A 96-week, Two-arm, Randomized, Single-masked, Multi-center, Phase III Study Assessing the Efficacy and Safety of Brolucizumab 6 mg Compared to Panretinal Photocoagulation Laser in Patients With Proliferative Diabetic Retinopathy
Phase: PHASE3
Conditions: Proliferative Diabetic Retinopathy
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development 
RTH258 
Clinical Trial Protocol CRTH258D2301 / NCT04278417 
A 96-week, two-arm, randomized, single-masked, multi-
center, phase III study assessing the efficacy and safety of 
brolucizumab 6 mg compared to panretinal 
photocoagulation laser in patients with proliferative 
diabetic retinopathy (CONDOR) 
Document type: 
Amended Protocol Version 
EUDRACT number: 
N/A 
Version number: 
02 (Clean) 
Clinical Trial Phase: 
III 
Release date: 
28-Sep-2021
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 2.0 (01-Aug-2018) 

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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 8 
Amendment 2 28-Sep-2021 ............................................................................................... 10 
Amendment 1 05-Jun-2020 ............................................................................................... 12 
Protocol summary .............................................................................................................. 14 
1 
Introduction ....................................................................................................................... 18 
1.1 
Background ............................................................................................................ 18 
1.2 
Purpose .................................................................................................................. 20 
2 
Objectives and endpoints ................................................................................................... 20 
3 
Study design ...................................................................................................................... 21 
4 
Rationale ............................................................................................................................ 23 
4.1 
Rationale for study design ..................................................................................... 23 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 24 
4.3 
Rationale for choice of comparator treatment ....................................................... 25 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 25 
4.5 
Risks and benefits .................................................................................................. 25 
5 
Population .......................................................................................................................... 26 
5.1 
Inclusion criteria .................................................................................................... 26 
5.2 
Exclusion criteria ................................................................................................... 27 
6 
Treatment ........................................................................................................................... 29 
6.1 
Study treatment ...................................................................................................... 29 
6.1.1 
Investigational drug ............................................................................... 29 
6.1.2 
Comparator treatment ............................................................................ 29 
6.1.3 
Additional study treatments .................................................................. 29 
6.1.4 
Treatment arms/group ........................................................................... 30 
6.1.5 
Treatment duration ................................................................................ 30 
6.2 
Other treatment(s) .................................................................................................. 30 
6.2.1 
Concomitant therapy ............................................................................. 30 
6.2.2 
Prohibited medication ........................................................................... 31 
6.3 
Subject numbering, treatment assignment, randomization .................................... 32 
6.3.1 
Subject numbering ................................................................................ 32 
6.3.2 
Treatment assignment, randomization .................................................. 32 
6.4 
Treatment masking ................................................................................................ 33 

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6.5 
Dose escalation and dose modification .................................................................. 33 
6.6 
Additional treatment guidance ............................................................................... 34 
6.6.1 
Treatment compliance ........................................................................... 34 
6.7 
Preparation and dispensation ................................................................................. 34 
6.7.1 
Handling of study treatment .................................................................. 34 
6.7.2 
Instruction for administering study treatment ....................................... 35 
7 
Informed consent procedures ............................................................................................ 37 
8 
Visit schedule and assessments ......................................................................................... 38 
8.1 
Screening ............................................................................................................... 43 
8.1.1 
Information to be collected on screening failures ................................. 43 
8.2 
Subject demographics/other baseline characteristics ............................................. 43 
8.3 
Efficacy .................................................................................................................. 44 
8.3.1 
Visual acuity .......................................................................................... 44 
8.3.2 
Color fundus photography and fluorescein angiography ...................... 44 
8.3.3 
Optical coherence tomography ............................................................. 45 
 
 46 
8.3.5 
Appropriateness of efficacy assessments .............................................. 46 
8.4 
Safety ..................................................................................................................... 47 
8.4.1 
Vital sign assessments ........................................................................... 47 
8.4.2 
Laboratory evaluations .......................................................................... 47 
8.4.3 
Pregnancy .............................................................................................. 48 
8.4.4 
Intraocular Pressure ............................................................................... 48 
8.4.5 
Ophthalmic examination ....................................................................... 48 
8.4.6 
Appropriateness of safety measurements .............................................. 49 
8.5 
Additional assessments .......................................................................................... 50 
8.5.1 
Clinical Outcome Assessments (COAs) ............................................... 50 
9 
Study discontinuation and completion .............................................................................. 51 
9.1 
Discontinuation ...................................................................................................... 51 
9.1.1 
Discontinuation of study treatment ....................................................... 51 
9.1.2 
Withdrawal of informed consent ........................................................... 52 
9.1.3 
Lost to follow-up ................................................................................... 53 
9.1.4 
Early study termination by the sponsor ................................................. 53 
9.2 
Study completion and post-study treatment .......................................................... 53 
10 Safety monitoring and reporting ........................................................................................ 54 
10.1 
Definition of adverse events and reporting requirements ...................................... 54 
10.1.1 
Adverse events ...................................................................................... 54 
10.1.2 
Serious adverse events .......................................................................... 55 

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10.1.3 
SAE reporting........................................................................................ 56 
10.1.4 
Pregnancy reporting .............................................................................. 57 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 57 
10.2 
Additional Safety Monitoring ................................................................................ 57 
11 Data Collection and Database management ...................................................................... 58 
11.1 
Data collection ....................................................................................................... 58 
11.2 
Database management and quality control ............................................................ 58 
11.3 
Site monitoring ...................................................................................................... 59 
12 Data analysis and statistical methods ................................................................................ 59 
12.1 
Analysis sets .......................................................................................................... 60 
12.2 
Subject demographics and other baseline characteristics ...................................... 60 
12.3 
Treatments ............................................................................................................. 60 
12.4 
Analysis of the primary endpoint(s) ...................................................................... 61 
12.4.1 
Definition of primary endpoint(s) ......................................................... 61 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 61 
12.4.3 
Handling of missing values/censoring/discontinuations ....................... 63 
12.4.4 
Sensitivity and supplementary analyses ................................................ 66 
12.5 
Analysis of secondary endpoints ........................................................................... 66 
12.5.1 
Efficacy endpoints ................................................................................. 66 
12.5.2 
Safety endpoints .................................................................................... 67 
 
 68 
12.7 
Interim analyses ..................................................................................................... 68 
12.8 
Sample size calculation .......................................................................................... 69 
12.8.1 
Primary endpoint(s) ............................................................................... 69 
12.8.2 
Secondary endpoint(s) ........................................................................... 69 
13 Ethical considerations and administrative procedures ...................................................... 70 
13.1 
Regulatory and ethical compliance ........................................................................ 70 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 70 
13.3 
Publication of study protocol and results............................................................... 70 
13.4 
Quality Control and Quality Assurance ................................................................. 70 
14 Protocol adherence ............................................................................................................ 71 
14.1 
Protocol amendments ............................................................................................. 71 
15 References ......................................................................................................................... 72 
16 Appendices ........................................................................................................................ 74 

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List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 20 
Table 6-1 
Investigational drug ............................................................................... 29 
Table 6-2 
Prohibited medications and surgical procedures ................................... 31 
Table 8-1 
Assessment Schedule ............................................................................ 39 
Table 8-2 
Laboratory assessments ......................................................................... 47 
Table 10-1 
Guidance for capturing the study treatment errors ................................ 57 
Table 12-1 
Primary, key secondary and supplementary estimands ......................... 64 
Table 12-2 
Power for primary endpoint .................................................................. 69 
List of figures 
Figure 3-1 
Study design .......................................................................................... 22 
Figure 6-1 
Treatment schedule (example) .............................................................. 37 
 

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List of abbreviations 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
AR 
Analysis restriction 
ATC 
Anatomical therapeutic chemical 
BCVA 
Best corrected visual acuity 
CFP 
Color fundus photography 
CFR 
Code of federal regulation 
CI 
Confidence interval  
CMH 
Cochran-Mantel-Haenszel 
COA 
Clinical outcome assessment 
COVID-
19 
Coronavirus disease-2019 
CRC 
Central reading center 
CRO 
Contract Research Organization 
CSFT 
Central sub-field thickness 
DM 
Diabetes mellitus 
DME 
Diabetic macular edema 
DR 
Diabetic retinopathy 
DRSS 
Diabetic retinopathy severity scale 
eCRF 
Electronic case report/record form 
EDC 
Electronic data capture 
EOS 
End of study 
EOT 
End of treatment 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
Fluorescein angiography 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
HbA1c 
Glycosylated hemoglobin A1c 
IB 
Investigator's brochure 
ICF 
Informed consent 
ICH 
International Council for Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
IEC 
Independent ethics committee 
IOI 
Intraocular inflammation 
IOP 
Intraocular pressure 
IRB 
Institutional review board 
IRT 
Interactive response technology 
IVT 
Intravitreal 
LOCF 
Last observation carried forward 
MedDRA 
Medical dictionary for regulatory activities 
mg 
milligram(s) 
mL 
milliliter(s) 

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nAMD 
neovascular age-related macular degeneration 
 
 
NIH 
National Institutes of Health 
OCT 
Optical coherent tomography 
 
 
PD 
Protocol deviation 
PDR 
Proliferative diabetic retinopathy 
PFS 
Prefilled syringe 
 
 
PPS 
Per protocol set 
 
 
PRP 
Panretinal photocoagulation 
q12w 
Every 12 weeks 
q6w 
Every 6 weeks 
q8w 
Every 8 weeks 
QoL 
Quality of life 
RBC 
Red blood cell(s) 
 
 
RO 
Retinal vascular occlusion 
RV 
Retinal vasculitis 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
scFv 
Single-chain antibody fragment 
SD 
Standard deviation 
SD-OCT 
Spectral domain optical coherence tomography  
SGOT 
Serum glutamic oxaloacetic transaminase 
GPT 
Serum glutamic pyruvic transaminase 
SUN 
Standardization of uveitis nomenclature  
SUSAR 
Suspected unexpected serious adverse reaction 
USM 
Urgent Safety Measures 
VEGF 
Vascular endothelial growth factor 
VEGFR 
VEGF receptor 
VF 
Visual function 
 
 
WBC 
White blood cell(s) 
WFCFP 
Wide field color fundus photography 
WHO 
World Health Organization 

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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Cohort 
A specific group of subjects fulfilling certain criteria 
Dosage 
Dose of the study treatment given to the subject in a time unit (e.g. 
100 mg once a day, 75 mg twice a day) 
Electronic data capture 
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical 
laboratory interfaces. EDC includes the use of Electronic Case 
Report Forms (eCRFs) which are used to capture data transcribed 
from paper source forms used at the point of care. 
Enrollment 
Point/time of subject entry into the study at which informed consent 
must be obtained (i.e. prior to starting any of the procedures 
described in the protocol) 
Estimand 
As defined in the ICH E9(R1) addendum, estimand is a precise 
description of the treatment effect reflecting the clinical question 
posed by the trial objective. It summarizes at a population-level 
what the outcomes would be in the same participants under 
different treatment conditions being compared. Attributes of an 
estimand include the population, variable (or endpoint) and 
treatment of interest, as well as the specification of how the 
remaining intercurrent events are addressed and a population-level 
summary for the variable. 
Intercurrent events 
Events occurring after treatment initiation that affect either the 
interpretation or the existence of the measurements associated with 
the clinical question of interest. 
Investigational drug 
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and Directive 
2001/20/EC and is synonymous with “investigational new drug” or 
“test substance” 
Investigational treatment 
All investigational drug(s) whose properties are being tested in the 
study as well as their associated treatment controls. This includes 
any placebos, any active controls, as well as approved drugs used 
outside of their indication/approved dosage or tested in a fixed 
combination. Investigational treatment generally does not include 
other treatments administered as concomitant background therapy 
required or allowed by the protocol when used within approved 
indication/dosage. 
Medication number 
A unique identifier on the label of each study drug package in 
studies that dispense study drug using an IRT system. 
Patient 
An individual with the condition of interest for the study 
Period 
A minor subdivision of the study timeline; divides phases into 
smaller functional segments such as screening, baseline, titration, 
washout, etc. 

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Premature subject 
withdrawal 
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and assessments; at this 
time all study drug administration is discontinued and no further 
assessments are planned. 
Randomization 
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine 
the assignments in order to reduce bias. 
Randomization number 
A unique identifier assigned to each randomized subject, 
corresponding to a specific treatment arm assignment 
Re-screening 
If a participant fails the initial screening and is considered as a 
Screen Failure, he/she can be invited once for a new Screening visit 
after medical judgment and as specified by the protocol 
Screen Failure 
A subject who is screened but is not treated or randomized 
Source Data/Documentation 
Source data refers to the initial record, document, or primary 
location from where data comes. The data source can be a 
database, a dataset, a spreadsheet or even hard-coded data, such 
as paper. 
Study completion 
Point/time at which the subject came in for a final evaluation visit or 
when study drug was discontinued whichever is later. 
Study drug discontinuation 
Point/time when subject permanently stops taking study drug for 
any reason; may or may not also be the point/time of premature 
subject withdrawal. 
Study treatment 
Any drug administered to the study participants as part of the 
required study procedures; includes investigational drug (s), 
control(s) or non-investigational medicinal product(s) 
Study treatment 
discontinuation 
When the subject permanently stops taking study treatment prior to 
the defined study treatment completion date 
Subject 
A trial participant (can be a healthy volunteer or a patient) 
Subject number 
A number assigned to each subject who enrolls in the study. When 
combined with the center number, a unique identifier is created for 
each subject in the study. 
Variable (or endpoint) 
The variable (or endpoint) to be obtained for each participant that is 
required to address the clinical question. The specification of the 
variable might include whether the participant experiences an 
intercurrent event. 
Withdrawal of study consent 
(WoC)/ Opposition to use of 
data /biological samples 
Withdrawal of consent from the study occurs when the participant 
explicitly requests to stop use of their data and biological samples 
(opposition to use data and biological samples) AND no longer 
wishes to receive study treatment, AND does not agree to further 
protocol required assessments. This request should be in writing 
(depending on local regulations) and recorded in the source 
documentation. 
Opposition to use data/biological samples occurs in the countries 
where collection and processing of personal data is justified by a 
different legal reason than consent. 

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Amendment 2 28-Sep-2021  
Amendment rationale  
The main purpose of this amendment is to implement the Urgent Safety Measures (USM) 
described in the 10-Aug-2021 Dear Investigator Letter (DIL) into the study protocol.  The USM 
were implemented for ongoing studies not achieving Last Patient Last Visit (LPLV) by 11-Aug-
2021 and in response to the identification of a causal immune-mediated mechanism of the 
previously identified risk of retinal vasculitis (RV), and/or retinal vascular occlusion (RO), 
typically in the presence of intraocular inflammation (IOI) indicating a requirement to 
discontinue treatment in patients who develop events of RV and/or RO. 
This amendment also includes information on gender imbalance on IOI following brolucizumab 
treatment and recommendations on the time window for a study subject to receive the 
COVID-19 vaccine or vitrectomy.  Some other administrative changes have also been 
incorporated. 
Changes to the protocol 
Protocol sections changed in relation to this emerging safety measure are: 
• 
Section 1.1 Background: Information added to describe Urgent Safety Measures 
• Section 4.5 Risk and benefits: Information added to describe Urgent Safety Measures and 
additional information on gender imbalance on IOI following brolucizumab treatment 
• Section 6.7.2 Instruction for administering study treatment: Requirement of treatment 
discontinuation was added if subject developed RV and/or RO, in both arms. 
• Section 8.4.5 Ophthalmic examination: Requirement of treatment discontinuation was 
added if subject developed RV and/or RO. 
• Section 9.1.1 Discontinuation of study treatment: Requirement of treatment 
discontinuation was added if subject developed RV and/or RO. 
Other changes incorporated in this amendment 
• The glossary of terms has been updated to the latest template wording 
• Section 6.2.1.1 Permitted concomitant therapy requiring caution and/or action: added 
recommendations on the time window for a study subject to receive the COVID-19 
vaccine or vitrectomy. 
• Use of prohibited treatment (see Section 6.2.2) 
• Section 8.4.3 Pregnancy: Correction for inconsistency. Requirement to apply the same 
pregnancy testing in both arms, throughout the study (see also Table 8-1). 
• Section 9.1.2 Clarified the definition of Withdrawal of Consent (WoC). 
• Other minor clarifications and corrections were made where applicable. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strikethrough red font for deletions and red underlined for insertions. 

