A Phase II, Multicenter, Randomized, Double Masked, Active Comparator-Controlled Study to Investigate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7200220 in Combination With Ranibizumab Administered Intravitreally in Patients With Diabetic Macular Edema
Phase: PHASE2
Conditions: Diabetic Macular Edema
Sponsor: Hoffmann-La Roche

Official Title: 
A Phase II, Multicenter, Randomized, Double Masked, Active 
Comparator-Controlled Study to Investigate the Efficacy, Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of 
RO7200220 in Combination With Ranibizumab Administered 
Intravitreally in Patients With Diabetic Macular Edema 
NCT Number: 
NCT05151744 
Document Date: 
Protocol Version 3: 23-Apr-2023 

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The information contained in this document, especially any unpublished data, is the property of 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. 
 
RO7200220 and RANIBIZUMAB—F. Hoffmann-La Roche Ltd 
Protocol BP43464, Version 3 
PROTOCOL 
TITLE: 
A PHASE II, MULTICENTER, RANDOMIZED, 
DOUBLE MASKED, ACTIVE COMPARATOR-
CONTROLLED STUDY TO INVESTIGATE THE 
EFFICACY, SAFETY, TOLERABILITY, 
PHARMACOKINETICS, AND 
PHARMACODYNAMICS OF RO7200220 IN 
COMBINATION WITH RANIBIZUMAB 
ADMINISTERED INTRAVITREALLY IN 
PATIENTS WITH DIABETIC MACULAR 
EDEMA 
PROTOCOL NUMBER: 
BP43464 
VERSION: 
3 
EUDRACT NUMBER: 
2021-004390-31 
IND NUMBER: 
125644 
TEST PRODUCT: 
RO7200220 in combination with ranibizumab 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1: 13-Sep-2021  
DATE AMENDED: 
Version 2: 11-Jul-2022 
Version 3: See electronic signature and date 
stamp on the final page of this document 

RO7200220 and RANIBIZUMAB—F. Hoffmann-La Roche Ltd 
2/Protocol BP43464, Version 3 
PROTOCOL ACCEPTANCE FORM 
TITLE: 
A PHASE II, MULTICENTER, RANDOMIZED, 
DOUBLE MASKED, ACTIVE COMPARATOR-
CONTROLLED STUDY TO INVESTIGATE THE 
EFFICACY, SAFETY, TOLERABILITY, 
PHARMACOKINETICS, AND 
PHARMACODYNAMICS OF RO7200220 IN 
COMBINATION WITH RANIBIZUMAB 
ADMINISTERED INTRAVITREALLY IN 
PATIENTS WITH DIABETIC MACULAR 
EDEMA 
PROTOCOL NUMBER: 
BP43464 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2021-004390-31 
IND NUMBER: 
125644 
TEST PRODUCT: 
R07200220 in combination with ranibizumab 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
Please keep the signed original form in your study files, and return a copy to your local 
Site Monitor. 

RO7200220 and RANIBIZUMAB—F. Hoffmann-La Roche Ltd 
3/Protocol BP43464, Version 3 
PROTOCOL AMENDMENT, VERSION 3:  
RATIONALE 
Protocol BP43464 Version 2 has been amended to reflect the changes that have been 
outlined 
 
Changes to the protocol, along with a rationale for each change, are summarized below. 
 
Sections 2.2.3 (Clinical Studies on RO7200220) 
 
 
Information of the 
 
 in two Phase II studies has been added. 
 
Section 5.2 (Exclusion Criteria) 
 
Exclusion criterion #26: Patients with 
 
 
 
Exclusion criterion #30: Clarification added that patients 
 
 
 
Section 7.1 (Discontinuation of Study Treatment) 
It has been specified that participants 
 
 
 
Section 8.2 (Safety Assessment) 
Overall safety measures for assessment of 
 
have been added. Further recommendation about additional 
 
 have been added. 
 
Section 8.9.2 (Assessment during Treatment) 
Information that at each study visit, a careful assessment for 
 
should be done. 
 
Section 8.9.5 (Assessments at the Occurrence of a 
 
 
 
It has been clarified which additional assessments are recommended in case of a 
. Further 
recommendation about additional 
 have been 
added. 
 
Additional minor changes have been made to improve clarity and consistency. 
Substantial new information appears in the font Book Antiqua italics. This amendment 
represents cumulative changes to the original protocol. 
 
 

RO7200220 and RANIBIZUMAB—F. Hoffmann-La Roche Ltd 
4/Protocol BP43464, Version 3 
 
TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................... 2 
1. 
PROTOCOL SUMMARY ............................................................... 12 
1.1 
Synopsis .................................................................................. 12 
1.2 
Schematic of Study Design ...................................................... 21 
1.3 
Schedule of Activities ............................................................... 21 
2. 
INTRODUCTION ........................................................................... 26 
2.1 
Study Rationale ....................................................................... 26 
2.2 
Background.............................................................................. 26 
2.2.1 
Background on IL-6 and Diabetic Macular Edema ................... 26 
2.2.2 
Background on RO7200220 .................................................... 27 
2.2.3 
Clinical Studies with RO7200220 ............................................. 27 
2.2.4 
Choice of Combination Treatment and Comparator ................ 28 
2.3 
Benefit/Risk Assessment ......................................................... 29 
3. 
OBJECTIVES AND ENDPOINTS ................................................. 30 
4. 
STUDY DESIGN ........................................................................... 34 
4.1 
Overall Design ......................................................................... 34 
4.1.1 
Length of the Study .................................................................. 35 
4.1.1.1 
Communication Strategy ......................................................... 35 
4.1.2 
Administrative Structure ........................................................... 35 
4.2 
Scientific Rationale for Study Design ....................................... 36 
4.2.1 
Rationale for Study Population ................................................ 36 
4.2.2 
Rationale for Control Group ..................................................... 36 
................................ 36 
4.2.4 
Rationale for Blood Biomarker Assessments ........................... 37 
4.3 
Justification for Dose ............................................................... 37 
4.4 
End of Study Definition ............................................................ 38 
5. 
STUDY POPULATION .................................................................. 38 
5.1 
Inclusion Criteria ...................................................................... 39 
5.2 
Exclusion Criteria ..................................................................... 40 
5.3 
Lifestyle Considerations ........................................................... 43 

RO7200220 and RANIBIZUMAB—F. Hoffmann-La Roche Ltd 
5/Protocol BP43464, Version 3 
5.4 
Screen Failures ........................................................................ 43 
5.5 
Recruitment Procedures .......................................................... 44 
6. 
TREATMENTS .............................................................................. 44 
6.1 
Treatments Administered ......................................................... 44 
6.1.1 
Medical Devices ....................................................................... 48 
6.2 
Preparation/Handling/Storage/Accountability........................... 48 
6.3 
Measures to Minimize Bias: Randomization and Masking ....... 49 
6.3.1 
Method of Treatment Assignment and Masking....................... 49 
....... 50 
....... 50 
6.3.4 
Masking ................................................................................... 51 
6.3.4.1 
Masked Roles .......................................................................... 51 
6.3.4.2 
Unmasked Roles ..................................................................... 52 
6.3.4.3 
Delegation Log ......................................................................... 53 
6.3.4.4 
Role Switching ......................................................................... 53 
6.3.4.5 
Study Backup Staff .................................................................. 53 
6.3.4.6 
Masking of Vendors, Sponsor's Agents, and 
Laboratory Personnel .............................................................. 53 
6.3.4.7 
Participant Masking ................................................................. 54 
6.3.5 
Unmasking ............................................................................... 54 
6.3.5.1 
Single-Participant Emergency Unmasking ............................... 54 
6.3.5.2 
Single-Participant Non-Emergency Unmasking ....................... 54 
6.3.5.3 
Single-Participant Unmasking for Health Authority 
Reporting Requirements .......................................................... 54 
6.4 
Treatment Compliance ............................................................ 54 
6.5 
Concomitant Therapy .............................................................. 54 
6.5.1 
Rescue Medicine and SOC treatment ..................................... 55 
6.5.1.1 
Rescue Medicine ..................................................................... 55 
...... 55 
6.5.2 
Permitted Therapy ................................................................... 55 
6.5.2.1 
Treatment of the Fellow Eye .................................................... 56 
6.5.3 
Prohibited Therapy .................................................................. 56 

RO7200220 and RANIBIZUMAB—F. Hoffmann-La Roche Ltd 
6/Protocol BP43464, Version 3 
6.6 
Dose Modification, Temporary Interruption and 
Rechallenge ............................................................................. 56 
6.6.1 
Temporary Interruption ............................................................ 57 
6.7 
Treatment after the End of the Study ....................................... 57 
7. 
DISCONTINUATION OF STUDY, STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ................... 57 
7.1 
Discontinuation of Study Treatment ......................................... 57 
7.2 
Participant Discontinuation/Withdrawal from the Study ........... 58 
7.3 
Lost to Follow-Up ..................................................................... 59 
8. 
STUDY ASSESSMENTS AND PROCEDURES ........................... 59 
8.1 
Efficacy Assessments .............................................................. 60 
8.2 
Safety Assessments ................................................................ 60 
8.2.1 
Physical Examinations ............................................................. 61 
8.2.2 
Vital Signs ................................................................................ 62 
8.2.3 
Electrocardiograms .................................................................. 62 
8.2.4 
Clinical Safety Laboratory Assessments .................................. 63 
8.2.4.1 
Urine assessments .................................................................. 63 
8.2.5 
Medical History and Demographic Data .................................. 64 
8.2.6 
Ophthalmological Assessments ............................................... 64 
8.2.6.1 
Best Corrected Visual Acuity ................................................... 64 
8.2.6.2 
IOP Measurement .................................................................... 65 
8.2.6.3 
Safety Finger Count Vision ...................................................... 65 
8.2.6.4 
Slit-Lamp Examination and Dilated Binocular Indirect High-
Magnification Ophthalmoscopy ................................................ 65 
8.2.6.5 
Ocular Imaging ........................................................................ 65 
8.2.7 
Immunogenicity Assessments ................................................. 66 
8.3 
Adverse Events and Serious Adverse Events ......................... 66 
8.3.1 
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information .................................. 67 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events ...................................................................................... 68 
8.3.3 
Follow-Up of Adverse Events and Serious Adverse Events .... 68 
8.3.3.1 
Investigator Follow-Up ............................................................. 68 
8.3.3.2 
Sponsor Follow-Up .................................................................. 68 

RO7200220 and RANIBIZUMAB—F. Hoffmann-La Roche Ltd 
7/Protocol BP43464, Version 3 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events ...................................................................................... 68 
8.3.4.1 
Emergency Medical Contacts .................................................. 69 
8.3.5 
Pregnancy................................................................................ 69 
8.3.6 
Non-serious Adverse Events of Special Interest 
(immediately reportable to Roche) ........................................... 69 
8.3.7 
Sight-threatening Adverse Events (immediately reportable 
to Roche) ................................................................................. 70 
8.3.8 
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as Adverse Events or Serious 
Adverse Events ........................................................................ 70 
8.3.9 
Medical Device Complaints (Including Malfunctions) ............... 70 
8.3.9.1 
Time Period for Detecting Medical Device Incidents ................ 70 
8.3.9.2 
Follow-up of Medical Device Incidents ..................................... 71 
8.3.9.3 
Prompt Reporting of Medical Device Incidents to Sponsor ...... 71 
8.3.9.4 
Regulatory Reporting Requirements for Medical Device 
Incidents .................................................................................. 71 
8.4 
Treatment of Overdose ............................................................ 71 
8.5 
Pharmacokinetics .................................................................... 72 
8.6 
Pharmacodynamics and Biomarkers Analyses ........................ 73 
8.7 
Samples for Research Biosample Repository.......................... 73 
8.7.1 
Overview of the Research Biosample Repository .................... 73 
8.7.2 
Sample Collection .................................................................... 74 
8.8 
Health Economics OR Medical Resource Utilization and 
Health Economics .................................................................... 75 
8.9 
Timing of Study Assessments .................................................. 75 
8.9.1 
Screening and Pre-treatment Assessments............................. 75 
8.9.2 
Assessments during Treatment ............................................... 76 
8.9.3 
Assessments at Study Treatment Completion (Week 
48)/Early Treatment Termination Visit ..................................... 76 
8.9.4 
Assessments at Off-Treatment Observation Period Visits ....... 77 
8.9.5 
Assessments at the Occurrence of a Sight-Threatening 
Adverse Event or Events of Intraocular Inflammation .............. 77 
9. 
STATISTICAL CONSIDERATIONS .............................................. 77 
9.1 
Sample Size Determination ..................................................... 78 

RO7200220 and RANIBIZUMAB—F. Hoffmann-La Roche Ltd 
8/Protocol BP43464, Version 3 
9.2 
Sets for Analyses ..................................................................... 79 
9.3 
Statistical Analyses .................................................................. 80 
9.3.1 
Demographics and Baseline Characteristics ........................... 80 
9.3.2 
Efficacy Analyses ..................................................................... 80 
9.3.3 
Safety Analyses ....................................................................... 82 
9.3.4 
Immunogenicity Analyses ........................................................ 84 
9.3.5 
Pharmacokinetic Analyses ....................................................... 84 
................................................... 85 
................ 85 
9.3.8 
Other Analyses ........................................................................ 85 
9.4 
Interim Analyses ...................................................................... 86 
9.5 
Summaries of Conduct of Study .............................................. 86 
10. 
REFERENCES.............................................................................. 87 
11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ...................................................................... 90 
 
 
LIST OF TABLES 
Table 1 
Schedule of Activities .................................................................. 22 
Table 2 
Objectives and Endpoints ........................................................... 31 
Table 3 
Summary of Treatments Administered ........................................ 47 
Table 4 
Analysis Sets .............................................................................. 79 
Table 5 
Efficacy Statistical Analysis Methods .......................................... 80 
Table 6 
Safety Statistical Analysis Methods ............................................ 82 
 
 
LIST OF FIGURES 
Figure 1 
Overview of Study Design ........................................................... 21 
.......... 46 
 
 
LIST OF APPENDICES 
Appendix 1 
 Regulatory, Ethical, and Study Oversight Considerations .......... 91 
Appendix 2 
 Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up and Reporting ........................................................... 101 

RO7200220 and RANIBIZUMAB—F. Hoffmann-La Roche Ltd 
9/Protocol BP43464, Version 3 
Appendix 3 
 Procedures for Recording Adverse Events .............................. 109 
Appendix 4 
 Clinical Laboratory Tests ......................................................... 115 
Appendix 5 
 Contraceptive and Barrier Guidance ........................................ 118 
Appendix 6 
 Grading Scale for Assessment of Anterior Chamber Cells or 
Flare, and Vitreous Haze .......................................................... 122 
Appendix 7 
 Grading Scale for Vitreous Hemorrhage .................................. 124 
Appendix 8 
  Sight-Threatening Adverse Events ......................................... 125 
 
 

 
RO7200220 and RANIBIZUMAB—F. Hoffmann-La Roche Ltd 
10/Protocol BP43464, Version 3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AC 
Anterior chamber 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AH 
Aqueous humor 
AUC 
Area under the concentration-time curve 
BCVA 
Best corrected visual acuity 
BP 
Blood pressure 
CI-DME 
Center-involving diabetic macular edema 
CSR 
Clinical study report 
CST 
Central subfield thickness 
CRC 
Central reading center 
DLE 
Dose limiting event 
DM 
Diabetes mellitus 
DME 
Diabetic macular edema 
DR 
Diabetic retinopathy 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EOS 
End of study 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
ETTV 
Early treatment termination visit 
E.U. 
European Union 
FcRn 
Neonatal Fc receptor 
FFA 
Fundus fluorescein angiography 
FP 
Fundus photography 
GLP 
Good Laboratory Practice 
HbA1c 
Hemoglobin A1c (glycosylated hemoglobin) 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IL 
Interleukin 
IMC 
Internal Monitoring Committee 

 
RO7200220 and RANIBIZUMAB—F. Hoffmann-La Roche Ltd 
11/Protocol BP43464, Version 3 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug 
IOI 
Intraocular inflammation 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
IVT 
Intravitreal 
IxRS 
Interactive voice and web response system 
LPLO 
Last participant, last observation 
MCP-1 
Monocyte chemotactic protein-1 
MMRM 
Mixed Model for Repeated Measurements 
nAMD 
Neovascular age-related macular degeneration 
NSAESI  
Non-serious adverse event of special interest 
OCT-A 
Optical coherence tomography angiography 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
QT 
QT interval 
Q4W 
Every 4 weeks 
Q6W 
Every 6 weeks 
Q8W 
Every 8 weeks 
RBR 
Research Biosample Repository 
SAE 
Serious adverse event 
SD-OCT 
Spectral domain optical coherence tomography 
SmPC 
Summary of Product Characteristic 
SoA 
Schedule of activities 
SoC 
Standard of Care 
SUN 
Standardization of Uveitis Nomenclature 
SUSAR 
Suspected unexpected serious adverse reaction 
TNF- 
Tumor necrosis factor-alpha 
ULN 
Upper limit of normal 
U.S. 
United States 
UME 
Uveitic macular edema 
UWF 
Ultra-wide-field 
VEGF 
Vascular endothelial growth factor 
VA 
Visual acuity 
VH 
Vitreous humor 
WOCBP 
Women of childbearing potential 
WONCBP 
Women of non-childbearing potential 

 
RO7200220 and RANIBIZUMAB—F. Hoffmann-La Roche Ltd 
12/Protocol BP43464, Version 3 
1. 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
PROTOCOL TITLE: 
A PHASE II, MULTICENTER, RANDOMIZED, DOUBLE MASKED, 
ACTIVE COMPARATOR-CONTROLLED STUDY TO INVESTIGATE 
THE EFFICACY, SAFETY, TOLERABILITY, 
PHARMACOKINETICS, AND PHARMACODYNAMICS OF 
RO7200220 IN COMBINATION WITH RANIBIZUMAB 
ADMINISTERED INTRAVITREALLY IN PATIENTS WITH DIABETIC 
MACULAR EDEMA 
SHORT TITLE 
PHASE II STUDY TO INVESTIGATE RO7200220 IN 
COMBINATION WITH RANIBIZUMAB IN DIABETIC MACULAR 
EDEMA 
PROTOCOL NUMBER: 
BP43464 
VERSION: 
3 
TEST PRODUCT: 
RO7200220 in combination with ranibizumab 
PHASE: 
II 
 
RATIONALE 
Persistent inflammation in the retina is present from the early stages of diabetes to the sight-
threatening advanced forms of diabetic retinopathy (DR). Indeed, a complex milieu of 
dysregulated proinflammatory factors is found in the diabetic retina, including interleukin (IL)-6, IL-
1β, IL-8, monocyte chemotactic protein-1, and tumor necrosis factor-. 
IL-6 levels in particular have been found frequently increased in ocular fluids of patients with 
conditions such as DR, diabetic macular edema (DME), neovascular age-related macular 
degeneration, uveitis, uveitic macular edema, and retinal vein occlusion. 
RO7200220 is a recombinant humanized immunoglobulin G2 isotype mono-clonal antibody that 
potently binds the cytokine IL-6. RO7200220 inhibits all known forms of IL-6 signaling (cis and 
trans). The antibody has specific mutations in the constant regions which reduce its affinity to 
neonatal Fc receptor (FcRn) to increase systemic clearance. It is intended for the treatment of 
retinal inflammatory diseases by intravitreal (IVT) administration. 
Since anti-IL-6 treatment is addressing a different molecular pathway than anti-VEGF Standard of 
Care (SoC) therapy, it may be possible that a combination of RO7200220 and ranibizumab 
(Lucentis) may improve vision in DME patients in an additive or even synergistic manner. In the 
 Besides efficacy (primary endpoint), it will 
further assess its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD). 
Careful monitoring of safety parameters, routine clinical ocular examinations, and well-defined 
participants characteristics will be implemented to ensure participant safety. 

