Clinical trial NCT02699450
Conditions: Diabetic Macular Edema
Sponsor: Hoffmann-La Roche
Start date: 2016-04-27; Completion date: 2017-12-14
Enrollment: 229 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multiple-center, multiple-dose, randomized, active comparator-controlled, double-masked, three parallel group, 36-week study in participants with center-involving diabetic macular edema (DME). Only one eye will be selected as the study eye. Where both eyes meet all eligibility criteria, the eye with the worse best corrected visual acuity (BCVA) will be defined as the study eye. The study will consist of a treatment period (20 weeks) and an observational period (up to 16 weeks). Treatment naive participants will be randomized in a 1:1:1 ratio to one of the Arms A, B and C, respectively. Participants previously treated with intravitreal (IVT) anti-vascular endothelial growth factor (VEGF) will be randomized in a 1:1 ratio to Arms A and C.

Detailed description:

Arms: arm 1: Participants will receive 0.3 milligrams (mg) ranibizumab every fourth week up to Week 20, for a total of 6 administrations, followed by an observational period up to Week 36. If a participant meets pre-specified criteria the participant will receive a single dose of 0.3 mg ranibizumab and exit the study. arm 2: Participants will receive 1.5 mg faricimab every fourth week up to Week 20, for a total of 6 administrations, followed by an observational period up to Week 36. If a participant meets pre-specified criteria the participant will receive a single dose of 0.3 mg ranibizumab and exit the study. arm 3: Participants will receive 6 mg faricimab every fourth week up to Week 20, for a total of 6 administrations, followed by an observational period up to Week 36. If a participant meets pre-specified criteria the participant will receive a single dose of 0.3 mg ranibizumab and exit the study.
Interventions: intervention 1: Faricimab intervention 2: Ranibizumab
Intervention descriptions: intervention 1: Faricimab will be administered by IVT injection in the study eye. intervention 2: Ranibizumab will be administered by IVT injection in the study eye.

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
 
A MULTIPLE-CENTER, MULTIPLE-DOSE, 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 DIABETIC MACULAR EDEMA 
NCT Number: NCT02699450 
Document Date: Protocol Version 3: 18-August-2016 
 
 


Clinical Study Report: RO6867461 - F. Hoffmann-La Roche Ltd
Protocol BP30099     Report Number 1083913
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Title
18-Aug-2016 16:24:31
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—F. Hoffmann-La Roche Ltd 
Protocol BP30099, Version 3 
PROTOCOL 
TITLE: 
A MULTIPLE-CENTER, MULTIPLE-DOSE, 
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 DIABETIC 
MACULAR EDEMA 
PROTOCOL NUMBER: BP30099 
VERSION: 
3 
EUDRACT NUMBER: 
NA 
IND NUMBER: 
119,225 
TEST PRODUCT: 
RO6867461 
SPONSOR: 
F. Hoffmann-La Roche Ltd
DATE FINAL: 
See electronic date stamp below. 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ...................................................................................... 9 
1. 
BACKGROUND AND RATIONALE............................................................. 21 
1.1 
Background on Disease......................................................... 21 
1.2 
Background on RO6867461 .................................................. 22 
1.2.1 
Previous Non-Clinical Studies ............................................... 22 
1.2.2 
Previous Clinical Studies ....................................................... 23 
1.2.2.1 
Safety and Tolerability ........................................................... 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 Objective .................................................................. 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 the Study Design ............................................... 27 
3.1.2 
Number of Patients................................................................ 28 
3.1.3 
Internal Monitoring Committee............................................... 29 
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 Measure ...................................... 32 
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3.3.3.2 
Secondary Efficacy Outcome Measures................................ 33 
3.3.3.3 
Pharmacodynamic Biomarker Outcome Measure ................. 33 
3.3.4 
Exploratory Outcome Measures ............................................ 33 
4. 
MATERIALS AND METHODS .................................................................... 34 
4.1 
Centers.................................................................................. 34 
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 
4.3.1.1 
Criteria for Treatment with Ranibizumab during 
Observational Period ............................................................. 38 
4.3.2 
Treatment Administration Procedure ..................................... 39 
4.3.3 
Masking ................................................................................. 39 
4.3.4 
Emergency Unmasking.......................................................... 40 
4.4 
Study Treatment.................................................................... 41 
4.4.1 
Formulation, Packaging, and Handling.................................. 41 
4.4.1.1 
RO6867461 and Placebo ...................................................... 41 
4.4.1.2 
Ranibizumab Active Comparator........................................... 42 
4.4.1.3 
Ranibizumab during Observational Period ............................ 42 
4.4.2 
Dosage, Administration, and Compliance.............................. 42 
4.4.2.1 
RO6867461 and Ranibizumab .............................................. 42 
4.4.3 
Investigational Medicinal Product Accountability ................... 43 
4.4.4 
Post-Trial Access to RO6867461 .......................................... 44 
4.5 
Concomitant Therapy ............................................................ 44 
4.5.1 
Permitted Therapy ................................................................. 45 
4.5.2 
Prohibited Therapy ................................................................ 45 
4.5.3 
Emergent/Recurrent Diabetic Macular Edema in 
the Fellow Eye....................................................................... 45 
4.6 
Study Assessments ............................................................... 46 
4.6.1 
General Safety Assessments ................................................ 46 
4.6.1.1 
Medical History and Demographic Data ................................ 46 
4.6.1.2 
Physical Examinations........................................................... 47 
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4.6.1.3 
Vital Signs.............................................................................. 47 
4.6.1.4 
Electrocardiograms................................................................ 47 
4.6.1.5 
Laboratory Assessments ....................................................... 48 
4.6.1.6 
Anti-Drug Antibody Assessments .......................................... 49 
 
 
4.6.2.1 
Blood Samples ...................................................................... 50 
 
 
 
 
 
4.6.3 
Clinical Genotyping Sample................................................... 51 
 
 
4.6.5 
Disease-Specific Assessments.............................................. 53 
4.6.5.1 
Ocular Safety Assessments................................................... 54 
4.6.5.2 
Efficacy and Pharmacodynamic Assessments ...................... 54 
 
 
4.6.6 
Amount of Blood to be Collected throughout the 
Study ..................................................................................... 57 
4.6.7 
Timing of Study Assessments ............................................... 57 
4.6.7.1 
Screening and Pretreatment Assessments............................ 57 
4.6.7.2 
Assessments during Treatment............................................. 58 
4.6.7.3 
Assessments at Early Termination Visit................................. 59 
4.6.7.4 
Assessments at Final Visit..................................................... 60 
4.6.7.5 
Assessments at Unscheduled Visits...................................... 60 
4.7 
Patient Withdrawal, Study, and Site 
Discontinuation...................................................................... 60 
4.7.1 
Patient Discontinuation.......................................................... 60 
4.7.1.1 
Discontinuation from Study Drug........................................... 60 
4.7.2 
Study and Site Discontinuation.............................................. 61 
5. 
ASSESSMENT OF SAFETY....................................................................... 62 
5.1 
Safety Parameters and Definitions ........................................ 62 
5.1.1 
Adverse Events ..................................................................... 62 
5.1.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 62 
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5.1.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor ............................... 63 
5.1.4 
Sight-Threatening Adverse Events (Immediately 
Reportable to the Sponsor).................................................... 63 
5.2 
Safety Plan ............................................................................ 64 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 64 
5.3.1 
Adverse Event Reporting Period ........................................... 64 
5.3.2 
Eliciting Adverse Event Information ....................................... 65 
5.3.3 
Assessment of Severity of Adverse Events ........................... 65 
5.3.4 
Assessment of Causality of Adverse Events ......................... 65 
5.3.5 
Procedures for Recording Adverse Events............................ 66 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 66 
5.3.5.2 
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 67 
5.3.5.3 
Persistent or Recurrent Adverse Events................................ 67 
5.3.5.4 
Abnormal Laboratory Values ................................................. 67 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 68 
5.3.5.6 
Abnormal Liver Function Tests.............................................. 68 
5.3.5.7 
Deaths ................................................................................... 69 
5.3.5.8 
Preexisting Medical Conditions.............................................. 69 
5.3.5.9 
Worsening of Diabetic Macular Edema or 
Diabetic Retinopathy ............................................................. 69 
5.3.5.10 
Hospitalization or Prolonged Hospitalization.......................... 70 
5.3.5.11 
Overdoses ............................................................................. 70 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 70 
5.4.1 
Emergency Medical Contacts................................................ 71 
5.4.2 
Reporting Requirements for Serious Adverse 
Events Non-Serious Adverse Events of Special 
Interest, and Sight-Threatening Adverse Events ................... 71 
5.4.3 
Reporting Requirements for Pregnancies.............................. 71 
5.4.3.1 
Pregnancies in Female Patients............................................ 71 
5.4.3.2 
Abortions ............................................................................... 71 
5.4.3.3 
Congenital Anomalies/Birth Defects ...................................... 72 
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5.5 
Follow-Up of Patients after Adverse Events .......................... 72 
5.5.1 
Investigator Follow-Up........................................................... 72 
5.5.2 
Sponsor Follow-Up ................................................................ 72 
5.6 
Post-Study Adverse Events................................................... 72 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 73 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 73 
6.1 
Determination of Sample Size ............................................... 73 
6.2 
Summaries of Conduct of Study............................................ 73 
6.3 
Analysis Populations ............................................................. 74 
6.3.1 
Safety Analysis Population .................................................... 74 
6.3.2 
Efficacy, Pharmacokinetic, and 
Pharmacodynamic Analysis Population................................. 74 
6.4 
Definition of Baseline............................................................. 74 
6.5 
Summaries of Treatment Group Comparability ..................... 74 
6.6 
Safety Analyses..................................................................... 74 
6.6.1 
Adverse Events ..................................................................... 74 
6.6.2 
Clinical Laboratory Test Results............................................ 74 
6.6.2.1 
Standard Reference Ranges and Transformation 
of Data................................................................................... 75 
6.6.2.2 
Definition of Laboratory Abnormalities................................... 75 
6.6.3 
Vital Signs.............................................................................. 75 
6.6.4 
Electrocardiogram Data Analysis........................................... 75 
6.6.5 
Anti-Drug Antibody Data Analysis.......................................... 75 
6.6.6 
Ocular Assessments.............................................................. 75 
6.6.7 
Concomitant Medications ...................................................... 76 
6.7 
Efficacy Analyses .................................................................. 76 
6.7.1 
Primary Efficacy Endpoint...................................................... 76 
6.7.2 
Secondary Efficacy Endpoints............................................... 76 
 
 
6.9 
Pharmacokinetic Analyses..................................................... 77 
6.10 
Exploratory Analyses............................................................. 78 
6.11 
Interim Analyses .................................................................... 78 
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7. 
DATA COLLECTION AND MANAGEMENT ............................................... 78 
7.1 
Data Quality Assurance......................................................... 78 
7.2 
Electronic Case Report Forms............................................... 79 
7.3 
Source Data Documentation.................................................. 79 
7.4 
Use of Computerized Systems .............................................. 80 
7.5 
Retention of Records............................................................. 80 
8. 
ETHICAL CONSIDERATIONS.................................................................... 80 
8.1 
Compliance with Laws and Regulations ................................ 80 
8.2 
Informed Consent .................................................................. 80 
8.3 
Institutional Review Board or Ethics Committee.................... 81 
8.4 
Confidentiality........................................................................ 82 
8.5 
Financial Disclosure .............................................................. 82 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 82 
9.1 
Study Documentation ............................................................ 82 
9.2 
Site Inspections ..................................................................... 83 
9.3 
Administrative Structure......................................................... 83 
9.4 
Publication of Data and Protection of Trade 
Secrets .................................................................................. 83 
9.5 
Protocol Amendments ........................................................... 84 
10. REFERENCES ........................................................................................... 85 
  
 
LIST OF TABLES 
Table 1 
Overall Adverse Event Profile for All Patients Enrolled in 
Study BP28936........................................................................... 24 
Table 2 
Dosage Strengths and Dilution ................................................... 43 
Table 3 
Adverse Event Severity Grading Scale ....................................... 65 
 
 
LIST OF FIGURES 
Figure 1 
Study Design............................................................................... 28 
 
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LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments........................................................... 87 
Appendix 2 
Grading Scale for Assessment of Anterior Chamber Flare or 
Cells, Vitreal Hemorrhage Density, and Vitreous Cells ............... 90 
Appendix 3 
Study Treatment Administration Procedure ................................ 92 
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PROTOCOL SYNOPSIS 
TITLE: 
A MULTIPLE-CENTER, MULTIPLE-DOSE, 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 DIABETIC MACULAR EDEMA 
PROTOCOL NUMBER: 
BP30099 
VERSION: 
1 
EUDRACT NUMBER: 
NA 
IND NUMBER: 
119,225 
TEST PRODUCT: 
RO6867461 
PHASE: 
II 
INDICATION: 
Diabetic macular edema (DME) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
OBJECTIVES 
Primary Objective 
The primary objective of this study is: 
To evaluate the efficacy of RO6867461 compared with the active comparator in treatment 
naïve patients with center-involving diabetic macular edema (CI-DME)  
Secondary Objectives 
The secondary objectives for 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 and anatomical outcomes informing on the mechanism 
of action of RO6867461 
• 
To investigate the formation of plasma anti-RO6867461 antibodies 
• 
To explore the duration of effect of RO6867461  
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To explore the predictive effect of previous IVT anti-VEGF treatment on efficacy of 
RO6867461 
• 
To evaluate the efficacy and safety of RO6867461 compared with the active comparator in 
patients with CI-DME with previous IVT anti-VEGF treatment. 
• 
 
 
• 
 
 
 
• 
To evaluate improvement in diabetic retinopathy (DR) severity score 
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STUDY DESIGN 
This is a multiple-center, multiple-dose, randomized, active comparator−controlled, 
double-masked, three parallel group, 36-week study in patients with CI-DME. 
The three groups of this study are as follows: 
• 
Arm A:  0.3 mg ranibizumab IVT  
• 
Arm B:  1.5 mg RO6867461 IVT  
• 
Arm C:  6 mg RO6867461 IVT  
Only one eye will be selected as the study eye.  Where both eyes meet all eligibility criteria, the 
eye with the worse BCVA will be defined as the study eye.  Where both eyes meet all eligibility 
criteria and have the same BCVA letter score at Day 1, study eye selection is at the 
investigator’s discretion. 
NUMBER OF PATIENTS 
Up to 210 patients will be randomized. 
Approximately 150 treatment-naïve patients and approximately 60 patients who have been 
previously treated with IVT anti-VEGF will be enrolled in the study. 
Approximately 50 treatment-naïve patients will be randomized on each arm (1:1:1 
randomization scheme) and approximately 30 patients previously treated with IVT anti-
VEGF will be randomized into arms A and C. 
TARGET POPULATION 
Male and female patients of ≥ 18 years of age with CI-DME. 
INCLUSION/EXCLUSION CRITERIA 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
Ocular criteria for study eye: 
• 
Macular edema associated with DR defined as macular thickening by spectral domain 
optical coherence tomography (SD-OCT) involving the center of the macula:  central 
subfield thickness (CST) of ≥ 325 μm with Spectralis (Heidelberg) at screening (where 
Spectralis is not available, the following devices and CST thresholds are acceptable:  
CST ≥ 315 μm for Cirrus, CST ≥ 315 μm for Topcon, CST ≥ 295 μm for Optovue).   
• 
Decreased visual acuity attributable primarily to DME, with best corrected visual acuity 
(BCVA) letter score of 73−24 letters (inclusive) on Early Treatment Diabetic Retinopathy 
Study (ETDRS)-like charts (20/40−20/320 Snellen equivalent) on Day 1 
• 
Clear ocular media and adequate pupillary dilatation to allow acquisition of good quality 
retinal images to confirm diagnosis 
 
General criteria: 
• 
Diagnosis of diabetes mellitus (DM; Type 1 or Type 2), as defined by the World Health 
Organization and/or American Diabetes Association 
• 
Able and willing to provide written informed consent and to comply with the study protocol 
according to International Conference on Harmonisation (ICH) and local regulations.  
Alternatively, a legally authorized representative must be able to consent for the patient 
according to ICH and local regulations. 
• 
Age ≥ 18 years 
• 
For women who are not postmenopausal (i.e. ≥12 months of non-therapy-induced 
amenorrhea, confirmed by FSH, if not on hormone replacement) 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 4 weeks after last dose. 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
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patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception; 
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. 
• 
For men:  agreement to use a barrier method of contraception during the treatment period 
for at least 4 weeks after the last dose of study drug 
• 
Patients must be willing not to participate in any other clinical trial including an 
investigational medical 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: 
• 
Any signs of high-risk PDR defined as: 
• 
any vitreous or pre-retinal hemorrhage 
• 
NVE  ≥  1/2 disc area within an area equivalent to the standard mydriatic ETDRS 7- 
field on clinical examination  
• 
NVD  ≥ 1/3 disc area on clinical examination  
• 
Any IVT anti-VEGF treatment within 3 months prior to Day 1 
• 
Any panretinal photocoagulation (PRP) treatment prior to Day 1 
• 
Any macular laser photocoagulation within 3 months prior to Day 1 
• 
History of vitreoretinal surgery 
• 
Any IVT or periocular corticosteroid treatment within 3months prior to Day 1. Any 
history of Iluvien or Ozurdex implants prior to Day 1 will not be permitted 
• 
Any cataract surgery or treatment for complications of cataract surgery with steroids within 
3 months prior to Day 1 
• 
History of incisional glaucoma surgery 
• 
Uncontrolled glaucoma (e.g., progressive loss of visual fields or defined as intraocular 
pressure [IOP] ≥ 25 mmHg despite treatment with anti-glaucoma medication) 
 
Concurrent ocular conditions in the study eye: 
• 
History of rubeosis  
• 
Any current or history of ocular disease other than DME that may confound assessment of 
the macula or affect central vision (e.g., age-related macular degeneration, retinal vein 
occlusion, uveitis, angioid streaks, histoplasmosis, active or inactive cytomegalovirus, 
pathological myopia, retinal detachment, macular traction, macular hole, significant 
cataract) 
• 
Any current ocular condition for which, in the opinion of the investigator, visual acuity 
loss would not improve from resolution of macular edema (e.g., foveal atrophy, pigment 
abnormalities, dense sub-foveal hard exudates, non-retinal condition) 
• 
Any active ocular infection on Day 1 
• 
Any active intraocular inflammation (grade trace or above) on Day 1 
 
Characteristics for fellow eye: 
• 
Any anti-VEGF treatment within 7 days prior to Day 1 
• 
Any retinal condition that, in the opinion of the investigator, might require anti-VEGF 
treatment within 7 days from Day 1 
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General criteria: 
• 
Any systemic anti-VEGF within 6 months prior to Day 1 
• 
Any major illness or major surgical procedure within 1 month prior to Day 1 
• 
Any febrile illness within 1 week prior to Day 1 
• 
Any stroke or myocardial infarction within 12 months prior to Day 1 
• 
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 needs to be controlled by 
antihypertensive medication, the patient should be taking the same medication continuously 
for at least 1 month prior to Day 1. 
• 
Patients with glycosylated hemoglobin HbA1c > 12% at screening 
• 
Untreated diabetes mellitus or initiation of oral anti-diabetic medication or insulin within 
4 months prior to Day 1 or anticipated change of anti-diabetic medications within the 
duration of the study 
• 
Renal failure requiring renal transplant, hemodialysis, or peritoneal dialysis within 6 months 
prior to Day 1 or anticipated to require hemodialysis or peritoneal dialysis at any time during 
the study 
• 
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 IMP 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 female 
• 
Use of systemic corticosteroids within 1 month prior to Day 1 
• 
Any known hypersensitivity to active comparator, fluorescein, any ingredient of the 
formulation used, dilating eye drops, or any anesthetics and microbial drops used 
• 
Any other restriction accorded to the use of the active comparator 
• 
Any treatment with an IMP in the 3 months prior to Day 1 
 
LENGTH OF STUDY 
The total duration of the study will be up to 40 weeks (from screening through study completion) 
for each enrolled patient as follows: 
• 
Screening:  up to 4 weeks 
• 
Baseline:  Day 1 
• 
Study treatment administration period:  from Day 1 to Week 20 
• 
Observational period:  From Week 20 up to Week 36 
• 
Safety follow up call: During the observational period and 7 days after ranibizumab 
administration  
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. 
OUTCOME MEASURES 
SAFETY OUTCOME MEASURES 
The safety outcome measures for this study are as follows: 
• 
Any relevant safety observations derived from BCVA (modified ETDRS charts), slit-lamp 
examination, dilated binocular indirect high-magnification ophthalmoscopy, IOP, fundus 
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Plasma PD biomarker outcome measure 
• 
Change in plasma levels of VEGF and Ang-2 
EXPLORATORY OUTCOME MEASURES 
The exploratory outcome measures for this study include but are not limited to the following: 
 
BCVA: 
• 
Difference in mean BCVA change from baseline between the treatment-naïve patients and 
patients with previous IVT anti-VEGF (differential effect of RO6867461) 
• 
Proportion of patients with BCVA  ≥  69 letters (20/40 or better) over time 
• 
Proportion of patients with BCVA   ≥ 84 letters (20/20 or better) over time 
 
Disease-related exploratory outcome measure: 
• 
Proportion of patients with DR severity improvement from baseline on the ETDRS-DRSS 
(diabetic retinopathy severity score) at Week 24 
 
Anatomic exploratory outcome measures: 
• 
Change from baseline in macular perfusion and leakage by FFA at Week 12 
• 
Change from baseline in peripheral perfusion and leakage by FFA at Week 24 
 
Durability-related exploratory outcome measures: 
• 
Time to increase of CST by  ≥ 50µm and/or loss of  ≥  5 letters of BCVA due to DME 
compared to values at Week 20  
• 
Time to treatment with 0.3 mg ranibizumab after Week 20 
 
 
 
 
 
 
 
 
 
 
BIOMARKER/GENOTYPING SAMPLE COLLECTION 
Mandatory Biomarkers Samples 
All patients who have been enrolled in the study will have mandatory PD and exploratory 
biomarker plasma samples taken at the timepoints indicated in the SoA.  The PD and 
exploratory plasma samples will be collected to investigate biomarkers in plasma related to 
angiogenesis and diabetic disease biomarkers.  
Clinical Genotyping Samples 
A mandatory whole blood sample will be taken for DNA extraction from every patient.  The DNA 
may be used to study genes related to DME, DR, and angiogenesis (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 other mandatory blood samples.  
This specimen will be destroyed up to 2 years after the final closure of the clinical database. 
 
 
 
 
 
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INVESTIGATIONAL MEDICINAL PRODUCT(S) 
Test Product: RO6867461 
Vials of sterile, colorless to brownish, preservative-free solution of RO6867461 (120 mg/mL) for 
IVT administration of either 1.5 mg or 6 mg dose every 4 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. 
A volume of 50 μL will be administered by IVT injection for all study drugs tested in this study. 
Comparator: ranibizumab 
Ranibizumab (nominal content 0.3 mg/0.05 mL) required for completion of this study will be 
provided by the Sponsor as a solution formulated at 6 mg/mL and supplied as a single-use vial. 
 
The double-masked design is achieved through strict independence of the pharmacist (or 
designated personnel) and investigators who are preparing and administering study drug, from 
the assessing investigators and remaining site personnel. 
PROCEDURES 
Detailed SoA and procedures are tabulated in Appendix 1 of the protocol. 
Screening 
Patients with CI-DME 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 females of childbearing potential, and safety laboratory 
parameters.  A predefined set of imaging criteria for eligibility will be confirmed by a Central 
Reading Center before enrollment. 
Treatment Period 
On Day 1, baseline assessments will be conducted on the eligible patients, according to the 
SoA.  Patients will receive their first IVT injection of either RO6867461 or comparator therapy 
according to the randomization schedule and following established standard procedures.  
Patients will return to the eye clinic every 4 weeks for study drug administration and 
assessments as outlined in the SoA.   
A post-treatment administration check of study eye will be performed for each patient 
immediately after study treatment administration by testing finger count vision, hand motion, and 
light perception, as appropriate.  On the day of dosing, IOP will be monitored at 30 minutes 
post-administration in the study eye, using either Goldmann tonometry or Tono-pen, and if IOP 
≥ 30 mmHg in the study eye, 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. 
 
 
 
Observational Period 
Patients will return for evaluation every 4th week.  If during any of these evaluations the 
patients meet the pre-specified criteria (see Section 4.3.1.1 ), the patients will receive a single 
dose of 0.3 mg ranibizumab, exit the study, and receive a follow up phone call 7 days after the 
dose of ranibizumab to evaluate any potential adverse events. Otherwise, patients will exit the 
study once they have completed the observational visit at week 36.   
STATISTICAL METHODS 
PRIMARY ANALYSIS 
The primary efficacy analyses will include all randomized patients, with patients grouped 
according to the treatment assigned at randomization. 
The primary efficacy variable is the BCVA change from baseline to Week 24.  The primary 
efficacy analysis will be performed using a Mixed Model for Repeated Measurement (MMRM) 
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model. 
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., 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 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. 
 
 
 
 
 
 
 
 
 
 
SAMPLE SIZE JUSTIFICATION 
The sample size is based on the primary efficacy outcome of mean change in BCVA from 
baseline at Week 24 in the treatment-naïve patients.  Each RO6867461 dose (Arms B and C) 
will be compared with the control group (Arm A). 
Consider 50 treatment-naïve patients randomized to Arm A, B, and C, with a drop-out rate of 
10%.  Assuming a standard deviation of 11 letters, this sample size provides approximately 
80% power to detect a true difference of 5 letters at the one-sided α level of 10%.  The 
minimum detectable difference is approximately 3 letters. 
Approximately 60 previously IVT anti-VEGF treated patients will be enrolled in addition for 
exploratory analyses. 
INTERIM ANALYSES 
Two efficacy interim analyses to inform about possible future development options for 
RO6867461 are foreseen. They will not influence the study conduct.  One  interim efficacy 
analysis is foreseen after approximately 28 treatment-naïve patients in each arm have 
completed the Week 24 visit, and one when approximately all patients have completed the 
Week 24 visit.  
A safety analysis will be performed if safety issues have been identified during ongoing review 
of the masked data.  
Up to two additional interim analyses may be conducted for efficacy. 
OTHER CONSIDERATIONS 
NA 
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LIST OF PROHIBITED MEDICATIONS 
Concomitant Therapy 
Patients who use maintenance therapy other than those required to treat DME should continue 
its use. 
PRP is permitted in either eye, if clinically indicated for the treatment of proliferative diabetic 
retinopathy or retinal holes or tears post randomization. 
The decision to administer antimicrobial drops before and after the IVT administration is at the 
discretion of the investigator. 
 
