Conditions: Branch Retinal Vein Occlusion
Keywords: Visual impairment Macular edema Branch retinal vein occlusion BRVO Brolucizumab Aflibercept Vascular endothelial growth factor VEGF anti-VEGF
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 450
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the efficacy and safety of brolucizumab in treatment of patients with macular edema (ME) secondary to branch retinal vein occlusion (BRVO).

Detailed description:
The study was comprised of a Screening period (Day -28 to Day -1), Double-masked treatment period (Day 1 to Week 72) and Post-treatment follow-up period (Week 72 to Week 76). Treatment visits were scheduled in 4-week intervals. After 6 initial monthly injections of brolucizumab or aflibercept (loading phase), subjects entered a one-year individualized flexible treatment (IFT) phase. During the IFT phase, an assessment of disease stability was performed at each monthly visit and subjects received either an active or a sham injection. Treatment with active was interrupted when disease stability was reached.

Arms:
arm 1: 1 intravitreal injection every 4 weeks for a total of 6 injections, followed by 48 weeks of individualized flexible treatment (IFT) arm 2: 1 intravitreal injection every 4 weeks for a total of 6 injections, followed by 48 weeks of individualized flexible treatment (IFT)

Interventions: intervention 1: Brolucizumab 6 mg intervention 2: Aflibercept 2 mg intervention 3: Sham injection
Intervention descriptions: intervention 1: Solution for injection (intravitreal use) intervention 2: Solution for injection (Intravitreal use) intervention 3: Empty sterile syringe without a needle administered as a sham injection for masking purposes.

From Week 24 to Week 72 inclusive, a sham treatment was performed to maintain subject masking in case treatment with brolucizumab or aflibercept was not deemed necessary by the investigator.

Protocol document:
Prot_000.pdf: 


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................8
Amendment 1 (08-Jun-2020) ............................................................................................10
Protocol summary..............................................................................................................12
1
Introduction .......................................................................................................................14
1.1
Background............................................................................................................14
1.2
Purpose ..................................................................................................................16
2
Objectives and endpoints...................................................................................................17
3
Study design ......................................................................................................................18
4
Rationale............................................................................................................................19
4.1
Rationale for study design .....................................................................................19
4.2
Rationale for dose/regimen and duration of treatment ..........................................20
4.3
Rationale for choice of comparator .......................................................................21
21
4.5
Risks and benefits..................................................................................................21
5
Population..........................................................................................................................22
5.1
Inclusion criteria ....................................................................................................22
5.2
Exclusion criteria...................................................................................................22
6
Treatment...........................................................................................................................24
6.1
Study treatment......................................................................................................24
6.1.1
Investigational and comparator drugs ...................................................24
6.1.2
Additional study treatments ..................................................................25
6.1.3
Treatment arms/group ...........................................................................25
6.1.4
Treatment duration................................................................................25
6.2
Other treatment(s)..................................................................................................25
6.2.1
Concomitant therapy.............................................................................25
6.2.2
Prohibited medication ...........................................................................26
6.2.3
Rescue medication ................................................................................26
6.3
Subject numbering, treatment assignment, randomization....................................27
6.3.1
Subject numbering ................................................................................27
6.3.2
Treatment assignment, randomization ..................................................27
6.4
Treatment masking ................................................................................................27
6.5
Dose escalation and dose modification..................................................................29


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6.6
Additional treatment guidance...............................................................................29
6.6.1
Treatment compliance...........................................................................29
6.6.2
Emergency breaking of assigned treatment code..................................29
6.7
Preparation and dispensation.................................................................................30
6.7.1
Handling of study treatment..................................................................30
6.7.2
Instruction for prescribing and taking study treatment .........................30
7
Informed consent procedures ............................................................................................33
8
Visit schedule and assessments .........................................................................................34
8.1
Screening ...............................................................................................................37
8.1.1
Information to be collected on screening failures.................................37
8.2
Subject demographics/other baseline characteristics.............................................37
8.3
Efficacy..................................................................................................................38
8.3.1
Visual acuity..........................................................................................38
8.3.2
Optical coherence tomography .............................................................38
39
8.3.4
Appropriateness of efficacy assessments..............................................40
8.4
Safety.....................................................................................................................40
8.4.1
Laboratory evaluations..........................................................................41
8.4.2
Pregnancy and assessments of fertility .................................................41
8.4.3
Ophthalmic examination.......................................................................42
8.4.4
Appropriateness of safety measurements..............................................43
8.5
Additional assessments..........................................................................................43
8.5.1
Clinical Outcome Assessments (COAs) ...............................................43
8.5.2
Imaging .................................................................................................44
8.5.3
Anti-drug antibodies (immunogenicity)................................................44
.44
9
Study discontinuation and completion ..............................................................................45
9.1
Discontinuation......................................................................................................45
9.1.1
Discontinuation of study treatment .......................................................45
9.1.2
Withdrawal of informed consent...........................................................46
9.1.3
Lost to follow-up...................................................................................47
9.1.4
Early study termination by the sponsor.................................................47
9.2
Study completion and post-study treatment ..........................................................48
10 Safety monitoring and reporting........................................................................................48
10.1
Definition of adverse events and reporting requirements......................................48
10.1.1
Adverse events ......................................................................................48
10.1.2
Serious adverse events ..........................................................................50


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10.1.3
SAE reporting........................................................................................50
10.1.4
Pregnancy reporting ..............................................................................51
10.1.5
Reporting of study treatment errors ......................................................51
10.2
Additional Safety Monitoring................................................................................52
10.2.1
Data Monitoring Committee .................................................................52
10.2.2
Adjudication Committee.......................................................................52
11 Data Collection and Database management......................................................................52
11.1
Data collection.......................................................................................................52
11.2
Database management and quality control............................................................53
11.3
Site monitoring ......................................................................................................54
12 Data analysis and statistical methods ................................................................................55
12.1
Analysis sets ..........................................................................................................55
12.2
Subject demographics and other baseline characteristics......................................56
12.3
Treatments .............................................................................................................56
12.4
Analysis of the primary endpoint(s) ......................................................................57
12.4.1
Definition of primary endpoint(s).........................................................57
12.4.2
Statistical model, hypothesis, and method of analysis..........................57
12.4.3
Handling of missing values/censoring/discontinuations.......................59
12.4.4
Sensitivity and supplementary analyses................................................60
12.5
Analysis of secondary endpoints ...........................................................................60
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................60
12.5.2
Safety endpoints....................................................................................61
62
12.5.4
Patient reported outcomes.....................................................................63
12.5.5
Anti-drug antibody................................................................................63
.63
63
12.8
Sample size calculation..........................................................................................63
12.8.1
Primary endpoint(s)...............................................................................63
13 Ethical considerations and administrative procedures ......................................................64
13.1
Regulatory and ethical compliance........................................................................64
13.2
Responsibilities of the investigator and IRB/IEC..................................................64
13.3
Publication of study protocol and results...............................................................64
13.4
Quality Control and Quality Assurance.................................................................64
14 Protocol adherence ............................................................................................................65
14.1
Protocol amendments.............................................................................................65
15 References .........................................................................................................................66


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16 Appendices ........................................................................................................................68
16.1
Appendix 1: Clinically notable laboratory values .................................................68
List of tables
Table 2-1
Objectives and related endpoints ..........................................................17
Table 6-1
Investigational and comparator drug.....................................................24
Table 6-2
Prohibited medications/procedures.......................................................26
Table 8-1
Assessment Schedule ............................................................................35
Table 8-2
Physical Assessments............................................................................41
Table 8-3
Laboratory Assessments........................................................................41
Table 10-1
Guidance for capturing the study treatment errors................................52
Table 12-1
Primary and supplementary estimands..................................................58
Table 16-1
Clinically notable laboratory values......................................................68
List of figures
Figure 3-1
Study design..........................................................................................18
Figure 6-1
Dose and treatment schedule.................................................................32


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List of abbreviations
ADA 
Anti-drug antibody
AE
Adverse event
AMD
Age-related macular degeneration
ANOVA
Analysis of variance
AR
Analysis restriction
BCVA
Best-corrected visual acuity
BRVO
Branch retinal vein occlusion
CFR
Code of Federal Regulation
CMO & PS
Chief Medical Office and Patient Safety
CO
Country Organization
COA
Clinical outcome assessment
COVID-19
Coronavirus disease 2019
CP
Color fundus photography
CRC
Central Reading Center
CRVO
Central retinal vein occlusion
CSFT
Central subfield thickness 
DDE
Direct data entry
DMC
Data Monitoring Committee
DME
Diabetic macular edema
eCRF
Electronic Case Report/Record Form
EDC
Electronic Data Capture
EOS
End of Study
EOT
End of Treatment
ESI
Event of special interest
ETDRS
Early Treatment Diabetic Retinopathy Study
FA
Fluorescein angiography
FAS
Full analysis set
FDA
Food and Drug Administration
g/dL
gram(s) per deciliter
GCP
Good Clinical Practice
GCS
Global clinical supply
hCG
Human chorionic gonadotropin
IB
Investigator's Brochure
ICH
International Council for Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IFT
Individualized Flexible Treatment
IOI
Intraocular inflammation
IOP
Intraocular pressure
IRB/IEC
Institutional Review Board/Independent Ethics Committee
IRF
Intraretinal fluid
IRT
Interactive Response Technology
IVT
Intravitreal injection
K/cu mm
thousand per cubic millimeter
kDA
kilo Dalton
LOCF
Last Observation Carried Forward
ME
Macular edema


