A Multiple-Center, Multiple-Dose and Regimen, Randomized, Active Comparator Controlled, Double-Masked, Parallel Group, 36 Week Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Efficacy of RO6867461 Administered Intravitreally in Patients With Choroidal Neovascularization Secondary to Age-Related Macular Degeneration
Phase: PHASE2
Conditions: Choroidal Neovascularization
Sponsor: Hoffmann-La Roche

 
 
Official Title:  
 
A MULTIPLE-CENTER, MULTIPLE-DOSE AND REGIMEN, 
RANDOMIZED, ACTIVE COMPARATOR CONTROLLED, DOUBLE-
MASKED, PARALLEL GROUP, 36 WEEK STUDY TO 
INVESTIGATE THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, AND EFFICACY OF RO6867461 
ADMINISTERED INTRAVITREALLY IN PATIENTS WITH 
CHOROIDAL NEOVASCULARIZATION SECONDARY TO AGE-
RELATED MACULAR DEGENERATION 
NCT Number: 
NCT02484690 
Document: 
Version & Date:  
PROTOCOL 
Version 3: 09-Sep-2016 
 

 
Title
09-Sep-2016 13:47:21
Date and Time (UTC)
Company Signatory
Approver's Name
 
FINAL PROTOCOL APPROVAL 
 
CONFIDENTIAL 
The information contained in this document, especially any unpublished data, is the property of 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 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
 
PROTOCOL 
TITLE: 
A MULTIPLE-CENTER, MULTIPLE-DOSE AND 
REGIMEN, RANDOMIZED, ACTIVE COMPARATOR 
CONTROLLED, DOUBLE-MASKED, PARALLEL 
GROUP, 36 WEEK STUDY TO INVESTIGATE THE 
SAFETY, TOLERABILITY, PHARMACOKINETICS, 
AND EFFICACY OF RO6867461 ADMINISTERED 
INTRAVITREALLY IN PATIENTS WITH 
CHOROIDAL NEOVASCULARIZATION 
SECONDARY TO AGE-RELATED MACULAR 
DEGENERATION 
PROTOCOL NUMBER: BP29647 
VERSION: 
3 
EUDRACT NUMBER: 
N/A 
IND NUMBER: 
119225 
TEST PRODUCT: 
RO6867461 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1: 13 March 2015 
DATE AMENDED: 
Version 2: 24 February 2016 
Version 3:  See electronic date stamp below. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3                                                                                                            2 
TABLE OF CONTENTS 
1. 
BACKGROUND AND RATIONALE............................................................. 21 
1.1
Background on Disease......................................................... 21 
1.2
Background on RO6867461 .................................................. 21 
1.2.1
Previous Nonclinical Studies ................................................. 22 
1.2.2
Previous Clinical Studies ....................................................... 23 
1.2.2.1 
Safety and Tolerability ........................................................... 24 
1.2.2.2 
Pharmacokinetics .................................................................. 24 
1.2.2.3 
Functional and Anatomical Pharmacodynamics.................... 25 
1.3 
Study Rationale and Benefit–Risk Assessment..................... 25 
2.
OBJECTIVES.............................................................................................. 26
2.1
Primary Objectives ................................................................ 26 
2.2
Secondary Objectives............................................................ 26 
2.3
Exploratory Objectives........................................................... 26 
3. 
STUDY DESIGN ......................................................................................... 27 
3.1
Description of Study .............................................................. 27 
3.1.1
Overview of Study Design ..................................................... 27 
3.1.2
Number of Patients................................................................ 28 
3.1.3
Internal Monitoring Committee............................................... 28 
3.1.4
End of Study.......................................................................... 29 
3.2
Rationale for Study Design.................................................... 29 
3.2.1
Rationale for Dosage Selection ............................................. 30 
3.2.2
Rationale for Study Population .............................................. 30 
3.2.3
Rationale for Control Group................................................... 31 
3.2.4 
Rationale for Biomarker Assessments................................... 31 
3.3
Outcome Measures ............................................................... 32 
3.3.1
Safety Outcome Measures .................................................... 32 
3.3.2
Pharmacokinetic Outcome Measures.................................... 32 
3.3.3 
Efficacy and Pharmacodynamic Outcome 
Measures............................................................................... 32 
3.3.3.1 
Primary Efficacy Outcome Measures .................................... 32 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
3 
3.3.3.2 
Secondary Efficacy Outcome Measures................................ 33 
3.3.3.3 
Pharmacodynamic Biomarker Outcome 
Measures............................................................................... 33 
3.3.4 
Exploratory Outcome Measures ............................................ 33 
4. 
MATERIALS AND METHODS .................................................................... 33 
4.1 
Center.................................................................................... 33 
4.2 
Study Population ................................................................... 34 
4.2.1 
Inclusion Criteria.................................................................... 34 
4.2.2 
Exclusion Criteria................................................................... 35 
4.3 
Method of Treatment Assignment and Masking .................... 37 
4.3.1 
Treatment Assignment........................................................... 37 
4.3.2 
Treatment Administration Procedure ..................................... 38 
4.3.3 
Masking ................................................................................. 38 
4.3.4 
Emergency Unmasking.......................................................... 39 
4.4 
Study Treatment.................................................................... 39 
4.4.1 
Formulation, Packaging, and Handling.................................. 39 
4.4.1.1 
RO6867461 and Placebo ...................................................... 39 
4.4.1.2 
Ranibizumab (Active Comparator)......................................... 40 
4.4.1.3 
Sham ..................................................................................... 41 
4.4.2 
Dosage, Administration, and Compliance.............................. 41 
4.4.2.1 
RO6867461, ranibizumab and Sham .................................... 41 
4.4.3 
Investigational Medicinal Product Accountability ................... 42 
4.4.4 
Sham Boxes Accountability ................................................... 43 
4.4.5 
Post-Trial Access to RO6867461 .......................................... 43 
4.5 
Concomitant Therapy ............................................................ 44 
4.5.1 
Concomitant Therapy ............................................................ 44 
4.5.2 
Excluded Therapy.................................................................. 44 
4.5.3 
CNV Secondary to AMD in the Fellow Eye............................ 44 
4.6 
Study Assessments ............................................................... 45 
4.6.1 
General Safety Assessments ................................................ 45 
4.6.1.1 
Medical History and Demographic Data ................................ 45 
4.6.1.2 
Physical Examinations........................................................... 46 
4.6.1.3 
Vital Signs.............................................................................. 46 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
4 
4.6.1.4 
Electrocardiograms................................................................ 46 
4.6.1.5 
Laboratory Assessments ....................................................... 47 
4.6.1.6 
Anti-Drug Antibody Assessments .......................................... 48 
4.6.2 
Pharmacokinetic Assessments.............................................. 49 
4.6.2.1 
Blood Samples ...................................................................... 49 
4.6.2.2 
Aqueous Humor Samples (optional)...................................... 49 
4.6.2.3 
Unscheduled Collection of Vitreous Samples 
(optional)................................................................................ 50 
4.6.3 
Clinical Genotyping (CG) Sample.......................................... 50 
4.6.4 
Disease-Specific Assessments.............................................. 50 
4.6.4.1 
Ocular Safety Assessments................................................... 51 
4.6.4.2 
Efficacy and Pharmacodynamic Assessments ...................... 51 
4.6.4.3 
Exploratory Assessments ...................................................... 52 
4.6.5 
Amount of Blood to be Collected throughout the 
Study ..................................................................................... 53 
4.6.6 
Timing of Study Assessments ............................................... 54 
4.6.6.1 
Screening and Pretreatment Assessments............................ 54 
4.6.6.2 
Assessments during Treatment............................................. 55 
4.6.6.3 
Assessments at Early Termination Visit................................. 56 
4.6.6.4 
Assessments at Final Visit..................................................... 56 
4.6.6.5 
Assessments at Unscheduled Visits...................................... 56 
4.7 
Patient Withdrawal, Study, and Site 
Discontinuation...................................................................... 56 
4.7.1 
Patient Discontinuation.......................................................... 56 
4.7.1.1 
Discontinuation from Study Drug........................................... 57 
4.7.2 
Study and Site Discontinuation.............................................. 57 
5. 
ASSESSMENT OF SAFETY....................................................................... 58 
5.1 
Safety Parameters and Definitions ........................................ 58 
5.1.1 
Adverse Events ..................................................................... 58 
5.1.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 59 
5.1.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 59 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
5 
5.1.4 
Sight-Threatening Adverse Events (Immediately 
Reportable to the Sponsor).................................................... 60 
5.2 
Safety Plan ............................................................................ 60 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 60 
5.3.1 
Adverse Event Reporting Period ........................................... 61 
5.3.2 
Eliciting Adverse Event Information ....................................... 61 
5.3.3 
Assessment of Severity of Adverse Events ........................... 61 
5.3.4 
Assessment of Causality of Adverse Events ......................... 62 
5.3.5 
Procedures for Recording Adverse Events............................ 62 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 63 
5.3.5.2 
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 63 
5.3.5.3 
Persistent or Recurrent Adverse Events................................ 63 
5.3.5.4 
Abnormal Laboratory Values ................................................. 64 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 64 
5.3.5.6 
Abnormal Liver Function Tests.............................................. 65 
5.3.5.7 
Deaths ................................................................................... 65 
5.3.5.8 
Preexisting Medical Conditions.............................................. 66 
5.3.5.9 
Worsening of AMD ................................................................ 66 
5.3.5.10 
Hospitalization, Prolonged Hospitalization, or 
Surgery.................................................................................. 66 
5.3.5.11 
Overdoses ............................................................................. 66 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 67 
5.4.1 
Emergency Medical Contacts................................................ 67 
5.4.2             Reporting Requirements for Pregnancies.............................. 67 
5.4.2.1 
Pregnancies in Female Patients............................................ 67 
5.4.2.2 
Abortions ............................................................................... 68 
5.4.2.3 
Congenital Anomalies/Birth Defects ...................................... 68 
5.5 
Follow-Up of Patients after Adverse Events .......................... 68 
5.5.1 
Investigator Follow-Up........................................................... 68 
5.5.2 
Sponsor Follow-Up ................................................................ 68 
5.6 
Post-Study Adverse Events................................................... 69 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
6 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 69 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 69 
6.1 
Determination of Sample Size ............................................... 69 
6.1.1 
Sample Size and Power for Treatment-Naive 
Population Evaluation............................................................ 69 
6.1.2 
Sample Size and Power for Anti-VEGF-
Incomplete-Responder Population Evaluation....................... 70 
6.2 
Summaries of Conduct of Study............................................ 70 
6.3 
Analysis Populations ............................................................. 70 
6.3.1 
Safety Analysis Population .................................................... 70 
6.3.2 
Efficacy, Pharmacokinetic, and 
Pharmacodynamic Analysis Population................................. 70 
6.3.2.1 
Population A: All Patient Randomized to Arms A, 
B, C, and D............................................................................ 70 
6.3.2.2 
Population B: All Patients Randomized to Arms A 
and E ..................................................................................... 71 
6.4 
Summaries of Treatment Group Comparability ..................... 71 
6.5 
Safety Analyses..................................................................... 71 
6.5.1 
Adverse Events ..................................................................... 71 
6.5.2 
Clinical Laboratory Test Results............................................ 71 
6.5.2.1 
Standard Reference Ranges and Transformation 
of Data................................................................................... 71 
6.5.2.2 
Definition of Laboratory Abnormalities................................... 72 
6.5.3 
Vital Signs.............................................................................. 72 
6.5.4 
ECG Data Analysis................................................................ 72 
6.5.5 
Anti-Drug Antibody Data Analysis.......................................... 72 
6.5.6 
Ocular Assessments.............................................................. 72 
6.5.7 
Concomitant Medications ...................................................... 72 
6.6 
Efficacy Analyses .................................................................. 73 
6.6.1 
Primary Efficacy Endpoint...................................................... 73 
6.6.1.1 
Evaluation in the Treatment-Naive Population....................... 73 
6.6.1.2 
Evaluation in the Anti-VEGF-Incomplete-
Responder Population ........................................................... 73 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
7 
6.6.2 
Secondary Efficacy Endpoints............................................... 74 
6.7 
Pharmacodynamic Analyses ................................................. 74 
6.8 
Pharmacokinetic Analyses..................................................... 75 
6.9 
Other Exploratory Analyses................................................... 75 
6.10 
Interim Analyses.................................................................... 75 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 75 
7.1 
Data Quality Assurance......................................................... 75 
7.2 
Electronic Case Report Forms............................................... 76 
7.3 
Source Data Documentation.................................................. 76 
7.4 
Use of Computerized Systems .............................................. 77 
7.5 
Retention of Records............................................................. 77 
8. 
ETHICAL CONSIDERATIONS.................................................................... 77 
8.1 
Compliance with Laws and Regulations ................................ 77 
8.2 
Informed Consent .................................................................. 78 
8.3 
Institutional Review Board or Ethics Committee.................... 79 
8.4 
Confidentiality........................................................................ 79 
8.5 
Financial Disclosure .............................................................. 79 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 80 
9.1 
Study Documentation ............................................................ 80 
9.2 
Site Inspections ..................................................................... 80 
9.3 
Administrative Structure......................................................... 80 
9.4 
Publication of Data and Protection of Trade 
Secrets .................................................................................. 80 
9.5 
Protocol Amendments ........................................................... 81 
10. REFERENCES ........................................................................................... 82 
 
LIST OF TABLES 
Table 1 
Overall Adverse Event profile for all Patients Enrolled in 
Study BP28936........................................................................... 24 
Table 2 
Dosage Strengths and Dilution ................................................... 42 
Table 3 
Adverse Event Severity Grading Scale ....................................... 61 
 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
8 
LIST OF FIGURES 
Figure 1 
Study Design............................................................................... 27 
 
LIST OF APPENDICES 
Appendix 1  
Schedule of Assessments........................................................... 83 
Appendix 2 
Schedule of Assessments Detail Table for Visits with 
Repeated Assessments .............................................................. 87 
Appendix 3 
Grading Scale for Assessment of Anterior Chamber Flare or 
Cells, Vitreal Hemorrhage Density, and Vitreous Cells ............... 88 
Appendix 4 
Study Treatment Administration Procedure ................................ 90 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
9 
 
SYNOPSIS OF PROTOCOL NUMBER BP29647 
TITLE 
 
A MULTIPLE-CENTER, MULTIPLE-DOSE AND REGIMEN, 
RANDOMIZED, ACTIVE COMPARATOR CONTROLLED, 
DOUBLE-MASKED, PARALLEL GROUP, 36-WEEK STUDY 
TO INVESTIGATE THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, AND EFFICACY OF RO6867461 
ADMINISTERED INTRAVITREALLY IN PATIENTS WITH 
CHOROIDAL NEOVASCULARIZATION SECONDARY TO 
AGE-RELATED MACULAR DEGENERATION 
PROTOCOL NUMBER: 
BP29647 
VERSION: 
3 
EUDRACT NUMBER: 
N/A 
IND NUMBER: 
119225 
TEST PRODUCT: 
RO6867461 
PHASE: 
II 
INDICATION: 
Choroidal neovascularization (CNV) secondary to age-related 
macular degeneration (AMD) 
SPONSOR: 
F. Hoffmann-La Roche Ltd. 
OBJECTIVES  
Primary: 
The primary objective of this study is as follows: 
• 
To evaluate the efficacy of RO6867461 compared to ranibizumab monotherapy in 
treatment-naive and anti-vascular endothelial growth factor (VEGF)−incomplete-responder 
patients with CNV secondary to AMD. 
 