 
RO7200220 and RANIBIZUMAB—F. Hoffmann-La Roche Ltd 
14/Protocol BP43464, Version 3 
 To investigate the effect of 
RO7200220 in combination 
with ranibizumab on 
anatomical outcome 
measures using SD-OCT 
 Change from baseline in Central Subfield Thickness 
(CST) at Week 48 
 Change from baseline in CST at Week 36 
 Change from baseline in CST at Week 24 
 Change from baseline in CST over time 
 Proportion of participants with absence of DME 
(CST <325 μm for Spectralis SD-OCT, or <315 μm 
for Cirrus SD-OCT or Topcon SD-OCT) over time 
 Proportion of participants with absence of intraretinal 
fluid and/or subretinal fluid over time 
* All BCVA values are measured on the ETDRS chart at a starting distance of 4 meters.  
 
OVERALL DESIGN 
STUDY DESIGN 
This is a multicenter, multiple-dose, randomized, active comparator-controlled, double-masked, 2-
parallel group, study in participants with center-involving DME (CI-DME). Anti-VEGF and 
corticosteroids treatment naïve & previously treated participants are eligible. 
Only one eye will be selected as the study eye. 
This proof-of-concept study will consist of a screening/randomization period (up to 4 weeks), a 
treatment period (from Day 1 to Week 44), and an observational period (from Week 44 up to 
Week 72). The total study length will thus be up to 76 weeks.  
The study will evaluate the effects of RO7200220 in combination with the anti-VEGF inhibitor 
ranibizumab (Lucentis) on visual function and retinal structure by assessing changes from 
baseline in best corrected visual acuity (BCVA; ETDRS letters) and anatomical outcomes 
(imaging assessments), respectively. The anti-VEGF inhibitor ranibizumab (Lucentis) will be the 
active comparator. In addition, the safety, tolerability, pharmacokinetics, and pharmacodynamics 
of RO7200220 in combination with ranibizumab will be evaluated.  
Participants will be carefully monitored for potential ocular adverse events (AEs) associated with 
the IVT injection procedure and for other potential ocular and systemic effects associated with the 
IVT administration of RO7200220 and ranibizumab, and will be managed appropriately. 
 
TREATMENT GROUPS AND DURATION 
The two groups of this study will be: 
 
Arm A:  1.0 mg RO7200220 IVT Q4W and ranibizumab 0.5 mg IVT Q4W 
 
Arm B:  0.5 mg ranibizumab IVT Q4W (active-control arm)  
Participants will be randomized 1:1 to one of the study arms. 
During the treatment period, the study drug will be administered to the participants on Day 1 and 
on every 4th week (Q4W), for a total of 12 injections. 
A sham procedure will be administered to participants in the ranibizumab only arm at applicable 
visits to maintain masking between treatment arms. 

 
RO7200220 and RANIBIZUMAB—F. Hoffmann-La Roche Ltd 
16/Protocol BP43464, Version 3 
INCLUSION/EXCLUSION CRITERIA 
INCLUSION CRITERIA 
Informed Consent 
1. Able and willing to provide written informed consent and to comply with the study protocol 
according to the International Council for Harmonisation (ICH) and local regulations. 
Alternatively, a legally authorized representative must be able to consent for the participant 
according to ICH and local regulations 
2. Willing to allow Aqueous Humor (AH) collection 
Age 
3. Age  18 years, at the time of signing the informed consent 
Type of Participants and Disease Characteristics 
4. Diagnosis of diabetes mellitus (DM; Type 1 or Type 2), as defined by the World Health 
Organization and/or American Diabetes Association 
Sex and Contraception guidance 
5. Male and female participants with contraception requirements: 
The contraception and abstinence requirements are intended to prevent conception. The 
reliability of sexual abstinence for female enrollment eligibility needs to be evaluated in 
relation to the duration of the clinical study and the preferred and usual lifestyle of the 
participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post ovulation 
methods) and withdrawal are not acceptable methods of preventing drug exposure. 
a) For female participants 
A female is eligible to participate if she is not pregnant, not breastfeeding, and at least one of 
the following conditions applies: 
 Women of non-childbearing potential (WONCBP), as defined in Protocol Appendix 4 
 Women of childbearing potential (WOCBP), who:  
- Have a negative pregnancy test (urine) at Day 1 prior to study treatment. 
- Agree to remain abstinent (refrain from heterosexual intercourse) or use at least one 
highly effective contraception method that results in a failure rate of  1% per year 
during the treatment period and for at least 12 weeks after the final dose of study 
treatment or any anti-VEGF given as SoC in this study. 
- Must not donate eggs during the study  
Examples of contraceptive methods with a failure rate of  1% per year are given in 
Appendix 5. 
b) For male participants 
No requirements  

 
RO7200220 and RANIBIZUMAB—F. Hoffmann-La Roche Ltd 
17/Protocol BP43464, Version 3 
Ocular Inclusion Criteria for the Study Eye 
6. Macular edema associated with DR defined as macular thickening by SD-OCT involving the 
center of the macula: CST of  325 m with Spectralis® (Heidelberg Engineering, 
Heidelberg, Germany; where Spectralis® is not available, Cirrus or Topcon would also be 
acceptable with a CST threshold of  315 m) at screening. Note: CST is not part of the 
eligibility reconfirmation on Day 1. 
7. Decreased visual acuity (VA) attributable primarily to DME, with BCVA letter score of 73 to 
19 letters (both inclusive; 20/40  20/400 Snellen equivalent) on ETDRS-like charts at 
screening. 
8. Clear ocular media and adequate pupillary dilation to allow acquisition of good quality retinal 
images to confirm diagnosis. 
 
EXCLUSION CRITERIA 
Participants are excluded from the study if any of the following criteria apply: 
 
Medical Conditions 
1. Any major illness or major surgical procedure within 4 weeks prior to Day 1 
2. Any febrile illness within 1 week prior to screening or Day 1 
3. Any stroke or myocardial infarction within 24 weeks prior to Day 1 
4. Renal failure requiring renal transplant, hemodialysis, or peritoneal dialysis within 24 weeks 
prior to Day 1 or anticipated to require hemodialysis or peritoneal dialysis at any time during 
the study 
5. Active malignancy within 1 year of screening except for appropriately treated carcinoma in 
situ of the cervix, non-melanoma skin carcinoma, and prostate cancer with a Gleason score 
of  6 and a stable prostate-specific antigen (PSA) for  1 year 
6. History of other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a condition that contraindicates the use of 
either of the Investigational Medicinal Products (IMPs) or that might affect interpretation of 
the results of the study or renders the participant at high risk for treatment complications in 
the opinion of the Investigator 
7. Any known hypersensitivity to any of the following compounds: fluorescein, biologic IVT 
agents such as Lucentis® (ranibizumab), Eylea® (aflibercept), Avastin® (bevacizumab), 
Beovu® (brolucizumab), any ingredient of the formulation used, dilating eye drops, or any 
anesthetics and antimicrobial drops used 
8. Evidence of HIV infection and/or positive human HIV antibodies; evidence of syphilis or 
tuberculosis and/or positive assay 
Prior/Concomitant Therapy 
9. Prior or concomitant periocular or IVT corticosteroids in the study eye: 
a. For treatment naïve participants: 
 Received any prior or concomitant IVT corticosteroid treatment 
b. For previously treated participants:  
 Received Triamcinolone within 16 weeks prior Day 1  
 Received Ozurdex (dexamethasone IVT implant) within 16 weeks prior Day 1 
 Used ILUVIEN or Retisert(fluocinolone acetonide IVT implant) within 3 years prior 
Day 1  
Note: Topical or IVT corticosteroids are allowed if required to treat AEs during the study. 
10. Prior or concomitant IVT with anti-VEGF component in the study eye: 
a. For treatment naïve participants: 

 
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 Received any prior or concomitant IVT treatment with anti-VEGF component 
b. For previously treated participants: 
 
Received the last IVT anti-VEGF treatment (e.g. Lucentis, Eylea, Avastin) within 
8 weeks prior to Day 1 (Note: prior Beovuis not permitted)  
 
Received the last IVT faricimab (Vabysmo) treatment within 16 weeks prior to 
Day 1 
11. Any previous or concomitant systemic corticosteroids within 4 weeks prior to Day 1 
12. Any previous or concomitant systemic anti-VEGF treatment within 24 weeks prior to Day 1 
13. Any previous or concomitant use of systemic anti-IL-6 or anti-IL-6-receptor treatment, 
including, but not restricted to: Actemra (tocilizumab), Plivensia™ (sirukumab), Kevzara 
(sarilumab), or Enspryng (satralizumab) 
14. Any concurrent use of biologics for immune-related diseases including, but not restricted to:  
 Anti-tumor necrosis factor drugs: e.g., Enbrel(etanercept), Humira(adalimumab), 
Remicade(Infliximab), Simponi® (golimumab), Cimzia® (certolizumab pegol);  
 Anti-IL-12: e.g., Stelara® (ustekinumab);  
 Anti-IL-1: e.g., Kineret (anakinra), Ilaris (canakinumab), Arcalyst (rilonacept);  
 Anti-IL-23: e.g., Tremfya (guselkumab); 
 Anti-IL-17, anti-IL-17A: e.g., Cosentyx (secukinumab), Taltz (ixekizumab) 
Prior/Concurrent Clinical Study Experience 
15. Participants who are currently enrolled or have participated in any other clinical study: 
 Involving brolucizumab (Beovu); 
 
 Involving any other investigational products or devices, or in any other type of medical 
research with the last drug administration or invasive assessment (incl. blood drawing) 
 12 weeks prior to Day 1. 
Diagnostic Assessments 
16. Uncontrolled blood pressure (BP), defined as systolic  180 mmHg and/or 
diastolic  100 mmHg while participant at rest. If a participant’s initial reading exceeds these 
values, a second reading may be taken either  30 minutes later on the same day or on 
another day during the screening period. If the participant’s BP needs to be controlled by 
antihypertensive medication, the participant should be on stable medication for at least 
1 month prior to Day 1 
17. Participants with HbA1c  12% at screening 
Exclusion criteria for study eye 
18. Any proliferative DR defined as: 
 Any neovascularization of the optic disc; 
 Any neovascularization elsewhere; 
 Any neovascularization of iris; 
 Any neovascularization of irido-corneal angle; 
 Vitreous or pre-retinal hemorrhage; 
19. Any panretinal photocoagulation prior to Day 1 
20. Macular (focal, grid, or micropulse) laser treatment prior to Day 1 
21. History of vitreoretinal surgery/pars plana vitrectomy, including PDS with ranibizumab 
implant/explant surgery 
22. Any cataract surgery within 12 weeks prior to Day 1 or any planned surgery during the study 

 
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23. History of any glaucoma surgery (Note: laser glaucoma procedures are allowed if > 12 
weeks prior Day 1) 
24. Uncontrolled glaucoma (e.g., progressive loss of visual fields or defined as intraocular 
pressure (IOP)  25 mmHg at screening despite treatment with anti-glaucoma medication) 
25. History of rubeosis iridis 
26. Any concurrent ocular conditions
 cataract, age-related macular degeneration, macular hole, 
retinal vein occlusion, infectious or noninfectious uveitis, angioid streaks, histoplasmosis, 
active or inactive cytomegalovirus retinitis, choroidal neovascularization, infectious/non-
infectious conjunctivitis, keratitis, scleritis, endophthalmitis) that, in the opinion of the 
Investigator, could either: 
 Require medical or surgical intervention during the study period to prevent or treat 
visual loss that might result from that condition; or 
 Likely contribute to worsening of BCVA over the study period if allowed to progress 
untreated; or 
 Preclude any visual improvement due to established structural damage. 
27. Rhegmatogenous or tractional retinal detachment, pre-retinal and/or sub-macular fibrosis, 
vitreomacular traction, foveal hard exudates, or epiretinal membrane involving the fovea or 
disrupting the macular architecture, as evaluated by the Central Reading Center (CRC) 
28. Actual or history of myopia  -8 diopters. 
29. Any active ocular or periocular infection on Day 1. 
30. Any presence of active intraocular inflammation on Day 1 (i.e., SUN criteria  0 or NEI 
vitreous haze grading > 0) or any history of intraocular inflammation (noninfectious or 
infectious uveitis of any type) 
Criteria for fellow (non-study) eye: 
31. Non-functioning non-study eye, defined as either: 
 BCVA  23 
 No physical presence (i.e., monocular) 
 Legally blind in the participant’s relevant jurisdiction  
 
NUMBER OF PARTICIPANTS 
With approximately 105 to 115 participants randomized per arm, the total number of participants 
will be approximately 210 to 230 (see also sample size description in the statistical analysis 
section in this synopsis). 
 
CONCOMITANT MEDICATIONS 
At the discretion of the investigator, participants may start or continue to receive all medications 
and standard treatments administered for other conditions, except for therapies listed under the 
exclusion criteria. 
Participants are not allowed to participate in any other clinical study during participation in Study 
BP43464.  
Retinal laser photocoagulation is permitted in either eye, if clinically indicated for the treatment of 
proliferative DR or retinal holes or tears post randomization. 
Administration of macular micropulse and focal or grid laser in study eye is prohibited throughout 
the duration of this study. 

 
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2. 
INTRODUCTION 
2.1 
STUDY RATIONALE 
In this study participants will receive RO7200220 in combination with ranibizumab or 
ranibizumab only. Besides efficacy (primary endpoint), this study will further assess the 
safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of RO7200220 
in combination with ranibizumab. 
 
 
 
(Funatsu et al 2004), 
  
Careful monitoring of safety parameters, routine clinical ocular examinations, and well-
defined participants characteristics will be implemented to ensure participant safety.  
The rationale for the study design is provided in Section 4.2. 
2.2 
BACKGROUND 
2.2.1 
Background on IL-6 and Diabetic Macular Edema 
DME is defined by the accumulation of fluid within the macular area of patients with 
diabetic retinopathy (DR). It is a major cause of vision loss worldwide affecting 
predominantly the working-age population, and the most common cause of moderate to 
severe visual impairment in patients with DR (Resnikoff et al 2004; Cheung et al 2010).  
Persistent inflammation in the retina is present from the early stages of diabetes to the 
sight-threatening advanced forms of DR (Simó-Servat et al 2012). Indeed, a complex 
milieu of dysregulated proinflammatory factors is found in the diabetic retina, which 
includes interleukin (IL)-6, IL-1β, IL-8, Monocyte chemotactic protein-1 [MCP-1], and 
Tumor necrosis factor- (Simó-Servat et al 2012; Valle et al 2019). 
IL-6 levels in particular have been found frequently increased in ocular fluids of patients 
with conditions such as DR, DME, neovascular age-related macular degeneration 
(nAMD), uveitis, uveitic macular edema (UME), and retinal vein occlusion. In a recent 
meta-analysis of 18 studies with 362 cases of DR and 100 cases of DME, high 
intraocular levels of IL-6 were significantly correlated both with the risk of developing DR 
and DME (Wu et al 2019). Additionally,
 
 
  

 
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Moreover, the clinical efficacy of IVT corticosteroids (triamcinolone acetonide, 
dexamethasone and fluocinolone implants) in patients with DME highlights the 
prominent role of inflammation in this condition (Whitcup et al 2018; Cunningham et al 
2008). In addition, systemic inhibition of the IL-6 pathway (with e.g. tocilizumab or 
sarilumab) has been shown to be efficacious in multiple inflammatory conditions 
including noninfectious uveitis and UME (Ramanan et al 2020; Karkhur et al 2019; 
Vegas-Revenga et al 2019; Lopalco et al 2012; Sepah et al 2017). 
Since anti-IL-6 treatment is addressing a different molecular pathway than anti-VEGF 
Standard of Care (SoC) therapy, it may be possible that a combination of RO7200220 
and ranibizumab may improve vision in DME patients in an additive or even synergistic 
manner.
 
 
It thus seems reasonable to assume that anti-IL-6 treatment with RO7200220 in addition 
to anti-VEGF SoC treatment may improve functional and anatomical outcomes in DME 
patients, 
 
2.2.2 
Background on RO7200220 
RO7200220 is a recombinant humanized immunoglobulin G2 isotype mono-clonal 
antibody that potently binds the cytokine IL-6. RO7200220 inhibits all known forms of IL-
6 signaling (cis and trans). The antibody has specific mutations in the constant regions 
which reduce its affinity to neonatal Fc receptor (FcRn) to increase systemic clearance. 
It is intended for the treatment of retinal inflammatory diseases by intravitreal (IVT) 
administration.  
A detailed description of the chemistry, pharmacology, and safety of RO7200220 is 
provided in the RO72000220 Investigator’s Brochure (IB). 
2.2.3 
Clinical Studies with RO7200220 
 
 
 
 
 
  
 
 
 
 
 

 
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No apparent pattern of clinically significant abnormalities in ECG, vital sign or laboratory 
safety parameters was observed.  
 
 
 
 
 
  
Up to a dose of
RO7200220 displayed a favorable safety profile, with no SAEs 
related to study drug, and no unexpected safety findings observed. 
 
 
For more details see the RO7200220 IB.  
2.2.4 
Choice of Combination Treatment and Comparator 
Ranibizumab is an approved anti-VEGF treatment in patients with DR with or without 
DME. It demonstrated efficacy in controlled randomized clinical studies. In the United 
States, monthly dosing of 0.3 mg IVT ranibizumab is the approved treatment regimen 
based on data from the RIDE and RISE (Nguyen et al 2012) clinical studies. In territories 
outside of the United States, including the European Union, the approved treatment 
regimen is 3 monthly doses of 0.5 mg followed by as-needed (pro-re-nata) 0.5 mg IVT 
injections.  
RIDE and RISE evaluated monthly IVT injections of 0.3 and 0.5 mg ranibizumab over a 
period of 24 months. The results indicated that both the 0.3 and 0.5 mg doses show a 

 
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similar benefit in the management of DME, as well as the underlying DR, and both doses 
were generally well-tolerated. A meta-analysis conducted on systemic AEs associated 
with anti-VEGF IVT use (including ranibizumab, bevacizumab and aflibercept), 
suggested that anti-VEGF treatments do not increase the risk of systemic AEs (studies 
included different anti-VEGFs, different doses and regimens) (Thulliez et al 2018). 
For more information on ranibizumab, please refer to Lucentis EU Summary of Product 
Characteristic (SmPC).  
 