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MedDRA
Medical dictionary for regulatory activities
mEq/L
milliequivalent(s) per liter
mg
milligram(s)
mg/dL
milligram(s) per deciliter
mL
milliliter(s)
mmHg
millimeter(s) of mercury
mmol/L
millimole(s) per liter
nAMD
Neovascular age-related macular degeneration
NEI
National Eye Institute
NIM
Non-inferiority margin
OCT
Optical coherence tomography
PD
Protocol deviation
PPS
Per Protocol Set/Protocol analysis set
PRO
Patient reported outcome
q12w
every 12 weeks
q4w
every 4 weeks
q8w
every 8 weeks
RAS
Randomized Analysis Set
RAO
Retinal artery occlusion
RoW
Rest of World
RVO
Retinal vein occlusion
SAE
Serious adverse event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
scFv
Single-chain fragment variable
SD-OCT
Spectral domain optical coherence tomography
SOP
Standard operating procedure
SRF
Subretinal fluid
SUSAR
Suspected Unexpected Serious Adverse Reaction
VA
Visual acuity
VEGF
Vascular Endothelial Growth Factor
VFQ-25
Visual Function Questionnaire-25
WBC
White blood cell(s)
WHO
World Health Organization


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biological samples
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, 
urine, stool, etc. taken from a study subject
Control drug
A study drug (active or placebo) used as a comparator to reduce assessment bias, 
preserve masking 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 subject 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.
Enrollment
Point/time of subject entry into the study at which informed consent must be obtained.
eSource (DDE)
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications 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
Investigational 
drug/treatment
The study drug whose properties are being tested in the study
Masked/evaluating 
investigator
For the entire study duration and all study subjects, 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 number
A unique identifier on the label of each study drug package in studies that dispense 
study drug using an IRT system.
Part
A sub-division of a study used to evaluate specific objectives or contain different 
populations. For example, one study could contain a single dose part and a multiple 
dose part, or a part in subjects with established disease and in those with newly-
diagnosed disease.
Patient
An individual with the condition of interest for the study
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
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.
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned completion of all 
study drug administration and assessments; at this time all study drug administration is 
discontinued and no further assessments are planned.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding to a specific 
treatment arm assignment
Screen Failure
A subject who did not meet one or more criteria that were required for participation in 
the study
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.
Stage
A major subdivision of the study timeline; begins and ends with major study milestones 
such as enrollment, randomization, completion of treatment, etc.
Study completion
Point/time at which the subject came in for a final evaluation visit or when study drug 
was discontinued whichever is later.
Study drug/treatment
Any drug (or combination of drugs) administered to the subject as part of the required 
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Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the defined study 
treatment completion date (if any) for any reason; may or may not also be the 
point/time of study discontinuation
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed consent. This 
number is the definitive, unique identifier for the subject and should be used to identify 
the subject throughout the study for all data collected, sample labels, etc.
Treatment arm/group
A treatment arm/group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts.
Unmasked/treating 
investigator
For the entire study duration and all study subjects, the treating investigator only 
performs the treatment (injection active/sham) and assesses subject 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 subjects, the visual acuity assessor (which 
could be a masked/evaluating investigator) performs the BCVA assessment and is 
masked to the assigned treatment
Withdrawal of 
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 
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Protocol summary
Protocol number
CRTH258C2301
Full title
An Eighteen-Month, Two-Arm, Randomized, Double-Masked, Multi-center, Phase III
Study Assessing the Efficacy and Safety of Brolucizumab versus Aflibercept in Adult 
Patients with Visual Impairment due to Macular Edema secondary to Branch Retinal 
Vein Occlusion (RAPTOR)
Brief title
Phase III Study Assessing the Efficacy and Safety of Brolucizumab versus Aflibercept in 
Adult Patients with Macular Edema secondary to Branch Retinal Vein Occlusion
Sponsor and 
Clinical Phase
Novartis
Phase III
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
To evaluate the efficacy and safety of brolucizumab in the treatment of patients with 
macular edema (ME) secondary to branch retinal vein occlusion (BRVO) with the 
objective to evaluate the potential to reduce the treatment burden for patients
Primary 
objective(s) 
To demonstrate that brolucizumab is non-inferior to aflibercept with respect to the 
change in best-corrected visual acuity (BCVA) from baseline up to Month 6
Secondary 
objectives
1.
To assess the effect of brolucizumab as compared to aflibercept on BCVA
2.
To evaluate the anatomical outcome with brolucizumab relative to aflibercept
3.
To evaluate the treatment frequency with brolucizumab during the individualized 
flexible treatment (IFT) period relative to aflibercept
4.
To assess the safety and tolerability of brolucizumab relative to aflibercept
5.
To evaluate the effect of brolucizumab relative to aflibercept on patient-reported 
vision-related quality of life
6.
To assess the immunogenicity of brolucizumab
Study design
The study is an eighteen-month randomized, double-masked, multi-center, active-
controlled, non-inferiority, 2-arm study in subjects with visual impairment due to ME 
secondary to BRVO.
Subjects will be randomized in a 1:1 ratio to 1 of 2 treatment arms:

Brolucizumab 6 mg: 6 x every 4 weeks (q4w) followed by 48 weeks of 
individualized flexible treatment (IFT) from Week 24 onwards

Aflibercept 2 mg: 6 x q4w followed by 48 weeks of IFT from Week 24 onwards
Population
Approximately 625 adult patients will be screened (20% screening failure rate expected) 
so that approximately 500 patients (250 per arm, 10% dropout rate expected) will be 
randomized in a 1:1 ratio in approximately 110 centers worldwide. The maximum study 
duration for 1 subject is 80 weeks, including screening and safety follow-up.
Key inclusion 
criteria

Signed informed consent must be obtained prior to participation in the study

Male or female patients ≥18 years of age at screening

Patients with visual impairment due to ME secondary to BRVO diagnosed < 6 
months prior to screening (study eye)

Best-corrected visual acuity (BCVA) score between 78 and 23 letters, inclusive, 
using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing 
charts (approximate Snellen equivalent of 20/32 to 20/320) at both screening and 
baseline visit (study eye)




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1
Introduction
1.1
Background
Retinal vein occlusion (RVO) is the second most common retinal vascular permeability disorder 
after diabetic retinopathy and is a significant cause of visual impairment. The 5-year, 10-year 
and 15-year incidences of RVO have been estimated as 0.8, 1.6 and 2.3 per 100 persons, 
respectively (Klein et al 2000; Cugati et al 2006; Klein et al 2008). Macular edema (ME) is the 
most common cause of vision loss in patients with branch retinal vein occlusion (BRVO) or 
central retinal vein occlusion (CRVO). In an in vivo model, it has been demonstrated that 
vascular 
endothelial 
growth 
factor 
(VEGF) 
can 
increase 
vascular 
permeability 
(Aiello et al 1994) and that intraocular levels of VEGF in the eyes with RVO are elevated 
(Campochiaro et al 2009).
Previous and current available therapies
Until the approval of ranibizumab, the management of ME associated with RVO was largely 
based on the results from the Branch Vein Occlusion Study and the Central Vein Occlusion 
Study, where laser treatment in BRVO was shown to slow the progression of vision loss 
(The Branch Vein Occlusion Study 1984; Finkelstein 1986). Laser photocoagulation was then 
the standard of care in patients with BRVO despite many patients failing to gain vision. 
Pharmacologic treatment of RVO began with the use of corticosteroids and the approval of the 
intravitreal dexamethasone sustained-release implant (Ozurdex®) by the Food and Drug 
Administration (FDA) in 2009 and the European Medicines Agency (EMA) in 2010 
(Haller et al 2010).
More recently, anti-VEGF therapies have revolutionized the treatment of ME secondary to 
RVO and are currently the standard of care in this indication as VEGF is a major mediator for 
ME in RVO. The most commonly used VEGF inhibitors, i.e. bevacizumab (Avastin®), 
aflibercept (Eylea®) and ranibizumab (Lucentis®) have demonstrated compelling evidence for 
resolution of ME and improvement of visual acuity (VA) subsequent to the treatment with an 
anti-VEGF (Rabena et al 2007; Campochiaro et al 2010; Clark et al 2016).
Ranibizumab (0.5 mg) was globally approved (2010 by the FDA, 2011 by the Committee on 
Herbal Medicinal Products (CHMP) and 2013 by the Pharmaceutical and Medical Devices 
Agency (PMDA)) for the treatment of ME due to BRVO and CRVO, based on the results of 2 
Phase III studies (BRAVO for BRVO and CRUISE for CRVO) (Campochiaro et al 2010; 
Brown et al 2010). These studies showed that approximately 60% of BRVO and 48% of CRVO 
patients treated with monthly ranibizumab gained at least 15 letters of VA at 6 months, 
compared with 29% and 17% of those treated with sham, respectively. The VA gain was 
maintained on average until Month 12 using a pro re nata (PRN) treatment regimen, which was 
based on VA and anatomic parameters.
Aflibercept (2 mg) was approved for the treatment of ME following RVO at a global level (2014 
by the FDA, 2015 by the CHMP and PMDA) based on the results of 3 Phase III studies: 
COPERNICUS and GALILEO for CRVO (Pielen et al 2017) and VIBRANT for BRVO 
(Clark et al 2016). In these studies, approximately 60% of CRVO patients treated with monthly 
aflibercept gained ≥ 15 letters from baseline versus 17% in the sham group. Approximately 