Secondary:  
The secondary objectives of this study are as follows: 
• 
To assess the safety of multiple intravitreal (IVT) doses of RO6867461 
• 
To assess systemic pharmacokinetics of RO6867461 
• 
To investigate pharmacodynamics (PD) and anatomical outcomes informing on the 
mechanism of action of RO6867461 
• 
To investigate the formation of plasma anti-RO6867461 antibodies 
• 
To investigate 2 different RO6867461 dosing regimens 
 
Exploratory:  
The exploratory objectives of this study are as follows: 
• 
To evaluate RO6867461 effects on plasma levels of markers of angiogenesis and 
inflammation 
• 
To investigate RO6867461 concentration and, if sample volume allows, inflammatory and 
pro-angiogenic factors, in aqueous humor samples (optional) and vitreous (optional) 
• 
To evaluate the effect of genetic polymorphisms in genes associated with AMD and/or 
involved in angiogenesis and response to RO6867461 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
10 
STUDY DESIGN 
Description of Study 
Multiple-center, multiple-dose and regimen, randomized, active comparator controlled, 
double-masked, five parallel group, 36-week study in patients with CNV secondary to AMD 
The five groups of this study are as follows: 
• 
Arm A:  0.5 mg ranibizumab IVT every 4 weeks for 32 weeks (9 injections) 
• 
Arm B:  1.5 mg RO6867461 IVT every 4 weeks for 32 weeks (9 injections) 
• 
Arm C:  6 mg RO6867461 IVT every 4 weeks for 32 weeks (9 injections) 
• 
Arm D:  6 mg RO6867461 IVT every 4 weeks up to Week 12 (4 injections), followed by 
6 mg RO6867461 IVT every 8 weeks (i.e., on Weeks 20 and 28; 2 injections) 
• 
Arm E:  0.5 mg ranibizumab IVT every 4 weeks up to Week 8 (3 injections), followed by 
6 mg RO6867461 IVT every 4 weeks (6 injections) 
 
The study will allow evaluation of RO6867461 in a treatment-naive patient population 
(comparison of Arms A, B, C, and D) and an anti-VEGF−incomplete-responder patient 
population that meets a predefined criterion at Week 12 (comparison between Arms A and E).  
Only one eye will be chosen as the study eye. 
NUMBER OF PATIENTS 
In the initial recruitment period, up to 271 patients with CNV secondary to AMD are expected to 
be enrolled in the study.  Up to 45 (Arms B, C, and D) or 68 (Arms A and E) patients are 
expected to be randomized per arm of the study (3:2:2:2:3 randomization scheme). 
An interim analysis might be conducted to adapt the recruitment up to a maximum of 
343 patients in order to have approximately 80 patients in the anti-VEGF−incomplete-responder 
subgroup completing the study. 
TARGET POPULATION 
Male and female patients of  ≥ 50 years of age with treatment−naive CNV secondary to AMD. 
INCLUSION/EXCLUSION CRITERIA 
Inclusion Criteria: 
Patients must meet the following criteria at study entry: 
Ocular criteria for study eye: 
• 
Treatment-naïve with CNV secondary to AMD, with subfoveal CNV or juxtafoveal CNV with 
a subfoveal component related to the CNV activity by fundus fluorescein angiography 
(FFA) or spectral domain optical coherence tomography (SD-OCT) (such as subretinal 
fluid, subretinal hyper-reflective material, evidence of leakage, or hemorrhage) 
• 
Best corrected visual acuity (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.  Proportion of patients with BCVA letter score of 73 to 69 letters 
inclusive (20/40 Snellen equivalent) on Day 1 will be limited to a maximum of 40% of the 
planned sample size  
• 
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 (DAs) by FFA  
CNV component area of ≥ 50% of total lesion size by FFA 
Active CNV confirmed by FFA (evidence of leakage) 
CNV exudation confirmed by SD-OCT (presence of fluid) 
• 
Clear ocular media and adequate pupillary dilatation to allow acquisition of good quality 
retinal images to confirm diagnosis  
 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
11 
General Criteria: 
• 
Able and willing to provide written informed consent and to comply with the study protocol 
according to International Conference on Harmonization (ICH) and local regulations.  
Alternatively, a legally authorized representative must be able to consent for the patient 
according to the ICH and local regulations 
• 
Age  ≥ 50 years 
• 
For women who are not postmenopausal (i.e., ≥ 12 months of non-therapy-induced 
amenorrhea or surgically sterile (absence of ovaries and/or uterus) agreement to remain 
abstinent or use combined contraceptive methods that result in a failure rate of  < 1% per 
year during the treatment period and at least through Week 36. 
Examples of contraceptive methods with an expected failure rate of < 1% per year 
include male sterilization, hormonal implants, proper use of combined oral or injected 
hormonal contraceptives, and certain intrauterine devices.  Alternatively, two methods 
(e.g., two barrier methods such as a condom and a cervical cap) may be combined to 
achieve a failure rate of < 1% per year, barrier methods must always be supplemented 
with the use of a spermicide. 
• 
Males must agree to use a barrier method of contraception starting from first treatment 
administration for at least 2 months post-last treatment administration. 
• 
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 (CSC) 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, transplasminogen 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 
• 
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, etc.) that, in the opinion of the Investigator, could either reduce the potential for 
visual improvement or require medical or surgical intervention  
• 
Active intraocular inflammation (grade trace or above) in the study eye 
• 
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 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
12 
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 
 
General Criteria: 
• 
Any major illness or major surgical procedure within one month before screening  
• 
Patients with glycosylated hemoglobin HbA1C > 7.5% 
• 
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 either 30 or more minutes 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 within 12 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 
• 
For females of childbearing potential, a positive blood pregnancy test  
• 
Lactating women 
• 
Known hypersensitivity to ranibizumab, fluorescein, indocyanine green, any ingredients of 
the formulation used, dilating eye drops, or any of the anesthetic and antimicrobial drops 
used 
• 
Any other restriction accorded to the use of  
• 
Any treatment with an IMP in the 3 months prior to Day 1 
LENGTH OF STUDY 
The total duration of the study for each patient will be up to 40 weeks, divided as follows: 
• 
Screening:  up to 4 weeks 
• 
Baseline:  Day 1 
• 
Study Treatment Administration:  from Day 1 to Week 32  
• 
Final safety and efficacy period:  from Week 32 to Week 36 
 
END OF STUDY 
The end of the study is defined as the date when the last patient last observation (LPLO) 
occurs.  LPLO is expected to occur 36 weeks after the last patient is enrolled. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
13 
OUTCOME MEASURES 
SAFETY OUTCOME MEASURES 
Adverse events 
Adverse events and concomitant medications will be monitored throughout the entire study. 
Vital signs 
Body temperature (oral or tympanic) will be collected at the time-points indicated in the 
schedule of assessments (SoA). 
BP and pulse rate will be performed after the patient has rested for at least 5 minutes at the 
time-points indicated in the SoA. 
Electrocardiograms 
12-lead triplicate electrocardiogram (ECG) will be performed at the time-points indicated in the 
SoA. 
Ocular safety 
Visual acuity will be assessed using best correction determined from protocol refraction (BCVA) 
using ETDRS-like charts, slit lamp examination, dilated binocular indirect high-magnification 
ophthalmoscopy, IOP, fundus photography, SD-OCT, and angiography will be performed at the 
time-points indicated in the SoA. 
Laboratory tests 
Hematology, blood chemistry, and urinalysis, listed below, will be collected at the time-points 
indicated in the SoA. 
• 
Hematology:  Hemoglobin, hematocrit (HCT), red blood cell 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), erythrocyte sedimentation rate (ESR) 
• 
Coagulation (at screening only):  Activated partial thromboplastin time (APTT) and 
prothrombin time/International Normalized Ratio (PT/INR) 
• 
Blood chemistry:  Sodium, potassium, bicarbonate, phosphate, chloride, calcium, urea, 
creatinine, total bilirubin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), creatine phosphokinase (CPK), gamma glutamyl 
transferase (GGT), total protein, glucose, HbA1C (at screening and at final or early 
termination visits only), total cholesterol (TC), triglycerides (TG), C-reactive protein (CRP)  
• 
Urinalysis:  A midstream, clean-catch urine specimen will be collected for dipstick analysis 
of protein, blood, glucose, and pH.  Microscopy to be performed if abnormalities are 
observed and deemed necessary by the Investigator or Designee, in particular when blood 
or protein is positive or strong positive  
• 
Pregnancy test:  for females of childbearing potential, serum pregnancy test at screening 
Anti-drug antibodies 
Plasma samples will be collected at the time-points indicated in the SoA to evaluate the 
presence of anti-RO6867461 antibodies. 
PHARMACOKINETIC OUTCOME MEASURES 
Plasma levels of RO6867461 
Plasma concentrations will be measured by a specific enzyme-linked immunosorbent assay 
(ELISA) method.  The pharmacokinetic (PK) analysis is described in the statistical methods 
section.  Samples may also be analyzed for ranibizumab. 
Aqueous humor samples (optional) 
Samples will be collected from patients who provide additional (optional) consent to participate 
in aqueous humor collection.  Samples will be analyzed for RO6867461 and biomarker 
concentrations.  Samples may also be analyzed for ranibizumab. 
Unscheduled collection of vitreous samples (optional) 
If elective vitrectomy surgery is medically necessary, a vitreous sample can be obtained from 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
14 
the study eye from patients who provide additional (optional) consent to participate in vitreous 
collection for the measurement of RO6867461 and biomarker concentrations.  Samples may 
also be analyzed for ranibizumab.  A blood sample for PK measurement should be taken at the 
same time. 
EFFICACY OUTCOME MEASURES 
The primary efficacy outcome measure for this study is the mean change from baseline BCVA 
at Week 36 using the ETDRS-modified charts. 
The secondary efficacy outcome measures for this study include BCVA and anatomical PD 
imaging measures relevant to the mechanism of action of RO6867461 as follows: 
BCVA 
• 
Proportion of patients gaining ≥ 15 letters from baseline BCVA at Week 36 
• 
Proportion of patients with BCVA of 20/40 or better at Week 36 
• 
Proportion of patients with BCVA of 20/200 or worse at Week 36 
Anatomic outcome measures using SD-OCT 
• 
Mean change from baseline in foveal center point thickness at Week 36 
• 
Mean change from baseline in mean central subfield thickness (1 mm diameter) at Week 36 
• 
Proportion of patients with no intraretinal fluid, subretinal fluid, cysts, or pigment epithelial 
detachment at Week 36 
Anatomic outcome measures using FFA 
• 
Mean change from baseline in total area of CNV at Week 36 
• 
Mean change from baseline in total area of CNV component at Week 36 
• 
Mean change from baseline in total area of leakage at Week 36 
EXPLORATORY OUTCOME MEASURES 
The exploratory outcome measures for this study include but are not limited to the following: 
• 
Biomarkers in plasma related to angiogenesis and inflammation 
• 
Pro-angiogenic factors in aqueous humor and vitreous samples for patients who provide 
consent to participate 
BIOMARKER/GENOTYPING SAMPLE COLLECTION 
Biomarkers Plasma Samples 
All patients who have been enrolled in the study will have mandatory PD and exploratory 
biomarker plasma samples taken at the time-points indicated in the SoA.  The PD and 
exploratory plasma samples will be collected to investigate biomarkers in plasma related to 
angiogenesis and inflammation.  
Clinical Genotyping (CG) Samples 
A mandatory whole blood sample will be taken for DNA extraction from every subject.  The DNA 
may be used to study genes related to AMD (e.g., AMRS2. HTRA1, CFH, C3, etc.) as well as 
related to angiogenesis (e.g., VEGFA, VEGFR2, angiopoietin-2, angiopoietin-1 receptor [Tie-2], 
etc.), and the effect on the PK/PD/efficacy/safety of RO6867461.  Data arising from this sample 
will be subject to the same confidentiality as the rest of the study.  This specimen will be 
destroyed no later than 2 years after the final closure of the clinical database. 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
IMPs will include the two study drugs as follows: 
• 
RO6867461: Vials of sterile, colorless to brownish, preservative-free solution of 
RO6867461 (120 mg/mL), for IVT administration of either 1.5 or 6 mg dose every 4 or 
8 weeks 
Placebo is provided as sterile, colorless to slightly brownish, preservative-free liquid, used 
only for dilution of RO6867461 drug product to the appropriate clinical dose. 
• 
Comparator
Ranibizumab:  Vials containing ranibizumab solution (10 mg/mL), for IVT 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
15 
administration of a 0.5 mg dose every 4 weeks. 
 
The double-masked design is achieved through strict independence of the pharmacist (or 
designated personnel) and Investigators who are preparing and administering study treatment, 
from the assessing Investigators and remaining site personnel. 
NON-INVESTIGATIONAL MEDICINAL PRODUCTS 
• 
Sham:  Sham IVT administration will be delivered to patients in Arm D at Weeks 16, 24, 
and 32 to maintain double-masking throughout the study period. 
PROCEDURES 
Detailed SoAs and procedures are tabulated in Appendix 1 and Appendix 2 of the protocol. 
Screening 
Treatment-naive patients with CNV secondary to AMD who are willing to participate in the study 
and have given informed consent will undergo a thorough screening examination within 4 weeks 
of study treatment administration.  The screening procedures as outlined in the SoA will include 
review of inclusion and exclusion criteria, medical history, physical examination, assessment of 
vital signs and ECG, serum pregnancy test for female of childbearing potential, and safety 
laboratory parameters.  Imaging criteria for eligibility will be confirmed by a Central Reading 
Center before enrolment. 
Treatment period 
On Day 1, baseline assessments will be conducted on the eligible patients, according to the 
SoA.  Patients will receive their first IVT administration of either RO6867461 or comparator 
therapy according to the randomization schedule and following established standard 
procedures.  Patients will return to the eye clinic for study treatment administration (every 
4 weeks) and assessments as outlined in the SoA.  Patients will be administered the same 
study treatment throughout the study period, except for the patients randomized to Arms D and 
E: 
• 
Patients in Arm D will receive sham administrations on Weeks 16, 24, and 32 to maintain 
the double-masking throughout the every 8 weeks (Q8W) regimen period. 
• 
Patients in Arm E will initially receive 3 injections of ranibizumab followed by 6 injections of 
RO6867461. 
A post-treatment administration check of study eye will be performed for each patient 
immediately after treatment administration, by testing finger count vision, or hand motion and 
light perception.  On the day of dosing, IOP will be monitored at 30 minutes post-treatment 
administration in the study eye, and if IOP  ≥ 30 mmHg, IOP should be re-assessed at 1 hour 
post-treatment administration.  If IOP continues to be elevated, treatment should be undertaken 
at the discretion of the Investigator. 
Final period 
Patients will return for final visits with assessments as outlined in the SoA 4 weeks after the last 
study treatment administration. 
STATISTICAL METHODS 
SAFETY ANALYSES 
All patients who receive at least one administration of the study treatment will be included in the 
safety analysis.  The safety data, including adverse events, reasons for withdrawal from study, 
laboratory data, concomitant medications, vital signs, and physical examination results will be 
listed and summarized descriptively. 
As appropriate, listings, summary tables, and graphs (subject plot and/or mean plots) will be 
provided for safety and tolerability assessments. 
Anti-RO6867461 antibody results (positive/negative) will be listed. 
General adverse events will be listed and summarized by body system and preferred term using 
MedDRA.  Ophthalmologic adverse events will be listed and summarized. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
16 
For laboratory data subject listings will be presented with abnormalities flagged. 
 
PHARMACOKINETIC ANALYSES 
A nonlinear mixed effects modeling approach (with NONMEM software) will be used to analyze 
the concentration-time data of RO6867461.  Population and individual primary PK parameters 
(i.e., clearance and volumes) will be estimated and the influence of various covariates (e.g., 
gender, body weight, etc.) on these parameters will be investigated.  The data collected in this 
study may be pooled with data collected in the previous Phase I study as appropriate to build a 
PK model.  Secondary PK parameters such as area under the concentration-time curve (AUC) 
and maximum plasma concentration observed (Cmax) will be derived from the individual post-hoc 
predictions.  The results of this analysis will be reported in a separate document from the clinical 
study report. 
PHARMACODYNAMIC ANALYSES  
Individual and mean PD data and parameters will be presented by listings and descriptive 
summary statistics including means, geometric means, medians, ranges, standard deviations, 
and coefficients of variation. 
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 using a meta-analysis 
approach by integrating data from this study and ranibizumab clinical data.   
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 characterized.  The results will be 
reported in a separate document from the clinical study report. 
SAMPLE SIZE JUSTIFICATION 
Sample size and power for treatment-naive population evaluation 
The sample size is based on the primary efficacy outcome of BCVA mean change from baseline 
to Week 36.  Each RO6867461 dose or dose regimen group (Arms B, C, and D) will be 
compared to the control group (Arm A).  
The power calculation is based on 68 patients randomized to Arm A, and 45 randomized to 
each of Arms B, C, and D, with drop-out rate of 10%.  Assuming a standard deviation of 
13.5 letters, this sample size would provide approximately 80% power to detect a true difference 
of 5.9 letters at the one-sided α level of 10%.  The minimum detectable difference would be 
approximately 3.5 letters. 
Sample size and power for anti-VEGF−incomplete-responder population evaluation 
The sample size is based on the primary efficacy outcome of BCVA mean change from 
Week 12 to Week 36 in the subset of anti-VEGF−incomplete-responders, between Arm A and 
Arm E.  
The power calculation is based on 68 patients randomized to both Arms A and E, with 65% 
meeting the criteria for inclusion in anti-VEGF−incomplete-responder subgroup and a drop-out 
rate of 10%.  Assuming a standard deviation of 9.7 letters, this sample size would provide 
around 80% power to detect a true difference of 4.7 letters at the one-sided α level of 10%.  The 
minimum detectable difference would be approximately 2.7 letters. 
 