2.3 
BENEFIT/RISK ASSESSMENT 
Previous non-clinical and clinical studies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 

 
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Of note, an assessment was conducted to determine whether there is any impact of the 
COVID-19 pandemic on the benefit/risk assessment of this study protocol including, but 
not limited to, the patient population under study and study treatment being evaluated. 
On the basis of that assessment, no impact is anticipated and the existing safety 
monitoring and management guidelines, and risk mitigation measures provided in the 
study protocol are considered adequate. 
COVID-19 vaccine given to a trial participant has no anticipated study treatment-vaccine 
interaction and does not require advice on timing of the vaccine or the implementation of 
any other risk mitigation activities. COVID-19 vaccine should be considered as a 
concomitant medication. 
Careful monitoring of safety parameters, routine clinical ocular examinations, and well-
defined participants characteristics will be implemented to ensure participant safety (see 
Section 8.2). 
More detailed information about the known and expected benefits in the context of 
potential risks and reasonably expected AEs of RO7200220 is provided in the 
RO7200220 IB. 
3. 
OBJECTIVES AND ENDPOINTS 
The objectives and corresponding endpoints are provided in Table 2. 

 
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4. 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
STUDY DESIGN 
This is a multicenter, multiple-dose, randomized, active comparator-controlled, double-
masked, 2-parallel group, Phase II study in participants with CI-DME. Anti-VEGF and 
corticosteroids treatment naïve & previously treated participants are eligible.  
Only one eye will be selected as the study eye. 
This proof-of-concept study will consist of a screening/randomization period (up to 4 
weeks), a treatment period (from Day 1 to Week 44), and an observational period (from 
Week 44 up to Week 72). The total study length will thus be up to 76 weeks.  
The study will evaluate the effects of RO7200220 in combination with the anti-VEGF 
inhibitor ranibizumab (Lucentis) on visual function and retinal structure by assessing 
changes from baseline in BCVA (ETDRS letters) and anatomical outcomes (imaging 
assessments), respectively. The anti-VEGF inhibitor ranibizumab (Lucentis) will also be 
the active comparator. In addition, the safety, tolerability, pharmacokinetics, and 
pharmacodynamics of RO7200220 in combination with ranibizumab will be evaluated.  
Participants will be carefully monitored for potential ocular AEs associated with the IVT 
injection procedure and for other potential ocular and systemic effects associated with 
the IVT administration of RO7200220 and ranibizumab, and will be managed 
appropriately. 
A schematic of the study design is shown in Section 1.2. An overview of the scientific 
rationale for the study design is provided in Section 4.2. 
Treatment Groups and Duration  
The two groups of this study will be: 
 
Arm A: 1.0 mg RO7200220 IVT and ranibizumab 0.5 mg IVT as 
 
Q4W 
 
Arm B: 0.5 mg ranibizumab IVT Q4W (active-control arm)  
Participants will be randomized 1:1 to one of the study arms. 
During the treatment period, the study drug will be administered to the participants on 
Day 1 and on every 4th week (Q4W), for a total of 12 injections.  
A sham procedure will be administered to participants in the ranibizumab only arm 
(Arm B) at applicable visits to maintain masking between treatment arms (see 
Section 1.3).  
RO7200220 or Sham will be administered first followed by the injection of ranibizumab 
(
). 

 
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Off-treatment observational period 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
4.1.1 
Length of the Study 
The total study length will be up to 76 weeks, divided as follows: 
 
Screening/randomization period: up to 4 weeks 
 
Treatment period:  Day 1 to Week 44 
 
Observational period: Week 44 up to Week 72.  
 
4.1.1.1 
Communication Strategy 
Not applicable. 
4.1.2 
Administrative Structure  
A Roche Internal Monitoring Committee (IMC) will be responsible for the unmasked 
interim analysis of efficacy for operational/administrative/study related purposes and for 
safety data monitoring (Appendix 1).  
The IMC consists of a selected subset of Roche representatives including Statistician, 
Safety Representative, and a Clinical Science Representative. 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. 
To meet potential requests from health authorities, the IMC may share aggregated 
unmasked safety and PK results overall or from ethnic subgroups for potential 
submissions to local health authorities. 
 
 may 

 
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receive these aggregated unmasked safety and PK results. The unmasked results will 
not be shared with masked members of the study team. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
4.2.1 
Rationale for Study Population 
The study will be conducted in adult male and female participants over 18 years of age 
with diabetes mellitus (Type 1 and Type 2) and center-involving macular edema 
associated with DR as well as vision loss due to the DME. The primary aim is to 
evaluate the efficacy of RO7200220 in combination with ranibizumab compared to the 
active comparator (ranibizumab only) in treatment-naïve patients with CI-DME. Inclusion 
of previously anti-VEGF and/or IVT corticosteroid treated patients will allow the 
exploratory evaluation if these populations respond differently to treatment with 
RO7200220 in combination with ranibizumab. 
4.2.2 
Rationale for Control Group  
The control group will receive anti-VEGF treatment in the form of 0.5 mg IVT 
ranibizumab Q4W as active-comparator control (see Section 2.2.4 for details). 
 
 
 
 
 
 
 
 
 
 
 
a. 
 
 
  
b. 
 
  
c. 
 
 
 
 

 
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4.2.4 
Rationale for Blood Biomarker Assessments  
Both protein and genetic biomarkers may be analyzed as exploratory analysis to 
improve the understanding of the participants’ response to RO7200220 in combination 
with ranibizumab.  
 
 
 
 
 
 
4.3 
JUSTIFICATION FOR DOSE 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 

 
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Preliminary signals of functional and anatomical improvements (BCVA/CST) were seen 
across all dose-groups. 
The dose of 1.0 mg Q4W RO7200220 administered in combination with ranibizumab 
12 x Q4W for up to 44 weeks was selected, because 
 
 
 
 
 
. 
See Section 4.2.2 for the rational of the ranibizumab dose. 
Further details are provided in the Lucentis EU SmPC and the RO7200220 IB. 
4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he/she has completed all 
phases of the study, including the End-of-Study (EOS) visit. The end of the study is 
defined as the date when the last participant, last observation (LPLO) occurs. LPLO is 
expected to occur at the EOS visit 4 weeks after the last participant has received SoC 
treatment in the off-treatment observation period or at Week 72 latest. 
5. 
STUDY POPULATION 
The study population consists of male and female participants of  18 years of age with 
DM (Type 1 or Type 2) and CI-DME who fulfill all of the inclusion criteria and none of the 
exclusion criteria. 
The study population rationale is provided in Section 4.2.1. 
Prospective approval of protocol deviations, also known as protocol waivers or 
exemptions, is not permitted. 
One month is equivalent to a duration of 4 weeks (28 days). 

 
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5.1 
INCLUSION CRITERIA 
Informed Consent 
1. Able and willing to provide written informed consent and to comply with the study 
protocol according to the International Council for Harmonisation (ICH) and local 
regulations. Alternatively, a legally authorized representative must be able to 
consent for the participant according to ICH and local regulations 
2. Willing to allow Aqueous Humor (AH) collection 
Age 
3. Age  18 years, at the time of signing the informed consent 
Type of Participants and Disease Characteristics 
4. Diagnosis of diabetes mellitus (DM; Type 1 or Type 2), as defined by the World 
Health Organization and/or American Diabetes Association 
Sex and Contraception guidance 
5. Male and female participants with contraception requirements: 
The contraception and abstinence requirements are intended to prevent conception. 
The reliability of sexual abstinence for female enrollment eligibility needs to be 
evaluated in relation to the duration of the clinical study and the preferred and usual 
lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or post ovulation methods) and withdrawal are not acceptable 
methods of preventing drug exposure. 
 
a) For female participants 
A female is eligible to participate if she is not pregnant, not breastfeeding, and at 
least one of the following conditions applies: 
 Women of non-childbearing potential (WONCBP), as defined in Protocol 
Appendix 5 
 Women of childbearing potential (WOCBP), who:  
- Have a negative pregnancy test (urine) at Day 1 prior to study treatment. 
- Agree to remain abstinent (refrain from heterosexual intercourse) or use of at 
least one highly effective contraception method that results in a failure rate 
of  1% per year during the treatment period and for at least 12 weeks after 
the final dose of study treatment or any anti-VEGF given as SoC in this study. 
- Must not donate eggs during the study  
Examples of contraceptive methods with a failure rate of  1% per year are given 
in Appendix 5. 
b) For male participants 
No requirements. 

 
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Ocular Inclusion Criteria for the Study Eye 
6. Macular edema associated with DR defined as macular thickening by SD-OCT 
involving the center of the macula: CST of  325 m with Spectralis® (Heidelberg 
Engineering, Heidelberg, Germany; where Spectralis® is not available, Cirrus or 
Topcon would also be acceptable with a CST threshold of  315 m) at screening. 
Note: CST is not part of the eligibility reconfirmation on Day 1. 
7. Decreased visual acuity (VA) attributable primarily to DME, with BCVA letter score 
of 73 to 19 letters (both inclusive; 20/40  20/400 Snellen equivalent) on ETDRS-like 
charts at screening. 
8. Clear ocular media and adequate pupillary dilation to allow acquisition of good 
quality retinal images to confirm diagnosis. 
 
5.2 
EXCLUSION CRITERIA 
 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Any major illness or major surgical procedure within 4 weeks prior to Day 1 
2. Any febrile illness within 1 week prior to screening or Day 1 
3. Any stroke or myocardial infarction within 24 weeks prior to Day 1 
4. Renal failure requiring renal transplant, hemodialysis, or peritoneal dialysis within 24 
weeks prior to Day 1 or anticipated to require hemodialysis or peritoneal dialysis at 
any time during the study 
5. Active malignancy within 1 year of screening except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, and prostate cancer 
with a Gleason score of  6 and a stable prostate-specific antigen (PSA) for  1 year 
6. History of other disease, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding giving reasonable suspicion of a condition that 
contraindicates the use of either of the Investigational Medicinal Products (IMPs) or 
that might affect interpretation of the results of the study or renders the participant at 
high risk for treatment complications in the opinion of the Investigator 
7. Any known hypersensitivity to any of the following compounds: fluorescein, biologic 
IVT agents such as Lucentis® (ranibizumab), Eylea® (aflibercept), Avastin® 
(bevacizumab), Beovu® (brolucizumab), any ingredient of the formulation used, 
dilating eye drops, or any anesthetics and antimicrobial drops used 
8. Evidence of HIV infection and/or positive human HIV antibodies; evidence of syphilis 
or tuberculosis and/or positive assay 

 
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Prior/Concomitant Therapy 
9. Prior or concomitant periocular or IVT corticosteroids in the study eye: 
a. For treatment naïve participants: 
 Received any prior or concomitant IVT corticosteroid treatment 
b. For previously treated participants:  
 Received Triamcinolone within 16 weeks prior Day 1  
 Received Ozurdex (dexamethasone IVT implant) within 16 weeks prior 
Day 1 
 Used ILUVIEN or Retisert(fluocinolone acetonide IVT implant) within 3 
years prior Day 1  
Note: Topical or IVT corticosteroids are allowed if required to treat AEs during the 
study. 
10. Prior or concomitant IVT with anti-VEGF component in the study eye: 
a. For treatment naïve participants: 
 Received any prior or concomitant IVT treatment with anti-VEGF component 
b. For previously treated participants: 
 Received the last IVT anti-VEGF treatment (e.g. Lucentis, Eylea, 
Avastin) within 8 weeks prior to Day 1 (Note: prior Beovu is not permitted) 
 Received the last IVT faricimab (Vabysmo) treatment within 16 weeks 
prior to Day 1 
11. Any previous or concomitant systemic corticosteroids within 4 weeks prior to Day 1 
12. Any previous or concomitant systemic anti-VEGF treatment within 24 weeks prior to 
Day 1 
13. Any previous or concomitant use of systemic anti-IL-6 or anti-IL-6-receptor 
treatment, including, but not restricted to: Actemra (tocilizumab), Plivensia™ 
(sirukumab), Kevzara (sarilumab), or Enspryng (satralizumab). 
14. Any concurrent use of biologics for immune-related diseases including, but not 
restricted to:  
 Anti-tumor necrosis factor drugs: e.g., Enbrel(etanercept), 
Humira(adalimumab), Remicade(Infliximab), Simponi® (golimumab), 
Cimzia® (certolizumab pegol);  
 Anti-IL-12: e.g., Stelara® (ustekinumab);  
 Anti-IL-1: e.g., Kineret (anakinra), Ilaris (canakinumab), Arcalyst 
(rilonacept);  
 Anti-IL-23: e.g., Tremfya (guselkumab); 
 Anti-IL-17, anti-IL-17A: e.g., Cosentyx (secukinumab), Taltz (ixekizumab) 

 
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Prior/Concurrent Clinical Study Experience 
15. Participants who are currently enrolled or have participated in any other clinical 
study: 
 Involving brolucizumab (Beovu); 
 
 Involving any other investigational products or devices, or in any other type of 
medical research with the last drug administration or invasive assessment (incl. 
blood drawing)  12 weeks prior to Day 1. 
Diagnostic Assessments 
16. Uncontrolled blood pressure (BP), defined as systolic  180 mmHg and/or 
diastolic  100 mmHg while participant at rest. If a participant’s initial reading 
exceeds these values, a second reading may be taken either  30 minutes later on 
the same day or on another day during the screening period. If the participant’s BP 
needs to be controlled by antihypertensive medication, the participant should be on 
stable medication for at least 1 month prior to Day 1 
17. Participants with HbA1c  12% at screening 
Exclusion criteria for study eye 
18. Any proliferative DR defined as: 
 Any neovascularization of the optic disc; 
 Any neovascularization elsewhere; 
 Any neovascularization of iris; 
 Any neovascularization of irido-corneal angle; 
 Vitreous or pre-retinal hemorrhage; 
19. Any panretinal photocoagulation prior to Day 1 
20. Macular (focal, grid, or micropulse) laser treatment prior to Day 1 
21. History of vitreoretinal surgery/pars plana vitrectomy, including PDS with 
ranibizumab implant/explant surgery 
22. Any cataract surgery within 12 weeks prior to Day 1 or any planned surgery during 
the study 
23. History of any glaucoma surgery (Note: laser glaucoma procedures are allowed 
if > 12 weeks prior Day 1) 
24. Uncontrolled glaucoma (e.g., progressive loss of visual fields or defined as 
intraocular pressure (IOP)  25 mmHg at screening despite treatment with anti-
glaucoma medication) 
25. History of rubeosis iridis 

 
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26. Any concurrent ocular conditions (e.g., 
 
cataract, age-related macular degeneration, macular hole, retinal vein occlusion, 
infectious or noninfectious uveitis, angioid streaks, histoplasmosis, active or inactive 
cytomegalovirus retinitis, choroidal neovascularization, infectious/non-infectious 
conjunctivitis, keratitis, scleritis, endophthalmitis) that, in the opinion of the 
Investigator, could either: 
 Require medical or surgical intervention during the study period to prevent or 
treat visual loss that might result from that condition; or 
 Likely contribute to worsening of BCVA over the study period if allowed to 
progress untreated; or 
 Preclude any visual improvement due to established structural damage. 
27. Rhegmatogenous or tractional retinal detachment, pre-retinal and/or sub-macular 
fibrosis, vitreomacular traction, foveal hard exudates, or epiretinal membrane 
involving the fovea or disrupting the macular architecture, as evaluated by the 
Central Reading Center (CRC) 
28. Actual or history of myopia  -8 diopters. 
29. Any active ocular or periocular infection on Day 1. 
30. Any presence of active intraocular inflammation on Day 1 (i.e., SUN criteria  0 or 
NEI vitreous haze grading > 0) or any history of intraocular inflammation 
(noninfectious or infectious uveitis of any type) 
Criteria for fellow (non-study) eye: 
31. Non-functioning non-study eye, defined as either: 
 BCVA  23 
 No physical presence (i.e., monocular) 
 Legally blind in the participant’s relevant jurisdiction  
  
5.3 
LIFESTYLE CONSIDERATIONS 
There are no study-specific restrictions to meals and dietary requirements.  
Participants may experience temporary visual disturbances after an IVT injection and the 
associated eye examinations. Participants should be advised not to drive or use 
machinery until visual function has recovered sufficiently. 
5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the study but 
are not subsequently randomized to study treatment. Screen failures should be tracked 
separately. 
The Investigator will maintain a screening log to record details of all participants 
screened and to confirm eligibility or record reasons for screening failure. 

 
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Participants who do not meet the criteria for participation in this study (screen failure) 
may be re-screened at the discretion of the Investigator. Eligible participants could be re-
screened up to 3 times (i.e. up to a total of 4 screenings) if required. 
In order to re-screen a participant after the end of the initial 28 days screening window, 
all inclusion and exclusion criteria should be re-evaluated and all screening assessments 
repeated. Note: If a participant will be re-screened within the 28-day window, fundus 
photography (FP) and FFA need to be repeated only if they were performed more than 
14 days before the new screening date. 
If the originally chosen eye does not meet eligibility criteria, the second eye may be 
evaluated within the initial 28-day screening period. If the second eye meets the 
eligibility criteria, then the participant would retain the same screening number and 
would not be considered screen-failed. 
5.5 
RECRUITMENT PROCEDURES 
Participants will be identified for potential recruitment using, clinical database and/or 
Independent Ethics Committee(IEC)/Institutional Review Board (IRB) approved 
newspaper/radio/social-media advertisements prior to consenting to take part on this 
study. 
6. 
TREATMENTS 
Study treatment is defined as any investigational product (including placebo) or 
marketed product intended to be administered to a study participant according to the 
study protocol. 
The IMPs for this study are RO7200220 and ranibizumab 0.5 mg; with RO7200220 and 
ranibizumab administered each at a constant volume of 50 L IVT in the specified single 
study eye.  
All IMPs required for completion of this study will be provided by the Sponsor. Study 
drug will be administered at the study center by qualified treatment administrator (see 
the Procedures Manual for study administration procedures).  
Cases of accidental overdose or medication error along with any associated AEs, should 
be reported as described in Section 5.2 of Appendix 2. 
6.1 
TREATMENTS ADMINISTERED 
RO7200220 in combination with ranibizumab administered as 
 
 (in Arm A) and ranibizumab alone (in Arm B) will be administered to 
the participants on Day 1 and every 4th week (Q4W), for a total of 12 injections each. A 
sham procedure will be administered to participants in the ranibizumab only Q4W arm 
(Arm B) at applicable visits to maintain masking between treatment arms. 

 
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Participants enrolled under Version 1 of this protocol and who have consented to this 
version of the protocol will be handled as follows:  
 
 
 
 
 
 
 
 
 
 
 

 
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Table 3 summarizes the treatments administered. Guidelines for dosage modification 
and treatment interruption or discontinuation are provided in Section 6.6 or Section 7, 
respectively.  
Note: During the off-treatment observation period IVT anti-VEGF may be administered 
as SoC per discretion of the Investigator for those patients who show disease recurrence 
as defined in Section 6.5.1.2. Ranibizumab administered in this context is not considered 
IMP.  
Please see the LucentisEU SmPC for more details on ranibizumab (Lucentis). For 
RO7200220, please see the RO7200220 IB and pharmacy manual for RO200220 for 
more details.  