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53% of BRVO patients treated with monthly aflibercept gained ≥ 15 letters from baseline versus 
27% in the laser group.
Currently available anti-VEGF treatments require frequent regular intravitreal (IVT) injections, 
which can be burdensome to patients and health care professionals. Therefore, an unmet 
medical need to reduce the treatment burden with an effective alternative still exists.
Brolucizumab
Brolucizumab, formerly known as RTH258 and ESBA1008, is a humanized single-chain 
fragment variable (scFv) that binds to VEGF-A (i.e. interferes with activation of VEGF-R1 and 
R2 on endothelial cells) with a molecular weight of ~26 kDa. It is also being developed for the 
treatment of choroidal neovascularization (CNV) associated with neurovascular age-related 
macular degeneration (nAMD). The characteristics of brolucizumab allow delivery of a high 
molar dose via intravitreal injection. Higher molar doses are expected to lead to longer presence 
of relevant drug levels in the retina. In addition, a low molecular weight and high concentration 
gradient between the vitreous and the retina may increase and prolong drug distribution to the 
target site of action, supporting longer effective control of disease activity. This could 
potentially translate into a more durable efficacy and a reduced treatment burden (number of 
injections) for the patient and health care professional.
Brolucizumab in nAMD
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 6 mg (P = 0.036) versus ranibizumab, with the maximum effect on best-corrected 
visual acuity (BCVA) and central subfield thickness (CSFT) reached at Week 6 for 
brolucizumab versus Week 4 for ranibizumab. In a separate repeat dosing Phase II study (C-
12-006, OSPREY) comparing brolucizumab 6 mg (n = 44) every 8 weeks (q8w), then every 12 
weeks (q12w) administration, i.e. administration every q8w and q12w, respectively, against 
aflibercept (q8w administration, n = 45), brolucizumab achieved comparable visual outcome 
during the loading and q8w phase, with a lower number of patients requiring additional rescue 
treatments (5 out of 44 versus 10 out of 45, 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 RTH258-C001 (HAWK) and RTH258-C002 (HARRIER), 
brolucizumab demonstrated non-inferiority to aflibercept in mean change in BCVA from 
baseline to Week 48 in both trials using a non-inferiority margin (NIM) of 4 letters. 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 (every 12 weeks) dosing interval following 
the loading phase (baseline to Week 8) through Week 48. Significantly fewer patients on 
brolucizumab had disease activity at Week 16 (head-to-head comparison based on a matching 
dosing regimen) with a relative decrease of 30% (P = 0.0022) versus aflibercept. Significantly 
fewer patients on brolucizumab had intraretinal fluid (IRF) and/or subretinal fluid (SRF), with 
a 35% and 33% reduction relative to aflibercept at Week 16 (P < 0.001 for both) in HAWK and 
HARRIER, respectively, and a 31% and 41% reduction relative to aflibercept at Week 48 in 
HAWK and HARRIER, respectively (P < 0.0001 for both). Brolucizumab 6 mg achieved 


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superior reductions in CSFT versus aflibercept in both the head-to-head and maintenance 
phases (P = 0.0016 and P = 0.0023 at Week 16 and Week 48, respectively, in HAWK; P < 
0.0001 at both Week 16 and Week 48 in HARRIER). Brolucizumab safety was comparable to 
aflibercept, with the overall incidence of adverse events (AEs) balanced across all treatment 
groups in both studies.
Since the first marketing authorization approval in Oct-2019 for the treatment of nAMD, 
adverse events of retinal vasculitis and/or retinal vascular occlusion, 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®). Considering these events, the overall
risk/benefit assessment remains positive.
Summary
Ranibizumab, aflibercept and brolucizumab all inhibit the activity of VEGF-A, with all three 
having proven efficacy in the treatment of nAMD while both ranibizumab and aflibercept have 
also previously demonstrated efficacy in the treatment of patients with ME secondary to BRVO 
and CRVO. These findings support the evaluation of brolucizumab in RVO patients. 
Furthermore, the efficacy profile of brolucizumab in nAMD patients indicates a potential of 
brolucizumab to differentiate versus existing anti-VEGFs on duration of action and anatomical 
efficacy in BRVO patients:

The longer duration of action is supported by the following outcomes of the Phase I and II 
nAMD studies with brolucizumab 6 mg dose: 

Maximum improvements in BCVA and CSFT at Week 4 for ranibizumab versus 
Week 6 for brolucizumab

Greater CSFT stability during q8w maintenance versus aflibercept

Fewer rescue treatments versus aflibercept in q8w phase

The aforementioned results were confirmed by the nAMD (HAWK and HARRIER) 48-
week study results, which demonstrated: 

Visual gains at Week 48 achieved with 56% (HAWK) and 51% (HARRIER) of 
patients treated following a q12w regimen after the loading dose

Superior reduction in CSFT versus aflibercept

The potential for less frequent injections of brolucizumab as compared to aflibercept

Lower proportion of patients with intra- and/or subretinal fluid
Previous studies demonstrating efficacy with anti-VEGFs on BRVO, combined with the 
evidence detailed above support a loading phase with a q4w (i.e. every 4 weeks) regimen 
followed by an individualized flexible treatment (IFT) regimen in a maintenance phase based 
on disease stability for brolucizumab, thus potentially reducing the injection burden.
These considerations support the initiation of a Phase III program to evaluate the efficacy and 
safety of brolucizumab in the treatment of patients with ME secondary to BRVO with the 
objective to evaluate the potential to reduce the treatment burden for patients.
1.2
Purpose
The purpose of this study is to demonstrate the efficacy and safety of brolucizumab in the 
treatment of subjects with ME secondary to BRVO


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2
Objectives and endpoints
For the detailed description of the primary endpoint and its statistical analysis, please refer to 
Section 12.4. Details of the statistical analyses for secondary 
endpoints will be 
provided in the Statistical Analysis Plan (SAP). 
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 
change in best-corrected visual acuity 
(BCVA) from baseline up to Month 6

Change from baseline in BCVA at Week 24
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To assess the effect of brolucizumab as 
compared to aflibercept on best-corrected 
visual acuity (BCVA)

Change from baseline in BCVA averaged over Week 40 
to Week 52 and Week 64 to Week 76

Change from baseline in BCVA by visit up to Week 76

Proportion of study eyes with a gain ≥ 5, 10 and 15 
letters in BCVA by visit compared to baseline

Proportion of study eyes with a loss ≥ 5, 10 and 15 
letters in BCVA by visit compared to baseline

To evaluate the anatomical outcome with 
brolucizumab relative to aflibercept

Change from baseline in central subfield thickness 
(CSFT) averaged over Week 40 to Week 52 and Week 
64 to Week 76

Change from baseline in CSFT by visit up to Week 76

Proportion of study eyes with presence of retinal fluid 
(intra- and/or subretinal fluid) by visit up to Week 76 

Proportion of study eyes with a CSFT < 300 µM by visit 
up to Week 76

To evaluate the treatment frequency with 
brolucizumab during the individualized 
flexible treatment (IFT) period relative to 
aflibercept

Number of injections between Week 24 and Week 52 
and between Week 24 and Week 76

Time to first re-treatment between Week 24 and Week 
76

To assess the safety and tolerability of 
brolucizumab relative to aflibercept

Incidence of ocular and non-ocular AEs up to Week 52 
and Week 76

To evaluate the effect of brolucizumab 
relative to aflibercept on patient-reported 
vision-related quality of life

Change from baseline in patient reported outcomes 
(NEI VFQ-25) at Week 24, Week 52 and Week 76

To assess the immunogenicity of 
brolucizumab

Anti-drug antibody status at screening and Week 4, 
Week 12, Week 24, Week 36, Week 52 and Week 76


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3
Study design
The study is an 18-month, randomized, double-masked, multi-center, active-controlled, non-
inferiority, 2-arm study in subjects with visual impairment due to ME secondary to BRVO.
Subjects who consent will undergo screening assessments to evaluate their eligibility based on 
the inclusion and exclusion criteria. Subjects who meet all the inclusion and none of the 
exclusion criteria will be randomized in a 1:1 ratio to 1 of 2 treatment arms:

Brolucizumab 6 mg: 6 x q4w followed by 48 weeks of individualized flexible treatment 
(IFT) from Week 24 onwards

Aflibercept 2 mg: 6 x q4w followed by 48 weeks of IFT from Week 24 onwards
Approximately 625 adult subjects will be screened (20% screening failure rate expected) so that 
approximately 500 subjects (250 per arm, 10% dropout rate expected) will be randomized in a 
1:1 ratio in approximately 110 centers worldwide. The maximum study duration for 1 subject 
is 80 weeks, including screening and safety follow-up.
Figure 3-1
Study design
*Loading phase; IFT: Individualized flexible treatment
Screening period: Day -28 to Day -1
A screening period of up to 4 weeks will be used to assess subject eligibility.
One time reassessment of subjects is allowed, except for the purpose of capturing new BCVA 
assessments that previously failed to qualify the subject. As long as testing can be repeated 
within 14 days of the first screening, the other screening assessments do not need to be repeated. 








