A Two-year, Three-arm, Randomized, Double-masked, Multicenter, Phase III Study Assessing the Efficacy and Safety of Brolucizumab Versus Aflibercept in Adult Patients With Visual Impairment Due to Diabetic Macular Edema
Phase: PHASE3
Conditions: Diabetic Macular Edema
Sponsor: Novartis Pharmaceuticals



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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.................................................................................................................9
Amendment 4 ....................................................................................................................11
Summary of previous amendments ...................................................................................12
Amendment 3 ....................................................................................................................12
Amendment 2 ....................................................................................................................13
Amendment 1 ....................................................................................................................14
Protocol summary..............................................................................................................16
1
Introduction .......................................................................................................................20
1.1
Background............................................................................................................20
1.2
Purpose ..................................................................................................................22
2
Study objectives and endpoints .........................................................................................23
3
Investigational plan ...........................................................................................................24
3.1
Study design...........................................................................................................24
3.2
Rationale for study design .....................................................................................26
3.3
Rationale for dose/regimen, route of administration and duration of treatment....26
3.4
Rationale for choice of comparator .......................................................................27
3.5
Purpose and timing of interim analyses/design adaptations..................................27
3.6
Risks and benefits..................................................................................................27
4
Population..........................................................................................................................28
4.1
Inclusion criteria ....................................................................................................28
4.2
Exclusion criteria...................................................................................................29
5
Treatment...........................................................................................................................31
5.1
Study treatment......................................................................................................31
5.1.1
Investigational and control drugs..........................................................31
5.1.2
Additional treatment..............................................................................32
5.2
Treatment arms......................................................................................................32
5.3
Treatment assignment and randomization.............................................................32
5.4
Treatment masking ................................................................................................32
5.5
Treating the patient................................................................................................33
5.5.1
Patient numbering .................................................................................33
5.5.2
Dispensing the study drug.....................................................................34

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5.5.3
Handling of study and additional treatment..........................................34
5.5.4
Instructions for prescribing and taking study treatment........................34
5.5.5
Permitted dose adjustments and interruptions of study treatment ........37
5.5.6
Rescue medication/procedure ...............................................................37
5.5.7
Concomitant medications and treatments .............................................38
5.5.8
Prohibited medication ...........................................................................38
5.5.9
Emergency breaking of assigned treatment code..................................38
5.6
Study completion and discontinuation...................................................................39
5.6.1
Study completion and post-study treatment..........................................39
5.6.2
Discontinuation of study treatment .......................................................39
5.6.3
Withdrawal of informed consent...........................................................40
5.6.4
Loss to follow-up ..................................................................................40
5.6.5
Early study termination by the sponsor.................................................41
6
Visit schedule and assessments .........................................................................................41
6.1
Information to be collected on screening failures..................................................44
6.2
Patient demographics/other baseline characteristics .............................................44
6.3
Treatment exposure and compliance .....................................................................44
6.4
Efficacy..................................................................................................................44
6.4.1
Visual acuity..........................................................................................45
6.4.2
Optical coherence tomography .............................................................45
6.4.3
Color fundus photography and fluorescein angiography......................45
6.4.4
Appropriateness of efficacy assessments..............................................46
6.5
Safety.....................................................................................................................46
6.5.1
Physical examination ............................................................................46
6.5.2
Vital signs..............................................................................................46
6.5.3
Height and Weight ................................................................................47
6.5.4
Ophthalmic examination.......................................................................47
6.5.5
Laboratory evaluations..........................................................................48
6.5.6
Electrocardiogram (ECG) .....................................................................49
6.5.7
Pregnancy and assessments of fertility .................................................49
6.5.8
Appropriateness of safety measurements..............................................49
6.6
Other assessments..................................................................................................49
6.6.1
Clinical Outcome Assessments (COAs) ...............................................49
6.6.2
Resource utilization...............................................................................50
6.6.3
Pharmacokinetics ..................................................................................50
6.6.4
Anti-drug antibodies (immunogenicity)................................................50

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51
6.6.6
Other biomarkers...................................................................................51
7
Safety monitoring..............................................................................................................51
7.1
Adverse events.......................................................................................................51
7.2
Serious adverse events...........................................................................................53
7.2.1
Definition of SAE .................................................................................53
7.2.2
SAE reporting........................................................................................54
7.3
Liver safety monitoring .........................................................................................54
7.4
Renal safety monitoring.........................................................................................55
7.5
Reporting of study treatment errors.......................................................................56
7.6
Pregnancy reporting...............................................................................................56
8
Data review and database management.............................................................................56
8.1
Site monitoring ......................................................................................................56
8.2
Data collection.......................................................................................................57
8.3
Database management and quality control............................................................57
8.4
Data Monitoring Committee..................................................................................58
8.5
Adjudication Committee........................................................................................58
9
Data analysis......................................................................................................................58
9.1
Analysis sets ..........................................................................................................59
9.2
Patient demographics and other baseline characteristics.......................................60
9.3
Treatments .............................................................................................................60
9.4
Analysis of the primary and first key secondary endpoints...................................60
9.4.1
Primary and first key secondary endpoints ...........................................60
9.4.2
Additional key secondary endpoints .....................................................62
9.4.3
Sensitivity and supportive analyses ......................................................64
9.5
Analysis of secondary endpoints ...........................................................................64
9.5.1
Efficacy endpoints.................................................................................64
9.5.2
Safety endpoints....................................................................................66
9.5.3
Resource utilization...............................................................................67
9.5.4
Pharmacokinetics ..................................................................................67
9.5.5
Biomarkers............................................................................................67
9.5.6
PK/PD ...................................................................................................67
9.5.7
PRO (Patient Reported Outcome).........................................................67
9.5.8
Anti-drug antibodies..............................................................................67
68
68

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9.7
Interim analyses.....................................................................................................68
9.8
Sample size calculation..........................................................................................68
10 Ethical considerations........................................................................................................69
10.1
Regulatory and ethical compliance........................................................................69
10.2
Informed consent procedures.................................................................................69
10.3
Responsibilities of the investigator and IRB/IEC..................................................70
10.4
Publication of study protocol and results...............................................................70
10.5
Quality Control and Quality Assurance.................................................................70
11 Protocol adherence ............................................................................................................70
11.1
Protocol amendments.............................................................................................71
12 References .........................................................................................................................72
13 Appendix 1: Clinically notable laboratory values and vital signs.....................................73
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.....................................................................................................................74
15 Appendix 3: Specific Renal Alert Criteria and Actions....................................................75
List of tables
Table 2-1
Objectives and related endpoints ..........................................................23
Table 5-1
Prohibited medications / procedures.....................................................38
Table 6-1
Assessment schedule.............................................................................42
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................56
Table 9-1
Primary and supplementary estimands..................................................62
Table 13-1
Clinically notable laboratory values......................................................73
Table 14-1
Liver Event and Laboratory Trigger Definitions ..................................74
Table 15-1
Specific Renal Alert Criteria and Actions.............................................75
List of figures
Figure 3-1
Study design..........................................................................................25
Figure 5-1
Dosing schedule ....................................................................................36

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List of abbreviations
ADA
Anti-drug antibody
AE
Adverse Event
ALT
Alanine aminotransferase
AMD
Age-related macular degeneration
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
AR
Analysis restrictions
AST
Aspartate aminotransferase
BCVA
Best-corrected visual acuity
CFR
US Code of Federal Regulations
CI
Confidence interval
CNV
Choroidal neovascularization
CPO
Country Pharma Organization
COA
Clinical Outcome Assessment
CRC
Central Reading Center
eCRF
Case Report/Record Form (electronic)
COVID-19
Coronavirus disease 2019
CRO
Contract Research Organization
CSFT
Central subfield thickness 
CSFTns
Central Subfield Thickness-neurosensory retina 
DDE
Direct Data Entry
DM
Diabetes mellitus
DMC
Data monitoring committee
DME
Diabetic macular edema
DR
Diabetic retinopathy
DRSS
Diabetic retinopathy severity scale
DS&E
Drug Safety & Epidemiology
ECG
Electrocardiogram
EDC
Electronic Data Capture
ETDRS
Early Treatment Diabetic Retinopathy Study
FA
Fluorescein angiography
FAS
Full analysis set
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transpeptidase
HbA1c
Hemoglobin A1c
hCG
Human chorionic gonadotropin
HDL
High-density lipoprotein
IB
Investigator Brochure
ICH
International Conference on Harmonization
i.e.
Id est

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IEC
IOI
Independent Ethics Committee
Intraocular inflammation
IOP
Intraocular pressure
IN
Investigator notification
IP
Investigational product
IRB
Institutional Review Board
IRF
Intraretinal fluid
IRT
Interactive Response Technology
ITT
Intention-to-treat
IUD
Intrauterine device
IUS
Intrauterine system
IVT
Intravitreal Treatment
kDa
kilo Daltons
LDH
Lactate dehydrogenase
LDL
Low-density lipoprotein
LFT
Liver function test
LOCF
Last observation carried forward
MAR
Missing at random
MedDRA
Medical dictionary for regulatory activities
MMRM
Mixed model for repeated measures
nAMD
Neovascular age-related macular degeneration
n.a.
Not applicable
NEI
National Eye Institute
NIH
National Institutes of Health
NIM
Non-inferiority margin
OCT
Optical coherence tomography
PD
Protocol Deviation
PDR
Proliferative diabetic retinopathy
PFS
Pre-filled syringe
PK
Pharmacokinetic
PPS
Per Protocol Set/Protocol analysis set
PRO
Patient reported outcome
PT
Preferred Term 
QoL
Quality of Life
RBC
Red blood cells
RAO
Retinal artery occlusion
RO
Retinal vascular occlusion
RV
Retinal vasculitis
SAE
Serious Adverse Event
SAP
Statistical analysis plan
scFv
single-chain fragment variable
SD-OCT
Spectral domain optical coherence tomography
SGOT
Serum glutamic oxaloacetic transaminase

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SGPT
Serum glutamic pyruvic transaminase
SOC
System Organ Class
SRF
Subretinal fluid
SUN
Standardization uveitis nomenclature
SUSAR
Suspected Unexpected Serious Adverse Reactions
USM
Urgent safety measures
TC
Total cholesterol
TG
Triglycerides
TIA
Transient ischemic attack
VA
Visual acuity
VEGF
Vascular endothelial growth factor
VFQ-25
Visual Functioning Questionnaire-25
vs.
Versus
WBC
White blood cells
WHO
World Health Organization
WoC
Withdrawal of Consent
YAG laser
Yttrium aluminum garnet laser

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Glossary of terms
Cohort 
A specific group of patients fulfilling certain criteria
Control drug
Drugs(s) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the patient in a time unit 
Electronic Data Capture 
(EDC)
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.
eSource DDE
eSource Direct Data Entry (DDE) refers to the capture of clinical study 
data electronically, at the point of care. eSource Platform/Applications 
reduce the use of paper capture source data during clinical visits. 
eSource combines source documents and case report forms (eCRFs) 
into one application, allowing for the real time collection of clinical trial 
information to sponsors and other oversight authorities, as 
appropriate.
Enrollment
Point/time of patient entry into the study at which informed consent 
must be obtained (e.g. prior to starting any of the procedures 
described in the protocol)
Investigational drug
The drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.”
Masked/evaluating 
investigator
For the entire study duration and all study patients, the 
masked/evaluating investigator is responsible for all aspects of the 
study (the conduct/supervision of all assessments and treatment 
decisions except the injection procedures and the safety assessment 
following the active/sham injections)
Medication pack number
A unique identifier on the label of each investigational drug package
Part 
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: 
a single dose part and a multiple dose part, or a part in patients with 
established disease and in those with newly-diagnosed disease.
Patient ID 
A unique number assigned to each patient upon signing the informed 
consent 
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-
up) which are described in the Protocol. Periods define the study 
phases and will be used in clinical trial database setup and eventually 
in analysis
Randomization number
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Source Data/Document
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 or 
eSource.