Prohibited Therapy 
At the discretion of the investigator, patients may continue to receive all medications and 
standard treatments administered for other conditions, except the following: 
• 
Concurrent use of systemic anti-VEGF agents 
• 
Concurrent use of IVT anti-VEGF therapy in the fellow eye within 7 days preceding or 
following the study eye treatment 
• 
Concurrent use of IVT or subtenon corticosteroids in study eye, except as required to treat 
adverse events 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
anti-drug antibody 
AMD 
age-related macular degeneration 
Ang-1 
angiopoietin- 1 
Ang-2 
angiopoietin-2 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-inf
area under the concentration-time curve from time 0 to infinity 
AUC0-τ
area under the concentration–time curve during one dosing 
interval 
BCVA 
best corrected visual acuity 
bFGF 
basic fibroblast growth factor 
BP 
blood pressure 
BRB 
blood-retinal barrier 
CI 
center involvement 
CI-DME 
center-involving DME 
CL 
clearance 
CL/F 
apparent clearance 
CNV 
choroidal neovascularization 
Cmax
maximum concentration observed 
CRP 
C-reactive protein 
CSME 
clinically significant macular edema 
CST 
central subfield thickness 
DBP 
diastolic blood pressure 
DLE 
dose-limiting event 
DM 
diabetes mellitus 
DME 
diabetic macular edema 
DR 
diabetic retinopathy 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EDI 
enhanced depth imaging 
ESF 
Eligibility Screening Form 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
E.U. 
European Union 
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Abbreviation 
Definition 
Fab 
fragment antibody binding 
FDA 
U.S. Food and Drug Administration 
FFA 
fundus fluorescein angiography 
FP 
fundus photography 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
IMC 
Internal Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
IOP 
intraocular pressure 
IRB 
Institutional Review Board 
IVT 
intravitreal 
IxRS 
interactive (voice/web) response system 
LPLO 
last patient last observation 
mAb 
monoclonal antibody 
MAD 
multiple ascending dose 
MMRM 
Mixed Model for Repeated Measurement 
NOAEL 
no observed adverse effect level 
neovascularization of the optic disc 
NVD 
neovascularization elsewhere 
NVE 
OTC 
over the counter  
PD 
pharmacodynamic 
PDGF 
platelet-derived growth factor 
PDR 
proliferative diabetic retinopathy 
PI 
Principal Investigator 
PK 
pharmacokinetic 
PLGF 
placenta growth factor 
PRP 
panretinal photocoagulation 
QT 
QT interval 
QTc 
QT corrected for heart rate 
 
 
SAD 
single ascending dose 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
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Abbreviation 
Definition 
SD-OCT 
spectral domain optical coherence tomography 
SoA 
Schedule of Assessments 
SoC 
standard of care 
t1/2
half-life 
tmax
time to maximum concentration 
ULN 
upper limit of normal 
V 
volume 
VA 
visual acuity 
VEGF 
vascular endothelial growth factor 
VEGF-A 
vascular endothelial growth factor A 
VEGFR 
vascular endothelial growth factor receptor 
 
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1. 
BACKGROUND AND RATIONALE 
1.1 
BACKGROUND ON DISEASE 
Diabetes affects 382 million people worldwide, and its prevalence is expected to grow to 
592 million by 2035 (International Diabetes Federation 2013).  Diabetic retinopathy (DR) 
and diabetic macular edema (DME) are common microvascular complications in patients 
with diabetes and may have sudden and debilitating impact on visual acuity (VA).  DME 
is defined as retinal thickening within 2 disc diameters of the center of the macula (Albert 
and Jakobiec 2000) and is the major cause of central vision loss in patients with 
diabetes (Resnikoff et al. 2004).  DME occurs in approximately 14% of patients with 
diabetes and can be found in both Type 1 and Type 2 patients (Girach and 
Lund-Andersen 2007).  DME can develop at any stage of DR, but it occurs more 
frequently as the duration of diabetes and the severity of DR increase. 
Thickening of the basement membrane and reduction in the number of pericytes are 
believed to lead to increased permeability and incompetence of the retinal vasculature.  
Hypoxia produced by this mechanism is postulated to stimulate the production of 
vascular endothelial growth factor (VEGF).  In addition, the compromise of the 
blood-retinal barrier leads to the leakage of plasma constituents into the surrounding 
retina, with subsequent retinal edema (Antonetti et al. 1999).  In addition to VEGF, other 
inflammatory and angiogenic cytokine levels are also elevated in DME and proliferative 
diabetic retinopathy (PDR) (Aiello et al. 1994; Gardner et al. 2002).
The Early Treatment Diabetic Retinopathy Study (ETDRS) showed that macular laser 
photocoagulation reduced the risk of moderate vision loss by 50% (from 24% to 12% 
3 years after initiation of treatment).  However, few patients experience improvement in 
vision following laser alone for DME and persistent and recurrent macular edema is 
common (ETDRS Report No. 9 1991). 
Over the past few years, the use of anti-VEGF therapy to treat DME has improved visual 
outcomes.  Existing therapies include ranibizumab and aflibercept [EYLEA®].  Although 
anti-VEGF therapies have markedly improved the management of these patients and 
established a new efficacy paradigm in visual gain, a significant percentage of patients 
do not achieve clinically meaningful improvements in vision; furthermore, these therapies 
do not sufficiently improve macular vascular perfusion or target all DME-associated 
sequelae.  Due to its novel mode of action, it is anticipated that RO6867461 will improve 
efficacy over existing anti-VEGF therapies. 
Angiopoietin-1 (Ang-1) and Ang-2 are of key importance in the homeostasis of the 
vascular compartment, functioning as ligands of the Tie-2 receptor tyrosine kinase that is 
expressed on endothelial cells (Davis et al. 1996; Maisonpierre et al. 1997; Fiedler et al. 
2003).  Ang-1 is a homeostatic factor that stabilizes the mature vasculature by promoting 
recruitment of pericytes and smooth muscle cells.  In contrast, Ang-2 acts as an 
antagonist of Tie-2 by blocking Ang-1-dependent Tie-2 activation (Davis et al. 1996; 
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Maisonpierre et al. 1997; Fiedler et al. 2003).  Ang-2 acts as a destabilization factor and, 
under the influence of other angiogenic factors such as VEGF-A, renders the 
vasculature more plastic and amenable to endothelial barrier breakdown and sprouting.  
Ang-2 is also upregulated by VEGF and other pro-angiogenic factors. 
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 endothelial cell permeability in vitro.  In 
addition, their vitreous concentrations were shown to be significantly upregulated in 
patients with DR. (Park et al. 2014; Rangasamy et al. 2011) 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, and result in further improvement of visual and anatomic outcomes in patients 
with DME.  
RO6867461 is a humanized bispecific immunoglobulin G1 (IgG1) monoclonal antibody 
(mAb) that selectively binds VEGF-A and Ang-2.  The VEGF-binding fragment antigen 
(Fab) binds VEGF with high affinity, comparable to other anti-VEGF treatments (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 choroidal neovascularization (CNV).  Also see the 
RO6867461 Investigator’s Brochure  for details on nonclinical and clinical studies. 
 
1.2.1 
Previous Non-Clinical 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).  
In the absence of a suitable model of DME, pharmacological evaluation in vivo focused 
on well characterized models of choroidal vessel edema and neovascularization.  These 
evaluations demonstrated that RO6867461 reduces the formation of neovessels, 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 Version 4). 
 
 
 
 
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In a 2-month Good Laboratory Practice (GLP) study in cynomolgus monkeys, ocular and 
extra-ocular findings occurred following three IVT injections of the highest 3 and 
6 mg/eye/dose.  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.   
In both studies, findings generally correlated with the systemic presence of anti-drug 
antibodies (ADAs) against RO6867461 and exposure loss in the serum of animals.  In 
addition, immunohistochemistry confirmed the presence of immune-complex deposits in 
RO6867461-treated animals with ocular and extra-ocular findings (in the 3-month study).  
Therefore, these effects were consistent with an immune-mediated response to a 
humanized antibody like RO6867461 in non-human primates. 
RO6867461 did not induce any neurological (CNS) findings or effects on heart 
rate/electrocardiogram endpoints (including QT and QTc [corrected QT interval]), 
respiratory rate, or body temperature in cynomolgus monkeys up to 6 months treatment. 
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 CNV secondary to age-related macular 
degeneration (AMD) has been completed (Study 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).  
Please refer to the RO6867461 Investigator’s Brochure for details on Study BP28936. 
A multicenter, double-masked, Phase II study to investigate the safety, tolerability, 
pharmacokinetics, and efficacy of RO6867461 administered IVT in patients with CNV 
secondary to AMD is ongoing (Study BP29647 − AVENUE, clinicaltrials.gov: 
NCT02484690).  In Study BP29647, treatment-naive patients are randomized to receive 
either ranibizumab 0.5 mg every 4 weeks or 1.5 or 6 mg RO6867461 every 4 or 8 weeks 
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for 32 weeks.  To date, side effects observed in patients enrolled in Study BP29647 
(masked data) are consistent with the safety profile observed in the completed BP28936 
study described above. No other data are yet available. 
No clinical data are yet available for RO6867461 in patients with DME. 
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 (see Table 1).  No deaths and no dose-limiting events (DLEs) were reported. 
In the Phase I study (BP28936), one serious adverse event was reported, which was 
non-ocular, and was considered unrelated to the study drug by the Principal Investigator.  
One patient from the 3 mg dose group of Part A was withdrawn from the study because 
of a diagnosis of coronary heart disease, which was considered unrelated to study drug 
by the Investigator (see RO6867461 Investigator’s Brochure Version 4 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 
20 
10 
4 
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. 
 
 
 
 
 
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1.2.2.3 
Functional and Anatomical Pharmacodynamics 
Higher BCVA was observed in patients treated with RO6867461 compared to baseline in 
the Phase I study.  In the SAD part, a median 7 letter (range: 0 to 18; n = 11) higher 
BCVA was observed on Day 28 as compared to baseline across all patients.  In the 
MAD part, after the first, second, and third administration of 6 mg RO6867461, a median 
BCVA increase from baseline of −0.5, 3, and 7.5 letters, respectively, was observed, 
while no change in BCVA was seen with the 3 mg RO6867461. 
The changes in BCVA were associated with a reduction in central subfield thickness 
(CST).  A median change from baseline of −42 μm in CST on Day 28 pooled for all 
dose levels was observed in Part A.  For the patients treated with 3 mg RO6867461 in 
Part B, a median change from baseline of −13.5 μm, −25.0 μm, and −9.0 μm at 28 days 
after the first, second, and third drug administration, respectively, was observed.  
Patients in the 6 mg RO6867461 in Part B showed a consistent and durable reduction in 
CST, with an overall magnitude comparable to Part A.  The CST median change from 
baseline was −79.5 μm, −86 μm, and −117 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).
1.3 
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT 
There are limited clinical evaluations with anti-Ang-2 approaches in patients with DME.  
The Phase I RO6867461 study, which included a small number of patients with CNV 
secondary to AMD, 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 based on 
Phase I data is therefore favorable and justifies evaluation of RO6867461 efficacy as 
compared with SoC therapy in patients with DME.  
Nonclinical toxicology studies (see 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 DME. 
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. 
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This will be a Phase II proof-of concept study in patients with center-involving DME (CI-
DME).  This study is designed to evaluate the effects of RO6867461 on visual function 
and retinal structure by assessing changes from baseline in BCVA (ETDRS letters) and 
anatomy (imaging procedures), respectively.  In addition, the safety, tolerability, and 
pharmacokinetics will be evaluated in patients receiving up to 6 doses of RO6867461. 
Patients who will be enrolled in the 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 Section 4.4.2.  Treatment will be 
administered as necessary for any concurrent medical events. 
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 OBJECTIVE 
The primary objective of this study is: 
• 
To evaluate the efficacy of RO6867461 compared with the active comparator in 
treatment naïve patients with CI-DME.  
 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives for 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 explore the duration of effect of RO6867461  
 
2.3 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
• 
To explore the predictive effect of previous IVT anti-VEGF treatment on efficacy of 
RO6867461 
• 
To evaluate the efficacy and safety of RO6867461 compared with the active 
comparator in patients with CI-DME with previous IVT anti-VEGF treatment. 
• 
 
 
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• 
 
 
 
• 
To evaluate improvement in DR severity score 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is a multiple-center, multiple-dose, randomized, active comparator−controlled, 
double-masked, three parallel group, 36-week study in patients with CI-DME. 
3.1.1 
Overview of the Study Design 
The three groups of this study are as follows (see Figure 1): 
• 
Arm A:  0.3 mg ranibizumab IVT 
• 
Arm B:  1.5 mg RO6867461 IVT  
• 
Arm C:  6 mg RO6867461 IVT  
This study will consist of a treatment period (20 weeks) and an observational period (up 
to 16 weeks), for a total study length of up to 36 weeks. During the treatment period, 
the study drug will be administered to the patients on Day 1 and on every 4th week, for 
a total of 6 injections. During the observational period, patients will be evaluated every 
4th week.  If during any of these evaluations the patients meet the pre-specified criteria 
(see Section 4.3.1.1), the patients will receive a single dose of 0.3 mg ranibizumab, and 
exit the study. They will receive a follow up phone call 7 days after the dose of 
ranibizumab to evaluate any potential adverse events. Otherwise, patients will exit the 
study once they have completed the observational visit at week 36.   
 
Only one eye will be selected as the study eye (see Section 4.3.1). 
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Figure 1 Study Design 
 
 
Q4W = every 4 weeks. 
 
The total duration of the study for each patient will be up to 40 weeks, divided as follows 
(see Figure 1): 
• 
Screening:  Up to 4 weeks 
• 
Baseline:  Day 1 
• 
Study treatment administration period:  From Day 1 to Week 20 
• 
Observational period:  From Week 20 up to Week 36 
• 
Safety follow up call: During the observational period and 7 days after 
ranibizumab administration  
 
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 the Schedule of Assessments (SoA; see Appendix 1), are 
completed. 
If a site has an unexpected issue (e.g., the interactive voice and web response system 
(IxRS) is not able to assign the study kit), 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 
Up to 210 patients will be randomized. Approximately 150 treatment-naïve patients and 
approximately 60 patients who have been previously treated with IVT anti-VEGF will 
be enrolled in the study.  Approximately 50 treatment-naïve patients will be randomized 
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into each arm (1:1:1 randomization scheme) and approximately 30 patients previously 
treated with IVT anti-VEGF will be randomized into arms A and C. 
3.1.3 
Internal Monitoring Committee 
A Roche Internal Monitoring Committee (IMC) will be responsible in the event of an 
interim analysis of efficacy for operational/administrative/study related purposes and/or 
for safety data monitoring.  Two efficacy analyses are foreseen, one after approximately 
28 treatment naïve patients in each treatment arm have completed the Week 24 visit, 
and one when approximately all patients have completed the Week 24 visit.  A safety 
analysis may be performed if safety issues have been identified during ongoing review of 
the masked data.  
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.  The IMC Chair may provide members from other functions access to 
the unmasked reports or data.  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 DME. 
To ensure the safety of all patients during the conduct of the study, several safety 
assessments have been included:  e.g., regular ophthalmological monitoring and 
imaging assessments, adverse event monitoring (systemic and ophthalmologic), vital 
signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], and pulse rate), 
and laboratory safety tests. 
 
 
 
 
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3.2.1 
Rationale for Dosage Selection 
The first-in-human study (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 molar binding equivalent 
anti-VEGF dose to the 0.5 mg ranibizumab dose (approved ranibizumab dose for most 
indications and in most countries) due to the 3-fold higher molecular weight of the IgG 
antibody, RO6867461, as compared with 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; Dhoot et al. 2015).  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, 7 times every 4 weeks, intravitreally.  Due to the approximately 2-fold lower 
vitreous humor volume in cynomolgus monkey as compared with humans, a 3-mg dose 
administered to monkeys achieves similar IVT initial concentrations as compared with 
humans. 
Systemic exposure observed in patients following IVT administration is lower as 
compared with exposures observed in the cynomolgus monkey GLP toxicity study. 
Taken together, the nonclinical and clinical data suggest that the selected doses of 
1.5 mg and 6 mg RO6867461 administered every 4 weeks were safe and tolerated and 
allow a further testing in a Phase II study.  The same doses were selected for the 
ongoing Phase II study in patients with CNV secondary to AMD. 
3.2.2 
Rationale for Study Population  
This study will be conducted in patients with vision loss due to DME who meet all of the 
inclusion criteria and do not meet any of the exclusion criteria for this protocol (see 
Section 4.2.1 and Section 4.2.2). 
Both treatment naïve DME patients and prior IVT anti-VEGF treated DME patients 
will be included.  The aim is to evaluate the efficacy of RO6867461 compared with the 
active comparator in treatment naïve patients with CI-DME. Inclusion of treatment 
naïve and previously anti-VEGF treated patients will enable the exploratory evaluation 
of the predictive effect of previous IVT anti-VEGF treatment on efficacy of RO6867461. 
  
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3.2.3 
Rationale for Control Group 
This study is an interventional superiority study aiming to evaluate the efficacy of 
RO6867461, as compared with standard of care anti-VEGF therapy in patients with DME.  
Anti-VEGF therapy is a well-established SoC in patients with DME, and placebo, sham 
injection, or macular laser are no longer an ethically acceptable alternative given the 
improvements in visual and anatomic outcomes associated with anti-VEGF treatment. 
Ranibizumab is an approved treatment in patients with DME and has demonstrated 
improvement of VA in the target population in controlled, randomized clinical studies. 
Controlled, randomized clinical studies in patients with DME led to the approval of 
ranibizumab 0.3 mg monthly or 0.5 mg pro re nata after vision is stable for 3 consecutive 
monthly doses in the United States and rest of the world, respectively (Mitchell et al. 
2011; Nguyen et al. 2012). 
Therefore, we selected the ranibizumab 0.3 mg every 4 weeks approved regimen as an 
optimal active comparator for a superior efficacy design in the target population for this 
study conducted in the United States. 
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 DR (Goldberg 2009; 
Kaul et al. 2010) and DME.  Moreover, some genetic polymorphisms in genes involved 
in the mechanism of action of RO6867461, such as VEGF and VEGFR, have been 
described in the literature as associated with DR (Churchill et al. 2008) and with 
response to anti-VEGF therapy (Hermann et al. 2014). 
Therefore, both genetic markers and protein biomarkers of pathways involved in these 
processes may be analyzed to improve the understanding of the patient’s response to 
RO6867461 treatment.  
 
 
  
 
 
  
 
 
Genetic polymorphisms associated with DR and DME and related to angiogenesis such 
as VEGFA, Ang-2, and VEGFR may be analyzed. 
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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 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:  Clearance (CL) and volume (V) 
Secondary parameters:  Maximum concentration observed (Cmax), area under 
the concentration-time curve from time 0 to infinity (AUC0-inf), AUC0-τ, time to 
maximum concentration (tmax), t1/2
Compartmental analysis to assess IVT concentrations, as appropriate 
(exploratory) 
 
 
 
 
3.3.3 
Efficacy and Pharmacodynamic Outcome Measures 
The primary analysis population will be treatment naïve patients. Additional analyses 
may be performed in the overall population and in patients previously treated with IVT 
anti-VEGF. 
3.3.3.1 
Primary Efficacy Outcome Measure 
The primary efficacy outcome measure is the mean change in BCVA (ETDRS letters) 
from baseline at Week 24 in treatment-naïve patients. 
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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 BCVA at Week 24 
• 
Proportion of patients with BCVA ≥ 69 letters (20/40 or better) at Week 24 
• 
Proportion of patients with BCVA ≥ 84 letters (20/20 or better) at Week 24 
Anatomic outcome measures by SD-OCT: 
• 
Mean change from baseline in foveal center point thickness at Week 24  
• 
Mean change from baseline in mean CST (1 mm diameter) at Week 24  
• 
Proportion of patients with resolution of subretinal and intraretinal fluid at Week 24  
 
Anatomic outcome measures by FFA: 
• 
Proportion of patients with resolution of leakage at the macula at Week 24 
• 
Change from baseline in the size of the foveal avascular zone at Week 24 
3.3.3.3 
Pharmacodynamic Biomarker Outcome Measure 
Plasma PD biomarker outcome measure for this study is 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: 
BCVA: 
• 
Difference in mean BCVA change from baseline between the treatment-naïve 
patients and patients with previous IVT anti-VEGF (differential effect of 
RO6867461) 
• 
Proportion of patients with BCVA  69 letters (20/40 or better) over time 
• 
Proportion of patients with BCVA  ≥  84 letters (20/20 or better) over time 
Disease-related exploratory outcome measure: 
• 
Proportion of patients with DR severity improvement from baseline on the 
ETDRS-DRSS (diabetic retinopathy severity score) at Week 24 
 
Anatomic exploratory outcome measures: 
• 
Change from baseline in macular perfusion and leakage by  FFA at Week 12 
• 
Change from baseline in peripheral perfusion and leakage by FFA at Week 24 
 
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Durability-related exploratory outcome measures: 
• 
Time to increase of CST by  ≥ 50µm and/or loss of  ≥  5 letters of BCVA due to 
DME compared to values at Week 20  
• 
Time to treatment with 0.3 mg ranibizumab after Week 20 
 
 
 
 
 
 
 
 
 
 
4. 
MATERIALS AND METHODS 
4.1 
CENTERS 
This is a multicenter study to be conducted in the United States.  Additional site(s) in the 
United States will be included for back-up purposes and may be activated if needed.  
The site investigators will be qualified ophthalmologists/retinal specialists. 
Administrative and Contact Information and List of Investigators are provided separately.
4.2 
STUDY POPULATION 
4.2.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
Ocular criteria for study eye: 
• 
Macular edema associated with DR defined as macular thickening by spectral 
domain optical coherence tomography (SD-OCT) involving the center of the macula:  
CST of ≥ 325 μm with Spectralis (Heidelberg) at screening (where Spectralis is not 
available, the following devices and CST thresholds are acceptable:  CST ≥ 315 μm 
for Cirrus, CST ≥ 315 μm for Topcon, CST ≥ 295 μm for Optovue) 
• 
Decreased VA attributable primarily to DME, with BCVA letter score of 73−24 letters 
(inclusive) on ETDRS-like charts (20/40−20/320 Snellen equivalent) on Day 1 
• 
Clear ocular media and adequate pupillary dilatation to allow acquisition of good 
quality retinal images to confirm diagnosis 
 
General criteria: 
• 
Diagnosis of diabetes mellitus (DM; Type 1 or Type 2), as defined by the World 
Health Organization and/or American Diabetes Association 
• 
Able and willing to provide written informed consent and to comply with the study 
protocol according to International Conference on Harmonisation (ICH) and local 
regulations.  Alternatively, a legally authorized representative must be able to 
consent for the patient according to ICH and local regulations. 
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• 
Age ≥ 18 years 
• 
For women who are not postmenopausal (i.e. ≥ 12 months of non−therapy-induced 
amenorrhea, confirmed by FSH, if not on hormone replacement) 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 4 weeks after last dose. 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle 
of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception. 
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. 
• 
For men:  agreement to use a barrier method of contraception during the treatment 
period for at least 4 weeks after the last dose of study drug 
• 
Patients must be willing not to participate in any other clinical trial including an 
investigational medical 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: 
• 
Any signs of high-risk PDR defined as: 
o any vitreous or pre-retinal hemorrhage 
o NVE  ≥ 1/2 disc area within an area equivalent to the standard mydriatic 
ETDRS 7- field on clinical examination  
o NVD  ≥  1/3 disc area on clinical examination  
• 
Any IVT anti-VEGF treatment within 3 months prior to Day 1 
• 
Any panretinal photocoagulation (PRP) treatment prior to Day 1 
• 
Any macular laser photocoagulation within 3 months prior to Day 1 
• 
History of vitreoretinal surgery 
• 
Any IVT or periocular corticosteroid treatment within 3months prior to Day 
1, .  Any history of Iluvien or Ozurdex implants prior to Day 1 will not be 
permitted 
• 
Any cataract surgery or treatment for complications of cataract surgery with steroids 
within 3 months prior to Day 1 
• 
History of incisional glaucoma surgery 
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• 
Uncontrolled glaucoma (e.g., progressive loss of visual fields or defined as IOP 
≥ 25 mmHg despite treatment with anti-glaucoma medication) 
 
Concurrent ocular conditions in the study eye: 
• 
History of rubeosis  
• 
Any current or history of ocular disease other than DME that may confound 
assessment of the macula or affect central vision (e.g., AMD, retinal vein occlusion, 
uveitis, angioid streaks, histoplasmosis, active or inactive cytomegalovirus, 
pathological myopia, retinal detachment, macular traction, macular hole, significant 
cataract) 
• 
Any current ocular condition for which, in the opinion of the investigator, visual 
acuity loss would not improve from resolution of macular edema (e.g., foveal 
atrophy, pigment abnormalities, dense sub-foveal hard exudates, non-retinal 
condition) 
• 
Any active ocular infection on Day 1 
• 
Any active intraocular inflammation (grade trace or above) on Day 1 
 
Characteristics for fellow eye: 
• 
Any anti-VEGF treatment within 7 days prior to Day 1 
• 
Any retinal condition that, in the opinion of the investigator, might require anti-VEGF 
treatment within 7 days from Day 1 
 
General criteria: 
• 
Any systemic anti-VEGF within 6 months prior to Day 1 
• 
Any major illness or major surgical procedure within 1 month prior to Day 1 
• 
Any febrile illness within 1 week prior to Day 1 
• 
Any stroke or myocardial infarction within 12 months prior to Day 1 
• 
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 needs to be 
controlled by antihypertensive medication, the patient should be taking the same 
medication continuously for at least 1 month prior to Day 1. 
• 
Patients with glycosylated hemoglobin HbA1c > 12% at screening 
• 
Untreated diabetes mellitus or initiation of oral anti-diabetic medication or insulin 
within 4 months prior to Day 1 or anticipated change of anti-diabetic medications 
within the duration of the study 
• 
Renal failure requiring renal transplant, hemodialysis, or peritoneal dialysis within 
6 months prior to Day 1 or anticipated to require hemodialysis or peritoneal dialysis 
at any time during the study 
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• 
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 IMP 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 female 
• 
Use of systemic corticosteroids within 1 month prior to Day 1 
• 
Any known hypersensitivity to active comparator, fluorescein, any ingredient of the 
formulation used, dilating eye drops, or any anesthetics and microbial drops used 
• 
Any other restriction accorded to the use of the active comparator 
• 
Any treatment with IMP in the 3 months prior to Day 1 
 