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5
Population
The study population will be male and female patients, ≥ 18 years old diagnosed with visual 
impairment due to ME secondary to BRVO. Approximately 625 patients will be screened (20% 
screening failure rate expected) and approximately 500 (250 per arm, 10% dropout rate 
expected) patients will be randomized in a 1:1 ratio in approximately 110 centers worldwide.
If both eyes are eligible as per the inclusion and exclusion criteria described below, the eye with 
the worse visual acuity should be selected for study eye, unless the investigator deems it more 
appropriate to select the eye with better visual acuity, based on medical reasons or local ethical 
requirements.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Signed informed consent must be obtained prior to participation in the study.
2. Male or female patients ≥ 18 years of age at screening
Study eye:
3. Patients with visual impairment due to ME secondary to BRVO diagnosed < 6 months 
prior to screening.
4. BCVA score between 78 and 23 letters, inclusive, using ETDRS visual acuity testing 
charts (approximate Snellen equivalent of 20/32 to 20/320) at both screening and baseline 
visits.
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
Ocular conditions:
1. Concomitant conditions or ocular disorders in the study eye at screening or baseline 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. structural damage of the 
fovea, vitreous hemorrhage, retinal vascular occlusion other than BRVO, retinal 
detachment, macular hole, or choroidal neovascularization of any cause, diabetic 
retinopathy (except mild non-proliferative) and diabetic macular edema). Hemiretinal 
vein occlusion should be excluded.
2. 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
3. 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
4. Presence of amblyopia, amaurosis or ocular disorders in the fellow eye with BCVA < 
20/200 at screening (except when due to conditions whose surgery may improve VA, e.g. 
cataract)
Ocular treatments:


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5. Previous treatment with any anti-VEGF therapy or investigational drugs in the study eye 
at any time prior to baseline
6. Previous use of intraocular or periocular steroids in study eye at any time prior to baseline
7. Macular laser photocoagulation (focal/grid) in the study eye at any time prior to baseline 
and peripheral laser photocoagulation in the study eye within 3 months prior to the 
baseline
8. Intraocular surgery in the study eye during the 3month period prior to baseline
9. Vitreoretinal surgery in the study eye at any time prior to baseline
10. Aphakia with the absence of posterior capsule in the study eye
Systemic conditions or treatments:
11. Stroke or myocardial infarction during the 6month period prior to baseline
12. End stage renal disease requiring dialysis or renal transplant
13. Uncontrolled blood pressure defined as a systolic value ≥ 160 mmHg or diastolic value ≥ 
100 mmHg at screening or baseline. (In case there is an elevated blood pressure 
measurement, it should be repeated after 20 minutes. If the repeat measurement is 
elevated, then the patient is not eligible to be enrolled into the study)
14. Systemic anti-VEGF therapy during the 3-month period prior to baseline
15. 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 6month period prior to baseline, except temporary use for 
COVID-19 treatment
16. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
classes, or clinically relevant sensitivity to fluorescein dye as assessed by the investigator
17. 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
18. History of a medical condition (e.g. metabolic dysfunction disease 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
19. Use of systemic investigational drugs within 5 half-lives of baseline, (or within 30 
days/until the expected pharmacodynamic effect has returned to baseline), whichever is 
longer or longer if required by local regulations (observational clinical studies solely 
involving over-the-counter vitamins, supplements, or diets are not exclusionary)
Other:
20. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive human 
chorionic gonadotropin (hCG) pregnancy test
21. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during the study drug administration and for 3 months after stopping the investigational 
medication. Highly effective contraception methods include:


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
Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject

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 women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with 
or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before taking 
study treatment. In the case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment is she considered not of 
child-bearing potential.
If local regulations deviate from the contraception methods listed above to prevent pregnancy,
local regulations apply and will be described in the informed consent form.
6
Treatment
6.1
Study treatment
6.1.1
Investigational and comparator drugs
Table 6-1
Investigational and comparator drug
Investigational 
Drug
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor
Brolucizumab 6 mg 
Solution for 
injection
Intravitreal use
Glass vials or 
pre-filled syringe
Sponsor global
Comparator Drug
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor 
Aflibercept 2 mg
Solution for 
injection
Intravitreal use
Glass vials or 
pre-filled syringe
Sponsor global 


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Brolucizumab will be provided in a single use, sterile glass vial, or may be provided in a pre-
filled syringe (PFS) (in selected countries) containing sufficient brolucizumab to deliver a 6 mg 
dose when administering a volume of 0.05 mL.
Aflibercept will be provided in a single use, sterile glass vial, or may be provided in a pre-filled 
syringe (in selected countries) containing sufficient aflibercept to deliver a 2 mg dose when 
administering a volume of 0.05 mL.
The content of the study drug vials must not be split.
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.
6.1.2
Additional study treatments
No other treatment beyond investigational drug and comparator drug are included in this trial.
6.1.3
Treatment arms/group
Eligible subjects will be randomly assigned at Baseline/Day 1 to 1 of the following 2 treatment 
arms in a 1:1 ratio

Brolucizumab 6 mg: 6 x q4w followed by 48 weeks of IFT from Week 24 onwards

Aflibercept 2 mg: 6 x q4w followed by 48 weeks of IFT from Week 24 onwards
6.1.4
Treatment duration
The planned duration of treatment is 18 months (72 weeks). Discontinuation of study treatment 
for a subject occurs when study drug is stopped earlier than the protocol planned duration, and 
can be initiated by either the subject or the investigator.
Subjects who prematurely discontinue study treatment for any reason except withdrawal of 
consent should continue in the study and carry out the scheduled visits and assessments, at the 
discretion of the subject and investigator.
6.2
Other treatment(s)
6.2.1
Concomitant therapy
Prior medication, i.e. any medication taken within 90 days prior to screening, must be recorded 
on the appropriate Electronic Case Report Forms (eCRFs).
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject was enrolled into the study must be recorded 
on the appropriate eCRFs.
Each concomitant medication must be individually assessed against all exclusion 
criteria/prohibited medication. If in doubt, the investigator should contact the Novartis medical 
monitor before randomizing a subject or allowing a new medication to be started. If the subject 


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is already enrolled, contact Novartis to determine if the subject should continue to take study 
treatment or should discontinue study treatment but still continue participation in the study.
6.2.1.1
Permitted concomitant therapy
During the study, if the fellow eye develops visual impairment due to ME secondary to BRVO 
or other disease, it may also be treated with standard of care at the discretion of the investigator 
(i.e. treatment of the fellow eye with anti-VEGF medication other than brolucizumab is 
allowed). Fellow eye treatment will be captured in the eCRF. The fellow eye must be monitored 
according to routine practice and adverse events (AEs) captured in the eCRF.
In case of development of peripheral retinal neovascularization in the study eye, it may be 
treated with laser according to the investigator's routine practice. 
If needed, administration of topical ocular corticosteroids in the study eye is allowed during the 
study. Corticosteroids administered via intra-nasal, inhaled, intra-articular or non-extensive 
dermal route are also permitted during the study.
If cataract surgery or yttrium aluminum garnet (YAG) laser is necessary, it should be scheduled 
in a way not to disturb the schedule for study treatment.
6.2.2
Prohibited medication
Use of the treatments displayed in the below table is not allowed after screening.
Table 6-2
Prohibited medications/procedures
Medication / Procedures
Prohibition Period
Action Taken
Study eye
Any periocular injection or intraocular administration 
of corticosteroids (except if needed as short term 
treatment of AE)
Anytime
Discontinue study treatment 
(except if for treatment of AE)
Anti-VEGF therapy other than assigned study 
medication
Anytime
Discontinue study treatment
Laser photocoagulation (focal/grid)
Before Week 24
Continue study treatment at the 
investigator's discretion
Any investigational drug, biologic or device
Anytime
Discontinue study treatment
Systemic
Anti-VEGF therapy
Anytime
Discontinue study treatment
Any investigational drug, biologic or device
Anytime
Discontinue study treatment
Medications toxic to the lens, retina or optic nerve
(except temporary use for COVID-19 treatment)
Anytime
Discontinue study treatment
In the fellow eye, treatment with investigational product (drug, biologic or device) is prohibited. 
Any medication used to treat the fellow eye should be recorded in the appropriate eCRF page.
6.2.3
Rescue medication
Per the investigator's discretion, the study eye may receive rescue treatment with macular laser 
photocoagulation (focal or grid) from Week 24 onwards if ME worsening results in a ≥ 10-
letter loss in BCVA at 2 consecutive visits or a ≥ 15-letter loss in BCVA at 1 visit in the study 
eye compared to best previous measurement, and the study eye BCVA value is not better than 
the baseline value.


