Clinical trial NCT04265261
Conditions: Diabetic Retinopathy
Sponsor: Hoffmann-La Roche
Start date: 2020-06-05; Completion date: 2023-07-19
Enrollment: 139 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study's main purpose is to asses the safety, tolerability, and effect of oral administration of RG7774 on the severity of diabetic retinopathy (DR) in participants with moderately severe to severe non-proliferative diabetic retinopathy (NPDR) and good vision.

Detailed description:

Arms: arm 1: Participants will receive an oral dose of placebo matched to RG7774 once daily (QD) arm 2: Participants will receive a low oral dose of RG7774 QD arm 3: Participants will receive a high oral dose of RG7774 QD
Interventions: intervention 1: Placebo intervention 2: RG7774
Intervention descriptions: intervention 1: Participants will receive oral placebo matched to RG7774 intervention 2: Participants will receive oral RG7774

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
A Randomized, Double-Masked, 48-Week, Parallel-Group, Placebo-
Controlled, Proof-of-Concept Study to Investigate the Efficacy and 
Safety of RG7774 in Patients With Diabetes Mellitus Type 1 or Type 2 
With Treatment-Naive Diabetic Retinopathy 
NCT Number: 
NCT04265261 
Document Date: 
Protocol Version 5: 4-June-2021 
 
 


FINAL PROTOCOL APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
F. Hoffmann-La Roche Ltd (or under its control) and therefore, is provided to you in confidence as 
an investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Ethics Committee or Institutional Review Board. It is understood that this information 
will not be disclosed to others without written authorization from Roche except to the extent 
necessary to obtain informed consent from persons to whom the drug may be administered.
RG7774—F. Hoffmann-La Roche Ltd
Protocol BP41321, Version 5
PROTOCOL
TITLE:
A RANDOMIZED, DOUBLE-MASKED, 48-WEEK, 
PARALLEL-GROUP, PLACEBO-CONTROLLED, 
PROOF-OF-CONCEPT STUDY TO INVESTIGATE THE 
EFFICACY AND SAFETY OF RG7774 IN PATIENTS 
WITH DIABETES MELLITUS TYPE 1 OR TYPE 2 WITH 
TREATMENT-NAÏVE DIABETIC RETINOPATHY
PROTOCOL NUMBER:
BP41321
VERSION:
5
EUDRACT NUMBER:
2019-002067-10
IND NUMBER:
138,284
TEST PRODUCT:
RG7774
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1: 14 November 2019
DATE AMENDED:
Version 2: 17 December 2019
Version 3: 13 November 2020
Version 4: 03 February 2021
Version 5: See electronic stamp below
 
04-Jun-2021 13:01:12
Title
Approver's Name
Company Signatory
Date and Time (UTC)


RG7774—F. Hoffmann-La Roche Ltd
2/Protocol BP41321, Version 5
PROTOCOL ACCEPTANCE FORM
TITLE:
A RANDOMIZED, DOUBLE-MASKED, 48-WEEK, 
PARALLEL-GROUP, PLACEBO-CONTROLLED, 
PROOF-OF-CONCEPT STUDY TO INVESTIGATE THE 
EFFICACY AND SAFETY OF RG7774 IN PATIENTS 
WITH DIABETES MELLITUS TYPE 1 OR TYPE 2 WITH 
TREATMENT-NAÏVE DIABETIC RETINOPATHY
PROTOCOL NUMBER:
BP41321
VERSION NUMBER:
5
EUDRACT NUMBER:
2019-002067-10
IND NUMBER:
138,284
TEST PRODUCT:
RG7774
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.


RG7774—F. Hoffmann-La Roche Ltd
3/Protocol BP41321, Version 5
PROTOCOL AMENDMENT, VERSION 5
RATIONALE
Protocol BP41321 has been amended to optimize enrolment and execution of the study, 
by modifying some entry criteria and reducing the length of the visits. Changes to the 
protocol, along with a rationale for each change, are summarized below:

Section 1.3 (tables 1 and 2) has been modified to reduce the number of 
assessments and thus the duration of the visits as follows: 
o
Removal of patient-reported outcome questionnaires (i.e., the National 
Eye Institute Visual Functioning Questionnaire-25 [NEI VFQ-25] and the 
Low Luminance Questionnaire [LLQ])
o
Removal of the optional UWF-FP assessments
o
Visual Field assessment made optional
o
The two post-dose pharmacokinetic (PK) samples have been made 
optional
o
Perform Pelli-Robson and low luminance visual acuity (LLVA)
assessments only in the study eye
o
Additional Pelli-Robson assessment at Week-4 visit
o
Perform LLVA assessment only at visits on Day 1, at Week 36, and in 
case of early termination

To reflect the changes in Section 1.3, Table 3 (Section 3 Objectives and Endpoints), 
Sections 8.1.2.3 (Low-Luminance Visual Acuity), 8.1.2.4 (Contrast Sensitivity), 
8.1.2.5 (Visual Fields [Optional]), 8.2.1 (Ocular Examination), and Table 7 
(Section 9.4.2 Efficacy Analyses) have been updated; Section 8.1.2.1 
(Patient-Reported Outcomes), Appendix 8 (National Eye Institute Visual Functioning 
Questionnaire - 25 [NEI VFQ-25]), and Appendix 9 (Low Luminance Questionnaire 
[LLQ]) have been removed.

Entry criteria (Sections 5.1 and 5.2) have been modified to facilitate enrolment in the 
trial by: 
o
Adding an additional rescreening for inclusion criterion 3
o
Increasing the permitted HbA1c level from 10% to 12% (inclusion 
criterion 9)
o
Excluding recruitment of participants who had periocular pharmacological 
intervention (exclusion criterion 1)
o
Allowing recruitment of participants who were enrolled in other previous 
retinal/ ocular clinical trials, in specific circumstances (exclusion criteria 9
and 10)
o
Allowing enrolment of participants with no active HBV, HCV (exclusion 
criterion 22 and Appendix 4 Clinical Laboratory Tests)


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o
Allowing recruitment of participants who had COVID-19 more than 
30 days prior to screening (exclusion criterion 24)
o
Allowing the principal investigator decide on abuse of alcohol/ substances 
considering the results of the test and the medical history of the 
participant (exclusion criterion 26)

In addition, a new screening may be performed for those patients who failed
screening according to outdated inclusion/ exclusion criteria from the previous 
versions of the protocol that have been changed in the current version (Section 5.4).

Section 8.2.4 has been updated to clarify that evaluation for the ECG results as 
normal/ abnormal should be based on the report obtained by the central laboratory
to avoid potential errors in the interpretation of the results.

Section 8.2.6 has been updated with clarification on the rationale and background 
for implementation of the Columbia-Suicide Severity Rating Scale (C-SSRS)
questionnaire.

Section 9.4.2 has been updated to reflect that a careful consideration of missing
data treatment will be discussed in an external technical document. Moreover, the 
exact solution to assess the robustness of efficacy estimates in the presence of 
missing data will be discussed thoroughly in the aforementioned technical 
document.
Additional minor changes have been made to improve clarity and consistency. 
Substantial new information appears in Book Antiqua italics. This amendment represents 
cumulative changes to the original protocol.


RG7774—F. Hoffmann-La Roche Ltd
5/Protocol BP41321, Version 5
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 2
1.
PROTOCOL SUMMARY............................................................................. 14
1.1
Synopsis................................................................................ 14
1.2
Schematic of Study Design.................................................... 23
1.3
Schedule of Activities ............................................................ 23
2.
INTRODUCTION ........................................................................................ 29
2.1
Study Rationale ..................................................................... 29
2.2
Background ........................................................................... 29
2.2.1
Background on Disease......................................................... 29
2.2.2
RG7774 ................................................................................. 30
2.2.2.1
Previous Clinical Studies ....................................................... 31
2.3
Benefit/Risk Assessment....................................................... 32
3.
OBJECTIVES AND ENDPOINTS ............................................................... 33
4.
STUDY DESIGN......................................................................................... 36
4.1
Overall Design ....................................................................... 36
4.1.1
Treatment Groups ................................................................. 37
4.1.2
Length of the Study ............................................................... 37
4.1.3
Administrative Structure......................................................... 38
4.2
Scientific Rationale for Study Design..................................... 38
4.2.1
Rationale for Study Population .............................................. 38
4.2.2
Rationale for Control Group................................................... 39
4.2.3
Rationale for Primary Endpoint Assessment and 
Study Duration....................................................................... 39
4.2.4
Rationale for Response Definition and Study Eye 
Selection................................................................................ 39
4.2.5
Rationale for Exploratory Endpoints ...................................... 40
................................. 40
4.3
Justification for Dose ............................................................. 42
4.4
End of Study Definition .......................................................... 43
5.
STUDY POPULATION................................................................................ 43
5.1
Inclusion Criteria.................................................................... 44




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8.1.2
Ocular Assessments and Imaging......................................... 61
8.1.2.1
IOP Measurement ................................................................. 61
8.1.2.2
Best Corrected Visual Acuity ................................................. 61
8.1.2.3
Low-Luminance Visual Acuity................................................ 61
8.1.2.4
Contrast Sensitivity................................................................ 61
8.1.2.5
Visual Fields (Optional).......................................................... 62
8.1.2.6
Slit Lamp Examination and Dilated Binocular 
Indirect High-Magnification Ophthalmoscopy ........................ 62
8.1.2.7
Fundus Photography ............................................................. 62
8.1.2.8
Fundus Fluorescein Angiography.......................................... 62
8.1.2.9
Spectral Domain Optical Coherence Tomography ................ 63
8.2
Safety Assessments .............................................................. 63
8.2.1
Ocular Examination ............................................................... 63
8.2.2
Physical Examinations........................................................... 63
8.2.3
Vital Signs.............................................................................. 64
8.2.4
Electrocardiograms................................................................ 64
8.2.5
Clinical Safety Laboratory Assessments................................ 65
8.2.6
Suicidal Risk Monitoring ........................................................ 66
8.2.7
Medical History and Demographic Data ................................ 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
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
Adverse Events of Special Interest........................................ 69


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8.3.7
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as AEs or SAEs ............................ 70
8.3.8
Management of Specific Adverse Events .............................. 70
8.4
Treatment of Overdose.......................................................... 70
8.5
Pharmacokinetics .................................................................. 71
8.5.1
Aqueous Humor Samples (Optional) ..................................... 72
............... 72
............... 73
............... 73
............... 73
8.7
Pharmacodynamics and Biomarker Samples........................ 74
................ 75
................ 75
................ 75
................ 75
................ 76
8.9
Medical Resource Utilization and Health 
Economics............................................................................. 77
8.10
Timing of Study Assessments ............................................... 77
8.10.1
Screening and Pre-treatment Assessments .......................... 77
8.10.2
Assessments during Treatment............................................. 77
8.10.3
Assessments at Study Treatment Completion / 
Early Termination Visit........................................................... 78
8.10.4
Follow-Up Assessments ........................................................ 78
8.10.5
Assessments at Unscheduled Visits...................................... 78
9.
STATISTICAL CONSIDERATIONS ............................................................ 79
9.1
Statistical Hypotheses ........................................................... 79
9.2
Sample Size Determination ................................................... 79
9.3
Populations for Analyses ....................................................... 80
9.4
Statistical Analyses................................................................ 80
9.4.1
Demographics and Baseline Characteristics ......................... 80
9.4.2
Efficacy Analyses .................................................................. 80
9.4.3
Safety Analyses..................................................................... 83
9.4.4
Pharmacokinetic Analyses..................................................... 84


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................................................ 85
9.5
Interim Analyses .................................................................... 85
9.6
Summaries of Conduct of Study............................................ 86
10. REFERENCES ........................................................................................... 87
11. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.................................................................................... 90
LIST OF TABLES
Table 1
Schedule of Activities – Main Table ............................................ 24
Table 2
Schedule of Activities – Reduced Assessments as from the 
Time of Rescue Treatment and up to and including Week 36..... 28
Table 3
Objectives and Endpoints ........................................................... 34
Table 4
Estimated Margins of Safety for Phase II Dose........................... 43
Table 5
Summary of Treatments Administered........................................ 51
Table 6
Analysis Populations................................................................... 80
Table 7
Efficacy Statistical Analysis Methods.......................................... 82
Table 8
Safety Statistical Analysis Methods ............................................ 84
LIST OF FIGURES
Figure 1
Overview of Study Design........................................................... 23
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
Appendix 3
Procedures for Recording Adverse Events ............................... 110
Appendix 4
Clinical Laboratory Tests .......................................................... 115
Appendix 5
Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................ 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


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AE
Adverse event
AESI
Adverse event of special interest
AMD
Age-related macular degeneration
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
ASNV
Anterior segment neovascularization
AST
Aspartate aminotransferase
AUC
Area under the curve
BCVA
Best corrected visual acuity
BCRP
Breast cancer resistance protein
BM
Biomarker
BP
Blood pressure
BUN
Blood urea nitrogen
CB2
Cannabinoid 2
CB2R-TE
CB2 receptor Target Engagement
CBD
Cannabinoid
Cmax
Maximum concentration
CNR2
CB2 receptor
CNS
Central nervous system
COA
Clinical outcome assessments
COVID-19
Coronavirus disease 2019
CRP
C-reactive protein
CS
Contrast sensitivity
CSR
Clinical study report
C-SSRS
Columbia-Suicide Severity Rating Scale
CST
Central Subfield Thickness
CYP
Cytochrome P450
DDI
Drug-drug interaction
DM
Diabetes mellitus
DME
Diabetic macular edema
DNA
Deoxyribonucleic acid
DR
Diabetic retinopathy
DRSS
DR severity score
EC
Ethics committee


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Abbreviation
Definition
ECG
Electrocardiogram
eCOA
Electronic clinical outcome assessment
eCRF
Electronic case report form
EDC
Electronic data capture
EEA
European economic area
EFD
Embryofetal development
EIH
Entry-into-human
ETDRS
Early treatment diabetic retinopathy study
EU
European commission
FDA
Food and drug administration
FE
Food effect
FFA
Fundus fluorescein angiography
FSH
Follicle-stimulating hormone
G-CSF
Granulocyte colony stimulating factor
GEE
Generalized estimating equations
GFR
Glomerular filtration rate
HBsAg
Hepatitis B surface antigen
HBcAb
Total hepatitis B core antibody
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDL
High-density lipoproteins
HDPE
High-density polyethylene
HIPAA
Health insurance portability and accountability act
HIV
Human immunodeficiency virus
IB
Investigator’s brochure
ICH
International Council for Harmonisation
IEC
Independent ethics committee
IFNγ
Interferon gamma
IL
Interleukin
IMC
Internal monitoring committee
IMP
Investigational medicinal product
IOP
Intraocular pressure
IND
Investigational new drug (application)
INR
International normalized ratio
IRB
Institutional Review Board
ITT
Intent-to-treat
IUD
Intrauterine device


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12/Protocol BP41321, Version 5
Abbreviation
Definition
IVT
Intravitreal
IxRS
Interactive (voice/web) response system
LC-MS/MS
Liquid chromatography coupled to tandem mass 
spectrometry
LDL
Low-density lipoproteins
LLVA
Low luminance visual acuity
LPLO
Last participant last observation
LPS
Lipopolysaccharide
MD
Mean deviation
MAD
Multiple-ascending doses
NGS
Next-generation sequencing
NIMP
Non-investigational medicinal product
NOAEL
No-observed-adverse-effect level
NPDR
Non-proliferative DR
OTC
Over-the-counter
PD
Pharmacodynamic
PDR
Proliferative DR
PEMA
Patient Engagement Mobile Application
PK
Pharmacokinetic
PRO
Patient-reported outcome (also refers to participants)
PT
Prothrombin time
qCSF
Quantitative contrast sensitivity function
QD
Once daily
QRS
QRS complex
QT
QT interval
QTc
QT corrected for heart rate
QTcF
QT corrected for heart rate using the Fridericia’s 
correction factor
RBR
Research biosample repository
RNA
Ribonucleic acid
RR
RR interval
RVO
Retinal vein occlusion
SAD
Single-ascending dose
SAE
Serious adverse event
SAP
Standard automated perimetry
SD-OCT
Spectral domain optical coherence tomography
sICAM1
Soluble Intercellular Adhesion Molecule 1


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Abbreviation
Definition
SMT
Study Management Team
SNP
Single nucleotide polymorphism
SoA
Schedule of activities
SOC
Scientific oversight committee
SUSAR
Suspected unexpected serious adverse reactions
TNF
Tumor necrosis factor
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
US
United States
USPI
US product information
VEGF
Vascular endothelial growth factor
VA
Visual acuity
VF
Visual fields
WBC
White blood cell
WES
Whole exome sequencing
WGS
Whole genome sequencing
WOCBP
Women of childbearing potential
WONCBP
Women of non-childbearing potential


RG7774—F. Hoffmann-La Roche Ltd
14/Protocol BP41321, Version 5
1.
PROTOCOL SUMMARY
1.1
SYNOPSIS
PROTOCOL TITLE:
A RANDOMIZED, DOUBLE-MASKED, 48-WEEK, 
PARALLEL-GROUP, PLACEBO-CONTROLLED, 
PROOF-OF-CONCEPT STUDY TO INVESTIGATE THE 
EFFICACY AND SAFETY OF RG7774 IN PATIENTS WITH 
DIABETES MELLITUS TYPE 1 OR TYPE 2 WITH 
TREATMENT-NAÏVE DIABETIC RETINOPATHY
SHORT TITLE
Double-masked, Placebo-controlled, Phase II Study to 
investigate Efficacy and Safety of RG7774 in Patients with 
Treatment-Naïve Diabetic Retinopathy
PROTOCOL NUMBER:
BP41321
VERSION:
5
TEST PRODUCT:
RG7774
PHASE:
II
RATIONALE
RG7774 is a synthetic small molecule, highly selective and potent cannabinoid 2 (CB2) receptor 
agonist intended for the oral treatment of diabetic retinopathy (DR). Activation of CB2 receptor 
by RG7774 has shown to produce anti-inflammatory effects in the eye consequently preserving 
endothelial barrier function. The principle aim of study BP41321 is to assess the safety, 
tolerability and the effect of oral administration of RG7774 on the severity of DR in patients with 
moderately severe to severe non-proliferative diabetic retinopathy (NPDR) and good vision. The 
secondary objectives are to further evaluate the potential of RG7774 to prevent progression of 
DR and to assess the effect of RG7774 on best-corrected visual acuity (BCVA).
Study BP41321 builds upon experiences gained in a healthy volunteer entry into human study 
(EIH, BP40387), as well as the itraconazole drug-drug interaction (DDI) study (BP41274). The 
study results from the current study BP41321 will be used to support further clinical 
development of RG7774.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

Assess the effect of RG7774 on the 
severity of DR.

Proportion of participants with 2 step 
improvement in the Early Treatment 
Diabetic Retinopathy Study (ETDRS) 
DR severity score (DRSS) from 
baseline at Week 36 measured in the 
study eye.

Evaluate the safety and tolerability of 
RG7774.

Frequency and severity of adverse 
events.


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15/Protocol BP41321, Version 5
Objectives and Endpoints cont.

Secondary

Assess the effect of RG7774 on 
progression to vision-threatening DR.

Incidence of anterior segment 
neovascularization (ASNV), new 
proliferative diabetic retinopathy (PDR), 
new diabetic macular edema (DME), 
and pre-existing DME requiring 
intervention. 

Assess the effect of RG7774 on visual 
acuity.