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Study drug/ treatment
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug (s), 
placebo/comparator active drug run-ins or background therapy
Study Treatment 
Discontinuation (TD)
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date 
Unmasked/treating 
investigator
For the entire study duration and all study patients, the treating 
investigator only performs the treatment (injection active/sham) and 
assesses patient safety following the active/sham injections
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study
Visual acuity assessor
For the entire study duration and all study patients, the visual acuity 
assessor (which could be a masked/evaluating investigator) performs 
the BCVA assessment and is masked to the assigned treatment
Personal Data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples.
Withdrawal of study 
consent (WoC)
Withdrawal of consent from the study occurs only when a subject does 
not want to participate in the study any longer, and does not allow any 
further collection of personal data

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Amendment 4
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 with brolucizumab (RTH258) 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. Some other administrative changes have also been incorporated.
Changes to the protocol
Protocol sections changed in relation to this emerging safety issue are:
Section 1.1 Background: 

Information added to describe Urgent Safety Measures
Section 3.6 Risk and benefits:

Information added to describe Urgent Safety Measures and additional information on 
gender imbalance on IOI following brolucizumab treatment
Section 5.5.4 Instruction for prescribing and taking study treatment

Requirement of treatment discontinuation was added if subject developed RV and/or RO
Section 5.6.2 Discontinuation of study treatment:

Changes were made as follows:

Use of prohibited treatment (see Section 5)

Any situation in which study participation might result in a safety risk to the subject

Subject developing retinal vasculitis and/or retinal vascular occlusion event
Section 6.5.4 Ophthalmic examination:

Requirement of treatment discontinuation was added if subject developed RV and/or RO.
Other changes incorporated in this amendment
Section 5.5.7 Permitted concomitant therapy requiring caution and/or action:

Added recommendations on the time window for a study subject to receive the COVID-19 
vaccine.

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 strike through 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 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. 
Summary of previous amendments
Amendment 3
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 a new safety signal from 
post-marketing case reports and its impact on the benefit-risk balance.

Section 5.5.4 Instructions for prescribing and taking study treatment: Additional 
guidance is 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 6-1 Assessment schedule

Section 6.4.3 Color fundus photography and fluorescein angiography:

Section 6.5.4 Ophthalmic Examination

Section 6.5.8 Appropriateness of safety measurements
Modifications were made to include importance of Estimands per ICH E9 (R1) guidance in the 
following Sections:

Section 9.1 Analysis sets

Section 9.4.1.2 Handling of missing values/censoring/discontinuations

Section 9.4.3 Sensitivity and supportive analyses
Changes were incorporated to address the COVID-19 pandemic in the following sections:

Section 6 Visit Schedule and Assessments

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Protocol summary
Protocol number
RTH258B2301
Full Title
A two-year, three-arm, randomized, double-masked, multicenter, 
phase III study assessing the efficacy and safety of brolucizumab versus 
aflibercept in adult patients with visual impairment due to diabetic 
macular edema (KESTREL)
Brief title
Study of efficacy and safety of brolucizumab vs. aflibercept in patients 
with visual impairment due to diabetic macular edema
Sponsor and Clinical 
Phase
Novartis
Phase III
Investigation type
Drug
Study type
Interventional
Purpose and rationale
This study is designed to evaluate the efficacy and safety of 
brolucizumab in treatment of patients with visual impairment due to 
diabetic macular edema (DME)
Primary Objective(s) 
To demonstrate that brolucizumab is non-inferior to aflibercept with 
respect to the visual outcome after the first year of treatment 
Secondary Objectives
To assess the efficacy and the ocular and systemic safety of 
brolucizumab:

To demonstrate that brolucizumab is non-inferior to aflibercept with 
respect to visual outcome during the last 3 months of the first year of 
treatment

To estimate the proportion of patients treated at q12w frequency with 
brolucizumab

To estimate the predictive value of the first q12w cycle for 
maintenance of q12w treatment with brolucizumab

To evaluate the functional and anatomical outcome with 
brolucizumab relative to aflibercept 

To evaluate the effect of brolucizumab relative to aflibercept on the 
Diabetic Retinopathy status

To assess the safety of brolucizumab relative to aflibercept 

To evaluate the effect of brolucizumab relative to aflibercept on 
patient-reported outcomes (VFQ-25)
Study design
In this 2-year, randomized, double-masked, multicenter, active controlled 
study consenting patients will participate in a screening period, lasting up 
to 14 days. Eligible patients will be randomized in a 1:1:1 ratio to one of 
the three treatment arms:

Brolucizumab 3 mg:
5 x q6w loading then q12w/q8w maintenance

Brolucizumab 6 mg:
5 x q6w loading then q12w/q8w maintenance

Aflibercept 2 mg:
5 x q4w loading then q8w maintenance
Population
Approximately 534 randomized patients ≥18 years of age with either type 
1 or 2 controlled diabetes mellitus and visual impairment due to diabetic 
macular edema

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Key Inclusion criteria
General
1.
Patients must give written informed consent before any study related 
assessments are performed
2.
Patients ≥18 years of age at baseline
3.
Patients with type 1 or type 2 diabetes mellitus and HbA1c of ≤10% 
at screening
4.
Medication for the management of diabetes must have been stable 
within 3 months prior to randomization and is expected to remain 
stable during the course of the study
Study Eye
5.
Visual impairment due to DME with:
BCVA score between 78 and 23 letters, inclusive, using Early 
Treatment Diabetic Retinopathy Study (ETDRS) visual acuity 
testing charts at a testing distance of 4 meters (approximate 
Snellen equivalent of 20/32 to 20/320), at screening and baseline
DME involving the center of the macula, with central subfield 
retinal thickness (measured from RPE to ILM inclusively) of 
≥320 µm on SD-OCT at screening
If both eyes are eligible, the eye with the worse visual acuity will be 
selected for study eye. However, the investigator may select the eye 
with better visual acuity, based on medical reasons or local ethical 
requirements.
Key Exclusion criteria
1.
Previous treatment with any anti-VEGF drugs or investigational drugs 
in the study eye
2.
Active proliferative diabetic retinopathy in the study eye as per the 
investigator
3.
Concomitant conditions or ocular disorders in the study eye at 
screening or baseline which could, in the opinion of the investigator, 
prevent response to study treatment or may confound interpretation 
of study results, compromise visual acuity or require medical or 
surgical intervention during the first 12-month study period (e.g., 
cataract, vitreous hemorrhage, retinal vascular occlusion, retinal 
detachment, macular hole, or choroidal neovascularization of any 
cause) 
4.
Any active intraocular or periocular infection or active intraocular 
inflammation (e.g., infectious conjunctivitis, keratitis, scleritis, 
endophthalmitis, infectious blepharitis, uveitis) in study eye at 
screening or baseline
5.
Structural damage of the fovea in the study eye at screening likely to 
preclude improvement in visual acuity following the resolution of 
macular edema, including atrophy of the retinal pigment epithelium, 
subretinal fibrosis, laser scar(s), epiretinal membrane involving fovea 
or organized hard exudate plaques
6.
Uncontrolled glaucoma in the study eye defined as intraocular 
pressure (IOP) > 25 mmHg on medication or according to 
investigator’s judgment, at screening or baseline 
7.
Neovascularization of the iris in the study eye at screening or 
baseline
8.
Evidence of vitreomacular traction in the study eye at screening or 
baseline which, in the opinion of the investigator, affect visual acuity 
Study treatment

Brolucizumab 3 mg/0.05 mL

Brolucizumab 6 mg/0.05 mL

Aflibercept 2 mg/0.05 mL

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Key Efficacy 
assessments

BCVA testing using ETDRS chart

Anatomical markers on Spectral Domain Optical Coherence 
Tomography (SD-OCT) and Color Fundus photography

ETDRS DRSS score based on Color Fundus photography
Key safety 
assessments

Adverse events

Standard ophthalmic examination

Intraocular pressure measurement

Vital signs

Blood chemistry/hematology/urinalysis
Other assessments

Visual Function Questionnaire-25 (VFQ-25)

Anti-drug antibody (ADA)
Data analysis
Primary analysis data set:
The primary data set for efficacy evaluation is the full analysis set (FAS) 
with missing values imputed by last observation carried forward (LOCF). 
The FAS includes all randomized patients who receive at least one 
intravitreal (IVT) injection.
Sensitivity analyses will be performed using the per protocol analysis set 
(PPS) and alternative methods of handling missing and descriptive 
analyses based on observed data only.
Primary and key secondary endpoints:
The primary endpoint is the change from baseline in BCVA at Week 52.
The key secondary efficacy endpoint involved in confirmatory testing is 
the change from baseline in BCVA averaged over the period Week 40 to 
Week 52.
Additional key secondary endpoints are proportion of patients maintained 
at q12w up to Week 52 and proportion of patients maintained at q12w up 
to Week 52 within those patients that qualified for q12w at Week 36 (for 
brolucizumab treatment arms only)
Statistical Hypotheses and testing strategy:
The following non-inferiority hypotheses are related to a non-inferiority 
margin of 4 letters: 
B3 = Brolucizumab 3 mg - 5 x q6w loading then q12w/q8w maintenance
B6 = Brolucizumab 6 mg - 5 x q6w loading then q12w/q8w maintenance
A = Aflibercept 2 mg
- 5 x q4w loading then q8w maintenance
H01: μB6 – μA
≤ -4 letters vs.
HA1: μB6 – μA
> -4 letters
H02: B6 – A
≤ -4 letters vs.
HA2: B6 – A
> -4 letters
H03: μB3 – μA
≤ -4 letters vs.
HA3: μB3 – μA
> -4 letters 
H04: B3 – A
≤ -4 letters vs.
HA4: B3 – A
> -4 letters
Where μB6 μB3 and μA are the corresponding unknown true mean changes 
from baseline in BCVA at Week 52; B6, B3 and A are the corresponding 
unknown true mean changes from baseline in BCVA averaged over the 
period Week 40 to Week 52; 
These 4 hypotheses will be tested sequentially in the order of their 
numbering (HAn, n=1, 2, 3, 4), i.e, confirmatory testing of the second, third 
and fourth hypotheses requires rejection of each preceding null 
hypothesis. In this setting, each hypothesis will be assessed at a one-
sided significance level of 0.025, while keeping the global type I error rate 
at 0.025.
Primary statistical method:

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Analysis of variance (ANOVA) models will be used to test the treatment 
differences regarding the endpoints ‘change from baseline in BCVA at 
Week 52’ and ‘change from baseline in BCVA averaged over the period 
Week 40 to Week 52’. The models will include baseline BCVA category 
(≤65, >65 letters) and age category (<65, ≥65) as factors. Two-sided 95% 
confidence intervals (CI) for the least square means difference 
(brolucizumab - aflibercept) will be presented. Within the specified testing 
procedure, non-inferiority will be established if the lower limit of the 
corresponding 95% CI is greater than -4 letters.
Sample size justification:
A sample size of 160 patients per arm will allow demonstration of non-
inferiority (NIM of 4 ETDRS letters) of brolucizumab 6 mg or 3 mg (either 
treatment regimen) vs. aflibercept 2 mg with respect to the BCVA change 
from baseline at Week 52, with 90% power (disregarding the dependence 
within the sequential testing procedure, i.e. local power for 3 mg) at a 
one-sided alpha level of 0.025, assuming equal means and a common 
standard deviation of 11 letters. Based on its nature it can be assumed 
that the endpoint ‘change from baseline in BCVA averaged over the 
period Week 40 to Week 52’ will not present a higher standard deviation, 
so that a (local) power of at least 90% can also be expected for its non-
inferiority claim. 
To account for a drop-out rate of 10%, a total of 534 (178 per arm) 
patients will need to be randomized.
Key words
Diabetic Macular Edema, intravitreal injection, brolucizumab, aflibercept, 
double-masked

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1
Introduction
1.1
Background
Diabetes mellitus (DM) is the most common endocrine disease in developed countries, with 
prevalence estimates ranging between 2 to 5% of the world population. Diabetic 
retinopathy (DR) and diabetic macular edema (DME) are common microvascular 
complications in patients with diabetes and may have a debilitating impact on visual acuity 
(VA), eventually leading to blindness. DME is a frequent manifestation of DR (Lee et al., 2015) 
and is the major cause of visual loss in patients with DR.
For anti-VEGF agents like ranibizumab or aflibercept a favorable benefit risk ratio was 
demonstrated with superior efficacy versus the previous standard of care (laser 
photocoagulation) in large Phase 3 programs that consequently led to their approval for the 
treatment of DME. Anti-VEGF treatment led to clinically relevant improvements of BCVA, 
reduction of fluid accumulation and decreased severity of diabetic retinopathy.
Current standard therapy
The current treatment options for patients with DME are: laser photocoagulation, IVT 
corticosteroids, IVT corticosteroid implants, or IVT anti-VEGF. Due to the efficacy and safety 
profile of anti-VEGF therapy, it has become the first-line treatment. Corticosteroids are used as 
a second line treatment and focal / grid laser photocoagulation remains a therapeutic option, but 
with a lower expected benefit compared with steroid and anti-VEGF therapy (Ziemssen F 2017; 
Korobelnik JF 2014). 
Despite the treatment success of existing anti-VEGFs, there remains a need for further treatment 
options to improve response rate and/or reduce resource use and injection frequency in patients 
with DME (Mitchell et al., 2011; Smiddy, 2011; Lang et al., 2013; Virgili et al., 2014; Agarwal 
et al., 2015).
Brolucizumab
Brolucizumab, formerly known as RTH258 and ESBA1008, is a humanized single-chain 
fragment variable (scFv), binding to VEGF-A (i.e. interfering with activation of VEGF-R1 and 
R2 on endothelial cells) with a molecular weight of ~26 kDa (kilo Daltons) that is also being 
developed for the treatment of choroidal neovascularization (CNV) associated with neovascular 
age-related macular degeneration (nAMD). 
The characteristics of brolucizumab allow delivery of a high molar dose via intravitreal 
injection. A 6 mg dose of brolucizumab delivers a molar dose which is approximately 11 and 
22 times higher than aflibercept 2 mg and ranibizumab 0.5 mg, respectively. Higher molar doses 
are expected to lead to longer presence of relevant drug levels in the eye. In addition, a low 
molecular weight and high concentration gradient between the vitreous and the retina may 
increase drug distribution to the target site of action, supporting effective control of anatomical 
disease activity. 
In a single ascending dose Phase I study (C-10-083), the median time until patients fulfilled 
protocol defined criteria for receipt of standard of care treatment was 30 days longer for 
brolucizumab 3 mg (p=0.037) and 6 mg (p=0.036) versus ranibizumab. In a separate repeat 