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 (see Section 4.2.1 and Section 4.2.2) at the 
screening or Day 1 visit (as defined for each individual criterion in Section 4.2 and below) 
prior to randomization and first study treatment (see Section 4.6.7.1).  As part of the 
screening process, FP, FFA, 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. 
Only one eye will be selected as the study eye.  See Section 4.6.7.1 for details. 
After all patient eligibility requirements are confirmed on Day 1 visit (see Section 4.2), 
including: 
• 
Baseline BCVA letter score of 73 to 24 letters (inclusive) in the study eye 
• 
Absence of active intraocular inflammation in the 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). 
Treatment naïve patients will be randomized in a 1:1:1 ratio to one of the arms A, B and 
C, respectively. Patients previously treated with IVT anti-VEGF will be randomized in 
a 1:1 ratio to arms A and C.: 
• 
Arm A:  0.3 mg ranibizumab IVT  
• 
Arm B:  1.5 mg RO6867461 IVT  
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• 
Arm C:  6 mg RO6867461 IVT  
 
This study will consist of a treatment period (20 weeks) and an observational period (up 
to 16 weeks), for a total study length of up to 36 weeks. During the treatment period, 
the study drug will be administered to the patients on Day 1 and on every 4th week, for 
a total of 6 injections. During the observational period, patients will be evaluated every 
4th week.  If during any of these evaluations the patients meet the pre-specified criteria 
(see Section 4.3.1.1), the patients will receive a single dose of 0.3 mg ranibizumab and 
exit the study. They will receive a follow up phone call 7 days after the dose of 
ranibizumab to evaluate any potential adverse events. Otherwise, patients will exit the 
study once they have completed the observational visit at week 36.   
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.,  
Day 1 through week 20), the IxRS will assign the appropriate study treatment kit to be 
used. 
Randomization will be stratified for the factor below: 
• 
Baseline BCVA ETDRS letter score assessed on Day 1 (64 letters or better vs. 
63 letters or worse) 
• 
Previous Macular Laser treatment (Yes/No) 
• 
Previous IVT anti-VEGF treatment in study eye (Yes/No) 
 
Randomization with fixed permuted blocks will be used to obtain an approximate equal 
allocation  ratio between the different arms within each stratum. 
4.3.1.1 
Criteria for Treatment with Ranibizumab during 
Observational Period  
At each visit following the last dose of study treatment (week 20 visit), BCVA will be 
assessed and SD-OCT imaging will be performed (except for week 26 visit).  
BCVA and CST values obtained at week 24 will be compared to those obtained at visit 
week 20. BCVA and CST values obtained at weeks 28, 32 and 36 will be compared to 
those of week 24. 
If the patient meets both of the following criteria the patient should receive a single dose 
of 0.3 mg ranibizumab and will exit the study.: 
• 
CST increased by ≥ 50 µm 
• 
BCVA decreased by ≥ 5 letters due to DME 
 
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4.3.2 
Treatment Administration Procedure 
Study drug will be administered IVT.  The procedures are detailed in Appendix 3 and the 
Pharmacy Manual. Ranibizumab during the observational period should be 
administered as per local practice.  
At the discretion of the investigator, the sites may use either propacaine- or 
tetracaine-based ophthalmic drops, subconjunctival injection of lidocaine or lidocaine gel.  
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.   
Patients, study site personnel (with the exception of the pharmacist or designated 
personnel), BCVA examiners, vendors, Central Reading Center personnel, and the 
Sponsor and its agents (with the exception of drug accountability monitors and as 
defined in Section 4.3.3) will be masked to study drug assignment. 
There should be a minimum of two investigators per site to fulfill the masking 
requirements of this study.  At least one investigator will be designated as the assessor 
physician who will be masked to patients’ study drug 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 
could be unmasked to patients’ study drug assignment and will administer study 
treatment (RO6867461, ranibizumab). 
If only one investigator is available due to limited staffing resources, study drug 
administration can also be done by the assessing physician. In that case the treatment 
administrator physician(s) must not be involved in any aspects of un-masked study 
drug preparation. The preparation of the study drug must be done by trained staff 
under strict sterile condition. Detailed instructions for preparation are available in the 
pharmacy manual. 
The Principal Investigator must be masked to the patient’s treatment assignment.  All 
roles for each study staff member should be clearly documented in the site delegation 
log.  The delegation log should be signed by the Principal Investigator. An unmasked 
personnel cannot switch to a masked role, but a masked personnel can switch to an 
unmasked role. Any change should 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 
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assessor physician) for the duration of the study.  The treatment administrator 
physician(s) performing the study drug administration must not divulge study drug 
assignment to anyone. 
 The number of unmasked study personnel should be limited to ensure the integrity of 
this masked study.  There should 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 the Sponsor. 
For the duration of the study, the patient study drug assignment will not be unmasked 
unless required for patient safety. 
All study visit assessments, except those at screening, should be performed by masked 
site personnel only.  The treatment administrator physician performing the injection of 
study drug may also perform other assessments, including the post-injection 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 study drug 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 displays for the IMC 
meeting.Other Roche Study Management Team members will remain masked 
throughout the study. 
4.3.4 
Emergency Unmasking 
If complete unmasking is necessary for patient management (e.g., in the case of a 
serious adverse event), the investigator will be able to share the treatment code with the 
masked study personnel. Treatment codes should not be shared except in emergency 
situations. The Investigator should document all details and provide an explanation for 
any premature complete unmasking (e.g., accidental unmasking of non-Investigator 
study personnel or unmasking due to serious adverse events). 
Sponsor might become unmasked to study drug 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 
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4.4 
STUDY TREATMENT 
In this protocol, study drug includes IVT injections of RO6867461 and active comparator 
ranibizumab. 
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 
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 RO6867461 Investigator’s Brochure. 
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4.4.1.2 
Ranibizumab Active Comparator  
Ranibizumab (nominal content 0.3 mg/0.05 mL) required as comparator in this study will 
be provided by the Sponsor as a solution formulated at 6 mg/mL and supplied as a 
single-use vial. 
Ranibizumab packaging will be overseen by the Roche clinical trial supplies department 
and bear labels with the identification required by local law, the protocol number, drug 
identification, and strength. 
The packaging and labeling of ranibizumab will be in accordance with Roche standard 
and local regulations. 
Ranibizumab must be stored according to the details on the product label and the 
information provided in the Pharmacy Manual. 
Upon arrival of the masked investigational products at the site, site personnel should 
check them for damage and verify proper identity, quantity, integrity of seals, and 
temperature conditions and report any deviations or product complaints to the monitor. 
4.4.1.3 
Ranibizumab during Observational Period 
 
Ranibizumab will be provided by the Sponsor via the IxRS. Proper drug accountability 
will be performed by the site.   
4.4.2 
Dosage, Administration, and Compliance 
4.4.2.1 
RO6867461 and Ranibizumab 
Patients will be given 50 μL IVT injection of RO6867461 or ranibizumab into the study 
eye according the randomization schedule as described in the Overview of Study Design 
(see Section 3.1.1). 
• 
Arm A:  0.3 mg ranibizumab IVT  
• 
Arm B:  1.5 mg RO6867461 IVT  
• 
Arm C:  6 mg RO6867461 IVT  
The pharmacist or designee responsible for dispensing study drug will prepare the 
correct study drug (RO6867461 or ranibizumab), where applicable, as assigned by 
IxRS.  A fixed volume of 50 μL will be injected for all study drugs and doses. 
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. 
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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 
0.3 mg 
NA 
50 μL 
NA = not applicable; IVT = intravitreal. 
 
Detailed stepwise instructions for the preparation of RO6867461 or ranibizumab for 
administration and mandatory materials to be used will be provided by the Sponsor and 
are detailed in the Pharmacy Manual.  Pre- and post-study drug administration 
procedures as well as instructions for performing the IVT are provided in Appendix 3. 
A specified filter needle must be used for each dose preparation of RO6867461 or 
ranibizumab per the instructions provided in the Pharmacy Manual.  All materials to 
dilute/prepare and administer study drug 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, leftover 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] 
or 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 drugs under investigation.  Adequate 
records of the receipt (e.g., Drug Receipt Record) and disposition (e.g., Drug Dispensing 
Log) of the study drug must be maintained.  The Drug Dispensing Log must be kept 
current and should contain the following information: 
• 
The identification of the patient to whom the study drug was dispensed (for example, 
patient initials and date of birth) 
• 
The date(s) and quantity of the study drug dispensed to the patient 
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• 
All records and drug supplies must be available for inspection by the Roche Monitor. 
 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site’s method of IMP destruction must be agreed upon by the 
Sponsor.  Local or institutional regulations may require immediate destruction of used 
investigational medicinal product for safety reasons.  In these cases, it may be 
acceptable for investigational study site staff to destroy dispensed investigational 
product 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, destroyed and provided that adequate storage 
and integrity of drug has been confirmed. 
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Written documentation of destruction must contain the following: 
• 
Identity kit numbers of investigational products destroyed 
• 
Quantity of investigational products 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 Drug Inventory Log. 
 
4.4.4 
Post-Trial Access to RO6867461 
RO6867461 is an IMP product which safety and tolerability is under evaluation in an 
indication where SoC treatments are available.  Patients will not be allowed access to 
RO6867461 after study completion. 
4.5 
CONCOMITANT THERAPY 
Concomitant therapy includes any medication, e.g., prescription drugs, over-the-counter 
(OTC) drugs, approved dietary and herbal supplements, nutritional supplements used by 
a patient from within 30 days of study screening until the follow-up visit.  Patients who 
use maintenance therapy other than those required to treat DME should continue its use. 
All concomitant medications should be reported to the investigator and recorded on the 
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All therapy and/or medication administered to manage adverse events should be 
recorded on the Adverse Event eCRF. 
4.5.1 
Permitted Therapy 
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). 
PRP is permitted in either eye, if clinically indicated for the treatment of proliferative 
diabetic retinopathy or retinal holes or tears post randomization.  PRP should be 
recorded on the Adverse Event eCRF in the event it qualifies for worsening of DR, as 
defined in Section 5.3.5.9.
4.5.2 
Prohibited Therapy 
All medications (prescription and OTC) taken within 30 days of study screening will be 
recorded on the appropriate eCRF. 
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 anti-VEGF therapy for the fellow eye within 7 days preceding 
or following the study eye treatment 
• 
Concurrent use of IVT or subtenon corticosteroids in study eye, except as required 
to treat adverse events 
 
4.5.3 
Emergent/Recurrent Diabetic Macular Edema in the Fellow Eye 
Should DME emerge or recur and require treatment in the fellow eye during the study 
period, the patient may receive anti-VEGF SoC treatment.  Fellow eye treatment, if 
required, must be administered at least 7 days preceding or following the study eye 
treatment. 
 
 
 
 
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4.6 
STUDY ASSESSMENTS  
All examinations listed below will be performed according to the SoAs outlined in 
Appendix 1. 
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, definitely, 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.Optional IOP measurement at screening (with Tono-pen) 
Pupil dilation 
7-field or wide-field color FP 
Enhanced depth imaging (EDI) SD-OCT  
7-field or wide-field FFA  
Slit-lamp examination 
Dilated binocular indirect high-magnification ophthalmoscopy 
IOP (mandatory to be performed after all imaging assessments).  The method 
of IOP measurement (either Goldmann tonometer or Tono-pen) used should be 
recorded in the source document 
 
 and must remain the same throughout the 
study.
 
 
 
Imaging assessments (FP, EDI SD-OCT, FFA) will be performed for study eye only, 
except at screening where either eye has a potential to meet all eligibility criteria. 
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, 
and all medications (e.g., prescription drugs, OTC drugs, herbal or homeopathic 
remedies, nutritional supplements) used by the patient within 30 days prior to the 
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screening visit and within the screening period (other than reported as 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 timepoints indicated in the SoA (see 
Appendix 1).  Physical examination will include body weight at screening and either final 
or early termination visit and height at screening. 
The 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 Systemic Medical 
History 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 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 timepoints specified in the SoA (see 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, by 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 or borderline. 
4.6.1.4 
Electrocardiograms 
Triplicate 12-lead ECG (i.e., three useful ECGs without artifacts) will be collected at the 
timepoints specified in SoA.  To minimize variability, it is important that patient be in a 
resting position for at least 10 minutes prior to the 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. 
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Should the timepoints 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 by 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. 
Central Reading Center will transfer the relevant ECG characteristics (including heart 
rate, PQ [PR], QRS, QT, T, and U abnormalities; and RR, QTcB, and QTcF will be 
derived) and overall interpretation directly to the Sponsor.  Overall ECG interpretation 
will be documented on the eCRF by investigators or designees. 
4.6.1.5 
Laboratory Assessments 
Laboratory safety tests shall be collected at timepoints specified in the SoA, Details on 
sampling and procedures will be provided in supporting central and/or local Laboratory 
Manual.  
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. 
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        
Activated partial thromboplastin time (aPTT) and prothrombin 
time/International Normalized Ratio (PT/INR). 
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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), 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, in particular when blood or protein is positive or strong 
positive. 
Hormone panel  
(at screening only) 
For females, FSH and estradiol. 
Pregnancy test  
(at screening only) 
For females of childbearing potential, serum or plasma pregnancy 
test. 
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 
 
 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. 
This specimen will be destroyed once all results have been obtained. 
4.6.1.6 
Anti-Drug Antibody Assessments 
Details on sampling procedures, sample storage, and shipment are given in the 
supporting documentation/Lab Manual. 
Blood samples will be obtained for measurement of anti-RO6867461 antibodies by a 
validated ELISA.  Samples from patients receiving ranibizumab will be taken per the 
RO6867461 schedule to maintain the double-masked design of the study but will not be 
analyzed for ADA. 
Any residual material from ADA samples may be used for additional exploratory 
biomarker profiling, identification, assay development purposes, and assay validation 
during the development of the study or compound-related assays after the mentioned 
intended uses. 
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4.6.5 
Disease-Specific Assessments 
Except when noted otherwise (e.g., see SoA [Appendix 1] and below), 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 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. 
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The following ocular imaging assessments will be obtained for the study eye only, except 
at screening where either eye has a potential to meet all eligibility criteria, and will be 
forwarded to the Central Reading Center: 
• 
7-field or wide-field color FP 
• 
EDI SD-OCT  
• 
7-field FFA or wide-field FFA 
• 
 At study visit when different imaging assessments coincide, they should be 
obtained on the same day. 
 
4.6.5.1 
Ocular Safety Assessments 
Ocular assessments will be performed as detailed in the SoA (see Appendix 1): 
• 
BCVA using the ETDRS-like charts (see Section 4.6.5.2); performed prior to dilating 
eyes 
• 
Slit-lamp examination (scales for grading flare/cells and vitreous hemorrhage 
density are detailed in Appendix 2) 
• 
Dilated binocular indirect high-magnification ophthalmoscopy 
• 
Retinal imaging:  FP (including but not limited to DR severity grading), SD-OCT, and 
FFA.  Images will be forwarded to the Central Reading Center for grading and 
storage. 
• 
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.  The method of IOP measurement (either 
Goldmann tonometry or Tono-pen) used must remain the same throughout the 
study.   
• 
Assessment of ocular perfusion performed as soon as possible, but not later than 
15 minutes post-treatment by using finger counting, hand movement, or light 
perception, as appropriate 
 
4.6.5.2 
Efficacy and Pharmacodynamic Assessments 
Efficacy and PD assessments will be performed as detailed in the SoA (see Appendix 1) 
and will include functional (BCVA), imaging assessments (FP, SD-OCT, FFA), and 
plasma PD biomarkers.  
Additional PD sampling (e.g., where unscheduled PK sample is collected) and functional 
or imaging assessments can be performed at unscheduled visits at the discretion of the 
investigator (Section 4.6.7.5). 
4.6.5.2.1 
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 drug arm assignment. 
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BCVA will be measured by using the set of three Precision VisionTM or Lighthouse 
distance acuity charts (modified ETDRS Charts 1, 2, and R).  A VA 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 study eye and treatment assignment and will 
only perform the refraction and BCVA assessment (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 the patient’s refraction data from previous 
visits. The BCVA examiner is not allowed to perform any other tasks involving direct 
patient care. 
4.6.5.2.2 
Fundus Photography 
Seven-field or wide-field FP will be performed at the study sites by trained and Central 
Reading Center-certified personnel. Where both 7-field and wide-field devices are 
available, wide-field FP should be performed.  It is mandatory that the same device is 
used for the entire duration of the study. 
FP images might include red-free, color, and infra-red, as further specified in the Central 
Reading Center Manual. 
4.6.5.2.3 
Enhanced Depth Imaging Spectral Domain Optical Coherence 
Tomography  
Enhanced Depth Imaging 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.  Where Spectralis is not available at an investigational site, Cirrus, 
Topcon, or Optovue are acceptable devices.  It is mandatory that the same device is 
used for the entire duration of the study. 
Images should be acquired and transferred to the Central Reading Center according to 
specifications provided in the separate Central Reading Center Manual. 
4.6.5.2.4 
Fundus Fluorescein Angiography 
Seven-field FFA (30 degree field of view) or wide-field FFA (e.g., Optos, Spectralis) will 
be performed at all the study sites by trained and Central Reading Center-certified 
personnel.  Where both devices are available, wide-field FFA should be performed.  It is 
mandatory that the same device is used for the entire duration of the study. 
Images should be acquired and transferred to the Central Reading Center according to 
specifications provided in the Central Reading Center Manual. 
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4.6.5.2.5 
Plasma Pharmacodynamic Biomarkers 
Samples for plasma PD biomarkers will be taken at the time-points detailed in the SoA 
(see Appendix 1).  The following analyses will be performed: 
• 
Change from baseline in plasma levels of VEGF and Ang-2 
 
Any residual material from PD biomarker 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 samples will be destroyed up to 2 years after the final closure of the 
database and all intended data have been verified. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.6.6 
Amount of Blood to be Collected throughout the Study 
Throughout the study, a total of approximately 185 mL of blood will be drawn from each 
patient, to perform clinical laboratory assessments, determine plasma concentrations 
and perform genetic and PD/exploratory assessments. 
4.6.7 
Timing of Study Assessments 
4.6.7.1 
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 
for enrolled patient and for patients who are not subsequently enrolled will be maintained 
at the study site. 
All screening and pretreatment assessments must be completed and reviewed to 
confirm that patients meet all eligibility criteria, including Central Reading Center 
confirmation of eligibility for a predefined set of imaging criteria, and defined list of Day 1 
assessments (see below).  The investigator will maintain a screening log to record 
details of all patients screened and to confirm eligibility or record reasons for screening 
failure. 
Only one eye will be selected as the study eye.  Where both eyes meet all eligibility 
criteria, the eye with worse BCVA will be defined as the study eye.  Where both eyes 
meet all eligibility criteria and have the same BCVA letter score at Day 1, study eye 
selection is at the investigator’s discretion. 
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 examination within 4 weeks before study drug 
administration.  The list of screening procedures is outlined in the SoA (see Appendix 1) 
After the screening visit, ocular images of both eyes will be forwarded as soon as 
possible to the Central Reading Center for those patients who meet all non-ocular 
eligibility criteria (eligibility for safety labs, ECG, and pregnancy test, where appropriate, 
might be pending).  The Central Reading Center will assess the image data submitted 
and confirm eligibility for study eye imaging criteria.  Confirmation of eligibility by the 
Central Reading Center for the study eye imaging criteria is required. 
On Day 1 prior to enrollment, all patient eligibility requirements are reviewed, and 
relevant eligibility criteria (Section 4.2) are confirmed, including but not limited to the 
following criteria: 
• 
Baseline BCVA letter score of 73 to 24 letters (inclusive) in the study eye 
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• 
Absence of active intraocular inflammation in the study eye 
• 
Absence of febrile illness within one week prior to Day 1, 
 
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. 
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 reasons (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. If patients meet criteria upon re-screening, they will 
receive a new screening number and will be treated as a new patient. 
 For each patient, if one eye does not meet eligibility criteria, then the second eye may 
be evaluated within the initial screening period. If the second eye meets the eligibility 
criteria, then the patient would retain the same screening number and would not be 
screened-failed. 
4.6.7.2 
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 SoAs (see Appendix 1). 
Patients will receive their first IVT injection of either RO6867461 or comparator therapy 
into the study eye according to the randomization schedule and following established 
standard procedures.  Patients will return to the eye clinic for study drug administration 
(every 4 weeks) and assessments as outlined in the SoA.   
This study will consist of a treatment period (20 weeks) and an observational period (up 
to 16 weeks), for a total study length of up to 36 weeks. During the treatment period, 
the study drug will be administered to the patients on Day 1 and on every 4th week, for 
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4.6.7.4 
Assessments at Final Visit 
Patients will return to the investigational site every 4 weeks up to week 36 during 
observation period after their final dose of study drug at week 20. 
If during any of these evaluations the patients meet the pre-specified criteria (see 
Section 4.3.1.1), the patients will receive a single dose of 0.3 mg ranibizumab, exit the 
study, and receive a follow up phone call 7 days after the dose of ranibizumab to 
evaluate any potential adverse events. Otherwise, patients will exit the study once they 
have completed the observational visit at week 36.    
 
 
 
After the final visit, adverse events should be followed up as outlined in Section 5.6. 
4.6.7.5 
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 a patient from study drug or withdraw a 
patient from the study at any time.  In addition, patients have the right to voluntarily 
discontinue study drug or withdraw from the study at any time for any reason.  Reasons 
for discontinuation of study drug 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’s non-compliance 
 
4.7.1.1 
Discontinuation from Study Drug 
Patients must discontinue study drug if they experience any of the following: 
• 
Pregnancy 
• 
Drop in BCVA by ≥ 30 letters if considered to be adverse and related to study drug 
treatment in the study eye (compared with the last assessment of VA prior to the 
most recent treatment) and lasting more than 1 hour 
• 
Endophthalmitis in the study eye 
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• 
Severe intraocular inflammation (i.e., 4 + anterior chamber cell/flare or 4 + vitritis; see 
the definitions of intraocular inflammation in Section 5.3.5 and grading scales for 
assessment in Appendix 2. 
• 
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 drug prematurely will be asked to return to the clinic for 
an early termination visit (as defined in Section 4.6.7.3) and will undergo assessments 
as outlined in the SoA.  The primary reason for premature study drug 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 the consent has 
been withdrawn (see Section 4.6.7.3). 
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. 
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 GCP 
 
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5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, 
including serious adverse events (systemic and ocular), non-serious adverse events of 
special interest; 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 GCP, an adverse event is any untoward medical 
occurrence in a clinical investigation patient administered a pharmaceutical product, 
regardless of causal attribution.  An adverse event can therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.8 and 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 drug or concomitant 
treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study drug (e.g., screening invasive procedures 
such as angiographies) 
 
5.1.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Fatal (i.e., the adverse event actually causes or leads to death) 
• 
Life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
• 
This does not include any adverse event that had it occurred in a more severe form 
or was allowed to continue might have caused death 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.10) 
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• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an adverse event (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 adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.1.3 
 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 
in a patient exposed to a medicinal product.  This term applies only when a 
contamination of the study drug is suspected. 
• 
The Safety Science Responsible for the program is accountable for determining the 
non-serious Adverse Events of Special Interest (AESI) for a protocol. 
 
5.1.4 
Sight-Threatening Adverse Events (Immediately Reportable to 
the Sponsor) 
An adverse event 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 
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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 2). 
• 
In the opinion of the investigator, it may require medical intervention to prevent 
permanent loss of sight. 
 
5.2 
SAFETY PLAN 
Based on the first-in-human Study BP28936 and ongoing Phase 2 Study BP29647, 
there have been no safety signals.  The majority of adverse events were of mild and 
moderate intensity.  No deaths occurred during the study period, and no premature 
withdrawals from the study as a result of serious adverse events were reported. 
To 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, FP, and SD-OCT assessments), adverse event 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 adverse events (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 Section 5.4−5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.1.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record.  Adverse events will then be reported on the 
Adverse Event eCRF as follows: 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported 
(e.g., serious adverse events related to invasive procedures such as angiographies).  
Any other adverse event should not be reported. 
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After initiation of study drug through the final visit, all adverse events, regardless of 
relationship to study drug, will be reported. 
After the final visit and/or subsequent follow-up phone call, as applicable, investigators 
should report any deaths, serious adverse events, or other adverse events of concern 
that are believed to be related to prior treatment with study drug (see Section 5.6) 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?” 
 
5.3.3 
Assessment of Severity of Adverse Events 
Table 3 provides guidance for assessing adverse event severity. 
Table 3 
Adverse Event Severity Grading Scale 
Severity 
Description 
Mild 
Discomfort noticed, but no disruption of normal daily activity 
Moderate 
Discomfort sufficient to reduce or affect normal daily activity 
Severe 
Incapacitating with inability to work or to perform normal daily activity 
Note:  Regardless of severity, some events may also meet seriousness criteria.  Refer to 
definition of a serious adverse event (see Section 5.1.2). 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an adverse event is considered to be related to the study drug, indicating “yes” or 
“no” accordingly.  The following guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment−related factors that are known to be associated with the 
occurrence of the event 
 
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5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
For the purposes of reporting events of infection and inflammation of the eye, the 
following terms and definitions should be used. 
• 
Iritis:  the presence of inflammatory cells in the anterior chamber 
The presence of aqueous flare alone will not constitute iritis but should be 
documented as an anterior chamber flare for adverse event reporting purposes. 
• 
Iridocyclitis:  the presence of inflammatory cells in both the aqueous and vitreous 
• 
Vitritis:  the presence of active inflammation in the vitreous, demonstrated by the 
presence of inflammatory cells (trace or greater) 
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 RBCs or WBCs or the result of any ocular disorder should 
not be recorded as an adverse event.  Only one adverse event term should be recorded 
in the event field on the Adverse Event eCRF. 
5.3.5.1 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
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5.3.5.2 
Adverse Events Occurring Secondary to Other Events 
In general, adverse events 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 adverse events 
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 adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity 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 adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded 
separately on the Adverse Event eCRF. 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
should be reported as an adverse event if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study drug (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 adverse event. 
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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 adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should 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 adverse event.  A vital sign result should 
be reported as an adverse event if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study drug (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 
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., 
high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on the 
Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should 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 
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causes of hyperbilirubinemia is considered to be an indicator of severe liver injury.  
Therefore, investigators must report, as an adverse event, the occurrence of either of the 
following: 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
 
5.3.5.7 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of DME. 
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. 
5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors (e.g., 
“more frequent headaches”). 
5.3.5.9 
Worsening of Diabetic Macular Edema or Diabetic Retinopathy 
Medical occurrences or symptoms of deterioration that are anticipated as part of DME or 
DR should be recorded as an adverse event if judged by the investigator to have 
unexpectedly worsened in severity or frequency or changed in nature at any time during 
the study.  When recording an unanticipated worsening of DME or DR on the Adverse 
Event eCRF, it is important to convey the concept that the condition has changed by 
including applicable descriptors (e.g., “accelerated DME”). 
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5.3.5.10 
Hospitalization or Prolonged Hospitalization  
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious 
adverse event in Section 5.1.2), except as outlined below. 
The following hospitalization scenarios are not considered to be serious adverse events: 
• 
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 adverse event. 
 