Change from baseline in best corrected 
visual acuity (BCVA) at Week 36 in the 
study eye.
Study Design
This is a phase II, multi-center, randomized, three-parallel-group, placebo-controlled, double-
masked, proof-of-concept study. Participants will receive RG7774 or placebo for up to 36 weeks. 
Participants will be randomized in equal proportions to one of the following treatment groups:

Group A: placebo oral once daily (QD) 

Group B: 30 mg RG7774 oral QD

Group C: 200 mg RG7774 oral QD
Randomization will take place at the Day 1 visit prior to study treatment administration and after 
the assessments confirming eligibility of the participant. Randomization to the different treatment 
groups will be stratified on Day 1 using the following imaging features from screening:

DRSS 47 vs. DRSS 53.

Presence vs. absence of diabetic macular edema (DME).

Unilateral vs. bilateral moderately severe to severe NPDR.
The stratification factors will be assessed by a central reading center, based on information 
obtained at the screening visit. Safety assessments will be performed at every site visit. To 
ensure an adequate safety follow-up also between site visits, participants will receive phone 
calls from the site every 4 weeks (when no site visit is scheduled), during which participants will 
be asked for AEs and any changed or new concomitant medication.
Participants should not change their existing stable treatment for diabetes mellitus (DM) and its 
consequences during the study unless it is required for the treatment of an adverse event (AE) 
or as a result of potential DDI. If participants during the course of the study were to develop any 
disease-related events: 
(i)
Worsening of DME (when DME present at baseline) requiring treatment at the discretion of 
the Investigator or if any of the following criteria applies, e.g.:

Loss of 10 letters in BCVA as compared to baseline due to DME, or,

Loss of 5 letters in BCVA as compared to previous visit due to DME, or,

Increase in Central Subfield Thickness (CST) 100 m as compared to previous visit 
due to DME.
(ii)
Incident DME or PDR (not present at baseline) requiring treatment.
(iii)
Anterior Segment Neovascularization (ASNV).
then participants may receive rescue treatment for any eye at the Investigator’s discretion with 
any of the permitted therapies. Treatment with RG7774 or placebo (as applicable) should 
continue. In this situation, a reduced number of assessments will be performed for both eyes if


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16/Protocol BP41321, Version 5
the study eye receives rescue treatment. If the eye that receives rescue treatment is the 
non-study eye, the non-study eye will undergo the reduced schedule of assessments, while the 
study eye will undergo the full schedule of assessments. This schedule will continue for all 
remaining visits up to and including Week 36 visit. All participants will have the safety follow-up 
and Week 48 visit.
Investigational medicinal products (IMPs) for this study are RG7774 and placebo. Film-coated 
tablets will be provided by the Sponsor to achieve the doses of 30mg or 200 mg. Participants 
will have study treatment self-administered orally QD until the visit at Week 36, or earlier if 
discontinued. A 12-week observational, off-treatment period will follow until the last visit of the 
study, at Week 48.
Approved anti-vascular endothelial growth factor (VEGF) and/ or approved steroids (in cases 
where rescue therapy is needed) are considered non-investigational medicinal products 
(NIMPs).
Length of Study
The total duration of the study for each participant will be up to 52 weeks divided as follows:

Screening (from Day 28 to Day 7).

Day 1 (1 day).

Study treatment period with fixed dose (36 weeks).

Safety and efficacy follow-up period / washout period (28 days after last dose: Week 40 visit). 

Long-term follow-up period (8 weeks: from Week 40 visit to Week 48 visit).
End of Study
The end of study is defined as last visit of the last participant. The last participant last 
observation (LPLO) is expected to occur 48 weeks after the last participant is enrolled. 
Participants are considered to have completed the study if they have completed all the 
assessments as required in this protocol.
Data Monitoring Committee: 
The roles, responsibilities, membership, scope of activities, time of meetings and communication 
plan for the Sponsor’s Internal Monitoring Committee (IMC) and Scientific Oversight Committee 
(SOC) will be documented in an appropriate charter.
PARTICIPANT POPULATION
Participants of this study are adult patients with DM type 1 or type 2, with treatment-naïve 
moderately severe to severe NPDR, good vision, with or without DME who are not expected to 
require DME treatment for the duration of the study, fulfill all inclusion criteria and do not meet 
any exclusion criteria.
INCLUSION/ EXCLUSION CRITERIA
Patients who failed screening due to inclusion/exclusion criteria in the previous versions of 
the protocol that have been changed in the current version (e.g., HbA1c, serology) can be 
rescreened.
Only one eye will be selected as the study eye. If both eyes are eligible, the eye with DRSS 53 
will be the study eye. If both eyes are eligible and have equal DRSS, the right eye will be 
defined as the study eye.


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Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Informed Consent
1.
Able and willing to provide written informed consent and to comply with the study protocol 
according to International Council for Harmonisation and local regulations. 
Age / Gender
2.
Male and female patients of at least 18 years of age.
Ocular Criteria for study eye:
3.
Patients with treatment-naïve, moderately severe to severe NPDR defined as ETDRS DRSS 
47 or 53. NPDR will be evaluated at the site based on e.g. the 4:2:1 rule evident on clinical 
examination and on digital imaging. Confirmation of DRSS 47 or 53 by the central reading 
center is required. Note: One rescreening for this criterion is permitted for participants 
who score DRSS 43 at the screening visit. Rescreening should be scheduled at least 
16 weeks (approximately 4 months) after the initial screening visit.
4.
Patients are eligible with and without DME in either eye, defined as the presence of signs in 
the macula such as: swelling, leakage, exudates, cystoid changes and fluid. In addition, 
Central Subfield Thickness (CST) on SD-OCT needs to be 300µm to confirm diagnosis of 
DME. The presence of DME will be confirmed at screening by the central reading center.
5.
If present, DME has to be treatment-naïve and not expected to require treatment during the 
duration of the study in the opinion of the investigator at screening and Day 1.
6.
BCVA score at screening of at least 70 letters in study eyes without DME and at least 75 
letters in case DME is present, using ETDRS visual acuity testing charts at a testing distance 
of 4 meters (approximate Snellen equivalent of 20/40 or better - or 20/32 or better). 
7.
Clear ocular media and adequate pupillary dilation to allow acquisition of good quality retinal 
images.
General Criteria:
8.
Diagnosis of DM type 1 or type 2, as defined by the World Health Organization and/or 
American Diabetes Association, and:
(i) Current regular use of insulin or other injectable drugs for the treatment of DM
and/or
(ii) Current regular use of oral anti-hyperglycemic agents for the treatment of DM
9.
HbA1c 12%.
10. Allowed existing medication regimens for DM and associated conditions should be stable for 
at least 6 weeks before screening, with the intent to remain stable throughout the study. One 
rescreening for this criterion is permitted.
11. Patient is willing to refrain from non-topical cannabinoid (CBD) use (e.g., over-the-counter 
[OTC] CBD oil) for the entire duration of the study.


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Sex and Contraception/Barrier Requirements:
12. Male and/or female participants
Pregnancy of a female participant and fathering of a child by a male participant should be 
avoided during participation in this study. The contraception and abstinence requirements 
are intended to prevent exposure of an embryo to the study treatment. The reliability of 
sexual abstinence for male and/or 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)
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).

Women of childbearing potential (WOCBP), who:
–
Agree to remain abstinent (refrain from heterosexual intercourse) or use of two 
contraceptive methods that result in a failure rate of 1% per year during the treatment 
period and for at least 4 weeks  after the final dose of RG7774 or placebo. 
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal occlusion/ ligation, male sterilization, established proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices and copper 
intrauterine devices. Hormonal contraceptive methods must be supplemented by a 
barrier method.
–
Have a negative pregnancy test (urine) at screening. 
b)
Male Participants
During the treatment period and for at least 90 days after the final dose of study treatment, 
agreement to: 

Remain abstinent (refrain from heterosexual intercourse) or use barrier contraceptive 
measures such as a condom plus an additional contraceptive method that together result in a 
failure rate of 1% per year, with a partner who is a WOCBP.
With pregnant female partner, remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures such as a condom to avoid exposing the embryo.

Refrain from donating sperm.
Other:
13. In the Investigator’s opinion, the subject is deemed appropriate for participation in the study, 
capable of following the study schedule of assessments and complying with the study 
restrictions and participation in the study or discontinuation of prohibited medication will not 
pose undue risks to the participant.
Exclusion Criteria
Participants are not eligible if any of the following criteria apply:


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Ocular criteria for study eye:
1.
Prior treatment for DR or other retinal diseases with any approved therapy, including but not 
limited to intravitreal steroids, intravitreal anti-VEGF, light therapy, periocular 
pharmacological intervention, and laser (e.g., focal, grid, micropulse, or pan-retinal). 
Note: Focal laser in the retinal periphery due to other reasons than DR (e.g., due to retinal 
hole or tear) at least 12 weeks prior to screening is permitted. One rescreening for this 
criterion is permitted.
2.
Intraocular surgery less than 12 weeks prior to screening. One rescreening for this criterion is 
permitted.
3.
Aphakia or implantation of intraocular lens outside of the capsular bag.
4.
History of vitreoretinal surgery.
5.
Uncontrolled glaucoma (e.g., visual field loss or defined as intraocular pressure [IOP] 
25 mmHg despite treatment with anti-glaucoma medication). One rescreening for this 
criterion is permitted.
6.
Amblyopia.
7.
Any history of idiopathic or immune-mediated uveitis in either eye
8.
Any concurrent intraocular condition (e.g., age-related macular degeneration [AMD], retinal 
vein occlusion [RVO], retinal detachment, dense cataract, epiretinal membrane with traction, 
or vitreomacular traction, etc.) that in the opinion of the Investigator could reduce the 
potential for improvement, require medical surgical intervention or may confound the visual 
and functional assessment and interpretation of study results.
9.
Criteria for participation in previous ocular clinical trials for the study eye:

Participation in a clinical trial for an ocular disease involving an investigational 
device (e.g., implant, laser), gene therapy or cell-based therapy.

Participation in a clinical trial for a retinal disease with pharmacological intervention 
receiving active investigational treatment.

Participation in a clinical trial for ocular non-retinal diseases with pharmacological 
intervention receiving active investigational treatment within 12 weeks or 5 half-lives 
(whichever is longer) prior to screening. One rescreening for this criterion is 
permitted.
Ocular criteria for non-study eye:
10.
Criteria for participation in previous ocular clinical trials for the non-study eye:

Participation in a clinical trial for an ocular disease involving an investigational 
device, gene therapy, or cell-based therapy. Note: Laser treatment is permitted.

Participation in a clinical trial for ocular diseases with pharmacological intervention
receiving active investigational treatment within 2 weeks or 5 half-lives (whichever is 
longer) prior to screening. One rescreening for this criterion is permitted.
Concurrent ocular conditions in either eye:
11. Any active ocular infection. One rescreening for this criterion is permitted.
12. Any active intraocular inflammation. One rescreening for this criterion is permitted.


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General Criteria:
13. Previous systemic use of anti-VEGF drugs within 24 weeks prior to screening. One 
rescreening for this criterion is permitted.
14. Complications of DM such as end-stage renal disease or liver disease.
15. Currently untreated DM or previously untreated patients who initiated oral or injectable anti-
diabetic medication within 12 weeks prior to screening. One rescreening for this criterion is 
permitted.
16. Uncontrolled blood pressure ([BP] defined as systolic 180 mmHg and/or 
diastolic >100 mmHg while patient at rest). If a patient’s initial reading exceeds these values, 
a second reading may be taken either 30 or more minutes later on the same day, or on 
another day during the screening period. If the BP is controlled by antihypertensive 
medication, the patient should be taking the same medication continuously for at least 
6 weeks prior to screening. One rescreening for this criterion is permitted.
17. Confirmed (e.g., 2 consecutive measurements) clinically significant abnormality on ECG at 
screening. That includes but is not limited to a QTcF 450 ms for male participants and 
QTcF 470 ms for female participants, absence of dominating sinus rhythm, AV-block II or 
III. Additional examples of clinically significant abnormalities detected by ECG or otherwise 
related to abnormal cardiac function are cardiac insufficiency, coronary artery disease, 
cardiomyopathy, congestive heart failure, family history of congenital long QT syndrome, 
family history of sudden death, and atrial fibrillation.
18. History of coagulopathies, bleeding disorders or blood dyscrasias.
19. History of concurrent cardio-vascular disease not considered well controlled by the 
Investigator.
20. Risk of suicidal behavior in the opinion of the Investigator or as evidenced by a “yes” to 
questions 4 and/or 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) taken at 
screening, or any suicide attempt in the last 5 years.
21. Positive serology results for HIV-1 and HIV-2. Positive results for hepatitis B virus (HBV) 
and hepatitis C virus (HCV) are exclusionary only if the disease is confirmed to be active 
and/ or the patient is receiving treatment.
22. Any major illness or major surgical procedure within 4 weeks before screening. One 
rescreening for this criterion is permitted.
23. History of or currently active other diseases, viral and/or bacterial infections, metabolic 
dysfunction, physical examination finding, malignancies not considered cured, or clinical 
laboratory findings giving reasonable suspicion of a condition that contraindicated the use of 
the investigational medicinal drug or that might affect interpretation of the results of the study 
or renders the patient at high risk for treatment complications in the opinion of the 
investigator.
Note: Participants with symptoms or signs of acute or long SARS-CoV-2 infection or 
asymptomatic disease (positive test without symptoms) within 30 days of screening will be 
excluded from the study. One rescreening for this criterion is permitted.
24. Known hypersensitivity to any of the excipients of the drug used, fluorescein dye or dilating 
eye drops.
25. Alcohol and/or substance abuse/dependence during the last 12 months, assessed by the 
investigator considering the results of the tests and the medical history, in consultation 
with the Sponsor, if required. One rescreening for this criterion is permitted.


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26. Use of non-topical CBD (including OTC CBD oil) within 12 weeks prior to screening. One 
rescreening for this criterion is permitted.
27. Use of prohibited medications within 2 weeks prior to screening, or 5 half-lives (whichever is 
longer). One rescreening for this criterion is permitted.
28. Use of systemic medications known to be toxic to the lens, retina or optic nerve (e.g.,
deferoxamine, chloroquine/hydroxychloroquine, tamoxifen, phenothiazines and ethambutol) 
used during the 24-week period prior to screening or likely need to be used. One rescreening 
for this criterion is permitted. 
29. Participation in a clinical study involving an investigational medicinal product or device with 
exit from that study 

within 60 days prior to screening, or 

within less than 5 half-lives between last exposure to study treatment in the previous 
study and screening for the present study 
(whichever is longer). One rescreening for this criterion is permitted.
30. Blood donation or loss of blood 500 mL within 12 weeks prior to screening. One 
rescreening for this criterion is permitted.
NUMBER OF PARTICIPANTS
A total of 135 participants are expected to be enrolled in this study and will be randomized 1:1:1 
to the three groups (45 participants per group). Based on Fisher’s exact test, assuming the 
proportion of participants with 2 step improvement in the ETDRS DRSS to be 15% for placebo 
and 40% to 45% under active treatment, 40 participants completing the study per group provide 
between 74% and 88% power based on a 2-sided significance level of 0.1. Allowing for about 
10% of the participants randomized to not complete the study and hence not have an 
assessment of the primary endpoint at week 36, a total of 135 participants (45 participants per 
group) was selected to obtain 120 completers. If the rate of participants not completing the 
study is larger than 10%, the sample size may be increased beyond 135 participants with the 
aim of achieving approximately 45 completers per group.
CONCOMITANT MEDICATIONS
Permitted Therapy
Participants should not change their existing stable treatment for DM and its consequences 
during the study, unless it is required for the treatment of an AE or as a result of potential DDI. 
Potential DDI arising from co-administration of other drugs have been investigated in healthy 
volunteers only. Therefore, changed or new concomitant medication in general should be 
limited to the medical need of the participant and the medical judgement of the investigator, in 
consultation with the Sponsor. 
The Investigator should be aware of the potential for DDI when prescribing concomitant 
medications which are inhibitors or inducers of CYP3A and/or CYP2C19, or are substrates of 
CYP3A, OCT2, MATE1, MATE2-K, P-gp, and/or BCRP and should carefully monitor the 
tolerability and safety of RG7774. The Sponsor has included two visits to monitor if there is a 
need to adjust the dose of warfarin, if applicable. 
Therapies permitted for either eye in case of incidence or progression of DME/DR are:

Laser (grid or focal) and/or approved anti-VEGF (except brolucizumab, if applicable), and/ 
or approved steroids in case of worsening DME which requires treatment for participants 
presenting with DME at baseline.


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
Laser (grid or focal) and/or approved anti-VEGF (except brolucizumab, if applicable), and/ 
or approved steroids in case of incident DME requiring treatment

Laser (pan-retinal), vitrectomy and/or approved anti-VEGF (except brolucizumab, if 
applicable) in case of incident PDR. 
The administration of these permitted therapies will not automatically result in treatment 
discontinuation and participants should continue in the study as described.
Prohibited Therapy
Systemic medications known to be toxic to the lens, retina or optic nerve (e.g., deferoxamine, 
chloroquine/hydroxychloroquine, tamoxifen, phenothiazines and ethambutol) are prohibited 
within 24 weeks prior to baseline and during the study.
Systemic Medications Prohibited due to Effects Related to Cytochrome P450 Enzymes

Strong inhibitors of CYP3A including, but not limited to, grapefruit and the following drugs: 
e.g., ketoconazole, itraconazole, ritonavir, voriconazole, clarithromycin.

Moderate inhibitors of CYP3A including but not limited to the following drugs: e.g., 
erythromycin, ciprofloxacin, cimetidine. 

Strong and moderate inducers of CYP3A including but not limited to the following drugs: 
e.g. rifampicin, carbamazepine, phenytoin, St. John`s wort, bosentan and modafinil.

Strong inhibitors of CYP2C19 including but not limited to the following drugs: e.g., 
fluconazole, fluoxetine, fluvoxamine, and ticlopidine.

Strong and moderate inducers of CYP2C19 including but not limited to the following drugs: 
e.g., rifampicin, ritonavir, efavirenz, phenytoin, and enzalutamide.
The above list of medications is not comprehensive. The Investigator should consult the 
prescribing information when determining whether a concomitant medication can be safely 
administered with the study treatment. In addition, the Investigator should contact the study team 
if questions arise regarding medications not listed above.


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1.2
SCHEMATIC OF STUDY DESIGN
An overview of the study design is provided in Figure 1.
Figure 1
Overview of Study Design
The primary endpoint will be assessed at Week 36. An additional observational, off-treatment
period of 12 weeks will follow the last treatment administration at Week 36, until the final visit at 
Week 48.
1.3
SCHEDULE OF ACTIVITIES
The schedule of the activities is provided in Table 1 (Main Table) and Table 2 (Reduced 
Assessments).