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dosing study (C-12-006) comparing brolucizumab 6 mg (bimonthly [q8w], then quarterly 
[q12w] administration) against aflibercept (bimonthly administration [q8w]), brolucizumab 
achieved comparable visual outcome during the loading and q8w phase, with a lower number 
of patients requiring additional rescue treatments (5 vs. 10, respectively). Brolucizumab 
demonstrated a trend for greater improvements and more stability in retinal anatomy during the 
4 cycles of q8w dosing (up to Week 40), e.g. simultaneous resolution of intraretinal and 
subretinal fluid which was achieved in 61% of brolucizumab patients versus 35% of aflibercept 
patients at Week 40. 
In the Phase III studies (HAWK, HARRIER), brolucizumab demonstrated non-inferiority to 
aflibercept in mean change in best-corrected visual acuity from baseline to Week 48 in both 
trials. These results were achieved while a majority of patients on brolucizumab 6 mg – 56% in 
HAWK and 51% in HARRIER – were maintained on a q12w dosing interval following the 
loading phase through Week 48. Brolucizumab safety was comparable to aflibercept, with the 
overall incidence of adverse events balanced across all treatment groups in both studies.
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 
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.
Summary
Ranibizumab, aflibercept and brolucizumab all inhibit the activity of VEGF-A and all have 
demonstrated efficacy in the treatment of patients with nAMD. Both ranibizumab and 
aflibercept have also consistently demonstrated efficacy in the treatment of patients with visual 
impairment due to DME. These findings support the evaluation of brolucizumab in DME 
patients. Furthermore, the profile of brolucizumab in nAMD trials indicates a potential of 
brolucizumab to differentiate versus existing anti-VEGFs on duration of action and anatomical 
efficacy in DME patients:

The higher dose administered with brolucizumab is intended to provide a prolonged 
duration of action compared with ranibizumab and aflibercept 

The positive nAMD study results regarding the q12w/q8w regimen support the 
administration of q6w loading regimen for brolucizumab and q12w/q8w during the 
maintenance phase, extending the total duration of the loading phase whilst also reducing 
the injection burden 
The above supports the initiation of a Phase III program to evaluate the efficacy and safety of 
brolucizumab in treatment of patients with visual impairment due to DME with the intention of 
evaluating the potential to reducing the treatment burden for patients.

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1.2
Purpose
The purpose of this study is to evaluate the efficacy and safety of brolucizumab in treatment of 
patients with visual impairment due to DME.

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2
Study objectives and endpoints
For the detailed description of endpoints and their statistical analysis, please refer to Section 
9.4 for primary and key secondary endpoints, Section 9.5 for other secondary 
 
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 aflibercept with respect to the 
visual outcome after the first year of 
treatment

Change from baseline in BCVA at 
Week 52
Secondary Objective(s)
Endpoint(s) for secondary objective(s)

To demonstrate that brolucizumab is non-
inferior to aflibercept with respect to visual 
outcome during the last 3 months of the 
first year of treatment

Change from baseline in BCVA 
averaged over a period Week 40 to 
Week 52

To estimate the proportion of patients 
treated at q12w frequency with 
brolucizumab 

Proportion of patients maintained at 
q12w up to Weeks 52 & 100

To estimate the predictive value of the first 
q12w cycle for maintenance of q12w 
treatment with brolucizumab

Proportion of patients maintained  at 
q12w up to Weeks 52 & 100, within 
those patients that qualified for q12w 
at Week 36

To evaluate the functional and anatomical 
outcome with brolucizumab relative to 
aflibercept 

Change from baseline by visit up to 
Week 100 in BCVA and in parameters 
derived from SD-OCT, Color fundus 
photography and Fluorescein 
angiography

To evaluate the effect of brolucizumab 
relative to aflibercept on the Diabetic 
Retinopathy status

Change in ETDRS Diabetic 
Retinopathy Severity Scale (DRSS) 
score up to Week 100

To assess the safety and tolerability of 
brolucizumab relative to aflibercept 

Incidence of Ocular and Non-ocular 
AEs, vital signs and laboratory values 
up to Week 100

To evaluate the effect of brolucizumab 
relative to aflibercept on patient-reported 
outcomes (VFQ-25)

Change in patient reported outcomes 
(VFQ-25) total and subscale scores 
from baseline up to Week 100

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3
Investigational plan
3.1
Study design
The study is a randomized, double-masked, multi-center, active-controlled, 3 armed study in 
patients with DME. 
Patients who consent and meet all the inclusion and none of the exclusion criteria will be 
screened to evaluate eligibility. After confirmation of eligibility, patients will be randomized in 
a 1:1:1 ratio to one of three treatment arms:

Brolucizumab 3 mg:
5 x q6w loading then q12w/q8w maintenance

Brolucizumab 6 mg:
5 x q6w loading then q12w/q8w maintenance

Aflibercept     2 mg:
5 x q4w loading then q8w maintenance

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Patients withdrawn from the study prior to study completion will be asked to return for an early 
discontinuation visit (Visit 28), four weeks (±7 days) following their last study visit (see 
Section 5.6.2).
3.2
Rationale for study design
This study is designed as a multi-center, double-masked, 3 arm active controlled prospective 
study to demonstrate the safety and efficacy of brolucizumab 3 mg and 6 mg against the active 
control, aflibercept 2 mg, used per authorized label. Since the treatment schedule is different 
between arms, to ensure masking, the following will apply:

in addition to every 4-week visits for all patients for 2 years, extra visits are scheduled at 
Weeks 6 and 18 for all treatment arms

the patients will receive active/sham injection at each protocol visit except Weeks 20, 28 
and 100 visits (No scheduled treatment for any arm)

Disease activity assessment will be performed for all arms

to fulfil the double-masking requirement, the investigational site will have masked and 
unmasked staff
Non-inferiority testing related to the primary efficacy parameter BCVA 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 patient population will be described in more detail in the Section 4.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
The doses and regimen for brolucizumab and aflibercept are based on the following 
considerations:

Based on the Phase III brolucizumab studies in nAMD, brolucizumab 6 and 3 mg doses 
showed comparable efficacy and safety profiles to existing anti-VEGFs with numerical 
advantages related to efficacy for the higher dose. Both doses are included in order to 
evaluate the dose-response following multiple dosing with brolucizumab in patients with 
DME.

Current evidence from large anti-VEGF pivotal studies in DME indicates that in 
comparison to nAMD an extended period of intense treatment (loading regimen) is 
required to achieve maximal BCVA gain. Hence the loading regimen was extended to 
Week 24 for brolucizumab.

The high dose of brolucizumab administered is intended to provide a prolonged duration of 
action. The positive nAMD study results regarding the q12w/q8w regimen in HAWK and 
HARRIER (Phase III clinical trials in nAMD) support q12w/q8w dosing during the 
maintenance phase also for DME in which treatment frequencies in the maintenance phase 
are similar. At the same time, these results support stretching the interval between injections 
in the loading regimen to 6 weeks. Both, extended intervals in the loading regimen and 
q12w/q8w dosing aim at reducing the injection burden. 

Aflibercept is applied as per the current labels in the EU and US.

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
Based on the Phase III trials HAWK and HARRIER, 12 weekly disease activity 
assessments (DAA) were sufficient to verify whether patients were appropriately treated. 
Introduction of disease activity assessments 8 weeks following treatment (in HARRIER) 
did not result in earlier detection of disease activity attributable to the q12w status. Hence, 
disease activity assessments are scheduled every 12 weeks in this study.
Route of administration is intravitreal injection as for all anti-VEGF treatments currently 
approved for the treatment of DME. Study duration of 2 years (with treatment over 23 months) 
is warranted to assess longer-term efficacy and safety and to assess the q12w option for 
brolucizumab over time.
3.4
Rationale for choice of comparator
Aflibercept 2 mg q8w is an established standard of care option and has been chosen as 
comparator for this study due to the consistency of the approved dose and posology of 
aflibercept (Eylea®) across many countries especially EU and US for the targeted indication as 
compared to other approved anti-VEGF treatments. 
3.5
Purpose and timing of interim analyses/design adaptations
The primary analysis will be conducted when the first 534 randomized patients have completed 
their Week 52 visit or terminated the study prior to Week 52 (first interim database lock). Data 
for additional patients randomized in Japan beyond the study target of 534 patients will be 
analyzed within the total population once these patients have completed their Week 52 visit or 
terminated the study prior to Week 52 (second interim database lock). However, if any special 
circumstance compromises the feasibility of the approach described above (first and second 
interim database locks), then the primary analysis will be conducted when all randomized 
patients have completed their Week 52 visit or terminated the study prior to Week 52.  
Another analysis may be performed by locking the Week 76 data in case of regulatory request 
for supplemental data to be submitted during the review period.
Patients will remain in the study and will continue to receive masked treatment through the 
planned duration (100 weeks) to allow for further masked evaluation of efficacy and safety. 
Treatment masking of individual patients will remain intact for all patients, investigators and 
selected staff from the Sponsor who have contact with patients or investigators or those who 
are involved in the direct conduct of the study until the final database lock has occurred.
3.6
Risks and benefits
Ranibizumab and aflibercept (both approved inhibitors of VEGF-A) have consistently 
demonstrated efficacy in VEGF-driven retinal pathologies, including DME, with benefits 
outweighing the risks. Assuming a corresponding class-effect, it is justified to expect that 
brolucizumab (having the same mechanism of action as ranibizumab and aflibercept) will 
likewise be efficacious and have a similar safety profile in the DME indication. 
In both Phase III studies (HAWK, HARRIER) in nAMD, brolucizumab demonstrated non-
inferiority to aflibercept in mean change in BCVA from Baseline to Week 48. These results 
were achieved while a majority of patients on brolucizumab 6 mg – 56% in HAWK and 51% 

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in HARRIER – were maintained on a q12w dosing interval following the loading phase through 
Week 48, i.e. with a reduced treatment frequency compared to aflibercept.
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)
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.
The higher intravitreal dose of brolucizumab (5.5- and 11-times molar excess for 3 and 6 mg, 
respectively vs. 2 mg aflibercept) is expected to similarly (to nAMD) confer a longer duration 
of effect in DME that will translate into a reduced frequency of injections with non-inferior 
efficacy. A reduced treatment frequency will provide benefit to patients and 
caregivers/physicians. 
Further details of the known and potential risks and benefits associated with brolucizumab are 
presented in the Investigator’s Brochure.
4
Population
The study population will be male and female patients ≥18 years old with visual impairment 
due to DME. Approximately 700 patients will be screened (20% screening failure rate expected) 
and 534 (178 per arm) patients will be randomized in approximately 130 centers worldwide. 
Approximately 60 patients will be from Japan.
4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Patients ≥18 years of age at baseline 
3. Patients with type 1 or type 2 diabetes mellitus and HbA1c of ≤10% at screening. 
4. Medication for the management of diabetes must have been stable within 3 months prior 
to randomization and is expected to remain stable during the course of the study
Study Eye
1. Visual impairment due to DME with:

BCVA score between 78 and 23 letters, inclusive, using ETDRS visual acuity testing 
charts at a testing distance of 4 meters (approximate Snellen equivalent of 20/32 
to 20/320) at screening and baseline