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 adverse event, unless it results in untoward medical effects. 
Any study drug overdose or incorrect administration of study drug should be noted on 
the Additional Observation eCRF. 
All adverse events associated with an overdose or incorrect administration of study drug 
should be recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
serious 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 drug: 
• 
Serious adverse events 
• 
non-serious adverse events of special interest 
• 
Sight-threatening adverse events 
• 
Pregnancies 
 
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The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
To ensure the safety of study patients, access to the Medical monitors is available 
24 hours a day 7 days a week.  Medical monitors contact details are listed in the 
“Protocol Administrative and Contact Information & List of Investigators.” 
5.4.2 
Reporting Requirements for Serious Adverse Events 
Non-Serious Adverse Events of Special Interest, and Sight-
Threatening Adverse Events  
For reports of serious adverse events, non-serious adverse events of special interest , 
and sight-threatening adverse events (see Sections 5.1.2 and 5.1.3), investigators 
should record all case details that can be gathered on the Serious Adverse Reporting 
Form and forward this form to the Serious Adverse Event Responsible within 24 hours. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 3 months after the last 
dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed by 
the investigator and submitted to the Sponsor within 24 hours after 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. 
5.4.3.2 
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).
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5.4.3.3 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.  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 5.4.3. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, non-serious adverse events of special interest, sight-
threatening adverse events, and pregnancies, the Sponsor or a designee may follow up 
by telephone, fax, electronic mail, and/or a monitoring visit to obtain additional case 
details and outcome information (e.g., from hospital discharge summaries, consultant 
reports, autopsy reports) in order to perform an independent medical assessment of the 
reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
The investigator is not required to actively monitor patients for adverse events after the 
end of the adverse event reporting period (as defined in Section 5.3.1).  However, the 
Sponsor should be notified if the investigator becomes aware of any death, any other 
serious adverse event, or sight-threatening adverse events 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. 
 
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5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and sight-threatening 
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 the test product 
will be submitted to health authorities. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
6.1 
DETERMINATION OF SAMPLE SIZE 
The sample size is based on the primary efficacy outcome of mean change in BCVA 
from baseline at Week 24 in the treatment-naïve patients.  Each RO6867461 dose 
(Arms B and C) will be compared with the control group (Arm A). 
Consider 50 treatment-naïve patients randomized to Arms A, B, and C, with a drop-out 
rate of 10%.  Assuming a standard deviation of 11 letters, this sample size provides 80% 
power to detect a true difference of 5 letters at the one-sided α level of 10%.  The 
minimum detectable difference is approximately 3 letters. 
Approximately 60 previously IVT anti-VEGF treated patients will be enrolled in 
addition for exploratory analyses. 
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. 
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6.3 
ANALYSIS POPULATIONS 
6.3.1 
Safety Analysis Population 
All patients who have received at least one dose of the study drug, whether prematurely 
withdrawn from the study or not, will be included in the safety analysis. Patients will be 
grouped according to the actual treatment received.  
6.3.2 
Efficacy, Pharmacokinetic, and Pharmacodynamic Analysis 
Population 
All patients who have received at least one dose of the study drug will be included in the 
efficacy, PK, and PD analysis population, with patients grouped according to the 
treatment assigned at randomization.  
6.4 
DEFINITION OF BASELINE 
The baseline measurement is the latest non-missing observation before the first dose of 
study treatment. 
6.5 
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. 
6.6 
SAFETY ANALYSES 
All safety analyses will be based on the safety analysis population. 
6.6.1 
Adverse Events 
The original terms recorded on the eCRF by the investigator for adverse events will be 
standardized by the Sponsor. 
Adverse events will be summarized by mapped term and appropriate thesaurus level. 
6.6.2 
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 by 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. 
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6.6.2.1 
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 
that include AST, ALT, and alkaline phosphatase and total bilirubin.  Since 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. 
6.6.2.2 
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. 
6.6.3 
Vital Signs 
Vital sign 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. 
6.6.4 
Electrocardiogram 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. 
6.6.5 
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. 
6.6.6 
Ocular Assessments 
Results of the following ocular assessments will be summarized by timepoint using 
descriptive summaries:  BCVA, IOP, slit-lamp examination, indirect ophthalmoscopy, 
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FFA, FP, SD-OCT, and changes from baseline in these measurements will be tabulated.  
The presence of intraocular inflammation (see the definitions of intraocular inflammation 
in Section 5.3.5) and vitreous hemorrhage, as determined from the slit-lamp 
examination, will be tabulated by grade (according to grading scales for flare/cells and 
vitreous hemorrhage density; see Appendix 2). 
6.6.7 
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. 
6.7 
EFFICACY ANALYSES 
The primary and secondary efficacy analyses will include all randomized treatment-
naïve patients, with patients grouped according to the treatment assigned at 
randomization.  Patients with previous IVT anti-VEGF will be analyzed separately. 
Unless there is strong evidence for RO6867461 effect modification by previous IVT 
anti-VEGF, analyses will be repeated in all randomized patients. 
6.7.1 
Primary Efficacy Endpoint 
The primary efficacy variable is the BCVA change from baseline at Week 24.  The 
primary efficacy analysis will be performed using a Mixed Model for Repeated 
Measurement (MMRM) model.  The model will include the categorical covariates of 
treatment group, visit, and visit by treatment group interaction and the continuous 
covariate of baseline BCVA.  An unstructured covariance will be used to account for 
within-patient correlation, but another variance-covariance structure 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 and C) 
and the control group (Arm A) for mean BCVA change from baseline at Week 24 in the 
treatment-naïve patient population .  The model-based estimate of the difference 
between each of the treatment group (Arms B and C) and the control group (Arm A) at 
Week 24, together with 95% confidence and corresponding p-value will be reported as 
the primary efficacy measures in this population.  The mean and 95% CI within each 
treatment group and for the difference between RO6867461 treatment groups (Arms B 
and C) and the control group (Arm A) at the other time points will also be reported.  
There will be no formal correction for multiple testing. 
6.7.2 
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.  
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For binary endpoints, the 95% CI 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. 
Time to event endpoints will be tested with a two-sided stratified log rank test using 
the randomization stratification factors BCVA ETDRS letter score (64 letters or better 
vs. 63 letters or worse) and previous macular laser treatment as strata. Kaplan Meier 
curves will be displayed, and median time to event estimates and confidence limits of 
them will be computed. 
Effect modification will be tested by adding a previous IVT anti-VEGF treatment status, 
treatment arm by visit interaction, and a treatment arm by visit by previous IVT anti-
VEGF treatment status interaction terms to the above MMRM model. The treatment 
arm by visit by previous IVT anti-VEGF treatment status interaction term will be 
tested at a 10% type I error rate. 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
6.9 
PHARMACOKINETIC ANALYSES 
A non-linear mixed effects modeling approach (with NONMEM software [Beal and 
Sheiner 1998]) will be used to analyze the concentration-time data of RO6867461.  
Population and individual primary PK parameters (i.e., clearances and volumes) will be 
estimated, and the influence of various covariates (e.g., gender, body weight, 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.  
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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. 
6.10 
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. 
6.11 
INTERIM ANALYSES 
Two efficacy analyses to inform about possible future development options for 
RO6867461 are foreseen.  They will not influence the study conduct.  One interim 
efficacy analysis is foreseen after approximately 28 treatment-naïve patients in each 
treatment have completed the Week 24 visit and another one when approximately all 
patients have completed their Week 24 visit.  A safety analysis will be performed if safety 
issues have been identified during ongoing review of the masked data.  
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. 
The Sponsor will produce a Data Handling Manual that describes the quality checking to 
be performed on the data.  Central laboratory and reading center 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. 
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7.2 
ELECTRONIC CASE REPORT FORMS  
Data for this study will be captured via an on line 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 Principal Investigator 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. 
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. 
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To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The 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 Principal Investigator for at least 15 years 
after completion or discontinuation of the study or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of time, 
the documents may be destroyed, subject to local regulations.  No records may be 
disposed of without the written approval of the Sponsor.  Written notification should be 
provided to the Sponsor prior to transferring any records to another party or moving 
them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for GCP and 
the principles of the Declaration of Helsinki or the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the 
individual.  The study will comply with the requirements of the ICH E2A guideline 
(Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).  
Studies conducted in the United States or under a U.S. Investigational New Drug (IND) 
application will comply with U.S. Food and Drug Administration (FDA) regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union 
(E.U.)/European Economic Area will comply with the E.U. Clinical Trial Directive 
(2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form will be provided to each site.  If 
applicable, it will be provided in a certified translation of the local language.  The 
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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. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  In 
addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
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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). 
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 
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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 in the United States 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 storage of laboratory samples (e.g., anti-
RO6867461 antibody samples) prior to being shipped to Sponsor or its designee for 
analysis.  Central reading will be used for ECG interpretation, and for ocular imaging 
analyses (FP, FFAs, SD-OCT).  Data will be recorded by an EDC system using eCRFs 
(Section 7.2) or 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 
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. 
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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. 
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Protocol BP30099     Report Number 1083913
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RO6
86/Proto
867461—F. Hoffmann-La Roche Ltd 
col BP30099, Version 3 
Hermann MM, van Asten F, Muether PS, et al. Polymorphisms in vascular endothelial 
growth factor receptor 2 are associated with better response rates to ranibizumab 
treatment in age-related macular degeneration. Ophthalmology 2014;121:905−10. 
International Diabetes Federation (IDF). IDF Diabetes Atlas, 6th ed. 2013 [cited 
06 October 2015]. Available from: www.idf.org/diabetesatlas 
Investigator’s Brochure RO6867461, version 4, November 2015. 
Kaul K, Hodgkinson A, Tarr JM, et al. Is inflammation a common retinal-renal-nerve 
pathogenic link in diabetes? Curr Diabetes Rev. 2010;6:294−303. 
 
Maisonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural antagonist for Tie2 
that disrupts in vivo angiogenesis. Science 1997;277:55−60. 
Mitchell P, Banello F, Schmidt-Erfurth U, et al. The RESTORE study. Ophthalmol 
2011;118:615−25. 
Nguyen QD, Brown D, Marcus DM, et al. Ranibizumab for diabetic macular edema. 
Ophthalmol 2012;119:789−801. 
Park SW, Yun JH, Kim JH, et al. Angiopoietin 2 induces pericyte apoptosis via α3β1 
integrin signaling in diabetic retinopathy. Diabetes 2014;63:93057−68. 
Rangasamy S, Srinivasan R, Maestas J, et al. A potential role for angiopoietin 2 in the 
regulation of the blood–retinal barrier in diabetic retinopathy. IOVS 2011; 52:3784–
91. 
Resnikoff S, Pascolini D, Etya’ale D, et al. Global data on visual impairment in the year 
2002. Bull World Health Organ 2004;82:844−51. 
Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: estimates for the year 
2000 and projections for 2030. Diabetes Care 2004;27:1047−53. 
 


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Appendix 1  
Schedule of Assessments 
 
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Appendix 2  
Grading Scale for Assessment of Anterior Chamber Flare or 
Cells, Vitreal Hemorrhage Density, and Vitreous Cells 
GRADING SCALE FOR ANTERIOR CHAMBER FLARE OR CELLS 
 
Flare 
No protein is visible in the anterior chamber when viewed by an experienced observer 
using slit-lamp biomicroscopy; a small, bright, focal slit-beam of white light; and high 
magnification. 
0 
Trace amount of protein is detectable in the anterior chamber:  This protein is visible only 
with careful scrutiny by an experienced observer using slit-lamp biomicroscopy; a small, 
bright, focal slit-beam of white light; and high magnification. 
Trace 
Slight amount of protein is detectable in the anterior chamber:  the presence of protein in 
the anterior chamber is immediately apparent to an experienced observer using slit-lamp 
biomicroscopy and high magnification, but such protein is detected only with careful 
observation with the naked eye and a small, bright, focal slit-beam of white light. 
1 +  
Moderate amount of protein is detectable in the anterior chamber.  These grades are 
similar to 1+ but the opacity would be readily visible to the naked eye of an observer 
using any source of a focused beam of white light.  This is a continuum of moderate 
opacification, with 2 + being less apparent than 3 + . 
2-3 +  
A large amount of protein is detectable in the anterior chamber.  This grade is similar to 
3 +  , but the density of the protein approaches that of the lens.  Additionally, frank fibrin 
deposition is frequently seen in acute circumstances.  It should be noted that because 
fibrin may persist for a period of time after partial or complete restoration of the 
blood−aqueous barrier, it is possible to have resorbing fibrin present with lower numeric 
assignations for flare (e.g., 1 + flare with fibrin). 
4 +  
Cells 
No cells are seen in any optical section when a large slit-lamp beam is swept across the 
anterior chamber. 
0 
Few (1−3) cells are observed when the slit-lamp beam is swept across the anterior 
chamber.  When the instrument is held stationary, not every optical section contains 
circulating cells. 
Trace 
 3−10 cells/optical section are seen when the slit-lamp beam is swept across the anterior 
chamber.  When the instrument is held stationary, every optical section contains 
circulating cells. 
1 +  
2 +  
10−25 cells are seen when the slit-lamp beam is swept across the anterior chamber. 
When the instrument is held stationary, every optical section contains circulating cells. 
25−50 cells are seen when the slit-lamp beam is swept across the anterior chamber.  
When the instrument is held stationary, every optical section contains circulating cells.  
Keratic precipitates or cellular deposits on the anterior lens capsule may be present. 
3 +  
4 +  
More than 50 cells are seen when the slit-lamp beam is swept across the anterior 
chamber.  When the instrument is held stationary, every optical section contains cells or 
hypopyon is noted.  As for fibrin deposition, hypopyon may persist for some period of 
time after the active exudation of cells into the anterior chamber has diminished or 
ceased entirely, making it possible to have 1+ circulating cells in the anterior chamber 
with a resolving hypopyon. 
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Appendix 2  
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 slit-lamp examination. 
1 +  
Retinal detail is visible; some hemorrhage is visible by ophthalmoscopy. 
Large retinal vessels are visible, but central retinal detail is not visible by 
ophthalmoscopy. 
2 +  
Red reflex is visible, but no central retinal detail is seen posterior to the equator by 
ophthalmoscopy. 
3 +  
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. 
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Appendix 3  
Study Treatment Administration Procedure 
1. PRE-INJECTION PROCEDURES 
The following procedures will be used to minimize the risk of potential adverse events 
associated with intravitreal (IVT) injections (e.g., endophthalmitis). 
Aseptic technique will be observed by clinic staff involved in the administration tray 
assembly, anesthetic preparation, and study treatment preparation and administration.  
In addition to the procedures outlined below, any additional safety measures in 
adherence to specific institutional policies associated with IVT injections will be observed. 
The above procedures (except where noted) will be conducted by the physician 
performing the IVT administration of study treatment.  At the discretion of the investigator, 
patients will 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 
• 
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 
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Appendix 3  
Study Treatment Administration Procedure (cont.) 
• 
The treatment administrator physician will wear a surgical face mask, put on gloves, 
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 
Physician must refrain from talking, coughing, or sneezing during the injection. 
 
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 wear a surgical face mask, put on gloves, 
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 
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Appendix 3  
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 
• 
Physician must refrain from talking, coughing, or sneezing during the injection. 
 
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 wear a surgical face mask, put on gloves, 
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 
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Appendix 3  
Study Treatment Administration Procedure (cont.) 
• 
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 
Physician must refrain from talking, coughing, or sneezing during the injection. 
 
5. INTRAVITREAL ADMINISTRATION OF STUDY TREATMENT 
Study drug must be prepared according to the detailed instructions in the Pharmacy 
Manual.  The instructions in the Pharmacy Manual cover all steps until the syringe is 
ready for treatment administration. 
After preparing the study eye as outlined above, 
• 
For RO6867461 or ranibizumab administration:  insert the needle 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 5 for detailed 
post-injection procedures 
 
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. 
 
 
 
 
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Protocol  BP30099 
1 
AMENDMENT HISTORY FOR PROTOCOL BP30099, VERSION 3 
 
1. 
SUBJECT:  TITLE  
REASON FOR CHANGE:    
The title has been updated from a 28 week to a 36 week study to reflect the changes to 
the protocol. 
 
2. 
SUBJECT:  PROTOCOL SYNOPSIS  
REASON FOR CHANGE:    
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
 
3. 
SUBJECT: INCREASE OF SAMPLE SIZE 
REASON FOR CHANGE:  
The text has been amended to include the recruitment of patients who have been 
previously treated with IVT anti-VEGF and to increase the sample size from 150 to 210 
patients. The original sample size of 150 patients across the 3 arms was selected based 
on the primary efficacy outcome of mean change in BCVA from baseline at week 24 in 
treatment-naïve patients. However, it is not known if previously treated patients would 
benefit in the same way from RO6867461 treatment. To maintain the power of 80% to 
detect a true difference of 5 letters at the one-sided α level of 10%, 60 previously treated 
patients will be added to the original study sample of 150 treatment-naïve patients. 
These previously treated patients will be divided between the comparator arm A and the 
high dose RO6867461 arm C.  
 
SECTION 3.1.2 NUMBER OF PATIENTS 
New text: 
Up to 210 patients will be randomized. Approximately 150 treatment-naïve patients and 
approximately 60 patients who have been previously treated with IVT anti-VEGF will 
be enrolled in the study.  Approximately 50 treatment-naïve patients will be randomized 
oninto each arm (1:1:1 randomization scheme).) and approximately 30 patients 
previously treated with IVT anti-VEGF will be randomized into arms A and C. 
Old text: 
Approximately 150 patients will be enrolled in the study.  Approximately 50 patients will 
be randomized on each arm (1:1:1 randomization scheme). 
 


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SECTION 6.1 DETERMINATION OF SAMPLE SIZE  
New text: 
The sample size is based on the primary efficacy outcome of mean change in BCVA 
from baseline at Week 24. in the treatment-naïve patients.  Each RO6867461 dose 
(Arms B and C) will be compared with the control group (Arm A). 
Consider 50 treatment-naïve patients randomized to Arms A, B, and C, with a drop-out 
rate of 10%.  Assuming a standard deviation of 11 letters, this sample size provides 80% 
power to detect a true difference of 5 letters at the one-sided α level of 10%.  The 
minimum detectable difference is approximately 3 letters. 
Approximately 60 previously IVT anti-VEGF treated patients will be enrolled in 
addition for exploratory analyses 
Old text: 
The sample size is based on the primary efficacy outcome of mean change in BCVA 
from baseline at Week 24.  Each RO6867461 dose (Arms B and C) will be compared 
with the control group (Arm A). 
Consider 50 patients randomized to Arms A, B, and C, with a drop-out rate of 10%.  
Assuming a standard deviation of 11 letters, this sample size provides 80% power to 
detect a true difference of 5 letters at the one-sided α level of 10%.  The minimum 
detectable difference is approximately 3 letters. 
 
4. 
SUBJECT:   INCLUSION OF PREVIOUSLY IVT ANTI-VEGF 
TREATED PATIENTS 
REASON FOR CHANGE:    
Inclusion of patients previously treated with IVT anti-VEGF therapy will enable the 
exploratory evaluation of the predictive effect of previous IVT anti-VEGF treatment on 
the efficacy of RO6867461. The results of these evaluations will inform late stage 
development and influence the design of phase 3 studies that will include previously 
treated patients. 
SECTION  1.3. STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT  
New text: 
This will be a Phase II proof-of concept study in anti VEGF treatment naive patients with 
center-involving DME (CI-DME).  This study is designed to evaluate the effects of 
RO6867461 on visual function and retinal structure by assessing changes from baseline 
in BCVA (ETDRS letters) and anatomy (imaging procedures), respectively.  In addition, 
the safety, tolerability, and pharmacokinetics will be evaluated in patients receiving up to 
6 doses of RO6867461. 


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3 
Old text: 
None  
 
SECTION   2.1. PRIMARY OBJECTIVE,  
New text: 
The primary objective of this study is: 
• 
To evaluate the efficacy of RO6867461 compared with the active comparator in 
treatment naïve patients with CI-DME.  
Old text: 
The primary objective of this study is: 
• 
To evaluate the efficacy of RO6867461 compared with the active comparator in 
patients with CI-DME 
 
SECTION   2.3. EXPLORATIVE OBJECTIVE,  
New text: 
The exploratory objectives for this study are as follows: 
• 
To explore the predictive effect of previous IVT anti-VEGF treatment on efficacy of 
RO6867461 
• 
To evaluate the efficacy and safety of RO6867461 compared with the active 
comparator in patients with CI-DME with previous IVT anti-VEGF treatment. 
• 
 
 
• 
 
 
 
• 
To evaluate improvement in DR severity score 
Old text: 
The exploratory objectives for this study are as follows: 
• 
 
 
• 
 
 
 
• 
To evaluate improvement in DR severity score 
 
SECTION   3.1.3 INTERNAL MONITORING COMMITTEE,  
New text: 
A Roche Internal Monitoring Committee (IMC) will be responsible in the event of an 
interim analysis of efficacy for operational/administrative/study related purposes and/or 


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Protocol  BP30099 
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for safety data monitoring.  Two efficacy analyses are foreseen, one after approximately 
28 treatment naïve patients in each treatment arm have completed the Week 24 visit, 
and one when approximately all patients have completed the Week 24 visit.  A safety 
analysis may be performed if safety issues have been identified during ongoing review of 
the masked data. 
Old text: 
A Roche Internal Monitoring Committee (IMC) will be responsible in the event of an 
interim analysis of efficacy for operational/administrative/study related purposes and/or 
for safety data monitoring.  Two efficacy analyses are foreseen, one after approximately 
28 patients in each treatment arm have completed the Week 24 visit, and one when 
approximately all patients have completed the Week 24 visit.  A safety analysis may be 
performed if safety issues have been identified during ongoing review of the masked 
data.  
 
SECTION   3.2.2. RATIONALE FOR STUDY POPULATION,  
New text: 
This study will be conducted in patients with vision loss due to DME who meet all of the 
inclusion criteria and do not meet any of the exclusion criteria for this protocol (see 
Section 4.2.1 and Section 4.2.2). 
Both treatment naïve DME patients and prior IVT anti-VEGF treated DME patients 
will be included.  The aim is to evaluate the efficacy of RO6867461 compared with the 
active comparator in treatment naïve patients with CI-DME. Inclusion of treatment 
naïve and previously anti-VEGF treated patients will enable the exploratory evaluation 
of the predictive effect of previous IVT anti-VEGF treatment on efficacy of RO6867461. 
Old text: 
This study will be conducted in patients with vision loss due to DME who meet all of the 
inclusion criteria and do not meet any of the exclusion criteria for this protocol (see 
Section 4.2.1 and Section 4.2.2). 
 
SECTION   3.2.3 RATIONALE FOR CONTROL GROUP,  
New text: 
This study is an interventional superiority study aiming to evaluate the efficacy of 
RO6867461, as compared with standard of care anti-VEGF therapy in anti VEGF 
treatment naive patients with DME.  Anti-VEGF therapy is a well-established SoC in 
patients with DME, and placebo, sham injection, or macular laser are no longer an 
ethically acceptable alternative given the improvements in visual and anatomic 
outcomes associated with anti-VEGF treatment. 


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5 
Old text: 
This study is an interventional superiority study aiming to evaluate the efficacy of 
RO6867461, as compared with standard of care anti-VEGF therapy in anti-VEGF 
treatment-naive patients with DME.  Anti-VEGF therapy is a well-established SoC in 
patients with DME, and placebo, sham injection, or macular laser are no longer an 
ethically acceptable alternative given the improvements in visual and anatomic 
outcomes associated with anti-VEGF treatment. 
 
SECTION   3.3.3 EFFICACY AND PHARMACODYNAMICS OUTCOME 
MEASURES,  
New text: 
The primary analysis population will be treatment naïve patients. Additional analyses 
may be performed in the overall population and in patients previously treated with IVT 
anti-VEGF. 
Old text: 
None  
 
SECTION   3.3.3.1. PRIMARY EFFICACY OUTCOME MEASURE, 
New text: 
The primary efficacy outcome measure is the mean change in BCVA (ETDRS letters) 
from baseline in BCVA at Week 24 by using the ETDRS modified chartsin treatment-
naïve patients. 
Old text: 
The primary efficacy outcome measure is the mean change from baseline in BCVA at 
Week 24 by using the ETDRS-modified charts. 
 