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IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation.  
The changes herein affect the Informed Consent.  Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.  
 
 

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Amendment 1 05-Jun-2020  
Amendment rationale  
The main purpose of this amendment is to provide clarification and guidance on safety 
assessments in accordance to the urgent safety measure regarding the post-marketing reports 
with brolucizumab (Beovu®) in the treatment of nAMD, which were identified as retinal 
vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular 
inflammation, that may result in severe vision loss.  In addition, the amendment includes the 
modifications due to COVID-19 pandemic. 
Changes to the protocol 
Protocol sections changed in relation to this emerging safety issue are: 
• Section 1.1 Background: Information was added to describe new safety signal from post-
marketing case reports and its impact on the benefit-risk balance. 
• Section 6.7.2 Instructions for prescribing and taking study treatment: Additional guidance 
was added to this section emphasizing that if any sign of intraocular inflammation is 
present, an IVT injection must not be performed and patients should be treated for IOI 
according to clinical practice. 
• Additional examination and assessments included to fully characterize cases of intraocular 
inflammation were made in the following sections: 
• Table 8-1 Assessment schedule 
• Section 8.3.2 Color fundus photography and fluorescein angiography 
• Section 8.4 Safety 
• Section 8.4.5 Ophthalmic examination 
• Section 8.4.6 Appropriateness of safety measurements 
Changes incorporated in this amendment regarding the COVID-19 pandemic: 
• Section 5.2 Exclusion criteria 
• Section 6.2.2 Prohibited medication 
• Section 7 Informed Consent Procedures 
• Section 8 Visit Schedule and Assessments 
• Section 8.4 Safety 
• Section 8.4.2 Laboratory evaluation 
• Section 12 Data Analysis and statistical methods 
Other changes incorporated in this amendment: 
• Title Page:  Added approved study bird nickname. 
• Section 3 Study Design:  Protocol clarification regarding the window definition of the 
Baseline/Day 1 visit window and timing of EOS visit for early study discontinuation. 
• Section 5.2 Exclusion Criteria:  Protocol clarification regarding exclusion criteria Number 
8, 13 and Number 20. 

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• Section 6.3.1 Subject numbering:  To ensure protocol consistency with Section 8.1. 
• Section 6.4 Treatment masking: Clarification of masking language to accurately describe 
the masked study personnel for this protocol.  
• Section 7 Informed Consent procedures:  Clarification the timeframe of acceptable FA 
images can be used prior to the Screening Visit.  
• Section 8.1 Screening:  Clarification the timeframe of acceptable FA images can be used 
prior to the Screening Visit and clarification regarding a one-time reassessment of a 
subject. 
 
 
• Section 8.4.4 Ophthalmic examination: Post-injection IOP measurement timing was 
updated from approximately 30-60 minutes to read within 60 minutes. 
• Section 8.5.1 Clinical Outcome Assessments (COAs):  
 
 
• Section 10.1.3 SAE reporting:  The reporting period is clarified. 
• Section 12 Data analysis and statistical methods:  Clarification per ICH E9 (R1) 
guidelines. 
• Table 12-1 Primary, key secondary and supportive estimands:  clarified terms 
• Section 15 References 
• List of Abbreviations  
• Other minor clarifications were made where applicable. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
 
 IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation.  
The changes herein affect the Informed Consent.  Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.  

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Protocol summary 
Protocol 
number 
CRTH258D2301 
Full Title 
A 96-week, two-arm, randomized, single-masked, multi-center, phase III study 
assessing the efficacy and safety of brolucizumab 6 mg compared to panretinal 
photocoagulation laser in patients with proliferative diabetic retinopathy 
(CONDOR) 
Brief title 
Study of efficacy and safety of brolucizumab versus panretinal photocoagulation 
laser in patients with proliferative diabetic retinopathy 
Sponsor and 
Clinical Phase 
Novartis 
Phase III 
Investigation 
type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
To evaluate the efficacy and safety of brolucizumab compared to panretinal 
photocoagulation laser (PRP) in patients with proliferative diabetic retinopathy 
(PDR). 
Primary 
Objective(s) 
To demonstrate that brolucizumab is non-inferior to PRP with respect to the 
change from Baseline in visual acuity at Week 54 by assessing the change from 
Baseline in best corrected visual acuity (BCVA) at Week 54 
Secondary 
Objectives 
To demonstrate that brolucizumab is superior to PRP in reducing diabetic 
retinopathy (DR) severity after 54 weeks of treatment by assessing the proportion 
of subjects with no PDR at Week 54 
To demonstrate that brolucizumab is superior to PRP in preventing the 
development of center-involved diabetic macular edema (DME) up to Week 54 by 
assessing the proportion of subjects with center-involved DME up to Week 54 
To compare the effect of brolucizumab relative to PRP with respect to visual 
acuity by assessing the area under the curve in change from Baseline in BCVA up 
to Week 54 and Week 96 
To compare the effect of brolucizumab relative to PRP on DR status by assessing 
the change from Baseline in ETDRS diabetic retinopathy severity scale (DRSS) 
score at Week 54 and Week 96 and the proportion of subjects with no PDR at 
Week 96 
To compare the effect of brolucizumab relative to PRP on ocular complications by 
assessing the proportion of subjects developing vision-threatening complications 
associated with DR up to Week 54 and Week 96 and the proportion of subjects 
with center-involved DME up to Week 96 
To assess the safety and tolerability of brolucizumab relative to PRP 
Study design 
The study is a 96-week, two-arm, randomized, single-masked, multi-center, 
active-controlled, non-inferiority study in patients with proliferative diabetic 
retinopathy (PDR). 
Subjects who meet all the inclusion and none of the exclusion criteria will be 
randomized in a 1:1 ratio to one of the two treatment arms: 
• 
Brolucizumab 6 mg: 3 x q6w loading then q12w maintenance through Week 
90, with the option from Week 48 onwards to extend the treatment interval by 
6 weeks at a time up to 24 weeks. 
• 
PRP: initial treatment in 1-4 sessions up to Week 12, followed with additional 
PRP treatment (may split into 2-4 sessions) as needed up to Week 90. 

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Population 
Approximately 941 adult patients will be screened (25% screen failure rate 
expected) and approximately 706 patients (353 per arm, 15% dropout rate 
expected) will be randomized in a 1:1 ratio in approximately 180 centers 
worldwide. The maximum study duration for one subject is 99 weeks, including 
Screening and post-treatment follow-up. 
Key Inclusion 
criteria 
• 
Signed informed consent must be obtained prior to participation in the study. 
• 
Patients ≥ 18 years of age at Screening. 
• 
Participant cooperation sufficient for adequate fundus photographs and retinal 
images. 
• 
Patients diagnosed with diabetes mellitus (DM) type 1 or 2, and HbA1c 
≤  12% at Screening. 
• 
Any medication administered for the management of diabetes should be 
stable within 3 months prior to randomization and is expected to remain 
stable during the course of the study, as medically acceptable.  
• 
PDR in the study eye as assessed by the investigator using standard or wide-
field color fundus photography (CFP) and fluorescein angiography (FA), with 
no evidence of previous PRP, and that requires treatment with either anti-
Vascular Endothelial Growth Factor (VEGF) agent or PRP in the opinion of 
the investigator. 
• 
BCVA ≥ 34 ETDRS letters (Snellen equivalent 20/200) in the study eye at 
Screening and Baseline. 
Key Exclusion 
criteria 
• 
Concomitant conditions or ocular disorders in the study eye at Screening or 
Baseline as well as planned medical/surgical intervention during the first 54-
week study period that could compromise functional or structural response to 
study treatment, in the opinion of the investigator 
• 
Presence of center-involved DME in the study eye at Screening or Baseline, 
as assessed by the investigator. 
• 
Other ocular conditions in the study eye: 
• 
Any active intraocular or periocular infection or active intraocular 
inflammation (IOI) at Screening or Baseline. 
• 
Uncontrolled glaucoma in defined as intraocular pressure (IOP) > 25 
mmHg despite treatment with IOP lowering medication, or according to 
investigator’s judgment, at Screening or Baseline. 
• 
Iris or anterior chamber angle neovascularization, or neovascular 
glaucoma. 
• 
Moderate or dense pre-retinal or vitreous hemorrhage that prevents clear 
visualization of the macular and / or optic disc or prevents PRP treatment 
at Baseline. 
• 
Significant fibrovascular vitreoretinal proliferation or tractional retinal 
detachment. 
• 
Presence of amblyopia, amaurosis or ocular disorders in the fellow eye with 
BCVA < 20/200 at screening (except when due to conditions for which 
treatment or surgery may improve VA). 
• 
Ocular treatments in the study eye: 
• 
PRP any time prior to Baseline. 
• 
Intravitreal anti-VEGF treatment within six months prior to Baseline. 
• 
Vitreoretinal surgery at any time prior to Baseline or anticipated need for 
vitreoretinal surgery within the next 12 months. 
• 
Laser treatment of the macula within 3 months prior to Baseline.  

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• 
Treatment with fluocinolone acetonide intravitreal implant at any time 
prior to Baseline. Other intraocular or periocular corticosteroid injection 
within 6 months prior to Baseline. 
• 
Intraocular surgery within 3 months prior to Baseline or anticipated need 
for cataract extraction within the next 12 months. 
• 
Systemic conditions or treatments: stroke or myocardial infarction during the 
6-month period prior to baseline, end stage renal disease requiring dialysis or 
renal transplant, systemic anti-VEGF therapy at any time. 
Study 
treatment 
Brolucizumab 6 mg 
Panretinal photocoagulation 
Efficacy 
assessments 
BCVA using ETDRS-like chart 
ETDRS DRSS score based on 7-field CFP 
Anatomical markers based on spectral domain optical coherence tomography 
(SD-OCT) 
Key safety 
assessments 
Adverse event monitoring 
Ocular examinations 
Vital signs 
Monitoring of laboratory biomarkers (hematology, clinical chemistry, urinalysis) 
and pregnancy 
Other 
assessments 
 
 
 
 
Wide field CFP 
FA 
 
Data analysis 
The objective related to the primary endpoint is to demonstrate non-inferiority of 
brolucizumab versus PRP with respect to the change from Baseline in BCVA at 
Week 54, assuming a non-inferiority margin of 4 ETDRS letters. The primary 
estimand is defined as the between-treatment difference in change from Baseline 
in BCVA at Week 54, excluding the confounding effect of alternative 
DR/DME treatment(s) applied to the study eye. 
The hypothesis will be tested via an analysis of covariance (ANCOVA) 
model. The model will include treatment, baseline DR Severity category, age 
category, and region as factors, with baseline BCVA as a covariate. The two-
sided 95% confidence interval (CI) for the least square mean difference 
(brolucizumab - PRP) at Week 54 will be presented. Non-inferiority will be 
considered established if the lower limit of the corresponding 95% CI is greater 
than -4 letters. 
Superiority hypothesis for the primary endpoint may be further evaluated after 
non-inferiority for the primary endpoint and superiority for the first key secondary 
endpoint are established. 
The objective related to first key secondary endpoint is to demonstrate superiority 
of brolucizumab versus PRP with respect to increasing the proportion of subjects 
with no PDR at Week 54. It will be tested via Cochran-Mantel-Haenszel (CMH) 
test at a one-sided significance level of 0.025, after non-inferiority for the primary 
endpoint is established. 

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The objective related to the other key secondary endpoint is to demonstrate 
superiority of brolucizumab versus PRP with respect to reducing the proportion of 
subjects with center-involved DME up to Week 54. It will be tested via CMH test at 
a one-sided significance level of 0.025, after superiority is established for both 
primary endpoint and first key secondary endpoint.  
Summary statistics will be presented by treatment arm unless otherwise specified. 
Key words 
Proliferative diabetic retinopathy, retinal neovascularization, anti-VEGF, 
brolucizumab, intravitreal injection, panretinal photocoagulation 

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1 
Introduction 
1.1 
Background 
Diabetes mellitus (DM) is a global epidemic disease with significant morbidity and mortality 
in both developing and developed countries that was estimated to affect 451 million adults 
worldwide in 2017, with the numbers expected to rise to more than 690 million in 2045 
(Cho et al 2018). diabetic retinopathy (DR) is a common and microvascular complication of 
DM and remains the leading cause of preventable blindness in working-age people 
(Cheung et al 2010, Whitehead et al 2018). The two major sight-threatening complications of 
DR are diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). In 2010, 
DR accounted for 2.6% of all blindness and 1.9% of all moderate and severe vision impairment 
worldwide (Leasher et al 2016).  PDR is the end stage in the natural history of DR. The main 
pathological pathway involved is a severe hypoxia from retinal capillary closure, which leads 
to an increase in levels of the angiogenic vascular endothelial growth factor (VEGF) and retinal 
neovascularization (Wong et al 2016).  The new retinal vessels are fragile and prone to 
bleeding.  As they also tend to grow into the vitreous, they can be associated with retinal 
detachment and vitreous hemorrhage, which are vision-threatening complications. 
Treatment options for PDR include panretinal photocoagulation (PRP), anti-VEGF agents, and 
vitrectomy (Wong et al 2018). Vitrectomy is essentially reserved for cases of non-clearing 
vitreous hemorrhage or traction retinal detachment threatening or involving the macula. 
PRP has been the standard of care for PDR for over 40 years; it reduces the risk of severe visual 
loss by 50% or more (Diabetic Retinopathy Study Research Group 1981). However, PRP is a 
destructive procedure that is associated with permanent sequelae on visual function; these 
include final visual acuity below driving standards, peripheral visual field loss that precludes 
driving, night vision difficulties, loss of color vision, and reduced contrast sensitivity, as well 
as 
exacerbated 
macular 
edema 
(ETDRS Research Group 1991, 
Brucker et al 2009, 
Preti et al 2013, Subash et al 2016). Therefore, there is an unmet need for novel treatments that 
reduce the risk of severe visual loss in PDR while causing fewer adverse events. Anti-
VEGF therapies have recently demonstrated superior outcomes compared to PRP, both in terms 
of visual acuity (Sivaprasad et al 2017, Lang et al 2019) and peripheral visual field 
(Gross et al 2015, Sivaprasad et al 2017). Furthermore, anti-VEGF agents were associated with 
a reduction in emergent macular edema as well as vision-threatening complications of PDR, 
compared to PRP (Gross et al 2015, Sivaprasad et al 2017, Lang et al 2019). 
Brolucizumab 
Brolucizumab (RTH258, formerly known as ESBA1008), is a humanized single-chain antibody 
fragment (scFv) inhibitor of VEGF-A with a molecular weight of ~26 kDa. Brolucizumab binds 
to the receptor-binding site of the VEGF-A molecule, thereby preventing the interaction of 
VEGF-A with its receptors VEGFR1 and VEGFR2 on the surface of endothelial cells 
(Escher et al 2015). Brolucizumab is designed for ophthalmic use and is administered by 
intravitreal (IVT) injection. In this setting, the smaller molecular weight of the scFv is expected 
to have advantages over immunoglobulin G antibodies and larger antibody fragments due to the 
delivery of a higher molar dose (i.e. VEGF binding equivalents per mg protein), which may 
prolong the therapeutic effect, assuming comparable ocular half-lives and potency, and enable 
better tissue penetration at the retina. 