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
DME involving the center of the macula, with central subfield retinal thickness 
(measured from RPE to ILM inclusively) of ≥320 µm on SD-OCT at screening
If both eyes are eligible, the eye with the worse visual acuity will be selected for study eye. 
However, the investigator may select the eye with better visual acuity, based on medical reasons 
or local ethical requirements. 
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients:
1. Active Proliferative diabetic retinopathy in the study eye as per investigator
2. Concomitant conditions or ocular disorders in the study eye at screening or baseline which 
could, in the opinion of the investigator, prevent response to study treatment or may 
confound interpretation of study results, compromise visual acuity or require medical or 
surgical intervention during the first 12-month study period (e.g., cataract, vitreous 
hemorrhage, retinal vascular occlusion, retinal detachment, macular hole, or choroidal 
neovascularization of any cause) 
3. Any active intraocular or periocular infection or active intraocular inflammation 
(e.g., infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis, 
uveitis) in study eye at screening or baseline
4. Structural damage of the fovea in the study eye at screening likely to preclude 
improvement in visual acuity following the resolution of macular edema, including 
atrophy of the retinal pigment epithelium, subretinal fibrosis, laser scar(s), epiretinal 
membrane involving fovea or organized hard exudate plaques
5. Uncontrolled glaucoma in the study eye defined as intraocular pressure (IOP) > 25 mmHg 
on medication or according to investigator’s judgment at Screening or Baseline
6. Neovascularization of the iris in the study eye at screening or baseline 
7. Evidence of vitreomacular traction in the study eye at screening or baseline which in the 
opinion of the investigator, affects visual acuity
8. Presence of amblyopia, amaurosis or ocular disorders with vision <20/200 (35 letters) in 
the fellow eye at screening or baseline
9. History of idiopathic or autoimmune uveitis in the study eye
Ocular treatments
10. Previous treatment with any anti-VEGF drugs or investigational drugs in the study eye
11. Use of dexamethasone intravitreal implant (Ozurdex) or fluocinolone acetonide 
intravitreal implant (Iluvien) in study eye at any time. Prior use of other intraocular or 
periocular corticosteroids in the study eye is not an exclusion provided at least 6-month 
wash-out prior to baseline
12. Laser photocoagulation (focal/grid or panretinal) in the study eye during the 3-month 
period prior to baseline 
13. Intraocular surgery including yttrium aluminum garnet (YAG) laser in the study eye 
during the 3-month period prior to baseline 

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14. History of vitreoretinal surgery in study eye
15. Aphakia with the absence of posterior capsule in the study eye
Systemic conditions or treatments
16. Stroke or myocardial infarction during the 6-month period prior to baseline
17. Renal failure requiring dialysis or renal transplant
18. Uncontrolled blood pressure defined as a systolic value ≥160 mmHg or diastolic value 
≥100 mmHg at screening or baseline
19. Systemic anti-VEGF therapy during the 3-month period prior to baseline
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 
21. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical 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, regardless 
of whether there is evidence of local recurrence or metastases
23. History of a medical condition (disease, metabolic dysfunction with exception of type 1 or 
2 diabetes mellitus, physical examination finding, 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 
(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 hCG 
pregnancy test
26. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during the study. Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient). 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) or tubal ligation at least six weeks before baseline. 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 baseline). For female patients in the 
study, the vasectomized male partner should be the sole partner for that patient

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
Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS) 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 woman should have been stable on the same pill for a 
minimum of 3 months before taking investigational drug.
In case local regulations deviate from the contraception methods listed above, local regulations 
apply and will be described in the ICF.
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 ago. 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.
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
The investigational treatments used in this study are:

Brolucizumab 3 mg/0.05 mL

Brolucizumab 6 mg/0.05 mL
The control treatment is:

Aflibercept 2 mg/0.05 mL
Brolucizumab is formulated as a sterile solution aseptically filled in a sterile glass vial for single 
use or may be provided in a prefilled syringe (PFS) in selected countries and the content of the 
vial must not be split.
Brolucizumab study kits will consist of a carton that contains 1 single use, sterile glass vial or 
may be provided in a prefilled syringe (in selected countries) containing sufficient 
brolucizumab to deliver to brolucizumab 3 mg/0.05 mL or brolucizumab 6 mg/0.05 mL.
Aflibercept will be provided in a single use, sterile glass vial, or may be provided in a prefilled 
syringe in selected countries containing sufficient Aflibercept to deliver a 2 mg dose when 
administering a volume of 0.05 mL. Sham injections refer to an imitation of an intravitreal 
injection procedure using an empty sterile syringe without a needle. There will be no empty 
sham vial.
Novartis will ensure sufficient supplies of brolucizumab and aflibercept for treatment use to 
allow for completion of the study.

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5.1.2
Additional treatment
No additional treatment beyond investigational drug and control drug are included in this trial.
5.2
Treatment arms

Brolucizumab 3 mg/0.05 mL
5 x q 6w loading then q12w/q8w maintenance

Brolucizumab 6 mg/0.05 mL
5 x q6w loading then q12w/q8w maintenance

Aflibercept 2 mg/0.05 mL
5 x q4w loading then q8w maintenance
5.3
Treatment assignment and randomization 
At baseline visit, all eligible patients will be randomized via Interactive Response Technology 
(IRT) to one of the treatment arms, in a ratio of 1:1:1, stratification for Japanese ethnicity 
(Japanese vs. non-Japanese) will be considered. 
The investigator or her/his delegate will contact the IRT, after it was confirmed that the patient 
fulfills all the inclusion and none of the exclusion criteria. The IRT will assign a randomization 
number to the patient, which will link the patient to a treatment arm. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of patient 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 Novartis Drug Supply Management using a validated system 
that automates the random assignment of medication numbers.
The randomization scheme for patients will be reviewed and approved by a member of the 
Randomization Group.
5.4
Treatment masking
The intent of masking is to limit the occurrence of conscious and unconscious bias in the 
conduct and interpretation of the clinical study. 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 end points, the handling of withdrawals, and 
so on. The essential aim of masking, therefore, is to prevent identification of the treatments by 
the investigator, subject, and others associated with the conduct of the study until all such 
opportunities for bias have passed.
This study will be double-masked, with subjects randomized to be treated with brolucizumab 3 
mg, brolucizumab 6 mg or aflibercept 2 mg. All members of the Sponsor study team will be 
masked to treatment assignments until all randomized patients complete Week 52 visit or 
terminate the study prior to Week 52 (sequentially if first and second interim database locks 
occur).  Sponsor personnel who have access to treatment codes will not divulge the codes to 
subjects, investigators, site staff.
Unmasking of investigators and site personnel directly involved in the conduct of the study will 
only occur in the case of patient emergencies (see Section 5.6), and then at the time of the final 
analysis (see Section 3.5), at the conclusion of the study.

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In the event of a medical emergency or an adverse event (AE) during the study where the 
knowledge of subject treatment is required (e.g. in case of SUSAR), an individual investigator 
will have the ability to unmask the treatment assignment for a specific subject. The investigator 
should notify the Sponsor prior to unmasking a subject, if there is sufficient time. Further, the 
Sponsor must be informed whenever the randomization code is broken and be informed about 
the reasons for unmasking.
Each site must have both masked and unmasked investigators available. The investigator who 
performs the injection will be unmasked to the treatments as will any other site personnel who 
have been delegated responsibility for working with the IP. The unmasked site personnel and 
unmasked injecting investigator must not perform BCVA, complete ophthalmic examination, 
disease activity assessments or administer the VFQ-25. Also, the unmasked site personnel and 
unmasked injecting physician must not perform assessment of any ocular or non-ocular safety 
parameters, or assess causality AEs for subjects during the course of the study except an event 
reported immediately following IVT injection. 
The unmasked investigator/site personnel should, however, assess subject safety immediately 
following injection. Once the designated roles are determined, the unmasked investigator/site 
personnel roles must not be switched at any time after randomization to masked role. Every 
effort must be made to limit the number of unmasked study personnel to ensure the integrity of 
this masked study.
Treatment masking of individual subjects will remain intact until the final database lock has 
occurred by ensuring: Randomization data are kept strictly confidential until the time of 
unmasking and will not be accessible by anyone else involved in the study except the 
unmasked/treating investigator. During and after database lock at Week 52 and Week 100, the 
masked personnel and patients will remain masked to the treatment assignment until the 
conclusion of the study. 
Unmasked monitors will be available to perform study medication accountability and to deal
with study issues involving the unmasked investigator or unmasked site staff.
An independent, masked review of fundus photography, fluorescein angiography and optical 
coherence tomography (OCT) images for patients enrolled in the study will be performed at a 
CRC.
5.5
Treating the patient 
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
5.5.1
Patient numbering
Upon signing the informed consent form, the patient is assigned the next sequential number 
available in electronic data capture (EDC) system. The investigator or her/his staff will contact 
the IRT and provide the requested identifying information for the patient to register them into 
the IRT. Once assigned to a patient, the patient number will not be reused. If the patient fails to 
be randomized for any reason, the IRT must be notified within 2 days that the patient was not 

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randomized. The reason for not being randomized will be entered on the Screening Log, and 
the Demography Case Report/Record Form (electronic) (eCRF) should be completed.
5.5.2
Dispensing the study drug
Each study site will be supplied with study drug.
For brolucizumab, the study drug packaging has a 2-part label. A unique medication number is 
printed on each part of this label, which corresponds to one of the treatment arms. Investigator 
staff will identify the study drug package(s) to dispense to the patient by contacting the IRT and 
obtaining the medication number(s). Immediately before treating the patient, investigator staff 
will detach the outer part of the label from the packaging and affix it to the source document 
(Drug Label Form) for that patient’s unique patient number.
5.5.3
Handling of study and additional treatment
5.5.3.1
Handling of study treatment 
Study treatment 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 unmasked investigator and 
designees have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels. Clinical supplies are to be dispensed only in accordance 
with the protocol. Technical complaints are to be reported to the respective Novartis CPO 
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 study treatment but no information about 
the patient except for the medication number.
The unmasked investigator must maintain an accurate record of the shipment and dispensing of 
study treatment in a drug accountability log. Monitoring of drug accountability will be 
performed by unmasked 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.
5.5.3.2
Handling of additional treatment 
Not applicable.
5.5.4
Instructions for prescribing and taking study treatment
All kits of study treatment assigned by the IRT will be recorded/databased in the IRT.
There will be two treatment phases for IVT injections with different timing for brolucizumab 
and aflibercept treatment arms: 
Loading Phase

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Brolucizumab (3 and 6 mg): In the loading phase, treatment with brolucizumab will occur every 
6 weeks for five (5) consecutive injections (BL, Weeks 6, 12, 18 and 24). To preserve the 
masking, the patients assigned to this regimen will receive sham injection on Weeks 4, 8 and 
16.
Aflibercept: In the loading phase, treatment with aflibercept will occur every 4 weeks for five 
(5) consecutive injections (BL, Weeks 4, 8, 12 and 16). To preserve the masking, the patients 
assigned to aflibercept Arm will receive sham injection on Weeks 6 and 18.
Maintenance Phase
The treatment interval during the maintenance phase will be as follows:
Brolucizumab 3/6 mg:

From Week 24 onwards, patients will be scheduled to receive one injection of 
brolucizumab 6 mg / 3 mg every 12 weeks. If, however, disease activity is identified 
by the evaluating/masked investigator at Weeks 32, 36, 48, 60, 72, or 84, the patient 
will be assigned to receive treatment every 8 weeks (see Evaluation of Disease 
Activity below). A disease activity assessment will also be performed at Week 96 
but will not be entered into IRT and will have no effect on the subject’s treatment 
schedule.
Aflibercept 2 mg:

From Week 16 onwards, patients will receive one injection of aflibercept 2 mg every 
8 weeks (first injection after Week 16 to be given at Week 24) until Week 96 visit. 
Disease Activity assessments will be conducted by the evaluating/masked 
investigator for masking purposes and will not influence the treatment interval.
Evaluation of Disease Activity:
The concept of the brolucizumab q12w/q8w regimen is to allocate patients according to their 
individual treatment needs to either a q12w or a q8w treatment schedule. The initial schedule is 
q12w and a patient will remain on q12w as long as the masked investigator does not identify 
DME disease activity which in his opinion requires more frequent anti-VEGF treatment. 
Disease activity assessments (DAA) and a potential resulting adjustment of the treatment 
frequency are limited to pre-specified DAA-visits:

A more closely monitoring of the patients individual treatment need will take place during 
the first q12w treatment interval with DAAs at Week 32 and 36 (i.e. for brolucizumab 
patients 8 and 12 weeks after the last loading injection) to make sure that patients with a 
high treatment need are identified early on