PRIMARY ENDPOINT ANALYSIS 
Evaluation in the treatment naive population:  The primary efficacy variable is the mean BCVA 
change from baseline to Week 36.  The primary efficacy analysis will be performed using a 
Mixed Model for Repeated Measurement (MMRM) model. 
Evaluation in the anti-VEGF−incomplete-responder population:  The primary efficacy variable is 
the mean BCVA change from Week 12 to Week 36.  The primary efficacy analysis will be 
performed using a MMRM model. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
17 
INTERIM ANALYSES 
An interim analysis may be conducted to allow for adapting the sample size. 
An interim analysis of efficacy may be conducted for administrative reasons. 
Up to two additional interim analyses may be conducted for efficacy.  
OTHER CONSIDERATIONS 
N/A 
LIST OF PROHIBITED MEDICATIONS 
Concomitant therapy 
Patients who use maintenance therapy other than those required to treat wet AMD (wAMD) 
should continue its use. 
The decision to administer antimicrobial drops before and after the IVT administration is at the 
discretion of the Investigator. 
 
Excluded 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 either eye, except as required to treat 
adverse events 
• 
Concurrent use of photocoagulation or photodynamic therapy with verteporfin in the study 
eye for neovascular AMD 
 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
18 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA
anti-drug antibody 
AE
adverse event 
ALT
alanine aminotransferase 
bFGF
basic fibroblast growth factor 
AST
aspartate aminotransferase 
AMD
age-related macular degeneration 
Ang-1
angiopoietin-1 
Ang-2
angiopoietin-2 
AUC
area under the concentration–time curve 
BP
blood pressure 
BCVA
best corrected visual acuity 
CI
confidence interval 
CNV
choroidal neovascularization 
CSC
central serous chorioretinopathy 
CST
central subfield thickness 
DBP
diastolic blood pressure   
DLE
DME
dose-limiting event 
diabetic macular edema 
EC
Ethics Committee 
ECG
electrocardiogram 
eCRF
electronic Case Report Form 
EDC
electronic data capture 
ELISA
enzyme-linked immunosorbent assay 
EDI
enhanced depth imaging 
ETDRS
early treatment diabetic retinopathy study 
Fab
fragment antigen binding 
FAF
fundus autofluorescence 
FDA
U.S. Food and Drug Administration 
FFA
fundus fluorescein angiography 
FP
fundus photography 
GLP
Good Laboratory Practice 
HIPAA
Health Insurance Portability and Accountability Act 
IB
Investigator’s Brochure 
ICGA
indocyanine green angiography 
ICH
International Conference on Harmonisation 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
19 
Abbreviation 
Definition 
IMC
internal Monitoring Committee 
IMP
investigational medicinal product 
IND
Investigational New Drug 
IOP
intraocular pressure 
IRB
Institutional Review Board 
IVT
intravitreal 
IxRS
interactive (voice/web) response system 
LLD
low luminance deficit 
LLVA
low luminance visual acuity 
LPLV
last patient, last visit 
LPLO
last patient, last observation 
mAb
monoclonal antibody 
MAD
multiple ascending dose 
MMRM
mixed model for repeated measurement 
NOAEL
no observed adverse effect level 
PCV
polypoidal choroidal vasculopathy 
PD
pharmacodynamic 
PI
Principal Investigator 
PK
pharmacokinetic 
PT
prothrombin time 
PLGF
placental growth factor 
Q8W
every 8 weeks 
QT
QT interval 
QTc
corrected QT interval 
RAP
retinal angiomatous proliferation 
RPE
retinal pigment epithelium 
SAE
serious adverse event 
SAD
single ascending dose 
SBP
systolic blood pressure 
SD-OCT
spectral domain optical coherence tomography 
SoA
Schedule of Assessments 
SoC
standard of care 
t1/2
half-life 
ULN
upper limit of normal 
VA
visual acuity 
VEGF
vascular endothelial growth factor 
VEGFR
vascular endothelial growth factor receptor 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
20 
Abbreviation 
Definition 
wAMD
wet age-related macular degeneration 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
21 
1. 
BACKGROUND AND RATIONALE 
1.1 
BACKGROUND ON DISEASE 
Choroidal neovascularization (CNV) associated with age-related macular degeneration 
(AMD; alternative name wet AMD [wAMD]) can result in rapid and severe visual 
impairment and is the leading cause of blindness in people over the age of 50 years 
living in industrialized countries (Resnikoff et al. 2004; RO6867461 Investigator’s 
Brochure).  According to the National Eye Institute, 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 and 3.6 million in 2020 and 2030, respectively.  CNV secondary to AMD is 
characterized by the proliferation of choroidal capillaries that penetrate Bruch’s 
membrane in the form of choroidal neovascular membranes to migrate to the retinal 
pigment epithelium (RPE), causing a disruption in the outer retinal structure and 
function. 
Existing therapies for CNV secondary to AMD include photodynamic therapy and 
anti-vascular endothelial growth factor (VEGF)-targeted therapies.  Although anti-VEGF 
therapies have markedly improved the management of these patients and set a new 
efficacy paradigm in visual gain, they do not significantly improve vision in all patients, 
induce regression of neovascular membranes, or target all CNV-associated pathologies.  
Therefore, clinical evaluation of alternative anti-angiogenic targets or mechanisms of 
action are warranted to improve upon the clinical benefit of approved anti-VEGF 
therapies. 
Angiopoietin-2 (Ang-2) is of key importance in the homeostasis of the vascular 
compartment, functioning as an antagonist of the Tie-2 receptor tyrosine kinase 
expressed on endothelial cells.  Under hypoxic conditions, Ang-2 acts as a 
destabilization factor, rendering the vasculature more plastic and amenable to 
endothelial sprouting.  Nonclinical studies show that Ang-2 is an important factor driving 
neovascular diseases, and potentially acts as a pivotal angiogenic switch in retinal 
vascular diseases.  
1.2 
BACKGROUND ON RO6867461 
Nonclinical studies have shown that VEGF and Ang-2 act in concert to regulate the 
vasculature and cooperate to increase retinal EC permeability in vitro.  In addition, their 
vitreous concentration was shown to be both upregulated in diabetic retinopathy, retinal 
vein occlusion, and, to a lesser extent, in patients with AMD.  Therefore, selective 
neutralization of both VEGF and Ang-2 may further normalize the pathological ocular 
vasculature in comparison with the current standard of care (SoC), anti-VEGF therapies 
alone. 
RO6867461 is a humanized bispecific immunoglobulin G1 (IgG1) monoclonal antibody 
(mAb) that selectively binds VEGF-A and Ang-2.  The VEGF-binding fragment antigen 
binding (Fab) binds VEGF with high affinity, comparable to other anti-VEGF treatments 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
22 
(e.g., ranibizumab [Lucentis®]), and the Ang-2-binding Fab binds Ang-2, also with high 
affinity.  In vivo pharmacological evaluations in spontaneous and induced mouse and 
non-human primate models of neovascularization have confirmed the beneficial effects 
of RO6867461 in the reduction of CNV.  
Please refer to the RO6867461 Investigator’s Brochure for details on nonclinical and 
clinical studies. 
1.2.1 
Previous Nonclinical Studies 
Pharmacological studies were performed in vitro and in vivo to investigate the target 
binding affinity, specificity, and biological activity of RO6867461.  In vitro studies 
demonstrated that RO6867461 binds the target molecules VEGF and Ang-2 with high 
affinity.  Mutations in the Fc region of RO6867461 abolish binding to Fcγ receptors, 
located on effector cells, and the neonatal Fc receptor (FcRn). 
Pharmacological evaluation in vivo demonstrated that RO6867461 reduces the 
formation of CNV, the leakiness of existing CNV lesions, and subsequent injury to the 
retina due to lesion formation in a mutant mouse model of early bilateral CNV and a 
laser-induced model of CNV in cynomolgus monkeys (RO6867461 Investigator’s 
Brochure)  
Following single intravitreal (IVT) administration of 1.5 mg/eye RO6867461 in 
cynomolgus monkeys, flip-flop pharmacokinetics were observed with a strong correlation 
between exposure in vitreous humor, aqueous humor, and systemic circulation; with 
systemic bioavailability of 13%. 
In a 2-month Good Laboratory Practice (GLP) study in cynomolgus monkeys, the ocular 
and extra-ocular findings following three IVT injections of the highest 3 and 
6 mg/eye/dose were consistent with an immune-mediated response to a humanized 
antibody, like RO6867461, in nonhuman primates.  The no-observed-adverse-effect 
level (NOAEL) was established at a dose of 1.5 mg/eye/dose for IVT administration. 
In a 6-month GLP study in cynomolgus monkeys, no changes were observed following 
seven IVT injections every 4 weeks at the low dose of 0.5 mg/eye/dose comprising the 
NOAEL.  Dose-dependent ocular inflammatory cell infiltration and clinical signs of ocular 
inflammation occurred in RO6867461-treated eyes at 1.5 or 1.5/3 mg/eye/dose IVT 
following the same dosing schedule.  Ocular findings generally correlated with the 
systemic presence of anti-drug antibodies (ADAs) against RO6867461 and exposure 
loss in the serum of all animals.  Immunohistochemistry detection of immune-complex 
deposits in the affected eyes of RO6867461-treated animals is currently ongoing. 
RO6867461 did not induce any neurological (CNS) findings or effects on heart 
rate/electrocardiogram (ECG) endpoints (including QT and QTc [corrected QT interval]), 
respiratory rate, or body temperature in cynomolgus monkeys up to 6 months treatment. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
23 
See the RO6867461 Investigator’s Brochure for details on nonclinical studies. 
1.2.2 
Previous Clinical Studies 
A multicenter Phase I, open-label, single- and multiple-ascending-dose study to 
investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of 
RO6867461 administered IVT in patients with wAMD is currently ongoing (BP28936).  
Patients with CNV secondary to AMD previously treated with  ≥ 3 administrations of 
anti-VEGF medications within the last 6 months were enrolled. 
In Part A, single-ascending dose (SAD), single IVT doses of 0.5, 1.5, 3, or 6 mg were 
administered to a total of 12 patients (n = 3/dose).  In Part B, multiple-ascending dose 
(MAD), 3 IVT doses of 3 or 6 mg were administered 4 weeks apart to a total of 
12 patients (n = 6/dose).  All patients in the SAD group (Part A) and the 3 mg MAD group 
of Part B completed the study.  All patients of the 6 mg MAD group completed dosing 
and at least the Day 84 visit data (4 weeks after last dose) were available as of 
2 January, 2015 (data cutoff date). 
The plasma concentration-time profiles showed an approximately dose-proportional 
increase in drug plasma concentrations up to 3 mg RO6867461.  There was no apparent 
accumulation of plasma concentration following multiple dosing of RO6867461.  The 
estimated median apparent half-life (t1/2) ranged from 6 to 11.3 days.  
While the study was not designed to investigate efficacy of RO6867461, positive trends 
in best corrected visual acuity (BCVA) and mean central subfield thickness (CST) on 
spectral domain optical coherence tomography (SD-OCT) were observed.  
Please refer to the RO6867461 Investigator’s Brochure for details on Study BP28936. 
A multicenter, Phase II study to investigate the safety, tolerability, pharmacokinetics, 
and efficacy of RO6867461 administered IVT in patients with diabetic macular edema 
(DME) is ongoing (Study BP30099 − BOULEVARD; clinicaltrials.gov: 
NCT02699450). 
Ongoing review of masked safety data from the ongoing AVENUE study indicates that 
so far, the side effects observed in patients with choroidal neovascularization (CMV) 
due to age related macular degeneration (AMD) who are treated with IVT 
administration of RO6867461 are consistent with safety profile observed in 
Study BP28936; adverse events which are associated with IVT procedure; or natural 
progression of the disease.  At present no new or unexpected safety signals have been 
identified in AVENUE study. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
24 
1.2.2.1 
Safety and Tolerability 
Single and multiple administrations of RO6867461 were well tolerated up to the highest 
tested dose of 6 mg single dose and 6 mg multiple dose in patients with CNV secondary 
to AMD (Table 1).  No deaths and no dose-limiting events (DLEs) were reported.  
One serious adverse event has been reported to date, which was non-ocular, and was 
considered unrelated to the study drug by the Principal Investigator (PI).  One patient 
from the 3 mg dose group of Part A was withdrawn from the study because of an 
adverse event (see RO6867461 Investigator’s Brochure for further details).  
Table 1 
Overall Adverse Event profile for all Patients Enrolled in Study 
BP28936 
 
0.5 mg 
(SAD) 
(n = 3) 
1.5 mg 
(SAD) 
(n = 3) 
3 mg 
(SAD) 
(n = 3) 
3 mg 
(MAD) 
(n = 6) 
6 mg 
(SAD) 
(n = 3) 
6 mg 
(MAD) 
(n = 6) 
Total number of patients 
with at least one AE 
0 
2 (67%) 
3 (100%) 
5 (83%) 
2 (67%) 
2 (33%) 
Total number of events 
0 
5 
12 
19 
10 
3 
Total number of patients 
with at least one: 
⎯ 
⎯ 
⎯ 
⎯ 
⎯ 
⎯ 
AE with fatal outcome 
0 
0 
0 
0 
0 
0 
Serious AE 
0 
1 (33%) 
0 
0 
0 
0 
Related Serious AE 
0 
0 
0 
0 
0 
0 
Related AE 
0 
0 
1 (33%) 
0 
0 
1 (17%) 
Ocular AEs 
0 
1 (33%) 
2 (67%) 
4 (67%) 
2 (67%) 
1 (17%) 
Ocular AEs study eye 
0 
0 
2 (67%) 
4 (67%) 
2 (67%) 
1 (17%) 
Ocular AEs non-study eye 
0 
1 (33%) 
2 (67%) 
1 (17%) 
0 
1 (17%) 
Sight-threatening AE 
0 
0 
0 
0 
0 
0 
AE = adverse event; MAD = multiple-ascending dose; SAD = single-ascending dose. 
Notes:  Percentages are based on n. 
Multiple occurrences of the same event in one individual counted only once. 
6 mg MAD group incomplete (data cutoff:  2 January 2015) 
 
1.2.2.2 
Pharmacokinetics 
Plasma RO6867461 concentrations were available for all patients from the SAD part of 
the study.  As of the 2 January 2015 data cut-off, all RO6867461 plasma concentrations 
of the 3 mg MAD group were available and up to Day 35 of the 6 mg group. 
The plasma concentration-time profiles showed an approximately dose-proportional 
increase in drug plasma concentrations up to 3 mg RO6867461.  There was no apparent 
accumulation of plasma concentration following multiple dosing of RO6867461.  The 
estimated median apparent t1/2 ranged from 6 to 11.3 days. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
25 
1.2.2.3 
Functional and Anatomical Pharmacodynamics 
A positive trend for BCVA was observed in the study.  In the SAD part, a median 7 letter 
(range: 0 to 18; n = 11) improvement on Day 28 across all patients was observed.  For 
the patients in the MAD part, no change in mean BCVA was observed at 3 mg 
RO6867461.  However, for patients treated with 6 mg RO6867461, a positive trend for 
BCVA was observed following the second and third administrations, with a median 
BCVA increase 28 days after the first, second, and third administration of 0.5, 3, and 
7.5 letters, respectively.  
The positive BCVA trend was correlated with a positive trend for a reduction in CST on 
SD-OCT.  In Part A (SAD), a median -42 μm change from baseline, pooled for all dose 
levels (per-protocol population, n = 11), was observed on Day 28.  For the patients in the 
3 mg MAD group, a median change from baseline of -13.5 μm, −25.0 μm, and -9.0 μm 
change from baseline at 28 days after the first, second, and third drug administration, 
respectively.  Patients in the 6 mg MAD group showed a consistent and durable trend for 
a reduction in CST, with an overall comparable magnitude as compared to the SAD 
group.  The median CST change from baseline was -79.5 μm, -86 μm, and -126 μm at 
28 days after the first, second, and third drug administration, respectively. 
There was no overall apparent change in the fundus fluorescein angiography (FFA) but 
a single reader assessment will be carried out to ensure a consistent evaluation. 
1.3 
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT 
There are limited clinical efficacy evaluations with anti-Ang-2 approaches in patients with 
retinal disease.  The Phase I RO6867461 study, which included a small number of 
patients, showed good tolerability and safety profile and supportive signs of 
pharmacodynamic (PD) activity in a population of previously-treated patients with CNV 
secondary to AMD.  Taken together, the overall risk-benefit assessment is therefore 
favorable and justifies evaluation of RO6867461 efficacy over SoC therapy in patients 
with CNV secondary to AMD.  
Nonclinical toxicology studies (Section 1.2.1) 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 CNV secondary 
to AMD. 
When administered locally, RO6867461 was well tolerated up to the highest dose tested 
of 6 mg in previously treated patients with CNV secondary to AMD.  No DLEs or 
unexpected ocular adverse events were observed.  This safety/tolerability study did not 
raise any flags regarding systemic safety, drug-related serious adverse events, or 
severe adverse events. 
This will be a Phase II proof-of-concept study in treatment-naive and 
anti-VEGF−incomplete-responder patients with CNV secondary to AMD.  This study is 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
26 
designed to evaluate the effects of RO6867461 on visual function and retinal structure 
by assessing changes from baseline in BCVA and imaging procedures, respectively.  In 
addition, the safety, tolerability, and pharmacokinetics will be evaluated in patients 
receiving up to 9 doses of RO6867461. 
Patients who will be enrolled in the proposed study will fulfill the inclusion/exclusion 
criteria and will be monitored according to the protocol.  Detailed instructions on dosage, 
preparation, and administration of RO6867461 are provided in the protocol, and patients 
will be cautioned and intensively monitored as described.  Symptomatic treatment will be 
administered as necessary. 
Patients will be carefully monitored for potential serious ocular risks associated with the 
IVT injection procedure and for other potential systemic effects associated with the IVT 
administration of VEGF inhibitors (refer to RO6867461 Investigator’s Brochure) and 
managed as appropriate. 
2. 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVES 
The primary objective of this study is as follows: 
• 
To evaluate the efficacy of RO6867461 compared to monotherapy in 
treatment-naive and anti-VEGF−incomplete-responder patients with CNV secondary 
to AMD 
 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives of this study are as follows: 
• 
To assess the safety of multiple IVT doses of RO6867461 
• 
To assess systemic pharmacokinetics of RO6867461 
• 
To investigate pharmacodynamics and anatomical outcomes informing on the 
mechanism of action of RO6867461 
To investigate the formation of plasma anti-RO6867461 antibodies 
• 
To investigate 2 different RO6867461 dosing regimens 
 