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Table 1
Schedule of Activities – Main Table
Week
Screening
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 28
Week 32
Week 36
 Warfarin 
follow-up
 Week 40 
Safety 
follow-up1,2
Week 48 
Early 
Termination1 
(<14d after last 
site visit)
Early 
Termination2 
(>=14d after 
last site visit)
Day
D-28 to D-7
Day 13 
Day 74
Day 7
Day 28
Day 56
Day 84
Day 112
Day 140
Day 168
Day 196
Day 224
Day 252
Day 259 or 
earlier 4
Day 280
Day 336
Visit Window
none
-1/+ 3 days
+/- 3 days
+/- 7 days
+/- 7 days
+/- 7 days
+/- 7 days
+/- 7 days
+/- 7 days
+/- 7 days
+/- 7 days
+/- 7 days
-1/+ 3 days
+/- 7 days
+/- 7 days
Category
Assessments
Site Visit
Site Visit
Site Visit
Phone Call 5
Site Visit
Phone Call 5
Site Visit
Phone Call 5
Phone Call 5
Site Visit
Phone Call 5
Phone Call 5
Site Visit
Site Visit
Site Visit
Site Visit
Site Visit
Site Visit
Informed Consent
x
Inclusion/Exclusion criteria
x
x
Pregnancy Test6 
x
Demography
x
Medical History
x
Previous and Concomitant Treatments  / 
Medications
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Physical Examination 
x
7
x
x
x
x
7
x
7
x
7
x
7
Anthropometric Measurements7a
x
x
x
x
x
Vital Signs
x
x
x
x
x
x
x
x
x
Triplicate ECG-12 lead9
x
x
x
x
x
x
x
x
x
Hematology
x
x
x
x
x
x
x
x
Blood Chemistry
x
x
12
x
x
x
x
x
x
x
Coagulation
x
x
x
x
x
x
x
x
x
x
x
Viral Serology
x
Lipids
x
x
x
x
x
x
x
x
Thyroid Hormones
x
x
x
x
x
x
x
x
FSH10
x
HbA1c11
x
x
x
x
x
x
x
x
x
Urinalysis
x
x
x
x
x
x
x
x
Drug of abuse/Alcohol urine test
x
x
x
x
x
x
x
C-SSRS (Form "At Baseline")
x
C-SSRS (Form "Since Last Visit")8
x
x
x
x
x
x
x
x
Randomization
x
Laboratory 
analylsis
Week 1
Medical and 
clinical history




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Table 1
Schedule of Activities – Main Table (cont.)
1.
If participants discontinue or withdraw from the study treatment prematurely, the participants should complete the Early Termination visit 
and attend the Follow-up visit normally done at the end of the study, 4 weeks after the last dose of study medication. If the discontinuation 
or withdrawal happens less than 14 days after a site visit, participants will have a reduced number of assessments.
2.
If participants discontinue or withdraw from the study treatment prematurely, the participants should complete the Early Termination visit 
and attend the Follow-up visit normally done at the end of the study, 4 weeks after the last dose of study medication. If the discontinuation 
or withdrawal happens 14 days or more after a site visit, participants will have a full assessment. 
3.
The details of the specific order of assessments can be found in the Study Procedures Manual, which must be adhered to.
4.
Visits exclusively for participants on warfarin to monitor potential need for dose adjustment of warfarin. The visits will happen 7 days after 
the first dose of RG7774/ placebo (at Day 7) and 7 days after the last dose of RG7774/ placebo (typically on Week 37, or earlier in case of 
discontinuing the study prematurely).
5.
Telephone interview to assess for any clinically significant symptoms and/or new/ changed medication.
6.
Screening urine pregnancy test for women of child-bearing potential (WOCBP) prior to first dose of RG7774 or placebo. Additional 
pregnancy tests can be performed anytime during the study at the discretion of the Investigator.
7.
Full physical examination as per protocol.
7a.  Height and weight will be recorded at the Day 1 visit only. Only weight will be measured at the Week 36 or Early Termination visits.
8.
To be administered by masked site staff prior to any other visit assessments being performed on that day. If required, the questionnaires 
can be administered via telephone one business day prior to the visit. Confirmation that there are no changes should be obtained on the 
day of the site visit. 
9.
ECG (12-lead) will be obtained pre-dose on Day 1. All ECGs (12-lead) will be performed in triplicate, 1-2 minutes apart within 5 minutes.
10. Hormonal panel for postmenopausal women only.
11. HbA1c measurement is obtained from the same sample as hematology, except for Week 48.
12. Blood chemistry at Day 1 will only be analyzed for C-reactive protein (CRP).


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Table 1
Schedule of Activities – Main Table (cont.)
13. One PK sample to be collected at all visits prior to study treatment administration. At visits Day 1, Day 28, and Day 252 two additional
post-dose samples may be collected optionally. The two samples should be obtained, at 1-3 hours, and 3-5 hours post-dose, respectively. 
Timing between the two post-dose samples should be approximately 2 hours.
14.
 
15. Study eye only.
16. qCSF to be performed only if the site has the capabilities to perform this assessment. 
17. Optional Visual Field assessments should be performed in study eye only when the site has the capabilities to perform this assessment.
18a. Only one FFA modality will be performed in each patient: ultra-widefield-FFA will be performed preferentially, if the site has the 
capabilities to perform this assessment. If not available, 7F-FFA will be performed. 
18b. Fluorescein Angiography assessments not to be done more often than every 12 weeks.
19. Study medication will be administered to participants directly in the study clinic on the day of site visit. The participant has to avoid taking 
medication before going to the site on the day of site visit.
20. Adverse event collection will be done throughout the full length of the study.
21. Patient Engagement App (PEMA) will be used at discretion of the participant, if applicable, throughout the full length of the study (no time 
restriction on Day 1).




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2.
INTRODUCTION
2.1
STUDY RATIONALE
The endocannabinoid system has been involved in the pathology of diabetes mellitus 
(DM) and its complications, including diabetic retinopathy (DR) (Behl et al. 2016, Gruden 
et al. 2016). RG7774 (also referred to as RO6868847) is a synthetic small molecule that 
is a potent cannabinoid 2 (CB2) receptor agonist, with high selectivity for CB2 versus 
CB1 receptors, as shown by pharmacological data and by the lack of psychotropic 
effects of central CB1 receptor activation at the doses tested to date in humans. RG7774 
is being developed for patients suffering from DR.
The primary objective of the current study BP41321 is to assess the safety, tolerability 
and the effect of oral administration of RG7774 on the severity of DR in patients with 
moderately severe to severe non-proliferative diabetic retinopathy (NPDR) and good 
vision.
The secondary objectives are to further evaluate the potential of RG7774 to prevent 
progression of DR, as determined by the incidence of sight-threatening events (e.g., 
diabetic macular edema [DME] or proliferative diabetic retinopathy [PDR]), and to assess 
the effect of RG7774 on best-corrected visual acuity (BCVA).
Results from nonclinical pharmacology, pharmacokinetic (PK), and toxicology studies 
and the outcomes of the healthy volunteer entry-in-human single-ascending dose (SAD), 
multiple-ascending-dose (MAD), food-effect (FE) study (EIH, BP40387), as well as the 
itraconazole drug-drug interaction (DDI) study (BP41274) have been considered in the 
development of protocol BP41321. 
The study results from the current study BP41321 will be used to support further clinical 
development of RG7774.
2.2
BACKGROUND
2.2.1
Background on Disease
DR is a consequence of DM, and affects approximately one third of type 1 and type 2 
diabetic patients. The pathological mechanisms induced by sustained, increased levels 
of blood glucose include oxidative stress, inflammation, vascular dysfunction and 
neurodegeneration (Fong et al. 2004). In the retina, Müller cells, microglia, and 
endothelial cells produce chemokines that induce leukostasis, diapedesis, influx of 
monocytes into the retina, and increased production of cytokines including VEGF, tumor 
necrosis factor-(TNF-α, interleukin (IL)-1b, IL-6, metalloproteinase, and angiopoietin-
2. These inflammatory mediators are involved in the breakdown of endothelial cell-cell 
junctions forming the blood-retinal barrier seen in DR.
Increasing evidence points to a role of inflammation in DR, contributing to retinal 
vascular permeability and neovascularization (reviewed in Mesquida et al. 2019). 


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Beyond the vascular pathology, inflammation may also contribute to retinal 
neurodegeneration (Semeraro et al. 2019). 
DR is a serious condition that, if left untreated, can progress to vision-threatening stages 
and ultimately blindness. The severe sequelae of DR, proliferative DR (PDR) and DME, 
are treated with laser photocoagulation, intravitreal (IVT) injections of anti-vascular 
endothelial growth factor (VEGF), steroids and/or vitrectomy (Lee et al. 2015; Schmidt-
Erfurth et al. 2017; Wong et al. 2018). Moderately severe to severe NPDR that has not 
yet led to these sequelae is rarely treated with laser, as photocoagulation is destructive 
and associated with peripheral visual field defects and possible vision loss. Anti-VEGF 
injections have shown benefits in slowing down and improving DR with or without DME 
and in the absence of PDR (Ip et al. 2012; Boyer 2019), however they are rarely used. 
Reasons may include concerns about the potential risks of injecting eyes of patients with 
no visual acuity decline and the significant treatment burden of anti-VEGF therapy, 
aggravated when bilateral treatment is required. 
RG7774, by its proposed anti-inflammatory mode of action and convenient oral 
administration, can be an option to treat patients with unilateral or bilateral moderately 
severe to severe NPDR with good vision for whom anti-VEGF IVT is usually deferred in 
clinical practice.
2.2.2
RG7774
Many studies have shown that cannabinoids can suppress the production of cytokines in 
innate and adaptive immune responses, both in animal models and in human cell 
cultures (Klein 2005). Their suppression of pro-inflammatory cytokines and chemokines 
production indicates that these cannabinoidsspecifically CB2 receptor agonistsmay 
have anti-inflammatory effects and could therefore be used for the treatment of chronic 
inflammatory diseases such as DR. In fact, activation of CB2 receptors by reducing 
inflammatory, oxidative and fibrotic processes has shown beneficial effects in a wide 
range of inflammatory diseases including Crohn’s Disease, arthritis, myocardial 
infarction and others (Maurya and Velmurugan 2018).
RG7774 is a highly selective CB2 receptor agonist intended for the oral treatment of DR. 
CB2 receptor is mainly expressed in immune cells, including microglia in the retina.  
Activation of CB2 by RG7774 has been shown to produce anti-inflammatory effects in 
the eye, by inhibiting leukocyte adhesion and microglia activation, decreasing vascular 
permeability, and consequently preserving endothelial barrier function. 
The high selectivity of RG7774 for the CB2 receptor (greater than 10,000-fold) makes 
psychotropic effects by central CB1 receptor activation or the risk of an increased 
suicide rate via central CB1 receptor inhibition (Topol et al. 2010) highly unlikely.  
Current data suggest that RG7774 displays the highest selectivity compared with 
publicly known CB2 receptor agonists (Soethoudt et al. 2017).


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A detailed description of the chemistry, pharmacology, efficacy and safety of RG7774 is 
provided in the Investigator’s Brochure.
2.2.2.1
Previous Clinical Studies
RG7774 has been studied in a Phase I entry- into-human (EIH) study in healthy 
participants (Study BP40387; 129 participants). This was a single-center study 
consisting of a SAD part, a FE part, a multiple-ascending-dose (MAD) part, a fourth part 
to investigate the effects of RG7774 on CYP2B6 and CYP2C8 activity and a fifth part to 
investigate the inhibitory effects of RG7774 on multiple drug transporters using 
metformin and atorvastatin as probe substrates in healthy participants.
In Part 1 (SAD), single oral doses of 0.75 mg, 3 mg, 10 mg, 30 mg, 100 mg, and 300 mg 
RG7774 or placebo were administered under fasting conditions, with 4 participants per 
dose group for the 3 mg group (3 active and 1 placebo) and with 12 participants (9 active 
and 3 placebo) for the highest dose. The dose groups in between had 8 participants (6 
active and 2 placebo) per group. The starting dose of 0.75 mg was administered to 
5 participants (3 active and 2 placebo) due to the sentinel dosing.
In Part 2 (FE), 8 participants received a single oral dose of 100 mg RG7774 once after 
an overnight fast of at least 10 hours and once within 30 minutes after starting a high-
calorie, high-fat breakfast.
In Part 3 (MAD), multiple oral doses of 6 mg, 20 mg, 60 mg, 200 mg, and 300 mg 
RG7774 or placebo were administered in the fasted state for 14 days, with 8 participants 
per cohort (6 on active and 2 placebo).
In Part 4 (DDI), the effect of multiple oral doses of 300 mg RG7774 given once daily for 
14 consecutive days, on the pharmacokinetics of three different drug-metabolizing
Cytochrome P450 (CYP) enzymes, namely midazolam (CYP3A), bupropion (CYP2B6) 
and repaglinide (CYP2C8) was explored in 17 healthy participants. 
In Part 5 (transporter DDI), the effect of a single oral dose of 300 mg RG7774, on the 
pharmacokinetics of metformin (OCT2, MATE1, MATE2-K) and atorvastatin (OATP1B1, 
P-gp, BCRP) was studied in 18 healthy participants.
Study BP41274 investigated the effect of multiple oral doses of itraconazole, a strong 
CYP3A inhibitor, on the plasma pharmacokinetics of RG7774 in 16 healthy participants. 
Overall, 122 healthy participants have received RG7774. Detailed information on the 
effects of RG7774 in humans is described in the Investigator’s Brochure.
No clinical data are yet available for RG7774 in patients with NPDR.


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2.3
BENEFIT/RISK ASSESSMENT
The development program of RG7774 is designed to offer a treatment option for patients 
with NPDR, for whom both photocoagulation and IVT anti-VEGF therapy are commonly 
deferred in current practice.
Oral dosing is the preferred route of administration for patients with NPDR in order to 
achieve systemic and bilateral retinal exposure. Systemic exposure will target leukocytes 
to prevent attachment to vascular endothelial cells in the retina and other tissues, while 
retinal exposure will activate CB2 receptors in the microglia target cells. Furthermore, 
systemic exposure may influence additional complications of DM, such as diabetic 
nephropathy, which was shown to be ameliorated in the same nonclinical models as 
those used for the retinal microglia analysis (Zoja et al. 2016).
The non-clinical safety package completed to date in rats and cynomolgus monkeys 
showed an overall benign safety profile of RG7774, without any adverse findings up to 
the highest tested doses. 
 
 
 
No cardiovascular effects were detected in monkeys after single and repeated dosing up 
to the highest tested dose. At the same time, embryofetal development (EFD) dose-
range findings studies in rat and rabbit did not show any indication of teratogenicity up to 
the highest tested dose. 
The high selectivity of RG7774 towards CB2 vs. the CB1 receptor translated into no
adverse findings consistent with cannabinoid-related side effects (i.e., hypolocomotion, 
catalepsy and hypothermia) up to the highest achieved exposures. This confirmed the 
results obtained in vitro when assessing the selectivity of RG7774 in 78 receptors and 
ion channels in which RG7774 demonstrated excellent selectivity for CB2 receptor. In 
functional cellular assays, no activity of RG7774 was detected at 15-lipoxygenase, 
MAGL, diacylglycerol lipase, or FAAH enzymes of the endocannabinoid pathway. 
Clinical experience is currently limited to Study BP40387 (EIH study) and Study 
BP41274 (Itraconazole DDI study) in healthy participants. Across clinical trials, the 
administration of RG7774 has been found to be safe and very well tolerated for doses of 
RG7774 up to (and including) 300 mg once daily for 2 weeks and no pattern of adverse 
events (AEs) possibly characteristic for the use of RG7774 in humans has emerged to 
date. There was one serious adverse event (SAE) 
 


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To ensure the safety of all participants during the conduct of the current study BP41321, 
several safety assessments have been included: e.g., regular ophthalmological 
monitoring and imaging assessments, AE monitoring (systemic and ophthalmologic), 
vital signs (systolic BP, diastolic BP, ECG and pulse rate), warfarin (INR) monitoring for 
dose adjustments and other laboratory safety tests. In months for which no site visit is 
scheduled, participants will be interviewed via telephone call to assess for any clinically 
significant symptoms and/ or new medication.
To ensure the safety of study participants and staff and minimize their risk of COVID-19, 
appropriate trial- and site-specific COVID-19 risk mitigation measures will be 
implemented as required per local and site regulations.
Based on current evidence, a favorable benefit-risk balance is envisaged for RG7774 
and - given its systemic activity and non-invasive route of administration - RG7774 could 
encourage initiation of treatment of patients with NPDR who, in current practice, are not 
receiving immediate ophthalmologic treatment. Additionally, the expected benefits of 
improving the severity of DR and/or halting progression to PDR or DME would reduce 
the need for future intravitreal administration.
More detailed information about the known and expected benefits in the context of 
potential risks and reasonably expected AEs of RG7774 is provided in the Investigator’s 
Brochure.
3.
OBJECTIVES AND ENDPOINTS
The objectives and corresponding endpoints are provided in Table 3.


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Table 3
Objectives and Endpoints
Objectives
Endpoints
Primary

Assess the effect of RG7774 on the 
severity of DR.

Proportion of participants with ≥2 step 
improvement in the Early Treatment 
Diabetic Retinopathy Study (ETDRS) 
DR severity score (DRSS) from 
baseline at Week 36 measured in the 
study eye.

Evaluate the safety and tolerability of 
RG7774.

Frequency and severity of adverse 
events.
Secondary

Assess the effect of RG7774 on 
progression to vision-threatening DR.

Incidence of anterior segment 
neovascularization (ASNV), new PDR, 
new DME, and pre-existing DME 
requiring intervention. 

Assess the effect of RG7774 on visual 
acuity.

Change from baseline in BCVA at 
Week 36 in the study eye.
Exploratory

Assess the effect of RG7774 on DR 
worsening.

Proportion of participants with 2 step 
worsening in ETDRS DRSS from 
baseline at Week 36 measured in the 
study eye

Assess the effect of RG7774 on DR 
severity at a participant level.

Proportion of participants with 3 step 
improvement in ETDRS DRSS from 
baseline at post-baseline visits 
measured in both eyes 

Proportion of participants with 3 step 
worsening from baseline at post-
baseline visits measured in both eyes.


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Table 3
Objectives and Endpoints (cont.)
Objectives
Endpoints
Exploratory

Assess the durability of the effect of 
RG7774 on DR. 

Proportion of participants with either a 
stable (± 1 step change), worsened 
(>1 step increase) or improved 
(>1 step decrease) DRSS between 
Week 36 and Week 48.

Assess the efficacy of RG7774 on 
visual acuity and anatomical outcome 
measures using spectral 
domain optical coherence tomography 
(SD-OCT) among eyes with DME at 
baseline.

Change from baseline in participants 
with DME at baseline in:
–
BCVA (as measured on the 
ETDRS chart at a starting distance 
of 4 meters) at post-baseline visits.
–
Central subfield thickness on 
SD-OCT over time at post-baseline 
visits.

Proportion of participants with absence 
of signs of DME and normalized 
Central Subfield Thickness (CST) at
post-baseline visits.

Assess the effect of RG7774 on visual 
function.

Change from baseline in Contrast 
Sensitivity at post-baseline visits in the 
study eye (Pelli-Robson, qCSF) or in 
both eyes (qCSF).

Change from baseline in low 
luminance visual acuity (LLVA) at 
Week 36 visit in the study eye.

Assess the effect of RG7774 on visual 
fields.

Change from baseline in mean 
threshold at post-baseline visits.

Change from baseline in point-by-point 
Standard Automated Perimetry at post-
baseline visits.

Assess systemic pharmacokinetics and 
exposure-response/safety relationships 
of RG7774 (and its metabolite[s] as 
appropriate).

PK parameters of RG7774 (and its 
metabolite[s] as appropriate) in plasma 
and (if applicable) in optional aqueous 
humor.


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Table 3
Objectives and Endpoints (cont.)
Objectives
Endpoints
Exploratory

Explore the effect of RG7774 on 
markers of kidney function.

 
 

Explore potential effects of RG7774 on 
glycemic status.

Change from baseline in blood levels 
of HbA1c.

Assess the effect of RG7774 on 
systemic biomarkers of inflammation 
and disease in peripheral blood.