After this first q12w treatment interval DAA will take place together with the scheduled 
q12w treatment visits, i.e. at Week 48, Week 60, Week 72 and Week 84. An additional 
DAA will be performed at Week 96 to document the adequacy of the q12w treatment 
schedule at the end of the 2 year follow-up (without having impact on the subject’s 
treatment schedule)
The assessment of the disease activity is at the discretion of the masked investigator. He/she 
will assess DME disease activity in the study eye with reference to the patient’s disease status 

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Aflibercept patients will receive maintenance treatment every 8 weeks, regardless of the 
outcome of the Disease Activity Assessment as per approved regimen. 
The IVT injection procedure for brolucizumab and aflibercept, including aseptic and 
antimicrobial requirements, will be performed according to local clinical practice. 
The sham injection should mimic an IVT injection including the aseptic and antimicrobial 
requirements. The tip of the sham injection syringe (the hub without a needle) will be placed 
on the eye for the approximate amount of time it would take to perform an IVT injection.  
IVT injection is contraindicated in patients with active ocular or periocular infections and in 
patients with active intraocular inflammation (IOI); therefore, the investigators must verify that 
these conditions are not present in the study eye prior to every injection. 
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 6.5.4.).
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 a subject develops retinal vasculitis and/or retinal vascular occlusion based on the 
investigator’s evaluation, the study treatment must be discontinued.
At all applicable visits from Week 4 to Week 96, inclusive (with exception of Weeks 20 and 28 
where no treatment is scheduled), a sham treatment will be performed to maintain patient 
masking. For the sham treatment the tip of an injection syringe (the hub without a needle) will 
be used.
5.5.5
Permitted dose adjustments and interruptions of study treatment 
Treatment dose adjustments and/or interruptions are not permitted unless interruptions are 
warranted by an AE.
5.5.6
Rescue medication/procedure
The study eye, in all treatment groups, identified as needing q8w at a previous visit could 
receive rescue treatments with laser photocoagulation from week 36 onward if DME worsened 
causing a ≥10-letter loss at 2 consecutive visits or ≥15-letter at 1 visit best previous 
measurement, with BCVA not better than baseline. When applicable, patients could receive 
both laser photocoagulation and active study treatment as scheduled at the same visit. Patients 
can continue with the study treatment. 
Pan retinal photocoagulation is permitted at any time during the study as deemed necessary by 
the investigator, and the patient can continue the study.
In case the investigator deems it in the best interest of the patient to receive treatment in the 
study eye, which is prohibited by this protocol (aside from laser), instructions provided in Table 
5-1 should be followed.

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5.5.7
Concomitant medications and treatments
The investigator must instruct the patient 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 (e.g. blood transfusions) administered after the patient was 
enrolled into the study must be recorded in the appropriate eCRF page.
Each concomitant drug/procedure must be individually assessed against all exclusion 
criteria/prohibited medication. If in doubt the investigator should contact the Sponsor medical 
monitor before randomizing a patient or allowing a new medication to be started.
If the patient 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.
5.5.8
Prohibited medication
Table 5-1 becomes effective with screening.
Table 5-1
Prohibited medications / procedures
Medication / Procedures 
Prohibition period
Action taken
Study eye
Intra- or periocular 
corticosteroids (except if needed 
as short term treatment of AE) 
Any time
Discontinue study treatment 
(except if for treatment of AE)
Anti-VEGF therapy other than 
assigned study medication
Any time
Discontinue study treatment
Laser photocoagulation 
(focal/grid )
Prior or at the time of first 
identification of DAA 
Continuation of study 
treatment at the investigators 
discretion 
Systemic
Anti-VEGF therapy
Any time
Discontinue study treatment
Any investigational drug, biologic 
or device 
Any time
Discontinue study treatment
Standard of care or other treatments according to the investigators practice for DME and other 
diseases in the fellow eye are permitted at any time and must be recorded in the appropriate
eCRF page.
5.5.9
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a patient, he/she must provide the 
requested patient identifying information and confirm the necessity to break the treatment code 
for the patient. The investigator will then receive details of the investigational drug treatment 
for the specified patient and a fax or email confirming this information. The system will 

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automatically inform the Novartis monitor for the site and the Study Team that the code has 
been broken.
If the treatment code needs to be broken in the interest of patient safety, the investigator is 
encouraged to contact an appropriate Sponsor representative prior to unmasking if there is 
sufficient time.
It is the unmasked or masked investigator’s responsibility to ensure that there is a dependable 
procedure in place to allow access to the IRT at any time in case of emergency. The investigator 
will provide:

protocol number

study drug name (if available)

patient number
In addition, oral and written information to the patient must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. 
The appropriate personnel from the site and Sponsor will assess whether study treatment should 
be discontinued for any patient whose treatment code has been broken for any reason.
5.6
Study completion and discontinuation 
The investigator should discontinue study treatment for a given patient and/or withdraw the 
patient from study if, on balance, he/she believes that continuation would be detrimental to the 
patient’s well-being.
5.6.1
Study completion and post-study treatment 
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol.
The investigator and/or referring physician will recommend the appropriate follow-up medical 
care, if needed, for all patients who are prematurely withdrawn from the study.
5.6.2
Discontinuation of study treatment 
Discontinuation of study treatment for a patient occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by either the patient or the investigator. 
The investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation.
Study treatment must be discontinued under the following circumstances: 

Patient wish 

Pregnancy (see Section 6.5.7 and Section 7.6)

Use of prohibited treatment as per recommendations in Table 5-1

Any situation in which study participation might result in a safety risk to the patient

Subject develops a retinal vasculitis and/or a retinal vascular occlusion

Unsatisfactory therapeutic effect

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
Patient’s condition no longer requiring study treatment 
If discontinuation of study treatment occurs, the patient should NOT be considered withdrawn 
from the study. The investigator must determine the primary reason for the patient’s premature 
discontinuation of study treatment and record this information on the appropriate eCRF page. 
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.
If study drug discontinuation occurs because treatment code has been broken, please refer to 
Section 5.5.9
5.6.3
Withdrawal of informed consent 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject: 

Does not want to participate in the study anymore, and 

Does not allow further collection of personal data
In this situation, the investigator must make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the patient’s decision to withdraw his/her consent and 
record this information. 
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 patient are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in 
assessment Table 6-1 below.
Discontinued patients will not be replaced.
Novartis/sponsor will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until their time of withdrawal) according to 
applicable law. 
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.
5.6.4
Loss to follow-up
For patients 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 patient, e.g. dates of telephone 
calls, registered letters, etc. 

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5.6.5
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, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the patient 
must be seen as soon as possible and treated as a prematurely discontinued patient. 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 patient’s interests. The investigator will 
be responsible for informing the Institutional Review Board/Independent Ethics Committee 
(IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 lists all scheduled study visits and indicates with an “x” when a specific assessment 
is to be performed.
Patients must be seen for all visits on the designated day, or as close to it as possible. Missed or 
rescheduled visits should not lead to automatic discontinuation. Patients 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 final visit will be performed. 
If the COVID-19 pandemic limits or prevents on-site study visits, study treatment could not be 
performed, and other study assessments may not be performed alternative methods of providing 
continuing care 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 6-1
Assessment schedule
Visit
Screening
1
Baseline
2
3
4
5
6
7
8
9
10
11
12
13
Week
Up to
2 weeks
Day 1
4
6
8
12
16
18
20
24
28
32
36
40
Informed Consenta
X
Demographics
X
Medical History
X
Physical Examinationb
X
Concomitant Medications
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
Inclusion/Exclusion Criteria
X
Xd
Visual Function Questionnaire-25
X
X
FSH (Follicle Stimulating Hormone)m
X m
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogramj
Xj
Serum β-hCG Pregnancy teste
X
Urine Pregnancy Teste
X
X
X
X
X
X
X
X
X
X
X
Chemistry/Hematology/Urinalysis
X
X
Xf
Xf
Blood Sample: Anti-Drug Antibodies
X
X
X
X
X
Best-Corrected Visual Acuity
Xg
X
X
X
X
X
X
X
X
X
Xg
X
X
X
Intraocular pressure
Xg
X
X
X
X
X
X
X
X
X
Xg
X
X
X
Ophthalmic Examh, n
Xg
X
X
X
X
X
X
X
X
X
Xg
X
X
X
Spectral Domain Optical Coherence 
Tomography n
Xg
X
X
X
X
X
X
X
X
X
X
X
X
X
Color Fundus Photography
Fluorescein Angiography n
Xg
X
Disease Activity Assessment
X
X
Contact IRT
X
Xi
X
X
X
X
X
X
X
X
X
X
Treatment
X
X
X
X
X
X
X
X
X
X
X

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a
Must be signed/dated prior to performing any study procedures, including screening procedures
b
At Visit 1, significant findings present prior to the study start (or known to being started before) must be recorded 
in the relevant Medical History; and any changes during the study which meet the definition of an Adverse Event 
must be recorded as an Adverse Event
c
All exit procedures should be followed, regardless of when the patient exits the study (VFQ-25 will not be 
collected at early exit visit)
d
Verify that inclusion/exclusion criteria are met as per section 4.1 and 4.2 prior to assignment of study treatment
e
Women of childbearing potential only
f
HbA1c only
g
Both eyes
h
Includes fundus and slit lamp examination. Pupil dilation optional according to 
local practice
i
Patients will be randomized to one of the following treatments: brolucizumab 
3 mg/50 µL or brolucizumab 6 mg/50 µL or aflibercept 2 mg/50 µL
j
In Japanese sites only
l
When equipment available at study site
m
woman with the need to confirm child bearing potential
n
Additional ophthalmic examinations and images will be performed in case of 
any signs of intraocular inflammation
Visit
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28c
Exit
Week
44
48
52
56
60
64
68
72
76
80
84
88
92
96
100
Physical Examination
X
Concomitant Medications
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
Visual Function Questionnaire-25
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogramj
Xj
Xj
Serum β-hCG Pregnancy teste
X
X
Urine Pregnancy Teste
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry/Hematology/Urinalysis
X
Xf
Xf
Xf
X
Blood Sample: Anti-Drug Antibodies
X
X
X
Best-Corrected Visual Acuity
X
X
Xg
X
X
X
X
X
Xg
X
X
X
X
X
Xg
Intraocular pressure
X
X
Xg
X
X
X
X
X
Xg
X
X
X
X
X
Xg
Ophthalmic Examh, n
X
X
Xg
X
X
X
X
X
Xg
X
X
X
X
X
Xg
Spectral Domain Optical Coherence 
Tomography n
X
X
Xg
X
X
X
X
X
X
X
X
X
X
X
Xg
Color Fundus Photography / 
Fluorescein Angiography n
Xg
X
Xg
Disease Activity Assessment
X
X
X
X
X
Contact IRT
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Treatment
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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6.1
Information to be collected on screening failures 
All patients who have signed informed consent but not entered into the next period will have 
the study completion eCRF pages for the screening period, demographics, inclusion/exclusion, 
and serious adverse event (SAE) data collected. Adverse events that are not SAEs will be 
followed by the investigator and collected only in the source data.
6.2
Patient demographics/other baseline characteristics
The following information will be collected/documented at screening/baseline visit for each 
patient:

Date of birth, age

Gender

Race/Ethnicity

Type of diabetes

Vital signs

Study eye

Visual acuity

Macular edema characteristics

Intraocular pressure

HbA1c and other laboratory test results

Concomitant medications

Past medical history and current medical conditions
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
6.3
Treatment exposure and compliance
Every time the study treatment is to be administered, IRT needs to be accessed for the 
medication (kit) number. The date and time of all study treatment injections administered during 
the study and any deviations from the protocol treatment schedule will be captured by the 
unmasked investigator staff or by unmasked field monitor on the appropriate study treatment 
dispensing form.
Exposure to the study treatment will be based on the number of injections administered. 
Compliance with the study treatment will be assessed by the unmasked field monitor at each 
visit using vial counts and information provided by the pharmacist or by the investigator.
6.4
Efficacy 
The following tests will be performed to assess activity of brolucizumab and aflibercept on 
visual function, retinal structure and leakage:

Best-corrected visual acuity with ETDRS-like chart at initial testing distance of 4 meters

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exclusion criteria, at the screening or baseline visits, the blood pressure measurement should be 
repeated after 20 minutes. If the repeat measurement is elevated, then the patient is not eligible 
to be enrolled into the study.
On days when study drug is administered, vital signs will be measured before administration of 
study medication. The results will be recorded in the eCRF.
6.5.3
Height and Weight
Height and weight will be measured at the screening visit only. 
Height in centimeters (cm) and body weight (to the nearest kilogram (kg), in indoor clothing 
but without shoes) will be measured at screening only. The results will be recorded in the eCRF.
6.5.4
Ophthalmic examination
The ophthalmic exam will consist of the following:

Anterior 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 (fellow eye will be examined at screening and on discretion of the investigator). 
The outcome of the examination will be recorded in the source documents.
Slit lamp examination must be carefully performed before each study treatment. If there is any 
signs of IOI, severity of anterior chamber cells and flare should be assessed according to the 
standardization 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. 
Any clinically significant abnormalities should be recorded on the adverse event page of 
the eCRF (events identified pre-Baseline should be recorded on the medical history page) 

Intraocular pressure will be assessed in the study eye, pre-dose and post-dose at every 
scheduled visit. In the fellow eye IOP will be assessed at Screening, Weeks 28, 52, 76 and 
exit/premature discontinuation. The values recorded in mmHg will be entered into the eCRF.
Treatment and close monitoring of IOP should be performed by the investigator for any 
non-transient elevation in intraocular pressure (≥25 mmHg). Intravitreal procedure is not 
recommended unless normalization of the IOP has been achieved. Post dose IOP should be 
assessed after every IVT injection, within 60 minutes after injection and if ≥25 mmHg, 
assessment should be repeated until back to normal.
Any clinically significant abnormalities should be recorded on the adverse event page of the 
eCRF (events identified pre-Baseline should be recorded on the medical history page).