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6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the subject signs the informed consent form and is retained as the primary identifier for the 
subject throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (4 digit number for Center No. as assigned by Novartis to the investigative site) with a 
sequential subject number suffixed to it (3 digit number for Subject No.), so that each subject 
is numbered uniquely across the entire database. Upon signing the informed consent form, the 
subject is assigned to the next sequential Subject No. available in the electronic data capture 
(EDC) system.
Subjects who have been screen failures but are rescreened (see Section 8.1) will be assigned a 
new Subject No. if rescreening occurs beyond 14 days from the original screening date.
6.3.2
Treatment assignment, randomization
All screened subjects must be added to the Interactive Response Technology (IRT) system. At 
the Baseline Visit/Day 1, all eligible subjects will be randomized via IRT to 1 of the treatment 
arms, in a ratio of 1:1. The randomization will be stratified by the following demographic 
groups: Japanese region, Chinese region (including Taiwan and Hong Kong) and rest of world 
(RoW) region.
The unmasked investigator or his/her delegate will contact the IRT after receiving confirmation 
from the masked investigator that the subject fulfills all the inclusion/exclusion criteria. The 
IRT will assign a randomization number to the subject, which will be used to link the subject 
to a treatment arm and will specify a unique medication number for the study treatment 
packages (each containing 1 vial) to be dispensed to the subject. The randomization number 
will not be communicated to subject or site users.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 
randomization list will be produced using a validated system that automates the random 
assignment of subject numbers to randomization numbers. These randomization numbers are 
linked to the different treatment arms, which in turn are linked to medication numbers. A 
separate medication list will be produced by or under the responsibility of Novartis Global 
Clinical Supply (GCS) using a validated system that automates the random assignment of 
medication numbers to packs containing the study treatment.
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office.
6.4
Treatment masking
The intent of masking is to limit the occurrence of conscious and unconscious bias in the 
conduct 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 endpoints, the handling of withdrawals, and 
so on. The essential aim of masking, therefore, is to prevent identification of the treatments by 


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the investigator, subject, and others associated with the conduct of the study until all such 
opportunities for bias are no longer present.
This study will be double-masked, with subjects randomized to be treated with brolucizumab 6 
mg or aflibercept 2 mg. The clinical study team will be masked to treatment assignments until 
Week 52 Database lock and will be unmasked once the Week 52 Database lock is reached. 
However, masking to the original treatment assignment will be maintained at the site level 
(patients, masked study site personnel, masked monitors) until the end of the study.
Unmasking of investigators and site personnel directly involved in the conduct of the study will 
only occur in case of subject emergencies (see Section 6.6.2), and then at the time of the final 
analysis (see Section 4.4), at the conclusion of the study.
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 Suspected Unexpected Serious 
Adverse Reaction (SUSAR)), an 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 investigational product. The unmasked 
site personnel and unmasked injecting investigator must not perform BCVA assessments, 
complete ophthalmic examination, disease stability assessments or administer the National Eye 
Institute Visual Function Questionnaire-25 (NEI 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 of AEs for subjects during the course of the study.
The unmasked investigator/site personnel should, however, assess the subject's functional 
vision (e.g. finger counting) and may perform other safety assessments as needed immediately 
following injection.
After randomization, the unmasked investigator/site personnel must not change their role to 
perform a masked role. Only when a masked investigator needs to change to become an 
unmasked investigator, he/she may change as long as the person is not serving in the Principal 
Investigator role. This change must be agreed with the Sponsor. 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 database lock has occurred 
by ensuring that 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 76, the masked personnel at 
site and subjects 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.




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
subject number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-masking 
can be performed at anytime.
The appropriate personnel from the site and Sponsor will assess whether study treatment should 
be discontinued for any subject whose treatment code has been broken for any reason.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and comparator drugs (Section 6.1.1).For both brolucizumab and aflibercept, the study drug 
packaging has a 2-part label (base plus tear-off label). A unique medication number is printed 
on each part of this label, which corresponds to 1 of the treatment arms. Unmasked study 
personnel will identify the study medication kits to dispense to the subject by contacting the 
IRT and obtaining the medication number(s). Immediately before dispensing the medication kit 
to the subject, unmasked study personnel will detach the outer part of the label from the 
packaging and affix it to the source document (Drug Label Form) for that subject's unique 
subject number.
6.7.1
Handling of study treatment 
Study treatment must be received by a designated unmasked person at the study site, handled 
and stored safely and properly and kept in a secured location to which only the unmasked 
investigator and designated site personnel have access. Upon receipt, all study treatment must 
be registered in the IRT system and stored according to the instructions specified on the labels 
and in the Investigator’s Brochure. Clinical supplies are to be dispensed only in accordance 
with the protocol. Technical complaints are to be reported to the respective Novartis Country 
Organization (CO) 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 subject except for the medication number.
The unmasked study personnel 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 unmasked 
study personnel will return all unused study treatment, packaging, drug labels, and a copy of 
the completed drug accountability log to the unmasked Novartis monitor or to the Novartis 
address provided in the investigator folder at each site.
6.7.2
Instruction for prescribing and taking study treatment
All kits of study treatment assigned by the IRT will be recorded/databased in the IRT system.
There will be 2 treatment phases for IVT injections:
Loading Phase


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In the loading phase, treatment with either brolucizumab (6 mg) or aflibercept (2 mg) will occur 
every 4 weeks for six (6) consecutive injections (Baseline, Weeks 4, 8, 12, 16 and 20).
Every effort should be made to ensure that the subject adheres to the visit/treatment schedule.
Individualized Flexible Treatment (IFT) Phase
The IFT phase is defined as follows (see Figure 6-1):

The assessment of disease stability is performed at each visit by the masked investigator 
as of Week 24, and is guided by the stability of visual acuity and/or anatomical parameters 
(e.g. subretinal fluid, intraretinal fluid, retinal thickness (CSFT)), within the previous 3 
visits.

As long as there is no disease stability, subjects will receive active injections every 4 
weeks.

When disease stability is reached, treatment is interrupted.
The IRT system will allocate active/sham injections as per the masked investigator’s assessment 
of disease stability. A disease stability assessment will also be performed at Week 76/EOS visit, 
however, no study treatment will be administered.
Brolucizumab or aflibercept (or sham) should be administered in the study eye on the day of 
the study visit or, if this is not possible, the recommendation is for this to be performed within 
3 days after the occurrence of the study visit (except for Baseline/Day 1, in which case study 
treatment administration should occur within the next 24 hours), or no later than within the visit 
window as described in Section 3 and Section 8. If assessments and treatments take place on 
the same day, treatment must occur after completion of the efficacy assessments described 
in Section 8.3
and pre-injection safety measures (tonometry, slit lamp and fundus 
examinations) described in Section 8.4.3. If study visit assessments and the corresponding 
treatment occur on separate days, a repeat safety check-up should be performed prior to 
treatment of the eye and results documented in the source documents. If any safety concern 
arises related to the study eye that, in the opinion of the investigator, may be further impacted 
by the study treatment or injection procedure, treatment needs to be cancelled. Any adverse 
events must be recorded in the eCRF.
The assessment of the masked/evaluating investigator will be passed to the unmasked/treating 
investigator or delegate in order to be entered in the IRT system and obtain the applicable 
treatment, active or sham, as assigned by IRT.


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Figure 6-1
Dose and treatment schedule
V: Visit; BL: Baseline; IFT: Individualized Flexible Treatment
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 will be performed by the unmasked investigator.
IVT injection is contraindicated in subjects with active ocular or periocular infections and in 
subjects with active intraocular inflammation (IOI); therefore, the investigators must verify that 
these conditions are not present in the study eye prior to every injection.
If any signs of intraocular inflammation are present, then an IVT injection must not be 
performed. Additional ophthalmic examination and imaging should be performed to evaluate 
IOI (see Section 8.4.3). 
If IOI is confirmed, subjects should be treated for IOI according to clinical practice.
From Week 24 to Week 72 inclusive, a sham treatment will be performed to maintain subject 
masking in case treatment with brolucizumab or aflibercept is not deemed necessary by the 
investigator. For the sham treatment the tip of an injection syringe (the hub without a needle) 
will be used.