 
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Table 3 
Summary of Treatments Administered 
Study Treatment 
Name: 
RO7200220 (Drug Product) 
RO7200220 (Diluent) 
Ranibizumab 
SHAM 
Dose 
Formulation: 
 
 
 
  
 
 
 
Ranibizumab is provided in a 
single-use 0.5 mL prefilled 
syringe (buffered using a L-
histidine-HCl solution (pH 5.5) 
containing trehalose, 
polysorbate 20, and water. 
No dose 
 
IMP and NIMP 
IMP 
N/A (diluent) 
IMP 
N/A 
Concentration  
100 mg/mL 
0 mg/mL 
 
10 mg/mL 
- 
Dose: 
1.0 mg in Arm A 
Only used for dilution 
0.5 mg in Arms  A and B 
No dose 
Route of 
Administration: 
IVT injection 
Only used for dilution 
IVT injection 
The sham is a procedure that 
mimics an IVT injection and 
involves the blunt end of an 
empty syringe (without a needle) 
being pressed against the 
anesthetized eye. 
Sourcing: 
Provided centrally by the Sponsor 
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor  
Provided centrally by the 
Sponsor 
Packaging and 
Labeling: 
 
RO7200220 Drug Product will be 
provided in vials. Each vial will be 
labeled as required per country 
requirement. 
RO7200220 Diluent will be 
provided in vials. Each vial will 
be labeled as required per 
country requirement. 
Ranibizumab will be provided 
in prefilled syringes. Each 
syringe will be labeled as 
required per country 
requirement. 
Sham treatments will be 
provided as empty vials in 
cartons.  Each vial will be 
labelled as required per country 
requirement. 
Manufacturer 
Genentech 
Genentech 
Genentech or Novartis 
N/A 
Legend: IMP=investigational medicinal product; IVT = intravitreal; N/A = not applicable; NIMP = non-investigational medicinal product. 

 
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6.1.1 
Medical Devices 
The Sponsor-manufactured medical devices (or devices manufactured for the Sponsor 
by a third party) provided for use in this study are relating to pre-filled syringes with 
ranibizumab.  
The Investigator must report all medical device incidents to the Sponsor throughout the 
study (see Section 8.3.9). 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Study drug packaging will be overseen by the Sponsor’s clinical study supplies 
department and bear a label with the identification required by local law, the protocol 
number, drug identification and dosage.  
The packaging and labeling of the study medication will be in accordance with the 
Sponsor’s standard and local regulations.  
The study site should follow all instructions included with each shipment of IMP. The 
investigational site will acknowledge receipt of IMPs and confirm the shipment condition 
and content. Any damaged shipments will be replaced. The Investigator or designee 
must confirm that appropriate temperature conditions have been maintained during 
transit for all IMPs received and that any discrepancies have been reported and resolved 
before use of the IMPs. All IMPs must be stored in a secure, environmentally controlled, 
and monitored (manual or automated) area in accordance with the labeled storage 
conditions, with access limited to the Investigator and authorized staff. 
The study site (i.e., Investigator or other authorized personnel [e.g., pharmacist]) is 
responsible for maintaining records of IMP delivery to the site, IMP inventory at the site, 
IMP use by each participant, and disposition or return of unused IMP, thus enabling 
reconciliation of all IMP received, and for ensuring that participants are provided with 
doses specified by the protocol. Upon arrival of the IMPs at the site, site personnel will 
complete the following: 
 
Check the IMPs for damage. 
 
Verify proper identity, quantity, integrity of seals and temperature conditions. 
 
Report any deviations or product complaints to the Study Monitor upon discovery. 
 
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose according to the pharmacy manual for RO7200220 and as per the 
Lucentis EU SmPC for the combination and the comparator (i.e. ranibizumab).  
Only participants enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment. 

 
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The Investigator, Institution, or the Head of the Medical Institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation and final disposition records). 
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 
IMP for safety reasons. The site must obtain written authorization from the Sponsor 
before any IMP is destroyed, and IMP destruction must be documented on the 
appropriate form. Accurate records of all IMPs received at, dispensed from, returned to, 
and disposed of by the study site should be recorded on the drug accountability log. 
Refer to the pharmacy manual and/or the RO7200220 IB, or the Lucentis EU SmPC for 
ranibizumab for information on IMP formulation, IMP handling, including preparation and 
storage, and accountability. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND 
MASKING 
6.3.1 
Method of Treatment Assignment and Masking 
After written informed consent has been obtained, all participants will receive a 
screening number assigned through the interactive voice and web response system 
(IxRS). 
A participant must meet all eligibility criteria (see Section 5.1 and Section 5.2) at the 
screening or Day 1 visit prior to randomization and first study treatment (see 
Section 8.9). As part of the screening process, FP, FFA, and SD-OCT will be transferred 
to the CRC, and the images will be evaluated to provide an objective, masked 
assessment of certain eligibility criteria. 
After all participant eligibility requirements are confirmed on Day 1 visit, the site 
personnel will contact the IxRS for assignment of a participant identification number (a 
separate number from the screening number). 
Participants will be randomized on the same day the study treatment is to be initiated 
(Day 1 visit).  
Note: If a site has an unexpected issue (e.g., the IxRS is not able to assign the study kit), 
a participant’s randomization and first study treatment may be administered within 2 
business days of the Day 1 visit assessments, after consultation with the Medical 
Monitor. The following assessments will be repeated on the day of randomization and 
study treatment administration: urine pregnancy test (if applicable), slit lamp 
examination, indirect ophthalmoscopy, pre-treatment IOP measurements (recorded on 

 
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the Day 1 electronic case report form [eCRF] and dated accordingly), and any new 
concomitant medications.  
Randomization will be stratified for the factors below: 
 
Baseline BCVA ETDRS letter score assessed on Day 1 (categories:  38 letters; 
 38 to 64;  64). 
 
IVT anti-VEGF and/or periocular/IVT corticosteroids treatment naïve participants 
vs. previously treated participants (Note: treatment naïve and previously treated 
participants as defined in Section 5.2). 
Randomization will be used to obtain an approximate equal allocation ratio between the 
different arms within each stratum. All participants will be randomized in a 1:1 ratio to 
one of the two arms. Limits will be placed on the number of treatment naïve and 
previously treated participants to ensure the planned distribution of participants in these 
two populations, i.e. per treatment arm approximately n=70 to 75 for treatment naïve and 
approximately n=35 to 40 for previously treated participants. 
After randomization and at each visit with study treatment administration (i.e., Day 1 
through Week 44), the IxRS will assign the appropriate study treatment kit to be used.  
 
 
  
 
 
 
 
  
 
  
 
 

 
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6.3.4 
Masking 
6.3.4.1 
Masked Roles 
This is a double-masked study. There must be a minimum of two investigators per site to 
fulfill the masking requirements of this study, and both are required to be present at each 
scheduled study visit where study treatment is administered. 
Principal Investigator 
The Principal Investigator who will be a retina specialist (or the equivalent in ex-U.S. 
countries) must be in a masked role as he or she has to oversee the whole trial conduct 
at his or her site and must be masked to participants’ treatment assignment. In addition, 
the Principal Investigator can assume any other masked role for which he or she 
qualifies except for BCVA examiner tasks.  
Assessor Physician 
At least one investigator who will be a retina specialist (or the equivalent in ex-U.S. 
countries) will be designated as the assessor physician. He or she will be masked to 
participants’ treatment assignments and will evaluate all pre-treatment assessments, as 
well as all assessments performed at screening, Day 7, Week 48, throughout the off-
treatment observation period and at the EOS or early treatment termination visit (ETTV). 
The assessor physician will also evaluate the causality of all AEs reported by the 
treatment administrator. If qualified, this role can take on any other masked role tasks 
except tasks performed by the BCVA examiner. 
Photographer(s) and OCT Technician(s) 
If qualified, the photographers and OCT technicians can share any other masked role 
tasks except tasks performed by the BCVA examiner.  
Study Coordinator(s) 
If qualified, the study coordinator(s) can share any other masked role tasks except tasks 
performed by the BCVA examiner.  
BCVA Examiner  
The BCVA examiner will be masked to both the assigned treatment arm and the location 
(right vs. left) of the study eye. The BCVA examiner will have no access to participants’ 
medical charts or the VA scores from a participant’s previous visits and may have 
access only to a participant’s refraction data from previous visits. The BCVA examiner is 
not allowed to perform any other task involving direct participant care. 
Phlebotomist 
The phlebotomist’s tasks can be performed by a qualified masked or unmasked role 
individual except for BCVA examiner role.  

 
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Note: Vital signs and ECG assessments can also be done by a qualified masked or 
unmasked role, except for the BCVA examiner role.  
6.3.4.2 
Unmasked Roles 
Treatment Administrator 
At least one investigator will be designated as the treatment administrator and will be 
unmasked to the participants’ treatment assignment.  
The study treatment administrator must be an ophthalmologist, and ideally a retina 
specialist. It is the PI's responsibility to ensure that the treatment administrator 
ophthalmologist is suitably qualified to safely perform the IVT injection procedure, is able 
to manage any AEs that may occur following the IVT procedure, and is 
 
 
The treatment administrator(s) performing the study treatment administration 
(RO720220, ranibizumab, or sham) will also perform the post-treatment administration 
vision testing (finger-counting and, if applicable, hand movement and/or light perception 
tests) and will treat AEs that occur during or shortly after the study treatment 
administration. The person in this role, however, will not evaluate the causality of AEs, 
which is the responsibility of the masked assessor physician(s). The treatment 
administrator can also perform post-treatment IOP measurements, 
 
  
In addition, the qualifying treatment administrator can assist with and perform the 
screening and Day 1 visit assessments. The treatment administrator must not be 
involved in any other aspect of the study and must not divulge treatment assignment 
to anyone.  
Unmasked Assistant(s) and Pharmacist 
Sites should  have designated qualified unmasked assistant(s) who can, e.g., accept 
IMP packages, log them in IxRS, place them under correct conditions in the fridge, 
prepare study treatment incl. dilutions if applicable (as described in the Pharmacy 
manual), assemble study treatment supplies, prepare sterile field, prepare the 
participant’s study eye for treatment, discard all injection materials (i.e., syringes and 
needles) immediately following study treatment, and place vial in the kit box. The 
qualified unmasked assistant(s) can be assigned to measure post-dose IOP. If the site 
uses a pharmacy, then the unmasked role is also assigned to the pharmacist who can 
take on IMP-related tasks as applicable per delegation of authority log. In addition, 
qualifying unmasked assistant(s) can assist with and perform the screening and Day 1 
visit assessments.  
Number of Unmasked Personnel per Site 
Every effort must be made to limit the number of unmasked study personnel to ensure 
the integrity of this masked study. Typically, there should be no more than six unmasked 

 
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personnel (e.g., treatment administering physician[s] and assisting technician[s] if 
applicable) at an investigative site at one time. In certain circumstances, the total 
number of unmasked personnel might be increased after discussion with and approval 
by the Medical Monitor. If the site is using a pharmacist, then this person may be in an 
unmasked role in addition to the unmasked staff at the site.  
Any other study assisting personnel not listed above will be in the masked roles.  
6.3.4.3 
Delegation Log 
All roles for each study staff member should be clearly documented in the Site 
Delegation Log. The Site Delegation Log must be signed by the Principal Investigator. 
6.3.4.4 
Role Switching 
Once personnel assigned to the designated unmasked role start performing that role 
they cannot switch to a masked role during the study. Switching from a masked role to 
an unmasked role may be possible and must be documented in the Delegation Log. 
6.3.4.5 
Study Backup Staff 
Sites are strongly advised to have backup staff for key study roles. In case of an 
emergency (e.g., an unscheduled safety visit), participants should be seen preferably by 
the assessor physician. If the assessor physician is unavailable, then any clinic 
physician present, including the physician in the treatment administrator role, should see 
the participant. 
6.3.4.6 
Masking of Vendors, Sponsor's Agents, and 
Laboratory Personnel 
CRC personnel, study vendors, the Sponsor, and its agents will also be masked to 
treatment assignment, with the exception of individuals who require access to participant 
treatment assignments to fulfil their job roles during a clinical trial. These roles include 
the clinical supply chain managers, sample handling staff, operational assay group 
personnel, IxRS service provider, drug accountability clinical research associates, the 
images coordinator, IMC members and those responsible for preparing the IMC 
report(s). 
To maintain the masked design of the study, 
 
 will be obtained 
from consenting participants in any treatment arm. The laboratories responsible for 
performing sample analyses and Sponsor’s Bioanalytical Scientist will be unmasked to 
participants' treatment assignment to identify appropriate samples to be analyzed. 
Unmasking for analysis of the relevant biosamples during the conduct of the study will 
be performed by personnel outside of the study team (e.g. by the Sponsor`s 
pharmacometrician, PK/PD Data Scientist) and according to the Sponsor’s internal 
standard procedures to ensure the integrity of the data. The number of Roche 

 
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representative(s) and delegates who are unmasked will be kept to the minimum required 
to address the objective of the biosample analysis. 
 
6.3.4.7 
Participant Masking  
Participants will be masked to treatment assignment during the study and until study 
closeout, until the Sponsor indicates that the study can be unmasked.  
6.3.5 
Unmasking 
6.3.5.1 
Single-Participant Emergency Unmasking 
If unmasking is necessary for a medical emergency (e.g., in the case of an SAE for 
which participant management might be affected by knowledge of treatment 
assignment), the investigator will be able to break the treatment code by contacting the 
IxRS. The Investigator is not required to contact the Medical Monitor prior to breaking 
the treatment code; however, the treatment code should not be broken except in 
emergency situations. 
6.3.5.2 
Single-Participant Non-Emergency Unmasking 
If the investigator wants to know the identity of study drug for any reason other than a 
medical emergency, he or she should contact the Medical Monitor directly. The 
investigator should document and provide an explanation for any non-emergency 
unmasking. The investigator will be able to break the treatment code by contacting 
the IxRS.  
6.3.5.3 
Single-Participant Unmasking for Health Authority 
Reporting Requirements 
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all SUSARs (see Section 5 in Appendix 2) that are 
considered by the investigator or Sponsor to be related to study drug. The participant 
may continue to receive treatment, and the investigator, participant, and Sponsor 
personnel, with the exception of the Drug Safety representative and personnel who must 
have access to participant treatment assignments to fulfill their roles (as defined above) 
will remain masked to treatment assignment. 
6.4 
TREATMENT COMPLIANCE 
Not applicable.  
6.5 
CONCOMITANT THERAPY 
Treatments and procedures should be reported to the Investigator via the respective 
eCRF along with reason for use, dates of administration (including start and end dates) 
and dosage information (including dose and frequency) as follows: 
 
Any treatments pertinent to DR/DME (e.g. IVT with anti-VEGF component and/or 
IVT corticosteroids) used by a participant prior to Day 1 (at least for the year 

 
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preceding Day 1). Concomitant treatments for the fellow-eye should be recorded 
until the final visit. 
 
SoC treatment of the study eye during the off-treatment follow up period will be 
reported on a separate form. 
 
Any other medication or vaccine (including over-the-counter or prescription 
medicines, approved dietary and herbal supplements, nutritional supplements) used 
by a participant from 30 days prior to Day 1 until the final visit. 
 
Protocol-specified procedural medications (e.g., dilating drops or fluorescein dyes, 
proparacaine, or antimicrobials [if applicable]) will not be reported. 
 
Selected ocular procedures (e. g. cataract surgery, macular laser) done prior to Day 
1 will be reported on a separate form. 
 
All other procedures and therapies are not required to be recorded. 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. All medications administered to manage AEs should be 
recorded on the Adverse Event eCRF. 
6.5.1 
Rescue Medicine and SOC treatment  
6.5.1.1 
Rescue Medicine 
Not applicable. 
 
 
 
 
 
 
 
 
 
 
6.5.2 
Permitted Therapy 
Participants who use maintenance therapies should continue their use if not excluded 
per exclusion criteria. 

 
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Retinal laser photocoagulation is permitted in either eye, if clinically indicated for the 
treatment of proliferative DR or retinal holes or tears post randomization. 
Participants who use oral contraceptives (with a failure rate of  1% per year), hormone-
replacement therapy, or other maintenance therapy should continue their use (providing 
the regimen is stable for at least 12 weeks prior to Day 1 and expected to remain 
unchanged during the conduct of the study). For further details see Section 5.1). 
6.5.2.1 
Treatment of the Fellow Eye 
At the discretion of the masked physician, randomized patients may have their fellow 
(nonstudy) eye treated with anti-VEGF therapy licensed for ocular use if they are 
diagnosed with an ocular condition for which the selected anti-VEGF therapy is 
approved by the country regulatory agency. Consult with the region-specific anti-VEGF 
prescribing information for the recommended dose and frequency of treatment. The 
Sponsor will cover the cost of approved licensed ocular anti-VEGF therapy in 
accordance with local regulations. Note: Avastin (bevacizumab) is not licensed for 
ophthalmic use in any country; therefore, it is prohibited to be used.  
If (per the masked investigator's judgment) treatment with anti-VEGF is to be given to 
the fellow (non-study) eye at the same visit as the study eye treatment, all study eye 
assessments (including study eye study treatment administration) must be completed 
first. If there are no safety concerns, the site may proceed with the fellow eye treatment 
administered by the unmasked treatment administrator to preserve masking.  
Individual trays and sterile preparation must be separately prepared for each eye 
treatment. 
Note: If the fellow eye anti-VEGF treatment is performed outside of the study visit, then a 
qualified physician, either in masked or unmasked role, can administer the treatment. 
6.5.3 
Prohibited Therapy 
At the discretion of the Investigator, participants may start or continue to receive all 
medications and standard treatments administered for other conditions, except for those 
listed under the exclusion criteria (Section 5.2). 
Administration of macular micropulse and focal or grid laser in the study eye is prohibited 
throughout the duration of the study. 
Participants are not allowed to participate in any other clinical study during participation 
in Study BP43464. 
 
6.6 
DOSE MODIFICATION, TEMPORARY INTERRUPTION AND 
RECHALLENGE 
The dose and frequency of the study drug should not be modified. 

 
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6.6.1 
Temporary Interruption 
If study drug administration is temporary interrupted (participant misses one or more 
study treatment administration visits; see also Section 1.3 for visit window) the 
administration may resume at the next planned dosing date. A missed dose of study 
drug will not be made up for. 
6.7 
TREATMENT AFTER THE END OF THE STUDY 
RO7200220 is an IMP for which safety and tolerability are under evaluation in an 
indication where SoC treatments are available.  
The Sponsor does not intend to provide RO7200220 or other study interventions to 
participants after conclusion of the study or any earlier participant withdrawal. 
7. 
DISCONTINUATION OF STUDY, STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
Participants have the right to voluntarily withdraw from the study at any time for any 
reason. 
An excessive rate of withdrawals (either participants discontinuing study treatment or 
withdrawing from the study) can render the study non-interpretable. Therefore, 
unnecessary withdrawal of participants should be avoided and efforts should be taken to 
motivate participants to comply with all the study-specific procedures as outlined in this 
protocol. 
Details on study and site closures are provided in Section 4 of Appendix 1. 
7.1 
DISCONTINUATION OF STUDY TREATMENT 
For data to be collected at the time of treatment discontinuation and follow-up and for 
any further evaluations that need to be completed see the SoA (Section 1.3). 
Reasons for permanent discontinuation of study treatment (or withdrawal from the study) 
may include, but are not limited to, the following: 
 
Participant withdrawal of consent at any time. 
 