 
 
 
.

 
 
.

 
 
 
 

 
 

 
 

 
 

To contribute to the development and/ 
or evaluation of advanced analytics 
tool (artificial intelligence based tool) 
for the assessment of clinically relevant 
features

Performance of the advanced analytic 
tools
4.
STUDY DESIGN
4.1
OVERALL DESIGN
An overview of the study design is provided in Section 1.2.


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This is a phase II, multi-center, randomized, three parallel-group, placebo-controlled, 
double-masked, proof-of-concept study in treatment-naïve participants with moderately 
severe to severe NPDR and good vision. Participants will receive RG7774 or placebo for 
up to 36 weeks. Participants will be randomized in equal proportions to one of the 
treatment groups listed in Section 4.1.1.
Randomization will take place at the Day 1 visit prior to study treatment administration 
and after the assessments confirming eligibility of the participant. Starting at the Day 1 
visit, randomized participants will have study treatment self-administered orally once 
daily until the visit at Week 36 or earlier if discontinued (see Section 7). A 12-week 
observational, off-treatment period will follow until the last visit of the study, at Week 48. 
Randomization to the different treatment groups will be stratified on Day 1 based on the 
following imaging features from screening:

DR severity score (DRSS) 47 vs. DRSS 53.

Presence vs. absence of DME.

Unilateral vs. bilateral moderately severe to severe NPDR.
The stratification factors will be assessed by a central reading center, based on 
information obtained at the screening visit. Safety assessments will be performed at 
every site visit. To ensure an adequate safety follow-up also between site visits, 
participants will receive phone calls from the site every 4 weeks when no site visit is 
scheduled), during which participants will be asked for AEs and any changed or new 
concomitant medication.
4.1.1
Treatment Groups
Treatment naïve participants will be randomized in a 1:1:1 ratio to one of the groups A, B 
and C respectively, for a treatment period of 36 weeks (see Figure 1).

Group A: placebo oral once daily (QD)

Group B: 30 mg RG7774 oral QD

Group C: 200 mg RG7774 oral QD
4.1.2
Length of the Study
The total duration of the study for each participant will be up to 52 weeks divided as 
follows:

Screening (from Day 28 to Day 7)

Day 1 (1 day)

Study treatment period with fixed dose (36 weeks).

Safety and efficacy follow-up period / washout period (28 days after last dose, week 
40 visit).

Long-term follow-up period (8 weeks: from Week 40 visit to Week 48 visit).


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4.1.3
Administrative Structure 
The roles, responsibilities, membership, scope of activities, time of meetings and 
communication plan for the Sponsor’s Internal Monitoring Committee (IMC) and 
Scientific Oversight Committee (SOC) will be documented in an appropriate charter (see 
Appendix 1, Section 3.3).
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
The study rationale is provided in Section 2.1.
To allow for an unbiased evaluation of RG7774 as a treatment for participants with 
moderately severe to severe NPDR and good vision, a multi-center, randomized, three 
parallel-group, placebo-controlled, double-masked trial design was selected.
4.2.1
Rationale for Study Population 
This study will be conducted in participants with NPDR who meet all of the inclusion 
criteria and do not meet any of the exclusion criteria for this protocol (see Sections 5.1
and 5.2). 
Treatment of all forms of DR with and without DME is approved for anti-VEGF in the 
United States (ranibizumab [Lucentis] US product information [USPI], aflibercept 
[Eylea] USPI). Nevertheless, treatment initiation (with laser or anti-VEGF therapy) even 
in DR patients with DME was shown to be deferred for at least 1 year in a majority of 
patients, despite the potential to improve their DR severity (Ip et al. 2012; Brown et al.
2015, Willis et al. 2017). While patients with NPDR have no well-defined visual 
impairment, their underlying retinal pathology is progressive.  Moderately severe to 
severe NPDR, if left untreated, may progress to vision-threatening disease in about 41% 
of patients within 1 year (Boyer 2019).
Based on the above identified unmet medical need, the current Phase II Study BP41321 
will recruit treatment-naïve patients with T1/T2 DM as defined by the World Health 
Organization and/or American Diabetes Association, with glycated hemoglobin (HbA1c) 
of 12%. More specifically:

Patients presenting a clinical diagnosis of NPDR (DRSS 47 or 53 in the study 
eye). The more advanced stages of NPDR (i.e., DRSS 47 and 53) are associated 
with an increased risk of developing sight threatening complications of DR, 
comprising PDR, and/or DME, amongst others.

Patients with and without DME will be eligible for the study. Since there is limited 
information on the effect of DME on DRSS progression, this patient population is 
also included as it is likely that an improvement in DRSS will benefit both patients 
with and without DME.

Eligible patients will present a BCVA score of at least 70 letters (at least 75 
letters if DME is present) in the study eye, using Early Treatment Diabetic 


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Retinopathy Study (ETDRS) visual acuity (VA) testing charts at a testing distance 
of 4 meters (approximate Snellen equivalent of 20/40 or better – 20/32 for DME). 
Including this VA limit will ensure reduced probability of requirement for rescue 
therapy. 
To ensure the study results will be representative of the target population, the number of 
participants with DME will be capped to 50%.
4.2.2
Rationale for Control Group 
The control group in this study will receive placebo. Using placebo as study comparator 
allows an unbiased evaluation of the magnitude of any treatment effects. In addition, 
current practice for a relevant proportion of NPDR patients is observation.
4.2.3
Rationale for Primary Endpoint Assessment and Study 
Duration
The primary endpoint will be the proportion of participants with a 2-step improvement 
from baseline in ETDRS DRSS measured in the study eye at 36 weeks. 
The ETDRS DRSS is a well-established scale, with step changes that are associated 
with different risks of long-term vision loss (Nair et al. 2016). In addition, it has already 
been accepted by the US regulatory agency for the label approval of ranibizumab and 
aflibercept (ranibizumab USPI, aflibercept USPI).
Due to the systemic administration of RG7774, the primary endpoint will be supported by 
additional analysis at a participant level (sum of both eyes), including the response of 
non-study eyes with NPDR of DRSS categories 35, 43, 47 or 53 at baseline.
The evaluation at 36 weeks is considered an appropriate time point to evaluate the 
primary variable, as previous results in the same population have shown significant 
improvements as of Week 24, with treatment effects increasing up to 52 weeks (Boyer 
2019).
An exploratory efficacy endpoint will be obtained 12 weeks after the last dose of the 
study treatment with the objective of exploring the durability of RG7774 on DRSS 
change, as previous trials have shown that DRSS improvements may not be maintained 
once treatment has stopped (Sun et al. 2019).
4.2.4
Rationale for Response Definition and Study Eye Selection  
The primary endpoint will be the proportion of participants with a 2-step improvement 
from baseline in ETDRS DRSS at 36 weeks, measured in the study eye. At any time, 
new ASNV, new PDR, new DME and pre-existing DME requiring intervention (see 
permitted therapies Section 6.5.1), occurring in the study eye will classify a participant as 
a non-responder for the primary analysis, as all these events imply progression of the 
disease.


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Since RG7774 is an oral treatment with expected bilateral effects, the Sponsor will 
evaluate an in-patient (sum of both eyes) DRSS improvement of 3 steps in participants 
with two eligible eyes. At any time, new ASNV, new PDR, new DME and pre-existing 
DME requiring intervention (see permitted therapies Section 6.5.1), occurring in either 
eye, classifies a participant as a non-responder. An additional analysis will be conducted 
for each baseline DRSS level 35 and 43 in the non-study eye to allow for further 
characterization of RG7774 effects.
In cases where both eyes are eligible, the study eye will be the one with DRSS score of 
53. The risk of progression of the disease is higher in eyes with DRSS 53, meaning this 
population is the one with the higher unmet need (Ip et al. 2015; ETDRS report 1991). If 
both eyes have the same DR score, then the right eye will be selected as the study eye. 
4.2.5
Rationale for Exploratory Endpoints  
The primary endpoint is based on anatomic changes measured in color fundus images. 
The most commonly accepted measure of visual function, i.e. change in BCVA, is not 
expected to vary to a large extent in this population, with already good vision at baseline. 
Therefore, several additional measures of visual function will be explored in this study, 
including amongst others:

Contrast sensitivity: Previous studies have shown an inverse association 
between contrast sensitivity and severity of DR (Gella et al. 2017; Ip et al. 2017). 
Contrast sensitivity will be assessed using Pelli-Robson charts and the 
quantitative Contrast Sensitivity Function (qCSF) testing on the Manifold Contrast 
Vision Meter (Adaptive Sensory Technology, San Diego, CA, USA). 

Visual fields: There is evidence that visual fields (VF) dysfunction is capable of 
distinguishing different stages of DR (Joltikov et al. 2017) and that VF show 
progressive decline over time (Hellgren et al. 2014). In addition, VF deficits can 
be detected prior to other DR alterations, suggesting it can be a measure of early 
retinal neurodegeneration (Hellgren et al 2014). In the present study, VF is an 
optional assessment that will be measured using Standard Automated Perimetry
(SAP) and analyzed by a VF Reading Centre.
Optional aqueous humor samples will be collected from participants who require 
intravitreal rescue treatment with any of the permitted therapies (see Section 6.5.1) and 
who give additional consent. The samples will be analyzed with an aim to further 
understand the ocular PK of RG7774. Single (Krohne et al. 2012) and multiple 
(Campochiaro et al. 2013) aqueous humor sampling has previously been instrumental in 
the understanding of ocular PK.
 


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4.3
JUSTIFICATION FOR DOSE
The exploration of the doses of 30 mg and 200 mg RG7774 QD over 9 months in this 
Phase II study is supported by a favorable benefit-risk assessment based on the benign 
safety profile observed in the chronic GLP repeat-dose toxicity studies up to the highest 
tested doses, the safety and tolerability profiles observed in Study BP40387 and the 
safety monitoring in place in this study. These results will then help guide the optimum 
dose selection for Phase III studies.
As of 30th September 2019, in the entry-into-human study (Study BP40387) and the 
itraconazole DDI study (Study BP41274) a total of 75 healthy participants have received 
single oral doses of RG7774 ranging from 0.75 mg to 300 mg, and a further 47 healthy 
participants have received multiple oral doses ranging from 6 mg to 300 mg once-daily 
for 2 weeks. RG7774 was safe and well tolerated at all investigated doses. In Part 4 
(CYP induction DDI) of the amended EIH study one SAE (asymptomatic, abnormal 
T-wave morphology with tachycardia) was reported (see Section 2.3). This occurred at 
the highest tested dose in Phase I of 300 mg of RG7774 administered once-daily for 2 
weeks.
The dose selection for BP41321 was based in the results of study BP40387, as well as 
in several criteria, including preclinical information, CB2 receptor Target Engagement 
(CB2R-TE) and LPS assay:

Data obtained in preclinical animal models suggest that the predicted 
pharmacological active dose range in human lies between doses of 0.22 and 42 
mg per day. Assuming good translatability of this data to the clinic, the two 
selected doses of 30 mg and 200 mg will have pharmacological effects.

 
 
 
 
 
 
 
 
 
 
 
 
 


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
 
 
Further details are provided in the IB (including for Table 4).
Table 4
Estimated Margins of Safety for Phase II Dose
Mean Cmax,ss
(ng/mL)
M/F
Mean AUCtau,ss
(h.ng/mL)
M/F
26-week Rat Study (GLP) 
NOAEL
300 mg/kg (M), 60 mg/kg (F)
22,400/27,000
189,000/193,000
39-week Cynomolgus Monkey 
Study (GLP) NOAEL
300 mg/kg (M/F)
7,850/8,020
82,500/103,000
Predicted Exposure in Humans 
at 30 mg
352
3,780
Predicted Exposure in Humans 
at 200 mg
2,150
24,000
Exposure Multiples (30 mg) *
Rat
Cyno
64
22
50
21
Exposure Multiples (200 mg) *
Rat
Cyno
10
3
7
3
* Exposure multiples calculated based on lowest NOAEL exposure
4.4
END OF STUDY DEFINITION
The end of study is defined as last visit of the last participant. The last participant last 
observation (LPLO) is expected to occur 48 weeks after the last participant is enrolled.
Participants are considered to have completed the study if they have completed all the 
assessments as required in this protocol.
5.
STUDY POPULATION
Participants of this study are adult patients with DM type 1 or type 2, with treatment-
naïve moderately severe to severe NPDR, good vision, with or without DME who are not 


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expected to require DME treatment for the duration of the study, fulfill all inclusion 
criteria and do not meet any exclusion criteria.
Patients who failed screening due to inclusion/exclusion criteria in the previous 
versions of the protocol that have been changed in the current version (e.g., HbA1c, 
serology) can be rescreened (see Section 5.4).
Only one eye will be selected as the study eye. If both eyes are eligible, the eye with 
DRSS 53 will be the study eye. If both eyes are eligible and have equal DRSS, the right 
eye will be defined as the study eye.
The study population rationale is provided in Section 4.2.1.
Prospective approval of protocol deviations from recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
INCLUSION CRITERIA
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Informed Consent
1.
Able and willing to provide written informed consent and to comply with the study 
protocol according to International Council for Harmonisation (ICH) and local 
regulations.
Age / Gender
2.
Male and female patients of at least 18 years of age.
Ocular Criteria for study eye:
3.
Patients with treatment-naïve, moderately severe to severe NPDR defined as 
ETDRS DRSS 47 or 53. NPDR will be evaluated at the site based on e.g. the 4:2:1 
rule evident on clinical examination and on digital imaging. Confirmation of DRSS 47 
or 53 by the central reading center is required. Note: One rescreening for this 
criterion is permitted for participants who score DRSS 43 at the screening visit.
Rescreening should be scheduled at least 16 weeks (approximately 4 months) after 
the initial screening visit.
4.
Patients are eligible with and without DME in either eye, defined as the presence of 
signs in the macula such as swelling, leakage, exudates, cystoid changes and fluid. 
In addition, Central Subfield Thickness (CST) on SD-OCT needs to be 300µm to 
confirm diagnosis of DME. The presence of DME will be confirmed at screening by 
the central reading center. 
5.
If present, DME has to be treatment-naïve and not expected to require treatment 
during the duration of the study in the opinion of the investigator at screening and 
Day 1.


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6.
BCVA score at screening of at least 70 letters in study eyes without DME and at 
least 75 letters in case DME is present, using ETDRS visual acuity testing charts at 
a testing distance of 4 meters (approximate Snellen equivalent of 20/40 or better - or 
20/32 or better). 
7.
Clear ocular media and adequate pupillary dilation to allow acquisition of good 
quality retinal images.
General Criteria:
8.
Diagnosis of DM type 1 or type 2, as defined by the World Health Organization 
and/or American Diabetes Association, and:
(i) Current regular use of insulin or other injectable drugs for the treatment of DM
and/or
(ii) Current regular use of oral anti-hyperglycemic agents for the treatment of DM
9.
HbA1c 12%.
10. Allowed existing medication regimens for DM and associated conditions should be 
stable for at least 6 weeks before screening, with the intent to remain stable 
throughout the study. One rescreening for this criterion is permitted.
11. Patient is willing to refrain from non-topical cannabinoid (CBD) use (e.g., over-the-
counter [OTC] CBD oil) for the entire duration of the study.
Sex and Contraception/Barrier Requirements:
12. Male and/or female participants
Pregnancy of a female participant and fathering of a child by a male participant 
should be avoided during participation in this study. The contraception and 
abstinence requirements are intended to prevent exposure of an embryo to the 
study treatment. The reliability of sexual abstinence for male and/or 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)
Female Participants
A female is eligible to participate if she is not pregnant (see Appendix 5), not 
breastfeeding, and at least one of the following conditions applies:

Women of non-childbearing potential (WONCBP), as defined in Appendix 5.

Women of childbearing potential (WOCBP), who:
–
Agree to remain abstinent (refrain from heterosexual intercourse) or use of two 
contraceptive methods that result in a failure rate of 1% per year during the 
treatment period and for at least 4 weeks after the final dose of RG7774 or 
placebo. 
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal occlusion/ ligation, male sterilization, established proper use of 


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hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine 
devices and copper intrauterine devices (see Appendix 5). Hormonal 
contraceptive methods must be supplemented by a barrier method. Additionally 
see Section 6.5.1.
–
Have a negative pregnancy test (urine) at screening. 
b)
Male Participants
During the treatment period and for at least 90 days after the final dose of study 
treatment, agreement to: 

Remain abstinent (refrain from heterosexual intercourse) or use barrier contraceptive 
measures such as a condom plus an additional contraceptive method that together 
result in a failure rate of 1% per year, with a partner who is a WOCBP, as defined 
in Section 1 of Appendix 5.
With pregnant female partner, remain abstinent (refrain from heterosexual 
intercourse) or use contraceptive measures such as a condom to avoid exposing 
the embryo.

Refrain from donating unwashed sperm.
Other:
13. In the investigator’s opinion, the subject is deemed appropriate for participation in 
the study, capable of following the study schedule of assessments and complying 
with the study restrictions and participation in the study or discontinuation of 
prohibited medication will not pose undue risks to the participant.
5.2
EXCLUSION CRITERIA
Participants are not eligible if any of the following criteria apply:
Ocular criteria for study eye:
1.
Prior treatment for DR or other retinal diseases with any approved therapy, including 
but not limited to intravitreal steroids, intravitreal anti-VEGF, light therapy, periocular 
pharmacological intervention, and laser (e.g., focal, grid, micropulse, or pan-
retinal). 
Note: Focal laser in the retinal periphery due to other reasons than DR (e.g., due to 
retinal hole or tear) at least 12 weeks prior to screening is permitted. One 
rescreening for this criterion is permitted.
2.
Intraocular surgery less than 12 weeks prior to screening. One rescreening for this 
criterion is permitted. 
3.
Aphakia or implantation of intraocular lens outside of the capsular bag.
4.
History of vitreoretinal surgery.
5.
Uncontrolled glaucoma (e.g., visual field loss or defined as intraocular pressure 
[IOP] 25 mmHg despite treatment with anti-glaucoma medication). One 
rescreening for this criterion is permitted.


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6.
Amblyopia.
7.
Any history of idiopathic or immune-mediated uveitis in either eye.
8.
Any concurrent intraocular condition (e.g., age-related macular degeneration [AMD], 
retinal vein occlusion [RVO], retinal detachment, dense cataract, epiretinal 
membrane with traction, or vitreomacular traction, etc.) that in the opinion of the 
Investigator could reduce the potential for improvement, require medical surgical 
intervention or may confound the visual and functional assessment and 
interpretation of study results.
9.
Criteria for participation in previous ocular clinical trials for the study eye:

Participation in a clinical trial for an ocular disease involving an 
investigational device (e.g., implant, laser), gene therapy, or cell-based therapy.

Participation in a clinical trial for a retinal disease with pharmacological 
intervention receiving active investigational treatment.

Participation in a clinical trial for ocular non-retinal diseases with 
pharmacological intervention receiving active investigational treatment within 
12 weeks or 5 half-lives (whichever is longer) prior to screening. One 
rescreening for this criterion is permitted.
Ocular criteria for non-study eye:
10. Criteria for participation in previous ocular clinical trials for the non-study eye:

Participation in a clinical trial for an ocular disease involving an 
investigational device, gene therapy, or cell-based therapy. Note: Laser 
treatment is permitted.