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appropriately documented and confirmed by way of standard informed consent procedures at 
the earliest opportunity when the subject will be back at the trial site.
8
Visit schedule and assessments
The Assessment Schedule (Table 8-1) lists all of the assessments and indicates with an “X” the 
visits when they are performed. All data obtained from these assessments must be supported in 
the subject’s source documentation. Data must be entered as appropriate in the eCRF in a timely 
manner (see Section 11.1).
A planned study visit schedule will be established at Baseline/Day 1, randomization (first day 
of treatment), for all subjects. All post-baseline and/or subsequent scheduled visits will be 
calculated based on the Day 1 visit date. All efforts should be made to adhere to all scheduled 
visits and assessments as outlined in the assessment schedule (Table 8-1).
A ± 7 days visit window is allowed (except for Baseline/Day 1), should the subject be unable 
to return per scheduled visit. All efforts should be made to revert back to the planned visit 
schedule taking into consideration the restrictions on the minimum treatment interval for the 
study treatment, i.e. 2 consecutive injections should be spaced by at least 21 days. 
For a given protocol visit (except for Baseline/Day 1), assessments can be performed on 2 
consecutive days in which both days must occur within the ± 7 days visit window.
Treatment is intended to be administered on the day of study visit, or if this is not possible, 
within 3 days after the study visit at which the per-protocol assessments took place (except 
Baseline/Day 1, in which case study treatment administration should occur within the next 24 
hours).
For all visits, efficacy assessments (Section 8.3) and safety assessments (Section 8.4) should be 
performed prior to any administration of study treatment and/or rescue medication.
Missed or rescheduled visits should not lead to automatic discontinuation. Subjects who 
prematurely discontinue the study for any reason should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for the End of Study final visit will be 
performed.
If the COVID-19 pandemic limits or prevents on-site study visits, study treatment could not be 
administered and other study assessments may not be performed. Alternative methods of safety 
monitoring may be implemented. Depending on local regulations, site capabilities and subject’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 subject to visit the site 
again.


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Table 8-1
Assessment Schedule
Period Screening
Loading Phase
Individualized Flexible Treatment Phase
Follow-
up
Visit Name Screening Baseline / 
Day 1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19 / 
EOT
20 / 
EOS
Weeks
-4 to -1
1
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
Demography
X
Medical History/Current Medical 
Conditions
X
Prior/Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
Clinical Chemistry
X
X
X
X
Urinalysis
X
X
X
X
Pregnancy Test (serum)
X
X
X
Pregnancy Test (urine)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Visual Function Questionnaire-25 
(VFQ-25)2
X
X
X
X
Blood Collection for Anti-Drug 
Antibody (ADA)3
X
X
X
X
X
X
X
Blood Collection for Study Drug 
Systemic Exposure3
X
X
X
X
X
X
X
Best-corrected Visual Acuity 
(BCVA)
X4
X
X
X
X
X
X
X4
X
X
X
X
X
X
X4
X
X
X
X
X
X4
Intraocular Pressure (IOP)
X4
X
X
X
X
X
X
X4
X
X
X
X
X
X
X4
X
X
X
X
X
X4




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8.1
Screening
A screening period of up to 4 weeks will be used to assess subject eligibility.
For 
the purpose 
of 
screening, fluorescein angiography 
(FA) 
images 
from 
a 
previous routine evaluation may be used as long as FA was performed within 3 days of the 
screening 
visit 
using 
Central 
Reading 
Center 
(CRC)-certified 
equipment 
and 
technician/investigator.
One time reassessment of subjects is allowed, except for the purpose of capturing new BCVA 
assessments that previously failed to qualify the subject. As long as testing can be repeated 
within 14 days of the first screening, the other screening assessments do not need to be repeated. 
If rescreening is to occur beyond 14 days from the original screening visit date, then the subject 
must be reconsented and all screening procedures must be repeated. Medical judgment should 
be exercised to ensure that treatment of BRVO is not withheld in order for a subject to 
participate in the study.
8.1.1
Information to be collected on screening failures
Subjects who sign an informed consent form and who are subsequently found to be ineligible 
prior to randomization will be considered a screen failure. The reason for screen failure should 
be recorded on the appropriate eCRF page. The demographic information, informed consent, 
inclusion/exclusion and disposition eCRF pages must also be completed for screen failure 
subjects. No other data will be entered into the clinical database for subjects who are screen 
failures, unless the subject experienced a serious adverse event (SAE) during the screening 
phase (see SAE Section 10.1.2 for reporting details). Adverse events that are not SAEs will be 
followed by the investigator and collected only in the source data. If the subject is not eligible 
to be randomized, the IRT must be notified within 2 days of the screen fail that the subject was 
not randomized.
8.2
Subject demographics/other baseline characteristics
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with eCRF.
The following information will be collected/documented at screening/baseline visit for each 
randomized subject:

Age

Sex

Race/Ethnicity

Physical examination

Vital signs

Study eye

Best-corrected visual acuity

Macular edema characteristics

Intraocular pressure


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
Ophthalmic examinations

Retinal imaging

Laboratory test results

Pregnancy test

VFQ-25 questionnaire

Prior/concomitant medications

Medical history/current medical conditions

Adverse events
Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF whenever, in their judgment, the test abnormality occurred prior to the informed consent 
signature.
8.3
Efficacy
The following assessments will be performed to evaluate the effect of brolucizumab and 
aflibercept on visual function, retinal structure and vascular leakage:

Best-corrected visual acuity with ETDRS-like charts at an initial testing distance of 4 
meters

Anatomical retinal evaluation of Optical Coherence Tomography images,
All efficacy assessments should be performed prior to any administration of study treatment 
and/or rescue medication.
8.3.1
Visual acuity
Visual acuity will be assessed in the study eye at every study visit and in both eyes at screening, 
Week 24, Week 52 and Week 76/EOS visit using best correction determined from protocol 
refraction (BCVA). BCVA measurements will be taken in a sitting position using ETDRS–like 
visual acuity testing charts at an initial testing distance of 4 meters. The details of the refraction 
technique and VA testing, as well as training material, are provided in the applicable manual. 
Certification of the assessment procedures and VA assessors will occur prior to any evaluation 
of study subjects.
8.3.2
Optical coherence tomography
Spectral Domain Optical Coherence Tomography (SD-OCT) images will be obtained and 
assessed in the study eye at every study visit and in both eyes at screening, Week 24, Week 52 
and Week 76/EOS visit. Only SD-OCT machines can be used (e.g. no time domain OCT).
These assessments will be performed by a trained technician or investigator at the sites and 
should be performed after BCVA assessment and prior to any study drug administration. 
Masked investigators will evaluate the SD-OCT to assess the status of disease stability. The 
SD-OCT machine used for an individual subject should not change for the duration of the study.




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8.3.4
Appropriateness of efficacy assessments
The use of BCVA as a measure of retinal function as well as SD-OCT images to analyze 
anatomical changes are standard assessments in this indication and are required for a 
comparative evaluation of this trial with the existing evidence from previous trials.
8.4
Safety
Safety assessments will include physical examination, vital signs, ophthalmic examinations, 
laboratory evaluation, pregnancy testing as well as monitoring and recording type, frequency, 
and severity for all AEs.
If the COVID-19 pandemic limits or prevents on-site study visits, phone calls or virtual contacts
should be conducted for safety monitoring and discussion of the subject´s health status, until 
the subject can again visit the site.
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to Section 10.1.


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Table 8-2
Physical Assessments
Assessment
Specification
Physical 
examination
Physical examination will be performed at Screening and at EOS visit, as a general health 
check according to local clinical practice.
Clinically relevant findings that are present prior to signing informed consent must be 
included in the eCRF capturing Medical History. Significant findings identified after providing 
written informed consent which meet the definition of an Adverse Event must be recorded on 
the appropriate AE eCRF page.
Vital signs
Vital signs include assessment of sitting blood pressure (systolic and diastolic pressure in 
mmHg) and pulse rate (beats per minute) and will be collected at all visits. In case there is an 
elevated blood pressure measurement as specified in the exclusion criteria, at the screening 
and baseline visits, the blood pressure measurement should be repeated after 20 minutes. If 
the repeat measurement is elevated, then the subject 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.
8.4.1
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected at screening, Week 24, 
Week 52 and Week 76/EOS visit. Details on the collections, shipment of the samples and 
reporting of the results by the central laboratory are provided to investigators in the central 
laboratory manual.
If the COVID-19 pandemic limits or prevents on-site study visits, the collection of samples may 
be modified by Novartis if applicable and if modified, will be communicated to the Investigator.
Clinically notable laboratory findings are defined in Table 16-1 of Appendix 1.
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse event as appropriate.
Table 8-3
Laboratory Assessments
Test Category
Test Name
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
Clinical 
chemistry
Serum clinical chemistry tests
Serum electrolytes (sodium, potassium, chloride, phosphorus, calcium, magnesium), uric 
acid, urea nitrogen, creatinine, albumin, glucose, total protein, total bilirubin and direct 
bilirubin, serum glutamic oxaloacetic transaminase (SGOT)/ aspartate aminotransferase 
(AST), serum glutamic pyruvic transaminase (SGPT)/ alanine aminotransferase (ALT), 
gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) and lactate 
dehydrogenase (LDH)
Additional clinical chemistry tests
Lipids panel - triglycerides (TG), low-density lipoproteins (LDL), high-density lipoproteins 
(HDL), total cholesterol (TC)
Urinalysis
Dipstick measurements for specific gravity, pH, protein, glucose, ketones, bilirubin, nitrite, 
leucocyte and urine occult blood
8.4.2
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements. 