2.3 
EXPLORATORY OBJECTIVES 
The exploratory objectives of this study are as follows: 
• 
To evaluate RO6867461 effects on plasma levels of markers of angiogenesis and 
inflammation 
• 
To investigate RO6867461 concentration and, if sample volume allows, 
inflammatory and pro-angiogenic factors, in aqueous humor samples (optional) and 
vitreous (optional) 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
27 
• 
To evaluate the effect of genetic polymorphisms in genes associated with AMD 
and/or involved in angiogenesis and response to RO6867461 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is a multiple-center, multiple-dose and regimen, randomized, active comparator 
controlled, double-masked, five parallel group, 36-week study in patients with CNV 
secondary to AMD.  
3.1.1 
Overview of Study Design 
The five groups of this study (Figure 1) are as follows. 
• 
Arm A:  0.5 mg ranibizumab IVT every 4 weeks for 32 weeks (9 injections) 
• 
Arm B:  1.5 mg RO6867461 IVT every 4 weeks for 32 weeks (9 injections) 
• 
Arm C:  6 mg RO6867461 IVT every 4 weeks for 32 weeks (9 injections) 
• 
Arm D:  6 mg RO6867461 IVT every 4 weeks up to Week 12 (4 injections), followed 
by 6 mg RO6867461 IVT every 8 weeks (i.e., on Weeks 20 and 28; 2 injections) 
• 
Arm E:  0.5 mg ranibizumab IVT every 4 weeks up to Week 8 (3 injections), followed 
by 6 mg RO6867461 IVT every 4 weeks (6 injections) 
 
The study will allow evaluation of RO6867461 in a treatment-naive patient population 
(comparison of Arms A, B, C, and D) and an anti-VEGF−incomplete-responder patient 
population that meets a predefined criterion at Week 12 (comparison between Arms A 
and E).  Only one eye will be chosen as the study eye. 
 
Figure 1 Study Design 
Screening & 
Baseline 
Study Treatment Administration 
Final safety 
period 
 
Q4W = every 4 weeks; Q8W = every 8 weeks 
 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
28 
The total duration of the study for each patient will be up to 40 weeks, divided as follows: 
• 
Screening:  up to 4 weeks 
• 
Baseline:  Day 1 
• 
Study Treatment Administration:  from Day 1 to Week 32 
• 
Final safety and efficacy period:  from Week 32 to Week 36 
 
Patients will be admitted to the investigational site on Day 1 and for subsequent 
scheduled visits, and will be discharged the same day after all mandatory and safety 
assessments as specified in Schedule of Assessments (SoA) are completed.  
If a site has an unexpected issue (e.g., interactive voice and web response system [IxRS] 
is not able to assign the study kit, or the study treatment administration cannot be done 
on the same day due to unavailability of the unmasked investigators at the site), the 
patient’s study treatment may be administered within 3 working days of the scheduled 
treatment visit with the Medical Monitor’s permission.   
The interval between two study treatment administrations needs to be at least 21 days. 
3.1.2 
Number of Patients 
In the initial recruitment period, up to 271 patients with CNV secondary to AMD are 
expected to be enrolled in the study.  Up to 45 (Arms B, C, and D) or 68 (Arms A and E) 
patients are expected to be randomized per arm of the study (3:2:2:2:3 randomization 
scheme) in this initial recruitment period. 
The Roche Internal Monitoring Committee (IMC; see Section 3.1.3) may conduct an 
interim analysis at approximately 1 to 3 months before the end of the initial recruitment 
period to determine the proportion of patients meeting the criterion for anti-
VEGF−incomplete-responder at Week 12 (Section 3.2) in Arms A and E.  The IMC may 
recommend adapting the recruitment up to a maximum of 343 patients in order to have 
approximately 80 patients in the anti-VEGF−incomplete-responder subgroup completing 
the study.  The same 3:2:2:2:3 randomization scheme will be applied in any extension 
recruitment period. 
Further details on this possible interim analysis will be provided separately in the IMC 
agreement. 
3.1.3 
Internal Monitoring Committee 
The Roche IMC will be responsible in the event of an interim analysis for sample size 
evaluation (Section 3.1.2), operational/administrative purposes, and/or for safety data 
monitoring.  For other objectives, the IMC will review the safety data and will be 
responsible for evaluating efficacy data for instance where assessment of benefit-risk is 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
29 
warranted.  These analyses will take place at pre-defined time-points or on an ad-hoc 
basis. 
The IMC consists of a selected subset of Roche representatives including Statistician, 
Safety Representative, Clinical Science Representative, Clinical Pharmacology 
Representative, and Pharmacometrician.  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 might 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 agreement. 
3.1.4 
End of Study 
The end of the study is defined as the date when the last patient last observation (LPLO) 
occurs.  LPLO is expected to occur 36 weeks after the last patient is enrolled.  
3.2 
RATIONALE FOR STUDY DESIGN 
A multiple center, double-masked, randomized, comparator controlled trial design was 
selected to allow for an unbiased evaluation of RO6867461 as a treatment for patients 
with CNV secondary to AMD. 
The study will allow evaluation of the efficacy of RO6867461 in treatment-naive patients 
(including 2 dose levels and 2 dose regimens) and patients who are switched to 
RO6867461 treatment after 3 administrations of ranibizumab.  The latter group will allow 
for the assessment of RO6867461 in an anti-VEGF−incomplete-responder population 
using a predefined criterion based on a traditional secondary efficacy outcome in the 
target population (Sections 3.3.3.2 and 6.6.1.2): 
• 
Patients with BCVA ≤ 68 letters at Week 12 
The double-masked design is achieved through the strict independence of the 
pharmacists (or designated personnel) and Investigators who are preparing and 
administering study treatment, from the assessing Investigators and remaining site 
personnel. 
Sham administration will be delivered to patients in Arm D at Weeks 16, 24, and 32 to 
maintain double-masking throughout the study period. 
To ensure the safety of all patients during the conduct of the study, several safety 
assessments have been included: e.g., regular ophthalmological monitoring (ocular 
safety panel and SD-OCT assessments), adverse events monitoring (systemic and 
ophthalmologic), vital signs (systolic blood pressure [SBP], diastolic blood pressure 
[DBP], and pulse rate), and laboratory safety tests. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
30 
Optional aqueous humor samples will be collected in consenting patients with an aim to 
further understand the ocular pharmacokinetics of RO6867461 and assess biomarkers 
(see Section 4.6.2).  Single (Krohne et al. 2012) and multiple (Campochiaro et al. 2013) 
aqueous humor sampling has been instrumental in the understanding of ocular 
pharmacokinetics. 
3.2.1 
Rationale for Dosage Selection 
The 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.  RO6867461 was well tolerated in 23 patients up 
to 4 weeks after the last of 1−3 IVT administrations of up to the 6 mg dose level. 
The dose of 1.5 mg RO6867461 was selected based on its equivalent anti-VEGF dose 
to ranibizumab due to the 3-fold higher molecular weight of the IgG antibody, 
RO6867461, as compared to the antibody fragment ranibizumab. 
The dose of 6 mg RO6867461 was selected as the highest feasible dose of RO6867461 
in the first-in-human study.  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 BP28936 did not reveal a safety signal following 3-monthly 
IVT doses of up to 6 mg RO6867461 (n = 6) in patients with CNV secondary to AMD.  
The 6-month GLP toxicity study tested RO6867461 up to the 3 mg dose level, seven 
times every 4 weeks, intravitreally.  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 intravitreal initial concentrations as compared to humans.  Of 
note, the clinical 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 and 6 mg 
RO6867461 doses, respectively.  The formulation for the present study protocol utilizes 
a 120 mg/mL highest concentration, which translates to a 50 μL injection volume for the 
6 mg RO6867461 dose.  However, this difference in concentration injected intravitreally 
is covered by the higher concentration achieved in the monkey eye as discussed above. 
Systemic exposure observed in patients following IVT administration is lower as 
compared to exposures observed in the cynomolgus monkey GLP toxicity study. 
Taken together, the nonclinical and clinical data suggest that the selected doses of 1.5 
and 6 mg RO6867461 administered every 4 weeks were safe and tolerated and allow a 
further testing in a 36-week clinical study. 
3.2.2 
Rationale for Study Population  
This study will be conducted in patients with treatment-naive CNV secondary to AMD, 
who meet all of the inclusion criteria and do not meet any of the exclusion criteria for this 
protocol (Section 4.2.1 and Section 4.2.2). 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
31 
3.2.3 
Rationale for Control Group 
This study is an interventional superiority study aiming to evaluate the efficacy of 
RO6867461 in treatment-naive and in anti-VEGF−incomplete-responder patients.  
Anti-VEGF therapy is a well-established SoC in the target population, and placebo is no 
longer an ethically acceptable alternative. 
Ranibizumab was the first approved treatment demonstrating improvement of visual 
acuity (VA) in patients with CNV secondary to AMD.  Aflibercept demonstrated 
non-inferiority to ranibizumab in the target population (Heier et al. 2012; Schmidt-Erfurth 
et al. 2014), and is currently administered in medical practice with similar frequency as 
ranibizumab in many countries including the United States (Turpcu et al. 2014).  
In clinical studies aimed at evaluating dosing regimens of ranibizumab, a fixed treatment 
regimen every 4 weeks consistently showed a BCVA improvement of 1−2 letters above 
an as needed regimen at 12−24 months, although the difference was either 
non-significant (Busbee et al. 2013) or treatment regimen were non-inferior (The CATT 
Research Group, 2011). 
Therefore, we selected the ranibizumab every 4 week regimen as an optimal comparator 
control for a superior efficacy design in the target population. 
3.2.4 
Rationale for Biomarker Assessments 
Several biochemical and biological processes such as angiogenesis, inflammation, and 
oxidative stress are known to play a role in the pathogenesis of AMD (The  CATT 
Research Group, 2011; Turpcu et al. 2014).  Moreover, several genetic polymorphisms 
have been shown to be strongly associated with AMD prevalence and progression. 
Therefore, both genetic markers and protein biomarkers of pathways involved in these 
processes may be analyzed to improve the understanding of the patients’ response to 
RO6867461 treatment.  The molecular targets of RO6867461 (VEGF and Ang-2) will be 
measured in the systemic circulation and, if possible, in aqueous and vitreous humor.  
Other biomarkers of angiogenesis that may be measured are: angiopoietin-1 (Ang-1), 
vascular endothelial growth factor receptor (VEGFR), Tie-2, placental growth factor 
(PLGF), basic fibroblast growth factor (bFGF), and platelet-derived growth factor 
(PDGF).  Furthermore, biomarkers of inflammation and oxidative stress may be 
measured in plasma and, if possible, in aqueous humor.  
Genetic polymorphisms associated with AMD (e.g., AMRS2, HTRA1, CFH, and C3) as 
well as related to angiogenesis (e.g., VEGFA, VEGFR2, Ang-2, and Tie-2) may be 
analyzed. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
32 
3.3 
OUTCOME MEASURES  
3.3.1 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Any relevant safety observations derived from BCVA (modified early treatment 
diabetic retinopathy study [ETDRS] charts), slit lamp examination, dilated binocular 
indirect high-magnification ophthalmoscopy, intraocular pressure (IOP), fundus 
photography (FP), SD-OCT, and angiography 
• 
Incidence and severity of ocular adverse events 
• 
Incidence and severity of non-ocular adverse events 
• 
Incidence of laboratory abnormalities, based on hematology, clinical chemistry, and 
urinalysis test results 
• 
Incidence of anti-RO6867461 antibodies 
• 
ECGs 
• 
Vital signs 
 
3.3.2 
Pharmacokinetic Outcome Measures  
The pharmacokinetic (PK) outcome measures for this study are as follows: 
• 
PK profiles and parameters derived from the nonlinear mixed effects modeling 
approach following IVT administration of RO6867461, including the following 
parameters:  
Primary parameters:  CL and V 
Secondary parameters:  Cmax, AUCinf, AUC0-τ, tmax, t1/2 
Compartmental analysis to assess IVT concentrations, as appropriate 
(exploratory) 
RO6867461 concentrations in aqueous humor samples for patients who 
provide additional consent to participate (exploratory) 
 
3.3.3 
Efficacy and Pharmacodynamic Outcome Measures 
For the evaluation in the treatment-naive population, the baseline measurement is the 
latest non-missing observation before the first dose of study medication.  For the 
evaluation in the anti-VEGF−incomplete-responder population, the baseline is the 
observation from Study Week 12. 
3.3.3.1 
Primary Efficacy Outcome Measures 
The primary efficacy outcome measure is the mean change from baseline in BCVA at 
Week 36 using the ETDRS modified charts. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
33 
3.3.3.2 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures include functional (BCVA) and anatomical 
PD imaging measures relevant to the mechanism of action of RO6867461 as follows. 
BCVA: 
• 
Proportion of patients gaining ≥ 15 letters from baseline in BCVA at Week 36  
• 
Proportion of patients with BCVA of 20/40 or better at Week 36 
• 
Proportion of patients with BCVA of 20/200 or worse at Week 36 
 
Anatomic outcome measures by SD-OCT: 
• 
Mean change from baseline in foveal center point thickness at Week 36 
• 
Mean change from baseline in mean CST (1 mm diameter) at Week 36 
• 
Proportion of patients with no intraretinal fluid, subretinal fluid, cysts, or pigment 
epithelial detachment at Week 36 
 
Anatomic outcome measures by FFA: 
• 
Mean change from baseline in total area of CNV at Week 36 
• 
Mean change from baseline in total area of CNV component at Week 36 
• 
Mean change from baseline in total area of leakage at Week 36 
 
3.3.3.3 
Pharmacodynamic Biomarker Outcome Measures 
Plasma biomarker outcome measures for this study are as follows: 
• 
Change in plasma levels of VEGF and Ang-2  
 
3.3.4 
Exploratory Outcome Measures 
The exploratory outcome measures for this study include but are not limited to the 
following: 
• 
Biomarkers in plasma related to angiogenesis and inflammation, including but not 
limited to Ang-1, Tie-2, VEGFR, PLGF, bFGF, PDGF, IL-1b, IL-6, eotaxin, autotaxin 
• 
Pro-angiogenic factors in aqueous humor and vitreous samples for patients who 
provide additional consent to participate. 
 