Posterior segment (indirect fundus) examination 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 intravitreal injection can safely be performed. 
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 

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tear/detachment, hemorrhage and vascular occlusion, vasculitis, etc.) should be recorded in the 
source documents. If there is 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. Any clinically significant 
abnormalities of either eye will be recorded on the medical/ocular history page before Baseline 
and on the adverse event page of the eCRF for any findings identified after Baseline.
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 conduct OCT, fluorescein angiography and color fundus photography 
(
 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.
6.5.5
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected at applicable visits. 
Details on the collections, shipment of the samples and reporting of the results by the central 
laboratory are provided to investigators in the 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.
6.5.5.1
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.
6.5.5.2
Clinical chemistry

Glycosylated hemoglobin (HbA1c)

Serum biochemistry tests
Serum electrolytes (sodium, potassium, chloride, phosphorus, calcium), uric acid, urea 
nitrogen, creatinine, albumin, glucose, total protein, total bilirubin and direct bilirubin, 
SGOT (AST), SGPT (ALT), GGT, alkaline phosphatase and LDH

Additional chemistry tests: Lipids panel triglycerides (TG), low-density lipoprotein (LDL), 
high-density lipoprotein (HDL), and Total Cholesterol (TC)

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6.5.5.3
Urinalysis
Dipstick measurements for specific gravity, pH, protein, glucose, ketones, urobilinogen, 
bilirubin, nitrite, leucocyte, esterase and urine occult blood.
6.5.6
Electrocardiogram (ECG)
At sites in Japan, electrocardiograms will be recorded at baseline visit, Weeks 52 and 100/ 
premature termination visits. The heart rate, PR interval, QRS interval, QT interval and QTc 
(QT interval corrected) will be collected as source data. Clinically significant abnormalities 
must be recorded on the relevant adverse event section of the eCRFs.
6.5.7
Pregnancy and assessments of fertility
High effective contraception is required for woman of childbearing potential during the study 
and for 3 months after stopping the investigational medication.
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements.
If no sufficient profile to support the reproductive status of female patients, a FSH (Follicle 
Stimulating Hormone) test can be conducted for female patients at Screening visit only to 
confirm the child bearing potential.
A serum pregnancy test will be conducted for all women of childbearing potential to assess 
pregnancy before inclusion into the study at screening visit and then at Week 52 and exit visits. 
During study, monthly pregnancy testing will be performed and results captured in the source 
documents. 
6.5.8
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population. If there is 
any signs of IOI, additional assessment will be performed as described in Section 6.5.4.
6.6
Other assessments 
Additional assessments that will be performed:

Patient Reported Outcome: NEI VFQ-25

Anti-drug antibodies
6.6.1
Clinical Outcome Assessments (COAs)
6.6.1.1
Clinician Reported Outcomes (ClinRO)
Not applicable.
6.6.1.2
Patient Reported Outcomes (PRO)
The impact of brolucizumab on patient visual function will also be assessed by a visual function 
questionnaire using the National Eye Institute VFQ-25 which is a validated instrument that has 

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been used in many studies of patients with DME. The VFQ-25 was developed to address the 
need to measure a patient’s subjective assessment of vision-related QoL (Mangione, et al., 
2001). This is part of the 51-item NEI-VFQ which was developed based on feedback from 
patients to measure vision-targeted functioning and the impact of vision problems on 
Health-Related Quality of Life (HRQL) across a number of common eye conditions. This 
allowed the developers to identify the content areas and aspects of visual disability that were 
most important and relevant to AMD patients. In addition to its use in measuring the treatment 
effect on vision-related function in AMD patients, the VFQ-25 has been used to measure
treatment benefits in patients with DME (Klein et al., 2001).
At baseline and Weeks 28, 52, 76 and 100, the VFQ-25 will be completed and captured by 
masked site staff on behalf of the patients, at sites where local language versions are available, 
validated, and approved by the IEC/IRB. All these questionnaires should be completed before 
patients see the study physician where applicable.
A detailed training manual relating to the administrative procedures of the questionnaires will 
be provided to the sites.
Completed questionnaires will be reviewed and examined by the masked/evaluating 
investigator, before the clinical examination, for responses that may indicate potential AE or 
SAE. If AEs or SAEs are confirmed, then the physician must record the events as per 
instructions given in Section 7.1 and Section 7.2 of the protocol.
6.6.2
Resource utilization
Data for Healthcare Resource Allocation will not be collected for this study.
6.6.3
Pharmacokinetics
Not Applicable
6.6.4
Anti-drug antibodies (immunogenicity)
Collection of blood for ADA assessment will be done at Screening, Weeks 4, 12, 24, 36, 52, 76 
and exit/premature discontinuation. Systemic exposure of brolucizumab will be measured 
concomitantly with ADA levels for interpretation purposes, no pharmacokinetic parameters will 
be determined from brolucizumab systemic exposure.
Blood draws should take place prior to the injection/sham. A standardized procedure for the 
collection, processing, storage and shipment of these blood samples is provided by the central 
laboratory. Further details on sample collection, numbering, processing and shipment can be 
found in the Central Laboratory Manual.
Additional pharmacodynamic assessment (e.g. systemic VEGF) may be conducted on the 
samples.

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6.6.6
Other biomarkers 
Not applicable.
7
Safety monitoring
7.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation patient after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.
The occurrence of adverse events must be sought by non-directive questioning of the patient at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the patient during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
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, or

they require therapy. 

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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 patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. As a general guidance, alert ranges for laboratory and 
other test abnormalities are included in Appendix 1. 
Adverse events must be recorded in the appropriate eCRF capturing AEs under the signs, 
symptoms or diagnosis associated with them, accompanied by the following information:

the severity AE 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

its relationship to:

the study drug 

the ocular injection procedure 

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported

whether it constitutes a serious adverse event (SAE - See Section 7.2 for definition of 
SAE) and which seriousness criteria have been met.

action taken regarding [investigational] 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) 

[investigational] treatment interrupted/withdrawn

concomitant medication or non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition of 
SAE)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent, and assessment must be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions required 
to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the investigator Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any new 
information regarding the safety profile of the medicinal product that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator Notification or 
an Aggregate Safety Finding. New information might require an update to the informed consent 
and has then to be discussed with the patient.

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The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the investigator’s 
source documents; however, if the AE meets the criteria of an SAE, it must be reported to 
Novartis.
7.2
Serious adverse events 
7.2.1
Definition of SAE 
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:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

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 (specify what this includes)

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

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient 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 Annex IV, ICH-E2D Guideline).
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 patient or might 
require intervention to prevent one of the other outcomes listed above. 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 Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.

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7.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient 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. 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. 
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.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to each specific 
component of study treatment, (if study treatment consists of several components) complete the 
SAE Report Form in English, and submit the completed form within 24 hours to Novartis. 
Detailed instructions regarding the submission process and requirements for signature are to be 
found in the investigator folder provided to each site. 
Follow-up information is submitted as instructed in the investigator folder. Each re-occurrence, 
complication, or progression of the original event must be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not, and 
whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment a Drug Safety and Epidemiology 
Department associate may urgently require further information from the investigator for 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.
Note: SAEs must be reported to Novartis within 24 hours of the investigator learning of its 
occurrence/receiving follow-up information.
7.3
Liver safety monitoring
To ensure patient safety and to ensure that a full data package is collected to best understand 
events of liver dysfunction that emerge during the course of this study, a standardized process 
for evaluation of liver events has to be followed. This may involve referral of the patient to a 
suitable internal medicine physician.
This additional investigation is triggered by liver function test abnormalities and/or adverse 
events (irrespective of whether classified/reported as (S)AE and irrespective of investigator 
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Please refer to Table 14-1 in Appendix 2 as guidance for complete definitions of liver laboratory 
triggers and liver events.
Every liver laboratory test abnormality trigger or liver event as defined in Table 14-1 of 
Appendix 2 should be followed up by the investigator or designated personal at the trial site or 
a suitable internal medicine MD as summarized below.
For the liver laboratory test abnormality trigger, please use the guidance below:

If the elevation is confirmed as clinically significant, close observation of the patient will 
be initiated, including consideration of treatment interruption if deemed appropriate. This 
observation may be conducted by the investigator or through referral of the patient to a 
suitable internal medicine MD.
For the liver adverse events, consider referral of the patient to a suitable internal medicine MD 
and the guidance below:

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications)

An investigation of the liver event which needs to be followed until resolution.

If meeting SAE criteria, the event must be reported as per Section 7.2.2
All follow-up information, additional procedures performed and test results must be collected 
and documented at the study site.
7.4
Renal safety monitoring 
The following two categories of abnormal renal laboratory values have to be considered as 
guidance during the course of the study:

Serum event:

confirmed (after ≥24h) increase in serum creatinine of ≥25% compared to baseline 
during normal hydration status

Urine event

new onset (≥1+) proteinuria; confirmed by doubling in the urinary albumin-creatinine 
ratio (ACR) or urinary protein-creatinine ratio (PCR) (if applicable)

new onset (≥1+), hematuria or glycosuria 
Every renal laboratory trigger or renal event as defined in Table 15-1 in Appendix 3 as guidance 
and to  be followed up by the investigator or designated personnel at the trial site as summarized 
in Appendix 3. 
For the renal adverse events, consider referral of the patient to a suitable internal medicine 
physician. All follow-up information, additional procedures performed and test results must be 
collected and documented at the study site.

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7.5
Reporting of study treatment errors 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (EMA definition).
Misuse/ abuse is not applicable to this study as IVT injection is performed by the investigator.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the Dosing eCRF (date and time of the injection) and in the Dispensing Log at the Study site,
irrespective of whether or not associated with an AE/SAE and reported to Safety only if 
associated with an SAE. 
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error 
type
Document in eCRF 
(Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes (only date and 
time of injection)
No 
Only if associated with an 
SAE
7.6
Pregnancy reporting
To ensure patient safety, each pregnancy 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 must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
8
Data review and database management 
8.1
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 
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 patient 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 

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performed by a centralized Novartis CRA 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 patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
patient's file. [Data not requiring a separate written record will be defined before study start and 
will be recorded directly on the eCRFs.] The investigator must also keep the original informed 
consent form signed by the patient (a signed copy is given to the patient).
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 useed 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 
patients will be disclosed.
8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRFs) using fully validated secure web-enabled software that conforms 
to US CFR 21 Part 11 requirements. Designated investigator site staff will not be given access 
to the system until they have been trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site. 
8.3
Database management and quality control
Novartis personnel (or designated CRO) 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 is required to respond 
promptly to queries and to make any necessary changes to the data. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies 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 (or a designated CRO).