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In two large Phase III pivotal studies (RTH258-C001 [HAWK] and RTH258-C002 
[HARRIER]), neovascular Age-related Macular Degeneration (nAMD) subjects received 
brolucizumab every 12 weeks (q12w), with the option of adjusting to an 8-week dosing interval 
(q8w) based on disease activity, or aflibercept q8w, after three monthly loading 
doses.  Brolucizumab was non-inferior to aflibercept with regards to change from Baseline in 
best corrected visual acuity (BCVA) at Week 48, with over half of the subjects in the 
brolucizumab 6 mg arm maintained exclusively on the q12w dosing interval (56% in HAWK 
and 51% in HARRIER) (Dugel et al 2019).  The visual acuity gains observed in the first year 
were maintained in the second year. Significantly fewer subjects in the brolucizumab 6 mg arm 
had disease activity at Week 16 in a head-to-head comparison based on matched dosing 
intervals, with a relative decrease of 30% versus aflibercept (P = 0.0022). Significantly fewer 
subjects on brolucizumab had intraretinal fluid (IRF) and/or subretinal fluid (SRF), with a 35% 
and 33% reduction relative to aflibercept at Week 16 in HAWK and HARRIER, respectively 
(P < 0.001 for both), and a 31% and 41% reduction relative to aflibercept at Week 48 in HAWK 
and HARRIER, respectively (P < 0.0001 for both). Brolucizumab 6 mg achieved superior 
reductions in central subfield thickness (CSFT) versus aflibercept in both the matched dosing 
and maintenance phases (P = 0.0016 and P = 0.0023 at Week 16 and Week 48, respectively, in 
HAWK; P < 0.0001 at both Week 16 and Week 48 in HARRIER). These advantages for 
brolucizumab were maintained in the second year. Safety was comparable between the 
treatment arms over two years. 
Brolucizumab for PDR 
Ranibizumab, aflibercept, and brolucizumab all inhibit VEGF-A, a key mediator of retinal 
neovascularization and PDR. Both ranibizumab and aflibercept have demonstrated efficacy and 
safety in the treatment of subjects with PDR. These findings support the evaluation of 
brolucizumab in patients with PDR. 
The improved efficacy of anti-VEGF therapies in PDR subjects compared to the standard of 
care PRP and the efficacy profile of brolucizumab in nAMD subjects signal the potential for 
brolucizumab to differentiate from PRP in terms of reduction in DR severity as well as decrease 
in the rate of ocular complications, including emergent center-involved macular edema, with 
visual acuity outcomes at least comparable to PRP. 
There remains a need for anti-VEGF medicines with extended therapeutic durability that could 
support longer intervals between visits and treatment administration compared to current 
pharmaceutical options. The durability profile of brolucizumab in nAMD subjects, whose 
majority was maintained on a 12-week treatment interval in the first year of treatment, points 
to a potential for brolucizumab to address treatment and visit burden and warrants the concept 
of visit frequency every 6 weeks and the evaluation of treatment intervals up to 24 weeks. 
These considerations advocate the initiation of a Phase III clinical program to evaluate the 
efficacy and safety of brolucizumab in the treatment of patients with PDR, with the objective 
to evaluate the potential to improve therapeutic outcomes compared to the current standard of 
care, while minimizing treatment burden for subjects. 
Since the first marketing authorization approval in October 2019 for the treatment of nAMD, 
adverse events of retinal vasculitis (RV) and/or retinal vascular occlusion (RVO), that may 
result in severe vision loss and typically in the presence of intraocular inflammation, have been 

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reported from post-marketing experience with brolucizumab (Beovu®). Results of the 
mechanistic study BASICHR0049 on blood samples from nAMD patients exposed to 
brolucizumab and having subsequently developed retinal vasculitis and/or retinal vascular 
occlusion, taken together with accumulated data from HAWK, HARRIER and MERLIN, 
regarding the association of treatment-emergent immunogenicity and IOI, indicate a causal link 
between the treatment-emergent immune reaction against brolucizumab and the brolucizumab-
related retinal vasculitis and/or retinal vascular occlusion, typically in the presence of IOI. 
Considering the incidence of these events is uncommon, the overall risk/benefit assessment 
remains positive. 
1.2 
Purpose 
The purpose of this study is to evaluate the efficacy and safety of brolucizumab compared to 
PRP in subjects with PDR. 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To demonstrate that brolucizumab is non-
inferior to PRP with respect to the change 
from Baseline in visual acuity at Week 54 
• 
Change from Baseline in BCVA at Week 54 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To demonstrate that brolucizumab is 
superior to PRP in reducing diabetic 
retinopathy severity at Week 54 
• 
Proportion of subjects with no PDR at Week 
54  
• 
To demonstrate that brolucizumab is 
superior to PRP in preventing the 
development of center-involved DME up to 
Week 54 
• 
Proportion of subjects with center-involved 
DME up to Week 54 
• 
To compare the effect of brolucizumab 
relative to PRP with respect to visual acuity 
• 
Area under the curve in change from 
Baseline in BCVA up to Week 54 and Week 
96 
• 
To compare the effect of brolucizumab 
relative to PRP on diabetic retinopathy 
status 
• 
Change from Baseline in ETDRS Diabetic 
Retinopathy Severity Scale (DRSS) score at 
Week 54 and Week 96 
• 
Proportion of subjects with no PDR at Week 
96 
• 
To compare the effect of brolucizumab 
relative to PRP on ocular complications 
• 
Proportion of study eyes developing vision-
threatening complications associated with 
diabetic retinopathy up to Week 54 and 
Week 96 
• 
Proportion of subjects with center-involved 
DME up to Week 96 
• 
To assess the safety and tolerability of 
brolucizumab relative to PRP 
• 
Incidence of ocular and non-ocular adverse 
events (AE) up to Week 54 and Week 96 

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Objective(s) 
Endpoint(s) 
3 
Study design 
The study is a 96-week, two-arm, randomized, single-masked, multi-center, active-controlled, 
non-inferiority study in subjects with PDR. 
Subjects who consent will undergo screening assessments to evaluate their eligibility based on 
the inclusion and exclusion criteria. Subjects who meet all the inclusion and none of the 
exclusion criteria will be randomized in a 1:1 ratio to one of the following treatments (Figure 
3-1): 
• Brolucizumab 6 mg: 3 x q6w loading then q12w maintenance through Week 90, with the 
option from Week 48 onwards to extend the treatment interval by 6 weeks at a time up to 
24 weeks. 
• PRP: initial treatment in 1-4 sessions up to Week 12, followed with additional PRP 
treatment (may split into 2-4 sessions) as needed up to Week 90. 
Visits will occur every 6 weeks throughout the study, regardless of treatment or not. 
Approximately 941 adult subjects will be screened (25% screen failure rate expected) and 
approximately 706 subjects (353 per arm, 15% dropout rate expected) will be randomized in a 

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1:1 ratio in approximately 180 centers worldwide. The maximum study duration for one subject 
is 99 weeks, including Screening and post-treatment follow-up. 
There will be 3 periods in this study (see Figure 3-1): 
• Screening period: from Day -21 to Baseline (Day 1) 
• Single-masked treatment period: from Baseline (Day 1) to Week 90 (End-of-Treatment) 
• Post-treatment follow-up period: from Week 90 to Week 96 (End-of-Study). 
Figure 3-1 
Study design 
  
DAA: Disease activity assessment 
Screening period: Day -21 to Day -1 
Subjects will be screened for enrollment into the study at the Screening visit. The screening 
period may last up to 3 weeks to assess eligibility. Further details are provided in 
Section 8.1. The assessment of the PDR status will be carried out by the investigator at the 
Screening visit. The Central Reading Center (CRC) will not be involved in the assessment of 
the PDR status and the subject's eligibility during the Screening period. Only one study eye can 
be selected per subject. 
Single-masked treatment period: Day 1 to Week 90 
After confirmation of eligibility at the Baseline visit, defined as Baseline / Day 1, subjects will 
be randomized in a 1:1 ratio to one of the treatment arms. A study visit schedule will be 
established at the time of randomization for all subjects. All efforts should be made to adhere 
to this study visit schedule within a ±7‑day window (except Baseline / Day 1). For a given 
protocol visit, assessments can be performed on two consecutive days, provided both days are 
within the visit window. Treatment is intended to be administered on the day of study visit, or 

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if this is not possible, within 3 days after the study visit when the per-protocol assessments will 
have taken place. 
For all subjects, the last potential study treatment will be at the Week 90 visit.   
Brolucizumab arm: 
Loading phase (Baseline / Day 1 to Week 12): Subjects will receive three consecutive injections 
every 6 weeks at Baseline, Week 6 and Week 12 during the loading phase. 
Maintenance phase (Week 18 to Week 90): Subjects will then receive q12w injections in the 
maintenance phase. Additional assessment visits are planned for disease monitoring, not for 
treatment administration; however, injections may be administered at these visits if disease 
worsens, at the investigator’s discretion. After Week 48, the treatment interval may be extended 
by 6 weeks at a time, up to 24 weeks, at the investigator’s decision based on the assessment of 
diabetic retinopathy disease activity. The investigator may opt to revert to q12w injections if 
disease worsens. Further details are provided in Section 6.7.2. 
PRP arm: 
Subjects in the PRP arm will receive an initial treatment at Baseline / Day 1. The initial 
treatment may be split into 2-4 sessions up to Week 12, as per local clinical practice. Additional 
PRP may be performed in the study eye from Week 18 during the course of the study if disease 
worsens and may be split into 2-4 sessions, at the investigator’s discretion, according to local 
clinical practice.  
Post-treatment follow-up period: Week 90 to Week 96 
For all subjects completing the study, the End-of-Study (EOS) assessment will be performed at 
Week 96, six weeks (±7 days) following their last possible study treatment administration 
(Week 90). 
Subjects withdrawn from the study prior to study completion should be asked to return for an 
early discontinuation (EOS) visit. If study withdrawal occurred less than six weeks after the last 
study treatment, the EOS visit should take place at least six weeks following their last study 
treatment administration. 
4 
Rationale 
4.1 
Rationale for study design 
The study is designed as a 96-week, two-arm, randomized, single-masked, multi-center, active-
controlled, non-inferiority study to evaluate the efficacy and safety of brolucizumab compared 
to PRP in subjects with PDR. 
Because of the difference in the mode of administration of brolucizumab (the investigational 
drug) and PRP (the comparator treatment), the duration of the two procedures, and the visible 
scars resulting from PRP on color fundus photography (CFP), subjects as well as the evaluating 
and treating investigators will not be masked to treatment. However, at each site, BCVA 
 
 assessments will be carried out by masked certified personnel. Retinal 
images, e.g. 7-Field CFP and spectral domain optical coherence tomography (SD-OCT), will 
also be evaluated by masked independent readers at the CRC. 

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The primary efficacy endpoint is based on BCVA assessed by masked certified personnel. The 
change from baseline in BCVA at a selected time point has been used as primary endpoint in 
prior 
studies 
comparing 
anti-VEGF 
agent 
and 
PRP 
in 
subjects 
with 
PDR 
(Gross et al 2015, Sivaprasad et al 2017) as well as in studies evaluating brolucizumab in 
subjects with DME (RTH258B2301; RTH258B2302). The BCVA assessment has its own 
variability and, generally in the clinical practice, a change of BCVA > 5 letters would be 
considered as clinically relevant regardless of the underlying disease. In this study, non-
inferiority testing related to this primary efficacy parameter will be based on a margin of 4 
letters. This non-inferiority margin provides assurance that any proof of non-inferiority only 
occurs if the observed treatment differences are of no clinical relevance. 
The first key secondary endpoint will be based on the ETDRS DRSS score assessed on 7-Field 
CFP by independent readers masked to the study treatment, the study visit, and the investigator's 
disease activity assessment. The proportion of subjects with no PDR as defined by a DRSS 
score < 61 after 54 weeks of treatment will allow the assessment of the relative effectiveness of 
the study treatments in reducing the severity of diabetic retinopathy to non-proliferative stage. 
The primary analysis will be conducted after approximately one year of treatment (Week 54), 
in agreement with other non-inferiority studies in retinal vascular diseases, including diabetic 
macular edema and retinopathy, in which the primary endpoint is based on BCVA. The 54-
week duration is deemed long enough to evaluate the efficacy and safety of both study 
treatments. 
4.2 
Rationale for dose/regimen and duration of treatment 
The dose and regimen for brolucizumab are based on the following considerations: 
• Based on the Phase III brolucizumab studies in nAMD (RTH258-C001 - HAWK and 
RTH258-C002 - HARRIER studies), both brolucizumab 3 mg and/or 6 mg doses showed 
comparable functional efficacy and safety profiles to aflibercept, with numerical advantages 
related to efficacy for the 6 mg dose, compared to the 3 mg dose. 
• The dosing regimen comprises a loading phase of three injections followed by a 
maintenance phase of q12w injections in the first year of treatment, and the option of fewer 
treatments in the second year by extending the treatment interval up to 24 weeks. The 
estimated minimum of 6 injections in the first year and 2-3 injections in the second year are 
consistent with the treatment needs of subjects with PDR and no center-involved DME in 
prior studies with other anti-VEGF treatments (Gross et al 2015, Sivaprasad et al 2017, 
Lang et al 2019), in which visual acuity was at least preserved or even improved from 
Baseline, and a higher proportion of subjects were PDR-free after one or two years of 
treatment, when compared to PRP. 
• The 6 mg dose of brolucizumab administered is intended to provide a prolonged duration 
of action. The increase of 30 days to 75 days in the median time to retreatment in nAMD 
subjects initially treated with brolucizumab 6 mg vs ranibizumab 0.5 mg in the SEE study 
(RTH258-C10-083) as well as the positive nAMD Phase III study results regarding the 
q12w/q8w regimen in HAWK and HARRIER support stretching the minimum interval 
between injections to 6 weeks. 
• The route of administration is an intravitreal injection as for all anti-VEGF treatments 
currently approved for the treatment of retinal diseases, including DR. 

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Study duration of 96 weeks allows assessing the long-term efficacy and safety of brolucizumab 
and PRP in subjects with PDR. 
4.3 
Rationale for choice of comparator treatment 
Brolucizumab 6 mg will be compared to PRP laser. PRP has been the standard of care for the 
treatment 
of 
PDR 
worldwide 
for 
more 
than 
40 
years 
(Diabetic Retinopathy Study Research Group 1981, Moutray et al 2018), including the USA 
where Lucentis® and Eylea® have been recently approved for the treatment of DR. No anti-
VEGF agents have been approved for the treatment of PDR in other countries participating in 
the study. 
4.4 
Purpose and timing of interim analyses/design adaptations 
The primary analysis will be conducted when all ongoing subjects have completed their Week 
54 visit. Subjects will remain in the study and will continue to receive treatment through the 
planned duration of the treatment period up to Week 90, to allow for further evaluation of 
efficacy and safety. Treatment masking of individual subjects will remain in effect for the 
masked personnel at the sites and CRC until the final database lock has occurred. 
4.5 
Risks and benefits 
The risk to subjects in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring.  
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and must agree that in 
order to participate in the study they must adhere to the contraception requirements outlined in 
the exclusion criteria. If there is any question that the subject will not reliably comply, they 
should not be entered or continued in the study. 
The approved VEGF-A inhibitors ranibizumab and aflibercept have consistently demonstrated 
efficacy in VEGF-driven retinal pathologies, including PDR, with benefits outweighing the 
risks. Assuming an anti-VEGF class-effect, one can expect that the novel anti-
VEGF brolucizumab, which is approved in the USA for the treatment of nAMD, will likely 
demonstrate a favorable benefit / risk profile in PDR subjects.  
Intravitreal injections, including those with brolucizumab, have been associated with 
endophthalmitis and retinal detachments. Acute intraocular pressure (IOP) increases have also 
been reported.  Retinal vasculitis and/or vascular occlusion, typically in the presence of IOI 
have been reported following brolucizumab injection. These immune mediated adverse events 
may occur following the first intravitreal injection. Discontinuation of study treatment is 
required in subjects who develop these events. In addition, subjects who experience IOI may 
be at risk of developing retinal vasculitis and/or retinal vascular occlusion and should be closely 
monitored. 
Based on clinical studies, IOI related adverse events, including retinal vasculitis and retinal 
vascular occlusion, were reported more frequently in female patients treated with brolucizumab 
than male patients (e.g. 5.3% females vs. 3.2% males in HAWK and HARRIER, Novartis data 
on file).  