4. 
MATERIALS AND METHODS 
4.1 
CENTER 
This is a multi-center study to be conducted in the United States.  Additional site(s) will 
be included for back-up purposes and may be activated if needed.  The site 
Investigators will be qualified ophthalmologists/retinal specialists. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
34 
Administrative and Contact Information and List of Investigators are provided separately. 
4.2 
STUDY POPULATION 
Patients with CNV secondary to AMD who fulfill all the inclusion criteria listed in 
Section 4.2.1 will be enrolled in the study.  Patients meeting one or more of the 
conditions listed in Section 4.2.2 will be excluded from the study.  Written informed 
consent will be obtained before initiation of any study procedure. 
4.2.1 
Inclusion Criteria 
Patients must meet the following criteria at study entry. 
Ocular Criteria for Study Eye: 
• 
Treatment-naive with CNV secondary to AMD, with 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) 
• 
BCVA letter score of 73 to 24 letters (inclusive) on ETDRS-like charts (20/40 to 
20/320 Snellen equivalent) on Day 1.  Proportion of patients with BCVA letter score 
of 73 to 69 letters inclusive (20/40 Snellen equivalent) on Day 1 will be limited to a 
maximum of 40% of the planned sample size 
• 
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 (DAs) by FFA 
CNV component area of ≥ 50% of total lesion size by FFA 
Active CNV confirmed by FFA (evidence of leakage) 
CNV exudation confirmed by SD-OCT (presence of fluid) 
• 
Clear ocular media and adequate pupillary dilatation to allow acquisition of good 
quality retinal images to confirm diagnosis 
 
General Criteria: 
• 
Able and willing to provide written informed consent and to comply with the study 
protocol according to International Conference on Harmonization (ICH) and local 
regulations.  Alternatively, a legally authorized representative must be able to 
consent for the patient according to the ICH and local regulations 
• 
Age ≥ 50 years 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
35 
• 
For women who are not postmenopausal (i.e., ≥ 12 months of non-therapy−induced 
amenorrhea or surgically sterile (absence of ovaries and/or uterus) agreement to 
remain abstinent or use combined contraceptive methods that result in a failure rate 
of < 1% per year during the treatment period and at least through Week 36. 
Examples of contraceptive methods with an expected failure rate of < 1% per 
year include male sterilization, hormonal implants, proper use of combined oral 
or injected hormonal contraceptives, and certain intrauterine devices.  
Alternatively, two methods (e.g., two barrier methods such as a condom and a 
cervical cap) may be combined to achieve a failure rate of < 1% per year, 
barrier methods must always be supplemented with the use of a spermicide. 
• 
Males must agree to use a barrier method of contraception starting from first 
treatment administration for at least 2 months post-last treatment administration 
• 
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 
 
4.2.2 
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 (CSC) 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, transplasminogen 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 
• 
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 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
36 
Concurrent Ocular Conditions: 
• 
Any concurrent intraocular condition in the study eye (e.g., amblyopia, aphakia, 
retinal detachment, cataract, diabetic retinopathy or maculopathy, epiretinal 
membrane with traction, etc.) that, in the opinion of the Investigator, could either 
reduce the potential for visual improvement or require medical or surgical 
intervention  
• 
Active intraocular inflammation (grade trace or above) in the study eye 
• 
Current vitreous hemorrhage in the study eye 
• 
Uncontrolled glaucoma (e.g., progressive loss of visual fields or defined as IOP 
≥ 25 mmHg despite treatment with anti-glaucoma medication) in the study eye 
• 
Spherical equivalent of the 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 
 
General Criteria: 
• 
Any major illness or surgical procedure within one month before the screening 
examination  
• 
Patients with glycosylated hemoglobin HbA1C > 7.5% 
• 
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 either 30 or more minutes 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 within 12 months prior to Day 1 
• 
History of other disease, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding 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 
• 
For females of childbearing potential, a positive blood pregnancy test 
• 
Lactating women 
• 
Known hypersensitivity to ranibizumab, fluorescein, indocyanine green, any 
ingredients of the formulation used, dilating eye drops, or any of the anesthetic and 
antimicrobial drops used 
• 
Any other restriction accorded to the use of  
• 
Any treatment with an IMP in the 3 months prior to Day 1 
 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
37 
4.3 
METHOD OF TREATMENT ASSIGNMENT AND MASKING 
4.3.1 
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 (Section 4.2.1 and Section 4.2.2) at the 
screening and for selected criteria at the Day 1 visit (first study treatment) prior to 
randomization (Section 4.6.6.1).  As part of the screening process, FP, fundus 
autofluorescence (FAF), FFA, indocyanine green angiography (ICGA), and SD-OCT will 
be transferred to the central reading center, and a set of images will be evaluated to 
provide an objective, masked assessment of certain eligibility criteria. 
After all patient eligibility requirements are confirmed on Day 1 visit, including: 
• 
Day 1 baseline BCVA 
• 
Absence of active intraocular inflammation on Day 1 (study eye) 
• 
Absence of febrile illness within one week prior to Day 1, 
the site personnel will contact the IxRS for assignment of a patient identification number 
(a separate number from the screening number). 
Patients will be randomized in a 3:2:2:2:3 ratio to one of the study treatment arms: 
• 
Arm A:  0.5 mg ranibizumab IVT every 4 weeks for 32 weeks 
• 
Arm B:  1.5 mg RO6867461 IVT every 4 weeks for 32 weeks 
• 
Arm C:  6 mg RO6867461 IVT every 4 weeks for 32 weeks 
• 
Arm D:  6 mg RO6867461 IVT every 4 weeks up to Week 12 (4 injections), followed 
by 6 mg RO6867461 IVT every 8 weeks (i.e., on Weeks 20 and 28; 2 injections) 
• 
Arm E:  0.5 mg ranibizumab IVT every 4 weeks up to Week 8 (3 injections), followed 
by 6 mg RO6867461 IVT every 4 weeks (6 injections) 
 
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 the two factors below: 
• 
Presence of retinal angiomatous proliferation (RAP) or polypoidal choroidal 
vasculopathy (PCV) at screening as assessed by the Reading Center (presence of 
vs. absence of RAP or PCV) 
• 
Baseline BCVA ETDRS letter score assessed on Day 1 (69 letters or better vs. 
68 letters or worse) 
 
Randomization with fixed permuted blocks will be used to obtain an approximate 
3:2:2:2:3 ratio between the different arms within each stratum. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
38 
4.3.2 
Treatment Administration Procedure 
Study drug will be administered IVT.  The procedures are detailed in Appendix 4 and the 
Pharmacy Manual.  Sham will be used per the instructions in Section 4.4.1.3. 
At the discretion of the Investigator, the sites may use either propacaine- or 
tetracaine-based ophthalmic drops, or subconjunctival injection of lidocaine.  All efforts 
should be made to maintain the same anesthetic procedure throughout the study for a 
given patient to minimize bias and the risk of unmasking. 
At the discretion of the Investigator, the patient may self-administer ophthalmic 
broad-spectrum antimicrobial drops before and/or after study treatment administration. 
4.3.3 
Masking 
This is a double-masked study.  There must be a minimum of two Investigators per site 
to fulfill the masking requirements of this study.  All efforts should be made to schedule 
study visits when both Investigators are present.  At least one Investigator will be 
designated as the assessor physician who will be masked to patients’ treatment 
assignment and will evaluate all ocular assessments.  At least one other Investigator 
(and designated, unmasked assistant, as needed) will be designated as the treatment 
administrator physician who will be unmasked to patients’ treatment assignment and will 
administer study treatment (RO6867461, comparator, or sham). 
Once the designated roles are determined, unmasked study personnel cannot switch to 
a masked role during the conduct of the study. Switching from a masked to an 
unmasked role would be possible and would be documented in the delegation log.  In the 
event an alternate Investigator needs to be substituted for an Investigator, that alternate 
physician may assume only one role (i.e., treatment administrator physician or assessor 
physician) for the duration of the study.  The treatment administrator physician(s) 
performing the study treatment administration must not be involved in any other aspect 
of the study in any way and must not divulge treatment assignment to anyone. 
Patients, study site personnel (with the exception of the treatment administrator 
physician[s], assistant[s], and pharmacist or designated personnel, if any), the 
designated assessor physician(s), Central Reading Center personnel, and the Sponsor 
and its agents (with the exception of drug accountability monitors) will be masked to 
treatment assignment. 
Every effort must be made to limit the number of unmasked study personnel to ensure 
the integrity of this masked study.  There must be no more than five unmasked 
personnel at an investigative site at one time. Under certain circumstances, the total 
number of unmasked personnel might be increased after discussion and approval by 
Sponsor.  For the duration of the study, the patient treatment assignment will not be 
unmasked unless required for patient safety. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
39 
All study visit assessments, except those at screening, should be performed by masked 
site personnel only.  The unmasked treatment administrator physician will perform the 
injection of study treatment, and may also perform the post-treatment administration 
vision testing (finger counting and, if applicable, hand movement and/or light perception).  
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. 
IMC members (see Section 3.1.3) will be unmasked at the treatment group level.  The 
IMC agreement will also identify individuals unmasked at the individual patient level for 
safety analysis and for the purpose of preparing summary data display for the IMC 
meeting.  Other Roche Study Management Team members will remain masked 
throughout the study. 
4.3.4 
Emergency Unmasking 
If unmasking is necessary for patient management (e.g., in the case of a serious 
adverse event), the Investigator will be able to break the treatment code by contacting 
the IxRS system.  Treatment codes should not be broken except in emergency 
situations.  If the Investigator wishes to know the identity of the study treatment for any 
other reason, he or she should contact the Medical Monitor directly.  The Investigator 
should document all details and provide an explanation for any premature unmasking 
(e.g., accidental unmasking or unmasking due to serious adverse events).  
Sponsor might become unmasked to study treatment in the event of a serious adverse 
event reporting. 
As per health authority reporting requirements, the Sponsor will break the treatment 
code for all unexpected serious adverse events (see Section 5.1) that are considered by 
the Investigator to be related to study drug. 
4.4 
STUDY TREATMENT 
In this protocol, study treatment includes IVT administration of study drugs (RO6867461 
and active comparator ranibizumab) and sham IVT administration.  The latter is used to 
maintain double masking on Arm D throughout the fixed every 8 weeks (Q8W) regimen 
period. 
4.4.1 
Formulation, Packaging, and Handling 
4.4.1.1 
RO6867461 and Placebo 
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 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
40 
in L-histidine/HCl buffer solution (approximately pH 6.0) containing sodium chloride, 
sucrose, and polysorbate 20. 
Placebo will be provided with a nominal 1.0 mL fill of a sterile, colorless to slightly 
brownish, preservative-free liquid solution in 2 mL single-use vials, containing 
L-histidine/HCl buffer solution (approximately pH 6.0), sodium chloride, sucrose, and 
polysorbate 20 (excipient composition of the placebo is same as for RO6867461 Drug 
Product). 
In this study, Placebo will only be used for dilution of RO6867461 Drug Product to the 
appropriate clinical dose.  Detailed dilution instructions are provided separately in the 
Pharmacy Manual. 
RO6867461 Drug Product and Placebo required for completion of this study will be 
provided by the Sponsor.  
RO6867461 Drug Product and Placebo 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 and Placebo will be in 
accordance with Roche standard and local regulations. 
RO6867461 Drug Product and Placebo 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. 
For further details, see the IB. 
4.4.1.2 
Ranibizumab (Active 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. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
41 
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. 
4.4.1.3 
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 (Appendix 4). 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. 
4.4.2 
Dosage, Administration, and Compliance 
4.4.2.1 
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 in 
the Overview of Study Design (Section 3.1.1). 
• 
Arm A:  0.5 mg ranibizumab IVT every 4 weeks for 32 weeks (9 injections) 
• 
Arm B:  1.5 mg RO6867461 IVT every 4 weeks for 32 weeks (9 injections) 
• 
Arm C:  6 mg RO6867461 IVT every 4 weeks for 32 weeks (9 injections) 
• 
Arm D:  6 mg RO6867461 IVT every 4 weeks up to Week 12 (4 injections), followed 
by 6 mg RO6867461 IVT every 8 weeks (i.e.: on Weeks 20 and 28; 2 injections) 
• 
Arm E:  0.5 mg ranibizumab IVT every 4 weeks up to Week 8 (3 injections), followed 
by 6 mg RO6867461 IVT every 4 weeks (6 injections) 
  
Only one eye will be chosen as the study eye. 
The Pharmacist responsible for dispensing the study treatment or designated personnel 
will prepare the correct study treatment (ranibizumab, RO6867461, or sham) and dose, 
where applicable, as assigned by the IxRS. 
For the 6 mg dose, RO6867461 is administered without dilution whereas for the 1.5 mg 
dose, RO6867461 must be diluted with Placebo provided by the Sponsor to the 
appropriate dose, as described in the Pharmacy Manual. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
42 
Table 2 
Dosage Strengths and Dilution 
Drug 
Clinical Dose 
Dilution with Placebo 
Required 
(Yes/No/NA) 
Administered Volume 
for IVT treatment 
RO6867461 
1.5 mg 
Yes 
50 μL 
RO6867461 
6 mg 
No 
50 μL 
Ranibizumab 
0.5 mg 
NA 
50 μL 
NA = not applicable; IVT = intravitreal. 
 
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 4. 
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 
dilute/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 placebo, and vials of ranibizumab are for single-
use only (one injection preparation per patient per eye).  Vials used for one patient must 
not be used for any other patient.  Partially used vials, left over RO6867461 Drug 
Product, placebo, or ranibizumab vials as well as administration material must not be re-
used.  Only provided placebo vials should be used for dilutions and dose preparation 
should always be performed as per the instructions in the Pharmacy Manual.  Dilution 
procedure with placebo or concentrations to adjust the doses should not be changed 
without prior approval from the Sponsor. 
4.4.3 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (RO6867461 [including placebo for dilution] 
and ranibizumab) will be provided by the Sponsor.  The investigational site will 
acknowledge receipt of IMPs, to confirm the shipment condition and content.  Any 
damaged shipments will be replaced. 
The Investigator is responsible for the control of the treatment under investigation.  
Adequate records of the receipt (e.g., Treatment Receipt Record) and dispensing 
(e.g.Treatment Dispensing Log) of the study treatment must be maintained.  The 
Treatment Dispensing Log must be kept current and should contain the following 
information: 
• 
The identification of the patient to whom the study treatment was dispensed (for 
example patient initials and date of birth) 
• 
The date(s) and the quantity of the study drug dispensed to the patient 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
43 
• 
All records and treatment supplies must be available for inspection by the Roche 
Monitor 
 
IMPs will either be disposed at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed upon by the 
Sponsor.  Local or institutional regulations may require immediate destruction of used 
IMP for safety reasons.  In these cases, it may be acceptable for investigational study 
site staff to destroy dispensed IMP before a monitoring inspection provided that source 
document verification is performed on the remaining inventory and reconciled against 
the documentation of quantity shipped, dispensed, returned, and destroyed and provided 
that adequate storage and integrity of drug has been confirmed.  Written authorization 
must be obtained from the Sponsor at study start up before destruction. 
Written documentation of destruction must contain the following: 
• 
Identity kit numbers of investigational products destroyed 
• 
Quantity of investigational product[s] destroyed 
• 
Date of destruction 
• 
Method of destruction 
• 
Name and signature of responsible person or company who destroyed 
investigational products 
 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Treatment Inventory Log. 
4.4.4 
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 
(Section 4.4.3). 
4.4.5 
Post-Trial Access to RO6867461 
RO6867461 is an IMP product which safety and tolerability is under evaluation in an 
indication where alternative SoC treatments are available.  Patients will not be allowed 
access to RO6867461 after study completion. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
44 
4.5 
CONCOMITANT THERAPY 
4.5.1 
Concomitant Therapy 
Patients who use maintenance therapy other than those required to treat CNV 
secondary to AMD should continue its use. 
Concomitant medications are any prescription drugs or over-the-counter preparations 
(including but not limited to vitamins) other than protocol-specified procedural 
medications (e.g., dilating drops, fluorescein dye, etc.) and pre- and post-treatment 
administration medications (e.g., propacaine, antimicrobials, etc.) used by a patient 
within 7 days preceding Day 1 until conclusion of the patient’s study participation 
(Week 36) or early termination visit.  Administration of antimicrobials four times daily for 
3 days before and after the IVT administration may be prescribed at the discretion of the 
Investigator.  Where antimicrobials are administered, it must be recorded on the 
concomitant medication forms of the electronic Case Report Form (eCRF). 
All concomitant medications should be reported to the Investigator and recorded on the 
appropriate section of the eCRF. 
4.5.2 
Excluded Therapy 
At the discretion of the Investigator, patients may continue to receive all medications and 
standard treatments administered for other conditions except for the following: 
• 
Concurrent use of systemic anti-VEGF agents 
• 
Concurrent use of IVT or subtenon corticosteroids in either eye, except as required 
to treat adverse events 
• 
Concurrent use of photocoagulation or photodynamic therapy with verteporfin in the 
study eye for neovascular AMD 
 
4.5.3 
CNV Secondary to AMD in the Fellow Eye 
Should CNV secondary to AMD emerge or recur and require treatment in the fellow eye 
during the study period, the patient may receive anti-VEGF SoC treatment.   
When treatment in the fellow eye is scheduled on the same day than 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 may 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). 
This treatment also may be provided by the site through commercial supplies. However, 
commercial supplies will not be reimbursed by the sponsor. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
45 
4.6 
STUDY ASSESSMENTS 
All examinations listed below will be performed according to the SoA outlined in 
Appendix 1 and Appendix 2 . 
At time-points 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): 
• 
Triplicate 12-lead ECG:  mandatory to be performed as early as possible, before 
patient is exhausted, and before blood sampling 
• 
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:  At screening and Day 1 visits, BCVA can be performed before 12-lead 
ECG, 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. 
Low luminance visual acuity (LLVA) 
Slitlamp examination 
Pupil dilation 
SD-OCT  
FAF:  if FAF is performed after FP and/or indirect ophthalmoscopy, the subject 
should rest in dim light for 10 minutes between procedures. 
FP (+ infrared reflectance) 
FFA 
ICGA 
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) 
 
4.6.1 
General Safety Assessments 
4.6.1.1 
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 and all medications (e.g., prescription drugs, 
over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
46 
by the patient within 28 days prior to the screening visit and within the screening period 
(other than reported to treat an AE as defined in Section 5.3.1). 
Demographic data will include age, sex, and self‑reported race/ethnicity.  Race/ethnicity 
is recorded to allow association with any exploratory genetic risk factors which might be 
evaluated on patient genetic sample. 
4.6.1.2 
Physical Examinations 
A physical examination will be performed at the time-points indicated in the SoA 
(Appendix 1 and Appendix 2).  Physical examination will include body weight at 
screening and either final or early termination visit, and height at screening. 
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. 
4.6.1.3 
Vital Signs 
BP (SBP and DBP), pulse rate, and body temperature (tympanic or oral) will be recorded 
at the time-points specified in the SoA (Appendix 1 ). 
BP and pulse rate should be obtained in a quiet room at a comfortable temperature, with 
the patient’s arm unconstrained by clothing or other material.  All measurements will be 
obtained from the same arm and, with the same cuff size, using an automatic instrument 
with a digital readout, throughout the study.  To minimize variability, it is important that 
patient be in a resting position for at least 5 minutes prior to the evaluation.  Body 
position should be consistently maintained for each evaluation.  At the discretion of the 
Investigator, measurements can be repeated if the values are abnormal.  
4.6.1.4 
Electrocardiograms 
Triplicate 12-lead ECG (i.e., three useful ECGs without artifacts) will be collected at the 
time-points specified in SoA (Appendix 1).  To minimize variability, it is important that 
patient be in a resting position for at least 10 minutes prior to each ECG evaluation.  
Body position should be consistently maintained for each ECG evaluation to prevent 
changes in heart rate.  Environmental distractions (e.g., television, radio, conversation, 
mobile phones) should be minimized before and during ECG recording.  Triplicate ECGs 
will be obtained within a 5-minute interval.  