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Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (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).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unmasked and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
Development management.
8.4
Data Monitoring Committee 
An independent program level Data Monitoring Committee (DMC) is established to monitor 
the safety of the trial participants, to ensure that the trial is being conducted with the highest 
scientific and ethical standards, and make appropriate recommendations based on the data seen.
The DMC charter will include the DMC membership and responsibilities, the timing of DMC 
meetings, the content of the analysis report for the DMC meetings, and the communications 
with the Sponsor. The DMC will only make recommendations for changes in study conduct.
8.5
Adjudication Committee
Not required.
9
Data analysis
The primary safety and efficacy analysis will be based on the Week 52 data, i.e. all data up to 
and including Week 52. This analysis will be performed when the first 534 randomized patients 
completed their Week 52 visits or terminate the study before Week 52, while patients continue 
to receive masked treatment through the planned study duration of 100 Weeks. 
An additional analysis will be conducted when all of the patients randomized into the study 
have completed their Week 52 visit (or terminated the study before Week 52) to allow for a 
consistency assessment of data between the Japanese and non-Japanese patients. This analysis 
will include the Week 52 data from all randomized patients, and will be purely descriptive (no 
hypothesis testing for the primary and first key secondary endpoints), as further specified in the 

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SAP. However, if any special circumstance compromises the feasibility of the approach 
described above, then the additional analysis will not be conducted and the primary analysis 
will be performed when all randomized patients have completed their Week 52 visit or terminate 
the study prior to Week 52.  
The analysis of the data collected after the Week 52 visit will be performed once all patients 
completed or discontinued from the study.
Summary statistics will be presented by treatment group unless otherwise specified. For 
continuous variables, summary statistics will generally include: n, mean, standard deviation, 
median, quartiles, minimum, and maximum. For categorical variables, this will generally 
include: n, frequency and percentage in each category.
Additional analysis may be also conducted to evaluate the impact of COVID-19 
pandemic.Further technical details and discussions of the statistical considerations will be 
provided in the SAP.
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
9.1
Analysis sets 
The Randomized Set will consist of all randomized patients. Patients are considered 
randomized when they had been deemed eligible for randomization by the investigator and 
given a randomization number. Patients will be analyzed according to the treatment assigned to 
at randomization.
The Full Analysis Set (FAS) includes all randomized patients who receive at least one IVT 
injection of the study treatment. The full analysis set will serve as the primary analysis set for 
all efficacy analyses. Following the intent-to-treat principle, patients will be analyzed according 
to the treatment assigned to at randomization.
Supportive analyses of the primary and secondary endpoints will include analysis using the Per 
Protocol Set (PPS). PPS is a subset of the FAS and will exclude patients with protocol 
deviations (PDs) and analysis restrictions (ARs) that are expected to majorly affect the validity 
of the assessment of efficacy at Week 52 including for e.g. lack of compliance (including missed 
treatments and treatment misallocation), missing data, prohibited concomitant medication and 
deviation from inclusion/exclusion criteria. Confounded data or discontinuation from treatment 
due to lack of efficacy and/or safety do not constitute a reason for exclusion from the PPS. 
Before the Week 52 database lock the relevant protocol deviations will be identified at the 
patient level in the database. After the Week 52 database lock, analysis restrictions will be 
derived in the analysis database. Censoring applied in relation to the specific PDs / ARs will be
specified as well.
The FAS will be the analysis set for the primary estimand as defined in Table 9-1. However, 
when assessing the robustness of the overall efficacy conclusions, considerations will be given 
to the analysis based on the primary estimand using FAS and the supplementary estimand (see 
Table 9-1) using PPS, i.e., similar conclusions on non-inferiority based on both estimands are 
expected. Inconsistencies in key efficacy study results between the FAS and PPS will be 
examined and discussed in the clinical study report (CSR). The Safety Analysis Set (SAF) will 

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include all patients who receive at least one IVT injection. Patients in the safety analysis set 
will be analyzed according to the treatment arm from which they received majority of treatments 
up to and including Week 48.
9.2
Patient demographics and other baseline characteristics
Demographics and baseline characteristics will be summarized with descriptive statistics for all 
analysis sets by treatment group and overall.
Relevant medical history and current medical conditions will be tabulated by system organ class 
(SOC) and preferred term of the MedDRA dictionary for the FAS. 
Other relevant baseline information will be listed and summarized with descriptive statistics as 
appropriate. 
9.3
Treatments 
Study treatment
Descriptive statistics for exposure to study treatment will be provided for the safety set, FAS 
and PPS. For the efficacy analysis sets (FAS and PPS), the number of active and sham IVT 
injections will be presented by visit and cumulatively for the period baseline to Week 48 (Week 
96), including separate analysis for the loading phases, i.e. up to Week 16 (last treatment of the 
5*q4w loading of aflibercept) and up to Week 24 (last treatment of 5*q6w loading of 
brolucizumab), and maintenance phase. For the safety analysis set, summary will include 
exposure data up to Week 52 (Week 100).
Prior medication and concomitant therapies
The number and percentage of patients taking prior medication or concomitant therapies will 
be summarized by preferred term according to the WHO Drug Reference List dictionary using 
the Safety Set and FAS (in case there are differences between those two). The concomitant 
therapies (medications and procedures) will include all therapies received after start of study 
treatment including those already started prior to the start of study treatment.
9.4
Analysis of the primary and first key secondary endpoints
9.4.1
Primary and first key secondary endpoints
The primary endpoint is the change from baseline in BCVA at Week 52.
The first key secondary endpoint is average change in BCVA from Baseline over the period 
Week 40 through Week 52. For each patient, this endpoint is defined as the average of the 
changes from baseline to Weeks 40, 44, 48 and 52. The motivation for the choice of this 
endpoint is that, averaging the BCVA values over Week 40 to Week 52 will account for both 
random fluctuations and potential trough and peak values during the different treatment cycles. 
During the period Week 40 to Week 52, aflibercept and brolucizumab patients on q8w will have 
two assessments 4 weeks after the last dose, and two assessments 8 weeks after the last dose. 
Brolucizumab patients on a q12w regimen will have two assessments 4 weeks after the last dose, 
one assessment 8 weeks after the last dose, and one assessment 12 weeks after the last dose. 

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The primary analysis of the primary and first key secondary endpoints will be based on the FAS. 
9.4.1.1
Statistical model, hypotheses, and method of analysis
The objective related to the primary and first key secondary endpoints is to demonstrate non-
inferiority of brolucizumab to aflibercept with respect to change from baseline in BCVA, 
considering a margin of 4 ETDRS letters.
Let: 
B3 = Brolucizumab 3 mg
- 5 x q6w loading then q12w/q8w maintenance
B6 = Brolucizumab 6 mg
- 5 x q6w loading then q12w/q8w maintenance
A = Aflibercept 2 mg   
- 5 x q4w loading then q8w maintenance
The following non-inferiority hypotheses are related to a non-inferiority margin of 4 letters: 
H01: μB6 – μA
≤ -4 letters
vs.
HA1: μB6 – μA
> -4 letters
H02: B6 – A
≤ -4 letters
vs.
HA2: B6 – A
> -4 letters
H03: μB3 – μA
≤ -4 letters
vs.
HA3: μB3 – μA
> -4 letters
H04: B3 – A
≤ -4 letters
vs.
HA4: B3 – A
> -4 letters
where μB6 μB3 and μA are the corresponding unknown true mean changes from baseline in 
BCVA at Week 52; B6, B3 and A are the corresponding unknown true mean changes from 
baseline in BCVA averaged over the period Week 40 to Week 52; 
Based on the FAS, the above hypotheses will be tested via an analysis of variance (ANOVA) 
model. The model will include treatment, baseline BCVA (≤65, >65 letters) and age category 
(<65, ≥65) as factors. Two-sided 95% confidence interval (CI) for the least square means 
difference (brolucizumab - aflibercept) will be presented. Non-inferiority will be considered 
established if the lower limit of the corresponding 95% CI is greater than -4 letters.
These 4 hypotheses will be tested sequentially in the order of their numbering (HAn, n=1, 2, 3, 
4), i.e., confirmatory testing of the second, third and fourth hypotheses requires rejection of 
each preceding null hypothesis. 
In this setting, each hypothesis will be assessed at a one-sided significance level of 0.025, while 
keeping the global type I error rate at 0.025.
9.4.1.2
Handling of missing values/censoring/discontinuations
Missing BCVA values will be imputed by LOCF (Last Observation Carried Forward) as a 
primary approach. For patients with no post-baseline BCVA value, the baseline value will be 
carried forward. Data collected after start of alternative DME treatment in the study eye (e.g. 
other anti-VEGF treatment, laser or intraocular corticosteroids, as further detailed in the SAP) 
will be censored for the primary analysis. 
From an estimand perspective, the main focus is to adequately reflect in the analysis 
unfavorable study outcome related to the treatment (e.g. lack of efficacy, safety problems).

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The LOCF approach is expected to be sensitive to an early study termination due to lack of 
efficacy assuming that such lack of efficacy is reflected in the last observed BCVA 
measurement. In case of the use of alternative treatment for the underlying disease (DME), data 
collected after the start of such a treatment would be censored. LOCF will then be based on the 
last value prior to the start of this treatment, again expecting that this value would reflect the 
negative BCVA outcome under study treatment. In case of missing data due to lack of 
safety/tolerability with impairment of the function of the study eye the LOCF method would 
also provide a sensitive approach to capture such an unfavorable outcome.
In case of missing data occurring independently of the response to study treatment, the LOCF 
approach assumes stability which seems to be adequate based on historical data both for the 
maintenance treatment phase (i.e. stabilization of BCVA) and also in case of the absence of any 
treatment effect with an average natural disease progression in terms of BCVA of only 1-2-
letter loss over 1 year. In case of an early study termination during the loading phase, the LOCF 
method will result in a conservative estimate potentially underestimating the true outcome. 
LOCF is an established method within the assessment of efficacy of anti-VEGF treatments in 
terms of BCVA outcome. Non-inferiority studies should follow the main design features 
(primary variables, the dose of the active comparator, eligibility criteria, etc.) as the previously 
conducted superiority trials in which the active comparator demonstrated clinically relevant 
efficacy. The primary endpoint in aflibercept Ph III studies VIVID and VISTA was the BCVA 
change from Baseline to Week 52 with missing data imputed based on LOCF. Based on those 
studies, the percentage of missing data regarding BCVA is not considered critical (<10%) which 
limits the impact of the missing data imputation method.
Other methods of handling missing or confounded data within sensitivity analyses will be 
performed.
Table 9-1
Primary and supplementary estimands
Estimand
Estimand definition
Analysis 
set
Statistical methods (Including strategy for 
imputation/replacement of 
missing/censored data)
Primary 
estimand
Difference in change from 
baseline in BCVA at Week 52 
excluding the effect of 
switching to alternative DME 
medication in the study eye
FAS
Analysis of variance (ANOVA) model 
including terms for treatment, baseline BCVA 
(≤65, >65 letters) and age category (<65, 
≥65 years), and using LOCF 
imputation/replacement for missing/censored 
data.
Supplementary 
estimand
Difference in change from 
baseline in BCVA at Week 52 
for patients adhering to the 
protocol as per the PPS 
definition
PPS
ANOVA model as per the primary estimand.
LOCF imputation/replacement for 
missing/censored data
9.4.2
Additional key secondary endpoints
Additional key secondary endpoints are:

Proportion of patients maintained at q12w up to Week 52 (for brolucizumab treatment arms 
only)

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
Proportion of patients maintained at q12w up to Week 52, within those patients that 
qualified for q12w at Week 36 (for brolucizumab treatment arms only)
9.4.2.1
Statistical model, hypotheses, and method of analysis
The estimate for the proportion of patients with a positive q12w treatment status at Week 52 
will be derived from Kaplan Meier time-to-event analyses for the event ‘first q8w-need’ 
applying a ‘q8w-need’ allocation in case of missing or confounded data attributable to lack of 
efficacy and/or lack of safety.
The proportion of patients with a positive q12w treatment status at Week 52 will be derived as 
follows requiring duration of effect (as assessed by q8w need) together with ‘sufficient efficacy 
and safety’:

For the ‘duration of effect’ requirement patients will need to have the status of ‘q8w need = 
no’ at Weeks 32, 36 and 48 unless the ‘q8w need = yes’ is confounded by reasons other than 
lack of efficacy and/or safety (see censoring details below)

The requirement regarding ‘sufficient efficacy and safety’ will be addressed by considering 
patients – even without an explicit ‘q8w need = yes’ – as having a negative q12w status in 
case any of the following confounding factors is attributable to lack of efficacy and/or lack 
of safety of the study treatment (assessed based on a masked medical review): early 
treatment/study discontinuation, use of forbidden concomitant medications/procedures 
and/or other deviation from treatment schedule (e.g. due to a missed visit/treatment). The 
corresponding q8w need will be allocated to the next disease activity assessment visit 
following the occurrence of such a confounding factor
In case missing or confounded data regarding the q12w treatment status are attributable to 
reasons other than lack of efficacy and/or safety, the patient is censored within the q12w 
treatment status analysis according to the following specifications:

Early treatment/study discontinuation: censoring at the last valid disease activity 
assessment

Single missed visit with a relevant disease activity assessment: censoring at the last valid 
disease activity assessment prior to the missed visit

Prohibited concomitant medications/procedures: censoring at the last valid disease 
activity assessment prior to the corresponding application

Discrepancy between disease activity assessment by investigator and the actual 
treatment received: censoring at the corresponding visit

Other treatment allocations/applications deviating from the concept of ‘treatment 
allocation according to disease activity’: censoring at the last valid disease activity 
assessment
9.4.2.2
Handling of missing values/censoring/discontinuations
The details regarding handling of missing values and discontinuations including the timing of 
censoring within the time-to-event analyses for the event ‘first q8w-need’ are specified above. 