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Overall, brolucizumab was well tolerated in clinical studies with nAMD subjects when 
treatment interval is not less than every 8 weeks after the first 3 monthly initial doses (loading 
phase). The risk/benefit assessment for brolucizumab remains positive.  
PRP is still the standard of care and has a positive effect on the severity of DR. However, PRP 
is a destructive procedure and can reduce peripheral and night vision. In addition, it can 
transiently or permanently reduce central vision. Rarely, it can cause transient increase in IOP. 
In some cases, retrobulbar or peribulbar injection may be used to anesthetize the eye and to 
reduce eye movements during the administration of PRP, which may have potential rare 
complications. 
In view of the outcomes of recent trials comparing anti-VEGF agents and PRP in PDR subjects, 
subjects entering this trial may benefit from treatment with brolucizumab via better preservation 
of peripheral and central vision compared to PRP. In addition, brolucizumab may be more 
efficient than PRP in reducing the severity of DR and decreasing the risk of vision-threatening 
complications due to the disease as well as the risk of developing DME. 
Further details of the known and potential risks and benefits associated with brolucizumab are 
presented in the Investigator's Brochure (IB). 
5 
Population 
The study population will be adult male and female patients with type 1 or type 2 DM diagnosed 
with PDR, with no evidence of prior PRP in the study eye, and able to comply with study 
procedures. 
Assuming a 25% screening failure rate, approximately 941 patients will be screened and 
approximately 706 (353 per arm, 15% dropout rate expected) patients will be randomized in a 
1:1 ratio in approximately 180 centers worldwide. 
If both eyes are eligible as per the inclusion and exclusion criteria described below, the eye with 
the worse visual acuity should be selected as the study eye, unless the investigator deems it 
more appropriate to select the eye with better visual acuity, based on medical reasons or local 
ethical requirements. 
5.1 
Inclusion criteria 
Subjects eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study. 
2. Patients ≥ 18 years of age at Screening. 
3. Participant cooperation sufficient for adequate fundus photographs and retinal images. 
4. Patients diagnosed with type 1 or 2 DM, and HbA1c ≤ 12% at Screening. 
5. Any medication administered for the management of DM should be stable within 3 
months prior to randomization and is expected to remain stable during the course of the 
study, as medically acceptable.  
Study eye 

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6. PDR as assessed by the investigator using standard or wide-field CFP and FA, with no 
evidence of previous PRP, and that requires treatment with either anti-VEGF or PRP in 
the opinion of the investigator. 
7. BCVA ≥ 34 ETDRS letters (Snellen equivalent 20/200) at Screening and Baseline. 
5.2 
Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in this study. 
Ocular conditions 
1. Concomitant conditions or ocular disorders in the study eye at Screening or Baseline as 
well as planned medical/surgical intervention during the first 54-week study period that 
could compromise functional or structural response to study treatment, in the opinion of 
the investigator. 
2. Presence of center-involved diabetic macular edema in the study eye at Screening or 
Baseline, as assessed by the investigator. 
3. Any active intraocular or periocular infection or active intraocular inflammation (e.g. 
infectious conjunctivitis, keratitis, scleritis, infectious blepharitis, uveitis) in the study eye 
at Screening or Baseline. 
4. Uncontrolled glaucoma in the study eye defined as IOP > 25 mmHg despite treatment 
with IOP-lowering medication, or according to investigator’s judgment, at Screening or 
Baseline. 
5. Moderate or dense pre-retinal or vitreous hemorrhage that prevents clear visualization of 
the macular and /or optic disc or prevents PRP treatment in the study eye at Baseline. 
6. Significant fibrovascular vitreoretinal proliferation or tractional retinal detachment of the 
study eye. 
7. Iris or anterior chamber angle neovascularization, or neovascular glaucoma in the study 
eye. 
8. Presence of amblyopia, amaurosis, or ocular disorders in the fellow eye with BCVA 
< 20/200 at Screening (except when due to conditions for which treatment or surgery may 
improve VA, e.g. cataract). 
Ocular treatments in the study eye 
9. PRP any time prior to Baseline. 
10. Intravitreal anti-VEGF treatment within 6 months prior to Baseline. 
11. Vitreoretinal surgery at any time prior to Baseline or anticipated need for vitreoretinal 
surgery within the next 12 months. 
12.  Laser treatment of the macula within 3 months prior to Baseline.  
13. Treatment with fluocinolone acetonide intravitreal implant (e.g. ILUVIEN® or 
RETISERT®) at any time prior to Baseline. Other intraocular or periocular corticosteroid 
injection within 6 months prior to Baseline. 
14. Aphakia with the absence of posterior capsule. 
15. Intraocular surgery within 3 months prior to Baseline or anticipated need for cataract 
extraction within the next 12 months. 
Non-ocular conditions and treatments 

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16. Stroke or myocardial infarction during the 6-month period prior to baseline. 
17. End stage renal disease requiring dialysis or renal transplant. 
18. Uncontrolled blood pressure defined as a systolic value ≥ 180 mmHg or diastolic value ≥ 
100 mmHg at screening or baseline. (In case there is an elevated blood pressure 
measurement, it should be repeated after approximately 20 minutes. If the repeat 
measurement is elevated, then the patient is not eligible to be enrolled into the study). 
19. Systemic anti-VEGF therapy at any time. 
20. 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 6‑month period prior to Baseline except temporary use for 
Coronavirus 19 (COVID-19) treatment. 
21. History of hypersensitivity to any of the study drugs or their excipients or to drugs of 
similar classes, or clinically relevant sensitivity to fluorescein dye as assessed by the 
investigator. 
22. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in situ cervical cancer), treated or untreated, within the past 5 years prior to 
Screening, regardless of whether there is evidence of local recurrence or metastases. 
23. History of a medical condition (e.g. metabolic dysfunction disease with exception of type 
1 or 2 DM, or clinical laboratory finding) that, in the judgment of the investigator, would 
preclude scheduled study visits, completion of the study, or a safe administration of 
investigational product. 
24. Use of systemic investigational drugs within 5 half-lives of baseline, or within 30 days / 
until the expected pharmacodynamic effect has returned to baseline, whichever is longer; 
or longer if required by local regulations (observational clinical studies solely involving 
over-the-counter vitamins, supplements, or diets are not exclusionary). 
Other 
25. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive human 
chorionic gonadotropin pregnancy test. 
26. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during the study drug administration and for at least one month after stopping the 
investigational medication. Highly effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject 

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• Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device or intrauterine system, or other 
forms of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception. 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least 
six weeks before taking study treatment. In the case of oophorectomy alone, only when 
the reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child-bearing potential. 
If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the informed consent form. 
6 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational drug 
Table 6-1 
Investigational drug 
Investigational 
Drug 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor 
Brolucizumab 6 
mg (RTH258 6 
mg/ 0.05 mL) 
Solution for 
injection 
Intravitreal use 
Open label 
patient specific 
(Glass vials or 
PFS) 
Global 
Brolucizumab may be provided either in a single use, sterile glass vial, or in a prefilled syringe 
(PFS) in selected countries, containing sufficient brolucizumab to deliver a 6 mg dose when 
administering a volume of 0.05 mL. 
Novartis will ensure sufficient supplies of brolucizumab for treatment use to allow for 
completion of the study. 
6.1.2 
Comparator treatment 
The PRP procedure may be performed using conventional lasers or automated pattern delivery 
systems, at the investigator's discretion according to local clinical practice. Instructions for 
administering PDR treatment are provided in Section 6.7.2. 
6.1.3 
Additional study treatments 
No other treatment beyond investigational drug and PRP is included in this trial. 

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6.1.4 
Treatment arms/group 
Eligible subjects will be randomly assigned at Baseline / Day 1 to one of the following two 
treatment arms in a 1:1 ratio: 
• Brolucizumab 6 mg: 3 x q6w loading then q12w maintenance through Week 90, with the 
option from Week 48 onwards to extend the treatment interval by 6 weeks at a time up to 
24 weeks. 
• PRP: initial treatment in 1-4 sessions up to Week 12, followed with additional PRP 
treatment (may split into 2-4 sessions) as needed up to Week 90. 
6.1.5 
Treatment duration 
The planned duration of treatment is 90 weeks. Discontinuation of study treatment for a subject 
occurs when study treatment is stopped earlier than the protocol planned duration and can be 
initiated by either the subject or the investigator.  
Subjects who prematurely discontinue study treatment for any reason except withdrawal of 
consent should continue in the study and carry out the scheduled visits and assessments, at the 
discretion of the subject and investigator. 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
The investigator must instruct the subject to notify the study site about any new medications he 
/ she takes after signing the study informed consent. All medications, procedures and significant 
non-drug therapies (including physical therapy and blood transfusions) administered after the 
subject was enrolled into the study must be recorded on the appropriate electronic case report 
form (eCRF) page. 
Each concomitant medication must be individually assessed against all exclusion criteria / 
prohibited medications. If in doubt, the investigator should contact the Novartis medical 
monitor before randomizing a subject or allowing a new medication to be started. If the subject 
is already enrolled, contact Novartis to determine if the subject should continue receiving study 
treatment or participation in the study. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
Fellow eyes 
During the study, standard of care or other treatments for PDR and other diseases in the fellow 
eye are permitted at any time according to the investigator's practice and must be recorded in 
the appropriate eCRF page. Treatment of the fellow eye should be scheduled in a way not to 
disturb the schedule for visits and treatments in the study eye. The fellow eye must be monitored 
according to routine practice and AEs captured in the eCRF. 
Study eyes 
Administration of topical ocular medications, including corticosteroids, is allowed in the study 
eye during the study. Corticosteroids administered via intra-nasal, inhaled, intra-articular or 

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non-extensive dermal route (< 20% total body surface area) are also permitted during the 
study. For other routes of corticosteroid administration, refer to Table 6-2. 
If cataract surgery is necessary in the study eye, it should be attempted to schedule the surgery ≥ 
7 days after the most recent study treatment. Study treatment may be resumed ≥ 14 days after 
cataract surgery, assuming an absence of surgically-related complications.  
If yttrium aluminum garnet (YAG) laser is necessary, it should be performed ≥ 7 days prior to 
the scheduled study visit. 
If vitrectomy is necessary in the study eye, it should be attempted to schedule the surgery ≥ 14 
days after the most recent study treatment. Study treatment may be given during vitrectomy 
surgery if deemed necessary according to investigator’s discretion.  
If the subject is planning to receive a COVID-19 vaccine that is authorized by local regulation, 
it is recommended to receive the vaccine at least 7 days before or after the study treatment visit 
including Baseline (Day 1) visit. 
6.2.2 
Prohibited medication 
The treatments displayed in the table below are not allowed after Screening, unless otherwise 
indicated. 
Table 6-2 
Prohibited medications and surgical procedures 
Medication/Procedure 
Prohibition period 
Action taken 
Study eye 
  
  
Anti-VEGF therapy other than 
assigned study medication 
Anytime 
Discontinue study treatment 
PRP other than assigned study 
treatment 
Anytime 
Discontinue study treatment 
Any periocular injection or 
intraocular administration of 
corticosteroids (except if use of 
short-acting corticosteroids for 
the treatment of AE) 
Anytime 
Discontinue study treatment, 
except in the case of injections 
of short-acting corticosteroids 
(e.g. for the treatment of AE) 
Grid/focal laser 
photocoagulation for macula 
edema treatment (except if 
performed for the treatment of 
AE) 
Anytime 
Continuation of study treatment 
if performed for the treatment 
of AE 
Any other investigational drug, 
biologics or device 
Anytime 
Discontinue study treatment 
Non-ocular 
  
  
Anti-VEGF treatment 
Anytime 
Discontinue study treatment 
Any investigational drug, 
biologic or device 
Anytime 
Discontinue study treatment 

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Medication/Procedure 
Prohibition period 
Action taken 
Medications known to be toxic 
to the lens, retina or optic 
nerve, including ethambutol, 
chloroquine, 
hydroxychloroquine, 
deferoxamine, phenothiazines 
and tamoxifen except 
temporary use for COVID-19 
treatment 
Anytime 
Discontinue study treatment 
Any medication used according to medical practice or PRP to treat the fellow eye is permitted 
and should be recorded in the appropriate eCRF page; however, treatment of the fellow eye 
with any other investigational product (drug, biologic or device) is prohibited. 
 
6.3 
Subject numbering, treatment assignment, randomization 
6.3.1 
Subject numbering 
Each subject is identified in the study by a Subject Number (Subject No.) that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (4 digit number for Center No. as assigned by Novartis to the investigative site) with a 
sequential subject number suffixed to it (3 digit number for Subject No.), so that each subject 
is numbered uniquely across the entire database. Upon signing the informed consent form, the 
subject is assigned to the next sequential Subject No. available in the electronic data capture 
(EDC) system. 
Subjects who have been screen failures but are rescreened (see Section 8.1) will be assigned a 
new Subject No.  
6.3.2 
Treatment assignment, randomization 
All screened subjects must be added to the Interactive Response Technology (IRT) system. At 
the Baseline Visit / Day 1 all eligible subjects will be randomized via IRT to one of the two 
treatment arms in a ratio of 1:1. 
The investigator or his / her delegate will contact the IRT after receiving confirmation from the 
investigator that the subject fulfills all the inclusion / exclusion criteria. The IRT will assign a 
randomization number to the subject, which will be used to link the subject to a treatment arm 
and will specify a unique medication number for the investigational drug packages (each 
containing 1 vial or 1 PFS) to be dispensed to the subject. The randomization number will not 
be communicated to the masked site users. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from masked staff. A subject randomization 
list will be produced using a validated system that automates the random assignment of subject 
numbers to randomization numbers. These randomization numbers are linked to the different 
treatment arms. A separate medication list will be produced by or under the responsibility of 

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Novartis Global Clinical Supply using a validated system that automates the random assignment 
of medication numbers to packs containing the investigational drug. The randomization will be 
stratified by region. 
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office. 
6.4 
Treatment masking 
The intent of masking is to limit the occurrence of conscious and unconscious bias in the 
conduct of the clinical study and the interpretation of its results. Bias could arise from the 
influence that the knowledge of a specific treatment assignment may have on the recruitment 
and allocation of subjects, their subsequent care, the assessment of endpoints, the handling of 
withdrawals, and so on.  
This study will be single-masked with subjects randomized using IRT to be treated with 
brolucizumab 6 mg or PRP. Because of the difference in the mode of administration of 
brolucizumab (the investigational drug) and PRP (the comparator treatment), the duration of 
the two procedures, and the visible scars resulting from PRP on CFP, subjects as well as 
evaluating and treating investigators cannot be masked to treatment. 
To ensure single masking, the site personnel who will perform the BCVA 
 
assessments will be masked to the identity of the treatment from the time of randomization 
until the final database lock. The masked site personnel will be independent from the unmasked 
site staff who will perform the clinical evaluation and administer the study treatment. Once the 
designated roles are determined, the unmasked investigator/site personnel must not be switched 
at any time after randomization to masked role.  The source documentation specific to BCVA 
 assessments will be separately filled and provided to unmasked staff with no 
communication about treatment of the subject. The masked personnel will not have access to 
the other source documentation and the EDC system.  
Subjects, field monitors, and unmasked site staff will be asked not to communicate any 
information related to the study treatment to the masked site personnel, as documented in the 
patient informed consent form and in any other study form describing staff responsibilities. 
  Masking to the original treatment assignment will be maintained for the masked personnel at 
the site level until the end of the study. 
Additionally, an independent review of images collected at pre-defined time-points (see 
Section 8.3.2 and Section 8.3.3) for subjects enrolled in the study will be performed at a CRC. 
Independent readers of CFP images will be masked to the study treatment, the study visit 
number, and the investigator's disease activity assessment. 
6.5 
Dose escalation and dose modification 
No dose modification, nor deviation to dose intervals during the loading phase, nor dose 
adjustment during the whole study is allowed for the investigational drug. 
Interruption of study treatment is allowed if warranted by an AE. 

