamber.  
When the instrument is held stationary, every optical section contains circulating cells.  
Keratic precipitates or cellular deposits on the anterior lens capsule may be present. 
3 +  
More than 50 cells are seen when the slitlamp beam is swept across the anterior 
chamber.  When the instrument is held stationary, every optical section contains cells, or 
hypopyon is noted.  As for fibrin deposition, hypopyon may persist for some period of 
time after the active exudation of cells into the anterior chamber has diminished or 
ceased entirely, making it possible to have 1 + circulating cells in the anterior chamber 
with a resolving hypopyon. 
4 +  
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. 
RO6867461—F. Hoffmann-La Roche Ltd 
87/Protocol CR39521, Version 2 


Appendix 2  
Grading Scale for Assessment of Anterior Chamber Flare or 
Cells, Vitreal Hemorrhage Density, and Vitreous Cells (cont.) 
RO6867461—F. Hoffmann-La Roche Ltd 
88/Protocol CR39521, Version 2 
GRADING SCALE FOR VITREOUS 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 
0−1 
Clear 
0 
2−20 
Few opacities 
Trace 
21−50 
Scattered opacities 
1 
51−100 
Moderate opacities 
2 
101−250 
Many opacities 
3 
> 251 
Dense opacities 
4 
Notes:  The grading will be performed using a Hruby lens.  
Excerpted from:  Nussenblatt RB, Whitcup SM, Palestine AG. Uveitis. Fundamentals and clinical 
practice. 2nd rev. ed. New York: Mosby, 1996,p. 64. 
 


 
Appendix 3  
Study Treatment Administration Procedure 
1. PRE-INJECTION PROCEDURES 
The following procedures will be used to minimize the risk of potential adverse events 
associated with intravitreal (IVT) injections (e.g., endophthalmitis). 
Aseptic technique will be observed by clinic staff involved in the administration tray 
assembly, anesthetic preparation, and study treatment preparation and administration.  
In addition to the procedures outlined below, any additional safety measures in 
adherence to specific institutional policies associated with IVT injections will be observed. 
The above procedures (except where noted) will be conducted by the physician 
performing the IVT administration of study treatment.  At the discretion of the investigator, 
patients may self-administer ophthalmic broad-spectrum antimicrobial drops on days 
prior to study treatment administration. 
At the discretion of the investigator, the sites may use either ophthalmic drops or 
lidocaine injection for study eye anesthesia, and where possible the same method used 
throughout the study. 
2. PROCEDURE FOR PROPACAINE- OR TETRACAINE-BASED 
ANESTHESIA 
If using propacaine- or tetracaine-based ophthalmic drops for anesthesia, the treatment 
administrator physician or technician (if applicable) assembles the supplies and prepares 
a sterile field.  Supplies include 10% povidone iodine swabs, sterile surgical gloves, 
4 × 4 sterile pads, a pack of sterile cotton-tipped applicators, eyelid speculum, sterile 
ophthalmic drape, 5% povidone iodine ophthalmic solution, ophthalmic broad-spectrum 
antimicrobial solution (e.g., ofloxacin ophthalmic solution, trimethoprim-polymyxin B 
ophthalmic solution, moxifloxacin ophthalmic solution, or gatifloxacin ophthalmic solution 
single-use vial), and treatment administration supplies. 
• 
Instill two drops proparacaine- or tetracaine-based ophthalmic drops into the study 
eye, followed by, at the discretion of the investigator, ophthalmic antimicrobial 
solution. 
• 
Wait 90 seconds. 
• 
Instill two more drops of proparacaine- or tetracaine-based ophthalmic drops into 
the study eye, 
• 
Disinfect the periocular skin and eyelid of the study eye in preparation for study 
treatment administration.  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. 
RO6867461—F. Hoffmann-La Roche Ltd 
89/Protocol CR39521, Version 2 


Appendix 3  
Study Treatment Administration Procedure (cont.) 
RO6867461—F. Hoffmann-La Roche Ltd 
90/Protocol CR39521, Version 2 
• 
The treatment administrator 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-based 
drops and hold the swab against the planned IVT 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 patient to direct gaze away from syringe prior to study treatment 
administration. 
 