SECTION   3.3.4. EXPLORATORY OUTCOME MEASURES, 
New text: 
The exploratory outcome measures for this study include but are not limited to the 
following: 
BCVA: 
• 
Difference in mean BCVA change from baseline between the treatment-naïve 
patients and patients with previous IVT anti-VEGF (differential effect of 
RO6867461) 
• 
Proportion of patients with BCVA   ≥ 69 letters (20/40 or better) over time 
• 
Proportion of patients with BCVA   ≥  84 letters (20/20 or better) over time 


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Disease-related exploratory outcome measure: 
• 
Proportion of patients with DR severity improvement from baseline on the 
ETDRS-DRSS (diabetic retinopathy severity score) at Week 24 
 
Anatomic exploratory outcome measures: 
• 
Change from baseline in macular perfusion and leakage by  FFA at Week 12 
• 
Change from baseline in peripheral perfusion and leakage by FFA at Week 24 
 
Durability-related exploratory outcome measures: 
• 
Time to increase of CST by ≥  50µm and/or loss of  ≥  5 letters of BCVA due to 
DME compared to values at Week 20  
• 
Time to treatment with 0.3 mg ranibizumab after Week 20 
 
 
 
 
 
 
 
 
 
 
Old text: 
The exploratory outcome measures for this study include but are not limited to the 
following: 
Disease-related exploratory outcome measure: 
• 
Proportion of patients with DR severity improvement from baseline on the 
ETDRS-DRSS (diabetic retinopathy severity score) at Week 24 
 
Anatomic exploratory outcome measures: 
• 
Change from baseline in macular perfusion and leakage by  FFA at Week 12 
• 
Change from baseline in peripheral perfusion and leakage by FFA at Week 24 
 
 
 
 
 
 
 
 
 
 
 


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SECTION   4.2.2. EXCLUSION CRITERIA,  
New text: 
Patients who meet any of the following criteria will be excluded from study entry: 
Ocular criteria for study eye: 
• 
Any signs of high-risk PDR defined as: 
o any vitreous or pre-retinal hemorrhage 
o NVE   ≥  1/2 disc area within an area equivalent to the standard 
mydriatic ETDRS 7- field on clinical examination  
o NVD   ≥   1/3 disc area on clinical examination  
• 
Any IVT anti-VEGF treatment within 3 months prior to Day 1 
• 
Any panretinal photocoagulation (PRP) treatment prior to Day 1 
• 
Any macular laser photocoagulation within 3 months prior to Day 1 
• 
History of vitreoretinal surgery 
• 
Any IVT, or periocular corticosteroid, or corticosteroid implants  treatment  within 
3months prior to Day 1, except for management.  Any history of complication of 
cataract surgeryIluvien or Ozurdex implants prior to Day 1 will not be permitted 
• 
Any cataract surgery or treatment for complications of cataract surgery with steroids 
within 3 months prior to Day 1 
• 
History of incisional glaucoma surgery 
• 
Uncontrolled glaucoma (e.g., progressive loss of visual fields or defined as 
IOP ≥ 25 mmHg despite treatment with anti-glaucoma medication) 
 
Concurrent ocular conditions in the study eye: 
• 
History of rubeosis in the study eye 
• 
Any current or history of ocular disease in the study eye other than DME that may 
confound assessment of the macula or affect central vision (e.g., AMD, retinal vein 
occlusion, uveitis, angioid streaks, histoplasmosis, active or inactive 
cytomegalovirus, pathological myopia, retinal detachment, macular traction, macular 
hole, significant cataract) 
• 
Any current ocular condition for which, in the opinion of the investigator, visual 
acuity loss would not improve from resolution of macular edema (e.g., foveal 
atrophy, pigment abnormalities, dense sub-foveal hard exudates, non-retinal 
condition) 
• 
Any active ocular infection in the study eye aton Day 1 
• 
Any active intraocular inflammation (grade trace or above) in the study eye aton 
Day 1 
 
Characteristics for fellow eye: 
• 
Any anti-VEGF treatment for a retinal condition within 7 days prior to Day 1 


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• 
Any retinal condition that, in the opinion of the investigator, might require anti-VEGF 
treatment within 7 days from Day 1 
 
General criteria: 
• 
Any systemic anti-VEGF within 6 months prior to Day 1 
• 
Any major illness or major surgical procedure within 1 month prior to Day 1 
• 
Any febrile illness within 1 week prior to Day 1 
• 
Any stroke or myocardial infarction within 12 months prior to Day 1 
• 
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 
needs to be controlled by antihypertensive medication, the patient can become 
eligible ifshould be taking the same medication is taken continuously for at least 1 
month prior to Day 1. 
• 
Patients with glycosylated hemoglobin HbA1c ≥ 12% at screening 
• 
Untreated diabetes mellitus or initiation of oral anti-diabetic medication or insulin 
within 4 months prior to Day 1 or anticipated change of anti-diabetic medications 
within the duration of the study 
• 
Renal failure requiring renal transplant, hemodialysis, or peritoneal dialysis within 
6 months prior to Day 1 or anticipated to require hemodialysis or peritoneal dialysis 
at any time during the study 
• 
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 IMP 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 female 
• 
Use of systemic corticosteroids within 1 month prior to Day 1 
• 
Any known hypersensitivity to active comparator, fluorescein, any ingredient of the 
formulation used, dilating eye drops, or any anesthetics and microbial drops used 
• 
Any other restriction accorded to the use of the active comparator 
• 
Any treatment with IMP in the 3 months prior to Day 1 
 


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Old text: 
Patients who meet any of the following criteria will be excluded from study entry: 
Ocular criteria for study eye: 
• 
Any PDR 
• 
Any IVT anti-VEGF treatment prior to Day 1 
• 
Any panretinal photocoagulation (PRP) treatment prior to Day 1 
• 
Any macular laser photocoagulation within 3 months prior to Day 1 
• 
History of vitreoretinal surgery 
• 
Any IVT, periocular corticosteroid, or corticosteroid implants treatment prior to Day 1, 
except for management of complication of cataract surgery 
• 
Any cataract surgery or treatment for complications of cataract surgery with steroids 
within 3 months prior to Day 1 
• 
History of incisional glaucoma surgery 
• 
Uncontrolled glaucoma (e.g., progressive loss of visual fields or defined as IOP 
≥ 25 mmHg despite treatment with anti-glaucoma medication) 
 
Concurrent ocular conditions: 
• 
History of rubeosis in the study eye 
• 
Any current or history of ocular disease in the study eye other than DME that may 
confound assessment of the macula or affect central vision (e.g., AMD, retinal vein 
occlusion, uveitis, angioid streaks, histoplasmosis, active or inactive 
cytomegalovirus, pathological myopia, retinal detachment, macular traction, macular 
hole, significant cataract) 
• 
Any active ocular infection in the study eye at Day 1 
• 
Any active intraocular inflammation (grade trace or above) in the study eye at Day 1 
 
Characteristics for fellow eye: 
• 
Any anti-VEGF treatment for a retinal condition within 7 days prior to Day 1 
• 
Any retinal condition that, in the opinion of the investigator, might require anti-VEGF 
treatment within 7 days from Day 1 
 
General criteria: 
• 
Any systemic anti-VEGF within 6 months prior to Day 1 
• 
Any major illness or major surgical procedure within 1 month prior to Day 1 
• 
Any febrile illness within 1 week prior to Day 1 
• 
Any stroke or myocardial infarction within 12 months prior to Day 1 
• 
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 30 or more minutes later.  If the patient’s BP needs 


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to be controlled by antihypertensive medication, the patient can become eligible if 
medication is taken continuously for at least 1 month prior to Day 1. 
• 
Patients with glycosylated hemoglobin HbA1c > 12% at screening 
• 
Untreated diabetes mellitus or initiation of oral anti-diabetic medication or insulin 
within 4 months prior to Day 1 or anticipated change of anti-diabetic medications 
within the duration of the study 
• 
Renal failure requiring renal transplant, hemodialysis, or peritoneal dialysis within 
6 months prior to Day 1 or anticipated to require hemodialysis or peritoneal dialysis 
at any time during the study 
• 
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 IMP 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 female 
• 
Use of systemic corticosteroids within 1 month prior to Day 1 
• 
Any known hypersensitivity to active comparator, fluorescein, any ingredient of the 
formulation used, dilating eye drops, or any anesthetics and microbial drops used 
• 
Any other restriction accorded to the use of the active comparator 
• 
Any treatment with IMP in the 3 months prior to Day 1 
 
SECTION   4.3.1. TREATMENT ASSIGNMENT,   
New text: 
Patients Treatment naïve patients will be randomized in a 1:1:1 ratio to one of the study 
drug arms:arms A, B and C, respectively. Patients previously treated with IVT anti-
VEGF will be randomized in a 1:1 ratio to arms A and C.: 
• 
Arm A:  0.3 mg ranibizumab IVT every 4 weeks for 24 weeks (7 injections) 
• 
Arm B:  1.5 mg RO6867461 IVT every 4 weeks for 20 weeks (6 injections), followed 
by 1 sham administration at Week 24 
• 
Arm C:  6 mg RO6867461 IVT every 4 weeks for 20 weeks (6 injections), followed 
by 1 sham administration at Week 24 
 
This study will consist of a treatment period (20 weeks) and an observational period (up 
to 16 weeks), for a total study length of up to 36 weeks. During the treatment period, 
the study drug will be administered to the patients on Day 1 and on every 4th week, for 
a total of 6 injections. During the observational period, patients will be evaluated every 
4th week.  If during any of these evaluations the patients meet the pre-specified criteria 
(see Section 4.3.1.1), the patients will receive a single dose of 0.3 mg ranibizumab and 


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exit the study. They will receive a follow up phone call 7 days after the dose of 
ranibizumab to evaluate any potential adverse events. Otherwise, patients will exit the 
study once they have completed the observational visit at week 36.   
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 through week 20), the IxRS will assign the appropriate study treatment 
kit to be used. 
Randomization will be stratified for the factor below: 
• 
Baseline BCVA ETDRS letter score assessed on Day 1 (64 letters or better vs. 
63 letters or worse) 
• 
Previous Macular Laser treatment (Yes/No) 
• 
Previous IVT anti-VEGF treatment in study eye (Yes/No) 
 
Randomization with fixed permuted blocks will be used to obtain an approximate 
1:1:1equal allocation  ratio between the different arms within each stratum. 
 
Old text: 
Patients will be randomized in a 1:1:1 ratio to one of the study drug arms: 
• 
Arm A:  0.3 mg ranibizumab IVT every 4 weeks for 24 weeks (7 injections) 
• 
Arm B:  1.5 mg RO6867461 IVT every 4 weeks for 20 weeks (6 injections), followed 
by 1 sham administration at Week 24 
• 
Arm C:  6 mg RO6867461 IVT every 4 weeks for 20 weeks (6 injections), followed 
by 1 sham administration at Week 24 
 
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 factor below: 
• 
Baseline BCVA ETDRS letter score assessed on Day 1 (64 letters or better vs. 
63 letters or worse) 
• 
Previous Macular Laser treatment (Yes/No) 
 
Randomization with fixed permuted blocks will be used to obtain an approximate 
1:1:1 ratio between the different arms within each stratum. 
 


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SECTION   6.1. DETERMINATION OF SAMPLE SIZE, 
New text: 
The sample size is based on the primary efficacy outcome of mean change in BCVA 
from baseline at Week 24. in the treatment-naïve patients.  Each RO6867461 dose 
(Arms B and C) will be compared with the control group (Arm A). 
Consider 50 treatment-naïve patients randomized to Arms A, B, and C, with a drop-out 
rate of 10%.  Assuming a standard deviation of 11 letters, this sample size provides 80% 
power to detect a true difference of 5 letters at the one-sided α level of 10%.  The 
minimum detectable difference is approximately 3 letters. 
Approximately 60 previously IVT anti-VEGF treated patients will be enrolled in 
addition for exploratory analyses. 
 
Old text: 
The sample size is based on the primary efficacy outcome of mean change in BCVA 
from baseline at Week 24.  Each RO6867461 dose (Arms B and C) will be compared 
with the control group (Arm A). 
Consider 50 patients randomized to Arms A, B, and C, with a drop-out rate of 10%.  
Assuming a standard deviation of 11 letters, this sample size provides 80% power to 
detect a true difference of 5 letters at the one-sided α level of 10%.  The minimum 
detectable difference is approximately 3 letters. 
 
SECTION   6.7. EFFICACY ANALYSES,  
New text: 
The primary and secondary efficacy analyses will include all randomized treatment-
naïve patients, with patients grouped according to the treatment assigned at 
randomization.  Patients with previous IVT anti-VEGF will be analyzed separately. 
Unless there is strong evidence for RO6867461 effect modification by previous IVT 
anti-VEGF, analyses will be repeated in all randomized patients. 
 
Old text: 
The primary and secondary efficacy analyses will include all randomized patients, with 
patients grouped according to the treatment assigned at randomization. 
 
SECTION   6.7.1 PRIMARY EFFICACY ENDPOINT  
New text: 
The primary efficacy variable is the BCVA change from baseline at Week 24.  The 
primary efficacy analysis will be performed using a Mixed Model for Repeated 
Measurement (MMRM) model.  The model will include the categorical covariates of 


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treatment group, visit, and visit by treatment group interaction and the continuous 
covariate of baseline BCVA.  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 and C) 
and the control group (Arm A) for mean BCVA change from baseline at Week 24. in the 
treatment-naïve patient population .  The model-based estimate of the difference 
between each of the treatment group (Arms B and C) and the control group (Arm A) at 
Week 24, together with 95% confidence and corresponding p-value will be reported as 
the primary efficacy measures in this population.  The mean and 95% CI within each 
treatment group and for the difference between RO6867461 treatment groups (Arms B 
and C) and the control group (Arm A) at the other timepointstime points will also be 
reported.  There will be no formal correction for multiple testing. 
Old text: 
The primary efficacy variable is the BCVA change from baseline at Week 24.  The 
primary efficacy analysis will be performed using a Mixed Model for Repeated 
Measurement (MMRM) model.  The model will include the categorical covariates of 
treatment group, visit, and visit by treatment group interaction and the continuous 
covariate of baseline BCVA.  An unstructured covariance 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 and C) 
and the control group (Arm A) for mean BCVA change from baseline at Week 24.  The 
model-based estimate of the difference between each of the treatment group (Arms B 
and C) and the control group (Arm A) at Week 24, together with 95% confidence and 
corresponding p-value will be reported as the primary efficacy measures in this 
population.  The mean and 95% CI within each treatment group and for the difference 
between RO6867461 treatment groups (Arms B and C) and the control group (Arm A) at 
the other timepoints will also be reported.  There will be no formal correction for multiple 
testing. 
 
SECTION   6.11 INTERIM ANALYSIS  
New text: 
Two efficacy analyses to inform about possible future development options for 
RO6867461 are foreseen.  They will not influence the study conduct.  The firstOne 
interim efficacy analysis is foreseen after approximately 28 treatment-naïve patients in 
each treatment have completed the Week 24 visit and the secondanother one when 
approximately all patients have completed their Week 24 visit.  A safety analysis will be 
performed if safety issues have been identified during ongoing review of the masked 
data.  


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Old text: 
Two efficacy analyses to inform about possible future development options for 
RO6867461 are foreseen.  They will not influence the study conduct.  The first interim 
efficacy analysis is foreseen after approximately 28 patients in each treatment have 
completed the Week 24 visit and the second one when approximately all patients have 
completed their Week 24 visit.  A safety analysis will be performed if safety issues have 
been identified during ongoing review of the masked data.  
 
5. 
SUBJECT:   CHANGE IN STUDY DESIGN 
REASON FOR CHANGE:    
The study design was modified to enable the evaluation of whether the durability of 
effect is longer following treatment with RO6867461 than with ranibizumab, as measured 
by BCVA and SD-OCT. The original study design consisted of a fixed assessment at 8 
weeks after the last dose. The new design will add an additional observational period of 
up to 16 weeks. During this period, once the patient meets pre-specified criteria, they will 
be provided with a single dose of 0.3mg of Ranibizumab, which is the current standard-
of-care for DME. This approach will provide informative data for the phase 3 study 
design (inclusion of Q8W, Q12W, or Q16W arm). 
 
SECTION   3.1. DESCRIPTION OF STUDY,  
New text: 
This is a multiple-center, multiple-dose, randomized, active comparator−controlled, 
double-masked, three parallel group, 2836-week study in patients with CI-DME. 
Old text: 
This is a multiple-center, multiple-dose, randomized, active comparator−controlled, 
double-masked, three parallel group, 28-week study in patients with CI-DME. 
 
SECTION   3.1.1. OVERVIEW OF THE STUDY DESIGN,  
New text: 
The three groups of this study are as follows (see Figure 1): 
• 
Arm A:  0.3 mg ranibizumab IVT every 4 weeks for 24 weeks (7 injections) 
• 
Arm B:  1.5 mg RO6867461 IVT every 4 weeks for 20 weeks (6 injections), followed 
by 1 sham administration at Week 24 
• 
Arm C:  6 mg RO6867461 IVT every 4 weeks for 20 weeks (6 injections), followed 
by 1 sham administration at Week 24 
This study will consist of a treatment period (20 weeks) and an observational period (up 
to 16 weeks), for a total study length of up to 36 weeks. During the treatment period, 
the study drug will be administered to the patients on Day 1 and on every 4th week, for 
a total of 6 injections. During the observational period, patients will be evaluated every 


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4th week.  If during any of these evaluations the patients meet the pre-specified criteria 
(see Section 4.3.1.1), the patients will receive a single dose of 0.3 mg ranibizumab, and 
exit the study. They will receive a follow up phone call 7 days after the dose of 
ranibizumab to evaluate any potential adverse events. Otherwise, patients will exit the 
study once they have completed the observational visit at week 36.   
Only one eye will be selected as the study eye (see Section 4.3.1). 
Figure 1 Study Design 
 
 
 
Q4W = every 4 weeks. 
 
The total duration of the study for each patient will be up to 3240 weeks, divided as 
follows (see Figure 1Figure 1): 
• 
Screening:  upUp to 4 weeks 
• 
Baseline:  Day 1 
• 
Study treatment administration:  from period:  From Day 1 to Week 2420 


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• 
Final safety and efficacyObservational period:  From Week 20 up to Week 2836 
• 
Safety follow up call: During the observational period and 7 days after 
ranibizumab administration  
 
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 the Schedule of Assessments (SoA; see Appendix 1), are 
completed. 
If a site has an unexpected issue (e.g., the 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 unmasked and masked 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. 
Old text: 
The three groups of this study are as follows (see Figure 1): 
• 
Arm A:  0.3 mg ranibizumab IVT every 4 weeks for 24 weeks (7 injections) 
• 
Arm B:  1.5 mg RO6867461 IVT every 4 weeks for 20 weeks (6 injections), followed 
by 1 sham administration at Week 24 
• 
Arm C:  6 mg RO6867461 IVT every 4 weeks for 20 weeks (6 injections), followed 
by 1 sham administration at Week 24 
 
Only one eye will be selected as the study eye (see Section 4.3.1). 
The total duration of the study for each patient will be up to 32 weeks, divided as follows 
(see Figure 1): 
• 
Screening:  up to 4 weeks 
• 
Baseline:  Day 1 
• 
Study treatment administration:  from Day 1 to Week 24 
• 
Final safety and efficacy period:  up to Week 28 
 
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 the Schedule of Assessments (SoA; see Appendix 1), are 
completed. 
If a site has an unexpected issue (e.g., the 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 unmasked and masked investigators at 
the site), the patient’s study treatment may be administered within 3 working days of the 


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scheduled treatment visit with the Medical Monitor’s permission.  The interval between 
two study treatment administrations needs to be at least 21 days. 
 
SECTION   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 2836 weeks after the last patient is enrolled. 
Old text: 
The end of the study is defined as the date when the last patient last observation (LPLO) 
occurs.  LPLO is expected to occur 28 weeks after the last patient is enrolled. 
 
SECTION   3.3.3.2. SECONDARY EFFICACY OUTCOME MEASURES,  
New text: 
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 BCVA at Week 24 
• 
Proportion of patients with BCVA  ≥ 69 letters (20/40 or better) at Week 24 
• 
Proportion of patients with BCVA  ≥ 84 letters (20/20 or better) at Week 24 
• 
Mean change in BCVA from baseline to Week 28  
Anatomic outcome measures by SD-OCT: 
• 
Mean change from baseline in foveal center point thickness at Week 24 and 28 
• 
Mean change from baseline in mean CST (1 mm diameter) at Week 24 and 28 
• 
Proportion of patients with resolution of subretinal and intraretinal fluid at Week 24 
and 28 
 
Anatomic outcome measures by FFA: 
• 
Proportion of patients with resolution of leakage at the macula at Week 24 
• 
Change from baseline in the size of the foveal avascular zone at Week 24 
Old text: 
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 BCVA at Week 24 
• 
Proportion of patients with BCVA ≥ 69 letters (20/40 or better) at Week 24 
• 
Proportion of patients with BCVA ≥ 84 letters (20/20 or better) at Week 24 
• 
Mean change in BCVA from baseline to Week 28  


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Anatomic outcome measures by SD-OCT: 
• 
Mean change from baseline in foveal center point thickness at Week 24 and 28 
• 
Mean change from baseline in mean CST (1 mm diameter) at Week 24 and 28 
• 
Proportion of patients with resolution of subretinal and intraretinal fluid at Week 24 
and 28 
 
Anatomic outcome measures by FFA: 
• 
Proportion of patients with resolution of leakage at the macula at Week 24 
• 
Change from baseline in the size of the foveal avascular zone at Week 24 
 
SECTION   3.3.4 EXPLORATORY OUTCOME MEASURES,  
New text: 
The exploratory outcome measures for this study include but are not limited to the 
following: 
BCVA: 
• 
Difference in mean BCVA change from baseline between the treatment-naïve 
patients and patients with previous IVT anti-VEGF (differential effect of 
RO6867461) 
• 
Proportion of patients with BCVA   ≥ 69 letters (20/40 or better) over time 
• 
Proportion of patients with BCVA   ≥  84 letters (20/20 or better) over time 
Disease-related exploratory outcome measure: 
• 
Proportion of patients with DR severity improvement from baseline on the 
ETDRS-DRSS (diabetic retinopathy severity score) at Week 24 
 
Anatomic exploratory outcome measures: 
• 
Change from baseline in macular perfusion and leakage by  FFA at Week 12 
• 
Change from baseline in peripheral perfusion and leakage by FFA at Week 24 
 
Durability-related exploratory outcome measures: 
• 
Time to increase of CST by   ≥  50µm and/or loss of   ≥   5 letters of BCVA due to 
DME compared to values at Week 20  
• 
Time to treatment with 0.3 mg ranibizumab after Week 20 
 
 
 
 
 
 


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Old text: 
The exploratory outcome measures for this study include but are not limited to the 
following: 
Disease-related exploratory outcome measure: 
• 
Proportion of patients with DR severity improvement from baseline on the 
ETDRS-DRSS (diabetic retinopathy severity score) at Week 24 
 
Anatomic exploratory outcome measures: 
• 
Change from baseline in macular perfusion and leakage by  FFA at Week 12 
• 
Change from baseline in peripheral perfusion and leakage by FFA at Week 24 
 
 
 
 
 
 
 
 
 
 
 
SECTION   4.3.1 TREATMENT ASSIGNMENT,  
New text: 
Patients Treatment naïve patients will be randomized in a 1:1:1 ratio to one of the study 
drug arms:arms A, B and C, respectively. Patients previously treated with IVT anti-
VEGF will be randomized in a 1:1 ratio to arms A and C.: 
• 
Arm A:  0.3 mg ranibizumab IVT every 4 weeks for 24 weeks (7 injections) 
• 
Arm B:  1.5 mg RO6867461 IVT every 4 weeks for 20 weeks (6 injections), followed 
by 1 sham administration at Week 24 
• 
Arm C:  6 mg RO6867461 IVT every 4 weeks for 20 weeks (6 injections), followed 
by 1 sham administration at Week 24 
 
 
This study will consist of a treatment period (20 weeks) and an observational period (up 
to 16 weeks), for a total study length of up to 36 weeks. During the treatment period, 
the study drug will be administered to the patients on Day 1 and on every 4th week, for 
a total of 6 injections. During the observational period, patients will be evaluated every 
4th week.  If during any of these evaluations the patients meet the pre-specified criteria 
(see Section 4.3.1.1), the patients will receive a single dose of 0.3 mg ranibizumab and 
exit the study. They will receive a follow up phone call 7 days after the dose of 


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ranibizumab to evaluate any potential adverse events. Otherwise, patients will exit the 
study once they have completed the observational visit at week 36.   
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 through week 20), the IxRS will assign the appropriate study treatment 
kit to be used. 
Randomization will be stratified for the factor below: 
• 
Baseline BCVA ETDRS letter score assessed on Day 1 (64 letters or better vs. 
63 letters or worse) 
• 
Previous Macular Laser treatment (Yes/No) 
• 
Previous IVT anti-VEGF treatment in study eye (Yes/No) 
 
Randomization with fixed permuted blocks will be used to obtain an approximate 
1:1:1equal allocation  ratio between the different arms within each stratum. 
Old text: 
Patients will be randomized in a 1:1:1 ratio to one of the study drug arms: 
• 
Arm A:  0.3 mg ranibizumab IVT every 4 weeks for 24 weeks (7 injections) 
• 
Arm B:  1.5 mg RO6867461 IVT every 4 weeks for 20 weeks (6 injections), followed 
by 1 sham administration at Week 24 
• 
Arm C:  6 mg RO6867461 IVT every 4 weeks for 20 weeks (6 injections), followed 
by 1 sham administration at Week 24 
 
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 factor below: 
• 
Baseline BCVA ETDRS letter score assessed on Day 1 (64 letters or better vs. 
63 letters or worse) 
• 
Previous Macular Laser treatment (Yes/No) 
 
Randomization with fixed permuted blocks will be used to obtain an approximate 
1:1:1 ratio between the different arms within each stratum. 
 
SECTION   4.3.1.1. CRITERIA FOR TREATMENT WITH RANIBIZUMAB 
DURING OBSERVATIONAL PERIOD,  
New text: 
At each visit following the last dose of study treatment (week 20 visit), BCVA will be 
assessed and SD-OCT imaging will be performed (except for week 26 visit).  


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BCVA and CST values obtained at week 24 will be compared to those obtained at visit 
week 20. BCVA and CST values obtained at weeks 28, 32 and 36 will be compared to 
those of week 24. 
If the patient meets both of the following criteria the patient should receive a single dose 
of 0.3 mg ranibizumab and will exit the study.: 
• 
CST increased by ≥ 50 µm 
• 
BCVA decreased by ≥ 5 letters due to DME 
Old text: 
None 
 
SECTION   4.4 STUDY TREATMENT,  
New text: 
In this protocol, study treatmentdrug includes IVT injections of study drugs (RO6867461 
and active comparator ranibizumab) and sham administration.  The latter is used to 
maintain double masking on Arms B and C on Week 24 visit. 
Old text: 
In this protocol, study treatment includes IVT injections of study drugs (RO6867461 and 
active comparator ranibizumab) and sham administration.  The latter is used to maintain 
double-masking on Arms B and C on Week 24 visit. 
 
SECTION   4.4.1.3 RANIBIZUMAB DURING OBSERVATIONAL PERIOD,  
New text: 
Ranibizumab will be provided by the Sponsor via the IxRS. Proper drug accountability 
will be performed by the site.   
Old text: 
None 
 
SECTION   4.4.1.3 SHAM 
New text: 
None 
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 the study drug-filled syringe (Appendix 4)  Empty boxes 
identical to the other study treatment boxes will be supplied for sham administration. 


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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. 
 
SECTION   4.4.2.1. RO6867461 AND RANIBIZUMAB,  
New text: 
Patients will be given 50 µL IVT injection of RO6867461 or ranibizumab into the study 
eye or a sham administration according the randomization schedule as described in the 
Overview of Study Design (see Section 3.1.1.). 
• 
Arm A:  0.3 mg ranibizumab IVT every 4 weeks for 24 weeks (7 injections) 
• 
Arm B:  1.5 mg RO6867461 IVT every 4 weeks for 20 weeks (6 injections), followed 
by 1 sham administration at Week 24 
• 
Arm C:  6 mg RO6867461 IVT every 4 weeks for 20 weeks (6 injections),  followed 
by 1 sham administration at Week 24 
 
The pharmacist or designee responsible for dispensing study treatmentdrug will prepare 
the correct study treatmentdrug (RO6867461, or ranibizumab or sham), where 
applicable, as assigned by IxRS.  A fixed volume of 50 µL will be injected for all study 
drugs and doses. 
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. 
Table 1 
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 
0.3 mg 
NA 
50 µL 
NA 
 not applicable; IVT 
 intravitreal. 
 