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6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
Investigator will comply with IRT treatment assignment for the investigational drug and to their 
local practice for PRP. 
IRT needs to be accessed by unmasked study personnel at every visit.  Registration of all visits 
in the IRT system is necessary and when treatment is warranted, IRT will provide a medication 
(kit) number to administer the investigational drug to the subject. The date and time of all study 
treatments administered during the study and any deviations from the protocol treatment 
schedule will be captured by the unmasked study personnel or by field monitor on the 
appropriate study treatment dispensing form. 
Exposure to brolucizumab will be based on the number of injections administered. The field 
monitor will assess compliance with the investigational drug by using counts of vials and PFS 
as applicable, and information provided by the pharmacist or by the unmasked study personnel. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study medication in packaging as described under 
investigational drug section (Section 6.1.1). The study medication packaging has a 2-part 
label (base plus tear-off label). A unique medication number is printed on each part of this label, 
which corresponds to one of the treatment arms. Unmasked study personnel will identify the 
study medication kits to dispense to the subject by contacting the IRT and obtaining the 
medication number(s). Immediately before dispensing the medication kit to the subject, 
unmasked study personnel will detach the outer part of the label from the packaging and affix 
it to the source document (Drug Label Form) for that subject's unique subject number. 
6.7.1 
Handling of study treatment 
Investigational drug must be received by a designated person at the study site, handled and 
stored safely and properly and kept in a secured location to which only the investigator and 
designated site personnel have access. Upon receipt, all investigational drug must be stored 
according to the instructions specified on the labels and in the Investigator’s Brochure. Clinical 
supplies are to be dispensed only in accordance with the protocol. Technical complaints are to 
be reported to the respective Novartis Country Organization Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the investigational drug but no information 
about the subject except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of 
investigational drug in a drug accountability log. Monitoring of drug accountability will be 
performed by monitors during site visits or remotely and at the completion of the trial. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 

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6.7.2 
Instruction for administering study treatment 
Treatment schedules are illustrated in Figure 6-1. Visits will occur every 6 weeks. Every effort 
should be made to ensure that the subject adheres to the visit schedule. 
During the study, disease activity should be assessed in both treatment arms using retinal 
imaging and visual functional outcomes, at the investigator's discretion (e.g. standard or wide-
field CFP, fluorescein angiography (FA), BCVA). Disease activity will be assessed at each visit 
from Week 12 to Week 96 (EOS). The investigator’s disease activity assessment will be 
entered in the IRT system and eCRF. 
Arm 1: Brolucizumab 6 mg 
All kits of investigational drug assigned by the IRT will be recorded in the IRT system. 
Treatment schedule 
Loading phase (Baseline to Week 12): Subjects will receive three consecutive injections every 
6 weeks at Baseline, Week 6 and Week 12 during the loading phase. 
Maintenance phase (Week 18 to Week 90): 
• Subjects will receive q12w injections in the maintenance phase, i.e. at Week 24, Week 36, 
and Week 48 in the first year. 
• During the maintenance phase, the additional visits (e.g. Week 30) are planned for disease 
monitoring, not for treatment administration. However, additional injections may be 
administered at these visits at the investigator’s discretion only if disease worsens, e.g. 
new or expanding retinal neovascularization compared to the previous visit. No injection 
should be administered if retinal neovascularization has been stable. Any additional 
injection will not impact the q12w injection schedule, i.e. injections at Week 24, Week 36, 
and Week 48 will be nonetheless performed. 
• From Week 48 onwards,  
• The treatment interval may be extended by 6 weeks at a time, up to 24 weeks, at the 
investigator’s discretion if, based on the investigator’s assessment of disease activity, 
there is disease stability or regression, e.g. regressed or stabilized retinal 
neovascularization from the previous injection visit. 
• Thus, at Week 48 the investigator may elect to extend the treatment interval from 12 
weeks to 18 weeks and treat the study eye at Week 66, if the disease did not worsen, 
e.g. no new or expanding retinal neovascularization, between Week 36 and Week 48 
and there was no injection at Week 42. At Week 66, the investigator may elect to 
further extend the treatment interval from 18 weeks to 24 weeks, and treat the study 
eye at Week 90, if the disease did not worsen between Week 48 and Week 66, and 
there were no injections at Week 54 and Week 60.   
• The investigator may opt to revert to q12w injections if, in the investigator’s opinion 
based on disease activity assessment, the subject needs more frequent treatment. 
• The last potential brolucizumab injection may be administered at the Week 90 visit. 
Brolucizumab administration 

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The IVT injection will be carried out by the investigator under controlled, aseptic conditions 
and antimicrobial requirements according to local clinical practice. Every injection 
administered to the subject will be recorded in the eCRF. 
If any safety concern arises related to the study eye that, in the opinion of the investigator, may 
be further impacted by the study treatment or injection procedure, treatment should not be 
administered. IVT injection is contraindicated in subjects with active ocular or periocular 
infections and in subjects with active intraocular inflammation (IOI); therefore, the 
investigators must verify that these conditions are not present in the study eye prior to every 
injection. Any adverse events must be recorded in the eCRF.  
If any signs of intraocular inflammation are present, then an IVT injection must not be 
performed. Additional ophthalmic examination and imaging should be performed to evaluate 
IOI (see Section 8.4.5). 
If IOI is confirmed, subjects should be treated for IOI according to clinical practice and closely 
monitored since they may be at risk of developing retinal vasculitis and/or retinal vascular 
occlusion. If subject develops retinal vasculitis and/or retinal vascular occlusion based on the 
investigator’s evaluation, the study treatment must be discontinued. 
 
Arm 2: PRP 
Subjects in the PRP arm will receive an initial treatment at Baseline. The treatment may be split 
into 2-4 sessions up to Week 12 as per local clinical practice. The additional sessions should 
coincide with the visit schedules (i.e. Week 6 and Week 12), whenever possible, at the 
discretion of the investigator, as long as treatment is adequately administered to the subject. 
From Week 18, all subjects in the PRP arm will be assessed for treatment response every 6 
weeks. Additional PRP may be performed in the study eye if disease worsens, e.g. new or 
expanding retinal neovascularization compared to the previous visit, at the investigator’s 
discretion, according to local clinical practice. Additional PRP may be deferred until next visit 
if the ocular media are too hazy to perform the procedure.  
PRP is typically administered using conventional lasers or automated delivery pattern systems 
delivered through either a slit lamp system or indirect ophthalmoscope (headlamp/BIO). 
Approximately 1500-5000 burns may be administered in 1 to 4 sessions, according local clinical 
practice and applicable guidance for PRP.  
PRP performed as a day case hospitalization should not be recorded as a serious adverse event 
(SAE) despite hospitalization.  
If any safety concern arises related to the study eye that, in the opinion of the investigator, may 
be further impacted by PRP, treatment needs to be deferred. Any adverse events must be 
recorded in the eCRF.  
If subject develops retinal vasculitis and/or retinal vascular occlusion based on the 
investigator’s evaluation, the study treatment must be discontinued. 
The last potential PRP treatment may be administered at the Week 90 visit. 

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Figure 6-1 
Treatment schedule (example) 
 
BL: Baseline, V: visit 
7 
Informed consent procedures 
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), Institutional Review Board/Independent Ethics Committee (IRB / IEC)-
approved informed consent. 
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his / her understanding. If the subject is capable of doing so, he / she must indicate agreement 
by personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol), except for FA images that can be used from a previous 
routine evaluation that would have taken place no more than 14 days prior of the Screening visit 
(see Section 8.1). The process of obtaining informed consent must be documented in the subject 
source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the International Council for Harmonisation of Good Clinical Practice (ICH 
GCP) guidelines and regulatory requirements and is considered appropriate for this study. Any 
changes to the proposed consent form suggested by the investigator must be agreed by Novartis 
before submission to the IRB / IEC. 
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the subject informed consent and should 
be discussed with the subject during the study as needed. Any new information regarding the 
safety profile of the investigational drug that is identified between IB updates will be 
communicated as appropriate, for example, via an investigator notification or an aggregate 
safety finding. As new information becomes available,  informed consent to be updated and 
then must be discussed with the subject.Women of child bearing potential must be informed 
that taking the study treatment may involve unknown risks to the fetus if pregnancy were to 
occur during the study and agree that in order to participate in the study they must adhere to the 
contraception requirements. 

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A copy of the approved version of all consent forms must be provided to Novartis after IRB / 
IEC approval. 
During the COVID-19 pandemic that may challenge the ability to obtain a standard written 
informed consent due to limits that prevent an on-site visit, the Investigator may conduct 
the informed consent discussion remotely (e.g. telephone, videoconference). Guidance 
issued by local regulatory bodies on this aspect prevail and must be implemented and 
documented (e.g. the presence of an impartial witness, sign/dating separate ICFs by trial 
participant and person obtaining informed consent, etc). Remote informed consent should 
be appropriately documented and confirmed by way of standard informed consent 
procedures at the earliest opportunity when the subject will be back at the trial sites. 
8 
Visit schedule and assessments 
The Assessment Schedule (Table 8-1) lists all of the assessments and indicates with an “X” or 
“S” the visits when they are performed. All data obtained from these assessments must be 
supported in the subject’s source documentation. All data must be entered in the eCRF in a 
timely manner (see Section 11.1). 
A planned study visit schedule will be established at Baseline / Day 1, randomization (first day 
of treatment) for all subjects. All post-Baseline and/or subsequent scheduled visits will be 
calculated based on the Day 1 visit date. All efforts should be made to adhere to all scheduled 
visits and assessments as outlined in the assessment schedule (Table 8-1). 
A ± 7-day visit window is allowed, except for Baseline / Day 1, should the subject be unable to 
return per scheduled visit. All efforts should be made to revert back to the planned visit schedule 
taking into consideration the restrictions on the minimum treatment interval for brolucizumab, 
i.e. two consecutive injections should be at least 21 days apart.  
For a given protocol visit, assessments can be performed on 2 consecutive days, both of which 
should occur within the visit window. 
Treatment is intended to be administered on the day of study visit - if this is not possible, 
within 3 days after the study visit at which the per-protocol assessments took place - after 
completing all assessments required to be performed prior to the administration of study 
treatment. IOP will also be measured, and other ocular examinations may also be performed, 
after administration of study treatment for safety assessment. 
Missed or rescheduled visits should not lead to automatic discontinuation. Subjects who 
prematurely discontinue the study for any reason should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for the EOS final visit will be performed. 
 
If the COVID-19 pandemic limits or prevents on-site study visits, study treatment could not be 
administered and other study assessments may not be performed. Alternative methods of safety 
monitoring may be implemented.  Depending on local regulations, site capabilities and patient’s 
visit status in the study, phone calls or virtual contacts (e.g. teleconsult) can be performed for 
safety follow-up for the duration of the pandemic, until it is safe for the participant to visit the 
site again.  
 

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Table 8-1 
Assessment Schedule 
Period Screening 
Treatment 
Post-
Treatment 
Follow-Up 
Visit Name Screening Baseline 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16/EOT 
17/EOS 
Days 
-21 to -1 
1 
43 85 
127 
169 
211 
253 
295 
337 
379 
421 
463 
505 
547 
589 
631 
673 
Weeks 
-3 to -1 
0 
6 
12 
18 
24 
30 
36 
42 
48 
54 
60 
66 
72 
78 
84 
90 
96 
Informed 
consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demography 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion / 
Exclusion 
criteria 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical 
history/curren
t medical 
conditions 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Prior / 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1c 
X 
  
  
X 
  
X 
  
X 
  
  
X 
  
  
  
X 
  
  
X 
Hematology 
X 
  
  
  
  
X 
  
  
  
  
X 
  
  
  
X 
  
  
X 
Clinical 
chemistry 
X 
  
  
  
  
X 
  
  
  
  
X 
  
  
  
X 
  
  
X 
Urinalysis 
X 
  
  
  
  
X 
  
  
  
  
X 
  
  
  
X 
  
  
X 
Pregnancy 
test1 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 

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Period Screening 
Treatment 
Post-
Treatment 
Follow-Up 
Visit Name Screening Baseline 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16/EOT 
17/EOS 
Days 
-21 to -1 
1 
43 85 
127 
169 
211 
253 
295 
337 
379 
421 
463 
505 
547 
589 
631 
673 
Weeks 
-3 to -1 
0 
6 
12 
18 
24 
30 
36 
42 
48 
54 
60 
66 
72 
78 
84 
90 
96 
Trial feedback 
questionnaire 
(optional) 
  
X 
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
X 
Best 
corrected 
visual acuity11 
OU4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OU 
X 
X 
X 
X 
X 
X 
OU 
Intraocular 
pressure 
OU 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OU 
X 
X 
X 
X 
X 
X 
OU 
Ophthalmic 
examination10 
OU 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
7-Field color 
fundus 
photography5, 
10 
OU 
  
  
  
X 
  
  
  
  
  
OU 
  
  
X 
  
  
  
OU 
Fluorescein 
angiography5, 
10 
OU 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
X 

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Period Screening 
Treatment 
Post-
Treatment 
Follow-Up 
Visit Name Screening Baseline 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16/EOT 
17/EOS 
Days 
-21 to -1 
1 
43 85 
127 
169 
211 
253 
295 
337 
379 
421 
463 
505 
547 
589 
631 
673 
Weeks 
-3 to -1 
0 
6 
12 
18 
24 
30 
36 
42 
48 
54 
60 
66 
72 
78 
84 
90 
96 
Spectral 
domain 
optical 
coherence 
tomography10 
OU 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OU 
X 
X 
X 
X 
X 
X 
OU 
Wide-field 
color fundus 
photography, 
if available5 
OU 
  
  
  
X 
  
  
  
  
  
OU 
  
  
X 
  
  
  
OU 
Disease 
activity 
assessment 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contact IRT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse 
Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study 
treatment - 
brolucizumab 
arm 
  
X 
X 
X Option6 
X 
Option6 
X 
Option6 
X 
Option6 
Ext. 
period
7 
Ext. 
period
7 
Ext. 
period
7 
Ext. 
period
7 
Ext. 
period
7 
Ext. 
period7 
  

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Period Screening 
Treatment 
Post-
Treatment 
Follow-Up 
Visit Name Screening Baseline 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16/EOT 
17/EOS 
Days 
-21 to -1 
1 
43 85 
127 
169 
211 
253 
295 
337 
379 
421 
463 
505 
547 
589 
631 
673 
Weeks 
-3 to -1 
0 
6 
12 
18 
24 
30 
36 
42 
48 
54 
60 
66 
72 
78 
84 
90 
96 
Study 
treatment - 
PRP arm 
  
X8 
  
  
PRN9 
PRN 
PRN 
PRN 
PRN 
PRN 
PRN 
PRN 
PRN 
PRN 
PRN 
PRN 
PRN 
  
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 For all women of child-bearing potential. Serum pregnancy test to be conducted at the Screening and Week 96/EOS visits. Urine pregnancy test at the other visits. 
 
 
 
4 Oculus uterque,  both eyes 
5 May be performed at other visits, at the investigator's discretion 
6 Based on disease activity, e.g. new or worsening retinal neovascularization from previous visit.  Treatment should be held off if stabilized disease. 
7 Treatment interval can be extended by 6 weeks at a time, up to 24 weeks, based on disease stabilization or regression.  Treatment interval can revert to q12w if 
subject needs more frequent treatments. 
8 PRP treatment at Baseline can be split into 2-4 sessions until Week 12 
9 Pro re nata, based on disease activity. 
 