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
47 
Should the time-points coincide, ECGs will be collected before any vital sign 
measurements or blood sampling.  If an ECG is scheduled at the same time as a meal, 
the ECG must be obtained first. 
All ECG recordings must be performed using a standard high-quality, high-fidelity 
electrocardiograph machine equipped with computer-based interval measurements 
provided by the ECG Central Reading Center. 
Digital ECG recording should be transmitted immediately to the ECG Central Reading 
Center for interpretation.  Investigators or designees must review, sign, and date all ECG 
reports received from the Central Reading Center, which will be kept as part of the 
patient’s permanent study file at the site. 
ECG characteristics, including heart rate, QRS complex duration, and PQ (PR) and QT 
intervals, will be recorded on the eCRF.  QTcB (Bazett’s correction), QTcF (Fridericia’s 
correction), and RR will be calculated by the Sponsor.  Changes in T-wave and U‑wave 
morphology and overall ECG interpretation will be documented on the eCRF by 
investigators or designees.  T-wave information will be captured as normal or abnormal, 
U-wave information will be captured in two categories:  absent/normal or abnormal. 
4.6.1.5 
Laboratory Assessments 
Normal ranges for the study laboratory parameters must be supplied to Roche before 
the study starts.  Laboratory safety tests shall be collected locally at time-points specified 
in the SoA (Appendix 1). 
Additional blood or urine samples may be taken at the discretion of the Investigator if the 
results of any test fall outside the reference ranges, or clinical symptoms necessitate 
additional testing to monitor patient safety.  Where the clinical significance of abnormal 
lab results is considered uncertain, screening lab tests may be repeated to confirm 
eligibility.  In the event of unexplained abnormal clinically significant laboratory test 
values, the tests should be repeated immediately and followed up until they have 
returned to the normal range and/or an adequate explanation of the abnormality is 
found.  Results of clinical laboratory testing will be recorded on the eCRF. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
48 
Blood and Urine Sample Collection 
Blood and urine samples will be collected for the following clinical laboratory tests: 
Hematology 
Hemoglobin, hematocrit (HCT), red blood cell 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), erythrocyte sedimentation rate (ESR). 
Coagulation (at 
screening only) 
Activated partial thromboplastin time (aPTT) and prothrombin 
time/International Normalized Ratio (PT/INR). 
Blood chemistry 
Sodium, potassium, bicarbonate, phosphate, chloride, calcium, 
urea, creatinine, total bilirubin, alkaline phosphatase (ALP), 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
creatine phosphokinase (CPK), gamma glutamyl transferase (GGT), 
total protein, glucose, HbA1C (at screening and at final or early 
termination visits only), total cholesterol (TC), triglycerides (TG), 
C-reactive protein (CRP). 
Urinalysis 
A midstream, clean-catch urine specimen will be collected for 
dipstick analysis of protein, blood, glucose, and pH.  Microscopy to 
be performed if abnormalities are observed and deemed necessary 
by the Investigator or Designee, in particular when blood or protein 
is positive or strong positive. 
Pregnancy test 
For females of childbearing potential, serum pregnancy test at 
screening. 
 
Additional parameters could be assessed if judged to be clinically appropriate by the 
Investigator and the Scientific Responsible in order to further characterize the safety or 
PK/PD properties of the drug. 
Based on continuous analysis of the data in this study and other studies, any sample 
type not considered to be critical for safety may be stopped at any time if the data from 
the samples collected does not produce useful information. 
4.6.1.6 
Anti-Drug Antibody Assessments 
Blood samples will be obtained for measurement of anti-RO6867461 antibodies by a 
validated enzyme-linked immunosorbent assay (ELISA). 
Any residual material from ADA samples may be used for additional exploratory 
biomarker profiling, identification, assay development purposes, and assay validation 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
49 
during the development of the study or compound-related assays after the mentioned 
intended uses. 
This specimen will be destroyed no later than 2 years after the final closure of the clinical 
database. 
4.6.2 
Pharmacokinetic Assessments 
Details on sampling procedures, sample storage, and shipment are given in the 
supporting documentation/Lab Manual.  
Any residual material from PK samples (blood, aqueous humor, and vitreous humor 
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.  All PK samples will be 
destroyed no later than 2 years after the final closure of the clinical database. 
Additional PK sampling at unscheduled visits is at the discretion of the Investigator 
(Section 4.6.6.5). 
4.6.2.1 
Blood Samples 
Blood samples for determination of plasma concentrations of RO6867461 will be 
collected at time-points specified in the SoA (Appendix 1). Plasma concentrations 
of RO6867461 will be measured by a specific validated ELISA method.  
To maintain the double-masked design of the study, blood samples will also be taken 
from all patients receiving ranibizumab per the RO6867461 schedule. The samples from 
these patients may or may not be analyzed. Plasma ranibizumab concentrations will be 
analyzed for patients receiving ranibizumab who also provide consent to AH sampling. 
4.6.2.2 
Aqueous Humor Samples (optional) 
Aqueous humor samples will be collected from all patients who provide additional 
consent to participate.  Where patient consents to aqueous humor sampling, all efforts 
should be made to collect a baseline aqueous humor sample on Day 1 (pre-dose).  The 
SoA (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 pre-dose assessments have been completed, using an aseptic procedure and sterile 
field and according to local guidelines. 
Samples will be analyzed for RO6867461 and biomarkers (Section 4.6.4.3.4), and may 
also be analyzed for ranibizumab.  This specimen will be destroyed no later than 2 years 
after the final closure of the clinical database. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
50 
4.6.2.3 
Unscheduled Collection of Vitreous Samples (optional) 
Elective vitrectomy surgery is not allowed in the study eye during study participation; 
however, if the surgery is medically necessary and a vitreous sample can be obtained 
from the study eye, ~0.5 mL of undiluted vitreous humor should be collected according 
to the instructions for aqueous humor sampling and shipped to the Sponsor for 
measurement of RO6867461 and biomarker concentrations (Section 4.6.4.3.5), and may 
also be analyzed for ranibizumab.  A blood sample (for plasma preparation) should also 
be collected and shipped to the Sponsor. 
The Sponsor should be contacted prior to performing any vitrectomy surgeries in the 
study eye.  This specimen will be destroyed no later than 2 years after the final closure 
of the clinical database. 
4.6.3 
Clinical Genotyping (CG) Sample 
A mandatory whole blood sample will be taken for DNA extraction from every subject.  
The DNA may be used to study genes related to AMD (e.g., AMRS2. HTRA1, CFH, C3, 
etc.) as well as to angiogenesis pathways (e.g., VEGFA, VEGFR2, Ang-2, Tie-2, etc.), 
and the effect on the PK/PD/efficacy/safety of RO6867461.  Data arising from this 
sample will be subject to the same confidentiality as the rest of the study. 
This specimen will be destroyed up to 2 years after the final closure of the clinical 
database. 
4.6.4 
Disease-Specific Assessments 
Except when noted otherwise (e.g., SoA), all ocular assessments should be performed 
for both eyes. 
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, test images, and systems and software (where applicable) will 
be certified/validated by the reading center as specified in the Central Reading Center 
Manual.  All ocular images will be obtained only by trained and Central Reading Center 
certified personnel at the study sites and forwarded to the central reading center for 
storage and for independent analysis including confirmation of eligibility for defined 
imaging criteria. 
Ocular images to be obtained and forwarded to the Central Reading Center include the 
following: 
• 
FP 
• 
FAF 
• 
SD-OCT  
• 
FFA  

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
51 
• 
ICGA 
 
For FFA and ICGA, images of both eyes should be acquired and forwarded to the 
Central Reading Center. 
For SD-OCT, FP and FAF, images of fellow eyes should only be captured and 
forwarded to the Central Reading Center at the Screening, and Week 36 or Early 
termination visits.  At all other visits, only the study eye images need to be acquired 
and forwarded. 
SD-OCT must, and where possible FAF, FFA, and ICGA should be collected using 
Spectralis instrument (Heidelberg Engineering, Heidelberg, Germany), equipped with 
TrueTrack Active Eye Tracking, AutoRescan, and enhanced deep imaging (EDI). 
4.6.4.1 
Ocular Safety Assessments 
Ocular assessments will be performed as detailed in the SoA (Appendix 1 and 
Appendix 2) and include: 
• 
BCVA using the ETDRS-like charts (see Section 4.6.4.2); performed prior to dilating 
eyes. 
• 
Slit lamp examination (scales for grading flare/cells and vitreal hemorrhage density 
are detailed in Appendix 3)   
• 
Dilated binocular indirect high-magnification ophthalmoscopy 
• 
Retinal imaging:  FP, SD-OCT and angiographies  
• 
IOP measurement:  If IOP ≥ 30 mmHg at 30 (± 5) minutes post-treatment 
administration in the study eye, then it should be measured again at 60 (± 10) 
minutes post-treatment administration. 
• 
Assessment of ocular perfusion performed as soon as possible, but not later than 
15 minutes post-injection, using finger counting, hand movement, or light perception 
as appropriate 
 
4.6.4.2 
Efficacy and Pharmacodynamic Assessments 
Efficacy and PD assessments will be performed as detailed in the SoA (Appendix 1) and 
will include functional (BCVA), imaging assessments (SD-OCT, FFA), and plasma PD 
biomarkers. 
Additional PD sampling, functional or imaging assessments can be performed at 
unscheduled visits at the discretion of the Investigator (Section 4.6.6.5). 
4.6.4.2.1 
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 VA examiner masked to study treatment assignment. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
52 
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 
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., Visual acuity 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.  
4.6.4.2.2 
Spectral Domain Optical Coherence Tomography  
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 
EDI.  Images will be acquired and transferred to the Central Reading Center according 
specifications provided in the separate “Central Reading Center Procedures Manual”.  
The Heidelberg Eye Explorer (HEYEX) software will be used to review the images at the 
study site.  
4.6.4.2.3 
Fundus Fluorescein and Indocyanine Green Angiographies 
FFA and ICGA will be performed successively at the study sites by trained and Central 
Reading Center-certified personnel.  Images should be acquired and transferred to the 
Central Reading Center according to specifications provided in the “Central Reading 
Center Manual”.  
4.6.4.2.4 
Plasma Pharmacodynamic Biomarkers 
Samples for plasma PD biomarkers will be taken at the time-points detailed in the SoA 
(Appendix 1).  The following analyses will be performed: 
• 
Change from baseline in plasma levels of VEGF and Ang-2 
• 
Samples will be destroyed no later than 2 years after the final closure of the clinical 
database. 
 
4.6.4.3 
Exploratory Assessments 
4.6.4.3.1 
Low Luminescence Visual Acuity 
On Day 1, BCVA at a starting test distance of 4 meters under low luminescence (LLVA) 
will be measured prior to dilating eyes by trained and certified VA examiner masked to 
study treatment assignment.  
LLVA is mandatory at the Day 1 visit only. At the discretion of the Investigator and in 
agreement with the patient, LLVA (optional) can be assessed at the other time-points 
detailed in the SoA (Appendix 1).  Participation in the optional LLVA assessment will 
be recorded locally and data entered in the eCRF.  

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
53 
 
LLVA will be measured by placing a 2.0-log-unit neutral density filter (Kodak Wratten 2.0 
Neutral Density Filter) over the best correction for that eye and having the participant 
read the normally illuminated ETDRS chart (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 provided to the Investigators.  VA examiner and VA 
examination room certifications will be obtained before any VA examinations are 
performed. 
 
4.6.4.3.2 
Fundus Autofluorescence 
FAF will be performed at the study sites by trained personnel at the time-points detailed 
in the SoA (Appendix 1).  FAF may be considered as an exploratory safety assessment 
to monitor progression of atrophy. 
4.6.4.3.3 
Exploratory Plasma Biomarkers 
Samples for exploratory plasma biomarkers will be taken at the time-points detailed in 
the SoA (Appendix 1).  The following exploratory analyses may be performed: 
• 
Levels of Ang-1, Tie-2, VEGFR, PLGF, bFGF, and PDGF, but analyses may also be 
extended to other disease biomarkers (e.g., cytokines). 
 
Samples will be destroyed no later than 2 years after the final closure of the clinical 
database and all intended data have been verified. 
4.6.4.3.4 
Aqueous Humor Samples (optional) 
Aqueous humor samples will be analyzed primarily for RO6867461 concentrations and 
may also be analyzed for ranibizumab concentrations, as described in section 4.6.2.2; 
and the remaining samples may be analyzed for: 
• 
VEGF and Ang-2 concentrations, and possibly other biomarkers 
 
4.6.4.3.5 
Vitreous Humor Samples (optional) 
Vitreous humor samples will be analyzed primarily for RO6867461 concentrations and 
may also be analyzed for ranibizumab concentrations, as described in Section 4.6.2.3, 
and the remaining samples may be analyzed for: 
• 
VEGF and Ang-2 concentrations, and possibly other biomarkers 
 
The samples will be destroyed at the latest 2 years after the final closure of the database 
and finalization of the bioanalytical report 
4.6.5 
Amount of Blood to be Collected throughout the Study 
Throughout the study, a total of approximately 155 mL of blood will be drawn from each 
subject, to perform clinical laboratory assessments, determine plasma concentrations 
and to perform PD/exploratory assessments. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
54 
4.6.6 
Timing of Study Assessments 
4.6.6.1 
Screening and Pretreatment Assessments 
Written informed consent for participation in the study must be obtained before 
performing any study‑specific screening tests or evaluations.  Informed Consent Forms 
of enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site. 
All screening and pre-treatment 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. 
An Eligibility Screening Form (ESF) 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. 
Patients who are willing to participate in the study and have given informed consent will 
undergo a thorough screening medical examination within 4 weeks before study 
treatment administration.  The list of screening procedures is outlined in the SoA 
(Appendix 1). 
After the screening visit, ocular images (both eyes) of the patients who meet all 
screening eligibility criteria (eligibility for safety labs, pregnancy test where appropriate, 
and ECG might be pending) as judged by the Investigator will be forwarded as soon as 
possible to the Central Reading Center.  The Central Reading Center will assess the 
image data submitted and confirm eligibility for study eye imaging criteria.  In the event 
the Central Reading Center does not confirm eligibility, the patient will not be considered 
for enrollment. 
On Day 1 prior to enrollment, the following criteria will need to be assessed: 
• 
Day 1 BCVA eligibility 
• 
Absence of febrile illness in the week prior enrollment 
• 
Absence of intraocular inflammation on Day 1 (study eye) 
 
Patients will be enrolled if they meet all screening and Day 1 eligibility criteria. 
Where febrile illness is identified within 6 days of the scheduled Day 1 visit, or on the 
date of the visit, the Day 1 visit must be rescheduled at the earliest 7 days after the end 
of the febrile illness episode and no later than 4 weeks after the screening visit. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
55 
Patients who failed screening due to: 
• 
Febrile illness (where “end of febrile illness + 7 days” extends beyond the 4 week 
screening period) 
• 
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 
will be allowed to be re-screened. 
4.6.6.2 
Assessments during Treatment 
Under no circumstances will patients who enroll in this study be permitted to be 
allocated a new randomization number and re-enroll in the study.  
On Day 1, baseline assessments will be conducted on the eligible patients, according to 
the SoA (Appendix 1 and Appendix 2).  Patients will receive their first IVT administration 
of either RO6867461 or comparator therapy according to the randomization schedule 
and established standard administration procedures.  Patients will return to the eye clinic 
for study treatment administration (every 4 weeks) and assessments as outlined in the 
SoA.  Patients will be administered the same study treatment throughout the study 
period, except patients randomized to Arms D and E: 
• 
Patients in Arm D will receive sham administration on Weeks 16, 24, and 32 to 
maintain the double-masking throughout the Q8W regimen period. 
• 
Patients in Arm E will initially receive 3 injections of ranibizumab followed by 
6 injections of RO6867461. 
 