Detailed stepwise instructions for the preparation of RO6867461, or 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-study treatmentdrug 
administration procedures as well as instructions for performing the IVT are provided in 
Appendix 4 3. 
A specified filter needle must be used for each dose preparation of RO6867461 or 
ranibizumab per the instructions provided in the Pharmacy Manual.  All materials to 


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dilute/prepare and administer study treatmentdrug 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, leftover 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. 
Old text: 
Patients will be given 50 µL IVT injection of RO6867461 or ranibizumab into the study 
eye or a sham administration according the randomization schedule as described in the 
Overview of Study Design (see Section 3.1.1). 
• 
Arm A:  0.3 mg ranibizumab IVT every 4 weeks for 24 weeks (7 injections) 
• 
Arm B:  1.5 mg RO6867461 IVT every 4 weeks for 20 weeks (6 injections), followed 
by 1 sham administration at Week 24 
• 
Arm C:  6 mg RO6867461 IVT every 4 weeks for 20 weeks (6 injections),  followed 
by 1 sham administration at Week 24 
 
The pharmacist or designee responsible for dispensing study treatment will prepare the 
correct study treatment (RO6867461, ranibizumab or sham), where applicable, as 
assigned by IxRS.  A fixed volume of 50 µL will be injected for all study drugs and doses. 
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. 
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 
0.3 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 


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and are detailed in the Pharmacy Manual.  Pre- and post-study treatment administration 
procedures as well as instructions for performing the IVT are provided in Appendix 43.. 
A specified filter needle must be used for each dose preparation of RO6867461 or 
ranibizumab per the instructions provided in the Pharmacy Manual.  All materials to 
dilute/prepare and administer study treatment 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, leftover 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. 
 
SECTION   4.4.4 SHAM BOXES ACCOUNTABILITY,  
New text: 
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). 
Old text: 
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). 
 
SECTION   4.6.7.2. ASSESSMENT DURING TREATMENT,  
New text: 
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 SoAs (see Appendix 1 and Appendix 2). 






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evaluate any potential adverse events. Otherwise, patients will exit the study once they 
have completed the observational visit at week 36.    
 
 
 
After the final visit, adverse events should be followed up as outlined in Section 5.6. 
Old text: 
Patients will return for their final visit with assessments as outlined in the SoA at 
Week 28. 
Patients can receive SoC treatment for DME after all assessments are completed on 
Week 28.  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. 
 
SECTION   5.3.1 ADVERSE EVENT REPORTING PERIOD,  
New text: 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record.  Adverse events will then be reported on the 
Adverse Event eCRF as follows: 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported 
(e.g., serious adverse events related to invasive procedures such as angiographies).  
Any other adverse event should not be reported. 
After initiation of study drug through the final visit, all adverse events, regardless of 
relationship to study drug, will be reported until the final visit. 
After a period of 28 days from the last dose of study drugAfter the final visit and/or 
subsequent follow-up phone call, as applicable, investigators should report any deaths, 
serious adverse events, or other adverse events of concern that are believed to be 
related to prior treatment with study drug (see Section 5.6) 


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Old text: 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record.  Adverse events will then be reported on the 
Adverse Event eCRF as follows: 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported 
(e.g., serious adverse events related to invasive procedures such as angiographies).  
Any other adverse event should not be reported. 
After initiation of study drug, all adverse events, regardless of relationship to study drug, 
will be reported until the final visit. 
After a period of 28 days from the last dose of study drug, investigators should report 
any deaths, serious adverse events, or other adverse events of concern that are 
believed to be related to prior treatment with study drug (see Section 5.6) 
 
SECTION   6.7.2. SECONDARY EFFICACY ENDPOINTS,  
New text: 
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% CI 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. 
For the duration of drug effect, the same statistical models will be used. Change from 
baseline to week 28 and change from week 24 to week 28 will be analyzed as 
appropriate. 
Time to event endpoints will be tested with a two-sided stratified log rank test using 
the randomization stratification factors BCVA ETDRS letter score (64 letters or better 
vs. 63 letters or worse) and previous macular laser treatment as strata. Kaplan Meier 
curves will be displayed, and median time to event estimates and confidence limits of 
them will be computed. 
Effect modification will be tested by adding a previous IVT anti-VEGF treatment status, 
treatment arm by visit interaction, and a treatment arm by visit by previous IVT anti-
VEGF treatment status interaction terms to the above MMRM model. The treatment 
arm by visit by previous IVT anti-VEGF treatment status interaction term will be 
tested at a 10% type I error rate. 


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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. 
Old text: 
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% CI 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. 
For the duration of drug effect, the same statistical models will be used. Change from 
baseline to week 28 and change from week 24 to week 28 will be analyzed as 
appropriate. 
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. 


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SECTION   APPENDIX 1, SCHEDULE OF ASSESSMENTS 
Week
Screening
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24t
Week 26m
Week 28t
Week 32t
Week 36t
Early Termination 
Visit
Unscheduled 
Visit
Day
D-28 to D-1
Day 1
Day 7
Day 28
Day 56
Day 84
Day 112
Day 140
Day 168
Day 182
Day 196
Day 224
Day 252
Time Relative (h)
0
144
648
1320
1992
2664
3336
4008
4344
4680
5352
6024
Visit Window
+/-3
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+7
Assessments
Informed Consent
X
Eligibility
X
Xa
Demography
X
Medical History
X
Xa
Physical Examination
X
X
X
Anthropometric Measurements
X
X
X
Vital Signsa
X
Xk
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG-12 leada
X
X
X
X
Hematologya
X
X
Xn
X
X
Blood Chemistrya
X
X
Xn
X
X
Urinalysisa
X
X
Xn
X
X
Coagulationa
X
X
Xn
X
X
Hormone Panelb
X
Pregnancy Testb
X
X
Administration of Study Drugc,p
X
X
X
X
X
X
X
Administration of 0.3 mg 
ranibizumabc
Xr
Xr
Xr
Xr
Safety Finger Count Visionc,d
X
X
X
X
X
X
Xs
Xs
Xs
Xs
X
IOPa,l
X
Xk
X
X
X
X
X
X
X
X
X
X
X
X
X
BCVAa,e
X
Xk
X
X
X
X
X
X
X
X
X
X
X
X
X
Slit Lampa
X
Xk
X
X
X
X
X
X
X
X
X
X
X
X
X
Indirect Ophthalmoscopya
X
Xk
X
X
X
X
X
X
X
X
X
X
X
X
Fundus Photographya,c
X
Xk,o
X
Xq
Xq
Xq
X
X
SD-OCTa,c
X
Xk
X
X
X
X
X
X
X
X
X
X
X
X
Fundus Fluorescein Angiographya,c
X
X
X
Xq
Xq
Xq
X
X
Week 1
 






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Old text: 
Week 
Screening 
Week 1 
Week 4 
Week 8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
26  n 
Final 
Visit 
Week 28 
Early 
Termina-
tion Visit 
Unsche-
duled 
Visit 
Day 
D-28 to 
D-1 
Day 
1 
Day 
7 
Day 28 
Day 56 
Day 84 
Day 112 
Day 140 
Day 168 
Day 182 
Day 196 
 
 
Visit Window 
 
 
 ± 3 
 ± 7 
 ± 7 
 ± 7 
 ± 7 
 ± 7 
± 7 
± 7 
 ± 7 
 + 7 
 
Assessments 
  
  
  
  
  
  
  
  
 
 
  
  
  
Informed Consent 
x 
  
  
  
  
  
  
  
 
 
  
  
  
Eligibility 
x 
x a 
  
  
  
  
  
  
 
 
  
  
  
Demography 
x 
  
  
  
  
  
  
  
 
 
  
  
  
Medical History 
x 
x a 
  
  
  
  
  
  
 
 
  
  
  
Physical 
Examination 
x 
  
  
  
  
  
  
  
 
 
x 
x 
  
Anthropometric 
Measurements 
x 
  
  
  
  
  
  
  
 
 
x 
x 
  
Vital Signs a 
x 
x l 
x 
x 
x 
x 
x 
x 
x 
x n 
x 
x 
x 
ECG-12 Lead 
x 
  
  
  
  
  
  
  
 
 
x 
x 
x 
Hematology a 
x 
  
  
  
  
x 
  
  
x 
 
x o 
x 
x 
Blood Chemistry a 
x 
  
  
  
  
x 
  
  
x 
 
x o 
x 
x 
Urinalysis a 
x 
  
  
  
  
x 
  
  
x 
 
x o 
x 
x 
Coagulation a 
x 
  
  
  
  
x 
  
  
x 
 
x o 
x 
x 
Hormone Panel b 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test b 
x 
  
  
  
  
  
  
  
 
 
  
  
x 


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Week 
Screening 
Week 1 
Week 4 
Week 8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
26  n 
Final 
Visit 
Week 28 
Early 
Termina-
tion Visit 
Unsche-
duled 
Visit 
Day 
D-28 to 
D-1 
Day 
1 
Day 
7 
Day 28 
Day 56 
Day 84 
Day 112 
Day 140 
Day 168 
Day 182 
Day 196 
 
 
Visit Window 
 
 
 ± 3 
 ± 7 
 ± 7 
 ± 7 
 ± 7 
 ± 7 
± 7 
± 7 
 ± 7 
 + 7 
 
Assessments 
  
  
  
  
  
  
  
  
 
 
  
  
  
Administration of 
Study Treatment q 
  
x 
  
x 
x 
x 
x 
x 
x 
or 
sham 
 
  
  
 x 
Safety Finger Count 
Vision c,d 
  
x 
  
x 
x 
x 
x 
x 
x 
 
  
  
x 
IOP a,e 
x 
3 l,m 
x 
3 m 
3 m 
3 m 
3 m 
3 m 
3 m 
2 e,n 
x 
x 
x 
BCVA a,f 
x 
x l 
 x 
x 
x 
x 
x 
x 
x 
x n 
x 
x 
x 
Slit Lamp a 
x 
x l 
x 
x 
x 
x 
x 
x 
x 
x n 
x 
x 
x 
Indirect 
Ophthalmoscopy a 
x 
x l 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
Fundus 
Photography a,c 
x 
x l,p 
  
  
  
  
  
  
x 
 
x 
x 
x 
SD-OCT a,c 
x 
x l 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
Fundus Fluorescein 
Angiography a,c 
x 
  
  
  
  
x  
  
  
x 
 
 
x 
x 




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Week 
Screening 
Week 1 
Week 4 
Week 8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
26  n 
Final 
Visit 
Week 28 
Early 
Termina-
tion Visit 
Unsche-
duled 
Visit 
Day 
D-28 to 
D-1 
Day 
1 
Day 
7 
Day 28 
Day 56 
Day 84 
Day 112 
Day 140 
Day 168 
Day 182 
Day 196 
 
 
Visit Window 
 
 
 ± 3 
 ± 7 
 ± 7 
 ± 7 
 ± 7 
 ± 7 
± 7 
± 7 
 ± 7 
 + 7 
 
Assessments 
  
  
  
  
  
  
  
  
 
 
  
  
  
Adverse Events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x n 
x 
x 
x 
Previous and 
Concomitant 
Treatments 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x n 
x 
x 
x 
 
BCVA = best corrected visual acuity; EC = Ethics Committee; FFA = fundus fluorescein angiography; FP = fundus photography; IOP = intraocular pressure; 
PD = pharmacodynamic; PK = pharmacokinetic;
 SD-OCT = spectral domain optical coherence tomography. 
 
a Assessment prior to study treatment administration on days where study treatment is administered. 
b For females only 
c Assessment in study eye only; except at screening for imaging assessments (FP, SD-OCT, FFA), where either eye has a potential to meet all eligibility criteria. 
d Finger count vision assessment asap after, and within maximum of 15 min from study treatment administration. 
e Multiple assessments on a single visit day, details on timing in Appendix 2. 
f Performed prior to pupil dilation. 
 
 
h At Day 1 but can be done at any other visit if the sample not collected at baseline. 
i Mandatory, except in countries or at investigational sites where IRB/EC does not approve. 
 
 
 
 
 
 
l Baseline assessments. 


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m Assessment post-study treatment administration in the study eye only. If IOP  ≥ 30 mmHg at 30 ( ± 5) minutes post-treatment administration in the study eye, then 
IOP is measured again at 60 ( ± 10) minutes.  
 
 
o Only for the tests where abnormal values at Week 24 require follow-up, and at the discretion of the investigator 
p Optional at Day 1. 
q The interval between two administrations of study treatment needs to be at least 21 days. 
 
SECTION   APPENDIX 3 (5. INTRAVITREAL ADMINISTRATION OF STUDY TREATMENT) 
New text: 
• 
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 of 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. 
Old text: 
• 
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 of 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.


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6. 
SUBJECT:  INCLUSION OF LOW-RISK PDR AND 
MODIFICATION OF CORTICOSTERIOD EXCLUSION 
CRITERION 
REASON FOR CHANGE:    
A large proportion of patients with DME have DR. When used as a treatment of DME, 
intravitreous (IVT) anti-VEGF agents reduce the risk of PDR worsening and increase the 
chance of improvement. Therefore low-risk PDR patients will be included, to study DR 
severity improvement from baseline on the ETDRS-DRSS (diabetic retinopathy severity 
score) at Week 24 and exit visit. As the standard of care for high-risk PDR is pan retinal 
photocoagulation (PRP), patients with high-risk PDR will be excluded. 
Patients on short acting off-label IVT corticosteroids used for the treatment of DME, will 
be included in the study. The effect of this drug treatment lasts less than 3 months. 
Therefore, inclusion of patients provided the treatment > 3 months prior to day 1, will not 
compromise the scientific integrity of the study and may help improve recruitment. Long 
acting IVT corticosteroids Ozurdex and Iluvien are approved treatment for DME and 
patients who have been treated with these drugs will be excluded 
 
SECTION   4.2.2. EXCLUSION CRITERIA, 
New text: 
Patients who meet any of the following criteria will be excluded from study entry: 
Ocular criteria for study eye: 
• 
Any signs of high-risk PDR defined as: 
o any vitreous or pre-retinal hemorrhage 
o NVE   ≥  1/2 disc area within an area equivalent to the standard 
mydriatic ETDRS 7- field on clinical examination  
o NVD   ≥  1/3 disc area on clinical examination  
• 
Any IVT anti-VEGF treatment within 3 months prior to Day 1 
• 
Any panretinal photocoagulation (PRP) treatment prior to Day 1 
• 
Any macular laser photocoagulation within 3 months prior to Day 1 
• 
History of vitreoretinal surgery 
• 
Any IVT, or periocular corticosteroid, or corticosteroid implants  treatment  within 
3months prior to Day 1, except for management.  Any history of complication of 
cataract surgeryIluvien or Ozurdex implants prior to Day 1 will not be permitted 
• 
Any cataract surgery or treatment for complications of cataract surgery with steroids 
within 3 months prior to Day 1 
• 
History of incisional glaucoma surgery 
• 
Uncontrolled glaucoma (e.g., progressive loss of visual fields or defined as 
IOP ≥  25 mmHg despite treatment with anti-glaucoma medication) 


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Concurrent ocular conditions in the study eye: 
• 
History of rubeosis in the study eye 
• 
Any current or history of ocular disease in the study eye other than DME that may 
confound assessment of the macula or affect central vision (e.g., AMD, retinal vein 
occlusion, uveitis, angioid streaks, histoplasmosis, active or inactive 
cytomegalovirus, pathological myopia, retinal detachment, macular traction, macular 
hole, significant cataract) 
• 
Any current ocular condition for which, in the opinion of the investigator, visual 
acuity loss would not improve from resolution of macular edema (e.g., foveal 
atrophy, pigment abnormalities, dense sub-foveal hard exudates, non-retinal 
condition) 
• 
Any active ocular infection in the study eye aton Day 1 
• 
Any active intraocular inflammation (grade trace or above) in the study eye aton 
Day 1 
 
Characteristics for fellow eye: 
• 
Any anti-VEGF treatment for a retinal condition within 7 days prior to Day 1 
• 
Any retinal condition that, in the opinion of the investigator, might require anti-VEGF 
treatment within 7 days from Day 1 
 
General criteria: 
• 
Any systemic anti-VEGF within 6 months prior to Day 1 
• 
Any major illness or major surgical procedure within 1 month prior to Day 1 
• 
Any febrile illness within 1 week prior to Day 1 
• 
Any stroke or myocardial infarction within 12 months prior to Day 1 
• 
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 
needs to be controlled by antihypertensive medication, the patient can become 
eligible ifshould be taking the same medication is taken continuously for at least 1 
month prior to Day 1. 
• 
Patients with glycosylated hemoglobin HbA1c ≥ 12% at screening 
• 
Untreated diabetes mellitus or initiation of oral anti-diabetic medication or insulin 
within 4 months prior to Day 1 or anticipated change of anti-diabetic medications 
within the duration of the study 
• 
Renal failure requiring renal transplant, hemodialysis, or peritoneal dialysis within 
6 months prior to Day 1 or anticipated to require hemodialysis or peritoneal dialysis 
at any time during the study 


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• 
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 IMP 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 female 
• 
Use of systemic corticosteroids within 1 month prior to Day 1 
• 
Any known hypersensitivity to active comparator, fluorescein, any ingredient of the 
formulation used, dilating eye drops, or any anesthetics and microbial drops used 
• 
Any other restriction accorded to the use of the active comparator 
• 
Any treatment with IMP in the 3 months prior to Day 1 
Old text: 
Patients who meet any of the following criteria will be excluded from study entry: 
Ocular criteria for study eye: 
• 
Any PDR 
• 
Any IVT anti-VEGF treatment prior to Day 1 
• 
Any panretinal photocoagulation (PRP) treatment prior to Day 1 
• 
Any macular laser photocoagulation within 3 months prior to Day 1 
• 
History of vitreoretinal surgery 
• 
Any IVT, periocular corticosteroid, or corticosteroid implants treatment prior to Day 1, 
except for management of complication of cataract surgery 
• 
Any cataract surgery or treatment for complications of cataract surgery with steroids 
within 3 months prior to Day 1 
• 
History of incisional glaucoma surgery 
• 
Uncontrolled glaucoma (e.g., progressive loss of visual fields or defined as IOP 
≥ 25 mmHg despite treatment with anti-glaucoma medication) 
 
Concurrent ocular conditions: 
• 
History of rubeosis in the study eye 
• 
Any current or history of ocular disease in the study eye other than DME that may 
confound assessment of the macula or affect central vision (e.g., AMD, retinal vein 
occlusion, uveitis, angioid streaks, histoplasmosis, active or inactive 
cytomegalovirus, pathological myopia, retinal detachment, macular traction, macular 
hole, significant cataract) 
• 
Any active ocular infection in the study eye at Day 1 
• 
Any active intraocular inflammation (grade trace or above) in the study eye at Day 1 
 


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Characteristics for fellow eye: 
• 
Any anti-VEGF treatment for a retinal condition within 7 days prior to Day 1 
• 
Any retinal condition that, in the opinion of the investigator, might require anti-VEGF 
treatment within 7 days from Day 1 
 
General criteria: 
• 
Any systemic anti-VEGF within 6 months prior to Day 1 
• 
Any major illness or major surgical procedure within 1 month prior to Day 1 
• 
Any febrile illness within 1 week prior to Day 1 
• 
Any stroke or myocardial infarction within 12 months prior to Day 1 
• 
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 30 or more minutes later.  If the patient’s BP needs 
to be controlled by antihypertensive medication, the patient can become eligible if 
medication is taken continuously for at least 1 month prior to Day 1. 
• 
Patients with glycosylated hemoglobin HbA1c > 12% at screening 
• 
Untreated diabetes mellitus or initiation of oral anti-diabetic medication or insulin 
within 4 months prior to Day 1 or anticipated change of anti-diabetic medications 
within the duration of the study 
• 
Renal failure requiring renal transplant, hemodialysis, or peritoneal dialysis within 
6 months prior to Day 1 or anticipated to require hemodialysis or peritoneal dialysis 
at any time during the study 
• 
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 IMP 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 female 
• 
Use of systemic corticosteroids within 1 month prior to Day 1 
• 
Any known hypersensitivity to active comparator, fluorescein, any ingredient of the 
formulation used, dilating eye drops, or any anesthetics and microbial drops used 
• 
Any other restriction accorded to the use of the active comparator 
• 
Any treatment with IMP in the 3 months prior to Day 1 
 


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7. 
SUBJECT:   UPDATING PREVIOUS CLINICAL TRIALS SECTION 
REASON FOR CHANGE:    
The section was updated to reflect the most recent available data of ongoing clinical 
trials. 
 
SECTION   1.2.2. PREVIOUS CLINICAL STUDIES 
New text: 
A multicenter, double-masked, Phase II study to investigate the safety, tolerability, 
pharmacokinetics, and efficacy of RO6867461 administered IVT in patients with CNV 
secondary to AMD is ongoing (Study BP29647 − AVENUE, clinicaltrials.gov: 
NCT02484690).  In Study BP29647, treatment-naive patients are randomized to receive 
either ranibizumab 0.5 mg every 4 weeks or 1.5 or 6 mg RO6867461 every 4 or 8 weeks 
for 32 weeks.  As of 4 November 2015, 15 patients have been enrolled and no serious 
adverse events have been reported. To date, side effects observed in patients enrolled 
in Study BP29647 (masked data) are consistent with the safety profile observed in the 
completed BP28936 study described above. No other data are yet available. 
Old text: 
A multicenter, double-masked, Phase II study to investigate the safety, tolerability, 
pharmacokinetics, and efficacy of RO6867461 administered IVT in patients with CNV 
secondary to AMD is ongoing (Study BP29647 − AVENUE).  In Study BP29647, 
treatment-naive patients are randomized to receive either ranibizumab 0.5 mg every 
4 weeks or 1.5 or 6 mg RO6867461 every 4 or 8 weeks for 32 weeks.  As of 4 
November 2015, 15 patients have been enrolled and no serious adverse events have 
been reported.  No other data are yet available. 
 
8. 
SUBJECT:   CHANGES IN MASKING REQUIREMENTS 
REASON FOR CHANGE:    
The original study design contained a sham injection at week 24 for arms B and C, 
which required at least two investigators (treatment administrator and assessing 
physician) to maintain the double-blinding. However, by changing the study design, 
sham injection is no longer required. Treatment can be administered by the assessing 
physician, as long as the investigator is not involved in any aspects of drug-preparation. 
All roles must be documented throughout the study. The paragraph on unmasking IMC 
members has been updated to be in alignment with the other ongoing RO6867461 study 
BP29647.The section on emergency unmasking has been added because it is a current 
section in the protocol template and was not included in previous versions.  
 


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SECTION   4.3.3. MASKING 
New text: 
Masking at Investigational Site 
This is a double-masked study.   
Patients, study site personnel (with the exception of the pharmacist or designated 
personnel), BCVA examiners, vendors, Central Reading Center personnel, and the 
Sponsor and its agents (with the exception of drug accountability monitors and as 
defined in Section 4.3.3) will be masked to study drug assignment. 
There mustshould be a minimum of two investigators per site to fulfill the masking 
requirements of this study.  At least one investigator will be designated as the assessor 
physician who will be masked to patients’ study drug 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 
willcould be unmasked to patients’ study drug assignment and will administer study 
treatment (RO6867461, ranibizumab or sham). 
Once the designated roles are determined, the roles cannot be switched or reversed at 
any time during the conduct of the study.  If only one investigator is available due to 
limited staffing resources, study drug administration can also be done by the assessing 
physician. In that case the treatment administrator physician(s) must not be involved 
in any aspects of un-masked study drug preparation. The preparation of the study drug 
must be done by trained staff under strict sterile condition. Detailed instructions for 
preparation are available in the pharmacy manual. 
The Principal Investigator must be masked to the patient’s treatment assignment.  All 
roles for each study staff member should be clearly documented in the site delegation 
log.  The delegation log should be signed by the Principal Investigator. An unmasked 
personnel cannot switch to a masked role, but a masked personnel can switch to an 
unmasked role. Any change should 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 treatmentdrug administration must not be involved in 
any other aspect of the study in any way and must not divulge study drug 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 and as defined in 
Section 4.3.3) will be masked to study drug assignment. 


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Every effort must be made to limit the The number of unmasked study personnel should 
be limited to ensure the integrity of this masked study.  There mustshould 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 the Sponsor. 
For the duration of the study, the patient study drug assignment will not be unmasked 
unless required for patient safety. 
All study visit assessments, except those at screening, should be performed by masked 
site personnel only.  The unmasked treatment administrator physician will 
performperforming the injection of study drug and may also perform other assessments, 
including the post-injection vision testing (finger counting and, if applicable, hand 
movement and/or light perception). 
Masking at Sponsor and Delegates 
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 study drug group level as well 
as at the . The IMC agreement will also identify individuals unmasked at the individual 
patient level, if required. 
 for safety analysis and for the purpose of preparing summary data displays for the IMC 
meeting.Other Roche Study Management Team members will remain masked 
throughout the study. 
Old text: 
This is a double-masked study.  There must be a minimum of two investigators per site 
to fulfill the masking requirements of this study.  At least one investigator will be 
designated as the assessor physician who will be masked to patients’ study drug 
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’ study drug assignment and 
will administer study treatment (RO6867461, ranibizumab or sham). 
Once the designated roles are determined, the roles cannot be switched or reversed at 
any time during the conduct of the study.  The Principal Investigator must be masked to 
the patient’s treatment assignment.  All roles for each study staff member should be 
clearly documented in the site delegation log.  The delegation log should be signed by 


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the Principal Investigator.  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 study 
drug 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 and as defined in 
Section 4.3.3) will be masked to study drug 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 the 
Sponsor. 
For the duration of the study, the patient study drug assignment will not be unmasked 
unless required for patient safety. 
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 drug and may also perform the post-injection vision testing (finger 
counting and, if applicable, hand movement and/or light perception). 
Masking at Sponsor and Delegates 
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) and others, if deemed necessary by the IMC, will be 
unmasked at the study drug group level as well as at the patient level, if required. 
Other Roche Study Management Team members will remain masked throughout the 
study. 
 
SECTION   4.3.4. MASKING AT SPONSOR AND DELEGATES 
New text: 
None, incorporated into section 4.3.3 


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Old text: 
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) and others, if deemed necessary by the IMC, will be 
unmasked at the study drug group level as well as at the patient level, if required. 
Other Roche Study Management Team members will remain masked throughout the 
study. 
 
SECTION   4.3.4 EMERGENCY UNMASKING 
New text: 
If complete unmasking is necessary for patient management (e.g., in the case of a 
serious adverse event), the investigator will be able to share the treatment code with the 
masked study personnel. Treatment codes should not be shared except in emergency 
situations. The Investigator should document all details and provide an explanation for 
any premature complete unmasking (e.g., accidental unmasking of non-Investigator 
study personnel or unmasking due to serious adverse events). 
Sponsor might become unmasked to study drug 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 
Old text: 
None  
 
9. 
SUBJECT:   EMERGENT/RECURRENT DIABETIC MACULAR 
EDEMA IN THE FELLOW EYE SECTION 
REASON FOR CHANGE:    
The section has been updated to clarify that Ranibizumab will be provided by the 
sponsor and that other commercial supplies will not be reimbursed by the sponsor. 
 