11 BCVA will also be measured in the fellow eye if the BCVA in the study eye has dropped by 10 or more ETDRS letters from the previous visit 

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8.1 
Screening 
A screening period of up to 3 weeks will be used to assess subject eligibility. 
For the purpose of screening, FA images from a previous routine evaluation may be used as 
long as FA was performed within 14 days of the Screening visit using CRC-certified equipment 
operated by CRC-certified personnel. 
One time reassessment of subjects is allowed, except for the purpose of capturing new BCVA 
or imaging assessments that previously failed to qualify the subject. As long as testing can be 
repeated within 14 days of the first Screening, the other screening assessments do not need to 
be repeated. If rescreening is to occur beyond 14 days from the original Screening visit date, 
then the subject must be reconsented and all screening procedures must be repeated. Medical 
judgment should be exercised to ensure that treatment of PDR is not withheld in order for a 
subject to participate in the study. 
8.1.1 
Information to be collected on screening failures 
Subjects who sign an informed consent form and who are subsequently found to be ineligible 
prior to randomization will be considered a screen failure. The reason for screen failure should 
be recorded on the appropriate eCRF page. The demographic information, informed consent, 
inclusion/exclusion and disposition eCRF pages must also be completed for screen failure 
subjects. No other data will be entered into the clinical database for subjects who are screen 
failures, unless the subject experienced an SAE during the screening phase (see Section 10.1.3 
for reporting details). Adverse events that are not SAEs will be followed by the investigator and 
collected only in the source data. If the subject is not eligible to be randomized, the IRT should 
be notified within 2 days of the screen fail that the subject was not randomized. 
8.2 
Subject demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
Baseline characteristics in alignment with eCRF. 
The following information will be collected / documented at Screening and/or Baseline visit 
(see Table 8-1) for each randomized subject: 
• Age 
• Sex 
• Race / Ethnicity 
• History of primary diagnosis, including type of diabetes and PDR 
• Medical history / current medical conditions 
• Prior / concomitant medications and procedures, including anti-VEGF intravitreal 
injection or PRP for the treatment of PDR in the fellow eye that occurred within 20 weeks 
prior to the Baseline visit 
• Vital signs 
• BCVA 
• IOP 

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• Study eye 
• Retinal imaging 
• HbA1c and other laboratory test results 
 
 
 
 
Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF whenever, in their judgment, the test abnormality occurred prior to the informed consent 
signature. 
8.3 
Efficacy 
The following assessments will be performed to evaluate the effect of brolucizumab and PRP 
on visual function, DR status, retinal and vascular structure: 
• Best-corrected visual acuity with ETDRS-like charts at initial testing distance of 4 meters 
• ETDRS DRSS score based on 7-Field stereo CFP 
• Anatomical retinal evaluation by SD-OCT, FA, 
), Wide-field 
CFP 
 
 
All efficacy assessments should be performed prior to any administration of study treatment. 
8.3.1 
Visual acuity 
Visual acuity will be assessed in the study eye at every study visit and in the fellow eye at the 
Screening, Week 54 and Week 96/EOS visits using best correction determined from protocol 
refraction (BCVA). BCVA will also be measured in the fellow eye if the BCVA in the study 
eye has dropped by 10 or more ETDRS letters from the previous visit. 
BCVA measurements will be taken in a sitting position using ETDRS–like visual acuity testing 
charts at an initial testing distance of 4 meters. The details of the refraction technique and VA 
testing, as well as training material, are provided in the applicable manual. Certification of the 
assessment procedures and assessors will occur prior to any evaluation of study subjects. 
Subjects at sites in some Asian countries will undergo BCVA testing using numerical charts 
rather than letter charts. Therefore, all references in the protocol to changes in letters read will 
be changes in numbers in these countries. 
8.3.2 
Color fundus photography and fluorescein angiography 
Seven-Field stereo CFP, or equivalent as per the CRC manual, will be performed in both eyes 
at Screening, Week 54, and Week 96 / EOS and in the study eye at Week 18 and Week 72.  
At sites that have the applicable equipment, optional Wide-Field (at least 100 degrees) CFP 
(WFCFP) should be performed in both eyes at Screening, Week 54, and Week 96/EOS and in 
the study eye at Week 18 and Week 72. If WFCFP images were not taken at Screening, they 
should not be introduced at later visits. Additional CFP images may be captured at other visits, 
at the investigator's discretion. 

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7-Field standard (non-stereoscopic) or Wide-Field FA will be performed in the study eye 
at the Screening, Week 54, Week 96 / EOS visits and in the fellow eye at the Screening visit. 
FA may be performed at other visits, at the investigator’s discretion. The FA camera model 
used for an individual subject should not change for the duration of the study. 
For the purpose of screening, FA images from a previous routine evaluation may be used as 
long as FA was performed within 14 days of the Screening visit using CRC-certified equipment 
operated by CRC-certified personnel. 
In case of premature discontinuation from the study, there is no need to repeat the 7-Field CFP 
and FA if there was a 7-Field CFP and FA performed within the previous 12 weeks, except if 
there is significant disease worsening in the opinion of the investigator. 
The investigator will evaluate the images according to their standard of clinical practice and 
may use any of the CFP, WFCFP, and FA imaging findings to inform his/her decision for 
treatment. However, their findings of both quantitative and qualitative parameters will not be 
captured in the eCRF but should be included in the source documentation at the study site. 
The CRC will provide sites with a Study Manual and training materials for the specified study 
ocular images. Before any study images are obtained, site personnel, test images, systems and 
software will be certified and validated by the CRC as specified in the Study Manual. All 7-
Field CFP, WFCFP, and FA images will be obtained by trained and study-certified site 
personnel at the study sites and forwarded to the CRC for independent standardized analysis 
and for storage. 
The CRC will create a database with the agreed variables as indicated in the CRC grading 
charter (a separate document) and will transfer the data from this database to Novartis for 
analysis. The CRC data will be used for the evaluation of the objectives having 7-Field CFP 
and FA parameters and their change over time as endpoints to ensure a standardized evaluation. 
Grading for DRSS score will be performed at the CRC. 
For further procedural details, the investigator should refer to the applicable manual provided 
by the CRC. 
Additional images will be taken in case of any signs of intraocular inflammation. OCT, Color 
fundus photography and fluorescein angiography (preferably wide-field or with peripheral 
sweeps) should be performed for safety evaluation as described in Section 8.4.5. 
8.3.3 
Optical coherence tomography 
SD-OCT images will be obtained and assessed in both eyes at Screening, Week 54 and Week 
96/EOS visits, and in the study eye at all other visits. 
These assessments will be performed by a trained and CRC-certified technician or investigator 
at the sites and should be performed after BCVA assessment and prior to any study treatment. 
Investigators will evaluate the SD-OCT images to assess the status of macular edema. The SD-
OCT model used for an individual subject should not change for the duration of the study. 
 
 

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In addition to the standard
assessment, at sites that have the applicable equipment, 
wide-field or standard
should be performed at each visit in the study eye.
 
 
 
The investigators will evaluate the OCT images according to their clinical practice. Their 
findings about both quantitative and qualitative OCT parameters will not be captured in the 
eCRF but should be included in the source documentation at the study site. 
A CRC will be used in this study. The CRC will provide sites with a Study Manual and training 
materials for the specified study ocular images. Before any study images are obtained, site 
personnel, test images, systems and software will be certified and validated by the CRC as 
specified in the Study Manual. All SD-OCT 
 images will be obtained by trained and 
CRC-certified site personnel at the study sites. All SD-OCT 
 images will be 
forwarded to the CRC for independent standardized analysis and for storage. 
The CRC will create a database with the agreed variables as indicated in the CRC grading 
charter (a separate document) and will transfer the data from this database to Novartis for 
analysis. The CRC data will be used for the evaluation of the objectives having SD-OCT 
 
parameters to ensure a standardized evaluation. For further procedural details, the 
investigator should refer to the applicable manual provided by the CRC. 
 
 
 
 
 
 
 
 
 
 
 
. 
8.3.5 
Appropriateness of efficacy assessments 
The use of BCVA as a measure of retinal function as well as 7-Field CFP to analyze structural 
changes of the peripheral retina are standard assessments to monitor PDR and treatment effects 
both in clinical practice and in clinical trials. ETDRS DRSS assessed on 7-Field CFP is a 
standardized evaluation of the severity of DR in clinical trials. 
FA is also an established procedure used to identify retinal neovascularization and monitor its 
change. 
 

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SD-OCT images are routinely used in clinical trials and practice to assess 
 
 monitor the emergence and evolution of DME, a vision-threatening 
complication of diabetes, which may occur in PDR subjects. 
8.4 
Safety 
Safety assessments will include vital signs, ophthalmic examinations, laboratory evaluation as 
well as the monitoring and recording of the type, frequency, and severity for all AEs. 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 
If the COVID-19 pandemic limits or prevents on-site study visits, phone calls or virtual contacts 
should be conducted for safety monitoring and discussion of the subject´s health status, until 
the subject can again visit the site. 
For details on AE collection and reporting refer to Section 10.1. 
8.4.1 
Vital sign assessments 
Vital signs include assessment of sitting blood pressure (systolic and diastolic pressure in 
mmHg) and pulse rate (beats per minute) and will be collected at all visits. In case there is an 
elevated blood pressure measurement as specified in the exclusion criteria, at the Screening and 
Baseline visits, the blood pressure measurement should be repeated after approximately 20 
minutes. If the repeat measurement is elevated as specified in the exclusion criteria, then the 
subject is not eligible to be enrolled into the study. 
On 
days 
when 
study 
treatment 
is 
administered, 
vital 
signs 
will 
be 
measured before administration of study treatment. The results will be recorded in the eCRF. 
8.4.2 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens collected at Screening, Week 24, 
Week 54, Week 78, and Week 96/EOS visits. Blood samples will also be collected for HbA1c 
assessment at Week 12 and Week 36. Details on the collections, shipment of the samples and 
reporting of the results by the central laboratory are provided to investigators in the central 
laboratory manual. 
If the COVID-19 pandemic limits or prevents on-site study visits, the collection of samples 
may be modified by Novartis if applicable and if modified, will be communicated to the 
Investigator.   
Clinically significant abnormalities must be recorded in the relevant section of the medical 
history, current medical conditions or adverse event eCRF page as appropriate. 
Table 8-2 
Laboratory assessments 
Test Category 
Test Name 
HbA1c 
Glycosylated Hemoglobin 
Hematology 
Hematocrit, hemoglobin, red blood cell (RBC) count, white blood cell (WBC) 
count with differential (absolute and percentage of neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils), and quantitative platelet count. 

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Test Category 
Test Name 
Chemistry 
Serum biochemistry tests: 
Serum electrolytes (sodium, potassium, chloride, phosphorus, calcium), 
uric acid, blood urea nitrogen, creatinine, albumin, glucose, total protein, total 
bilirubin and direct bilirubin, serum glutamic oxaloacetic transaminase (SGOT)/ 
aspartate aminotransferase (AST), serum glutamic pyruvic transaminase 
(SGPT)/ alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), 
alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) 
Additional chemistry tests: 
Lipids panel-triglycerides (TG), low-density lipoproteins (LDL), high-density 
lipoproteins (HDL), total cholesterol (TC) 
Urinalysis 
Dipstick measurements for specific gravity, pH, protein, glucose, ketones, 
urobilinogen, bilirubin, nitrite, leucocyte, esterase and urine occult blood 
8.4.3 
Pregnancy 
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements. 
Highly effective contraception is required for women of child-bearing potential during the study 
drug administration and for one month after stopping the investigational medication. 
A serum pregnancy test will be conducted for all women of child-bearing potential to assess 
pregnancy before inclusion into the study at Screening visit, and then at Week 96/EOS visit. 
During the study, urine pregnancy testing will be performed before any study treatment at the 
other visits. If a urine test is positive after inclusion into the study, a serum pregnancy test must 
be performed for confirmation; if the serum test is positive, the subject must discontinue study 
treatment. Results of all pregnancy testing must be available as source documentation. 
8.4.4 
Intraocular Pressure 
IOP will be assessed in the study eye at all scheduled visits. At visits when study treatment is 
administered, pre-treatment and post-treatment IOP will be assessed. The same method of 
tonometry has to be used through the whole study. In the fellow eye, IOP will be assessed at 
Screening, Week 54 and Week 96 / EOS visit. The values recorded in mmHg for either eye will 
be entered into the eCRF. 
Treatment and close monitoring of IOP should be performed by the investigator for any non-
transient elevation in IOP (≥ 25 mmHg). Intravitreal injection is not recommended unless 
normalization of the IOP has been achieved. Post-dose IOP should be assessed in the  within 
60 minutes after study treatment and if  ≥ 25 mmHg, it is recommended that assessment should 
be repeated until back to normal. Perfusion of the optic nerve head should also be monitored 
and managed appropriately, at the discretion of the investigator and/or according to local 
requirements / practice. Results of these procedures will be recorded as appropriate in the source 
documents, and if the findings constitute an AE, it should be recorded in the eCRF. 
8.4.5 
Ophthalmic examination 
The ophthalmic examination will consist of the following: 

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• Biomicroscopy (slit lamp examination) will be completed at every (scheduled and 
unscheduled) visit to examine the anterior segment structures (e.g., eyelids/lashes, 
conjunctiva, cornea, anterior chamber, iris, lens and anterior part of the vitreous) of the 
study eye according to local clinical practice. At visits when study treatment is 
administered, the examination will be performed pre-treatment; if needed, an additional 
examination may be performed post-treatment. The fellow eye will be examined at 
Screening for eligibility, and at other visits at the discretion of the investigator. The results 
of the examination of either eye should be recorded in the source documents as 
appropriate. 
Slit lamp examination must be carefully performed before each study treatment. If there are any 
signs of IOI, severity of anterior chamber cells and flare should be assessed according to the 
standardization of uveitis nomenclature (SUN) working group grading system (Jabs et al 2005). 
The test results will be recorded in the source documents (e.g., ophthalmic examination tool) 
and captured in the appropriate eCRF as applicable. 
Ophthalmoscopy will be conducted by the investigator at the Screening visit for both eyes. An 
examination of the peripheral retina must also be conducted to ensure that the study treatment 
can be safely performed. As of Baseline visit, the fundus examination will be performed only 
in the study eye at every scheduled visit. Posterior segment examination must be performed 
carefully before each study treatment. The results of the examination including any 
abnormalities (e.g. vitreous cells/haze, retinal tear/detachment, hemorrhage and vascular 
occlusion, vasculitis, etc.) should be recorded in the source documents. If there are any signs of 
IOI, vitreous cells and haze should be assessed using National Institutes of Health (NIH) 
grading system (Nussenblatt et al 1985). The outcome of the examination will be documented 
in the source document (e.g., ophthalmic examination tool) and appropriate eCRF page as 
applicable.  Pupil dilation for slit lamp examination and ophthalmoscopy is optional, at the 
discretion of the investigator or according to local clinical practice.  
 
Instruct the patient to contact the site for any changes in vision or any symptoms of 
inflammation between scheduled visits. Every effort should be made to bring the subject for 
immediate examination. When IOI, retinal vasculitis, and/or Retinal Artery Occlusion (RAO) 
is present or suspected during a visit, investigators must perform thorough ophthalmic 
examination, and will conduct OCT, fluorescein angiography and color fundus photography 
(preferably wide-field or with peripheral sweeps). These additional assessments will be 
documented in the source and appropriate eCRF pages as applicable. The images are requested 
to be uploaded onto the CRC portal.  If subject develops retinal vasculitis and/or retinal vascular 
occlusion based on the investigator’s evaluation, the study treatment must be discontinued. In 
addition, as some of the subjects who experience IOI may be at risk of developing retinal 
vasculitis and/or retinal vascular occlusion, the subject should be closely monitored and 
managed according to clinical practice. 
8.4.6 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/subject population. 
If there is any signs of IOI, additional assessment will be performed as described in Section 
8.4.5. 