Participation in a clinical trial for ocular diseases with pharmacological 
intervention receiving active investigational treatment within 2 weeks or 
5 half-lives (whichever is longer) prior to screening. One rescreening for this 
criterion is permitted.
Concurrent ocular conditions in either eye:
11. Any active ocular infection. One rescreening for this criterion is permitted.
12. Any active intraocular inflammation. One rescreening for this criterion is permitted.
General Criteria:
13. Previous systemic use of anti-VEGF drugs within 24 weeks prior to screening. One 
rescreening for this criterion is permitted.
14. Complications of DM such as end-stage renal disease or liver disease.
15. Currently untreated DM or previously untreated patients who initiated oral or 
injectable anti-diabetic medication within 12 weeks prior to screening. One 
rescreening for this criterion is permitted.
16. Uncontrolled BP (defined as systolic 180 mmHg and/or diastolic >100 mmHg while 
patient at rest). If a patient’s initial reading exceeds these values, a second reading 
may be taken either 30 or more minutes later on the same day, or on another day 


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during the screening period. If the BP is controlled by antihypertensive medication, 
the patient should be taking the same medication continuously for at least 6 weeks 
prior to screening. One rescreening for this criterion is permitted.
17. Confirmed (e.g., 2 consecutive measurements) clinically significant abnormality on 
ECG at screening. That includes but is not limited to QTcF 450 ms for male 
participants and QTcF 470 ms for female participants, absence of dominating 
sinus rhythm, AV-block II or III. Additional examples of clinically significant 
abnormalities detected by ECG or otherwise related to abnormal cardiac function 
are cardiac insufficiency, coronary artery disease, cardiomyopathy, congestive heart 
failure, family history of congenital long QT syndrome, family history of sudden 
death, and atrial fibrillation.
18. History of coagulopathies, bleeding disorders or blood dyscrasias.
19. History of concurrent cardio-vascular disease not considered well controlled by the 
Investigator.
20. Risk of suicidal behavior in the opinion of the Investigator or as evidenced by a “yes” 
to questions 4 and/or 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) 
taken at screening, or any suicide attempt in the last 5 years.
21. Positive serology results for HIV-1 and HIV-2. Positive results for hepatitis B virus 
(HBV) and hepatitis C virus (HCV) are exclusionary only if the disease is 
confirmed to be active and/ or the patient is receiving treatment.
22. Any major illness or major surgical procedure within 4 weeks before screening. One 
rescreening for this criterion is permitted.
23. History of or currently active other diseases, viral and/or bacterial infections, 
metabolic dysfunction, physical examination finding, malignancies not considered 
cured, or clinical laboratory findings giving reasonable suspicion of a condition that 
contraindicated the use of the investigational medicinal drug or that might affect 
interpretation of the results of the study or renders the patient at high risk for 
treatment complications in the opinion of the investigator.
Note: Participants with symptoms or signs of acute or long SARS-CoV-2 infection 
or asymptomatic disease (positive test without symptoms) within 30 days of 
screening will be excluded from the study. One rescreening for this criterion is 
permitted.
24. Known hypersensitivity to any of the excipients of the drug used, fluorescein dye or 
dilating eye drops.
25. Alcohol and/or substance abuse/dependence during the last 12 months, assessed by 
the investigator considering the results of the tests and the medical history, in 
consultation with the Sponsor, if required. One rescreening for this criterion is 
permitted.
26. Use of non-topical CBD (including OTC CBD oil) within 12 weeks prior to screening. 
One rescreening for this criterion is permitted.


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27. Use of prohibited medications within 2 weeks prior to screening, or 5 half-lives 
(whichever is longer) as listed in Section 6.5.2. One rescreening for this criterion is 
permitted.
28. Use of systemic medications known to be toxic to the lens, retina or optic nerve 
(e.g., deferoxamine, chloroquine/hydroxychloroquine, tamoxifen, phenothiazines 
and ethambutol) used during the 24-week period prior to screening or likely need to 
be used. One rescreening for this criterion is permitted.
29. Participation in a clinical study involving an investigational medicinal product or 
device with exit from that study 

within 60 days prior to screening, or 

within less than 5 half-lives between last exposure to study treatment in the 
previous study and screening for the present study
(whichever is longer). One rescreening for this criterion is permitted.
30. Blood donation or loss of blood 500 mL within 12 weeks prior to screening. One 
rescreening for this criterion is permitted.
5.3
LIFESTYLE CONSIDERATIONS
5.3.1
Meals and Dietary Restrictions
In vitro data and clinical data suggest that RG7774 is metabolized predominantly by 
CYP3A and to a minor extent by CYP2C19 and thus there is a potential for drug-drug 
interaction with any food product that moderately or strongly inhibits or induces these 
enzymes. Therefore, the following food products are prohibited:

Any nutrients known to modulate CYP3A activity (e.g., grapefruit, grapefruit juice, 
Seville orange) within 2 weeks prior to first study drug administration and up to 
follow-up

Any nutrients known to modulate CYP2C19 activity (e.g., pungent ginger) within 
2 weeks prior to first study drug administration and up to follow-up
The above list of food products is not necessarily comprehensive. The investigator 
should contact the Medical Monitor if questions arise regarding food products not listed 
above.
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.
The Investigator will maintain a screening log to record details of all participants 
screened and to confirm eligibility or record reasons for screening failure.
Re-screening will be allowed based on eligibility criteria as specified in Sections 5.1
and 5.2. If participants meet criteria upon re-screening, they will receive a new screening 


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number and will be treated as a new participant. For re-screenings allowed per 
inclusion/exclusion criteria there is no need to repeat other assessments as long as 
these were performed within 28 days prior to randomization. A maximum of two 
re-screenings per participant will be allowed.
For each participant, if one eye does not meet eligibility criteria, then the second eye 
may be evaluated within the initial screening period. If the second eye meets the 
eligibility criteria, then the participant will retain the same screening number and will not 
be screen-failed.
In addition, re-screening is allowed for participants who were screened in the study and 
met study inclusion/exclusion criteria but failed to be randomized within 28 days after the 
start of screening period because of an administrative reason. In order to re-screen such 
a participant, all inclusion and exclusion criteria should be re-evaluated and all 
applicable screening assessments repeated. In this case, participants will receive a new 
screening number and will be treated as a new participant.
A new screening may be performed for those patients who failed screening due to 
inclusion/ exclusion criteria in the previous versions of the protocol that have been 
changed in the current version (e.g., HbA1c, serology) (see Sections 5.1 and 5.2). These 
patients will receive a new screening number and will need to undergo the full 
screening assessments.
5.5
RECRUITMENT PROCEDURES
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations. Informed Consent Forms 
for enrolled participant and for participants who are not subsequently enrolled will be 
maintained at the study site.
All screening and pretreatment assessments must be completed and reviewed to 
confirm that participants meet all eligibility criteria, including Central Reading Center 
confirmation of eligibility for a predefined set of imaging criteria, and defined list of Day 1 
assessments. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure.
Participants who are willing to participate in the study and have given informed consent 
will undergo a thorough screening examination within 28 days prior to study treatment 
administration. The list of screening procedures is outlined in the SoA (see Section 1.3).
6.
TREATMENTS
Study intervention is defined as any investigational product (including placebo) or 
marketed product intended to be administered to a study participant according to the 
study protocol.


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All investigational medicinal products (IMPs) required for completion of this study 
(RG7774 and placebo) will be provided by the Sponsor. Approved anti-VEGF, and/ or 
steroids (in cases where rescue therapy is needed, see Section 6.5.3) are considered 
non-investigational medicinal products (NIMPs).
Cases of overdose, medication error, drug abuse, or drug misuse, along with any 
associated AEs, should be reported as described in Appendix 2, Section 5.2.
6.1
TREATMENTS ADMINISTERED
The first study treatment will be self-administered on the same day as randomization. 
The administration of the first study treatment will happen only after eligibility has been 
confirmed at Day 1, based on review of applicable inclusion/ exclusion criteria (see 
Section 5). For confirmation of some of these criteria an ophthalmological examination 
with dilation may be required. Please refer to the Study Procedures Manual for further 
details. 
The participants are required to take the study treatment QD at approximate the same 
time of the day (preferably with breakfast) with the exception of the days when site visits 
are scheduled. On days of site visits the participants should take their treatment at the 
clinic as additional PK samples at specific timepoints may be taken (see Section 1.3). 
Table 5 summarizes the treatments administered.
Table 5
Summary of Treatments Administered
Study Treatment 
Name:
RG77741
Placebo
IMP and NIMP
IMP
IMP
Dose Formulation:
film-coated tablet
film-coated tablet
Unit Dose 
Strength(s)/Dosage 
Level(s):
30 mg or 100 mg
(NA)
Dose:
30 mg or 200 mg
(NA)
Route of 
Administration:
oral
oral
Sourcing:
Provided centrally by the 
Sponsor
Provided centrally by the 
Sponsor
Packaging and 
Labeling:
RG7774 will be provided in 
high-density polyethylene
(HDPE) bottles. Each HDPE 
bottle will be labeled as 
required per country 
requirement.
Placebo will be provided in 
HDPE bottles. Each HDPE 
bottle will be labeled as 
required per country 
requirement.
1 RG7774 is also called RO6868847.


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All permitted rescue therapies as per Section 6.5.1 are considered NIMP and will be 
administered at the discretion of the investigators.
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 6.6 or Section 7, respectively.
Please see the IB and Pharmacy Manual for more details.
6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY
Study treatment packaging will be overseen by the Sponsor clinical trial 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 treatment will be in accordance with Sponsor 
standard and local regulations.
The investigational site will acknowledge receipt of IMPs and confirm the shipment 
condition and content. Any damaged shipments will be replaced.
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 randomization/treatment assignment schedule and the 
Pharmacy Manual.
The Investigator or delegate must confirm that appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
Only participants randomized in the study may receive study treatment and only 
authorized site staff may supply study treatment. All study treatments 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 site staff.
The Investigator 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 


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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.
Further guidance and information for the final disposition of unused study treatment are 
provided in the Pharmacy Manual.
6.2.1
Assessments to be Completed by Participant at Home
Accountability and participant compliance will be assessed by maintaining adequate 
study treatment dispensing records. Participants will be asked to return all used and 
unused drug supply containers at each mandatory site visit and at the end of treatment 
as a measure of compliance. The Investigator is responsible for ensuring that dosing is 
administered in compliance with the protocol. Delegation of this task must be clearly 
documented and approved by the Investigator.
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND 
MASKING
6.3.1
Method of Treatment Assignment
After the screening visit and initial assessment of eligibility, images of both eyes will be 
forwarded as soon as possible to the Central Reading Center for those participants 
deemed eligible (eligibility for safety labs, ECG, and pregnancy test, where appropriate, 
might be pending). The Central Reading Center will assess the imaging data submitted 
and confirm eligibility based on the described criteria (see Section 5.1). 
On Day 1 prior to randomization, all participants’ eligibility requirements are reviewed, 
and eligibility criteria (See Sections 5.1 and 5.2) are re-assessed by the Investigator.
Participants will be enrolled and randomized if they meet all screening and Day 1 
eligibility criteria. For each participant, if one eye does not meet eligibility criteria, then 
the second eye may be evaluated within the initial screening period (see Section 5.4).
Once all eligibility criteria have been confirmed on Day 1, the site personnel will contact 
the Interactive Voice/Web Response System (IxRS) for assignment of a participant 
identification number (a separate number from the screening number). All participants 
will be centrally assigned to randomized study treatment using an IxRS. Before the study 
is initiated, the telephone number and call-in directions and/or the log in information & 
directions for the IxRS will be provided to each site. Study treatment will be dispensed at 
the study visits summarized in SoA. Returned study treatment should not be re-
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6.3.2
Masking
This is a double-masked study, i.e., the study participants, the Investigators, and all 
individuals at the investigative site and the Sponsor Study Management Team (SMT) will 
be masked. Participants will receive either an active or a size-matched placebo tablet or 
tablets. The number of tablets depends on the group that participants are randomized to. 
This strategy has been chosen to minimize the number of tablets administered to 
potentially multimedicated participants and to simplify dosing schedule.
If unmasking is necessary for participant management (e.g., in case the knowledge is 
needed for treatment of a SAE), the Investigator will be able to break the treatment code 
using IxRS. Treatment codes should not be broken except in emergency situations. The 
Investigator should document and provide an explanation for any premature unmasking 
(e.g., accidental unmasking, unmasking due to a SAE). The randomization list will be 
made available to the individual responsible for PK sample bioanalysis and the staff at 
bioanalytical laboratories, to statisticians or statistical programmers and any other 
person considered necessary by the Sponsor’s study team to assist with the decision 
and support the IMC and SOC (see Section 4.1.3). Also, members of the IMC and SOC, 
as well as any individuals who provide relevant information to the IMC for review, will be 
unmasked. PK data can be received and cleaned on an ongoing basis. The data will be 
handled and cleaned in a secure area that is not accessible by any masked SMT 
member.
As per Health Authority reporting requirements, the Sponsor will break the treatment 
code for all unexpected SAE (see Section 8.3.4 and Appendix 2) that are considered by 
the Investigator to be related to study treatment. Whenever disclosure of the identity of 
the test medication is necessary, adequate procedures will be in place to ensure integrity 
of the data.
6.4
TREATMENT COMPLIANCE
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose according to the randomization schedule. This individual will write the date 
dispensed and participant number on the study treatment bottle label and on the Drug 
Accountability Record. This individual will also record the medication number received 
by each participant during the study.
For drug accountability and assessment of compliance by the site, participants are 
requested to bring back the bottles at every site visit.
In order to increase treatment compliance, the sites are encouraged to offer the 
participants the option to use a Patient Engagement Mobile Application (PEMA; see 
Appendix 1, Section 2.1.6). PEMA is an optional service that participants can use to 
remind them of activities or tasks relevant to the study such as when to take their study 
treatment or attend clinical site visits. The application also provides study information 
and any study related supportive instructions. Reminders are delivered to the 


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participants via push notifications to encourage them to continue their participation and 
comply with the study. 
The study site will assess adherence of the participants to the treatment at every site 
visit and at every phone call, as specified in the provided script (see Study Procedures 
Manual). Whenever a participant is, under the opinion of the investigator, not expected 
to comply with the treatment, the investigator is requested to encourage the study 
participants and to monitor closely in future visits their adherence. 
No diaries will be provided as part of this study.
6.5
CONCOMITANT THERAPY
Any medication or vaccine used by a participant from 30 days prior to screening until the 
safety follow-up visit must be recorded along with reason for use, dates of administration 
(including start and end dates) and dosage information (including dose and frequency) in 
the Previous and Concomitant Medications eCRF.
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
All concomitant medications should be reported to the Investigator and recorded on the 
Concomitant Medications electronic Case Report Form (eCRF).
All therapy and/or medication administered to manage AEs should be recorded on the 
treatment section of the Adverse Event eCRF.
6.5.1
Permitted Therapy
Participants should not change their existing stable treatment for DM and its 
consequences during the study, unless it is required for the treatment of an AE or as a 
result of potential DDI. Potential DDI arising from co-administration of other drugs have 
been investigated in healthy volunteers only. Therefore, changed or new concomitant 
medication in general should be limited to the medical need of the participant and the 
medical judgement of the investigator, in consultation with the Sponsor. 
For all concomitant medication, therapeutic drug monitoring has to be done at the 
judgement of the investigator to the uses and administration requirements of the 
product/package insert. 
The Investigator should be aware of the potential for DDI when prescribing concomitant 
medications which are inhibitors or inducers of CYP3A and/or CYP2C19, or are 
substrates of CYP3A, OCT2, MATE1, MATE2-K, P-gp, and/or BCRP and should 
carefully monitor the tolerability, safety and efficacy of the respective medication. The 
Sponsor has included two visits to monitor if there is a need to adjust the dose of
warfarin, if applicable (see SoA in Section 1.3 and Section 8.10.2). 


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Due to the observed CYP3A enzyme induction of RG7774 at doses of 200 mg and 300 
mg administered once-daily, caution should be exercised when co-administrating drugs 
predominantly metabolized by CYP3A and/or the CYP2C9 family, including oral 
contraceptives or hormonal replacement therapeutics. Therefore, female participants of 
childbearing potential taking hormonal contraceptives must supplement with a barrier 
method. 
Therapies permitted for either eye in case of incidence or progression of DME/DR are:

Laser (grid or focal) and/or approved anti-VEGF (except brolucizumab, if 
applicable), and/ or approved steroids in case of worsening DME which requires 
treatment for participants presenting with DME at baseline.

Laser (grid or focal) and/or approved anti-VEGF (except brolucizumab, if 
applicable), and/ or approved steroids in case of incident DME requiring treatment

Laser (pan-retinal), vitrectomy and/or approved anti-VEGF (except brolucizumab, if 
applicable) in case of incident PDR.
The administration of these permitted therapies will not automatically result in treatment 
discontinuation and participants should continue in the study as described in Section 7.
6.5.2
Prohibited Therapy
As a general rule, no concomitant medication will be permitted, with the exception of 
medications to treat AEs, unless the rationale for exception is discussed and clearly 
documented between the Investigator and the Sponsor.
Systemic medications known to be toxic to the lens, retina or optic nerve (e.g., 
deferoxamine, chloroquine/hydroxychloroquine, tamoxifen, phenothiazines and 
ethambutol) are prohibited within 24 weeks prior to baseline and during the study.
6.5.2.1
Systemic Medications Prohibited due to Effects Related to 
Cytochrome P450 Enzymes

Strong inhibitors of CYP3A including, but not limited to, the following drugs: e.g., 
ketoconazole, itraconazole, ritonavir, voriconazole, clarithromycin.

Moderate inhibitors of CYP3A including but not limited to the following drugs: e.g., 
erythromycin, ciprofloxacin, cimetidine. 

Strong and moderate inducers of CYP3A including but not limited to the following 
drugs: e.g. rifampicin, carbamazepine, phenytoin, St. John`s wort, bosentan and 
modafinil.

Strong inhibitors of CYP2C19 including but not limited to the following drugs: e.g., 
fluconazole, fluoxetine, fluvoxamine, and ticlopidine.

Strong and moderate inducers of CYP2C19 including but not limited to the following 
drugs: e.g., rifampicin, ritonavir, efavirenz, phenytoin, and enzalutamide.
The above list of medications is not comprehensive. The investigator should consult the 
prescribing information when determining whether a concomitant medication can be 


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safely administered with the study treatment. In addition, the investigator should contact 
the study team if questions arise regarding medications not listed above.
6.5.3
Rescue Medicine and Follow-Up
If participants during the course of the study were to develop any disease-related events: 
(i)
Worsening of DME (when DME present at baseline) requiring treatment at the 
discretion of the Investigator or if any of the following criteria applies, e.g.:

Loss of 10 letters in BCVA as compared to baseline due to DME, or,

Loss of 5 letters in BCVA as compared to previous visit due to DME, or,

Increase in CST 100 m as compared to previous visit due to DME.
(ii)
Incident DME or PDR (not present at baseline) requiring treatment.
(iii)
Anterior-Segment Neovascularization (ASNV).
then participants may receive rescue treatment for any eye at the Investigator’s 
discretion with any of the permitted therapies outlined in Section 6.5.1. The date and 
time of rescue medication administration as well as the name and dosage regimen of the 
rescue medication must be recorded. Treatment with RG7774 or placebo (as applicable) 
should continue.
In this situation, a reduced number of assessments will be performed for both eyes if the 
study eye receives rescue treatment. 
If the eye that receives rescue treatment is the non-study eye, the non-study eye will 
undergo the reduced schedule of assessments, while the study eye will undergo the full 
schedule of assessments. 
This schedule will continue for all remaining visits (until week 36 included; see 
Section 1.3 and Table 2). This strategy will enable collection of relevant data in 
participants being treated with the permitted therapies but with a reduced burden for the 
participants.
6.6
DOSE MODIFICATION
There are no significant safety findings from all nonclinical and clinical data available for 
the doses studied in this trial at the time of writing, suggesting that dose modifications of 
the IMP may not be required during the study (see Sections 2.3 and Section 2.2.2).
6.7
TREATMENT AFTER THE END OF THE STUDY
The Sponsor does not intend to provide RG7774 or other study interventions to 
participants after conclusion of the study or any earlier participant withdrawal.