SECTION   4.5.3 EMERGENT/RECURRENT DIABETIC MACULAR EDEMA IN 
THE FELLOW EYE 
New text: 
Every effort should be made to treat with ranibizumab, where 


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When anti-VEGF therapy is recommended and ranibizumab warranted.  If 
emergent/recurrent DME in the fellow eye is treated, every effort should be made to treat 
with ranibizumab, it will. This treatment can either be provided by the Sponsor as long 
asduring the patient remainspatient’s enrollment in the study.  The supply of 
ranibizumab will  or be inprovided by the currently availablesite through commercial 
supplies.  When provided by the Sponsor, it will be in the commercial formulation for 
ranibizumab but labelled for investigational use only.  The same process of (dispatched 
by IxRS), and the site will need to maintain their own drug accountability.  Commercial 
supplies will apply to this supply of ranibizumab as to the study drugnot be reimbursed. 
Old text: 
Should DME emerge or recur and require treatment in the fellow eye during the study 
period, the patient may receive anti-VEGF SoC treatment.  Fellow eye treatment, if 
required, must be administered at least 7 days preceding or following the study eye 
treatment. 
Every effort should be made to treat with ranibizumab, where anti-VEGF therapy is 
recommended and ranibizumab warranted.  If emergent/recurrent DME in the fellow eye 
is treated with ranibizumab, it will be provided by the Sponsor as long as the patient 
remains in the study.  The supply of ranibizumab will be in the currently available 
commercial formulation for ranibizumab but labelled for investigational use only.  The 
same process of drug accountability will apply to this supply of ranibizumab as to the 
study drug. 
 
10. 
SUBJECT:   CLARIFICATION ON RE-SCREENING 
REASON FOR CHANGE:    
The text was modified to clarify the terms of when a re-screening would be permitted 
and the conditions under which the second eye may be evaluated within the initial 
screening period to become the study-eye. 
SECTION   4.6.7.1 SCREENING AND PRETREATMENT ASSESSMENTS 
New text: 
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. Where it 
extends beyond the 4 week screening period, the patient will be allowed to be re
screened. 
Patients who failed screening due to : 
• 
febrile illness (where "end of febrile illness + 7 Days" extends beyond the 4 
week screening period) 


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• 
uncontrolled blood pressure  
• 
administrative reasons (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. If patients meet criteria upon re-screening, they will 
receive a new screening number and will be treated as a new patient. 
 For each patient, if one eye does not meet eligibility criteria, then the second eye may 
be evaluated within the initial screening period. If the second eye meets the eligibility 
criteria, then the patient would retain the same screening number and would not be 
screened-failed.  
Old text: 
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. Where it 
extends beyond the 4 week screening period, the patient will be allowed to be re-
screened. 
Patients who failed screening due to uncontrolled blood pressure will be allowed to be 
re-screened. 
 
11. 
SUBJECT:   ADDITION OF NON-SERIOUS ADVERSE EVENTS 
OF SPECIAL INTEREST 
REASON FOR CHANGE:    
In response to safety requests and the current protocol template, several safety sections 
have been updated to include the assessment and reporting of non-serious events of 
special interest (AESI). 
 
SECTION   5.1. SAFETY PARAMETERS AND DEFINITIONS,  
New text: 
Safety assessments will consist of monitoring and recording adverse events, 
including serious adverse events (systemic and ocular);), non-serious adverse events of 
special interest; 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]). 


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Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
Old text: 
Safety assessments will consist of monitoring and recording adverse events, 
including serious adverse events (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. 
 
SECTION   5.1.3 NON-SERIOUS ADVERSE EVENTS OF SPECIAL INTEREST 
(IMMEDIATELY REPORTABLE TO THE SPONSOR), 
New text: 
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 Error! Reference source not found. 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 Error! Reference source not found. 
(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 
in a patient exposed to a medicinal product.  This term applies only when a 
contamination of the study drug is suspected. 
• 
The Safety Science Responsible for the program is accountable for determining the 
non-serious Adverse Events of Special Interest (AESI) for a protocol. 
Old text: 
None 
 
SECTION    5.4. IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR,  
New text: 
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 


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place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
Serious adverse events 
• 
non-serious adverse events of special interest 
• 
Sight-threatening adverse events 
• 
Pregnancies 
Old text: 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
Serious adverse events 
• 
Sight-threatening adverse events 
• 
Pregnancies 
 
SECTION   5.4.2 REPORTING REQUIREMENTS FOR SERIOUS ADVERSE 
EVENTS, NON-SERIOUS ADVERSE SECTION   EVENTS OF SPECIAL 
INTEREST, AND SIGHT-THREATENING ADVERSE EVENTS,  
New text: 
For reports of serious adverse events, non-serious adverse events of special interest , 
and sight-threatening adverse events (see Sections 5.1.2  and 5.1.3), investigators 
should record all case details that can be gathered on the Serious Adverse Reporting 
Form and forward this form to the Serious Adverse Event Responsible within 24 hours. 
Old text: 
For reports of serious adverse events and sight-threatening adverse events (see 
Sections 5.1.2  and 5.1.3), investigators should record all case details that can be 
gathered on the Serious Adverse Reporting Form and forward this form to the Serious 
Adverse Event Responsible within 24 hours. 
 
SECTION   5.5.2. SPONSOR FOLLOW-UP,  
New text: 
For serious adverse events, non-serious adverse events of special interest, sight-
threatening adverse events, 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 


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reports, autopsy reports) in order to perform an independent medical assessment of the 
reported case.. 
Old text: 
For serious adverse events, sight-threatening adverse events, 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. 
 
SECTION   5.6. POST-STUDY ADVERSE EVENTS,  
New text: 
The investigator is not required to actively monitor patients for adverse events after the 
end of the adverse event reporting period (as defined as 28 days after the last dose of 
study drug).in Section 5.3.1).  However, the Sponsor should be notified if the 
investigator becomes aware of any death or, any other serious adverse event, or sight-
threatening adverse events 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. 
Old text: 
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 drug).  However, the Sponsor should be notified if the investigator becomes aware 
of any death or any other serious adverse event occurring after the end of the adverse 
event reporting period, if the event is believed to be related to prior study drug treatment. 
 
12. 
SUBJECT:   EDITORIAL CHANGES 
REASON FOR CHANGE:    
• 
alignment with protocol template 
• 
correction of typos 
• 
references added 
• 
changes for general updates and clarifications 
• 
changing of study treatment to study drug throughout the document as sham 
injection was removed 


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• 
Appendix 2 removed 
applicable to section: glossary,  
1. Background and Rationale, 1.1 Background on Disease, 1.2 Background on 
RO6867461, 1.2.2. Previous Clinical Studies, 1.2.2.1 Safety and Tolerability, 3.2. 
Rationale for Study Design, 3.2.1. Rationale for Dosage selection, 3.3.1. Safety 
Outcome Measures, 4.2.2. Exclusion Criteria, 4.3.2. Treatment Administration Procedure, 
4.4.1.1. RO6867461 and Placebo, 4.4.1.2 Ranibizumab Active Comparator,  4.4.2.1. 
RO6867461 and Ranibizumab, 4.5.1 Permitted Therapy, 4.6 Study Assessments, 
4.6.1.1 Medical History and demographic Data, 4.6.1.3. Vital Signs, 
 
 4.6.5 Disease-Specific Assessments, 4.6.5.2.1. Best 
Corrected Visual Acuity, 4.6.7.1. Screening and Pretreatment Assessments, 4.6.7.3 
Assessments at Early Termination Visit, 4.7.1 Patient Discontinuation, 4.7.1.1. 
Discontinuation from study Drug, 5.1.1. Adverse Events, 5.3.5.4. Abnormal Laboratory 
Values, 5.3.5.5. Abnormal Vital Sign Values, 5.6 Post-Study adverse Events, 5.7. 
Expedited Reporting to Health authorities, Investigators, Institutional Review Boards, 
and Ethics Committees, 6.3.1. Safety Analysis Population, 6.3.2 Efficacy, 
Pharmacokinetic, and Pharmacodynamics Analysis Population, 10. References, 
Appendix 2 Schedule of Assessment Detail Table 

SAP_001.pdf: 
 
Official Title: 
 
A MULTIPLE-CENTER, MULTIPLE-DOSE, 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 DIABETIC MACULAR EDEMA 
NCT Number: NCT02699450 
Document Date: SAP Version 2: 31-July-2017 
 
 


Clinical Study Report: RO6867461 - F. Hoffmann-La Roche Ltd
Protocol BP30099     Report Number 1083913
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RO687461—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP30099 
 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A MULTIPLE-CENTER, MULTIPLE-DOSE,  
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 DIABETIC 
MACULAR EDEMA 
 
PROTOCOL NUMBER: 
BP30099 
STUDY DRUG: 
RO687461 
VERSION NUMBER: 
2.0 
IND NUMBER: 
119225 
EUDRACT NUMBER: 
N/A 
SPONSOR: 
F. Hoffmann-La Roche Ltd. 
PLAN PREPARED BY: 
 
 
DATE FINAL: 
July 31 2017 
 


Clinical Study Report: RO6867461 - F. Hoffmann-La Roche Ltd
Protocol BP30099     Report Number 1083913
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Statistical Analysis Plan BP30099 
 
 
TABLE OF CONTENTS 
 
STUDY DESIGN ........................................................................................... 3 
1.
1.1 
Protocol Synopsis .................................................................... 5 
1.2 
Outcome Measures ................................................................. 5 
1.2.1 
Safety Outcome Measures ...................................................... 5 
1.2.2 
Pharmacokinetic Outcome Measures ...................................... 5 
1.2.3 
Efficacy and Pharmacodynamic Outcome 
Measures 5 
1.2.3.1 Primary Efficacy Outcome Measure ....................................... 5 
1.2.3.2 Secondary Efficacy Outcome Measures ................................ 6 
1.2.3.3 Pharmacodynamic Biomarker Outcome 
Measure 7 
1.2.4 
Exploratory Outcome Measures .............................................. 7 
1.3 
Determination of Sample Size ................................................. 7 
1.4 
Analysis Timing ....................................................................... 8 
 
STUDY CONDUCT ....................................................................................... 8 
2.
2.1 
Randomization ......................................................................... 8 
2.2 
Independent Review Facility .................................................... 8 
2.3 
Data Monitoring ....................................................................... 9 
 
STATISTICAL METHODS ............................................................................ 9 
3.
3.1 
Analysis Populations ............................................................... 9 
3.1.1 
Safety Analysis Population ...................................................... 9 
3.1.2 
Efficacy, Pharmacokinetic, and 
Pharmacodynamic Population ................................................................... 9 
3.2 
Analysis of Study Conduct ....................................................... 9 
3.3 
Analysis of Treatment Group Comparability ............................ 9 
3.4 
General Considerations ........................................................... 9 
3.4.1 
Visit Windows .......................................................................... 9 
3.4.2 
Baseline ................................................................................. 10 
3.5 
Efficacy Analysis .................................................................... 10 
3.5.1 
Primary Efficacy Endpoint ...................................................... 10 
3.5.2 
Secondary Efficacy Endpoints ............................................... 11 
3.5.3 
Exploratory Efficacy Endpoints .............................................. 11 
3.5.4 
Sensitivity Analyses ............................................................... 11 
3.5.5 
Subgroup Analyses ............................................................... 12 


Clinical Study Report: RO6867461 - F. Hoffmann-La Roche Ltd
Protocol BP30099     Report Number 1083913
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Statistical Analysis Plan BP30099 
 
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3.6 
Safety Analyses ..................................................................... 12 
3.6.1 
Adverse Events ..................................................................... 12 
3.6.2 
Clinical Laboratory Test Results ............................................ 12 
3.6.2.1 Standard Reference Ranges and 
Transformation of Data ....................................................................... 12 
3.6.2.2 Definition of Laboratory Abnormalities .................................. 13 
3.6.3 
Vital Signs .............................................................................. 13 
3.6.4 
ECG Data Analysis ................................................................ 13 
3.6.5 
Anti-Drug Antibody Data Analysis .......................................... 13 
3.6.6 
Ocular Assessments .............................................................. 13 
3.6.7 
Concomitant Medications ...................................................... 13 
3.6.8 
Exposure to Study Medication ............................................... 14 
3.7 
Missing Data .......................................................................... 14 
3.8 
Interim Analyses .................................................................... 14 
APPENDIX ......................................................................................................... 15 
 
 
LIST OF TABLES 
Figure 1 
Study Design ................................................................................. 4 


Clinical Study Report: RO6867461 - F. Hoffmann-La Roche Ltd
Protocol BP30099     Report Number 1083913
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Statistical Analysis Plan BP30099 
 
 
Background 
This Statistical Analysis Plan (SAP) documents the statistical methods for 
summarizing and analyzing the efficacy and safety data from study BP30099. The 
main purpose of this SAP is to describe the data handling rules, derivation rules, and 
statistical analysis methods.  
 
STUDY DESIGN 
1.
This is a multiple-center, multiple-dose, randomized, active comparator−controlled, 
double-masked, three parallel group, 36-week study in patients with CI-DME. 
The three groups of this study are as follows (see Figure 1): 
• 
Arm A:  0.3 mg ranibizumab IVT 
• 
Arm B:  1.5 mg RO6867461 IVT  
• 
Arm C:  6 mg RO6867461 IVT  
This study will consist of a treatment period (20 weeks) and an observational 
period (up to 16 weeks), for a total study length of up to 36 weeks. During the 
treatment period, the study drug will be administered to the patients on Day 1 
and on every 4th week, for a total of 6 injections. During the observational 
period, patients will be evaluated every 4th week.  If during any of these 
evaluations the patients meet the pre-specified criteria, the patients will 
receive a single dose of 0.3 mg ranibizumab, and exit the study. They will 
receive a follow up phone call 7 days after the dose of ranibizumab to 
evaluate any potential adverse events. Otherwise, patients will exit the study 
once they have completed the observational visit at week 36.   
Only one eye will be selected as the study eye. 
 


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Figure 1 Study Design 
 
 
Q4W = every 4 weeks. 
 
The total duration of the study for each patient will be up to 40 weeks, divided as 
follows (see Figure 1): 
• 
Screening:  Up to 4 weeks 
• 
Baseline:  Day 1 
• 
Study treatment administration period:  From Day 1 to Week 20 
• 
Observational period:  From W eek 20 up to Week 36 
• 
Safety follow up call: During the observational period and 7 days after 
ranibizumab administration  
 
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 the Schedule of Assessments (SoA; see 0), are 
completed. 
If a site has an unexpected issue (e.g., the interactive voice and web response 
system (IxRS) is not able to assign the study kit), 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. 
 
 


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1.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is described in Appendix 1.  For additional details, see the 
Schedule of Assessments in Appendix 2. 
1.2 
OUTCOME MEASURES 
1.2.1 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Any relevant safety observations derived from BCVA (modified 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 
 
1.2.2 
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:  Clearance (CL) and volume (V) 
Secondary parameters:  Maximum concentration observed (Cmax), area 
under the concentration-time curve from time 0 to infinity (AUC0-inf), AUC0-τ, 
time to maximum concentration (tmax), t1/2 
Compartmental analysis to assess IVT concentrations, as appropriate 
(exploratory) 
 
 
 
 
1.2.3 
Efficacy and Pharmacodynamic Outcome Measures 
The primary analysis population will be treatment naïve patients. Additional 
analyses may be performed in the overall population and in patients 
previously treated with IVT anti-VEGF. 
1.2.3.1 
Primary Efficacy Outcome Measure 
The primary efficacy outcome measure is the mean change in BCVA (ETDRS 
letters) from baseline at Week 24 in treatment-naïve patients. 


Clinical Study Report: RO6867461 - F. Hoffmann-La Roche Ltd
Protocol BP30099     Report Number 1083913
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Statistical Analysis Plan BP30099 
 
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1.2.3.2 
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 BCVA at Week 24 
• 
Proportion of patients with BCVA ≥ 69 letters (20/40 or better) at Week 24 
• 
Proportion of patients with BCVA ≥ 84 letters (20/20 or better) at Week 24 
Anatomic outcome measures by SD-OCT: 
• 
Mean change from baseline in foveal center point thickness at Week 24  
• 
Mean change from baseline in mean CST (1 mm diameter) at Week 24  
• 
Proportion of patients with resolution of subretinal and intraretinal fluid at Week 
24  
 
Anatomic outcome measures by FFA: 
• 
Proportion of patients with resolution of leakage at the macula at Week 24 
• 
Change from baseline in the size of the foveal avascular zone at Week 24 
 
 
Table 1 Description of Secondary Outcome Measures 
Secondary 
EndPoint 
Detailed Definition 
Variable names used by central reading 
center 
Foveal Center 
Point thickness 
(Central Foveal 
Thickness) 
Thickness from Inner Limiting 
Membrane to the Retinal Pigment 
Epithelial at the horizontal slice 
closest to the center of the fovea 
OCTCentralRetinalThickness1-3 
mean CST 
Mean thickness from Inner 
Limiting Membrane to the Retinal 
Pigment Epithelial over the 1 mm 
central subfield 
OCTCentralSubfieldThickness1-3 
 
intra-retinal fluid 
(IRF) 
Presence of fluid within the retina 
OCTIntraRetinalFluid 
sub-retinal fluid 
SRF) 
Presence of fluid between the 
retina and the retinal pigment 
epithelium 
OCTSubretinalFluidThicknessNotPresent 
Resolution of 
leakage at the 
macula 
Resolution of fluorescein leakage 
at the macula 
FAMaculaMELeakageArea1-3 or 
FAMaculaMELeakage 
Size of the foveal 
avascular zone 
Size of the foveal avascular zone 
(FAZ) by FFA 
FAMaculaFAZArea1-3 
FAMaculaFAZAreaIB1-3 


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1.2.3.3 
Pharmacodynamic Biomarker Outcome Measure 
Plasma PD biomarker outcome measure for this study is as follows: 
• 
Change in plasma levels of VEGF and Ang-2 
 
1.2.4 
Exploratory Outcome Measures 
The exploratory outcome measures for this study include but are not limited to the 
following: 
BCVA: 
• 
Difference in mean BCVA change from baseline between the treatment-
naïve patients and patients with previous IVT anti-VEGF (differential 
effect of RO6867461) 
• 
Proportion of patients with BCVA  69 letters (20/ 40 or better) over time 
• 
Proportion of patients with BCVA  ≥  84 letters (20/ 20 or better) over time 
Disease-related exploratory outcome measure: 
• 
Proportion of patients with DR severity improvement from baseline on the 
ETDRS-DRSS (diabetic retinopathy severity score) at Week 24 
 
Anatomic exploratory outcome measures: 
• 
Change from baseline in macular perfusion and leakage by  FFA at Week 12 
• 
Change from baseline in peripheral perfusion and leakage by FFA at Week 24 
 
Durability-related exploratory outcome measures: 
• 
Time to increase in CST by  ≥ 50µm and/ or loss of  ≥  5 letters of BCVA 
due to DME compared to values at Week 20  
• 
Time to treatment with 0.3 mg ranibizumab after Week 20 
 
 
 
 
 
 
 
 
 
 
 
  
1.3 
DETERMINATION OF SAMPLE SIZE 
The sample size is based on the primary efficacy outcome of mean change in BCVA 
from baseline at Week 24 in the treatment-naïve patients.  Each RO6867461 dose 
(Arms B and C) will be compared with the control group (Arm A). 
Consider 50 treatment-naïve patients randomized to Arms A, B, and C, with a drop-
out rate of 10%.  Assuming a standard deviation of 11 letters, this sample size 


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Statistical Analysis Plan BP30099 
 
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provides 80% power to detect a true difference of 5 letters at the one-sided α level of 
10%.  The minimum detectable difference is approximately 3 letters. 
Approximately 60 previously IVT anti-VEGF treated patients will be enrolled 
in addition for exploratory analyses. 
1.4 
ANALYSIS TIMING 
The primary analysis will be performed at the end of the study, after the last patient 
has completed Week 24 final visit. 
 
STUDY CONDUCT 
2.
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. 
2.1 
RANDOMIZATION 
After written informed consent has been obtained, all patients will receive a screening 
number assigned through the Interactive Voice and Web Response System (IxRS). 
After all patient eligibility requirements are confirmed on Day 1 visit the site personnel 
will contact the IxRS for assignment of a patient identification number (a separate 
number from the screening number).  
Approximately 50 treatment-naïve patients will be randomized on each arm (1:1:1 
randomization scheme) and approximately 30 patients previously treated with 
IVT anti-VEGF will be randomized into arms A and C. Randomization will be 
stratified for the three factors below: 
• 
Baseline BCVA ETDRS letter score assessed on Day 1 (64 letters or better vs. 
63 letters or worse) 
• 
Previous Macular Laser treatment (Yes/No) 
Previous IVT anti-VEGF treatment in study eye (Yes/No) 
2.2 
INDEPENDENT REVIEW FACILITY 
A Roche internal monitoring committee (IMC) will be responsible in the event of an 
interim analysis for sample size evaluation, 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 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 a 
biostatistician, 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. 


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Full details regarding the IMC will be provided separately in the IMC agreement. 
2.3 
DATA MONITORING 
An IMC will review safety data, and may review efficacy data to assess benefit-risk. 
 
STATISTICAL METHODS 
3.
3.1 
ANALYSIS POPULATIONS 
The following analysis populations will be defined: “Efficacy, Pharmacokinetic, and 
Pharmacodynamic Population” and safety population. 
3.1.1 
Safety Analysis Population 
All patients who have received at least one dose of the study drug, whether 
prematurely withdrawn from the study or not, will be included in the safety analysis. 
Patients will be grouped according to the actual treatment received.  
3.1.2 
Efficacy, Pharmacokinetic, and Pharmacodynamic 
Population 
All randomized patients (Intent to Treat, ITT) will be included in the efficacy, PK, and 
PD analysis population. Patients who receive study drug in the study eye different 
that to which they were randomized will be included in the group to which they were 
randomized. Separate ITT populations for the treatment-naïve and previously anti-
VEGF-treated patients will be defined. 
3.2 
ANALYSIS OF STUDY CONDUCT 
The number of patients who are enrolled, discontinued, and completed the study as 
well as the major protocol violations will be summarized. Demographic and baseline 
characteristics will be summarized with descriptive statistics by previous anti-VEGF 
treatment status. 
3.3 
ANALYSIS 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 arm and previous anti-VEGF treatment status 
using frequency tables and summary statistics providing means, medians, standard 
deviations, first and third quartiles, and extreme values. 
3.4 
GENERAL CONSIDERATIONS 
3.4.1 
Visit Windows 
Visit windowing will be performed for this study with nominal visits/assessments 
falling outside of allowable protocol-defined visit windows, being reassigned to an 
appropriate visit for use in analyses. 
If multiple valid (non-missing) values for a variable are recorded in the same visit 
window, one record will be selected for summary/analysis of the data by the following 
priority: 
• 
The originally scheduled visit assessment 


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• 
The assessment closest to the target/planned assessment day.  
If scheduled assessments were grouped into multiple visits, the assessments will 
be assigned to a single visit provided all assessments fall within the same visit 
window. 
Note that unscheduled visits could potentially be included in summaries and 
analyses following the application of these visit assignment rules. 
Assessments that fall outside of the protocol-defined visit windows will be 
assigned to the closest target visit.  
Unless otherwise specified, all analyses and summaries involving visit, will use 
visits assigned after visit windowing has been performed. 
3.4.2 
Baseline 
The baseline measurement is the latest non-missing observation before the first dose 
of study medication. 
3.5 
EFFICACY ANALYSIS 
The List of Planned Outputs (LoPO) contains the full list of reports for the efficacy 
analysis. 
The primary and secondary efficacy analyses will include all randomized treatment-
naïve patients, with patients grouped according to the treatment assigned at 
randomization.  Patients with previous IVT anti-VEGF will be analyzed 
separately. Unless there is strong evidence for RO6867461 effect 
modification by previous IVT anti-VEGF, primary efficacy analyses will be 
repeated in all randomized patients (see 3.5.3). 
3.5.1 
Primary Efficacy Endpoint 
The primary efficacy variable is the study eye BCVA change from baseline at Week 
24.  The primary efficacy analysis will be performed using a Linear Mixed Effects 
Model for Repeated Measurements (MMRM) model.  The model will include the 
categorical covariates of treatment group, categorical visit, and visit by treatment 
group interaction term, randomization stratification factors, and a continuous 
covariate of baseline BCVA.  An unstructured covariance will be used to account for 
within-patient correlation (General Linear Model), but another variance-covariance 
structure such as AR(1) + random patient effect may be selected in case of 
convergence issues.  The primary statistical test will aim to test the null hypothesis: 
H0: There is no difference between either of the RO6867461arms (Arms B and C) 
and the control group (Arm A) for mean BCVA change from baseline at 
Week 24 in the treatment-naïve patient population vs. 
HA:  Arm B or C is different from arm A. 
The model-based estimate of the difference between each of the treatment 
groups (Arms B and C) and the control group (Arm A) at Week 24, together with 80% 
confidence interval and corresponding p-value will be reported as the primary 


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efficacy measures.  The mean and 80% CI within each treatment group and for the 
difference between RO6867461 treatment groups (Arms B and C) and the control 
group (Arm A) at the other time points will also be reported.  There will be no formal 
correction for multiple comparisons. Tests for arms B vs A and C vs A will be carried 
out at one-sided 10% alpha. 
3.5.2 
Secondary Efficacy Endpoints 
For all key secondary endpoints measured on a continuous scale, a MMRM model 
described in section 3.5.1 will be used. Nominal p-value will be reported without 
correction for multiple comparisons.   
Binary key secondary endpoints will be analyzed using Generalized Estimating 
Equations (GEE) with a binomial distribution, logit link function for odds ratios and 
identity link for risk differences, and unstructured covariance. In case of convergence 
issues, AR(1) covariance structure will be used. The model will include the 
categorical covariates of treatment group, visit, and visit by treatment group 
interaction term. Least squares means on the probability scale for each treatment 
arm with the corresponding 80% confidence intervals and odds ratios relative to the 
control arm will be computed. 
 