Any medical condition that the Investigator or Sponsor determines may jeopardize 
the participant’s safety if he or she continues in the study. 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the participant. 
Participants must discontinue study treatment if they experience any of the following: 
 
Pregnancy 
 
Retinal detachment or retinal tear in the study eye 
 
Vitreous hemorrhage that will preclude examination of the macula and obtaining 
adequate retinal imaging in the study eye 

 
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 
Surgical intervention (i.e. vitreoretinal surgery, vitreous tap, or biopsy with IVT 
injection of anti-infectives or laser or retinal cryopexy with gas) to prevent permanent 
loss of sight 
 
 
 
o 
o 
o 
o 
o 
 
Every effort should be made to obtain information on participants who withdraw from the 
study but have not withdrawn consent. Participants who discontinue study treatment 
prematurely will be asked to return to the clinic for an ETTV (see Section 8.9.3) and may 
undergo follow-up safety assessments if required (see Section 8.9.4), unless the 
participant withdrew consent. The primary reason for premature study treatment 
discontinuation should be documented on the appropriate eCRF. Participants who 
discontinue study treatment prematurely will not be replaced. 
For temporary interruption of study treatment see Section 6.6.1. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE 
STUDY 
Participants have the right to voluntarily withdraw from the study at any time for any 
reason. 
In addition, the Investigator has the right to withdraw a participant from the study for 
medical conditions that the Investigator or Sponsor determines, may jeopardize the 
participant’s safety if he/she continues in the study. 
If possible, information on reason for withdrawal from the study should be obtained. The 
primary reason for withdrawal from the study should be documented on the appropriate 
eCRF. Participants will not be followed for any reason after consent has been withdrawn. 
This includes the follow-up assessments. 
When a participant voluntarily withdraws from the study, or is withdrawn by the 
Investigator, samples collected until the date of withdrawal will be analyzed, unless the 

 
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participant specifically requests for these to be discarded or local laws require their 
immediate destruction. However, if samples have been tested prior to withdrawal, results 
from those tests will be used as part of the overall research data. A participant's 
withdrawal from this study does not, by itself, constitute withdrawal of samples donated 
to the Research Biosample Repository (RBR). 
Participants who withdraw from the study for safety or other reasons will not be replaced.  
For data to be collected at the time of study discontinuation and for any further 
evaluations that need to be completed see SoA (Section 1.3). 
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if the participant repeatedly fails to 
return for scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
 
The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible, counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study. 
 
Before a participant is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the participant. These contact attempts 
should be documented in the participant’s medical record. 
 
Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study. 
Discontinuation of sites or of study as a whole are handled as part of Appendix 1. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timepoints are summarized in the SoA (Section 1.3). 
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment (see Section 7.1). 
Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of the Informed Consent Form (ICF) may 
be utilized for screening or baseline purposes provided the procedure met the 
protocol-specified criteria and was performed within the time-frame defined in the SoA. 

 
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At timepoints with multiple assessments, the following sequence is suggested; at the 
discretion of the Investigator, the order can be adjusted to optimize site personnel and 
participant’s time management or to accommodate site’s best practices:  
1. 
12-lead ECG: must be performed before blood sampling, and as early as possible  
2. 
Vital signs  
3. 
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. 
4. 
Ocular assessments and imaging: 
 
BCVA: At screening, BCVA can be performed before 12-lead ECG, vital signs, 
and blood sampling, to avoid unnecessary investigations in those participants 
who may be a screen failure as a result of BCVA letter score 
 
IOP (may be performed after imaging assessments, see Section 8.2.6.2) 
 
Slit-lamp examination 
 
Dilated binocular indirect high-magnification ophthalmoscopy 
 
FP 
 
SD-OCT 
 
OCT-A (mandatory for those sites where available) 
 
FFA 
5. 
 
6. 
IOP measurement 
The IRB/IEC will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the ICF. 
8.1 
EFFICACY ASSESSMENTS 
Efficacy assessments will be performed as detailed in the SoA (Section 1.3) and will 
include functional (BCVA) and imaging assessments (SD-OCT). 
8.2 
SAFETY ASSESSMENTS 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
Safety assessments will consist of monitoring and recording AEs, including SAEs and 
non-serious AEs of special interest (NSAESI); measurement of protocol-specified safety 
laboratory assessments; measurement of protocol-specified vital signs, ECGs; ocular 
safety assessments like BCVA, slit-lamp examination, binocular high-magnification 
ophthalmoscopy, IOP and retinal imaging, and other protocol-specified tests that are 
deemed critical to the safety evaluation of the study. 

 
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8.2.1 
Physical Examinations 
A physical examination will be performed by trained medical personnel at the study 
center. 
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, dermatological and neurological, 
musculoskeletal in addition to head, eyes, ears, nose, throat, neck and lymph nodes 
systems. Further examination of other body systems may be performed in case of 
evocative symptoms at the Investigator’s discretion. 
Weight and height as outlined in the SoA (see Section 1.3) will also be recorded. The 
body-mass-index will be calculated form the screening measurements. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 

 
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Any abnormality identified at baseline (prior to first study drug administration) should be 
recorded on the General Medical History and Baseline Conditions eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Changes from baseline abnormalities should be 
recorded in participant’s notes. New or worsened clinically significant abnormalities 
should be recorded as AEs on the Adverse Event eCRF. 
8.2.2 
Vital Signs 
Body temperature (tympanic or oral), pulse rate, and BP will be assessed. 
BP and pulse measurements should be assessed with a completely automated device, if 
available. When possible, the same arm should be used for all blood pressure 
measurements. 
BP and pulse measurements should be preceded by  5 min of rest for the participant in 
a quiet setting without distractions (e.g., television, cell phones). 
Single measurements of vital signs will be taken (before blood collection for laboratory 
tests but after ECG collection at applicable timepoints). At the discretion of the 
Investigator, measurements can be repeated if the values are abnormal or borderline. 
8.2.3 
Electrocardiograms 
Triplicate 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3). The full 
set of triplicates should be completed in less than 5 minutes using the ECG machine 
provided by the ECG central reading center. 
To minimize variability, it is important that participants be in a resting position for 
 10 minutes prior to each ECG evaluation. Body position should be consistently 
maintained for each ECG evaluation to prevent changes in heart rate. Environmental 
distractions (e.g., television, radio, conversation, cell phones) should be avoided during 
the pre-ECG resting period and during ECG recording. ECGs should be performed prior 
to meals and any scheduled vital sign measurements and blood draws. In some cases it 
may be appropriate to repeat abnormal ECGs to rule out improper lead placement 
potentially contributing to the ECG abnormality. 
The digital ECG recordings should be transmitted immediately to the ECG central 
reading center for interpretation. Investigators or designees must review, sign, and date 
all ECG reports received back from the CRC, which will be kept as part of the 
participant’s permanent stud file at the site. Printouts directly from the ECG machine (not 
centrally reviewed) are not considered as valid ECG reports. The CRC will transfer the 
relevant ECG characteristics (including heart rate, PQ [PR], QRS, QT, with derived RR, 
and QTcF, T and U abnormalities) and overall interpretation directly to the Sponsor. 
Investigators or designees will document overall ECG interpretation on the eCRF. 

 
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8.2.4 
Clinical Safety Laboratory Assessments 
This study will use a central laboratory for all laboratory analyses. 
Normal ranges for the study laboratory parameters from the central laboratory will be 
supplied to the Sponsor before the study starts. A list of clinical laboratory tests to be 
performed is provided in Appendix 4 and these assessments must be conducted in 
accordance with the separate laboratory manual and the SoA (Section 1.3). 
The following samples will be taken for safety laboratory assessments: 
 
Blood 
 
Urine 
Results of clinical laboratory testing will be received as electronically produced 
laboratory reports submitted directly from the central laboratory.  
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes (see Section 4 of Appendix 3) occurring during the study in 
the AE section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which are not 
associated with the underlying disease, unless judged by the Investigator to be more 
severe than expected for the participant's condition. 
 
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. 
 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor 
notified. 
 
If laboratory values from non-protocol specified laboratory assessments performed 
at a local laboratory require a change in participant management or are considered 
clinically significant by the Investigator (e.g., SAE or AE or dose-modification) then, 
the results must be recorded in the eCRF. 
 
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 participant safety. 
Where the clinical significance of abnormal laboratory results at screening is considered 
uncertain, screening laboratory tests may be repeated to confirm eligibility. 
8.2.4.1 
Urine assessments 
Urine pregnancy tests for WOCBP will be done at the investigational site. If positive, a 
serum pregnancy test will be performed. If the serum pregnancy test is positive, study 
treatment or SoC should not be administered.  

 
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Safety Urinalysis will be performed (see Table 1 in Appendix 4) 
Urine samples will be destroyed no later than 2 years after the date of final clinical study 
report (CSR). 
8.2.5 
Medical History and Demographic Data 
 
Medical history (general and ophthalmic) includes clinically significant diseases, 
reproductive status, smoking history, and any medications or vaccine (including 
over-the-counter or prescription medicines, approved dietary and herbal supplements, 
and nutritional supplements) used by the participant as outlined in Section 6.5.2). 
Demographic data will include age, sex, and self-reported race/ethnicity. Race/ethnicity 
is recorded
 
 
diseases (Zhang et al 2018).  
8.2.6 
Ophthalmological Assessments 
The following ocular assessments will be performed at the study sites by qualified 
personnel. All assessments should be performed for both eyes, except when specified 
for study eye only. 
 
BCVA  
 
IOP measurement 
 
Slit-lamp examination  
 
Dilated binocular indirect high-magnification ophthalmoscopy  
 
FP 
 
SD-OCT  
 
OCT-A (mandatory for those sites where available) 
 
FFA  
 
Safety finger counting to assess ocular perfusion after IVT 
Ophthalmological assessments will be performed at timepoints as tabulated in the SoA 
(Section 1.3) and at the discretion of the Investigator at any other time 
 
 if deemed 
appropriate. 
 
8.2.6.1 
Best Corrected Visual Acuity 
Refraction and BCVA will be measured for both eyes and prior to dilating eyes by trained 
and certified personnel at the study sites and at each study visit. The BCVA will be 
measured by using the set of three Precision visionTM or Lighthouse distance acuity 
charts (modified ETDRS Charts 1, 2 and R). The BCVA assessment data will be entered 

 
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in the BCVA specific eCRF. The refractive error at screening will also be recorded on the 
eCRF. 
The VA examiner will be masked to the study eye and treatment arm assignment.  
A VA specifications document, procedure manual, and training materials will be provided 
to the study sites, and examiner certification will be obtained from a third party vendor. 
The VA examination room also must be certified before any VA examinations are 
performed. 
8.2.6.2 
IOP Measurement 
The IOP measurements will be done at the timepoints specified in the SoA (Section 1.3). 
The detailed procedure and the methods of IOP measurements will be provided in the 
Procedures Manual.  
8.2.6.3 
Safety Finger Count Vision 
In the study eye, a post-administration optic nerve head perfusion will be assessed for 
each participant immediately after IVT administration of study treatment or SoC 
(maximum within 15 minutes after treatment administration) by using testing finger count 
vision, hand motion, or light perception, as appropriate. 
8.2.6.4 
Slit-Lamp Examination and Dilated Binocular Indirect High-
Magnification Ophthalmoscopy 
Slit-lamp biomicroscopy and dilated binocular indirect high-magnification 
ophthalmoscopy will be performed at each study visit for each eye. Observations will be 
graded as normal or abnormal. Abnormal findings will be specified as not clinically 
significant (NCS) or clinically significant (CS). Abnormal findings (CS and NCS) will be 
described. The slit-lamp biomicroscopy examination will consist of the evaluation of 
anterior and posterior chambers (including grading scales for anterior chamber [AC] cells 
or flare and for vitreous haze, vitreous cells (optional), and vitreous hemorrhage, as 
detailed in Appendix 6 and Appendix 7, respectively. A fluorescent dye may be applied 
in order to assist eye examination. All findings will be recorded on the eCRF. Further 
information will be provided in the Procedures Manual. 
8.2.6.5 
Ocular Imaging 
The CRC(s) will provide sites with the CRC(s) manual and training materials for 
specified study ocular images. Before any study images are obtained, site personnel, 
test images, systems and software (where applicable) will be certified and validated by 
the CRC(s) as specified in the CRC manual. All ocular images will be obtained by 
trained and certified site personnel at the study sites and forwarded to the CRC(s) for 
independent analysis and/or storage. Ocular imaging assessments will be done for both 
eyes, unless otherwise specified, at timepoints specified in the SoA (Section 1.3). It is 
mandatory to use the same device for each modality throughout the study. 
Fundus Photography (FP) 

 
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Ultra-wide field (UWF-FP; Optos) will preferentially be performed. Sites that do not 
possess UWF equipment can use other equipment, as detailed in the CRC manual.   
Spectral Domain Optical Coherence Tomography (SD-OCT) 
SD-OCT will be performed on a Spectralis instrument (Heidelberg Engineering, 
Heidelberg, Germany), equipped with TrueTrack Active Eye Tracking, and AutoRescan. 
Where Spectralis is not available at an investigational site, Cirrus or Topcon are also 
considered acceptable devices. 
Optical Coherence Tomography Angiography (OCT-A) 
Optional OCT-A will be performed at the sites with OCT-A capabilities. 
Fundus Fluorescein Angiography (FFA) 
Ultra-wide field (UWF-FFA; Optos) will preferentially be performed. Sites that do not 
possess UWF equipment can use other equipment, as detailed in the CRC manual. 
8.2.7 
Immunogenicity Assessments 
Since RO7200220 is a humanized monoclonal antibody, there is a risk that ADAs 
against RO7200220 could develop, potentially reducing its efficacy and/or potentially 
resulting in symptomatic hypersensitivity reaction, in particular immune-complex 
reactions. 
 
  
 
 The actual date and time of each 
sample will be recorded in the eCRF. 
If required, remaining ADA samples may also be used for assay development/validation 
experiments and to further characterize the immune response on an exploratory basis.  
The 
 will be destroyed no later than 2 years 
after the date of the final CSR.  
For details on sampling procedures see the Procedures Manual. Details on sample 
storage and shipment are given in the Laboratory Manual.  
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
The definitions of AEs or SAEs can be found in Appendix 2. The non-serious adverse 
events of special interest (NSAESI), the sight-threatening AEs, and disease-related 
events and/or disease-related outcomes not qualifying as AEs or SAEs, are discussed in 
Sections 8.3.6, 8.3.7, and 8.3.8 
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(including assessment of seriousness, severity and causality; see Appendix 2) are 
recorded on the Adverse Event eCRF and reported to the Sponsor in accordance with 
instructions provided in this section and in Appendix 2. 
Procedures used for recording AEs are provided in Appendix 3: 
 
Diagnosis versus signs and symptoms 
 
AEs occurring secondary to other events 
 
Persistent or recurrent AEs 
 
Abnormal laboratory values 
 
Abnormal vital sign values 
 
Abnormal liver function tests 
 
Overdose (see also Section 8.4) 
 
Deaths 
 
Preexisting medical condition, including worsening of DME 
 
Worsening of disease (DME) being studied 
 
Hospitalization or prolonged hospitalization 
 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 2. 
Investigators will seek information on AEs at each participant’s contact. All AEs, whether 
reported by the participant or noted by study personnel, will be recorded in the 
participant’s medical record and on the Adverse Event eCRF as follows: 
After informed consent has been obtained but prior to initiation of study treatment, 
only SAEs caused by a protocol-mandated intervention should be reported (e.g., SAEs 
related to invasive procedures such as angiographies). Any other AE should not be 
reported. 
After initiation of study treatment, all AEs, regardless of relationship to study 
treatment, will be reported until the final study visit (i.e. ETTV, EOS, or Week 72, 
whatever occurs first). 
Post-study AEs and SAEs: The Investigator is not required to actively monitor 
participants for AEs after the end of the AE reporting period (i.e. ETTV, EOS, or 
Week 72, whatever occurs first).  
However, if the Investigator learns of any SAE (including a death) or other AEs of 
concern that are believed to be related to prior treatment with study treatment, at any 

 
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time after a participant has been discharged from the study, and the Investigator 
considers the event to be reasonably related to the study treatment or study 
participation, the Investigator must promptly notify the Sponsor. For the procedure of 
reporting, see Appendix 2. 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence. 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all participant evaluation timepoints. 
8.3.3 
Follow-Up of Adverse Events and Serious Adverse Events 
8.3.3.1 
Investigator Follow-Up 
The Investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the Investigator, the event is otherwise 
explained, the participant is lost to follow-up (Section 7.3), or the participant withdraws 
consent. Every effort should be made to follow all SAEs considered to be related to 
study treatment or study-related procedures until a final outcome can be reported. 
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the participant’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 8.3.5. 
8.3.3.2 
Sponsor Follow-Up 
For SAEs, NSAESIs, and pregnancies, the Sponsor or a designee may follow up by 
telephone, fax, electronic mail, and/or a monitoring visit to obtain additional event 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 
event. 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events 
Immediate notification by the Investigator to the Sponsor of an SAE regardless of 
relationship to study drug is essential so that legal obligations and ethical responsibilities 
towards the safety of participants and the safety of a study treatment under clinical 
investigation are met. 

 
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The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.  
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.  
An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then, file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
For immediate (i.e., no more than 24 hours after learning of the event) and expedited 
reporting requirements from Investigator to Sponsor and from Sponsor to Health 
Authority, investigators, IRB and EC, see Section 5 of Appendix 2. 
8.3.4.1 
Emergency Medical Contacts 
To ensure the safety of study participants, access to the Medical Monitors is available 
24 hours a day 7 days a week. Details will be available separately. 
8.3.5 
Pregnancy 
WOCBP will be instructed to immediately inform the Investigator if they become 
pregnant during the study, or within 12 weeks after the last dose of study treatment, or 
within 12 weeks after the dose of SoC, if applicable.  
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the pregnancy reporting process as detailed 
in Appendix 5. All pregnancies reported during the study should be followed until 
pregnancy outcome, with follow-up information on the infant collected according to 
procedures outlined in Appendix 5. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs (Appendix 5). 
8.3.6 
Non-serious Adverse Events of Special Interest (immediately 
reportable to Roche) 
Non-serious AEs 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 
Appendix 2 for reporting instructions). 

 
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AEs of special interest (AESIs) 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 6 of Appendix 3).  
 