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7.
DISCONTINUATION OF STUDY, STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
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 whenever possible.
Details on study and site closures are provided in Appendix 1.
7.1
DISCONTINUATION OF STUDY TREATMENT
See the SoA (Section 1.3) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that need to be completed.
Reasons for discontinuation of study treatment may include, but are not limited to, the 
following:

Participant withdrawal of consent at any time

Participant non-compliant to study treatment

Pregnancy

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the participant.
Every effort should be made to obtain information regarding the reason why participants 
withdraw from study treatment, including cases of non-compliance with treatment 
administration. The primary reason for premature study treatment discontinuation should 
be documented on the appropriate eCRF. 
Participants who terminate study treatment prematurely for any reason will be asked to 
return to the clinic for a study completion/early termination visit (see Section 8.10.3) and 
may undergo follow-up assessments (see Section 8.10.4), unless the participant 
withdrew consent. Two different sets of assessments will be available to the participants 
depending on the date of discontinuation relative to the last site visit (see Section 1.3). 

If the discontinuation happens within 14 days after a site visit, fewer assessments 
will be performed. This will avoid the unnecessary repetition of assessments whose 
outcomes generally do not vary in such time window. 

If the early termination visit happens more than 14 days after a site visit a complete 
set of assessments needs to be performed.
Please refer to Section 8.10.2 for those participants taking warfarin.
For participants who require rescue medication due to disease-related events (see 
Section 6.5.3 and Section 8.3.7) that are considered natural disease progression by the 


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Investigator, the study treatment should not be discontinued. However, if the 
disease-related events are not considered natural progression of the disease and thus 
qualify as AEs, study treatment may be discontinued upon Investigator discretion or 
Sponsor decision. The occurrence and type of events leading to rescue medication must 
be recorded.
Please refer to SoA for further details (Section 1.3) for data to be collected at the time of 
study discontinuation and at safety and follow-up visits, and for any further evaluations 
that need to be completed.
Participants who discontinue study treatment prematurely will not be replaced.
7.1.1
Temporary Interruption
Before permanently discontinuing study treatment (regardless of whether initiated by the 
participant, the Investigator or Sponsor), an interruption should be considered. 
Participants who have temporarily interrupted study treatment should be considered to 
restart as soon as medically justified in the opinion of the Investigator. Participants can 
resume treatment if this has been interrupted during less than 7 days. Treatment 
interruption is to be recorded in eCRF.
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.
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 
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 for other reasons will not be 
replaced.


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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 cannot be reached 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 time-points are summarized in the Schedules of Activities 
(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.
Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of ICF may be utilized for screening or 
Day 1 purposes provided the procedure met the protocol-specified criteria and was 
performed within the time-frame defined in the SoA.
8.1
EFFICACY ASSESSMENTS
8.1.1
Efficacy Assessments to be Completed by Participant or 
Clinician at Site Visits
Efficacy and PD assessments will be performed as detailed in the SoA (see Section 1.3) 
and will include functional and imaging assessments. All ocular assessments will be 
performed in both eyes unless otherwise indicated in the SoA.  
The Study Procedures Manual details the suggested sequence of assessments for time 
points with multiple assessments.


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8.1.2
Ocular Assessments and Imaging
The ocular and imaging assessments performed in this study are described below. 
Independent of the objectives of the present protocol, ocular images can be used in 
support of research aiming at the development of analytical tools.
8.1.2.1
IOP Measurement
The method of IOP measurement (either Goldmann tonometry or Tonopen) used should 
be recorded in the source document and must remain the same throughout the study. 
IOP should occur prior or after pupil dilation, but should be consistent throughout the 
study and recorded. If IOP measurement is done with Goldmann tonometry any 
fluorescein should be carefully washed-out with saline prior to imaging assessment.
If IOP is 30 mmHg, IOP measurement should be repeated.
8.1.2.2
Best Corrected Visual Acuity
BCVA will be measured by a qualified VA examiner prior to dilating pupils. 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 examiner will perform the refraction and BCVA assessment according to the 
Study Procedures Manual. The BCVA examiner will be masked to the study treatment 
assignment as well as to the previous BCVA letter scores of a participant. 
8.1.2.3
Low-Luminance Visual Acuity
BCVA under low luminescence (LLVA) will be measured prior to dilating pupils. LLVA 
will be measured only in the study eye by placing a 2.0-log-unit neutral density filter 
(Kodak Wratten 2.0 Neutral Density Filter) over the best correction for that eye and 
having the participant read the normally illuminated ETDRS chart (using the set of three 
Precision VisionTM or Lighthouse distance acuity charts [modified ETDRS Charts 1, 2, 
and R]). Instructions on how to perform the assessment are provided in the Study 
Procedures Manual.
The LLVA examiner will be masked to the study treatment assignment as well as to the 
previous LLVA letter scores of a participant.
8.1.2.4
Contrast Sensitivity
Contrast Sensitivity (CS) is assessed in two ways: Pelli-Robson and qCSF.
Pelli-Robson will be performed only in the study eye. Instructions on how to perform 
Pelli-Robson are provided in the Study Procedures Manual.
The qCSF will be performed twice at each visit as specified in the SoA (See Section 1.3), 
once for the study eye and once for binocular vision. The qCSF will be performed only in 
sites with capabilities to perform this assessment. Instructions for qCSF are provided in 
the qCSF Procedures Manual.


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The CS assessment(s) will be performed by a trained and qualified examiner masked to 
study treatment assignment and to the previous CS data of a participant.
8.1.2.5
Visual Fields (Optional)
Visual fields will be assessed in the study eye only, using standard automated perimetry 
(SAP) by a trained and certified examiner masked to study treatment assignment and to 
the previous VF data of a participant. Visual field assessment will be performed
optionally. Field setting, grid choice, assessment program as well as number of 
assessments on respective visit days (see Section 1.3) will be detailed in the VF manual 
of procedures. The participants undergoing visual field assessments should complete 
the assessments at all visits as specified in the SoA (See Section 1.3).
The VF manual of procedures will also define the reliability measures (e.g., fixation 
errors, false positive and negative results), the indicators of field function (Mean 
deviation [MD], e.g., foveal threshold) and the indicators of longitudinal changes (e.g., 
MD change from baseline).
8.1.2.6
Slit Lamp Examination and Dilated Binocular Indirect High-
Magnification Ophthalmoscopy
Slit-lamp biomicroscopy will be performed during the study for each eye. Observations 
will be graded as normal or abnormal. Abnormal findings will be specified as not 
clinically significant or clinically significant. Abnormal findings (clinically significant and 
not clinically significant) will be described. The biomicroscopy examination will consist 
of the evaluation of anterior and posterior chambers (including grading scales for
anterior chamber cells or flare and for vitreous haze/vitreous hemorrhage, as detailed in 
Appendix 6 and Appendix 7) and dilated binocular indirect high-magnification 
ophthalmoscopy).
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 Study Procedures Manual. 
8.1.2.7
Fundus Photography
Seven-field stereo color fundus photography will be performed at the study sites by 
trained and Central Reading Center-certified personnel. It is mandatory that the same 
device is used for the entire duration of the study. 
FP image specifications will be detailed in the Central Reading Center Manual. 
8.1.2.8
Fundus Fluorescein Angiography
Seven-field FFA (30-degree field of view) or wide-field FFA (e.g., Optos, Spectralis) will 
be performed at all the study sites by trained and Central Reading Center-certified


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personnel. Where both devices are available then wide-field FFA should be performed 
only. It is mandatory that the same device is used for the entire duration of the study.
Images should be acquired and transferred to the Central Reading Center according to 
specifications provided in the Central Reading Center Manual.
8.1.2.9
Spectral Domain Optical Coherence Tomography
Imaging 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, Topcon, or Optovue 
are acceptable devices (see Central Reading Center Manual). It is mandatory that the 
same device is used for the entire duration of the study. Additional specifications on data 
capturing, reading and data storage will be provided in the Central Reading Center 
Manual.
8.2
SAFETY ASSESSMENTS
Planned time-points for all safety assessments are provided in the SoA (Section 1.3).
Safety assessments will consist of ocular and systemic monitoring and recording AEs, 
including SAEs and adverse events of special interest (AESIs); protocol specified ocular 
clinical assessments and measurement of protocol-specified safety laboratory 
assessments; measurement of protocol-specified vital signs, ECGs; and other protocol-
specified tests that are deemed critical to the safety evaluation of the study. In addition, 
telephone interviews will be performed to assess for any clinically significant symptoms 
and/or new medication. 
8.2.1
Ocular Examination
Ocular safety assessments include data obtained from functional tests such as BCVA, 
visual fields (when available) and IOP measurement, ophthalmic investigations using slit 
lamp and indirect ophthalmoscopy, and ocular imaging including fundus photographs, 
OCT and fluorescein angiography. 
8.2.2
Physical Examinations
The physical examination should cover head and neck including lymph nodes, and the 
cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
neurological systems, and others, as applicable. Height, weight, and body mass index 
will also be measured and recorded (see Section 1.3). Further examination of other body 
systems may be performed in case of evocative symptoms at the Investigator’s 
discretion.
The physical exam will not include pelvic, rectal or breast exams.
Any abnormality identified at baseline should be recorded on the Medical History eCRF.


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At subsequent visits (or as clinically indicated), limited, symptom-directed physical
examinations should be performed. Changes from baseline abnormalities should be
recorded in the participant’s notes. New or worsened clinically significant abnormalities
should be recorded as AEs on the Adverse Event eCRF.
8.2.3
Vital Signs
Body temperature (tympanic, oral, or non-contact methods), pulse rate, and systolic and 
diastolic BP will be assessed. BP and pulse measurements will be assessed with a 
completely automated device. Manual techniques will be used only if an automated 
device is not available. When possible, the same arm and the same device should be 
used for all BP measurements.
BP and pulse measurements should be preceded by at least 5 minutes 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 when scheduled at the same time-point. At the 
discretion of the Investigator, measurements can be repeated if the values are abnormal 
or borderline.
8.2.4
Electrocardiograms
Triplicate 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals.
At each time-point at which triplicate ECGs are required, three individual ECG tracings 
should be obtained as closely as possible in succession, with 1 to 5 minutes apart. The 
average of the three readings will be used to determine ECG intervals (i.e., PR (PQ), 
QRS, QT, QTcF and RR). Any clinically significant ECG abnormalities should be 
captured on the eCRF.
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) should be avoided during the pre-ECG 
resting period and during ECG recording. ECGs should be performed prior to 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 as 
contributing to the ECG abnormality.
For safety monitoring purposes, the Investigator or designee must review, sign, and date 
all ECG tracings. Paper or electronic copies will be kept as part of the participant’s 
permanent study file at the site. ECGs will be analyzed at a central laboratory and will be 
electronically captured.


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QTcF (Fridericia’s correction) and RR will be calculated. Changes in T‑wave and 
U-wave morphology and overall ECG interpretation will be documented on the eCRF. 
T-wave information will be captured as normal or abnormal, U-wave information will be 
captured in two categories: absent/normal or abnormal. The interpretation of the ECG 
results as normal or abnormal should be based on the revised report received by the 
central laboratory.
The timings of assessments may be amended or the number of assessments increased
during study conduct based on emerging data in order to allow for optimal 
characterization of the study treatment effect profile.
8.2.5
Clinical Safety Laboratory Assessments
Normal ranges for the study laboratory parameters must 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 Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. 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 the 
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.
Results of clinical laboratory testing will be recorded on the eCRF or be received as 
electronically produced laboratory reports submitted directly from the local or central 
laboratory.
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.


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Where the clinical significance of abnormal lab results at screening is considered 
uncertain, screening lab tests may be repeated before randomization to confirm 
eligibility.
If there is an alternative explanation for a positive urine or blood test for drugs of abuse, 
e.g., previous occasional intake of a medication or food containing for example, codeine, 
benzodiazepines or opiates, the test could be repeated to confirm washout.
8.2.6
Suicidal Risk Monitoring
Even though RG7774 is not considered to be central nervous system (CNS)-active due 
to its 10,000-fold greater affinity to CB2 receptors with respect to CB1 receptors, the 
FDA strongly recommends that prospective suicidal ideation and behavior assessment 
is carried out in all clinical trials for all drugs that are pharmacologically similar to
those with potential CNS activity. A suicidal monitoring strategy has been implemented 
using the Columbia-Suicide Severity Rating Scale (C-SSRS). This is a clinical-rated tool 
used to assess the recent suicidality of a subject (C-SSRS screening to be used at
screening) as well as any new instances of suicidality (C-SSRS since last visit, to be 
used at subsequent visits). The C-SSRS incorporates a structured interview to prompt 
recollection of suicidal ideation, including the intensity of the ideation, behavior and 
attempts with actual/potential lethality.
Participants showing suicidal behavior may be discontinued from the study at the 
Investigator’s discretion.
8.2.7
Medical History and Demographic Data
Medical history (general and ophthalmology) includes clinically significant diseases, 
surgeries, reproductive status, smoking history, and all medications or vaccines (e.g., 
prescription drugs, OTC drugs, herbal or homeopathic remedies, nutritional 
supplements) used by the participant regularly or within 30 days prior to the screening 
visit.
Demographic data will include age, sex, and self‑reported race/ethnicity.
8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
The definitions of an AE or SAE can be found in Appendix 2. AESIs are discussed in 
Sections 8.3.6.
The Investigator and any qualified designees are responsible for ensuring that all AEs 
(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.


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Procedures used for recording AEs are provided in Appendix 3:

Diagnosis versus signs and symptoms:
–
Other AEs

AEs occurring secondary to other events

Persistent or recurrent AEs

Abnormal laboratory values

Abnormal vital sign values

Abnormal liver function tests

Deaths

Preexisting medical conditions

Lack of efficacy or worsening of the condition 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). Any other AE should not be reported.
After initiation of study treatment, all AEs, regardless of their relationship to study 
treatment, will be reported until 28 days after the final dose of study treatment.
Post-study treatment adverse events and serious adverse events: The Investigator 
is not required to actively monitor participants for AEs after the end of the AE reporting 
period (28 days after the final dose of study treatment).
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 
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.


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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 AE 
information at all participant evaluation time-points.
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 trial-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, AESIs, and pregnancies, the Sponsor or a designee may follow up by 
telephone, fax, electronic mail, and/or a monitoring visit to obtain additional case details 
and outcome information (e.g., from hospital discharge summaries, consultant reports, 
autopsy reports) in order to perform an independent medical assessment of the reported 
case.
8.3.4
Regulatory Reporting Requirements for Serious Adverse 
Events
Prompt notification by the Investigator to the Sponsor of a SAE 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.
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. 


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Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing a 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 and expedited reporting requirements from Investigator to Sponsor and 
from Sponsor to Health Authority, investigators, IRB and EC, see 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
Female participants of childbearing potential will be instructed to immediately inform the 
Investigator if they become pregnant during the study or within 90 days after the final 
dose of study treatment 
Male participants will be instructed through the Informed Consent Form to immediately 
inform the Investigator if their female partner becomes pregnant during the study or 
within 90 days after the final dose of study treatment.
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.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs (Appendix 5).
8.3.6
Adverse Events of Special Interest
AESIs 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).
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 Appendix 3.

Suspected transmission of an infectious agent by the study treatment, as defined 
below:


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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.

Serious complications of DM, including but not limited to, amputations, ulcers, and/or 
DM-related surgeries

Sight-threatening AEs: an AE is considered to be sight-threatening and should be 
reported expeditiously if it meets one or more of the following criteria:
–
Causes a decrease of 30 letters in VA score (compared with the last 
assessment of VA prior to the most recent assessment) lasting more than 1 hour 
–
Requires surgical or medical intervention (i.e., conventional surgery, vitrectomy, 
vitreous tap or biopsy with IVT injection of anti-infective treatments, or laser or 
retinal cryopexy with gas or a medication) to prevent permanent loss of sight
–
Is associated with severe intraocular inflammation (i.e., endophthalmitis, 
Grade 4anterior chamber cells/flare; see Appendix 6 for intraocular grading 
scales).
All of the above listed sight-threatening AEs should be reported as SAEs (see 
Appendix 2), listing the underlying cause (if known) of the event as the primary event 
term.
8.3.7
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs
Natural progression of the disease may include development of DME, worsening of DME 
(if present at baseline), development of ASNV or development of PDR. These events are 
thus not considered AEs. However, it is upon the Investigator’s opinion to determine if 
the above events are to be considered AEs. In this case they will be reported following 
the usual procedure (see Appendix 2 for further details on AE reporting).
8.3.8
Management of Specific Adverse Events
This section does not apply to study BP41321.
8.4
TREATMENT OF OVERDOSE
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 Section 5 and 
5.2 of Appendix 2 for further details). For RG7774 no specific information regarding 
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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, no further RG7774 should be administered and 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 analysis within 24 hours from the date of the final 
dose of study treatment, 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.
For further information see the Investigator’s Brochure.
8.5
PHARMACOKINETICS
Blood samples for pharmacokinetic determination of plasma concentrations of RG7774 
(and its metabolite[s] as appropriate) will be collected as specified in the Schedule of 
Assessments Table.
The actual date and time of the PK blood sampling needs to be precisely entered into 
the corresponding eCRF section.
Plasma concentrations of RG7774 will be measured by a specific and validated LC-
MS/MS method. Plasma concentrations of RG7774-derived metabolite(s) may be 
measured (as appropriate) for exploratory metabolite(s) quantification purposes, with the 
use of non-validated LC-MS/MS method(s). Any residual material from blood PK 
samples may be used for additional exploratory biomarker profiling, identification, assay 
development purposes, and assay validation or compound-related assays after the 
mentioned intended use. All PK samples will be destroyed at the latest 5 years after the 
final clinical study report (CSR). Details on sampling procedures, sample storage and 
shipment are given in the Sample Handling Manual.
Additional PK sampling at unscheduled visits is allowed at the discretion of the 
investigator for safety purposes (see Section 8.4).
Study treatment concentration information that may unmask the study, will not be 
reported to investigative sites or masked personnel until the study has been unmasked.
Any changes in the timing or addition of time-points for any planned study assessments 
must be documented and approved by the relevant study team member and then, 


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archived in the Sponsor and site study files, but this will not constitute a protocol 
amendment. The IRB/IEC will be informed of any safety issues that require alteration of 
the safety monitoring scheme or amendment of the ICF.
8.5.1
Aqueous Humor Samples (Optional)
An optional aqueous humor sample will be collected from either eye receiving intravitreal 
rescue treatment with the therapies permitted in Section 6.5.1 and who provide 
additional consent to participate. Aqueous humor samples must not be collected from 
monocular participants. Where participants consent to aqueous humor sampling, all 
efforts should be made to collect a baseline aqueous humor sample prior to the 
administration of rescue treatment. Unscheduled sampling could be performed at other 
or additional planned visits at the discretion of the Investigator in agreement with the 
participant.
The aqueous humor sample (0.1 mL) should be collected by a qualified physician after 
all other assessments have been completed but before rescue therapy is provided as 
per Table 2 (Section 1.3), using an aseptic procedure and sterile field and according to 
local guidelines.
Determination of RG7774 (and its metabolite[s], as appropriate) concentration in 
aqueous humor for exploratory quantification purposes may be performed with the non-
validated LC-MS/MS method(s).
 
 identification, assay 
development purposes, and assay validation or compound-related assays after the 
mentioned intended use. These specimens will be destroyed no later than 5 years after 
the date of final CSR.
The informed consent form will contain a separate section that addresses the use of 
aqueous humor samples for optional exploratory biomarker research. A separate 
signature will be required to document a participant's agreement to allow this sample to 
be taken and used for exploratory research.
 