Data transformation (e.g., logarithmic transformation) may be applied as appropriate.  
Other statistical models and additional analyses may also be performed as 
appropriate. Fisher’s exact test may be used for binary endpoints in case GEE 
models do not converge. 
In addition, the influence of baseline parameters on the primary endpoint will be 
evaluated as covariates in the linear model and in subgroup analysis as appropriate 
(see 4.4.5). 
3.5.3 
Exploratory Efficacy Endpoints 
Time to event endpoints will be tested with a two-sided stratified log rank test using 
the randomization stratification factors BCVA ETDRS letter score (64 letters or better 
vs. 63 letters or worse) and previous macular laser treatment as strata. Kaplan Meier 
curves will be displayed, and median time to event estimates will be computed.  
Effect modification will be tested in the overall (treatment-naïve and previously 
treated combined) ITT population by adding a previous IVT anti-VEGF treatment 
status and a treatment arm by visit by previous IVT anti-VEGF treatment status 
interaction terms to the Linear model described in section 3.5.1. The treatment arm 
by visit by previous IVT anti-VEGF treatment status interaction term will be tested at 
a 10% significance level. 
3.5.4 
Sensitivity Analyses 
Effects of prognostic factors on the BCVA change from baseline will be investigated 
using the MMRM model described in section 3.5.1. The measurement at BL 
(baseline) of each of the following variables may be used as covariates in the model: 
• 
Age 


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3.5.5 
Subgroup Analyses 
For the sub-group analysis the MMRM for change from baseline in BCVA will be 
used in the following subgroups defined at baseline:  
• 
Previous macular laser treatment (from eCRF) 
• 
Gender 
• 
BCVA strata (64 letters or better vs. 63 letters or worse, from eCRF). 
• 
BCVA Categories at BL (20/40 or better, 20/200 or better), 
The sub-group analyses will be performed separately in each sub-group. 
3.6 
SAFETY ANALYSES 
All safety analyses will be based on the safety analysis population. The LoPO 
contains the full list of reports for safety analyses. 
3.6.1 
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, including separate exploratory analyses of ATE 
events (Appendix 3). 
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.  
3.6.2 
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. 
3.6.2.1 
Standard Reference Ranges and Transformation of Data 
Roche standard reference ranges, rather than the reference ranges of the 
Investigator or central lab, 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. 


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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 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. 
3.6.2.2 
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. 
3.6.3 
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. 
3.6.4 
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. 
3.6.5 
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, except for treatment 
arm A. 
3.6.6 
Ocular Assessments 
Results of the following ocular assessments will be summarized by time point for the 
study eye using descriptive summaries:  BCVA (also for the non-study eye), IOP 
(also for the non-study eye), and changes from baseline in these measurements will 
be tabulated.   
3.6.7 
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. 


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Concomitant medications will be presented in summary tables and listings, separated 
into ocular and non-ocular categories. 
3.6.8 
Exposure to Study Medication 
The following extent to study medication will be summarized by treatment arm: 
• 
Duration of treatment, to be calculated as first day to last day to masked study 
medication  
• 
Relative extent of exposure as number of given intravitreal injections divided 
by number of planned intravitreal injections of masked study medication 
during the treatment duration of a patient. 
3.7 
MISSING DATA 
An analysis of the sensitivity of the assumptions on missing values may be 
performed for the primary efficacy variable. 
The primary analysis assumes that the data are missing at random (MAR). 
As a sensitivity analysis the LOCF imputation will be used in the analysis of the 
primary endpoint. 
3.8 
INTERIM ANALYSES 
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. 
List of interim analysis outputs is described in the interim LoPO document. 


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APPENDIX 1 
PROTOCOL SYNOPSIS 
TITLE: 
A MULTIPLE-CENTER, MULTIPLE-DOSE, 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 DIABETIC MACULAR EDEMA 
PROTOCOL NUMBER: 
BP30099 
VERSION: 
1 
EUDRACT NUMBER: 
NA 
IND NUMBER: 
119,225 
TEST PRODUCT: 
RO6867461 
PHASE: 
II 
INDICATION: 
Diabetic macular edema (DME) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
OBJECTIVES 
Primary Objective 
The primary objective of this study is: 
To evaluate the efficacy of RO6867461 compared with the active comparator in 
treatment naïve patients with center-involving diabetic macular edema (CI-DME)  
Secondary Objectives 
The secondary objectives for 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 and anatomical outcomes informing on the 
mechanism of action of RO6867461 
• 
To investigate the formation of plasma anti-RO6867461 antibodies 
• 
To explore the duration of effect of RO6867461  
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To explore the predictive effect of previous IVT anti-V EGF treatment on efficacy of 
RO6867461 
• 
To evaluate the efficacy and safety of RO6867461 compared with the active 
comparator in patients with CI-DME with previous IVT anti-VEGF treatment. 
 
 
 
 
 
 
 
• 
To evaluate improvement in diabetic retinopathy (DR) severity score 


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STUDY DESIGN 
This is a multiple-center, multiple-dose, randomized, active comparator−controlled, 
double-masked, three parallel group, 36-week study in patients with CI-DME. 
The three groups of this study are as follows: 
• 
Arm A:  0.3 mg ranibizumab IVT  
• 
Arm B:  1.5 mg RO6867461 IVT  
• 
Arm C:  6 mg RO6867461 IVT  
Only one eye will be selected as the study eye.  Where both eyes meet all eligibility criteria, 
the eye with the worse BCVA will be defined as the study eye.  Where both eyes meet all 
eligibility criteria and have the same BCVA letter score at Day 1, study eye selection is at 
the investigator’s discretion. 
NUMBER OF PATIENTS 
Up to 210 patients will be randomized. 
Approximately 150 treatment-naïve patients and approximately 60 patients who have been 
previously treated with IV T anti-VEGF will be enrolled in the study. 
Approximately 50 treatment-naïve patients will be randomized on each arm (1:1:1 
randomization scheme) and approximately 30 patients previously treated with IVT anti-
VEGF will be randomized into arms A and C. 
TARGET POPULATION 
Male and female patients of ≥ 18 years of age with CI-DME. 
INCLUSION/EXCLUSION CRITERIA 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
Ocular criteria for study eye: 
• 
Macular edema associated with DR defined as macular thickening by spectral domain 
optical coherence tomography (SD-OCT) involving the center of the macula:  central 
subfield thickness (CST) of ≥ 325 µm with Spectralis (Heidelberg) at screening (where 
Spectralis is not available, the following devices and CST thresholds are acceptable:  
CST ≥ 315 µm for Cirrus, CST ≥ 315 µm for Topcon, CST ≥ 295 µm for Optovue).   
• 
Decreased visual acuity attributable primarily to DME, with best corrected visual acuity 
(BCVA) letter score of 73−24 letters (inclusive) on Early Treatment Diabetic Retinopathy 
Study (ETDRS)-like charts (20/40−20/320 Snellen equivalent) on Day 1 
• 
Clear ocular media and adequate pupillary dilatation to allow acquisition of good quality 
retinal images to confirm diagnosis 
 
General criteria: 
• 
Diagnosis of diabetes mellitus (DM; Type 1 or Type 2), as defined by the World Health 
Organization and/or American Diabetes Association 
• 
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 ICH and local regulations. 
• 
Age ≥ 18 years 
• 
For women who are not postmenopausal (i.e. ≥12 months of non-therapy-induced 
amenorrhea, confirmed by FSH, if not on hormone replacement) 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 4 weeks after last dose. 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of 
the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post 
ovulation methods) and withdrawal are not acceptable methods of contraception; 
Examples of contraceptive methods with an expected failure rate of < 1% per year 
include male sterilization, hormonal implants, proper use of combined oral or 


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17 
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. 
• 
For men:  agreement to use a barrier method of contraception during the treatment 
period for at least 4 weeks after the last dose of study drug 
• 
Patients must be willing not to participate in any other clinical trial including an 
investigational medical 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: 
• 
Any signs of high-risk PDR defined as: 
• 
any vitreous or pre-retinal hemorrhage 
• 
NVE  ≥  1/2 disc area within an area equivalent to the standard mydriatic ETDRS 
7- field on clinical examination  
• 
NVD  ≥ 1/3 disc area on clinical examination  
• 
Any IVT anti-VEGF treatment within 3 months prior to Day 1 
• 
Any panretinal photocoagulation (PRP) treatment prior to Day 1 
• 
Any macular laser photocoagulation within 3 months prior to Day 1 
• 
History of vitreoretinal surgery 
• 
Any IVT or periocular corticosteroid treatment within 3months prior to Day 1. A ny 
history of Iluvien or Ozurdex implants prior to Day 1 will not be permitted 
• 
Any cataract surgery or treatment for complications of cataract surgery with 
steroids within 3 months prior to Day 1 
• 
History of incisional glaucoma surgery 
• 
Uncontrolled glaucoma (e.g., progressive loss of visual fields or defined as intraocular 
pressure [IOP] ≥ 25 mmHg despite treatment with anti-glaucoma medication) 
 
Concurrent ocular conditions in the study eye: 
• 
History of rubeosis  
• 
Any current or history of ocular disease other than DME that may confound assessment 
of the macula or affect central vision (e.g., age-related macular degeneration, retinal 
vein occlusion, uveitis, angioid streaks, histoplasmosis, active or inactive 
cytomegalovirus, pathological myopia, retinal detachment, macular traction, macular 
hole, significant cataract) 
• 
Any current ocular condition for which, in the opinion of the investigator, visual 
acuity loss would not improve from resolution of macular edema (e.g., foveal atrophy, 
pigment abnormalities, dense sub-foveal hard exudates, non-retinal condition) 
• 
Any active ocular infection on Day 1 
• 
Any active intraocular inflammation (grade trace or above) on Day 1 
 
Characteristics for fellow eye: 
• 
Any anti-VEGF treatment within 7 days prior to Day 1 
• 
Any retinal condition that, in the opinion of the investigator, might require anti-VEGF 
treatment within 7 days from Day 1 
 
General criteria: 
• 
Any systemic anti-VEGF within 6 months prior to Day 1 
• 
Any major illness or major surgical procedure within 1 month prior to Day 1 
• 
Any febrile illness within 1 week prior to Day 1 
• 
Any stroke or myocardial infarction within 12 months prior to Day 1 


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• 
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 needs to be controlled by 
antihypertensive medication, the patient should be taking the same medication 
continuously for at least 1 month prior to Day 1. 
• 
Patients with glycosylated hemoglobin HbA1c > 12% at screening 
• 
Untreated diabetes mellitus or initiation of oral anti-diabetic medication or insulin within 
4 months prior to Day 1 or anticipated change of anti-diabetic medications within the 
duration of the study 
• 
Renal failure requiring renal transplant, hemodialysis, or peritoneal dialysis within 
6 months prior to Day 1 or anticipated to require hemodialysis or peritoneal dialysis at 
any time during the study 
• 
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 IMP 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 female 
• 
Use of systemic corticosteroids within 1 month prior to Day 1 
• 
Any known hypersensitivity to active comparator, fluorescein, any ingredient of the 
formulation used, dilating eye drops, or any anesthetics and microbial drops used 
• 
Any other restriction accorded to the use of the active comparator 
• 
Any treatment with an IMP in the 3 months prior to Day 1 
 
LENGTH OF STUDY 
The total duration of the study will be up to 40 weeks (from screening through study 
completion) for each enrolled patient as follows: 
• 
Screening:  up to 4 weeks 
• 
Baseline:  Day 1 
• 
Study treatment administration period:  from Day 1 to Week 20 
• 
Observational period:  From W eek 20 up to W eek 36 
• 
Safety follow up call: During the observational period and 7 days after ranibizumab 
administration  
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. 
OUTCOME MEASURES 
SAFETY OUTCOME MEASURES 
The safety outcome measures for this study are as follows: 
• 
Any relevant safety observations derived from BCVA (modified ETDRS charts), slit-lamp 
examination, dilated binocular indirect high-magnification ophthalmoscopy, 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 
 




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• 
Proportion of patients with DR severity improvement from baseline on the ETDRS-
DRSS (diabetic retinopathy severity score) at Week 24 
 
Anatomic exploratory outcome measures: 
• 
Change from baseline in macular perfusion and leakage by FFA at Week 12 
• 
Change from baseline in peripheral perfusion and leakage by FFA at Week 24 
 
Durability-related exploratory outcome measures: 
• 
Time to increase of CST by  ≥ 50µm and/or loss of  ≥  5 letters of BCVA due to DME 
compared to values at W eek 20  
• 
Time to treatment with 0.3 mg ranibizumab after W eek 20 
 
 
 
 
 
 
 
 
 
 
BIOMARKER/GENOTYPING SAMPLE COLLECTION 
Mandatory Biomarkers 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 diabetic disease biomarkers.  
Clinical Genotyping Samples 
A mandatory whole blood sample will be taken for DNA extraction from every patient.  The 
DNA may be used to study genes related to DME, DR, and angiogenesis (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 other mandatory 
blood samples.  This specimen will be destroyed up to 2 years after the final closure of the 
clinical database. 
 
 
 
 
 


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INVESTIGATIONAL MEDICINAL PRODUCT(S) 
Test Product: RO6867461 
Vials of sterile, colorless to brownish, preservative-free solution of RO6867461 (120 mg/mL) 
for IVT administration of either 1.5 mg or 6 mg dose every 4 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. 
A volume of 50 µL will be administered by IVT injection for all study drugs tested in this 
study. 
Comparator: ranibizumab 
Ranibizumab (nominal content 0.3 mg/0.05 mL) required for completion of this study will be 
provided by the Sponsor as a solution formulated at 6 mg/mL and supplied as a single-use 
vial. 
 
The double-masked design is achieved through strict independence of the pharmacist (or 
designated personnel) and investigators who are preparing and administering study drug, 
from the assessing investigators and remaining site personnel. 
PROCEDURES 
Detailed SoA and procedures are tabulated in Appendix 1 of the protocol. 
Screening 
Patients with CI-DME 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 females of childbearing potential, and safety 
laboratory parameters.  A predefined set of 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 injection of either RO6867461 or comparator 
therapy according to the randomization schedule and following established standard 
procedures.  Patients will return to the eye clinic every 4 weeks for study drug administration 
and assessments as outlined in the SoA.   
A post-treatment administration check of study eye will be performed for each patient 
immediately after study treatment administration by testing finger count vision, hand motion, 
and light perception, as appropriate.  On the day of dosing, IOP will be monitored at 30 
minutes post-administration in the study eye, using either Goldmann tonometry or Tono-
pen, and if IOP ≥ 30 mmHg in the study eye, 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. 
 
 
 
Observational Period 
Patients will return for evaluation every 4th week.  If during any of these evaluations the 
patients meet the pre-specified criteria, the patients will receive a single dose of 0.3 mg 
ranibizumab, exit the study, and receive a follow up phone call 7 days after the dose of 
ranibizumab to evaluate any potential adverse events. Otherwise, patients will exit the 
study once they have completed the observational visit at week 36.   
STATISTICAL METHODS 
PRIMARY ANALYSIS 
The primary efficacy analyses will include all randomized patients, with patients grouped 
according to the treatment assigned at randomization. 
The primary efficacy variable is the BCVA change from baseline to Week 24.  The primary 
efficacy analysis will be performed using a Mixed Model for Repeated Measurement 
(MMRM) model. 


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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., 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 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. 
 
 
 
 
 
 
 
 
 
 
SAMPLE SIZE JUSTIFICATION 
The sample size is based on the primary efficacy outcome of mean change in BCVA from 
baseline at Week 24 in the treatment-naïve patients.  Each RO6867461 dose (Arms B and 
C) will be compared with the control group (Arm A). 
Consider 50 treatment-naïve patients randomized to Arm A, B, and C, with a drop-out rate 
of 10%.  Assuming a standard deviation of 11 letters, this sample size provides 
approximately 80% power to detect a true difference of 5 letters at the one-sided α level of 
10%.  The minimum detectable difference is approximately 3 letters. 
Approximately 60 previously IVT anti-VEGF treated patients will be enrolled in addition 
for exploratory analyses. 
INTERIM ANALYSES 
Two efficacy interim analyses to inform about possible future development options for 
RO6867461 are foreseen. They will not influence the study conduct.  One  interim efficacy 
analysis is foreseen after approximately 28 treatment-naïve patients in each arm have 
completed the Week 24 visit, and one when approximately all patients have completed the 
Week 24 visit.  
A safety analysis will be performed if safety issues have been identified during ongoing 
review of the masked data.  
Up to two additional interim analyses may be conducted for efficacy. 
OTHER CONSIDERATIONS 
NA 


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LIST OF PROHIBITED MEDICATIONS 
Concomitant Therapy 
Patients who use maintenance therapy other than those required to treat DME should 
continue its use. 
PRP is permitted in either eye, if clinically indicated for the treatment of proliferative 
diabetic retinopathy or retinal holes or tears post randomization. 
The decision to administer antimicrobial drops before and after the IVT administration is at 
the discretion of the investigator. 
 
Prohibited Therapy 
At the discretion of the investigator, patients may continue to receive all medications and 
standard treatments administered for other conditions, except the following: 
• 
Concurrent use of systemic anti-VEGF agents 
• 
Concurrent use of IVT anti-VEGF therapy in the fellow eye within 7 days preceding or 
following the study eye treatment 
• 
Concurrent use of IVT or subtenon corticosteroids in study eye, except as required to 
treat adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






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c 
Assessment in study eye only; except at screening for imaging assessments (FP, EDI SD-OCT, FFA), where either eye has a potential to meet all eligibility criteria 
d 
Finger count vision assessment asap after, and within maximum of 15 min from study drug or ranibizumab administration 
  
  
  
 
Performed prior to pupil dilation 
  
  
  
  
  
  
  
  
  
  
  
f 
 
 
  
  
  
  
  
  
  
  
g 
At day 1 but can be done at any other visit if the 
sample not collected at baseline 
  
  
  
  
  
  
  
 
M andatory, except in countries or at investigational sites where 
IRB/ EC does not approve 
  
  
  
  
  
  
 
 
  
j 
 
k 
Baseline assessments 
  
  
  
  
  
  
  
  
  
  
  
  
 
IOP to be performed in both study and fellow eye. At visits with either study drug or ranibizumab administration the assessment post-treatment administration is in the study eye only. If IOP ≥ 30 mmHg at 30 ( 5) minutes post-treatment 
administration in the study eye, then IOP is measured again at 60 (±10) minutes. 
 
 
m 
 
  
  
  
  
  
  
  
  
n 
At the discretion of the investigator abnormal values might be followed-up 
at an unscheduled visit 
  
  
  
  
  
o 
Optional at Day 1 
  
  
  
  
  
  
  
  
  
  
  
  
  
p 
The interval between two administrations of study drug needs to be at least 21 days 
  
  
  
  
  
  
q 
when this visit becomes the 
final visit 
  
  
  
  
  
  
  
  
  
  
  
r 
if pre-specified criteria are met 
  
  
  
  
  
  
  
  
  
  
  
s 
if patient receives ranibizumab at 
that visit 
  
  
  
  
  
  
  
  
  
  
t 
visit becomes final visit when patient receives 0.3 mg ranibizumab based on meeting pre-
specified criteria 
  
  
  
  
u 
7 days after 
0.3 mg 
ranibizumab 
administration 
(+/ - 3 days) 
  
  
  
  
  
  
  
  
  


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Appendix 3 
 
Definition of ATE 
ATE events are non-fatal stroke, non-fatal myocardial infarction, or vascular death 
(including deaths of unknown cause). They are defined as the following MedDRA 
terms/baskets: 
Myocardial infarction 
 
SMQ Broad | Myocardial infarction (SMQ)  
PT | Coronary arterial stent insertion  
PT | Coronary artery bypass 
PT | Coronary endarterectomy 
PT | Coronary revascularisation 
 
Non-myocardial arterial thromboembolic events (ATEs) 
 
SMQ Narrow | Haemorrhagic cerebrovascular conditions 
SMQ Narrow | Ischaemic cerebrovascular conditions 
PT | Amaurosis 
PT | Amaurosis fugax 
PT | Aortic bypass  
PT | Aortic embolus 
PT | Aortic surgery 
PT | Aortic thrombosis 
PT | Aortogram abnormal 
PT | Arterectomy 
PT | Arterectomy with graft replacement 
PT | Arterial bypass operation 
PT | Arterial graft 
PT | Arterial occlusive disease 
PT | Arterial stent insertion 
PT | Arterial therapeutic procedure 
PT | Arterial thrombosis 
PT | Arteriogram abnormal 
PT | Arteriogram carotid abnormal 
PT | Atherectomy 
PT | Blindness transient 
PT | Carotid angioplasty 
PT | Cerebral hypoperfusion 
PT | Coeliac artery occlusion 
PT | Embolia cutis medicamentosa 
PT | Embolism 
PT | Embolism arterial 
PT | Endarterectomy 
PT | Femoral artery embolism 
PT | Femoral artery occlusion  
PT | Hepatic artery embolism  
PT | Hepatic artery occlusion  
PT | Hepatic artery thrombosis  
PT | Hypothenar hammer syndrome  


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PT | Iliac artery embolism 
PT | Iliac artery occlusion  
PT | Intra-aortic balloon placement 
PT | Intraoperative cerebral artery occlusion 
PT | Leriche syndrome  
PT | Mesenteric arteriosclerosis  
PT | Mesenteric artery embolism 
PT | Mesenteric artery stenosis  
PT | Mesenteric artery stent insertion  
PT | Mesenteric artery thrombosis  
PT | Microembolism  
PT | Penile artery occlusion  
PT | Percutaneous coronary intervention  
PT | Peripheral arterial occlusive disease 
PT | Peripheral arterial reocclusion  
PT | Peripheral artery angioplasty  
PT | Peripheral artery bypass  
PT | Peripheral artery stent insertion  
PT | Peripheral artery thrombosis 
PT | Peripheral embolism  
PT | Peripheral endarterectomy  
PT | Popliteal artery entrapment syndrome  
PT | Pulmonary artery therapeutic procedure 
PT | Pulmonary artery thrombosis  
PT | Pulmonary endarterectomy 
PT | Renal artery angioplasty 
PT | Renal artery occlusion  
PT | Renal artery thrombosis  
PT | Renal embolism  
PT | Splenic embolism 
PT | Stress cardiomyopathy 
PT | Subclavian artery embolism  
PT | Subclavian artery occlusion  
PT | Subclavian artery thrombosis 
PT | Superior mesenteric artery syndrome  
PT | Thromboembolectomy 
PT | Thrombotic microangiopathy 
PT | Thrombotic thrombocytopenic purpura  
PT | Truncus coeliacus thrombosis 
PT | Visual acuity reduced transiently 
 
Venous thromboembolism 
 
PT | Axillary vein thrombosis  
PT | Budd-Chiari syndrome  
PT | Catheterisation venous  
PT | Cavernous sinus thrombosis 
PT | Central venous catheterisation  
PT | Cerebral venous thrombosis  
PT | Compression stockings application 
PT | Deep vein thrombosis  


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PT | Deep vein thrombosis postoperative 
PT | Embolism  
PT | Embolism venous  
PT | Hepatic vein occlusion 
PT | Hepatic vein thrombosis 
PT | Homans' sign positive  
PT | Iliac vein occlusion  
PT | Inferior vena cava syndrome 
PT | Inferior vena caval occlusion  
PT | Intracranial venous sinus thrombosis  
PT | Intravenous catheter management 
PT | Jugular vein thrombosis  
PT | May-Thurner syndrome  
PT | Mesenteric vein thrombosis 
PT | Obstetrical pulmonary embolism  
PT | Obstructive shock 
PT | Ovarian vein thrombosis  
PT | Paget-Schroetter syndrome  
PT | Pelvic venous thrombosis  
PT | Penile vein thrombosis  
PT | Phlebectomy  
PT | Phleboplasty  
PT | Portal vein cavernous transformation  
PT | Portal vein occlusion  
PT | Portal vein thrombosis  
PT | Post procedural pulmonary embolism  
PT | Post thrombotic syndrome 
PT | Postoperative thrombosis  
PT | Postpartum venous thrombosis  
PT | Pulmonary embolism  
PT | Pulmonary infarction  
PT | Pulmonary microemboli  
PT | Pulmonary thrombosis 
PT | Pulmonary vein occlusion 
PT | Pulmonary veno-occlusive disease  
PT | Pulmonary venous thrombosis  
PT | Renal vein embolism  
PT | Renal vein occlusion  
PT | Renal vein thrombosis  
PT | SI QIII TIII pattern  
PT | Splenic vein occlusion 
PT | Splenic vein thrombosis  
PT | Subclavian vein thrombosis  
PT | Superior sagittal sinus thrombosis  
PT | Superior vena cava syndrome 
PT | Thrombophlebitis  
PT | Thrombophlebitis migrans  
PT | Thrombophlebitis neonatal  
PT | Thrombophlebitis superficial  
PT | Thrombosed varicose vein  
PT | Thrombosis corpora cavernosa  


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PT | Transverse sinus thrombosis  
PT | Vascular graft  
PT | Vena cava embolism  
PT | Vena cava filter insertion 
PT | Vena cava thrombosis  
PT | Venogram abnormal  
PT | Venoocclusive disease  
PT | Venoocclusive liver disease 
PT | Venous occlusion  
PT | Venous operation  
PT | Venous recanalisation  
PT | Venous stent insertion 
PT | Venous thrombosis  
PT | Venous thrombosis in pregnancy  
PT | Venous thrombosis limb  
PT | Venous thrombosis neonatal 


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Appendix 4 
 
Imaging Variables not listed as primary or secondary endpoints 
Imaging 
Modality 
Outcome 
Variable 
Detailed Definition 
Variable names used by central 
reading center 
SD-OCT 
Total macular 
volume 
Cube Volume (mm3) ILM-RPE - 
Reader 1-3 
OCTTotalMaculaVolume1-3 
Epiretinal 
Membrane 
 
OCTEpiretinalMembrane 
FFA 
Macular 
perfusion and 
leakage 
 
FAMaculaIschemiaArea1-3 
FAMaculaIschemiaAreaIB1-3 
FAMaculaIschemiaNone 
Peripheral 
perfusion and 
leakage 
 
FANonMaculaCapillaryNonperfusionArea 
FANonMaculaCapillaryNonperfusionAreaIB1-
3 
FANonMaculaCapillaryNonperfusionNone 
Prior Macular 
Laser 
Prior Macular Laser by FFA-
Red-free present 
RFPriorMacularLaser 
Prior Macular 
Laser 
Prior Macular Laser by FFA 
present 
FAMaculaPriorMacularLaserNone 
Prior PRP 
Prior panretinal 
photocoagulation by FFA 
present 
FANonMaculaPriorPRP 
Focal Edema 
Macula focal leakage 
FAMaculaMEFocalLeakage 
Diffuse Edema 
Macula diffuse leakage 
FAMaculaMEDiffuseLeakage 
Cystoid Edema 
Cystoid edema 
FAMaculaCystoidEdema 
Fundus Color 
Photography 
Cup/Disk Ratio 
 
ColorCuptoDiskRatio1-3 
Diabetic 
retinopathy 
severity scale 
 
DRSS 
Prior Macular 
Laser 
Prior Macular Laser by FP 
present 
ColorPriorMacularLaser 
Prior PRP 
Prior panretinal 
photocoagulation by FP present 
ColorNonMaculaPriorPRP 
 
Baseline Ocular Characteristics 


Clinical Study Report: RO6867461 - F. Hoffmann-La Roche Ltd
Protocol BP30099     Report Number 1083913
3605
 
 
RO6867461 (VEGF/Ang2)—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP30099 
32 
1. Cataracts - Use Medical History as source for the Baseline Ocular table.  
2. Pan Retinal Photocoagulation laser - Targeted Surgeries and Procedures eCRF page 
3. Peripheral Ischemia/Perfusion - Use FANonMaculaCapillaryNonperfusionNone, 
alongside FANonMaculaCapillaryNonperfusionArea for area size