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 using testing finger count vision, or hand motion or 
light perception as appropriate. 
On the day of dosing, IOP will be monitored at 30 minutes post-treatment administration, 
and if IOP is ≥ 30 mmHg in the study eye, IOP should be re-assessed at 1 hour 
post-treatment administration.  Patients will be discharged at the discretion of the 
Investigator. 
Patients will be instructed to report any signs or symptoms of intraocular inflammation 
(uveitis) or endophthalmitis which may be a clinical sign and include symptoms such as 
pain, photophobia, redness, or reduced vision. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
56 
4.6.6.3 
Assessments at Early Termination Visit 
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 
monitoring of all adverse events (serious and non-serious), as well as for assessments 
specified in the early termination visit as outlined in the SoA (Appendix 1 and 
Appendix 2). 
Patients could receive SoC treatment for CNV secondary to AMD after all assessments 
are completed on early termination visit.  SoC treatment after the early termination visit 
will not be supplied by the Sponsor. 
After the early termination visit, adverse events should be followed up as outlined in 
Section 5.5.1 and Section 5.5.2. 
4.6.6.4 
Assessments at Final Visit 
Patients will return for their final visit with assessments as outlined in the SoA 
(Appendix 1 and Appendix 2) at Week 36. 
Patients can receive SoC treatment for CNV secondary to AMD after all assessments 
are completed on Week 36.  SoC treatment after the final visit will not be supplied by the 
Sponsor. 
After the final visit, adverse events should be followed up as outlined in Section 5.6. 
4.6.6.5 
Assessments at Unscheduled Visits 
Assessments (e.g., for safety or for PK/PD sampling purpose) performed in case of an 
unscheduled visit(s) are at the discretion of the Investigator. 
4.7 
PATIENT WITHDRAWAL, STUDY, AND SITE 
DISCONTINUATION 
4.7.1 
Patient Discontinuation 
The Investigator has the right to discontinue or withdraw a patient from the study at any 
time.  In addition, patients have the right to voluntarily discontinue study treatment or 
withdraw from the study at any time for any reason.  Reasons for discontinuation of 
study treatment or 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, including worsening of the 
disease 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
• 
Patient non-compliance 
 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
57 
4.7.1.1 
Discontinuation from Study Drug 
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+vtritis; 
see the definition of intraocular inflammation in Section 5.3.5  and grading scales 
for assessment in Appendix 3) 
• 
Retinal detachment in the study eye 
• 
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 (see Section 4.6.6.3) and may undergo assessments as 
outlined in the SoA.  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. 
4.7.2 
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 and Health Authorities if the study is placed on 
hold, or if the Sponsor decides to discontinue the study or development program. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
58 
The Sponsor has the right to replace a site at any time.  Reasons for replacing 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 ICH guideline for Good Clinical Practice 
 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events (AEs), 
including serious adverse events (SAEs) (systemic and ocular); measurement of 
protocol-specified safety laboratory assessments; measurement of protocol-specified 
vital signs (SBP, DBP), ECGs; and other protocol-specified tests that are deemed critical 
to the safety evaluation of the study (i.e., regular ophthalmological monitoring [ocular 
safety panel and SD-OCT assessments]).  
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.1.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an AE is any untoward 
medical occurrence in a clinical investigation subject administered a pharmaceutical 
product, regardless of causal attribution.  An AE 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, angiography) 
that is associated with symptoms or leads to a change in study treatment or 
concomitant treatment or discontinuation from study treatment. 
• 
AEs 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). 
 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
59 
5.1.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
An SAE is any adverse event that meets any of the following criteria: 
• 
Fatal (i.e., the AE actually causes or leads to death). 
• 
Life threatening (i.e., the AE, in the view of the Investigator, places the patient at 
immediate risk of death). 
This does not include any AE 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 AE results in 
substantial disruption of the patient’s ability to conduct normal life functions). 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study treatment. 
• 
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 AE (rated as mild, moderate, or severe); the event itself may be of relatively minor 
medical significance (such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each AE recorded on 
the eCRF. 
SAEs 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). 
5.1.3 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-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 an elevated ALT or AST in combination with either an elevated bilirubin 
or clinical jaundice, as defined in Section 5.3.5.6 (Abnormal Liver Function Tests). 
• 
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 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
60 
in a patient exposed to a medicinal product.  This term applies only when a 
contamination of the study drug is suspected. 
5.1.4 
Sight-Threatening Adverse Events (Immediately Reportable to 
the Sponsor) 
An AE is considered to be sight threatening and serious, 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 
• 
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 3 
• 
In the opinion of the Investigator, it may require medical intervention to prevent 
permanent loss of sight 
 
5.2 
SAFETY PLAN 
Based on the BP28936 First-in-Human study, there have been no safety signals 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 AEs were of mild 
and moderate intensity.  No deaths occurred during the study period and no premature 
withdrawals from the study as a result of SAEs were reported.  
To ensure the safety of all patients during the conduct of the study, several safety 
assessments will be performed, including: regular ophthalmological monitoring (ocular 
safety panel and SD-OCT assessments), AE monitoring (systemic and ophthalmologic), 
vital signs (SBP, DBP), and laboratory safety tests. 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The Investigator is responsible for ensuring that all AEs (see Section 5.1.1 for definition) 
are recorded on the Adverse Event eCRF and reported to the Sponsor in accordance 
with instructions provided in this section and in Sections 5.4-5.6. 
For each AE recorded on the Adverse Event eCRF, the Investigator will make an 
assessment of seriousness (see Section 5.1.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4). 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
61 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All AEs, 
whether reported by the patient or noted by study personnel, will be recorded in the 
patient’s medical record.  AEs will then be reported on the Adverse Event eCRF as 
follows: 
After informed consent has been obtained but prior to initiation of study treatment, 
only SAEs caused by a protocol-mandated intervention should be reported (e.g., SAEs 
related to invasive procedures such as angiographies).  Any other AE should not be 
reported. 
After initiation of study treatment, all AEs, regardless of relationship to study 
treatment, will be reported until the final visit. 
After a period of 28 days from the last dose of study treatment, Investigators should 
report any deaths, SAEs, or other AEs of concern that are believed to be related to prior 
treatment with study treatment (see Section 5.6). 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all patient-evaluation time-points.  Examples of non-directive questions 
include the following: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?” 
 
5.3.3 
Assessment of Severity of Adverse Events 
Table 3 provides guidance for assessing AE 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 5.1.2). 
 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
62 
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 or 
not an AE is considered to be related to the study treatment, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study treatment 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug 
• 
Known association of the event with the study treatment 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 AEs 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 AE 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) 
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 slit lamp examination that are 
caused by dilation and are not red blood cells (RBCs) or white blood cells (WBCs) or the 
result of any ocular disorder should not be recorded as an AE. 
Only one AE term should be recorded in the event field on the Adverse Event eCRF. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
63 
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 AEs based on 
signs and symptoms should be nullified and replaced by one AE 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 Occurring Secondary to Other Events 
In general, AEs occurring 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.  However, medically significant AEs occurring secondary to 
an initiating event that are separated in time should be recorded as independent events 
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 subsequent fracture, all three events should be 
reported separately on the eCRF. 
 
All AEs should be recorded separately on the Adverse Event eCRF if it is unclear as to 
whether the events are associated. 
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between 
patient-evaluation time-points.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity of the event should be recorded, and the 
severity should be updated to reflect the most extreme severity any time the event 
worsens.  If the event becomes serious, the Adverse Event eCRF should be updated to 
reflect this. 
A recurrent AE is one that resolves between patient evaluation time-points and 
subsequently recurs.  Each recurrence of an AE should be recorded separately on the 
Adverse Event eCRF. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
64 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an AE.  A laboratory test result should be 
reported as an AE if it meets any of the following criteria: 
• 
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 
• 
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 AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 times the upper limit of normal [ULN] 
associated with cholecystitis), only the diagnosis (i.e., cholecystitis) should be recorded 
on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium", as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the AE.  For example, an elevated serum potassium level of 7.0 mEq/L 
should be recorded as “hyperkalemia”. 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an AE.  A vital sign result should be reported 
as an AE if it meets any of the following criteria: 
• 
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 
• 
Clinically significant in the Investigator’s judgment 
 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
65 
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 AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., 
high BP), 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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
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.  
Therefore, Investigators must report as an AE 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 SAE. 
5.3.5.7 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see 
Section 5.3.1), regardless of relationship to study treatment, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (Section 5.3.1). 
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 only be used 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 of 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. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
66 
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 Systemic or Ocular Medical History eCRF. 
A preexisting medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study.  When recording such 
events on the Adverse Event eCRF, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g., “more 
frequent headaches”). 
5.3.5.9 
Worsening of AMD 
Medical occurrences or symptoms of deterioration that are anticipated as part of AMD 
should be recorded as an AE 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”). 
5.3.5.10 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as a serious AE (per the definition of SAE in Section 5.1.2), except as 
outlined below. 
The following hospitalization scenarios are not considered to be serious AEs: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol  
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not suffered an AE 
 
5.3.5.11 
Overdoses 
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied.  An overdose or incorrect administration of study drug is not 
an AE unless it results in untoward medical effects. 
Any study drug overdose or incorrect administration of study treatment should be noted 
on the Additional Observation eCRF. 
All AEs associated with an overdose or incorrect administration of study treatment 
should be recorded on the Adverse Event eCRF.  If the associated AE fulfills serious 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
67 
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). 
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 treatment: 
• 
SAEs 
• 
Non-serious AESI 
• 
Sight-threatening AEs 
• 
Pregnancies 
 