 
 
 


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8.7
PHARMACODYNAMICS AND BIOMARKER SAMPLES
The samples may also be used for research purposes to identify biomarkers useful for 
predicting and monitoring response to RG7774, identifying biomarkers useful for 
predicting and monitoring RG7774 safety, assessing pharmacodynamic effects of 
RG7774, and investigating mechanism of therapy resistance. Additional markers may be 
measured in the case that a strong scientific rationale develops.
Based on continuous analysis of the data in this study and other studies, any sample 
type and/or analysis not considered to be critical for safety may be stopped at any time if
the data from the samples collected does not produce useful information. 
Unless otherwise specified below, samples (including blood, slides, extracts, etc.) will be 
destroyed no later than 5 years, and for genetics/ genomics samples up to 15 years, 
after the date of final CSR.
 
 
 
 
 
 
 
Details on processes for collection and shipment of these samples can be found in 
separate sample documentation.


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8.9
MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS
This section does not apply to study BP41321.
8.10
TIMING OF STUDY ASSESSMENTS
8.10.1
Screening and Pre-treatment Assessments
Written or electronic (eConsent) informed consent for participation in the study must be 
obtained before performing any study-specific screening tests or evaluations. Informed 
Consent Forms 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.
At any study visit (including screening visit), each category of assessments (i.e., sample 
collection, imaging procedures, PROs, etc.) is recommended to be performed following 
the order specified in the SoA table (see Section 1.3). 
Screening and pre-treatment assessments will be performed during 21 days, Day 28 to 
Day 7 prior to Day 1, unless otherwise specified, to allow for sufficient time to process 
samples and receive external eligibility reports.
8.10.2
Assessments during Treatment
Under no circumstances will participants who enroll in this study and have completed 
treatment as specified, be permitted to be allocated a new randomization number and 
re-enroll in the study.
All assessments must be performed as per SoA (see Section 1.3). 
The Sponsor has included two visits to monitor if there is a need to adjust the dose of 
warfarin. These visits will take place 7 days after the first dose of the study treatment (on 
Day 7) and 7 days after the last dose of the study treatment (i.e. at around Week 37 for 
participants completing the treatment period and at individually determined time-points 
for participants discontinuing treatment or the study prematurely). The visits are required
for all participants on warfarin and will include a blood test for clinical parameters of 
coagulation. The Investigator will communicate the results to the participant’s regular 
diabetologist/ endocrinologist. All participants will be managed according to the best 
judgment of their treating physicians as informed by current local clinical practice 
guidelines and the best clinical evidence for patients with DR. 


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See also Sections 8.1 and 8.2 for further details.
8.10.3
Assessments at Study Treatment Completion / Early 
Termination Visit
Participants who complete the 36-week treatment phase will be asked to return to the 
clinic for two visits with fewer assessments compared to the regular visits: 
o
A safety follow-up visit, 28 (7) days after the final dose of study 
treatment (week 40 visit), 
o
An efficacy visit, 84 (7) days after the final dose of study treatment 
(week 48 visit). 
Participants who discontinue from the study treatment phase early, will have an early 
termination visit and be asked to return to the clinic 28 (7) days after the final dose of 
study treatment for a safety follow‑up visit.
o
if the early termination visit occurs within 14 days of the last site visit, the list 
of assessments to be performed will be reduced. 
o
If the early termination visit happens more than 14 days after a site visit a 
complete set of assessments needs to be performed. 
See Section 1.3 (Table 2), and Sections 8.1 and 8.2 for further details.
8.10.4
Follow-Up Assessments
After the study completion/early termination visit, AEs should be followed as outlined in 
Sections 8.3.1 and 8.3.3.
8.10.5
Assessments at Unscheduled Visits
Please see Section 1.3 for activities that are required to be performed in case of an 
unscheduled visit. Assessments (e.g., for safety or for PK/PD sampling purpose) 
performed in case of an unscheduled visit(s) are at the discretion of the investigator. 
Participants will be instructed to contact the investigator at any time if they have any 
health-related concerns. If warranted, participants will be asked to return to the clinic as 
soon as possible for an unscheduled safety assessment visit. Assessments performed at 
unscheduled safety visits are at the discretion of the investigator. It is recommended to 
perform ocular assessments on both eyes.


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9.
STATISTICAL CONSIDERATIONS
9.1
STATISTICAL HYPOTHESES
Denoted by pk the proportion of participants with ≥ 2 step improvement in ETDRS DRSS 
from baseline at Week 36 measured in the study eye in treatment group k (k = 0 for 
placebo and k = 1, 2, for low, and high dose, respectively), the hypotheses
p0 = pk, k = 1, 2, 
will each be tested at the two-sided 10% level. Due to the exploratory dose finding 
nature of the study no adjustments for multiplicity will be made. Hypothesis testing will 
be performed using the framework of Generalized Estimating Equations (GEE), as it 
takes into account repeated measures within each participant and can provide unbiased 
effect estimates even if the correlation structure between measures is misspecified.
9.2
SAMPLE SIZE DETERMINATION
A total of 135 participants are expected to be randomized 1:1:1 to the three groups 
(45 participants per group). Based on Fisher’s exact test, assuming the proportion of 
participants with ≥2 step improvement in the ETDRS DRSS to be 15% for placebo and 
40% to 45% under active treatment, 40 participants completing the study per group 
provide between 74% and 88% power based on a 2-sided significance level of 0.1. 
Allowing for about 10% of the participants randomized to not complete the study and 
hence not have an assessment of the primary endpoint at week 36, a total of 135 
participants (45 participants per group) was selected to obtain 120 completers. If the rate 
of participants not completing the study is larger than 10%, the sample size may be 
increased beyond 135 participants with the aim of achieving approximately 
45 completers per group. 


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9.3
POPULATIONS FOR ANALYSES
For purposes of analysis, the following populations are defined in Table 6.
Table 6
Analysis Populations
Population
Description
Intent-to-treat
The Intent-to-Treat (ITT) population is defined as all 
participants who give informed consent, are randomized, and 
receive at least one dose of study treatment (active or 
placebo).  For the ITT population, data will be analyzed 
according to the treatment participants were randomized to. 
The ITT population is the primary population of interest. 
Safety
The Safety population is defined as all participants who give 
informed consent, receive at least one dose of study 
medication (active or placebo) and will be grouped according 
to the actual treatment received. The Safety population will be 
used for the analyses of all safety endpoints.
Efficacy
The ITT population will be used for the analyses of all efficacy 
endpoints.
Pharmacokinetic
All participants in the safety population who have data from at 
least one post-dose sample will be included in the PK analysis 
population. Participants will be excluded from the PK analysis 
population if they significantly violate the inclusion or exclusion
criteria, deviate significantly from the protocol, or if data are 
unavailable or incomplete which may influence the PK 
analysis. Excluded cases will be documented together with the 
reason for exclusion. All decisions on exclusions from the 
analysis will be made prior to database closure.
9.4
STATISTICAL ANALYSES
9.4.1
Demographics and Baseline Characteristics
Demographics, baseline characteristics (including subject disposition and medical 
history) and all baseline laboratory values will be summarized descriptively by treatment 
using frequency tables and summary statistics providing means, medians, standard 
deviations, and extreme values.
Definition of baseline: Baseline for all efficacy and safety analyses is defined as the 
last non-missing value recorded prior to or on the first study drug administration.
9.4.2
Efficacy Analyses
For the primary and exploratory efficacy analyses, see Table 7.
All efficacy data will be summarized by randomized treatment group and visit for the ITT 
population.


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Participants in whom any of the events (i) to (iii) described in Section 6.5.3 occur in 
either eye, or participants who require rescue treatment prior to the week 36 assessment 
will still be considered as completing participants and will enter the analysis as non-
responders at the visit at which the event occurs as well as all subsequent visits.
The primary endpoint will be analyzed using GEE with a binomial distribution using a 
logit link function for odds ratios and unstructured covariance. In case of convergence 
issues, an alternative covariance structure will be used. The model will include 
categorical covariates for treatment group, visit, and visit by treatment group interaction 
term.  Also the baseline stratification factors will be added.  Least squares means on the 
probability scale for each treatment group with the corresponding 90% confidence 
intervals and odds ratios relative to the placebo group will be computed for each visit. 
Full details of the statistical analysis will be described in a separate document prior to 
any unmasking of the study.
In accordance with the ITT principle, assessments at all visits will be included in the 
analysis. This includes any assessments made at visits while the participant is on 
randomized study treatment as well as any assessments made at visits after randomized 
study treatment has been terminated.
If visits occur as described in Section 1.3, a response assessment at week 36 will be 
available for all participants. Despite best efforts, there may be missing response 
assessments at week 36 (e.g., for participants withdrawing consent or being lost to 
follow-up). The statistical methodology to deal with missing data will be described in a 
separate technical document prior to any unmasking of the study.
The proposed methodology is known to render unbiased effect estimates only under the 
restrictive missing completely at random assumption (Liang and Zeger, 1986). 
Therefore, if the amount of total missing data (across patients and visits) exceeds 10% 
of all expected data, sensitivity analyses will be carried out (Molenbergs and Verbeke,
2005).


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Table 7
Efficacy Statistical Analysis Methods
Endpoints
Statistical Analysis Methods
Primary
Proportion of participants with ≥2 step 
improvement in ETDRS DRSS from baseline 
at Week 36 measured in the study eye.
Generalized Estimating Equations (GEE) with a 
binomial distribution taking into account repeated 
measures within each participant.
Secondary
Incidence of ASNV, new PDR, new DME, and 
pre-existing DME requiring intervention.
Descriptive summaries of the number, frequency 
and percentage of participants experiencing the 
types of events.
Change from baseline in BCVA at Week 36 in 
the study eye.
Analysis of variance model for longitudinal data 
taking into account repeated measures within 
each participant
Exploratory
Proportion of participants with 2 step 
worsening in ETDRS DRSS from baseline at 
Week 36 measured in the study eye.
GEE with a binomial distribution taking into 
account repeated measures within each 
participant.
Proportion of participants with 3 step 
improvement in ETDRS DRSS from baseline 
measured in both eyes at post-baseline visits.
Analysis performed in subgroup of ITT population 
with bilateral disease.  Modeling will be similar as 
for the primary endpoint.
Proportion of participants with 3 step 
worsening in ETDRS DRSS from baseline 
measured in both eyes at post-baseline visits.
Analysis performed in subgroup of ITT population 
with bilateral disease. Modeling will be similar as 
for the primary endpoint.
Proportion of participants with either a stable 
(± 1 step change), worsened (>1 step 
increase) or improved (<1 step decrease) 
DRSS between week 36 and week 48.
Modeling will be similar as for the primary 
endpoint.


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Table 7
Efficacy Statistical Analysis Methods (cont.)
Change from baseline in participants with DME 
at baseline in:

BCVA (as measured on the ETDRS 
chart at a starting distance of 4 meters) 
at post-baseline visits.

Central subfield thickness on SD-OCT 
at post-baseline visits.
Proportion of participants with absence of signs 
of DME and normalized CST over time
Analysis of variance model for longitudinal data 
taking into account repeated measures within 
each participant.
Change from baseline in Contrast Sensitivity at 
post-baseline visits in the study eye 
(Pelli-Robson, qCSF) or in both eyes (qCSF).
Analysis of variance model for longitudinal data 
taking into account repeated measures within 
each participant.
Change from baseline in LLVA at Week 36 visit 
in the study eye.
Analysis of variance model for longitudinal data 
taking into account repeated measures within 
each participant.
Absolute change from baseline in mean 
threshold and in point-by-point Standard
Automated Perimetry at post-baseline visits.
Analysis of variance model for longitudinal data 
taking into account repeated measures within 
each participant.
PK parameters of RG7774 (and its 
metabolite(s) as appropriate) in plasma and (if 
applicable) in optional aqueous humor.
Descriptive summaries of the PK parameters 
(e.g., Cmax, AUC, etc.) 
Change from baseline in blood levels of 
HbA1c.
Descriptive summaries by treatment group and 
visit
Performance of the advanced analytic tools
Analysis of the exploratory efficacy endpoints 
9.4.3
Safety Analyses
All safety analyses will be based on the safety analysis population according to the 
treatment assigned at randomization. A summary of key safety analyses is provided in 
Table 8 below.


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Table 8
Safety Statistical Analysis Methods
Endpoint
Statistical Analysis Methods
Adverse events
The original terms recorded on the eCRF by the Investigator for adverse 
events will be coded by the Sponsor.  Adverse events will be summarized 
by mapped term and appropriate thesaurus level.
Ocular 
investigations and 
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 listings with flagging of abnormal results. Summary and change 
from baseline in laboratory parameters of clinical significance will be 
provided.
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 by individual listings. In addition, tabular 
summaries will be used for raw values as well as changes from baseline.
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 in summary tables and listings.
9.4.4
Pharmacokinetic Analyses
Analyses will be carried out on the PK analysis population. All pharmacokinetic 
parameters will be presented by listings and descriptive summary statistics (mean, 
standard deviation, coefficient of variation, median, minimum, and maximum) separately 
by group or cohorts.
A nonlinear mixed effects modeling approach will be used to analyze the sparse 
sampling dose-concentration-time data of RG7774 (and its metabolite(s) as appropriate) 
collected in this study. Those data collected may be pooled with data collected in 
previous phase I studies as appropriate to build the pharmacokinetic model. Population 
and individual primary pharmacokinetic parameters (e.g., apparent clearances and 
volumes) will be estimated and the influence of various covariates on these parameters 
will be investigated. Secondary PK parameters such as AUC and Cmax will be derived 
from the individual post-hoc predictions. Graphical exploration of the relationship 
between RG7774 concentrations and DRSS, other selected clinical endpoints, 
biomarkers and safety endpoints may be performed. If indicated by such exploration, 
more formal analyses of the PK/PD relationship using non-linear mixed effects modelling 
method will be undertaken.
Details of the modelling analyses will be described in a Modelling and Simulation 
Analysis Plan. The results of this analysis will be reported in a separate document from 
the Clinical Study Report.




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9.6
SUMMARIES OF CONDUCT OF STUDY
All protocol deviations will be listed. Data for study treatment administration and 
concomitant medication will be summarized and listed. The number of participants who 
were randomized, discontinued and completed the study will be summarized and listed.


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10.
REFERENCES
Aflibercept [Eylea] USPI.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125387lbl.pdf
Behl T, Kaur I, Kotwani A. Role of endocannabinoids in the progression of diabetic 
retinopathy. Diabetes Metab Res Rev. 2016;32:251-259.
Boyer DS. Treatment of Moderately Severe to Severe Nonproliferative Diabetic 
Retinopathy with Intravitreal Aflibercept Injection: 52-Week Results from the Phase 
3 PANORAMA Study. Invest. Ophthalmol Vis. Sci. 2019; 60(9):1731.
Brown DM, Schmidt-Erfurth U, Do DV et al. Intravitreal Aflibercept for Diabetic 
Macular Edema: 100-Week Results From the VISTA and VIVID Studies. 
Ophthalmology 2015;122:2044-2052.
Campochiaro PA, Channa R, Berger BB, et al. Treatment of diabetic macular edema 
with a designed ankyrin repeat protein that binds vascular endothelial growth 
factor: a phase I/II study. Am J Ophthalmol 2013;155:697−704.
Early Treatment Diabetic Retinopathy Study (ETDRS) report number 12. 
Ophthalmology. 1991;98:823-833.
Fong DS, Aiello L, Gardner TW. Retinopathy in diabetes. Diabetes Care. 2004:27 
(Suppl. 1): S84(7).
Gella L, Raman R, Pal SS. Contrast sensitivity and its determinants in people with 
diabetes. SN-DREAMS-II. Report No. 6. Eye (Lond). 2017;31:460-66.
Gruden G, Barutta F, Kunos G, et al. Role of endocannabinoid system in diabetes and 
diabetic complications. British Journal of Pharmacology. 2016;173: 1116-1127.
Hellgren KJ, Agardh E, Bengtsson B. Progression of early retinal dysfunction in diabetes 
over time: results of a long-term prospective clinical study. Diabetes. 
2014;63:3104–3111 | DOI: 10.2337/db13-1628.
RO6868847 Investigator’s Brochure.
Ip MS, Domalpally A, Hopkins JJ. Long-term effects of ranibizumab on diabetic 
retinopathy severity and progression. Arch Ophthalmol. 2012 Sep;130(9):1145-52.
Ip MS, Domalpally A, Sun JK. Long-term effects of therapy with ranibizumab on diabetic 
retinopathy severity and baseline risk factors for worsening retinopathy. 
Ophthalmology 2015;122:367-374. 
Ip MS, Zhang J, Ehrlich JS. The Clinical Importance of Changes in Diabetic Retinopathy 
Severity Score. Ophthalmology. 2017 May;124(5):596-603.
Joltikov KA, de Castro VM, Davila JR, et al. Multidimensional Functional and Structural 
Evaluation Reveals Neuroretinal Impairment in Early Diabetic Retinopathy. Invest. 
Ophthalmol Vis. Sci. 2017; Sept;58: BIO277-BIO290.


RG7774—F. Hoffmann-La Roche Ltd
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Klein TW. Cannaboid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol. 
2005; 5:400-11.
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.
Lee R, Wong TY, Sabanayagam C, et al. Epidemiology of diabetic retinopathy, diabetic 
macular edema and related vision loss. Eye and Vision (2015) 2:17.
Liang KY, Zeger SL. Longitudinal data analysis using generalized linear models. 
Biometrika 1986;73:13-22.
Linnemann, B, Voigt W, Nobel W, et al. C-reactive protein is a strong independent 
predictor of death in type 2 diabetes: association with multiple facets of the 
metabolic syndrome. Exp Clin Endocrinol Diabetes. 2006;114(3): 127-134.
Maurya N, Velmurugan BK. Therapeutic application of cannabinoids. Chemico-Biological 
Interactions. 2018; 293: 77-88
Mesquida M, Drawnel F, Fauser S. The role of inflammation in diabetic eye disease. 
Semin Immunopathol. 2019; Jul;41(4):427-445.
Molenberghs G, Verbeke G. Simple methods, direct likelihood, and weighted 
generalized estimating equations. In: Molenberghs G, Verbeke G, editors. Models 
for Discrete Longitudinal Data. New York: Springer Series in Statistics. 2005; 489-
509.
Nair P, Aiello LP, Gardner TW, et al. Report From the NEI/FDA Diabetic Retinopathy 
Clinical Trial Design and Endpoints Workshop. Invest. Ophthalmol Vis. Sci.
2016;Oct 1;57(13):5127-5142.
Owsley C, McGwin G Jr, Scilley K, et al. Development of a questionnaire to assess 
vision problems under low luminance in age-related maculopathy. Invest 
Ophthalmol Vis Sci. 2006;47(2):528–535.
Ranibizumab [Lucentis] USPI 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125156s105lbl.pdf
Schmidt-Erfurth U, Garcia-Arumi J, Bandello F, et al, for the Management of Diabetic 
Macular Edema by the European Society of Retina Specialists (EURETINA). 
Ophthalmologica 2017;237:185–222.
Semeraro F et al. Diabetic Retinopathy, a vascular and inflammatory diseases: 
Therapeutic implications. Diabetes Metab. 2019 Apr 18. pii: S1262-
3636(19)30062-X (article in press).
Simó-Servat O, Simó R, Hernández C. Circulating Biomarkers of Diabetic Retinopathy: 
An Overview Based on Physiopathology. Journal of Diabetes Research. 2016; 
Article ID 5263798, 13 pages.
Soethoudt M, Grether U, Fingerle J, et al. Cannabinoid CB2 receptor ligand profiling 
reveals biased signalling and off-target activity. Nat Commun. 2017; 8:13958.