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Highly effective contraception is required for women of child-bearing potential during the study 
drug administration and for 3 months after stopping the investigational medication.
A serum pregnancy test will be conducted for all women of child-bearing potential to assess 
pregnancy before inclusion into the study at Screening visit and then at Week 52 and Week 
76/EOS visit. During the study, monthly urine pregnancy testing will be performed at visits 
when serum pregnancy testing will not be conducted. Results of all pregnancy testing must be 
available as source documentation.
Assessment of fertility
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child-
bearing potential must also be available as source documentation in the following cases:
1. Surgical bilateral oophorectomy without a hysterectomy
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile.
In the absence of the above medical documentation, Follicle Stimulating Hormone (FSH) 
testing is required of any female subject, regardless of reported reproductive/menopausal status 
at screening/baseline.
8.4.3
Ophthalmic examination
The ophthalmic exam will consist of the following:

Intraocular pressure (IOP) will be assessed in the study eye, pre-dose and post-dose at 
every scheduled visit. The method used for measuring a subject’s IOP must remain 
consistent throughout the study. In the fellow eye, IOP will be assessed at screening, 
Week 24, Week 52 and Week 76/EOS visit. The values recorded in mmHg for either eye 
will be entered into the eCRF. 

Post-dose IOP should be assessed within 60 minutes after every IVT/sham injection and 
if, ≥ 25 mmHg, assessment should be repeated until back to normal. Treatment and close 
monitoring of an elevated IOP should be performed by the investigator according to local 
clinical practice.

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, Week 24, Week 52 and Week 
76/EOS visit and at the discretion of the investigator). The results of the examination of 
either eye must be recorded in the source documents.
Slit lamp examination must be carefully performed before each study treatment. If there
are any signs of IOI, severity of anterior chamber cells and flare should be assessed 
according to the standardization of uveitis nomenclature (SUN) working group grading 
system (Jabs et al 2005). The test results will be recorded in the source documents (e.g. 
ophthalmic examination tool) and captured in the appropriate eCRF as applicable.

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 be safely performed. As of baseline 


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visit, the posterior segment examination will be performed at every visit in the study eye 
(the fellow eye will be examined) at Week 24, Week 52 and Week 76/EOS visit and at the 
discretion of the investigator). The results of the examination of either eye must be 
recorded in the source documents.
Posterior segment examination must be performed carefully before each study treatment. 
The results of the examination including any abnormalities (e.g. vitreous cells/haze, retinal 
tear/detachment, hemorrhage and vascular occlusion, vasculitis, etc.) should be recorded 
in the source documents. If there are any signs of IOI, vitreous cells and haze should be 
assessed using National Institutes of Health (NIH) grading system (Nussenblatt et al 
1985). The outcome of the examination will be documented in the source document (e.g. 
ophthalmic examination tool) and appropriate eCRF page as applicable.
Pupil dilation for slit lamp and posterior segment examination is optional according to local 
practice.
Clinically significant abnormal findings (as judged by the masked investigator) from slit lamp 
or posterior segment examination should be recorded as an AE in the eCRF.
Instruct the patient to contact the site for any changes in vision or any symptoms of 
inflammation between scheduled visits. Every effort should be made to bring the subject for 
immediate examination. When IOI, retinal vasculitis, and/or retinal artery occlusion (RAO) is 
present or suspected during a visit, investigators must perform thorough ophthalmic 
examination, and will conduct OCT, fluorescein angiography and color fundus photography 
(preferably wide-field or with peripheral sweeps). These additional assessments will be 
documented in the source and appropriate eCRF pages as applicable. The images are requested 
to be uploaded onto the CRC portal.
8.4.4
Appropriateness of safety measurements
The safety assessments selected are standard for this indication and subject population. If there 
are any signs of IOI, additional assessment will be performed as described in Section 8.4.3.
8.5
Additional assessments
8.5.1
Clinical Outcome Assessments (COAs)
8.5.1.1
Patient Reported Outcomes (PRO)
The impact of brolucizumab and aflibercept on subject visual function will also be assessed by 
a visual function questionnaire using the National Eye Institute NEI VFQ-25 which is a 
validated instrument that has been used in many studies of subjects with RVO. The NEI VFQ-
25 was developed to address the need to measure a subject’s subjective assessment of vision-
related Quality of Life (QoL) (Mangione et al 2001 It is part of the 51-item NEI-VFQ which 
was developed based on feedback from subjects to measure vision-targeted functioning and the 
impact of vision problems on HealthRelated 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 subjects with age-related macular 
degeneration (AMD). In addition to its use in measuring the treatment effect on vision-related 




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9
Study discontinuation and completion
9.1
Discontinuation
The investigator should discontinue study treatment for a given subject and/or withdraw the 
subject from the study if, on balance, he/she believes that continuation would be detrimental to 
the subject’s well-being.
A subject will be considered to have completed the study when the subject has completed the 
last visit planned in the protocol.
The investigator and/or referring physician will recommend the appropriate follow-up medical 
care, if needed, for all subjects who are prematurely withdrawn from the study.
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration, and can be initiated by either the subject or the investigator.
The investigator must discontinue study treatment for a given subject if he/she believes that 
continuation would negatively impact the subject's well-being.
Study treatment must be discontinued under the following circumstances:

Subject/guardian decision

Pregnancy (see Section 8.4.2 and Section 10.1.4)

Use of prohibited treatment (see Section 6.2.2)

Any situation in which continuation with study treatment might result in a safety risk to 
the subject

Following emergency unmasking (see Section 6.6.2)
If premature discontinuation of study treatment occurs, the following should be done as 
appropriate:

The investigator must contact the IRT to register the subject’s discontinuation from study 
treatment.


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
The investigator should make a reasonable effort to understand and document the primary 
reason for the subject’s premature discontinuation of study treatment using the appropriate 
eCRF page.

Subjects who prematurely discontinue study treatment for any reason, except for 
withdrawal of consent (refer to Section 9.1.2), should continue in the study with all the 
scheduled visits and assessments (except disease stability assessment, administration of 
study treatment, post-injection assessment and adherence to prohibited medication list) 
until EOS, at the discretion of the investigator or the subject.

Subjects who decide not to participate in the study further should NOT be considered 
withdrawn from the study, UNLESS they withdraw their consent (see Section 9.1.2 ). 
Where possible, subjects should return for the EOS visit assessments to be 
performed as scheduled in Table 8-1.

If a subject fails to return for study visits without stating an intention to discontinue or 
withdraw, the investigator must show "due diligence" by documenting in the source 
documents steps taken to contact the subject, e.g. dates of telephone calls, registered 
letters, etc. A subject should not be considered as lost to follow-up until due diligence has 
been completed (see Section 9.1.3).If the subject cannot or is unwilling to return at any 
visit(s), the site staff should maintain regular telephone contact with the subject, or with a 
person pre-designated by the subject. This telephone contact should preferably be done 
according to the study visit schedule.

After premature study treatment discontinuation, at a minimum, in abbreviated visits, the 
following data should be collected at clinic visits or via telephone/email contact: 

New/concomitant treatments

Adverse events/Serious Adverse Events
In the event that premature study treatment discontinuation occurs because treatment code has 
been broken, please refer to Section 6.6.2.
9.1.1.1
Replacement policy
Subjects who started treatment but prematurely discontinued treatment and/or study will not be 
replaced.
9.1.2
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 should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’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.
The investigator must contact the IRT to register the subject's withdrawal of consent.


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Further attempts to contact the subject 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 subject’s study withdrawal should be made as detailed in the 
assessment table (Table 8-1).
Novartis 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.
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc.
A subject should not be considered as lost to follow-up until due diligence has been completed.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time. Reasons for early termination may 
include:

Unexpected, significant, or unacceptable safety risk to subjects enrolled in the study

Decision based on recommendation from the Data Monitoring Committee (DMC) after 
review of safety and efficacy data

Discontinuation of study drug development

Practical reasons, including slow enrollment

Regulatory or medical reasons
In taking the decision to terminate, Novartis will always consider the subject welfare and safety. 
Should early termination be necessary, subjects must be seen as soon as possible and treated as 
a prematurely withdrawn subject. The investigator may be informed of additional procedures 
to be followed in order to ensure that adequate consideration is given to the protection of the 
subject’s interests. The investigator or sponsor depending on local regulation will be 
responsible for informing IRBs/IECs of the early termination of the trial.


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9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes their EOS visit, and any repeat 
assessments associated with this visit have been documented and followed-up appropriately by 
the Investigator, or in the event of an early study termination decision, the date of that decision.
After study completion the subject might receive standard of care if needed.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
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 subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events may also be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Adverse events must be recorded in the Adverse Events eCRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information (as far as possible) 
(if the event is serious refer to Section 10.1.2):
1. the severity grade
mild: usually transient in nature and generally not interfering with normal activities
moderate: sufficiently discomforting to interfere with normal activities
severe: prevents normal activities
2. its relationship to the study treatment or the ocular injection procedure. If the event is due 
to lack of efficacy or progression of underlying illness (i.e. progression of the study 
indication) the assessment of causality will usually be ‘Not suspected’. The rationale for 
this guidance is that the symptoms of a lack of efficacy or progression of underlying illness 
are not caused by the trial drug, they happen in spite of its administration and/or both lack 
of efficacy and progression of underlying disease can only be evaluated meaningfully by an 
analysis of treatment arms, not on a single subject
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported


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4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. action taken with the study treatment. All adverse events must be treated appropriately. 
Treatment may include one or more of the following:

no action taken (e.g. further observation only)

(investigational) treatment interrupted/withdrawn

concomitant medication or non-drug therapy given

subject hospitalized/subject's hospitalization prolonged (see Section 10.1.2 for 
definition of SAE)
6. its outcome:

not recovered/not resolved;

recovered/resolved;

recovered/resolved with sequelae;

fatal or unknown.
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued until 30 days after last administration of study 
treatment.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator Brochure (IB).
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease. Investigators have the responsibility for managing the safety of 
individual subjects and identifying adverse events. Clinically notable laboratory values are 
included in Section 16.