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8.5 
Additional assessments 
8.5.1 
Clinical Outcome Assessments (COAs) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 

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Trial Feedback Questionnaire 
During the treatment period, subjects will be asked to complete an optional anonymized 
questionnaire, the "Trial Feedback Questionnaire", to provide feedback on their clinical trial 
experience at Baseline, Week 54 and Week 96/EOS visits. Subjects may opt in or opt out of 
completing this questionnaire. 
Responses will not be reviewed by investigators. Responses will be used to understand where 
improvements can be made in the clinical trial process. This questionnaire is not meant to collect 
data about the subject's disease, symptoms or adverse events, and therefore will not be 
considered trial data.  
9 
Study discontinuation and completion 
9.1 
Discontinuation 
The investigator should discontinue study treatment for a given subject and/or withdraw the 
subject from the study if, on balance, he/she believes that continuation would be detrimental to 
the subject's well-being. 
A subject will be considered to have completed the study when the subject has completed the 
last visit planned in the protocol (see Table 8-1). 
The investigator and/or referring physician will recommend the appropriate follow-up medical 
care, if needed, for all subjects who are prematurely withdrawn from the study. 
9.1.1 
Discontinuation of study treatment 
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration and can be initiated by either the subject or the investigator. 
The investigator must discontinue study treatment for a given subject if he / she believes that 
continuation would negatively impact the subject's well-being. 
Study treatment must be discontinued under the following circumstances: 
• Subject/guardian decision 
• Pregnancy (see Section 8.4.3 and Section 10.1.4) 
• Use of prohibited treatment (see Section 6.2.2) 
• Any situation in which study participation might result in a safety risk to the subject 
• Subject develops a retinal vasculitis and/or a retinal vascular occlusion Unsatisfactory 
therapeutic effect 
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information. 
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 9.1.2). Where possible, they should return for the assessments 
indicated in the Assessment Schedule (Table 8-1). If they fail to return for these assessments 

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for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be made to contact the 
subject/pre-designated contact as specified in the lost to follow-up section (Section 9.1.3). This 
contact should preferably be done according to the study visit schedule. 
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule. 
After study treatment discontinuation, at a minimum, the following data should be collected at 
clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment. 
9.1.1.1 
Replacement policy 
Subjects who started study treatment but prematurely discontinued study treatment and/or study 
will not be replaced. 
9.1.2 
Withdrawal of informed consent 
Withdrawal of consent/opposition to use data/biological samples occurs when a participant: 
• Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples) 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts) 
This request should be in writing (depending on local regulations) and recorded in the source 
documentation. 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their 
consent/opposition to use data/biological samples and record this information. 
Where consent to the use of Personal and Coded Data is not required in a certain country's legal 
framework, the participant therefore cannot withdraw consent. However, they still retain the 
right to object to the further collection or use of their Personal Data. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 

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If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/opposition to use data/biological samples should be made as detailed in the assessment 
table (refer to Section 8). 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation, including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition. 
9.1.3 
Lost to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed. 
9.1.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit / risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety. Should early termination be 
necessary, subjects must be seen as soon as possible and treated as a prematurely withdrawn 
subject. The investigator may be informed of additional procedures to be followed in order to 
ensure that adequate consideration is given to the protection of the subject’s interests. The 
investigator or sponsor depending on the local regulation will be responsible for informing IRBs 
/ IECs of the early termination of the trial. 
9.2 
Study completion and post-study treatment 
Study completion is defined as when the last randomized subject finishes their EOS visit and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision. 
All randomized and / or treated subjects should have a safety follow-up call conducted 
approximately 30 days after last administration of study treatment, unless they have completed 
the EOS visit at least 6 weeks after the last treatment administration. The information collected 
is kept as source documentation. All SAEs reported during this time period must be reported as 
described in Section 10.1.3. Documentation of attempts to contact the subject should be 
recorded in the source documentation. 
After study completion, the subject may receive standard of care or other treatments, at the 
discretion of the investigator and / or referring physician, if needed. 

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10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An AE is any untoward medical occurrence (e.g. any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a subject or clinical 
investigation subject after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product or medical device. 
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through laboratory test findings or other assessments. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The severity grade:  
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
2. Its relationship to the study treatment (e.g. study drug, the intravitreal injection procedure, 
or laser procedure). If the event is due to lack of efficacy or progression of underlying 
illness (i.e. progression of the study indication) the assessment of causality will usually be 
‘Not suspected.’ The rationale for this guidance is that the symptoms of a lack of efficacy 
or progression of underlying illness are not caused by the study treatment, they happen in 
spite of its administration and/or both lack of efficacy and progression of underlying 
disease can only be evaluated meaningfully by an analysis of cohorts, not on a single 
subject 
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported 
4. Whether it constitutes an SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken regarding with study treatment. All adverse events must be treated 
appropriately. Treatment may include one or more of the following: 
• No action taken (e.g. further observation only) 
• Study treatment interrupted/withdrawn 
• Concomitant medication or non-drug therapy given 

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• Subject hospitalized/ Subject's hospitalization prolonged (see Section 10.1.2 for 
definition of SAE) 
6. its outcome  
• not recovered / not resolved; 
• recovered / resolved; 
• recovered / resolved with sequelae; 
• fatal; 
• unknown. 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the IB. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
Baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease. 
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of an SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 

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• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of an SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are 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 dependency or abuse (please refer to the ICH-
E2D Guidelines). 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.  
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3 
SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days following the last study visit, must be reported to 
Novartis safety within 24 hours of learning of its occurrence. Detailed instructions regarding 
the submission process and requirements are to be found in the investigator folder provided to 
each site. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the study treatment, a Chief Medical Office & Patient Safety (CMO & 
PS) Department associate may urgently require further information from the investigator for 

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health authority reporting. Novartis may need to issue an Investigator Notification (IN) to 
inform all investigators involved in any study with the same study treatment that this SAE has 
been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
Any SAEs experienced after the 30 day period following the last study visit, should only be 
reported to Novartis Safety if the investigator suspects a causal relationship to study treatment 
administration. 
10.1.4 
Pregnancy reporting 
To ensure subject safety, each pregnancy (female participants only) occurring after signing the 
informed consent must be reported to Novartis within 24 hours of learning of its occurrence. 
The pregnancy should be followed up to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded and reported by the investigator to the Novartis CMO & PS 
Department. Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to brolucizumab (investigational treatment) with any 
pregnancy outcome. 
Any SAE experienced during pregnancy must be reported.  
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (European Medicines Agency definition). 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate eCRF irrespective of whether or not associated with an AE / SAE and reported 
to Safety only if associated with an SAE. 
Table 10-1 
Guidance for capturing the study treatment errors 
Treatment error type 
Document in Dosing 
eCRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
No 
Only if associated with 
an SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
Section 10.1.1, Section 10.1.2, and Section 10.1.3. 
10.2 
Additional Safety Monitoring 
Not applicable. 

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11 
Data Collection and Database management 
11.1 
Data collection 
Designated unmasked investigator staff will enter the data required by the protocol into the 
eCRF. Masked staff will not have access to the EDC system to maintain single-masking. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
CFR Part 11 requirements. Investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs, allow modification and/or verification of the entered data by the investigator staff. 
The investigator / designee is responsible for assuring that the data (entered into eCRF) is 
complete, accurate, and that entry and updates are performed in a timely manner. The 
Investigator must certify that the data entered are complete and accurate 
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control 
Novartis personnel (or designated Contract Research Organization) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff are 
required to respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the anatomical 
therapeutic chemical (ATC) classification system. Medical history / current medical conditions 
and adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology. 
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis. CFPs, FAs, and OCT images will be processed centrally by the CRC and the results 
will be sent electronically to Novartis. COA data will be processed centrally by designated 
vendors and the results will be sent electronically to Novartis. The Data management staff will 
review data received from the CRC, central lab, and COA (except Trial Feedback 
Questionnaire) vendors. Data Review will be done for data structure and data 
completeness/accuracy as defined in Vendor Data Transfer Specifications. 
Randomization codes and data about all study treatments dispensed to the subject will be 
tracked using an IRT. The system will be supplied by a vendor, who will also manage the 
database. The data will be sent electronically to Novartis (or a designated CRO) at specific 
timelines. 
The occurrence of relevant protocol deviations will be determined prior to the Week 54 
Database Lock and again prior to the final Database Lock. Once all the necessary actions have 
been completed and the database has been declared to be complete and accurate, it will be 

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locked and the treatment codes will be unmasked and made available for data analysis. However, 
masking to the original treatment assignment will be maintained at the site level i.e., BCVA 
 
) after the Week 54 Database Lock until the end of the study 
(see Section 6.4). Any changes to the database after that time can only be made after written 
agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis (or 
designated CRO) representative will review the protocol and data capture requirements (i.e. 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality / integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of subject records, the accuracy 
of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis (or designated CRO) Clinical Research Associates 
organization. Additionally, a central analytics organization may analyze data & identify risks 
& trends for site operational parameters, and provide reports to Novartis clinical teams to assist 
with trial oversight. 
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, retinal images (e.g. CFP, FA, OCT), and the results of any other 
tests or assessments. All information on eCRFs must be traceable to these source documents in 
the subject’s file.  The investigator must also keep the original informed consent form signed 
by the subject (a signed copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and / or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion / exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed. 
12 
Data analysis and statistical methods 
The database including all Week 54 data will be locked once all initially planned subjects have 
completed the Week 54 visit or terminated the study prior to Week 54. The primary analysis 
based on Week 54 data, will be derived from this database. All subjects still in the study beyond 
Week 54 will continue to receive study treatment as scheduled through the planned study 
duration. The analysis of the data collected after the Week 54 visit will be performed once all 
subjects complete the EOS visit or discontinue from the study.   
Summary statistics will be presented by treatment arm unless otherwise specified. For 
continuous variables, summary statistics will generally include: n, mean, standard deviation, 

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median, quartiles, minimum, and maximum. For categorical variables, these will generally 
include: n, frequency and percentage in each category. Further technical details and discussions 
of the statistical considerations will be provided in the Statistical Analysis Plan (SAP). 
Additional analysis  may be also conducted to evaluate the impact of COVID-19 pandemic. 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
Analysis sets 
The All-Enrolled Set includes all subjects who have signed informed consent and are assigned 
subject numbers. 
The Randomized Set will consist of all randomized subjects. Subjects are considered 
randomized when they have been deemed eligible for randomization by the investigator and 
given a randomization number. Subjects will be analyzed according to the treatment assigned 
to them at randomization. 
The Full Analysis Set (FAS) comprises all randomized subjects who receive at least one study 
treatment. Subjects in the FAS will be analyzed according to the treatment assigned to them at 
randomization. 
The Safety Analysis Set (SAF) includes all subjects who receive at least one study treatment. 
Subjects in the SAF will be analyzed according to the actual study treatment they 
received, where treatment received is defined as the randomized/assigned treatment if the 
subject took at least one dose of that treatment, or the first treatment received if the 
randomized/assigned treatment was never received. 
The Per Protocol Set (PPS) is a subset of the FAS and will exclude or censor data from subjects 
with important protocol deviations (PDs) and analysis restrictions (ARs) that are expected to 
majorly affect the validity of the assessment of efficacy at Week 54 . 
Before the Week 54 database lock the relevant protocol deviations will be identified at the 
subject level in the database. Censoring applied in relation to specific PDs and ARs will be 
specified as well. 
12.2 
Subject demographics and other baseline characteristics 
Demographics and baseline characteristics will be summarized with descriptive statistics for 
the FAS by treatment arm and overall. Relevant medical history and current medical conditions 
will be listed for ocular and non-ocular events. Other relevant baseline information will be listed 
and summarized with descriptive statistics as appropriate. 
12.3 
Treatments 
Descriptive summary statistics for exposure to study treatment will be provided for the SAF.  
Ocular and non-ocular prior and concomitant medications will be listed for each treatment arm. 
Ocular medications will be listed for the study eye and the fellow eye separately. 
Anti-VEGF medications will be summarized by ATC class and preferred term for systemic 
route, the study eye, and the fellow eye separately. 

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12.4 
Analysis of the primary endpoint(s) 
12.4.1 
Definition of primary endpoint(s) 
The primary endpoint is the change from Baseline in BCVA at Week 54. BCVA is defined in 
Section 8.3.1. 
The key secondary endpoints are the proportion of subjects with no PDR in the study eye 
at Week 54, and the proportion of subjects with center-involved DME in the study eye up to 
Week 54. The endpoints are defined as follows: 
• The event "no PDR" is defined as a DRSS score < 61. The DRSS score will be assessed 
by the CRC using 7-field CFP images. 
• Subjects that have at least one center-involved DME event in the study eye after Baseline 
will be classified as with center-involved DME. Center-involved DME will be defined 
according to CRC evaluation of predefined anatomical parameters. 
All endpoints are defined with respect to the study eye. The different estimands of interest for 
this study are detailed in Table 12-1. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
12.4.2.1 Analysis of change from baseline in BCVA at Week 54 
The objective related to the primary endpoint is to demonstrate non-inferiority of brolucizumab 
versus PRP with respect to the change from Baseline in BCVA at Week 54, assuming a non-
inferiority margin of 4 ETDRS letters. 
Let: 
B = Brolucizumab 6 mg 
P = PRP 
Consider the following non-inferiority hypotheses related to a non-inferiority margin of 4 
letters: 
H01: μB – μP ≤ -4 letters versus HA1: μB – μP > -4 letters 
where μB and μP are the corresponding unknown true mean changes from Baseline in BCVA at 
Week 54 in the brolucizumab and PRP arms, respectively. 
The primary estimand associated with the above hypotheses is defined as the between-treatment 
difference in change from Baseline in BCVA at Week 54, excluding the confounding effect of 
alternative DR/DME treatment(s) applied to the study eye (e.g. alternative anti-VEGF 
treatments,  as further detailed in Section 6.2.2 and in the SAP). The analysis set for the primary 
estimand will be the FAS as described in Table 12-1. 
Based on the FAS, the above hypotheses will be tested via an analysis of covariance 
(ANCOVA) model. The model will include treatment, Baseline DR Severity category 
(Moderate PDR or better, High-risk PDR or worse), age category (< 55, ≥ 55) and region as 
factors, with Baseline BCVA as a covariate.  

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The two-sided 95% confidence interval (CI) for the least square mean difference (brolucizumab 
- PRP) at Week 54 will be presented. Non-inferiority will be considered established if the lower 
limit of the corresponding 95% CI is greater than -4 letters. 
The following superiority hypotheses for the primary endpoint may be further evaluated after 
non-inferiority for the primary endpoint and superiority for the first key secondary endpoint are 
established: 
H02: μB – μP ≤ 0 letters versus HA2: μB – μP > 0 letters. 
Superiority in BCVA will be considered established if the lower limit of the corresponding 95% 
CI from the same ANCOVA model used to assess for non-inferiority analysis is greater than 0 
letters. 
Multiplicity 
control 
of 
primary 
endpoint 
and 
key 
secondary 
endpoints 
is 
discussed in Section 12.4.2.4. 
12.4.2.2 Analysis of PDR status at Week 54 
The objective related to this key secondary endpoint is to demonstrate superiority of 
brolucizumab versus PRP with respect to increasing the proportion of subjects with no PDR at 
Week 54. The following hypotheses are defined: 
H03: πB – πP ≤ 0 versus HA3: πB – πP > 0 
where πB and πP are the corresponding unknown true proportions of subjects with no PDR in 
the study eye at Week 54 in the brolucizumab and PRP arms, respectively. 
The above hypotheses will be tested via Cochran-Mantel-Haenszel (CMH) test at a one-sided 
significance level of 0.025 using the FAS, after non-inferiority for the primary endpoint is 
established. The CMH test will include baseline DR Severity category (Moderate PDR or better, 
High-risk PDR or worse), age category (< 55, ≥ 55) and region as adjusting factors. Multiplicity 
control is discussed in Section 12.4.2.4. 
The difference in proportion between treatment arms will be estimated using the weighted 
average of the proportion differences over adjusting factors using the Mantel-Haenszel 
weights. Adjusting factors will be the same as for the CMH test. 
12.4.2.3 Analysis of emergent center-involved DME up to Week 54 
The objective related to this key secondary endpoint is to demonstrate superiority of 
brolucizumab versus PRP with respect to reducing the proportion of subjects with center-
involved DME up to Week 54. The following hypotheses are defined: 
H04: λB – λP ≥ 0 versus HA4: λB – λP < 0 
where λB and λP are the corresponding unknown true proportions of subjects with at least one 
center-involved DME event in the study eye up to Week 54 in the brolucizumab and PRP arms, 
respectively. 
The above hypotheses will be tested via CMH test at a one-sided significance level of 
0.025 using the FAS. The CMH test will include the same adjusting factors as for the first key 
secondary endpoint described in Section 12.4.2.2. Multiplicity control is discussed later in 
Section 12.4.2.4. 