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 Institutional Review Board (IRB)/Ethics 
Committee (EC). 
5.4.1 
Emergency Medical Contacts 
To ensure the safety of study patients, access to the Medical Monitors is available 
24 hours a day 7 days a week.  Medical Monitor contact details are listed in the “Protocol 
Administrative and Contact Information & List of Investigators”. 
5.4.2 
Reporting Requirements for Pregnancies 
5.4.2.1 
Pregnancies in Female Patients 
Female patients of child-bearing potential will be instructed to immediately inform the 
Investigator if they become pregnant during the study or within 3 months after the last 
dose of study treatment.  A Clinical Trial Pregnancy Reporting Form should be 
completed by the Investigator and submitted to the Sponsor within 24 hours after 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
68 
learning of the pregnancy.  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. 
5.4.2.2 
Abortions 
Any spontaneous abortion should be classified as a serious adverse event (as the 
Sponsor considers spontaneous abortions to be medically significant events), recorded 
on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Section 5.4.2). 
5.4.2.3 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient 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 or sight-threatening adverse events considered to be 
related to study treatment 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.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF. 
All pregnancies reported during the study should be followed until pregnancy outcome 
and reported according to the instructions provided in Section 5.4.2. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, non-serious adverse events of special interest and sight-
threatening adverse events 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. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
69 
5.6 
POST-STUDY ADVERSE EVENTS 
The Investigator is not required to actively monitor patients for adverse events after the 
end of the adverse event reporting period (defined as 28 days) after the last dose of 
study treatment).  However, the Sponsor should be notified if the Investigator becomes 
aware of any death, other serious adverse event, non-serious adverse events of special 
interest, or sight-threatening adverse events immediately reportable to the Sponsor 
occurring after the end of the adverse event reporting period, if the event is believed to 
be related to prior study drug treatment.  The event should be reported directly to the 
Sponsor or its designee, either by faxing or by scanning and emailing the Serious 
Adverse Event Reporting Form using the fax number or email address provided to 
investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events 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 US 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 
6.1.1 
Sample Size and Power for Treatment-Naive Population 
Evaluation 
The sample size for the treatment-naive population is based on the primary efficacy 
outcome of mean change in BCVA from baseline to Week 36.  Each RO6867461 dose 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
70 
or dose regimen group (Arms B, C, and D) will be compared to the control group 
(Arm A).  
Consider 68 patients randomized to Arm A and 45 randomized to each of Arms B, C, 
and D, with a drop-out rate of 10%.  Assuming a standard deviation of 13.5 letters, this 
sample size would provide approximately 80% power to detect a true difference of 
5.9 letters at the one-sided α level of 10%.  The minimum detectable difference would be 
approximately 3.5 letters. 
6.1.2 
Sample Size and Power for Anti-VEGF-Incomplete-Responder 
Population Evaluation 
The sample size for anti-VEGF−incomplete-responder population is based on the 
primary efficacy outcome of mean change in BCVA from Week 12 to Week 36 in the 
subset of anti-VEGF−incomplete-responders, between Arm A and Arm E.  
Consider 68 patients randomized to both Arms A and E with 65% meeting the criteria for 
inclusion in anti-VEGF−incomplete-responder subgroup and a drop-out rate of 10%.  
Assuming a standard deviation of 9.7 letters, this sample size would provide 
approximately 80% power to detect a true different of 4.8 letters at the one-sided α level 
of 10%.  The minimum detectable difference would be approximately 2.8 letters.  If only 
50% meet the criteria for inclusion in anti-VEGF−incomplete-responder subgroup, this 
sample size would provide approximately 80% power to detect a true different of 
5.4 letters at the one-sided α level of 10%.  The minimum detectable difference would be 
approximately 3.3 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 
ANALYSIS POPULATIONS 
6.3.1 
Safety Analysis Population 
All patients who have received at least one dose of the study treatment, whether 
prematurely withdrawn from the study or not, will be included in the safety analysis. 
6.3.2 
Efficacy, Pharmacokinetic, and Pharmacodynamic Analysis 
Population 
All randomized patients will be included in the efficacy, PK, and PD analysis population. 
6.3.2.1 
Population A: All Patient Randomized to Arms A, B, C, and D 
Population A consists of all patients randomized to the treatment arms A, B, C, and D.  
In this population, the baseline reference is the latest non-missing observation before 
start of study treatment.  Population A will be used for the evaluation of efficacy in the 
treatment-naive population. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
71 
6.3.2.2 
Population B: All Patients Randomized to Arms A and E 
Population B consists of all patients randomized to the treatment arms A and E.  In this 
population, the Week 12 visit is the reference for all efficacy and PD analyses.  For 
example, the primary endpoint is BCVA change from Week 12.  A subgroup of 
Population B will be used for the evaluation of efficacy in the 
anti-VEGF−incomplete-responder population. 
6.4 
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 using frequency tables and summary statistics providing 
means, medians, standard deviations, first and third quartiles, and extreme values. 
6.5 
SAFETY ANALYSES 
All safety analyses will be based on the safety analysis population. 
6.5.1 
Adverse Events 
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.  SAEs will be 
summarized similarly.  Adverse events leading to discontinuation from the study will be 
listed and tabulated. 
6.5.2 
Clinical Laboratory Test Results 
All clinical laboratory data will be stored on the database in the units in which they were 
reported.  Patient listings and summary statistics at each assessment time will be 
presented using the International System of Units (SI units; Système International 
d’Unités).  Laboratory data not reported in SI units will be converted to SI units before 
processing. 
Laboratory test values will be presented by individual listings with flagging of values 
outside the normal ranges. 
6.5.2.1 
Standard Reference Ranges and Transformation of Data 
Roche standard reference ranges, rather than the reference ranges of the Investigator, 
will be used for all parameters.  For most parameters, the measured laboratory test 
result will be assessed directly using the Roche standard reference range.  Certain 
laboratory parameters will be transformed to Roche’s standard reference ranges. 
A transformation will be performed on certain laboratory tests that lack sufficiently 
common procedures and have a wide range of Investigator ranges, e.g., enzyme tests 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
72 
that include AST, ALT, and alkaline phosphatase and total bilirubin.  Given that the 
standard reference ranges for these parameters have a lower limit of zero, only the 
upper limits of the ranges will be used in transforming the data. 
6.5.2.2 
Definition of Laboratory Abnormalities 
For all laboratory parameters included, there exists a Roche predefined standard 
reference range.  Laboratory values falling outside this standard reference range will be 
labeled “H” for high or “L” for low in Patient listings of laboratory data. 
In addition to the standard reference range, a marked reference range has been 
predefined by Roche for each laboratory parameter.  The marked reference range is 
broader than the standard reference range.  Values falling outside the marked reference 
range that also represent a defined change from baseline will be considered marked 
laboratory abnormalities (i.e., potentially clinically relevant).  If a baseline value is not 
available for a patient, the midpoint of the standard reference range will be used as the 
patient’s baseline value for the purposes of determining marked laboratory 
abnormalities.  Marked laboratory abnormalities will be labeled in the patient listings as 
“HH” for very high or “LL” for very low. 
6.5.3 
Vital Signs 
Vital signs data will be presented by individual listings with flagging of values outside the 
normal ranges and flagging of marked abnormalities.  In addition, tabular summaries will 
be used, as appropriate. 
6.5.4 
ECG Data Analysis 
ECG data will be presented by individual listings with flagging of values outside the 
normal ranges and flagging of marked abnormalities.  In addition, tabular summaries will 
be used, as appropriate. 
6.5.5 
Anti-Drug Antibody Data Analysis 
The number and percentage of patients who test positive for plasma antibodies to 
RO6867461 at baseline and at the study visits will be tabulated. 
6.5.6 
Ocular Assessments 
Results of the following ocular assessments will be summarized by time-point using 
descriptive summaries:  BCVA, IOP, slit lamp examination, indirect ophthalmoscopy, 
FFA, ICGA, FP, SD-OCT, and FAF. 
6.5.7 
Concomitant Medications 
The original terms recorded on the patients’ eCRF by the Investigator for concomitant 
medications will be standardized by the Sponsor by assigning preferred terms. 
Concomitant medications will be presented in summary tables and listings. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
73 
6.6 
EFFICACY ANALYSES 
6.6.1 
Primary Efficacy Endpoint 
6.6.1.1 
Evaluation in the Treatment-Naive Population 
For the evaluation of efficacy in the treatment-naïve population, all patients in 
Population A will be used.  Population A includes all randomized patients, with patients 
grouped according to the treatment assigned at randomization.  For all relevant efficacy 
evaluation, the baseline reference will be latest non missing observation before start of 
study drug. 
The primary efficacy variable is the BCVA change from baseline to Week 36.  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.  Randomization stratification factors such as baseline 
BCVA (≥ 69 letters vs. ≤ 68 letters), and presence of RAP and PCV may also be 
incorporated in the statistical analysis as appropriate.  An unstructured covariance 
structure will be used to account for within-patient correlation, but another 
variance-covariance structure may be selected in case of convergence issues.  The 
primary statistical test will aim to test the null hypothesis (H0) of no difference between 
each of the treatment group (Arms B, C, and D) and the control group (Arm A), for mean 
BCVA change from baseline to Week 36.  The model-based estimate of the difference 
between each of the treatment group (Arms B, C, and D) and the control group (Arm A) 
at Week 36, together with 95% Confidence and corresponding p-value will be reported 
as the primary efficacy measures in this population.  The mean and 95% confidence 
interval (CI) within each treatment group and for the difference between RO6867461 
treatment groups (Arms B, C, and D) and the control group (Arm A) at the other 
time-points will also be reported.  There will not be formal correction for multiple testing. 
6.6.1.2 
Evaluation in the Anti-VEGF−Incomplete-Responder Population 
For the evaluation of efficacy in anti-VEGF−incomplete-responder population, Population 
B and a subgroup of Population B will be used.   
The subgroup is defined as: 
• 
Patients with BCVA ≤ 68 Letters at Week 12 
The study Week 12 visit will be considered the baseline for all efficacy evaluations for 
the anti-VEGF⎯incomplete-responder population. 
The primary efficacy variable is BCVA change from Week 12 to Week 36.  The primary 
efficacy analysis will be performed using a MMRM model.  The model will include the 
categorical covariates of treatment group, visit, and visit by treatment group interaction, 
and the continuous covariate of Week 12 BCVA.  Other covariates including the 
categorical stratification factors of baseline BCVA (≥ 69 letters vs. ≤ 68 letters) and 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
74 
presence of RAP or PCV may also be incorporated as appropriate.  An unstructured 
covariance structure will be used to account or within patient correlation, but another 
variance-covariance structure may be selected in case of convergence issues.  
The primary statistical test will aim to test the null hypothesis (H0) of no difference 
between the treatment group (Arm E) and the control group (Arm A), in terms of BCVA 
mean change from Week 12 to Week 36.  The model-based estimate of the difference 
between the treatment group (Arm E) and the control group (Arm A) at Week 36, 
together with 95% Confidence and corresponding p-value will be reported as the primary 
efficacy measure in this population. 
The mean and 95% CI within each treatment group and for the difference between 
RO6867461 treatment group and the control group at the other time-points will also be 
reported.  There will be no formal correction for multiple testing. 
6.6.2 
Secondary Efficacy Endpoints 
For all secondary endpoints measured on a continuous scale, the same MMRM model 
used for the change from baseline BCVA will be employed.  Nominal p-value will be 
reported without correction for multiple testing. 
For binary endpoints, the 95% confidence interval for the proportion of “responders” in 
each treatment group, the difference in response rate, as well as odds ratio will be 
presented.  Fisher’s exact test will be used for the comparison between the two groups. 
Data transformation (e.g., logarithmic transformation) may be applied as appropriate.  
Other statistical models and additional analyses may also be performed as appropriate.  
In addition, the influence of baseline parameters may be evaluated as covariates in the 
MMRM model and/or in subgroup analysis as appropriate. 
6.7 
PHARMACODYNAMIC ANALYSES 
Individual and mean PD data and parameters will be presented by listings and 
descriptive summary statistics including means, geometric means, medians, ranges, 
standard deviations, and coefficients of variation. 
An empirical drug-disease model of longitudinal BCVA previously developed on the 
database will be used to analyze the effect of RO6867461 on BCVA using a 
meta-analysis approach by integrating data from this study and clinical data. 
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 
characterized.  The results will be reported in a separate document from the clinical 
study report. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
75 
6.8 
PHARMACOKINETIC ANALYSES 
A nonlinear mixed effects modeling approach (with NONMEM software [Beal S 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, etc.) on 
these parameters will be investigated.  The data collected in this study may be pooled 
with data collected in the previous Phase I study as appropriate to build a PK model.  
Secondary PK parameters such as AUC and 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. 
6.9 
OTHER EXPLORATORY ANALYSES 
Additional exploratory analyses may be performed as warranted in order to more fully 
understand the relationship over time between parameters and either nominal dose or 
concentration of RO6867461.  
Exploratory analysis of ranibizumab in plasma and aqueous humor will be conducted 
where the data would be available.  
6.10 
INTERIM ANALYSES 
The Sponsor may conduct one interim analysis to allow for adaption of the sample size 
(see Section 3.1.2) and one interim analysis of efficacy for administrative reasons. 
Given the hypothesis-generating nature of this study, the Sponsor may conduct up to 
two additional interim analyses of efficacy.  The decision to conduct such an interim 
analysis and its timing will be documented in the Sponsor’s study master file prior to the 
conduct of the interim analysis.  The Clinical Study Report will also document that such 
an interim analysis occurred.  The interim analysis, should it occur, will be performed 
and interpreted by members of the IMC and management who would then be unmasked 
at the treatment group level.  Access to treatment assignment information will follow the 
Sponsor’s standard procedures.   
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.  Sites will be responsible for data entry into the Electronic Data 
Capture (EDC) system. 
A comprehensive validation check program will verify the data.  Discrepancies will be 
generated automatically in the system at the point of entry or added manually for 
resolution by the Investigator. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
76 
The Sponsor will produce a Data Handling Manual that describes the quality checking to 
be performed on the data.  Central laboratory data and other electronic data will be sent 
directly to the Sponsor, using the Sponsor’s standard procedures to handle and process 
the electronic transfer of these data. 
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  
Data for this study will be captured via an online EDC system.  The data collected in the 
source documents is entered onto the study eCRF.  An audit trail will maintain a record 
of initial entries and changes made; reasons for change; time and date of entry; and user 
name of person authorizing entry or change.  For each patient enrolled, an eCRF must 
be completed and electronically signed by the PI or authorized delegate from the study 
staff. If a patient withdraws from the study, the reason must be noted on the eCRF.  If a 
patient is withdrawn from the study because of a treatment‑limiting adverse event, 
thorough efforts should be made to clearly document the outcome. 
The Investigator should ensure the accuracy, completeness and timeliness of the data 
reported to the Sponsor in the eCRFs and in all required reports. 
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
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. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
77 
Before study initiation, data to be entered directly into the eCRFs (i.e., no prior written or 
electronic record of the data) and considered source data must be defined in the Trial 
Monitoring Plan. 
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 investigational site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational 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 PI 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 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. Food and Drug 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
78 
Administration (FDA) regulations and applicable local, state, and federal laws.  Studies 
conducted in the EU/EEA will comply with the EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form 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. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  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. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
79 
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 PI 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 PI 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 9.5). 
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 only be 
disclosed to third parties 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. 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other 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 one year after completion of the study (i.e., last patient last 
visit [LPLV]). 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
80 
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, which includes an audit trail containing a complete record of all changes 
to data. 
It is the understanding of the Sponsor that this protocol (and any modifications) as well 
as appropriate consent procedures and advertisements, will be reviewed and approved 
by an IRB.  This board must operate in accordance with the current Federal Regulations.  
The Sponsor will be sent a letter or certificate of approval prior to initiation of the study, 
and also whenever subsequent amendments /modifications are made to the protocol.  
Roche shall also submit an IND Annual Report to FDA according to local regulatory 
requirements and timelines. 
9.2 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The Investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.3 
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 (FAF, FP, FFA, ICGA, and 
SD-OCT), which will be forwarded to Sponsor electronically. 
9.4 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
prior to submission.  This allows the Sponsor to protect proprietary information and to 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
81 
provide comments based on information from other studies that may not yet be available 
to the Investigator. 
The Sponsor will comply with the requirements for publication of study results.  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. 
Any formal publication of the study in which contribution of Sponsor personnel exceeded 
that of conventional monitoring will be considered as a joint publication by the 
Investigator and the appropriate Sponsor personnel. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements 
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. 
9.5 
PROTOCOL AMENDMENTS 
Any substantial protocol amendments will be prepared by the Sponsor.  Substantial 
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 any non-substantial changes, as defined by 
regulatory requirements. 

RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
82 
10. 
REFERENCES 
Beal S and Sheiner L (Eds.). NONMEM users guides, NONMEM projects group. 
University of California, San Francisco. 1998. 
Busbee BG, Ho AC, Brown DM, et al. Twelve-month efficacy and safety of 0.5 mg or 
2 mg  in patients with subfoveal neovascular age-related macular degeneration. 
Ophthalmol 2013;120:1046-4056.  
Campochiaro PA, Channa R, Berger BB, et al. Treatment of diabetic macular edema 
with a designed ankyrin repeat protein that binds vascular endothelial growth 
factor: a phase I/II study. Am J Ophthalmol 2013;155:697-704. 
Heier JH, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF Trap-eye) in wet 
age-related macular degeneration. Ophthalmol 2012;119:2537-2548. 
Investigator’s Brochure, RO6867461. Fourth version, November 2015. 
Krohne TU, Liu Z, Holz FG, et al. Intraocular pharmacokinetics of  following a single 
intravitreal injection in humans. Am J Ophthalmol 2012;154:682-686. 
Resnikoff S, Pascolini D, Etya'ale D, et al. Global data on visual impairment in the year 
2002. Bull World Health Organ. 2004;82:844-851. 
Schmidt-Erfurth U, Kaiser P, Korobelnik JF, et al. Intravitreal aflibercept injection for 
neovascular age-related macular degeneration–Ninety-six-week results of the 
VIEW studies. Ophthalmol 2014;121:193-201. 
The CATT research group.  and bevacizumab for neovascular age-related macular 
degeneration. N. Engl. J. Med 2011;364:1897-1908. 
Turpcu A, Dugel PU, Kiss S, et al. Patterns of anti-VEGF use in neovascular age-related 
macular degeneration: a United States administrative claims database analysis. 
37th Annual Macula Society Meeting, 2014 
 

 
RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
87 
Appendix 2  
Schedule of Assessments Detail Table for Visits with Repeated Assessments 
 
 
Week 1 Week 4
Week 8 
Week 12
Week 16
Week 20 
Week 24 
Week 28 
Week 32 
 
Day 1 
Day 28
Day 56 
Day 84 
Day 112 
Day 140 
Day 168 
Day 196 
Day 224 
Scheduled Time 
 
 
 
 
 
 
 
 
 
Pre-dose 
x 
x 
x 
x 
x 
x 
x 
x 
x 
30 minutes 
x 
x 
x 
x 
x 
x 
x 
x 
x 
60 minutes 
x 
x 
x 
x 
x 
x 
x 
x 
x 
IOP = intraocular pressure. 
a  If IOP  ≥  30 mmHg at 30 ( ± 5) minutes post-treatment administration in the study eye, then measure again at 60 ( ± 10) minutes. 
 
 

 
RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
88 
Appendix 3  
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 
0 
No protein is visible in the anterior chamber when viewed by an experienced observer 
using slitlamp biomicroscopy; a small, bright, focal slit-beam of white light; and high 
magnification. 
Trace 
Trace amount of protein is detectable in the anterior chamber:  This protein is visible only 
with careful scrutiny by an experienced observer using slitlamp biomicroscopy; a small, 
bright, focal slit-beam of white light; and high magnification. 
1 +  
Slight amount of protein is detectable in the anterior chamber:  the presence of protein in 
the anterior chamber is immediately apparent to an experienced observer using slitlamp 
biomicroscopy and high magnification, but such protein is detected only with careful 
observation with the naked eye and a small, bright, focal slit-beam of white light. 
2-3 +  
Moderate amount of protein is detectable in the anterior chamber.  These grades are 
similar to 1+ but the opacity would be readily visible to the naked eye of an observer 
using any source of a focused beam of white light.  This is a continuum of moderate 
opacification, with 2 + being less apparent than 3 + . 
4 +  
A large amount of protein is detectable in the anterior chamber.  This grade is similar to 
3 +  , but the density of the protein approaches that of the lens.  Additionally, frank fibrin 
deposition is frequently seen in acute circumstances.  It should be noted that because 
fibrin may persist for a period of time after partial or complete restoration of the 
blood−aqueous barrier, it is possible to have resorbing fibrin present with lower numeric 
assignations for flare (e.g., 1 + flare with fibrin). 
Cells 
0 
No cells are seen in any optical section when a large slitlamp beam is swept across the 
anterior chamber. 
Trace 
Few (1−3) cells are observed when the slitlamp beam is swept across the anterior 
chamber.  When the instrument is held stationary, not every optical section contains 
circulating cells. 
1 +  
 3−10 cells/optical section are seen when the slitlamp beam is swept across the anterior 
chamber.  When the instrument is held stationary, every optical section contains 
circulating cells. 
2 +  
10−25 cells are seen when the slitlamp beam is swept across the anterior chamber. 
When the instrument is held stationary, every optical section contains circulating cells. 
3 +  
25−50 cells are seen when the slitlamp beam is swept across the anterior chamber.  
When the instrument is held stationary, every optical section contains circulating cells.  
Keratic precipitates or cellular deposits on the anterior lens capsule may be present. 
4 +  
More than 50 cells are seen when the slitlamp beam is swept across the anterior 
chamber.  When the instrument is held stationary, every optical section contains cells, or 
hypopyon is noted.  As for fibrin deposition, hypopyon may persist for some period of 
time after the active exudation of cells into the anterior chamber has diminished or 
ceased entirely, making it possible to have 1 + circulating cells in the anterior chamber 
with a resolving hypopyon. 

 
RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
89 
Appendix 3  
Grading Scale for Assessment of Anterior Chamber Flare or 
Cells, Vitreal Hemorrhage Density, and Vitreous Cells (cont.)  
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. 
 
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. 
 
 

 
RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
90 
Appendix 4  
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. 
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, at the discretion of the Investigator, by two drops of ophthalmic 
antimicrobial solution. 
• 
Wait 90 seconds. 
• 
Instill two more drops of proparacaine- or tetracaine-based ophthalmic drops into 
the study eye, 

 
RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
91 
Appendix 4  
Study Treatment Administration Procedure (cont.)  
• 
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. 
 
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 two 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. 

 
RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
92 
Appendix 4  
Study Treatment Administration Procedure (cont.)  
• 
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. 
• 
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 

 
RO6867461 VEGF/Ang2—F.Hoffmann-La Roche Ltd 
Protocol BP29647, Version 3 
93 
Appendix 4  
Study Treatment Administration Procedure (cont.)  
• 
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 
 
5. INTRAVITREAL ADMINSTRATION 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  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 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.