3. PROCEDURE FOR LIDOCAINE INJECTION-BASED ANESTHESIA 
If using lidocaine injection for anesthesia, treatment administrator physician or technician 
(if applicable) assembles the supplies and prepares a sterile field.  Supplies include 10% 
povidone iodine swabs, sterile surgical gloves, 4 × 4 sterile pads, a pack of sterile 
cotton-tipped applicators, eyelid speculum, sterile ophthalmic drape, 0.5% proparacaine 
hydrochloride, 5% povidone iodine ophthalmic solution, 1% lidocaine for injection, 
ophthalmic antimicrobial solution, and treatment administration supplies. 
• 
Instill two drops of 0.5% proparacaine hydrochloride into the study eye, followed, at 
the discretion of the investigator, by drops of broad-spectrum antimicrobial solution 
(e.g., ofloxacin ophthalmic solution, trimethoprim-polymyxin B ophthalmic solution, 
moxifloxacin ophthalmic solution, or gatifloxacin ophthalmic solution single-use vial). 
• 
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 treatment administrator 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 IVT injection site for 10 seconds in 
preparation for the subconjunctival injection of 1% lidocaine hydrochloride 
ophthalmic solution for injection (without epinephrine). 
• 
Inject 1% lidocaine (without epinephrine) subconjunctivally. 


Appendix 3  
Study Treatment Administration Procedure (cont.) 
RO6867461—F. Hoffmann-La Roche Ltd 
91/Protocol CR39521, Version 2 
• 
Use a sterile 4 × 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 treatment 
administration. 
 
4. PROCEDURE FOR LIDOCAINE-GEL BASED ANESTHESIA 
If using lidocaine-gel for anesthesia, the treatment administrator physician or technician 
(if applicable) assembles the supplies and prepares a sterile field.  Supplies include 10% 
povidone iodine swabs, sterile surgical gloves, 4 × 4 sterile pads, a pack of sterile 
cotton-tipped applicators, eyelid speculum, sterile ophthalmic drape, 5% povidone iodine 
ophthalmic solution, ophthalmic broad-spectrum antimicrobial solution (e.g., ofloxacin 
ophthalmic solution, trimethoprim-polymyxin B ophthalmic solution, moxifloxacin 
ophthalmic solution, or gatifloxacin ophthalmic solution single-use vial), and treatment 
administration supplies. 
• 
Instill two drops of 5% povidone iodine ophthalmic solution in the study eye, 
followed at the discretion of the investigator, by two drops of ophthalmic 
antimicrobial solution. 
• 
Wait 90 seconds 
• 
Instill lidocaine gel onto the planned injection site in the study eye 
• 
Wait 3 minutes 
• 
Instill lidocaine gel onto the planned injection site in the study eye 
• 
Disinfect the periocular skin and eyelid of the study eye in preparation for study 
treatment administration.  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 treatment administrator 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-based 
drops and hold the swab against the planned IVT 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 patient to direct gaze away from syringe prior to study treatment 
administration 
 


Appendix 3  
Study Treatment Administration Procedure (cont.) 
RO6867461—F. Hoffmann-La Roche Ltd 
92/Protocol CR39521, Version 2 
5. INTRAVITREAL ADMINISTRATION OF STUDY TREATMENT 
Study treatment must be prepared according to the detailed instructions in the Pharmacy 
Manual.  The instructions in the Pharmacy Manual cover all steps until the syringe is 
ready for treatment administration. 
After preparing the study eye as outlined above: 
• 
For RO6867461 or ranibizumab administration:  insert the syringe through an area 
3.0 to 4.0 mm posterior to the limbus (aphakic/pseudophakic patients 3.0−3.5 mm), 
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.  Refer to Section 6 below for 
detailed post-injection procedures. 
• 
For sham administration:  the patients do not receive an actual injection.  The 
treatment administrator physician will withdraw the tuberculin syringe plunger to the 
0.1 mL mark on the syringe, then place the hub of the syringe (without the needle) 
against the pre-anesthesized conjunctival surface.  The treatment administrator 
physician will then press the syringe hub firmly against the globe and then slowly 
depress the plunger, mimicking the action of an injection.  
 
The injection site should be rotated at every study treatment visit. 
6. POST-INJECTION PROCEDURES 
At the discretion of the investigator, drops of ophthalmic antimicrobial drops could be 
instilled in the study eye after study treatment administration and for the days following 
study treatment administration. 
Discard all administration materials (i.e., syringe, needles) in the sharps container.