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The difference in proportions between treatment arms will be estimated using the weighted 
average of the proportion differences over adjusting factors using the Mantel-Haenszel 
weights. Adjusting factors will be the same as for the CMH test. 
Kaplan-Meier estimates of the proportions of subjects with center-involved DME over time 
and at Week 54 will also be presented for each treatment arm. 
12.4.2.4 Multiplicity control of primary and key secondary endpoints 
To control the overall type I error rate at a one-sided 0.025 level, testing of non-inferiority 
for the primary endpoint, superiority for the primary endpoint and superiority for the key 
secondary endpoints will be conducted in a hierarchical sequence as described below: 
1. Non-inferiority for primary endpoint (BCVA): H01 versus HA1 
2. Superiority for key secondary endpoint 1 (PDR): H03 versus HA3 
3. Superiority for primary endpoint (BCVA): H02 versus HA2 
4. Superiority for key secondary endpoint 2 (center-involved DME): H04 versus HA4 
12.4.3 
Handling of missing values/censoring/discontinuations 
The primary estimand and other supplementary estimands of interest are noted in Table 12-1 
below together with their key attributes, including the handling of intercurrent events associated 
with the intake of alternative treatments for DR/DME in the study eye. The estimands outlined 
below will be discussed in further detail in the SAP, including the handling of additional 
intercurrent events of interest. 

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Table 12-1 
Primary, key secondary and supplementary estimands 
Endpoint 
Estimand 
Estimand 
definition 
Analysis set 
Data 
included in 
analysis[1] 
Statistical 
methods 
(including 
missing data 
strategy) 
BCVA 
Primary 
estimand 
Difference in 
change from 
Baseline in 
BCVA at 
Week 54 
excluding the 
effect of 
alternative 
DR/DME 
treatment(s) 
FAS 
All data 
captured until 
the start of 
alternative 
DR/DME 
treatment(s) 
will be 
included 
ANCOVA 
model as 
specified 
in Section 12.
4.2.1. Last 
observation 
carried 
forward (LOC
F) imputation / 
replacement 
for missing 
data (e.g data 
unavailable 
due to lost to 
follow-up) 
/censored 
data (e.g. data 
unavailable 
due to use of 
alternative 
anti-VEGF). 
BCVA 
Sensitivity 
to primary 
estimand 
Same as 
above 
Same as 
above 
Same as 
above 
ANCOVA 
model as per 
the primary 
estimand and 
alternative 
methods of 
handling 
missing or 
confounded 
data. 
BCVA 
Supplementar
y estimand A0 
Difference in 
change from 
Baseline in 
BCVA at 
Week 54 
regardless of 
alternative 
DR/DME 
treatment(s) 
FAS 
All data 
captured will 
be included 
ANCOVA 
model as per 
the primary 
estimand. 
LOCF 
imputation for 
missing data. 

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Endpoint 
Estimand 
Estimand 
definition 
Analysis set 
Data 
included in 
analysis[1] 
Statistical 
methods 
(including 
missing data 
strategy) 
BCVA 
Supplementar
y estimand B0 
Difference in 
change from 
Baseline in 
BCVA at 
Week 54 
excluding the 
effect of 
alternative 
DR/DME 
medication(s) 
and important 
protocol 
deviations/AR
s as per the 
definition of 
the PPS 
PPS 
All data 
captured until 
the start of 
alternative 
DR/DME 
treatment(s) 
will be 
included  
ANCOVA 
model as per 
the primary 
estimand. 
LOCF 
imputation / 
replacement  
for 
missing /cens
ored data. 
DRSS 
Key 
secondary 
estimand 1 
Difference in 
proportions of 
subjects with 
no PDR at 
Week 
54 excluding 
the effect of 
alternative 
DR/DME 
treatment(s) 
FAS 
All data 
captured until 
the start of 
alternative 
DR/DME 
treatment(s) 
will be 
included 
CMH test and 
weighted 
proportion 
difference as 
specified 
in Section 12.
4.2.2 LOCF 
imputation/ 
replacement 
for missing / 
censored data 
DRSS 
Sensitivity 
to key 
secondary 
estimand 1 
Same as 
above 
Same as 
above 
Same as 
above 
CMH test and 
weighted 
proportion 
difference with 
alternative 
methods of 
handling 
missing or 
confounded 
data. 
DRSS 
Supplementar
y estimand A1 
Difference in 
proportions of 
subjects with 
no PDR at 
Week 
54 regardless 
of alternative 
DR/DME 
treatment(s) 
FAS 
All data 
captured will 
be included 
CMH test and 
weighted 
proportion 
difference as 
specified in 
Section 12.4.2
.2. 
LOCF 
imputation for 
missing data. 

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Endpoint 
Estimand 
Estimand 
definition 
Analysis set 
Data 
included in 
analysis[1] 
Statistical 
methods 
(including 
missing data 
strategy) 
Center-
involved DME 
Key 
secondary 
estimand 2 
Difference in 
proportions of 
subjects with 
center-
involved DME 
up to Week 
54. 
FAS 
All data 
captured will 
be included 
Subjects who 
receive 
alternative 
DME 
treatment(s) 
will be 
classified as 
with center-
involved DME. 
CMH test and 
weighted 
proportion 
difference as 
specified 
in Section 12.
4.2.3. 
 
[1] Other intercurrent events of interest may be defined in the SAP. 
12.4.4 
Sensitivity and supplementary analyses 
Sensitivity and supplementary analyses for the primary endpoint and key secondary endpoints 
are specified in Table 12-1. 
The following subgroup analyses will be explored using the FAS for primary endpoint: 
• Age category 
• Sex 
• Baseline BCVA categories 
• Diabetes type  
• Baseline HbA1c categories 
• Baseline DR severity categories 
• Region 
Further description of the supplementary and sensitivity analyses will be detailed in the SAP. 
12.5 
Analysis of secondary endpoints 
12.5.1 
Efficacy endpoints 
All endpoints related to secondary objectives are defined with respect to the study eye. 
Secondary efficacy endpoints related to diabetic retinopathy status: 
• Proportion of subjects with at least 2 steps improvement from Baseline in ETDRS DRSS 
score at Week 54 and Week 96 
• Proportion of subjects with at least 3 steps improvement from Baseline in ETDRS DRSS 
score at Week 54 and Week 96 
• Proportion of subjects with no PDR at Week 96 

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Secondary efficacy endpoints related to visual acuity: 
• Area under the curve in change from Baseline in BCVA up to Week 54 and Week 96 
Secondary efficacy endpoints related to ocular complications: 
• Proportion of subjects developing vision-threatening complications associated with DR up 
to Week 54 and Week 96 
• Proportion of subjects with center-involved DME up to Week 96 
Details and other additional analyses (e.g. efficacy presentation by visit) for the secondary 
endpoints will be described in SAP. 
12.5.2 
Safety endpoints 
Safety endpoints are based on the variables from safety assessments, which include: 
• Adverse events 
• IOP 
• Vital signs 
• Laboratory results 
There are no formal safety hypotheses in this study. All safety analyses will be performed using 
the safety analysis set SAF. 
Adverse events 
The number (and percentage) of subjects with treatment-emergent adverse events (events 
started after the first study treatment or events present prior to start of study treatment but which 
increased in severity based on preferred term) will be summarized in the following ways: 
• by treatment, primary system organ class and preferred term 
• by treatment, primary system organ class, preferred term and maximum severity 
Separate summaries will be provided for study treatment related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation of study treatment 
or the study. In addition, a separate summary for death including on-treatment and post-
treatment deaths will be provided. Separate presentations will be provided related to ocular 
events in the study eye and fellow eye and non-ocular events. Additional summaries will be 
provided by severity and causality (separately assessed for the treatment procedure and the 
drug). 
Subject listings of all adverse events will be provided. Deaths and other serious or clinically 
significant non-fatal adverse events will be listed separately. A subject with multiple adverse 
events within a primary system organ class is only counted once towards the total of the primary 
system organ class. 
The number (and proportion) of subjects with adverse events of special interest will be 
summarized by treatment. 

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IOP, vital signs and clinical laboratory evaluations 
Pre-treatment and post-treatment IOP measurements will be presented descriptively . Vital 
signs and laboratory results will be summarized descriptively.  
12.7 
Interim analyses 
The database including all Week 54 data will be locked once all subjects have completed the 
Week 54 visit or terminated the study prior to Week 54. The primary analysis based on Week 
54 data will be derived from this database. Formal testing of the primary endpoint and key 
secondary endpoints will be performed at the primary analysis time point. 

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12.8 
Sample size calculation 
A sample size of 300 subjects per arm will allow the assessment of brolucizumab 6 mg versus 
PRP for non-inferiority with respect to the primary endpoint and superiority with respect to the 
key secondary endpoints. 
To account for a drop-out rate of 15%, a total of approximately 706 (353 per arm) subjects will 
need to be randomized. 
12.8.1 
Primary endpoint(s) 
A sample size of 300 subjects per arm will allow assessment of non-inferiority (using a non-
inferiority margin of 4 ETDRS letters) of brolucizumab 6 mg versus PRP with respect to the 
change from Baseline in BCVA at Week 54. Assuming that the BCVA changes follow a normal 
distribution with equal means between treatments, and a common standard deviation of 10 
letters, for a one‑sided alpha level of 0.025, there is >99% power to reject the null hypothesis 
that brolucizumab 6 mg is inferior to PRP. Sensitivity to the assumptions used to assess power 
for both non-inferiority and superiority testing is shown in Table 12-2. 
Table 12-2 
Power for primary endpoint 
True treatment 
difference for 
brolucizumab vs PRP 
(letters) 
SD (letters) 
Power for non-
inferiority test 
Power for superiority 
test 
0 
10 
> 99% 
2.5% 
0 
13 
96% 
2.5% 
3 
10 
> 99% 
96% 
3 
13 
> 99% 
81% 
5 
10 
> 99% 
> 99% 
5 
13 
> 99% 
> 99% 
12.8.2 
Secondary endpoint(s) 
A sample size of 300 subjects per arm will allow assessment of superiority of brolucizumab 6 
mg versus PRP with respect to increasing the proportion of subjects with no PDR at Week 54. 
Assuming that the proportion of such events in the PRP arm is 15%, and the difference in 
proportion is 11% (i.e. the proportion in the brolucizumab arm is 26%), for a one‑sided alpha 
level of 0.025, nominally there is 90% power to reject the null hypothesis that brolucizumab 6 
mg is not superior to PRP. 
A sample size of 300 subjects per arm will allow assessment of superiority of brolucizumab 6 
mg versus PRP with respect to reducing the proportion of subjects with central-involved DME 
up to Week 54. Assuming that the proportion of such events in the PRP arm is 16%, and the 
difference in proportion is 9% (i.e. the proportion in the brolucizumab arm is 7%), for a 
one‑sided alpha level of 0.025, nominally there is 92% power to reject the null hypothesis that 
brolucizumab 6 mg is not superior to PRP. 
The above calculations use the normal approximation for the binomial distribution with a 
continuity correction. 

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13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the International Council on Harmonisation (ICH) Harmonized Tripartite Guidelines for 
Good Clinical Practice, with applicable local regulations (including European Directive 
2001/20/EC, US CFR 21), and with the ethical principles laid down in the Declaration of 
Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board / Independent Ethics Committee (IRB / IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment procedures 
(e.g. advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs / IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion and finalization of the study report 
the results of this trial will be submitted for publication and posted in a publicly accessible 
database of clinical trial results, such as the Novartis clinical trial results website and all required 
Health Authority websites (e.g. Clinicaltrials.gov, EudraCT etc.). Results from the interim 
analyses may be published prior to study completion. 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System that includes all activities involved in 
quality assurance and quality control, to ensure compliance with written Standard Operating 
Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols, and internal Standard Operating Procedures, and are performed according to written 
Novartis processes. 

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14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 

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15 
References 
References are available upon request 
Brucker AJ, Qin H, et al (2009) Observational study of the development of diabetic macular 
edema following panretinal (scatter) photocoagulation given in 1 or 4 sittings. Arch. 
Ophthalmol. p. 132-40. 
Cheung N, Mitchell P, Wong TY (2010) Diabetic retinopathy. Lancet p. 124-36. 
Cho NH, Shaw JE, Karuranga S, et al (2018) IDF Diabetes Atlas: Global estimates of diabetes 
prevalence for 2017 and projections for 2045. Diabetes Res. Clin. Pract. p. 271-281. 
Dugel PU, Koh A, Ogura Y, et al (2019) HAWK and HARRIER: Phase 3, Multicenter, 
Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular 
Degeneration. Ophthalmology. 
ETDRS Research Group (1991) Early photocoagulation for diabetic retinopathy. ETDRS 
report number 9. Ophthalmology p. 766-85. 
Escher D, Schmidt A, Steiner P, et al (2015) Single-chain antibody fragments in 
ophthalmology. EURETINA Congress. 
Gross JG, Glassman AR, Jampol LM, et al (2015) Panretinal Photocoagulation vs 
Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical 
Trial. JAMA p. 2137-2146. 
Jabs DA, Nussenblatt RB, Rosenbaum JT; (2005) Standardization of uveitis nomenclature for 
reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. 
0(3):509-16. 
Lang GE, Stahl A, Voegeler J, et al (2019) Efficacy and safety of ranibizumab with or without 
panretinal laser photocoagulation versus laser photocoagulation alone in proliferative diabetic 
retinopathy - the PRIDE study. Acta Ophthalmologica. Accepted for publication. 
Leasher JL, Bourne RR, Flaxman SR, et al (2016) Global Estimates on the Number of People 
Blind or Visually Impaired by Diabetic Retinopathy: A Meta-analysis From 1990 to 2010. 
Diabetes Care p. 1643-9. 
Moutray T, Evans JR, Lois N, et al (2018) Different lasers and techniques for proliferative 
diabetic retinopathy. Cochrane Database Syst Rev p. CD012314. 
Nussenblatt RB, Palestine AG, Chan CC, Roberge F. (1985) Standardization of vitreal 
inflammatory activity in intermediate and posterior uveitis. Ophthalmology. 2(4):467-71. 
Preti RC, Ramirez LM, Monteiro ML, et al (2013) Contrast sensitivity evaluation in high risk 
proliferative diabetic retinopathy treated with panretinal photocoagulation associated or not 
with intravitreal bevacizumab injections: a randomised clinical trial. Br J Ophthalmol p. 885-
9. 
Sivaprasad S, Prevost AT, Vasconcelos JC, et al (2017) Clinical efficacy of intravitreal 
aflibercept versus panretinal photocoagulation for best corrected visual acuity in patients with 

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proliferative diabetic retinopathy at 52 weeks (CLARITY): a multicentre, single-blinded, 
randomised, controlled, phase 2b, non-inferiority trial. Lancet p. 2193-2203. 
Subash M, Comyn O, Samy A, et al (2016) The Effect of Multispot Laser Panretinal 
Photocoagulation on Retinal Sensitivity and Driving Eligibility in Patients With Diabetic 
Retinopathy. JAMA Ophthalmol p. 666-72. 
The Diabetic Retinopathy Study Research Group (1981) Photocoagulation treatment of 
proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) 
findings, DRS Report Number 8. Ophthalmology p. 583-600. 
Whitehead M, Wickremasinghe S, Osborne A, et al (2018) Diabetic retinopathy: a complex 
pathophysiology requiring novel therapeutic strategies. Expert Opin Biol Ther p. 1257-1270. 
Wong TY, Cheung CM, Larsen M, et al (2016) Diabetic retinopathy. Nat Rev Dis Primers p. 
16012. 
Wong TY, Sun J, Kawasaki R, et al (2018) Guidelines on Diabetic Eye Care: The 
International Council of Ophthalmology Recommendations for Screening, Follow-up, 
Referral, and Treatment Based on Resource Settings. Ophthalmology p. 1608-1622. 

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16 
Appendices 
Not applicable.