Suspected transmission of an infectious agent by the study treatment, 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 participant exposed to a medicinal 
product. This term applies only when a contamination of the study treatment is 
suspected.  
8.3.7 
Sight-threatening Adverse Events (immediately reportable to 
Roche) 
Sight-threatening AEs are defined in Appendix 8.  
Sight-threatening AEs, regardless if considered serious or non-serious, 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 Appendix 2 for reporting instructions). 
The follow-up actions for sight-threatening AEs are defined in Section 8.9.5. 
8.3.8 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as Adverse Events or Serious Adverse Events 
Not applicable. 
8.3.9 
Medical Device Complaints (Including Malfunctions) 
Medical devices being provided for use in this study are pre-filled syringes with 
ranibizumab. In order to fulfill regulatory reporting obligations worldwide, the Investigator 
must report all device deficiencies to the Sponsor in the form of a medical device 
complaint. A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance, and it can include 
malfunctions, use errors, and inadequate labeling. 
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 8.3.3 and Appendix 2. 
8.3.9.1 
Time Period for Detecting Medical Device Incidents 
Medical device incidents or malfunctions of the device that result in an incident will be 
detected, documented, and reported during all periods of the study in which the medical 
device is used. 

 
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If the Investigator learns of any incident at any time after a participant has been 
discharged from the study, and such incident is considered reasonably related to a 
medical device provided for the study, the Investigator will promptly notify the Sponsor. 
8.3.9.2 
Follow-up of Medical Device Incidents 
All medical device incidents involving an AE will be followed and reported in the same 
manner as other AEs (see Section 8.3). This applies to all participants, including those 
who discontinue the study treatment. 
The Investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the incident. 
New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the Investigator. 
8.3.9.3 
Prompt Reporting of Medical Device Incidents to Sponsor 
The Investigator must report all medical device complaints, including AEs and SAEs, to 
the Sponsor. The Investigator should document as much information as possible on the 
IMP Deviation Form, including the product batch number, and forward the form to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event. Refer to 
the pharmacy manual for further details.  
If the medical device results in an AE to the study participant, the event must be reported 
on the Adverse Event eCRF and submitted through the electronic data capture (EDC) 
system. If the event is serious, the Adverse Event eCRF must be completed immediately 
(i.e., no more than 24 hours after learning of the event), as outlined in Section 5 of 
Appendix 2. 
8.3.9.4 
Regulatory Reporting Requirements for Medical Device 
Incidents 
The Investigator will promptly report all incidents occurring with any medical device 
provided for use in the study in order for the Sponsor to fulfill the legal responsibility to 
notify appropriate regulatory authorities and other entities about certain safety 
information relating to medical devices being used in clinical studies. 
The Investigator, or responsible person according to local requirements (e.g., the Head 
of the Medical Institution) will comply with the applicable local regulatory requirements 
relating to the reporting of incidents to the IRB/IEC. 
 
8.4 
TREATMENT OF OVERDOSE 
For this study, study treatment overdose is the accidental administration of a drug in a 
quantity that is higher than the assigned dose. An overdose or incorrect administration of 
study treatment is not an AE unless it results in untoward medical effects (see 
Sections 5 and 5.2 of Appendix 2 for further details). 

 
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Decisions regarding dose-interruptions or modifications (if applicable) will be made by 
the Investigator in consultation with the Medical Monitor based on the clinical evaluation 
of the participant. 
In the event of an overdose, the Investigator should: 
1. 
Contact the Sponsor’s Medical Monitor immediately. 
2. 
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
resolved 
3. 
Obtain a blood sample for PK, if requested by the Medical Monitor (determined on a 
case-by-case basis). 
4. 
Document the quantity of the excess dose, as well as the duration of the overdose, 
in the eCRF. 
8.5 
PHARMACOKINETICS 
Mandatory samples to evaluate concentrations of study treatment will be collected from 
all participants. 
 
 
 The date of each sample collection will be 
recorded in the eCRF. RO7200220 levels, and ranibizumab levels (when applicable and 
if deemed necessary), will be analyzed by using validated assays.
 
  
The following samples will be taken for PK analysis.  
 
  
 
  
For details on sampling procedures see the Procedures Manual. Details on sample 
storage and shipment are given in the Laboratory Manual.  
Any volume of 
 remaining after the specified analyses may 
be used for additional exploratory biomarker profiling and/or identification, development 
and validation of assays, 
 
 All PK samples will be 
destroyed no later than 2 years after the date of final CSR 
Drug concentration information that would unblind the study, will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 

 
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8.6 
PHARMACODYNAMICS AND BIOMARKERS ANALYSES 
 
  
 
 
 
 
  
For details on sampling procedures see the Procedures Manual. Details on sample 
storage and shipment are given in the Laboratory Manual and Flowchart.  
The following analyses will be performed: 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
For participants who consent to RBR, leftover samples will be transferred to RBR (see 
Section 8.7). 
 
8.7 
SAMPLES FOR RESEARCH BIOSAMPLE REPOSITORY. 
8.7.1 
Overview of the Research Biosample Repository 
The Roche RBR is a centrally administered group of facilities for the long-term storage of 
human biologic samples, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides). The collection, storage and analysis of the RBR 
samples will facilitate the rational design of new pharmaceutical agents and the 

 
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development of diagnostic tests, which may allow for individualized drug therapy for 
participants in the future. 
These samples will be derived only from participants who give specific consent to 
participate in this optional RBR. RBR samples can be used (but not limited to) to achieve 
the following objectives: 
 
To study the association of biomarkers with efficacy or progressive disease. 
 
To identify safety biomarkers that are associated with susceptibility to developing 
AEs or can lead to improved AE monitoring or investigation. 
 
To increase knowledge and understanding of disease biology and drug safety. 
 
To study treatment response, including drug effects and the processes of drug 
absorption and disposition.  
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays. 
 
8.7.2 
Sample Collection 
RBR samples will be derived from any residual material from
 
 
 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to RO7200220 or diseases: 
 
Any leftover samples: 
o 
 
o 
  
Participants will not be identified by name or any other personally identifying information. 
Data generated from RBR samples will be analyzed in the context of this study but will 
also be explored in aggregate with data from other studies. The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. For all samples, dates of consent and 
sample collection should be recorded on the associated RBR page of the eCRF. Details 
on processes for collection and shipment of these samples can be found in separate 
sample documentation.  
RBR samples will be stored and used until no longer needed or until they are exhausted. 
The RBR storage period will be in accordance with the IRB/EC‑approved Informed 
Consent Form and applicable laws (e.g., Health Authority requirements). 
The repository specimens will be subject to the confidentiality standards (as described 
under Confidentiality and in Appendix 1). 
 

 
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8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION 
AND HEALTH ECONOMICS 
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study. 
8.9 
TIMING OF STUDY ASSESSMENTS 
8.9.1 
Screening and Pre-treatment Assessments 
Written informed consent for participation in the study must be obtained before 
performing any study‑specific screening tests or evaluations. ICFs for enrolled 
participant and for participants who are not subsequently enrolled will be maintained at 
the study site. 
All screening and all pre-treatment assessments (related to entry criteria) must be 
completed and reviewed to confirm that participants meet all eligibility criteria. The 
Investigator will maintain a screening log to record details of all participants screened 
and to confirm eligibility or record reasons for screening failure. 
An Eligibility Screening Form documenting the Investigator’s assessment of each 
screened participant with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the Investigator and kept at the investigational site. 
On Day 1 prior to enrollment, all participant eligibility requirements are reviewed and 
relevant eligibility criteria (see Section 5) are confirmed, including but not limited to the 
following criteria: 
 
Absence of ocular or periocular infections in the study eye 
 
Absence of active intraocular inflammation in the study eye 
 
Absence of febrile illness within 1 week prior to Day 1 
 
For WOCBP: Absence of pregnancy confirmed by urine pregnancy test 
Screening and pre-treatment assessments will be performed as outlined in the SoA (see 
Section 1.3) unless otherwise specified.  
Ocular images of both eyes performed at the screening visit will be forwarded as soon 
as possible to the CRC for those participants who meet all non-ocular eligibility criteria. 
The CRC will assess the image data submitted and confirm eligibility for study eye 
imaging criteria. Confirmation of eligibility by the CRC for the study eye imaging criteria 
is required before enrollment. 

 
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8.9.2 
Assessments during Treatment 
Under no circumstances will participants who enroll in this study and have completed 
treatment as specified, be permitted to re-enroll in the study. 
On Day 1, baseline assessments will be conducted on the eligible participants prior 
receiving study treatment according to the SoA (see Section 1.3).  
Participants will come to the clinic for each visit and assessments as outlined in the SoA 
(see Section 1.3). Assessments scheduled on the day of study treatment administration 
or prior receiving SoC (as applicable) should be performed prior to administration of 
study treatment, unless otherwise noted in the SoA (see Section 1.3). 
 
 
In the study eye, a post-administration optic nerve head perfusion will be assessed for 
each participant immediately after IVT administration of study treatment or SoC by using 
testing finger count vision, hand motion, or light perception, as appropriate 
(Section 8.2.6.3). 
On the days of IVT administration of the study treatment, IOP must be monitored during 
clinical assessment and before discharge of the participant. Note: The first IOP 
measurement must be taken during clinical assessment before any intervention, i.e. 
before IVT administration of 
 (Section 8.2.6.2 and 
Section 1.3). Note: The 
 (i.e., ranibizumab) can only be given once IOP 
has returned to normal as per discretion of the Investigator. 
Participants will be discharged at the discretion of the Investigator. 
On the days without IVT administration of the study treatment or SoC, but when 
 is 
sampled, IOP must be measured before sampling. IOP measurements will be repeated 
 (see also Section 8.2.6.2 and 
Section 1.3). 
Participants will be instructed to report any signs or symptoms of new or worsened 
intraocular inflammation (uveitis) or endophthalmitis that may be a clinical sign and 
include symptoms such as pain, photophobia, redness, or reduced vision. 
8.9.3 
Assessments at Study Treatment Completion (Week 48)/Early 
Treatment Termination Visit 
Participants who complete the study treatment administration period (up to Week 44) as 
planned will return to the investigational site for the Week 48 visit assessments, as 
outlined in the SoA (see Section 1.3). Participants who are withdrawn from the study 
during the study treatment administration period but have not withdrawn consent should 

 
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return for an ETTV for monitoring of all AEs (serious and non-serious), as well as for 
assessments specified in the ETTV as outlined in the SoA (see Section 1.3). 
8.9.4 
Assessments at Off-Treatment Observation Period Visits 
Participants will return to the investigational site every 4 weeks up to Week 72 during the 
off-treatment observation period after their final dose of study drug at Week 44 for follow-
up visits with assessments as outlined in the SoA (see Section 1.3) and in Section 4.1.1.  
If during any of these visits the participants
 
 for the EOS visit (see SoA in 
Section 1.3). If the participants meet the criteria at Week 72 they would also receive a 
dose of SoC and the visit would become the EOS visit. 
8.9.5 
Assessments at the Occurrence of a Sight-Threatening 
Adverse Event or Events of Intraocular Inflammation 
At the occurrence of sight-threatening AEs potentially linked to IMP (see Section 8.3.7 
and Appendix 8) or events of intraocular inflammation (IOI), additional assessments are 
recommended to be done (if not anyway required at the visit) and will be reported in the 
eCRF: 
 
 
 
Blood sample for laboratory safety analyses 
 
 
 
Ophthalmological assessments including imaging 
 
9. 
STATISTICAL CONSIDERATIONS 
The primary efficacy endpoint is change in BCVA from baseline over the average of 
Weeks 44/48 in treatment naïve population. The estimated changes in the RO7200220 
in combination with ranibizumab arm (Arm A), and the differences to the control arm 

 
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Clinical laboratory tests 
All clinical laboratory data will be stored on the database in the units 
in which they were reported. Laboratory test values will be 
presented in International System of Units (SI units; Système 
International d’Unités) by individual outputs with flagging of 
abnormal results. 
Summary tables of change from baseline over time will be 
displayed. Shifts in NCI CTCAE v5.0 grades (published on 27 
November 2017) from baseline to the worst grade observed during 
treatment will be presented for selected laboratory parameters. 
Vital signs 
Vital signs data will be presented by individual listings with flagging 
of values outside the normal ranges and flagging of abnormalities. 
In addition, tabular summaries will be used, as appropriate. 
ECG data analysis 
ECG data will be presented using appropriate outputs. In addition, 
tabular summaries will be used, as appropriate. 
Concomitant medications 
 
 
 
The original terms recorded on the participants’ eCRF by the 
Investigator for concomitant medications will be standardized by the 
Sponsor by utilizing a mapped term and appropriate drug dictionary 
level. 
Concomitant medications will be presented using appropriate 
outputs. 
BCVA, SD-OCT 
 
Data will be presented as individual listings and descriptive 
summary statistics. 
FFA, FP, IOP, indirect 
ophthalmoscopy, OCT-A, 
slit lamp 
Data will be presented as individual listings and descriptive 
summary statistics where appropriate. 
ADA 
Incidence and titers of ADAs will be presented as individual listings 
and descriptive summary statistics where appropriate 
ADA anti-drug antibody, AE=adverse event, BCVA best corrected visual acuity, ECG 
electrocardiogram, eCRF=electronic case report form, FFA fundus fluorescein angiography, FP fundus 
photography, IOP intraocular pressure, NCI CTCAE=National Cancer Institute Common Terminology 
Criteria for Adverse events, OCT-A=optical coherence tomography angiography, SD-OCT spectral domain 
optical coherence tomography (-angiography).  
 
Safety analyses will be based on the safety-evaluable population. 
 
Verbatim descriptions of treatment-emergent AEs will be mapped to Medical Dictionary 
for Regulatory Activities (MedDRA) thesaurus terms, and their incidence and severity will 
be summarized by treatment arm. A treatment-emergent AE is defined as any new AE 
reported or any worsening of an existing condition on or after the first dose of study drug. 
AEs will be tabulated by System Organ Class and preferred term. In addition, summaries 
will be generated for SAEs, deaths, AEs leading to discontinuation of study drug, AESI, 
and AEs judged to be related to study treatment. Separate summaries will be prepared 
for systemic (non-ocular) and ocular AEs. 
Results of the ocular assessments will be summarized by timepoint and by eye (study 
vs. fellow) using descriptive summaries. In addition, changes from baseline in pre-dose 
IOP measurements and changes between pre-dose and post-dose IOP measurements 
will also be summarized. 

 
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9.3.4 
Immunogenicity Analyses  
The immunogenicity analyses will include all participants with at least one ADA 
assessment, irrespective of whether or not the participant receives any 
treatment (Shankar et al 2014). 
The numbers and proportions of ADA-positive participants and ADA-negative 
participants at baseline (baseline prevalence) and after study drug administration (post-
baseline incidence during both the treatment and follow-up periods) will be summarized.  
 
Participants are considered to be ADA positive if they are ADA negative or have 
missing data at baseline but develop an ADA response following study drug 
administration (treatment-induced ADA response), or if they are ADA positive at 
baseline and the titer of one or more post-baseline samples is at least 4-fold greater 
than the titer of the baseline sample (treatment-enhanced ADA response).  
 
Treatment-induced ADA responses will be further categorized as either: 
o Transient ADA response: defined as a) ADA negative or missing data at 
baseline and b) at least one post-treatment ADA-positive sample and c) only 
one ADA positive sample or the time between the first and last ADA-positive 
sample is less than 16 weeks and d) the last ADA sample is negative 
o Persistent ADA response: defined as a) ADA negative or missing data at 
baseline and b) post-treatment ADA-positive samples over 16 weeks or more or 
the last ADA timepoint is positive (Shankar et al 2014) 
 
Participants are considered to be ADA negative if they are ADA negative or have 
missing data at baseline and all post-baseline samples are negative, or if they are 
ADA positive at baseline but do not have any post-baseline samples with a titer that 
is at least 4-fold greater than the titer of the baseline sample (treatment unaffected). 
 
 and reported descriptively in a separate document from the main CSR. 
9.3.5 
Pharmacokinetic Analyses 
 
 
 
 
 
  
 
 
 
  

 
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9.3.8 
Other Analyses 
Biomarker exploratory analyses, Population PK/PD analyses, may be performed and will 
be presented separately from the main clinical study report.  
 
 

 
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9.4 
INTERIM ANALYSES 
Efficacy analyses to inform possible future development options are foreseen. They will 
not influence the conduct of this study. 
 
 
 
 
 
 
  
A safety analysis will be performed if safety issues have been identified during ongoing 
review of the masked data. 
The interim analyses, should they occur, will be performed and interpreted by members 
of the IMC (see Section 4.1.2) and appropriate project and management personnel, who 
would then be unmasked at the treatment group level. Access to treatment assignment 
information will follow the Sponsor’s standard procedures. 
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct 
 The decision to conduct an 
optional interim analysis and the timing of the analysis will be documented in the 
Sponsor’s trial master file prior to the conduct of the interim analysis. 
 
9.5 
SUMMARIES OF CONDUCT OF STUDY 
The number of patients randomized will be tabulated by country, site, and treatment arm. 
Patient disposition (the number of patients randomized, treated, and completing through 
to the primary endpoint timing, as well as the end of study) will be tabulated by treatment 
arm. Premature study drug discontinuation and study discontinuation, as well as reasons 
for discontinuations, will be summarized. Eligibility criteria exceptions and other major 
protocol deviations will be summarized by treatment arm.  
 