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Sun JK, Wang P-W, Taylor S, et al, Durability of Diabetic Retinopathy Improvement with 
As-Needed Ranibizumab: open-label extension of RIDE and RISE studies. 
Ophthalmology 2019; 126:712-720.
Topol EJ, Bousser MG, Fox KA, et al. Rimonabant for prevention of cardiovascular 
events (CRESCENDO): a randomised, multicentre, placebo-controlled trial. Lancet 
2010;376:517-23.
Willis JR, Chia Y, Morse LS, Rich WL, et al. Treatment patterns for diabetic macular 
edema in the United States: analysis of the IRISRegistry (Intelligent Research in 
Sight) [abstract]. Presented at the Annual Meeting of the American Academy of 
Ophthalmology; New Orleans, LA. Nov 2017; 1114.
Wong TW et al, Ophthalmology. 2018; 125(10):1608-1622. 
Yao, Y, Li R, Du J, et al. Tumor necrosis factor-and diabetic retinopathy: Review and 
meta-analysis. Clinica Chimica Acta. 2018;485 210-217.
Zoja C, Locatelli M, Corna D, et al. Therapy with a Selective Cannabinoid Receptor Type 
2 Agonist Limits Albuminuria and Renal Injury in Mice with Type 2 Diabetic 
Nephropathy. Nephron. 2016;132(1):59-69.


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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
The following section includes standard appendices such as 

Appendix 1 (Regulatory, Ethical and Study Oversight Considerations),

Appendix 2 (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, and 
     Vitreous Haze)

Appendix 7 (Grading Scale for Vitreous Hemorrhage)


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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 ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. 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 ICFs, any information to be given to the participant (e.g. 
advertisements, diaries etc), and relevant supporting information must be submitted to 
the IRB/EC by the Principal Investigator and reviewed and approved by the IRB/EC 
before the study is initiated. In addition, any 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 adverse events (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.
1.3.
INFORMED CONSENT
The Sponsor’s Master Informed Consent Form (and ancillary sample ICFs such as a 
Child’s Assent or Caregiver's Informed Consent Form, if applicable) will be provided to 
each site. If applicable, it will be provided in a certified translation of the local language. 
Participants must be informed that their participation is voluntary. Participants 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/IEC or study center. The Sponsor 


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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.
The Consent Forms must be signed and dated by the participant 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 Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the 
participant to take part. The final revised IRB/EC-approved Consent Forms must be 
provided to the Sponsor for Health Authority submission purposes if required as per local 
regulations.
Participants must be re-consented to the most current version of the Consent Forms (or 
to a significant new information/findings addendum in accordance with applicable laws 
and IRB/EC policy) during their participation in the study. For any updated or revised 
Consent Forms, the case history or clinical records for each participant shall document 
the informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the participant. All signed and 
dated Consent Forms must remain in each participant’s 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 28 days from the previous ICF signature date.
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR. The investigator or authorized designee will explain to each 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 eCRF.


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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 Consent Form 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 Informed Consent Form 
by each site's Institutional Review Board or Ethics Committee (IRB/EC) and, if 
applicable, an appropriate regulatory body. If a site has not been granted approval for 
RBR sampling, this section of the protocol will not be applicable at that site
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 trial 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 trial is closed. A participant's withdrawal from Study BP41321 
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 
BP41321. 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. 


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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 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.
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 the Sponsor’s 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 Informed Consent Form (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 policy of the Sponsor 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 Roche, except where agreed otherwise.


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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 
Informed Consent Form. 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 Roche. The site will permit monitoring, audits, IRB/EC 
review, and Health Authority inspections by providing direct access to source data and 
documents related to the 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 
course of the study and for one year after completion of the study (i.e., LPLO).
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 electronic CRF 
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 eCRF.
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
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 eCRF 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.


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2.1.2.
Clinical Outcome Assessment Data
2.1.2.2.
Paper Clinical Outcome Assessment Data
Paper booklets will be used to capture COA data. The data from the questionnaires will 
be entered into the EDC system by site staff. All original forms on which participants 
records responses are source documentation as described in Section 2.1.3. of this 
Appendix.
2.1.3.
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, COAs (paper or eCOA), 
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 trial.
Before study initiation, data to be entered directly into the eCRFs (i.e., no prior written or 
electronic record of the data) and considered source data must be defined in the Trial 
Monitoring Plan.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described 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.
2.1.4.
Use of Computerized Systems
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with Health Authority requirements pertaining to computerized systems used 
in clinical research. An acceptable computerized data collection system allows 
preservation of the original entry of data. If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change.
2.1.5.
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 


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study. In addition, safety biomarker data will not inform decisions on participant 
management.
2.1.6.
Patient Engagement Mobile Application
The Patient Engagement Mobile Application (PEMA) Smartphone app is an optional 
service that participants can opt-in to use to remind them of activities or tasks relevant to 
the study like when to take their study treatment or attend clinical site visits. The app 
also provides supportive guides to help volunteers be aware of visit procedures, study 
information and any study related supportive instructions. Reminders are delivered to the 
participants via push notifications to encourage them to continue their participation and 
comply with the study. The features of PEMA include the following modules:

Information: targeted important and useful information related to study that can be 
accessed by participants any time throughout the duration of the study.

Tasks: inform study participants about what they need to do via a daily to do list. 
Once a task has been completed, participants can mark it as done.

Schedule: is predefined based on planned site visits according to the study 
schedule of assessments. Reminders related to upcoming visits are sent to 
participants to plan for visits and upcoming tasks.

Achievements: are awarded to participants for completing assigned tasks or 
activities.

Contacts: participants can enter site contacts details for primary investigator, study 
coordinator etc.
The app is available for download to smartphone devices that support iOS or Android. 
The app will contain study-specific information only once activated by a participant. The
study coordinator will provide the participant with a secure activation code, which they 
can use to activate the app upon their first use. The App does not collect any participant 
identifiable information or clinical data. This app is intended for informational purposes 
only. It is not a substitute for professional medical advice. Participants should contact the 
study site Investigator or coordinator with any medical questions or concerns.
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.


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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.
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. 
The Sponsor shall also submit an Annual Safety Report once a year to the IEC and CAs 
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
A description of this clinical trial will be available at http://www.ClinicalTrials.gov.
2.3.4.
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
3.3.
INTERNAL MONITORING COMMITTEE (IMC) AND SCIENTIFIC 
OVERSIGHT COMMITTEE (SOC)
The IMC consists of a selected subset of the Sponsor’s representatives including 
Statistician, Safety Representative and Clinical Science Representative. The SOC 
includes independent external experts with relevant experience in the field. The IMC 
Chair may approve other individuals to get access to the unmasked reports or unmasked 
participant level data if this is required for the IMC and SOC to make an assessment. 
Additional the Sponsor’s representatives might be unmasked to produce/process the 
unmasked listing/data to be reviewed by the IMC and SOC. The IMC and SOC will 
review safety data on an ad-hoc basis. The SOC will function as a consultative body to 
the Sponsor, providing individual expert opinions. The Sponsor retains all decision 
making authority for this study. More details of the role and remit of the IMC and SOC 
will be described in a separate IMC and SOC agreement. Access to treatment 
assignment information will follow the Sponsor’s standard procedures.
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 AEs in this or other studies indicates a potential health 
hazard to participants.

Participant enrollment is unsatisfactory.
The Sponsor will notify the Investigator and Health Authorities if the study is placed on 
hold, or if the Sponsor decides to discontinue the study or development program.
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.


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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 ICH guideline for Good Clinical Practice, an adverse event (AE) is 
any untoward medical occurrence in a participant or clinical investigation subject 
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, X-ray) 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 pre-existing condition, including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though they may have been present before the start of the study.

AEs that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (e.g., screening invasive procedures such as 
biopsies).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE unless the progression is unexpectedly accelerated and 
not in line with the natural history of the disease. If the “Lack of efficacy” would not 
require safety reporting such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy will be reported as AE or SAE if they fulfill the definition of an AE or SAE.
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.


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
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).

Anticipated day-to-day fluctuations of pre-existing 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 pre-existing 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.

Is sight-threatening: an AE is considered to be sight-threatening and should be 
reported expeditiously if it meets one or more of the following criteria:


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–
Causes a decrease of 30 letters in VA score (compared with the last 
assessment of VA prior to the most recent assessment) lasting more than 
1 hour. 
–
Requires surgical or medical intervention (i.e., conventional surgery, vitrectomy, 
vitreous tap or biopsy with IVT injection of anti-infective treatments, or laser or 
retinal cryopexy with gas or a medication) to prevent permanent loss of sight
–
Is associated with severe intraocular inflammation (i.e., endophthalmitis, 
Grade 4anterior chamber cells/flare; see Appendix 6 for intraocular grading 
scales).

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 
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, or development of drug dependency 
or drug abuse.
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 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 sponsor. 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 sponsor.
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.


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3.1.
ASSESSMENT OF 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 pre-defined grading 
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. 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).
Serious adverse events are required to be reported by the Investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event).
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, where 
applicable.

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.
For participant receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.


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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 sponsor 
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.
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 
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:

SAEs

AESIs

Pregnancies (see Section 8.3.5)
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 SAEs to the local Health 
Authority and IRB/EC.


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5.1
REPORTING REQUIREMENTS OF SERIOUS ADVERSE
EVENTS AND 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 Serious 
Adverse Event/Adverse Event of Special Interest Reporting 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 and AESIs (Section 8.3.6) that occur after initiation of study 
treatment (Section 8.3.1; from Day 1 to Week 36) and including the safety follow-up 
period of 4 weeks (from Week 36 to Week 40), 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 electronic data capture (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 Serious Adverse Event/Adverse 
Event of Special Interest Reporting 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 Off-Treatment Observational Period and Post-Study Adverse Events 
and Serious Adverse Events
If the Investigator becomes aware of any other SAEs occurring during the observational 
off-treatment period after the end of the AE reporting period (study-treatment period + 28 
days after final dose of study treatment) or after the study ends, the event should be 
reported if it is believed to be related to prior study treatment. The report must be 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 OVERDOSE, 
MEDICATION ERROR, DRUG ABUSE, OR DRUG MISUSE
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(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

Intentional overdose: intentional administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.

Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm

Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse
In cases where drug is to be self-administered by the participant, drug misuse 
could involve the drug being administered to someone other than the 
participant.
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. 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 RG7774 and 
placebo, 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.

Intentional overdose:  Enter the AE term. Check the "Intentional overdose" box. If 
drug abuse is suspected, check the "Drug abuse" box. If drug abuse is not 
suspected, check the "Drug misuse" box.

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. 

Drug abuse that does not qualify as an overdose:  Enter the AE term. Check the 
"Drug abuse" box.

Drug abuse that qualifies as an overdose: Enter the AE term. Check the "Intentional 
overdose" and "Drug abuse" boxes.

Drug misuse that does not qualify as an overdose:  Enter the AE term. Check the 
"Drug misuse" box.


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
Drug misuse that qualifies as an overdose:  Enter the AE term. Check the 
"Intentional overdose" and "Drug misuse" boxes.
In addition, all special situations associated with RG7774 and placebo 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.

Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term. Check the "Intentional overdose" box. If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box.

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.

Drug abuse that does not qualify as an overdose: Enter the drug name and "drug 
abuse" as the event term. Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose: Enter the drug name and "intentional 
overdose" as the event term. Check the "Intentional overdose" and "Drug abuse" 
boxes.

Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term. Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose: Enter the drug name and "intentional 
overdose" as the event term. Check the "Intentional overdose" and "Drug misuse" 
boxes.

Drug administered to someone other than the participant: Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box.
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.


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6.
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all SAEs and AESIs 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 document for RG7774:

Investigator’s Brochure
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 AEs on 
the Adverse Event eCRF. Avoid colloquialisms and abbreviations.
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 AE report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis.
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 


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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).

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.


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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.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high BP), only the diagnosis (i.e., hypertension) should be recorded on the 
Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
6.
ABNORMAL LIVER FUNCTION TESTS
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury. 
Therefore, investigators must report as an AE the occurrence of either of the following:

Treatment-emergent ALT or AST3ULN in combination with total 
bilirubin 2ULN.

Treatment-emergent ALT or AST3ULN in combination with clinical jaundice.
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Appendix 2) and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event), either as an SAE or an AESI (see Section 8.3.6).
7.
DEATHS
All deaths that occur during the protocol-specified AE 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. 


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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").
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.
LACK OF EFFICACY OR WORSENING OF DIABETIC 
RETINOPATHY
Medical occurrences or symptoms of deterioration that are anticipated as part of diabetic 
retinopathy 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 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 retinopathy”).
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 


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
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:

Hospitalization for an AE that would ordinarily have been treated in an outpatient 
setting had an outpatient clinic been available.
11.
PATIENT-REPORTED OUTCOME DATA (COA DATA 
REPORTED DIRECTLY BY PATIENT)
Adverse event reports will not be derived from patient-reported outcome (PRO) data by 
the Sponsor, and safety analyses will not be performed using PRO data. Sites are not 
expected to review the PRO data for AEs. 


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Appendix 4
Clinical Laboratory Tests
The tests detailed in Table 1 will be performed by the central laboratory. For the local 
laboratory results, the results must be captured in source documentation and entered 
into the eCRF. Local laboratory results are only required in the event that the central 
laboratory results are not available in time for either study treatment administration 
and/or response evaluation. If a local sample is required, it is important that the sample 
for central analysis is obtained at the same time. Additionally, if the local laboratory 
results are used to make either a study treatment decision or response evaluation, the 
results must be captured in source documentation and entered as a comment into the 
eCRF.
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.


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Table 1
Protocol-Required Safety Laboratory Assessments
All study-required laboratory assessments will be performed by a central laboratory.
Laboratory Assessments
Parameters
Hematology

Leukocytes, erythrocytes, hemoglobin, hematocrit, 
platelets, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes).
Blood Chemistry

Sodium, potassium, chloride, bicarbonate, glucose, 
urea, creatinine, protein, albumin, phosphate, 
calcium, total and direct bilirubin, ALT, AST, ALP, 
BUN, CRP, CPK, HbA1c.
Coagulation

INR, aPTT, PT.
Viral Serology

HIV (specific tests HIV-1 antibody, HIV-1/2 
antibody, HIV-2 antibody), hepatitis B surface 
antigen (HBsAg), total hepatitis B core antibody 
(HBcAb), hepatitis B DNA hepatitis C virus (HCV) 
antibody, hepatitis C RNA.
Lipids

Cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides.
Thyroid Hormones

Thyroid stimulating hormone (TSH)
Hormones

Follicle-stimulating hormone (FSH; in females).
Pregnancy Test

Urine human chorionic gonadotropin (hCG) 
pregnancy test (as needed for women of 
childbearing potential).
Urinalysis

Specific gravity

Albumin concentration, creatinine concentration, 
and ratio (albumin/creatinine).

Dipstick: pH, glucose, protein, blood, ketones, 
albumin.

If there is a clinically significant positive result 
(confirmed by a positive repeated sample), urine 
will be sent to the 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 (RBCs, WBCs, casts, 
crystals, epithelial cells, bacteria), if blood or 
protein is abnormal.
Other Screening Tests

Urine alcohol and drug screen (to include at 
minimum: amphetamines, barbiturates, cocaine, 
opiates, cannabinoids and benzodiazepines).
Investigators must document their review of each laboratory safety report.


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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 lab tests. 
In this scenario, the Sponsor’s standard reference ranges, rather than the reference 
ranges of the Investigator, can be used for specific parameters. For these parameters, 
the measured laboratory test result will be assessed directly using the Sponsor’s 
standard reference range. Certain laboratory parameters will be transformed to 
Sponsor’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 Sponsor’s 
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 Sponsor 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 
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 Guidance and Collection of Pregnancy 
Information
1.
DEFINITIONS

Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
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.
2.
CONTRACEPTION GUIDANCE

Female Participants
Female participants of childbearing potential are eligible to participate if they agree to 
use highly effective method of contraception consistently and correctly as described in 
Table 1 below.
Per ICH 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.


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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-Independent
(Failure rate of 1% per year)

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationa

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion/ ligation
Vasectomized partner
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.
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 spermicide b

Cap, diaphragm or sponge with spermicide b
a) Hormonal contraception may be susceptible to interaction with the 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.


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3.
PREGNANCY TESTING
For WOCBP enrolled in the study, urine pregnancy tests will be performed according to 
Schedule of Activity tables (see Section 1.3). 
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

Male participants with partners who become pregnant
The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study 
(see Section 8.3.5 Pregnancy). This applies only to male participants who receive 
RG7774.
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male participant exposed to study treatment. The 
Investigator will record pregnancy information on the Clinical Trial Pregnancy Reporting 
Form and submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. 
When permitted by the site, the pregnant partner would need to sign an Authorization for 
Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy. If the authorization has been signed, the Investigator should update the 
Clinical Trial Pregnancy Reporting Form with additional information on the course and 
outcome of the pregnancy when available. An Investigator who is contacted by the male 
participant or his pregnant partner may provide information on the risks of the pregnancy 
and the possible effects on the fetus, to support an informed decision in cooperation with 
the treating physician and/or obstetrician. The female partner will be followed to 
determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to the Sponsor. Monitoring of the participant’s partner should 
continue until conclusion of the pregnancy. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.

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 appropriate 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.


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While pregnancy itself is not considered to be an AE or SAE, and should not be 
recorded on the Adverse Event eCRF, any pregnancy complication will be reported as 
an AE or SAE. A spontaneous 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. 
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 embryo-fetal toxicity should also 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; 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 or female 
partner of a male 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
Reference: 
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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Appendix 6
Grading Scale for Assessment of Anterior Chamber Cells or 
Flare, and Vitreous Haze (cont.)
Grading Scale for Vitreous Haze
Score
Description
0
No evident vitreal 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
Reference:
Nussenblatt RB, Palestine AG, Chan CC, Roberge F. Standardization of vitreal inflammatory 
activity in intermediate and posterior uveitis. Ophthalmology. 1985;92(4):467-71.


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Appendix 7
Grading Scale for Vitreous Hemorrhage
Grading Scale for Vitreous Hemorrhage
None (0)
Retina is visible.
1
Retinal detail is visible; some hemorrhage is visible by ophthalmoscopy.
2
Large retinal vessels are visible, but central retinal detail is not visible by 
ophthalmoscopy.
3
Red reflex is visible, but no central retinal detail is seen posterior to the equator 
by ophthalmoscopy.
4
No red reflex by ophthalmoscopy.
Reference:
Nussenblatt RB, Whitcup SM, Palestine AG. Uveitis. Fundamentals and clinical practice. 2nd 
rev.ed. New York: Mosby, 1996, p. 64.