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From an estimand perspective, the assessment of failing study completion according to protocol 
due to lack of efficacy/safety is considered adequately represented by a negative q12w-status. 
Alternative methods of handling missing or confounded data within sensitivity analyses will 
include an approach with ‘q8w-need’ allocation only in case of missing or confounded data 
attributable to lack of efficacy and an ‘as observed’ approach, i.e. an analysis without ‘q8w-
need’ allocation.
9.4.3
Sensitivity and supportive analyses 
Sensitivity analyses will be performed for primary and all key secondary endpoints using the 
per protocol analysis set (PPS), alternative methods of handling missing values (Section 9.4.1.2
and Section 9.4.2.2) and descriptive analyses based on observed data only (with and without 
censoring of data collected after use of alternative treatment for DME in the study eye, e.g. 
other anti-VEGF treatment, laser, intraocular corticosteroids, as further detailed in the SAP).
The following subgroup analyses will be conducted in FAS applying the primary analysis 
approach as specified above:

Age category (<65, ≥65 years)

Gender (male, female)

Diabetes type (Type 1, Type 2)

Baseline HbA1c (<7.5, ≥7.5%)

Baseline BCVA categories (≤65, >65 letters)

Duration of DME (≤3, >3-<12, ≥12 months)

DME type (focal, diffuse) as per CRC 

Baseline CSFT (<450, ≥450-<650, ≥650 µm)

Baseline status of IRF (presence, absence)

Baseline status of SRF (presence, absence)

Ethnicity (Japan, non-Japan)
Further description of the supportive analyses will be detailed in the SAP.
9.5
Analysis of secondary endpoints
9.5.1
Efficacy endpoints
Secondary efficacy endpoints based on BCVA:

Change from baseline in BCVA at each visit up to Week 100

Average change from baseline in BCVA over the period Week 88 to Week 100. 

Average change from baseline in BCVA over the period Week 4 to Week 52/100. 

Average change from baseline in BCVA over the period Week 20 to Week 52/100 and 
Week 28 to Week 52/100.

Gain in BCVA of ≥5,≥10 and ≥15 ETDRS letters from baseline to each post-baseline visit
Note: Patients with BCVA value of 84 letters or more at a post-baseline visit will be 
considered as responders for the corresponding endpoint. This is to account for a ceiling 

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effect, e.g. for the’ ≥15-letter gain’ endpoint, for those patients with BCVA values at 
baseline ≥ 70 letters.

Time to achieve gain of ≥5, ≥10 and ≥15 ETDRS letters from baseline (or reaching a score 
of 84 or more)

Loss in BCVA of ≥5, ≥10 and ≥15 ETDRS letters from baseline to each post-baseline visit

Absolute BCVA ≥73 ETDRS letters at each post-baseline visit 
Secondary efficacy endpoints related to dosing regimen:

Proportion of patients maintained at q12w up to Week 64 (after three q12w- treatment 
intervals) and 100 (for brolucizumab treatment arms only)

Proportion of patients maintained at q12w up to Week 64 (after three q12w- treatment 
intervals) and 100, within those patients that qualified for q12w at Week 36 (for 
brolucizumab treatment arms only)

q8w treatment need status assessed at Week 32 
Secondary efficacy endpoints related to anatomy:

Change from baseline in central subfield thickness (CSFT, as determined by SD-OCT from 
the central reading center) at each assessment visit

Average change in CSFT from baseline over the period Week 40 through Week 52 / Week 
88 through Week 100

Average change in CSFT from baseline over the period Week 4 to Week 52 / 96

Patient status regarding normal CSFT thickness (<280 microns) at each assessment visit

Proportion of patients with presence of SRF, IRF and simultaneous absence of SRF and IRF 
at each assessment visit

Proportion of patients with presence of leakage on FA at Weeks 52 and 100
Secondary efficacy endpoints related to the status of Diabetic Retinopathy:

Patient status regarding a ≥2- and ≥3-step improvement or worsening from baseline in the 
ETDRS Diabetic Retinopathy Severity Scale (DRSS) score at each assessment visit

Incidence of progression to PDR as assessed by ETDRS-DRSS score of at least 61 by Week 
52 and Week 100

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9.5.2
Safety endpoints
Safety endpoints are based on the variables from safety assessments which include:

Extent of exposure

Adverse events

Ophthalmic examinations

Vital signs

Laboratory results
There are no formal safety hypotheses in this study. All safety analyses will be performed using 
the Safety Set.
Adverse events
A treatment-emergent adverse event is defined as any adverse event that develops after 
initiation of the study treatment or any event already present that worsens following exposure 
to the study treatment. Only treatment-emergent adverse events will be presented in the 
summary tables.
Adverse events will be coded using the MedDRA dictionary and presented by system organ 
class (SOC) and preferred term (PT). Treatment-emergent AEs will be analyzed based on the 
number and percentage of patients with at least one AE in the category of interest. Separate 
presentations will be provided related to ocular events in the study eye and fellow eye and 
systemic events. Additional summaries will be provided by severity and causality (separately 
assessed for the injection procedure and the drug). Serious adverse events and adverse events 
leading to discontinuation of study treatment will also be summarized separately.

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9.7
Interim analyses
The analysis based on the Week 52 data will be the primary efficacy analysis for this study. The 
database including all Week 52 data will be locked when the first 534 randomized patients have 
completed the Week 52 visit or terminated the study prior to Week 52.
An additional analysis will be conducted once all enrolled patients have completed the Week 
52 visit or terminate the study prior to Week 52. This will include the original study target of 
534 patients plus additional patients enrolled in Japan to assess consistency of data between 
Japanese and non-Japanese patients.
Another analysis may be performed by locking the Week 76 data in case of regulatory request 
of supplemental data to be submitted during the review period.
9.8
Sample size calculation
A sample size of 160 patients per arm will allow to demonstrate a non-inferiority (NIM of 4 
ETDRS letters) of brolucizumab 6 mg or 3 mg (either treatment regimen) vs. aflibercept 2 mg 
with respect to the BCVA change from baseline at Week 52, with 90% power (disregarding the 
dependence within the sequential testing procedure, i.e. local power for 3 mg) at a one-sided 
alpha level of 0.025, assuming equal means and a common standard deviation of 11 letters. 
Assuming that averaging over the 4 time points will not lead to an increase in the standard 
deviation a power of at least 90% can also be expected for its corresponding non-inferiority 
claim. 
To account for a drop-out rate of 10%, a total of 534 (178 per arm) patients will need to be 
randomized.

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documented and confirmed by way of standard informed consent procedures at the earliest 
opportunity when the subject will be back at the trial sites.
10.3
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, 
informed consent form, consent form updates, patient recruitment procedures (e.g., 
advertisements) and any other written information to be provided to patients. 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.
10.4
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results.
10.5
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance, a group 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 SOPs, and are performed according to written Novartis processes.
11
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 patients 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, data, information, observation 
would be incidentally collected, the investigator shall immediately disclose it to Novartis and 

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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. 
11.1
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 intended to eliminate an apparent immediate hazard 
to patients 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 patient included in this study, even if this action 
represents a deviation from the protocol. In such cases, the reporting requirements identified in 
Section 7 Safety Monitoring must be followed.

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12
References 
References are available upon request.
Agarwal A, Sarwar S, Sepah YJ, et al. (2015) What have we learnt about the management of 
diabetic macular edema in the antivascular endothelial growth factor and corticosteroid era? 
Current Opinion in Ophthalmology; 26(3):177-83.
Jabs DA, Nussenblatt RB, Rosenbaum JT (2005) Standardization of Uveitis Nomenclature 
(SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. 
Results of the First International Workshop. Am J Ophthalmol; 140(3):509-16.
Klein R, Moss SE, Klein BE, et al. (2001) The NEI-VFQ-25 in People With Long-term Type 
1 Diabetes Mellitus: The Wisconsin Epidemiologic Study of Diabetic Retinopathy. Arch 
Ophthalmol; 119(5):733-40.
Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. (2014) Intravitreal aflibercept for diabetic 
macular edema.  Ophthalmology; 121(11):2247-54.
Lang GE, Berta A, Eldem BM, et al. (2013) Two-year safety and efficacy of ranibizumab 0.5 
mg in diabetic macular edema: Interim analysis of the RESTORE extension study. 
Ophthalmology; 120(10):2004-12.
Lee R, Wong TY, Sabanayagam C (2015) Epidemiology of diabetic retinopathy, diabetic
macular edema and related vision loss. Eye Vis (Lond) 2 : 17.
Mangione CM, Lee PP, Guiterrez PR, et al. (2001) Development of the 25-Item National Eye 
Institute Visual Function Questionnaire. Arch Ophthalmol; 119(7):1050-8.
Mitchell P, Bandello F, Schmidt-Erfurth U, et al. (2011) The RESTORE study: Ranibizumab 
monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. 
Ophthalmology; 118(4):615-25.
Nussenblatt RB, Palestine AG, Chan CC, et al. (1985) Standardization of vitreal inflammatory 
activity in intermediate and posterior uveitis. Ophthalmology; 92(4):467-71.
Smiddy WE, (2011) Economic considerations of macular edema therapies. Ophthalmology;
118(9):1827–33.
Virgili G, Parravano M, Menchini F, et al. (2014) Cost-effectiveness of treatments for diabetic 
macular oedema: should we pay more attention to the appraisal and reporting of economic 
evaluations? Br J Ophthalmol; 98(4):421-2
Ziemssen F, Cruess A, Dunger-Baldauf C, et al. (2017) Ranibizumab in Diabetic Macular 
Oedema - A Benefit-risk Analysis of Ranibizumab 0.5 mg PRN Versus Laser Treatment. Eur 
Endocrinol; 13(2):91-8.

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14
Appendix 2: Liver event and Laboratory trigger Definitions 
and Follow-up Requirements
Table 14-1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
LIVER LABORATORY TRIGGERS

3 x ULN < ALT/AST 5 x ULN

1.5 x ULN <TBL 2 x ULN
LIVER EVENTS

ALT or AST >5 × ULN

ALP >2 × ULN (in the absence of known bone pathology)

TBL >2 × ULN (in the absence of known Gilbert syndrome)

ALT or AST >3 × ULN and INR >1.5 

Potential Hy’s Law cases (defined as ALT or AST >3 × ULN and 
TBL >2 × ULN [mainly conjugated fraction] without notable 
increase in ALP to >2× ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST >3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash with 
eosinophilia

Any adverse event potentially indicative of a liver toxicity*
* These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms
TBL: total bilirubin; ULN: upper limit of normal 

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15
Appendix 3: Specific Renal Alert Criteria and Actions 
Table 15-1
Specific Renal Alert Criteria and Actions
Serum Event
Serum creatinine increase
25 – 49% compared to baseline
Confirm 25% increase after 24-48h 
Follow up within 2-5 days
Acute Kidney Injury: Serum creatinine increase 
50% compared to baseline
Follow up within 24-48h if possible
Consider study treatment interruption 
Consider patient hospitalization /specialized treatment
Urine Event
New dipstick proteinuria ≥1+
Albumin- or Protein-creatinine ratio increase ≥2-fold
Albumin-creatinine ratio (ACR) ≥30 mg/g or ≥3 
mg/mmol;
Protein-creatinine ratio (PCR )≥150 mg/g or >15 
mg/mmol
Confirm value after 24-48h
Perform urine microscopy
Consider study treatment interruption / or 
discontinuation 
New dipstick glycosuria ≥1+ not due to diabetes
Blood glucose (fasting)
Perform serum creatinine, ACR 
New dipstick hematuria ≥1+ not due to trauma
Urine sediment microscopy
Perform serum creatinine, ACR 
For all renal events:
Document contributing factors in the eCRF: co-medication, other co-morbid conditions, and additional 
diagnostic procedures performed 
Monitor patient regularly (frequency at investigator’s discretion) until either: 
Event resolution: sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline, or
Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio stabilization at a 
new level with ±50% variability over last 6 months.