 
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10. 
REFERENCES 
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of California, San Francisco. 1998. 
Chakravarthy U, Bailey C, Brown D, et al. Phase I Trial of Anti–Vascular Endothelial 
Growth Factor/Anti-angiopoietin 2 Bispecific Antibody RG7716 for Neovascular 
Age-Related Macular Degeneration. Ophthalmology Retina;2017;1:474-85 
Cunningham MA, Edelman JL, Kaushal S. Intravitreal steroids for macular edema: the 
past, the present, and the future. Surv Ophthalmol 2008;53:139–149 
Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet 2010;376:124–136 
Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for 
diabetic retinopathy. ETDRS Report Number 9. Ophthalmol 1991;98(5 
Suppl):76685. 
Fauser S, Muether PS. Clinical correlation to differences in ranibizumab and aflibercept 
vascular endothelial growth factor suppression times. Br J Ophthalmol 
2016;100(11):1494–8. 
Funatsu H, Yamshita H, Noma H, et al. Aqueous humor levels of cytokines are related to 
vitreous levels and progression of diabetic retinopathy in diabetic patients. 
Graefe's Archive for Clinical and Experimental Ophthalmology 2005;243:3-8  
Hutton-Smith LA, Gaffney EA, Byrne HM, et al. Ocular pharmacokinetics of therapeutic 
antibodies given by intravitreal injection: estimation of retinal permeabilities using a 
3-compartment semi-mechanistic model. Mol Pharm 2017;14(8):2690–6. 
Investigator’s Brochure for RO7200220. 
Investigator’s Brochure for RO7200220 Version 6 Addendum. 
Karkhur S, Hasanreisoglu M, Vigil E, et al. Interleukin-6 inhibition in the management of 
non-infectious uveitis and beyond. J Ophthalmic Inflamm Infect. 2019;9:17 
Kitazawa K, Sotozono C, Koizumi N, et al. Safety of anterior chamber paracentesis 
using a 30-gauge needle integrated with a specially designed disposable pipette. 
Br J Ophthalmol 2017;101(5):548–50. 
Krohne TU, Liu Z, Holz FG, et al. Intraocular pharmacokinetics of ranibizumab following 
a single intravitreal injection in humans. Am J Ophthalmol 2012;154:6826. 
Lopalco G, Fabiani C, Sota J, et al. IL-6 blockade in the management of non-infectious 
uveitis. Clin Rheumatol 2017;36(7):1459−69. Missel PJ. Simulating intravitreal 
injections in anatomically accurate models for rabbit, monkey, and human eyes. 
Pharm Res 2012;29:3251−72. 
Lucentis EU Summary of Product Characteristics 

 
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Muether PS, Droege KM, Fauser S. Vascular endothelial growth factor suppression 
times in patients with diabetic macular oedema treated with ranibizumab. Br J 
Ophthalmol. 2014;98(2):179–81. 
Nguyen QD, Brown D, Marcus DM, et al. Ranibizumab for diabetic macular edema. 
Ophthalmol 2012;119:789801. 
O’Neill CA, Miller PE, Christian BJ, et al. 26-Week IVT injection toxicity study 
with rhuFab vegf in Cynomolgus monkeys with an 8-weeek recovery. Invest 
Ophthalmol Vis Sci 2003;44: Abstract 3929. 
Ponce R, Abad L, Amaravadi L, et al. Immunogenicity of biologically-derived 
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Ramanan AV, Dick AD, Guly C, et al. Tocilizumab in patients with anti-TNF refractory 
juvenile idiopathic arthritis-associated uveitis (APTITUDE): a multicentre, single-
arm, phase 2 trial. Lancet Rheumatol. 2020;2(3):e135-e141 
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. 
Sahni J, Patel SS, Dugel PU, et al. Simultaneous Inhibition of Angiopoietin-2 and 
Vascular Endothelial Growth Factor-A with Faricimab in Diabetic Macular Edema: 
BOULEVARD Phase 2 Randomized Trial. Ophtalmology 2019;126:1155-70 
Sahni J, Dugel PU, Patel SS, et al. Safety and Efficacy of Different Doses and Regimens 
of Faricimab vs Ranibizumab in Neovascular Age-Related Macular Degeneration 
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2020;138:955-63 
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Study: Evaluating the Safety, Tolerability, and Efficacy of Tocilizumab in Patients 
With Noninfectious Uveitis. Am J Ophthalmol 2017;183:71−80.  
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Shankar G, Arkin S, Cocea L, et al. Assesment and Reporting of the Clinical 
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and Tactical Recommendations. The AAPS Journal. 2014;16(4):658-673 
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Trivedi D, Denniston AK, Murray PI. Safety profile of anterior chamber paracentesis 
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interleukin-6 trans-signaling prevents inflammation and endothelial barrier 
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25 Patients. Am J Ophthalmol. 2019;200:85-94. 
Whitcup SM, Cidlowski JA, Csaky KG, Ambati J. Pharmacology of corticosteroids for 
diabetic macular edema. Invest Ophthalmol Vis Sci 2018;59:1–12 
Wu J, Zhong Y, Yue S, et al. Aqueous Humor Mediator and Cytokine Aberrations in 
Diabetic Retinopathy and Diabetic Macular Edema: A Systematic Review and 
Meta-Analysis. 2019; 2019: 6928524 
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11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
 
The following section includes standard appendices (Nrs. 1-5) and additional appendices 
describing grading scales and sight-threatening AEs (Nrs. 6-8) used in this study: 
 
Appendix 1 (for regulatory, ethical and study oversight considerations),  
 
Appendix 2 (for AE definitions, reporting) and  
 
Appendix 3 (procedures of recording Adverse Events) 
 
Appendix 4 (clinical laboratory tests),  
 
Appendix 5 (contraceptive guidance and collection of pregnancy information).  
 
Appendix 6 (Grading Scale for Assessment of Anterior Chamber Cells or Flare, 
Vitreous Cells, and Vitreous Haze) 
 
Appendix 7 (Grading Scale for Vitreous Hemorrhage) 
 
Appendix 8 (Sight-threatening AEs) 
 

 
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Appendix 1  
Regulatory, Ethical, and Study Oversight Considerations 
1. 
REGULATORY AND ETHICAL CONSIDERATIONS 
1.1. 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the International Conference on 
Harmonisation E6 guideline for Good Clinical Practice (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 (U.S.) 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 EU/EEA will comply with the EU 
Clinical Trial Directive (2001/20/EC). 
1.2. 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms (ICFs), any information to be given to the 
participant (e.g. advertisements, diaries etc), and relevant supporting information must 
be submitted to the Institutional Review Board (IRB)/Ethics Committee (EC) by the 
Principal Investigator and reviewed and approved by the IRB/EC before the study is 
initiated. In addition, any participant recruitment materials must be approved by the 
IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC. Investigators are also 
responsible for promptly informing the IRB/EC of any protocol amendments 
(Section 2.3.1 of this Appendix). 
The Investigator should follow the requirements for reporting all AEs to the Sponsor. 
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. 

 
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1.3. 
INFORMED CONSENT 
The Sponsor’s Master ICF (and ancillary sample ICFs such as a Child’s Assent or 
Caregiver's ICF, if applicable, as well as Pregnant Partner Authorization Form and Infant 
Authorization Form) will be provided to each site. If applicable, it will be provided in a 
certified translation of the local language. Participants must be informed that their 
participation is voluntary. Participants or their legally authorized representative will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/Independent EC (IEC) or study 
center. The Sponsor or its designee must review and approve any proposed deviations 
from the Sponsor's sample ICFs 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. Participants must be re-
consented to the most current version of the ICF(s) during their participation in the study. 
A copy of the ICF(s) signed by all parties must be provided to the participant or the 
participant’s legally authorized representative. 
The ICFs must be signed and dated by the participant or the participant’s legally 
authorized representative before his or her participation in the study. The case history or 
clinical records for each participant shall document the informed consent process and 
that written informed consent was obtained prior to participation in the study. 
The ICFs should be revised whenever there are changes to study procedures or when 
new information becomes available that may affect the willingness of the participant to 
take part. The final revised IRB/EC-approved ICFs must be provided to the Sponsor for 
Health Authority submission purposes if required as per local regulations. 
If the ICFs are revised (through an amendment or an addendum) while a participant is 
participating in the study, the participant or a legally authorized representative may be 
re-consented by signing the most current version of the ICFs or the addendum, in 
accordance with applicable laws and IRB/EC policy. For any updated or revised ICFs, 
the case history or clinical records for each participant shall document the informed 
consent process and that written informed consent was obtained using the 
updated/revised ICFs for continued participation in the study. The study team will 
provide guidance for which participants need to re-consent in the event of an update to 
the ICF. 
A copy of each signed ICF must be provided to the participant or the participant’s legally 
authorized representative. All signed and dated ICFs must remain in each participant’s 

 
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study file or in the site file and must be available for verification by study monitors at any 
time. 
A participant who is re-screened is not required to sign another ICF if the re-screening 
occurs within 60 days from the previous ICF signature date. 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. A separate signature will be required to 
document a participant's agreement to allow any remaining specimens to be used for 
exploratory research. 
Consent to Participate in the Research Biosample Repository 
The ICF will contain a separate section that addresses participation in the Research 
Biosample Repository (RBR). The Investigator or authorized designee will explain to 
each participant the objectives, methods, and potential hazards of participation in the 
RBR. Participants will be told that they are free to refuse to participate and may withdraw 
their samples at any time and for any reason during the storage period. A separate, 
specific signature will be required to document a participant’s agreement to provide 
optional RBR samples. Participants who decline to participate will not provide a separate 
signature. 
The Investigator should document whether or not the participant has given consent to 
participate by completing the RBR Sample Informed Consent electronic case report form 
(eCRF). 
In the event of death or loss of competence of a subject who is participating in the 
Research, the participant's samples and data will continue to be used as part of the 
RBR. 
For sites in the United States, each ICF may also include participant 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 participant 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. 
Approval by the Institutional Review Board or Ethics Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the ICF by each site's 
IRB/EC and, if applicable, an appropriate regulatory body. If a site has not been granted 
approval for RBR sampling, this section of the protocol will not be applicable at that site 

 
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Withdrawal from the Research Biosample Repository 
Participants who give consent to provide samples for the RBR have the right to withdraw 
their samples at any time for any reason. If a participant wishes to withdraw consent to 
the testing of his or her samples, the Investigator must inform the Medical Monitor and 
Site Monitor in writing of the participant’s wishes using the RBR Withdrawal Form and, if 
the study is ongoing, must enter the date of withdrawal on the RBR Withdrawal of 
Informed Consent eCRF. The participant will be provided with instructions on how to 
withdraw consent after the study is closed. A participant's withdrawal from Study 
BP43464 does not, by itself, constitute withdrawal of samples from the RBR. Likewise, a 
participant’s withdrawal from the RBR does not constitute withdrawal from Study 
BP43464. Data already generated before time of withdrawal of consent to RBR will still 
be used. 
1.4. 
CONFIDENTIALITY 
Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.  
The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant.  
Medical information may be given to a participant’s personal physician or other 
appropriate medical personnel responsible for the participant’s welfare, for treatment 
purposes. 
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
Study data, which may include data on germline mutations, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study. These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease. In addition, redacted clinical study reports and 
other summary reports will be provided upon request. 

 
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Confidentiality for Research Biosample Repository 
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local Health Authorities, and Roche monitors, 
representatives, and collaborators, as appropriate. 
Participant medical information associated with RBR samples is confidential and may 
only be disclosed to third parties as permitted by the ICF (or separate authorization for 
use and disclosure of personal health information) signed by the participant, unless 
permitted or required by law. 
Data derived from RBR sample analysis on individual participants will generally not be 
provided to study investigators unless a request for research use is granted. The 
aggregate results of any conducted research will be available in accordance with the 
effective Roche policy on study data publication. 
Genetic research data and associated clinical data may be shared with researchers who 
are not participating in the study or submitted to government or other health research 
databases for broad sharing with other researchers. Participants will not be identified by 
name or any other personally identifying information. Given the complexity and 
exploratory nature of these analyses, genetic data and analyses will not be shared with 
Investigators or participants unless required by law. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR sample data will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
Monitoring and Oversight Research Biosample Repository 
Samples collected for the RBR will be tracked in a manner consistent with Good Clinical 
Practice by a quality-controlled, auditable, and appropriately validated laboratory 
information management system, to ensure compliance with data confidentiality as well 
as adherence to authorized use of samples as specified in this protocol and in the ICF. 
The Sponsor’s monitors and auditors will have direct access to appropriate parts of 
records relating to participant participation in RBR for the purposes of verifying the data 
provided to the Sponsor. The site will permit monitoring, audits, IRB/EC review, and 
Health Authority inspections by providing direct access to source data and documents 
related to the samples. 
1.5. 
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 

 
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course of the study and for one year after completion of the study (i.e., Last Patient Last 
Observation). 
2. 
DATA HANDLING AND RECORD 
2.1. 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
2.1.1. 
Data Quality Assurance 
All participant data relating to the study will be recorded on printed or eCRF unless 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the case report form (CRF). 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
2.1.2. 
Source Data Records 
Source documents (paper or electronic) are those in which participant 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, clinical outcome assessments 
(COAs; paper or electronic COA), 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, participant files, and records kept at pharmacies, 
laboratories, and medico‑technical departments involved in a clinical study. 
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. 

 
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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 below. 
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. 
2.1.3. 
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. 
2.1.4. 
 
Safety Biomarker Data 
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study. In addition, safety biomarker data will not inform decisions on participant 
management. 
2.2. 
RETENTION OF RECORDS 
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the Investigator for at least 15 years after study 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 destroyed during the 
retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor. 
The Sponsor will retain study data for 25 years after the final study results have been 
reported or for the length of time required by relevant national or local health authorities. 

 
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2.3. 
STUDY RECORDS 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully reconstructed, including but not limited to the protocol, protocol 
amendments, ICFs, and documentation of IRB/EC and governmental approval.  
Roche shall also submit an Annual Safety Report once a year to the IEC and Competent 
Authorities according to local regulatory requirements and timelines of each country 
participating in the study. 
2.3.1. 
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 participants or any non-substantial changes, as 
defined by regulatory requirements. 
2.3.2. 
Publication Policy 
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 
for approval 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. 
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. 

 
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2.3.3. 
Dissemination of Clinical Study Data 
Regardless of the outcome of this study, the Sponsor is dedicated to openly provide 
information on the study to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries (e.g. www.ClinTrials.gov), and in peer-reviewed 
journals. The Sponsor will comply with all requirements for publication of study results. 
Study data may be shared with others who are not participating in this study (see 
confidentiality in Section 1.4 of this appendix), and redacted Clinical Study Reports and 
other summary reports will be made available upon request, provided the requirements 
of Roche’s global policy data sharing have been met. For more information, refer to the 
Roche Global Policy on Sharing of Clinical Trial Data at: 
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf 
2.3.4. 
 
Management of Study Quality 
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring participant safety and data 
integrity. Prior to first participant entry into the study, the Sponsor will identify and 
evaluate potential risks associated with critical trial processes and data and will 
implement controls for the communication, review and reporting of these risks. Details 
regarding the applied approach for the study will be provided in the integrated Risk 
Based Quality Management Plan.  
2.3.5. 
Site Inspections 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, participants’ 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. 
3. 
ADMINISTRATIVE STRUCTURE 
See Section 4.1.2. 
4. 
STUDY AND SITE CLOSURE 
The Sponsor (or designee) has the right to close the study site or 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 participants. 
 
Participant enrollment is unsatisfactory. 
 

 
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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. 
Study sites will be closed upon study completion. A study site is considered closed when 
all required documents and study supplies have been collected and a study-site closure 
visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include 
but are not limited to: 
 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local Health Authorities, the Sponsor's procedures, or GCP guidelines. 
 
Inadequate recruitment of participants by the Investigator. 
 
Discontinuation of further study treatment development. 

 
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Appendix 2  
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up and Reporting 
1. 
DEFINITION OF ADVERSE EVENTS 
According to the E2A International Council on Harmonisation guideline for Good Clinical 
Practice, an adverse event (AE) is any untoward medical occurrence in a participant or 
clinical investigation participant administered a pharmaceutical product and which does 
not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be: 
 
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. 
 
Events Meeting the AE Definition: 
 
Deterioration in a laboratory value (hematology, clinical chemistry, or urinalysis) or 
other clinical test (e.g., ECG, angiography) that is associated with symptoms or 
leads to a change in study treatment or concomitant treatment or discontinuation 
from study treatment (see Appendix 3, Section 4). 
 
Exacerbation of a chronic or intermittent preexisting condition, including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as angiographies). 
  
Events NOT Meeting the AE Definition: 
 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the Investigator to be more severe than expected for the participant’s condition. 
 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE. 
 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 

 
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 
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
 
2. 
DEFINITION OF SERIOUS ADVERSE EVENTS 
If an event is not an AE per definition above, then it cannot be a serious adverse event 
(SAE) even if serious conditions are met (e.g., hospitalization for signs/symptoms of the 
disease under study, death due to progression of disease). 
An SAE is defined as any untoward medical occurrence that at any dose: 
 
Results in death. 
 
Is life-threatening. 
The term "life-threatening" in the definition of "serious" refers to an event in which 
the participant was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe. 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
(see Appendix 3). 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE. 
 
Results in persistent or significant disability/incapacity 
Disability means substantial disruption of the participant’s ability to conduct normal 
life functions. 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
 
Is a congenital anomaly/birth defect. 
 
Other significant events: 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 

 
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jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization.  
 
3. 
RECORDING OF ADVERSE EVENT AND/OR SERIOUS 
ADVERSE EVENT 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
The Investigator will then record all relevant AE/SAE information in the electronic case 
report form (eCRF). 
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to Medical Monitor in lieu of completion of the eCRF. 
There may be instances when copies of medical records for certain cases are requested 
by the Medical Monitor. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the Medical Monitor. 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
3.1. 
ASSESSMENT OF SEVERITY 
The Investigator will make an assessment of severity for each AE and SAE reported 
during the study and assign it to one of the categories provided in Table 1 below (as a 
guidance for assessing AE severity).  
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of 
an AE (rated as mild, moderate, or severe, or according to a predefined grading criteria 
[e.g., National Cancer Institute Common Terminology Criteria for AEs criteria); the event 
itself may be of relatively minor medical significance (such as severe headache without 
any further findings). 
Severity and seriousness need to be independently assessed for each AE recorded on 
the eCRF. 

 
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SAEs are required to be reported by the Investigator to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event). 
Table 1 
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 above). 
 
3.2. 
ASSESSMENT OF CAUSALITY 
Investigators should use their knowledge of the participant, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to 
determine whether or not an AE is considered to be related to the study treatment, 
indicating "yes" or "no" accordingly. The following guidance should be taken into 
consideration: 
 
Temporal relationship of event onset to the initiation of study treatment. 
 
Course of the event, considering especially the effects of dose-reduction, 
discontinuation of study treatment, or reintroduction of study treatment. 
 
Known association of the event with the study treatment or with similar treatments. 
 
Known association of the event with the disease under study. 
 
Presence of risk factors in the participant 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. 
 
4. 
FOLLOW-UP OF AES AND SAES 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Medical 
Monitor to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.  
Assessments at the occurrence of a sight-threatening AE or events of Intraocular 
Inflammation are described in Section 8.9.5  
If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any post-mortem findings 

 
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(if available) including histopathology. New or updated information will be recorded in the 
originally completed eCRF. 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
5. 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The Investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the Investigator learns of the event. The following is a list 
of events that the Investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study treatment: 
 
Serious adverse events (see Section 2 in Appendix 2) 
 
Non-serious Adverse events of special interest (AESI)(see Section 8.3.6) 
 
Sight-threatening AEs (see Section 8.3.7  
 
Pregnancies (see Section 8.3.5) 
 
Medical device incidents (see Section 8.3.9 for details on medical device incidents). 
 
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 SAEs to the local 
Health Authority and IRB/EC. 

 
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5.1 
REPORTING REQUIREMENTS OF SERIOUS ADVERSE 
EVENTS AND NON-SERIOUS ADVERSE EVENTS OF SPECIAL 
INTEREST 
Events that Occur prior to Study Treatment Initiation 
After informed consent has been obtained but prior to initiation of study treatment, only 
SAEs caused by a protocol-mandated intervention should be reported. The Clinical Trial 
Adverse Event/Special Situations Form provided to Investigators should be completed 
and submitted to the Serious Adverse Event Responsible immediately (i.e., no more 
than 24 hours after learning of the event). 
Events that Occur after Study Treatment Initiation 
For reports of SAEs, non-serious AESI (Section 8.3.6), and sight-threatening AES 
(Section 8.3.7) that occur after initiation of study treatment (Section 8.3.1), Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the appropriate Adverse Event of Special Interest/ Serious 
Adverse Event eCRF form and submit the report via the EDC system. A report will be 
generated and sent to the Sponsor’s Safety Risk Management department. 
In the event that the EDC system is unavailable, the Clinical Trial Adverse Event/Special 
Situations Form provided to investigators should be completed and submitted to the 
Serious Adverse Event Responsible immediately (i.e., no more than 24 hours after 
learning of the event).  
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system.  
Reporting of Post-Study Adverse Events and Serious Adverse Events 
If the Investigator becomes aware of any other SAE occurring after the end of the AE 
reporting period, and if the event is believed to be related to prior study treatment, the 
event should be reported directly to the Sponsor or its designee, either by faxing or by 
scanning and emailing the SAE Reporting Form using the fax number or email address 
provided to investigators. 

 
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5.2 
REPORTING REQUIREMENTS FOR CASES OF ACCIDENTAL 
OVERDOSE OR MEDICATION ERROR  
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows: 
 
Accidental overdose: accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error: accidental deviation in the administration of a drug  
Note: In some cases, a medication error may be intercepted prior to 
administration of the drug. 
 
Special situations are not in themselves AEs, but may result in AEs. Each AE associated 
with a special situation should be recorded separately on the Adverse Event eCRF. 
Special situations and AEs (non-serious) associated with special situations need to be 
reported to Roche within 30 calendar days. If the associated AE fulfills seriousness 
criteria, the event should be reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event). For RO7200220 and ranibizumab, AEs associated 
with special situations should be recorded as described below for each situation: 
 
Accidental overdose: Enter the AE term. Check the "Accidental overdose" and 
"Medication error" boxes. 
 
Medication error that does not qualify as an overdose: Enter the AE term. Check the 
"Medication error" box. 
 
Medication error that qualifies as an overdose: Enter the AE term. Check the 
"Accidental overdose" and "Medication error" boxes.  
 
In addition, all special situations associated with RO7200220 and ranibizumab, 
regardless of whether they result in an AE, should be recorded on the Adverse Event 
eCRF and should be recorded as described below: 
 
Accidental overdose: Enter the drug name and "accidental overdose" as the event 
term. Check the "Accidental overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose: Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term. Check the "Medication error" box. 
 
Medication error that qualifies as an overdose: Enter the drug name and "accidental 
overdose" as the event term. Check the "Accidental overdose" and "Medication 
error" boxes. Enter a description of the error in the additional case details. 
 
Intercepted medication error: Enter the drug name and "intercepted medication 
error" as the event term. Check the "Medication error" box. Enter a description of the 
error in the additional case details. 

 
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As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache. The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages. 
6. 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all SAEs and non-serious AESI against cumulative 
product experience to identify and expeditiously communicate possible new safety 
findings to investigators, IRBs, ECs, and applicable Health Authorities based on 
applicable legislation. 
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the following reference documents: 
 
RO7200220: 
- use RO7200220 IB 
Ranibizumab:  
- use Lucentis EU SmPC. 
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. 

 
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Appendix 3  
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events (AEs) on the Adverse Event electronic case report from (eCRF). Avoid 
colloquialisms and abbreviations. 
For the purposes of reporting events of infection and inflammation of the eye, the 
following terms and definitions should be used: 
 
Iritis: the presence of inflammatory cells in the anterior chamber 
The presence of aqueous flare alone will not constitute iritis but should be documented 
as an anterior chamber flare for AE reporting purposes. 
 
Iridocyclitis: the presence of inflammatory cells in both the aqueous and vitreous 
 
Vitritis: the presence of active inflammation in the vitreous, demonstrated by the 
presence of inflammatory cells (trace or greater) 
Active inflammation in the vitreous should be clinically differentiated from cellular debris 
from prior episodes of inflammation, hemorrhage, or other causes. 
 
Endophthalmitis: diffuse intraocular inflammation predominantly involving the 
vitreous cavity but also involving the anterior chamber, implying a suspected 
underlying infectious cause 
Note: Trace benign, aqueous pigmented cells visible on slit-lamp examination that are 
caused by dilation and are not red blood cells or white blood cells or the result of any 
ocular disorder should not be recorded as an AE.  
Only one AE term should be recorded in the event field on the Adverse Event eCRF. 
1. 
DIAGNOSIS VERSUS SIGNS AND SYMPTOMS 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases). However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF. If a diagnosis is subsequently established, all previously reported AEs based on 
signs and symptoms should be nullified and replaced by one 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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2. 
ADVERSE EVENTS OCCURRING SECONDARY TO OTHER 
EVENTS 
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events. However, medically significant AEs occurring secondary to an 
initiating event that are separated in time should be recorded as independent events on 
the Adverse Event eCRF. For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
 
If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF. 
 
All AEs should be recorded separately on the Adverse Event eCRF if it is unclear as to 
whether the events are associated. 
3. 
PERSISTENT OR RECURRENT ADVERSE EVENTS 
A persistent AE is one that extends continuously, without resolution, between participant 
evaluation time-points. Such events should only be recorded once on the Adverse Event 
eCRF. The initial severity of the event should be recorded, and the severity should be 
updated to reflect the most extreme severity any time the event worsens. If the event 
becomes serious, the Adverse Event eCRF should be updated to reflect this. 
A recurrent AE is one that resolves between participant evaluation time-points and 
subsequently recurs. Each recurrence of an AE should be recorded separately on the 
Adverse Event eCRF. 
4. 
ABNORMAL LABORATORY VALUES 
Not every laboratory abnormality qualifies as an AE. A laboratory test result should be 
reported as an AE if it meets any of the following criteria: 
 
Accompanied by clinical symptoms. 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation). 

 
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 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy. 
 
Clinically significant in the Investigator’s judgment. 
 
It is the Investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 times the upper limit of normal [ULN] 
associated with cholecystitis), only the diagnosis (i.e., cholecystitis) should be recorded 
on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium", as opposed to "abnormal potassium"). If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the AE For example, an elevated serum potassium level of 7.0 mEq/L 
should be recorded as “hyperkalemia”. 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5. 
ABNORMAL VITAL SIGN VALUES 
Not every vital sign abnormality qualifies as an AE. A vital sign result should be reported 
as an AE if it meets any of the following criteria: 
 
Accompanied by clinical symptoms. 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation). 
 
Results in a medical intervention or a change in concomitant therapy. 
 
Clinically significant in the Investigator’s judgment. 
 
It is the Investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an AE. 

 
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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. 
6. 
ABNORMAL LIVER FUNCTION TESTS 
The finding of an elevated ALT or AST in combination with either an elevated total 
bilirubin or clinical jaundice in the absence of cholestasis or other causes of 
hyperbilirubinemia is considered to be an indicator of potential severe liver injury. 
Therefore, investigators must report as an AE the occurrence of either of the following: 
 
Treatment-emergent ALT or AST  5  ULN value in combination with total 
bilirubin  2  ULN (of which  35% is direct bilirubin). 
 
Treatment-emergent ALT or AST  5  ULN value in combination with clinical 
jaundice. 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Appendix 2) and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event), either as a serious adverse event (SAE) or a non-serious AESI (see 
Section 8.3.6). 
7. 
DEATHS 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5 of Appendix 2), regardless of relationship to study treatment, must be recorded 
on the Adverse Event eCRF and immediately reported to the Sponsor.  
Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF. Generally, only one such event should be 
reported. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the Adverse Event eCRF. If the 
cause of death later becomes available (e.g., after autopsy), “unexplained death” should 
be replaced by the established cause of death. The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 

 
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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 AE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such 
events on the Adverse Event eCRF, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g., “more 
frequent headaches”). 
9. 
WORSENING OF DISEASE (DIABETIC MACULAR EDEMA; 
DIABETIC RETINOPATHY) BEING STUDIED 
Medical occurrences or symptoms of deterioration that are anticipated as part of diabetic 
macular edema (DME) or diabetic retinopathy (DR) should be recorded as an AE if 
judged by the Investigator to have unexpectedly worsened in severity or frequency or 
changed in nature at any time during the study. When recording an unanticipated 
worsening of diabetic macular edema or diabetic retinopathy on the Adverse Event 
eCRF, it is important to convey the concept that the condition has changed by including 
applicable descriptors (e.g., “accelerated Diabetic Macular Edema”). 
10. 
HOSPITALIZATION OR PROLONGED HOSPITALIZATION 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE (per the definition of SAE in Appendix 2), except as outlined 
below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an AE or an SAE: 
 
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 participant has not suffered an AE. 
An event that leads to hospitalization under the following circumstances is not 
considered to be an SAE, but should be reported as an AE instead: 

 
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 
Hospitalization for an AE that would ordinarily have been treated in an outpatient 
setting had an outpatient clinic been available. 
 

 
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Appendix 4  
Clinical Laboratory Tests 
The tests detailed in Table 1 below will be performed by the central laboratory with the 
exception of local dipstick urinalysis. 
The tuberculosis (interferon gamma release assay) and syphilis assessment may be 
done locally after Sponsor’s approval. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2, respectively, of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
Table 1 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Leucocytes, erythrocytes, hemoglobin, hematocrit, platelets, 
differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes). 
Clinical Chemistry 
Sodium, potassium, chloride, bicarbonate, glucose, HbA1C, urea, 
creatinine, protein, albumin, phosphate, calcium, total and direct 
bilirubin, alkaline phosphatase (ALP), alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), urate, LDH, CRP.  
Coagulation 
INR, aPTT, PT. 
Serology/testing 
for infection 
screening 
HIV (specific tests HIV-1/2 antibody), hepatitis B surface antigen 
(HBsAg), total hepatitis B core antibody (HBcAb), hepatitis C virus 
(HCV) antibody. 
Tuberculosis (interferon gamma release assay), syphilis 
Lipids 
Cholesterol, LDL cholesterol, HDL cholesterol, triglycerides. 
Hormone  
For women of unclear menopausal status (at the discretion of the 
Investigator): Estradiol, follicle-stimulating hormone (FSH), in 
females 
Pregnancy Test 
All women of childbearing potential (including those who have had 
a tubal occlusion) will have a blood pregnancy test at screening. 
Urine pregnancy tests will be performed at specified subsequent 
visits. If a urine pregnancy test is positive, it must be confirmed by 
a blood pregnancy test. 

 
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Urinalysis 
Specific gravity 
Dipstick: pH, glucose, protein and blood 
o If there is a clinically significant positive result for blood or 
protein (confirmed by a positive repeated sample), urine will 
be sent to the central laboratory for microscopy and culture. 
If there is an explanation for the positive dipstick results 
(e.g., menses), it should be recorded and there is no need to 
perform microscopy and culture. 
Microscopic examination (sediment, RBCs, WBCs, casts, crystals, 
epithelial cells, bacteria), if blood or protein is abnormal. 
Investigators must document their review of each laboratory safety report. 
Additional Statistical Considerations for Clinical Laboratory Data 
 
Standard Reference Ranges and Transformation of Data 
Potential analysis considerations for analyzing Laboratory data includes the use of 
Standard Reference Ranges and potential transformation of data for specific laboratory 
tests.  
In this scenario, Roche standard reference ranges, rather than the reference ranges of 
the central laboratory, can be used for specific parameters. For these 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. 
 
Definition of Laboratory Abnormalities 
For all laboratory parameters included in this analysis, 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 participant listings of laboratory data. 
In addition to the standard reference range, a marked reference range has been 
predefined by Roche for these laboratory parameters. 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 participant, the midpoint of the standard reference range will be used as 
the participant’s baseline value for the purposes of determining marked laboratory 

 
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abnormalities. Marked laboratory abnormalities will be labeled in the participant listings 
as “HH” for very high or “LL” for very low. 

 
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Appendix 5  
Contraceptive and Barrier Guidance  
1. 
DEFINITIONS 
 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile. The definition of childbearing potential may be adapted for 
alignment with local guidelines or requirements. 
 
Women in the following categories are considered to be Woman of Non-
Childbearing Potential (WONCBP) 
a) Pre-menarchal 
b) Pre-menopausal female with one of the following: 
– 
Documented hysterectomy. 
– 
Documented bilateral salpingectomy. 
– 
Documented bilateral oophorectomy. 
Note: Documentation can come from the site personnel’s: review of 
participant’s medical records, medical examination, or medical history interview. 
c) 
Post-menopausal female 
– 
A post-menopausal state is defined as no menses for  12 months without an 
alternative medical cause other than menopause. A high follicle-stimulating 
hormone (FSH) level in the post-menopausal range may be used to confirm a 
post-menopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
a single FSH measurement is insufficient. 
– 
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of post-menopausal status before study enrollment. 
– 
Only discontinue HRT to allow confirmation of post-menopausal status before study 
enrollment. 

 
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2. 
CONTRACEPTION GUIDANCE 
 
Female Participants 
Female participants of childbearing potential are eligible to participate if they agree to 
use at least one highly effective method of contraception consistently and correctly as 
described in Table 1 below. 
Per International Council on Harmonisation M3(R2), highly effective methods of birth 
control are defined as those, alone or in combination, that result in a low failure rate (i.e. 
less than 1% per year) when used consistently and correctly as described in Table 1 
below. 
Table 1 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User-Dependenta 
(Failure rate of  1% per year when used consistently and correctly) 
 
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
o Oral 
o Intravaginal 
o Transdermal 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o Oral 
o Injectable  
Highly Effective Methods That Are User-Independenta 
(Failure rate of < 1% per year) 
 
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation 
 
Intrauterine device 
 
Intrauterine hormone-releasing system 
 
Bilateral tubal occlusion 
Azoospermic partner (vasectomized or due to medical cause)  
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study 
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant. 

 
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Acceptable Birth Control Methods Which May Not Be Considered As Highly Effective 
(Failure rate of > 1% per year when used consistently and correctly) 
 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action 
 
Male or female condom with or without spermicideb 
 
Cap, diaphragm or sponge with spermicideb 
a) 
Hormonal contraception may be susceptible to interaction with the investigational 
medicinal product (IMP), which may reduce the efficacy of the contraception method. 
 
Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies. 
b) 
A combination of male condom with either cap, diaphragm or sponge with spermicide 
(double barrier methods) are also considered acceptable, but not highly effective, birth 
control methods. i.e., when the risk of teratogenicity and genotoxicity is unlikely. 
 
 
Male Participants 
No requirements 
 
3. 
PREGNANCY TESTING 
For WOCBP enrolled in the study, blood sample and urine pregnancy tests will be 
performed according to Schedule of Activity tables (see Section 1.3). If a urine 
pregnancy test is positive, it must be confirmed by a blood pregnancy test. 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected and according to local practice. 
4. 
COLLECTION OF PREGNANCY INFORMATION 
 
Female participants who become pregnant 
The Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study (see Section 8.3.5 Pregnancy). 
Information will be recorded on the Clinical Trial Pregnancy Reporting Form and 
submitted to the Sponsor within 24 hours of learning of a participant's pregnancy. The 
participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on the participant and the neonate, which will be 
forwarded to the Sponsor. Monitoring of the participant should continue until conclusion 
of the pregnancy. Any termination of pregnancy will be reported, regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 
While pregnancy itself is not considered to be an adverse event (AE) or serious AE 
(SAE), and should not be recorded on the Adverse Event electronic case report form 
(eCRF), any pregnancy complication will be reported as an AE or SAE. A spontaneous 

 
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abortion is always considered to be an SAE and will be reported as such. Any post-study 
pregnancy related SAE considered reasonably related to the study treatment by the 
Investigator, will be reported to the Sponsor as described in Appendix 2. While the 
Investigator is not obligated to actively seek this information in former study participants, 
he/she may learn of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating in the study will 
discontinue study treatment. 
Additionally, attempts should be made to collect and report infant health information. 
When permitted by the site, an Authorization for the Use and Disclosure of Infant Health 
Information would need to be signed by one or both parents (as per local regulations) to 
allow for follow-up on the infant. If the authorization has been signed, the infant's health 
status at birth should be recorded on the Clinical Trial Pregnancy Reporting Form. In 
addition, the Sponsor may collect follow-up information on the infant's health status at 6 
and 12 months after birth. 
5 
ABORTIONS 
Any spontaneous abortion should be classified as an SAE (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 of Appendix 2). 
Any induced abortion due to maternal toxicity and/or embryofetal toxicity should also be 
classified as SAE, 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 of 
Appendix 2). 
Elective or therapeutic abortion not associated with an underlying maternal or 
embryofetal toxicity (e.g., induced abortion for personal reasons) does not require 
expedited reporting but should be reported as outcome of pregnancy on the Clinical Trial 
Pregnancy Reporting Form.  
6 
CONGENITAL ANOMALIES/BIRTH DEFECTS 
Any congenital anomaly/birth defect in a child born to a female participant exposed to 
study treatment should be classified as an SAE, recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event).  

 
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Appendix 6  
Grading Scale for Assessment of Anterior Chamber Cells or 
Flare, and Vitreous Haze 
Grading Scales for Anterior Chamber Cells or Flare 
The SUN Working Group Grading Scale for Anterior Chamber Cells 
Grade 
Cells in Fielda 
0 
< 1 
0.5+ 
1-5 
1+ 
6-15 
2+ 
16-25 
3+ 
26-50 
4+ 
> 50 
The SUN Working Group Grading Scale for Anterior Chamber Flare 
Grade 
Description 
0 
None 
1+ 
Faint 
2+ 
Moderate (iris and lens details clear) 
3+ 
Marked (iris and lens details hazy) 
4+ 
Intense (fibrin or plastic aqueous) 
SUN = Standardization of uveitis nomenclature 
a: Field size is a 1 mm by 1 mm slit beam 
Source: Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature (SUN) Working 
Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International 
Workshop. Am J Ophthalmol. 2005;140(3):509-16. 
 

 
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Grading Scale for Vitreous Haze 
Score 
Description 
0 
No evident vitreous haze 
0.5+ 
Slight blurring of the optic disc margin because of the haze; 
normal striations and reflex of the nerve fiber layer cannot be 
visualized 
1+ 
Permits a better definition of both the optic nerve head and the 
retinal vessels (compared to higher grades) 
2+ 
Permits better visualization of the retinal vessels (compared to 
higher grades) 
3+ 
Permits the observer to see the optic nerve head, but the 
borders are quite blurry 
4+ 
Optic nerve head is obscured 
Source: Nussenblatt RB, Palestine AG, Chan CC, Roberge F. Standardization of vitreal 
inflammatory activity in intermediate and posterior uveitis. Ophthalmology. 1985;92(4):467-71. 
 
 
Grading Scale for Vitreous Cells 
Grade 
Description 
0 
No cells 
0.5+ 
1 - 10 
1+ 
11 - 20 
2+ 
21 - 30 
3+ 
31 - 100 
4+ 
> 100 
Source: Mahendradas P, Khanna A, Kawal A, et al Quantification of inflammation in inflammatory 
eye diseases. IJRCI. 2014;2(S1):SR4 
 
 
 
 

 
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Appendix 7  
Grading Scale for Vitreous Hemorrhage 
 
Grading Scale for Vitreous Hemorrhage 
None (0) 
Retina is visible. 
1   
Retinal details are visible; some hemorrhage/s are visible by ophthalmoscopy. 
2   
Large retinal vessels are visible, but central retinal details are not visible by 
ophthalmoscopy. 
3   
Red reflex is visible, but no central retinal details are seen posterior to the 
equator by ophthalmoscopy. 
4   
No red reflex by ophthalmoscopy. 
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 8  
 Sight-Threatening Adverse Events 
An adverse event is considered to be sight-threatening if it meets one or more of the 
following criteria: 
 
It causes a decrease of  30 letters in best corrected visual acuity (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 intravitreal 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 grading scales for assessment in Appendix 6 
 
In the opinion of the Investigator, it may require medical intervention to prevent 
permanent loss of sight. 
 

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