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10.1.2
Serious adverse events
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines).
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.
10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last study visit must be reported to 


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Novartis safety within 24 hours of learning of its occurrence. Detailed instructions regarding 
the submission process and requirements are to be found in the investigator folder provided to 
each site.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a Chief Medical Office & Patient 
Safety (CMO & PS) Department associate may urgently require further information from the 
investigator for 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 (EC) in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 30 day period after the last study visit should only be reported 
to Novartis Safety if the investigator suspects a causal relationship to study treatment.
10.1.4
Pregnancy reporting
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence (female participants only).
The pregnancy (for female participants) should be followed up to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications.
Pregnancy should be recorded and reported by the investigator to the Novartis CMO & PS 
Department. Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to brolucizumab (investigational) and/or aflibercept, 
with any pregnancy outcome. 
Any SAE experienced during pregnancy must be reported.
10.1.5
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, subject or 
consumer (EMA definition).
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the dose administration record in the eCRF 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.


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Table 10-1
Guidance for capturing the study treatment errors
Treatment error type
Document in Dose Administration 
(DAR) eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE 
form
Unintentional study 
treatment error
Yes
(only date and time of injection)
Only if associated 
with an AE
Only if associated 
with an SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections (Section 10.1.1, Section 10.1.2 and Section 10.1.3).
10.2
Additional Safety Monitoring
10.2.1
Data Monitoring Committee
The RTH258 program level Data Monitoring Committee (DMC) will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will assess at defined intervals the progress 
of the clinical trial and, based on the safety data and critical efficacy variables recommend to 
the sponsor whether to continue, modify or terminate the trial.
Specific details regarding composition, responsibilities, data monitoring and meeting frequency, 
and documentation of DMC reports, minutes, and recommendations will be described in a 
separate charter that is established between the sponsor and the DMC.
10.2.2
Adjudication Committee
Not required.
11
Data Collection and Database management
11.1
Data collection
All data must be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
Designated masked investigator staff will enter the data required by the protocol into the 
Electronic Case Report Forms (eCRF). The eCRFs have been built using fully validated secure 
web-enabled software that conforms to 21 CFR Part 11 requirements. Investigator site staff will 
not be given access to the EDC system until they have been trained. Automatic validation 
programs check for data discrepancies in the eCRFs, allow modification and/or verification of 
the entered data by the investigator staff.
The investigator/designee is responsible for assuring that the data (entered into eCRF) is 
complete, accurate, and that entry and updates are performed in a timely manner. The 
investigator must certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigative site.
eSource
eSource is a data collection system allowing electronic capture of source data and study data, 
as required per protocol. eSource is intended to be used for this study. eSource replaces the need 


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for using an eCRF. If it is not possible to use eSource for source data capture due to exceptional 
circumstances, data capture and data management will revert to paper and other electronic 
methods as appropriate.
This study will incorporate electronic technology (eSource Direct Data Entry (DDE)) to capture 
source documents and source data electronically, consistent with final (Center for Drug 
Evaluation and Research [CDER] 2013) FDA guidance regarding electronic source and 
regulations related to the maintenance of adequate subject case histories (21 CFR 312.62 [b]). 
All electronic source documentation and data collected in this study will “meet the same 
fundamental elements of data quality (e.g. attributable, legible, contemporaneous, original, and 
accurate) that are expected of paper records” into a system that is fully validated and conforms 
to 21 CFR Part 11 requirements. Investigator site staff will not be given access to the system(s) 
until they have been appropriately trained.
Study sites using eSource DDE will be supplied with a tablet personal computer to directly 
record subject data and clinical observations on electronic forms with a similar look, feel, and 
behavior to paper forms. The system will permit the collection of both structured and 
unstructured information including ad-hoc comments, drawings, and relevant clinical notes the 
investigative site deems important. Information to be originally captured and reviewed 
electronically shall include details of the subject visit and the protocol required assessments 
performed as a part of these visits, medical history, and concomitant medications.
Certain data may be captured via other source documentation (such as safety laboratory data 
report, imaging) and then transcribed, uploaded or transferred into the eSource DDE system. 
This, and any additional data treated in this manner, will be source data verified by the study 
field monitor per the monitoring plan and the location of source data (i.e. source, paper or a 
local electronic system) will be documented prior to study start. The eSource system has the 
ability to illustrate when a document has been entered from another source. When using an 
electronic source record as the original point of data capture, there is no additional data entry 
step for the site for data collected directly into the application. Rather, the electronic source 
record directly populates the study database.
Automatic validation programs check for data discrepancies and, by generating appropriate 
error messages, allow the data to be confirmed or corrected before transfer of the data to the 
vendor working on behalf of Novartis.
Remote monitoring of the original electronic source records will take place, however on-site 
monitoring inspections will continue to take place in order to review data entry of source 
documentation directly captured on paper and transcribed into the system, to ensure protocol 
adherence, to assess site operational capabilities, and to perform other monitoring activities that 
cannot be performed remotely.
The investigator must certify that the data entered into eSource are complete and accurate.
11.2
Database management and quality control
Novartis personnel will review the data entered by investigative 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 investigative site via the 


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EDC system. Designated masked investigator site staff are required to respond promptly to 
queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis. Color fundus photographs, fluorescein angiograms, and OCT images will be 
processed centrally by the Central Reading Center and the results will be sent electronically to 
Novartis. VFQ-25 data will be processed centrally by a designated vendor and the results will 
be sent electronically to Novartis. The data management staff will perform a reconciliation of 
the data entered on the eCRF versus what is received from the central reading center and central 
labs.
Randomization codes and data about all study treatment (s) dispensed to the subject and all 
dosage changes will be tracked and managed using an Interactive Response Technology (IRT). 
The system will be supplied by a vendor who will also manage the database. The IRT data will 
be sent electronically to Novartis.
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. Once all the necessary 
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.
11.3
Site monitoring
Before study initiation, at a site initiation visit and/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 subject records, the accuracy 
of data capture/data entry, the adherence to the protocol and to Good Clinical Practice, the 


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progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis Clinical Research Associates (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 subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, retinal images (OCT, CP, FA, wide-field imaging), and the results 
of any other tests or assessments. All information on eCRFs must be traceable to these source 
documents in the subject’s file. The investigator must also keep the original informed consent 
form signed by the subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed.
12
Data analysis and statistical methods
The database including all Week 52 data will be locked once all subjects have completed the 
Week 52 visit or terminated the study prior to Week 52. Data for the primary endpoint, change 
from baseline in BCVA at Week 24, will be derived from this database. All subjects still in the 
study beyond Week 52 will continue to receive masked treatment as scheduled through the 
planned study duration of 76 weeks. The analysis of the data collected after the Week 52 visit 
will be performed once all subjects complete the EOS visit or discontinue 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, these will generally 
include: n, frequency and percentage in each category. Further technical details and discussions 
of the statistical considerations will be provided in the SAP.
Additional analyses may also be conducted to evaluate the impact of the COVID-19 pandemic.
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
The All-Enrolled Analysis Set includes all subjects who have signed informed consent and are 
assigned subject numbers.
The Randomized Analysis Set (RAS) consists of all enrolled subjects who are randomized in 
IRT. Subjects are considered randomized when they have been deemed eligible for 


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randomization by the investigator and given a randomization number. Subjects will be analyzed 
according to the treatment assigned to them at randomization.
The Full Analysis Set (FAS) comprises all randomized subjects who receive at least 1 IVT 
injection of the study treatment. Subjects in the FAS will be analyzed according to the treatment 
assigned to them at randomization.
The Safety Analysis Set (SAF) includes all subjects who receive at least 1 IVT injection of the 
study treatment. Subjects in the Safety Set will be analyzed according to the study treatment 
from which they received the majority of treatments up to and including Week 52.
The Per Protocol Set (PPS) is a subset of the FAS and will exclude or censor data from subjects 
with protocol deviations (PDs) and analysis restrictions (ARs) that are expected to majorly 
affect the validity of the assessment of efficacy at Week 24 and/or Week 52 including, for e.g. 
lack of compliance (including missed treatments and treatment misallocation), missing data, 
prohibited concomitant medication, and deviations from inclusion/exclusion criteria. 
Confounded data or discontinuation from study treatment due to lack of efficacy and/or safety 
do not constitute, in itself, a reason for exclusion from the PPS.
Before the Week 52 database lock the relevant protocol deviations and analysis restrictions will 
be identified at the subject level in the 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 12-1
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 (refer to Table 12-1) using PPS, i.e. similar conclusions on non-inferiority based on
both estimands are expected. Inconsistencies in the results will be examined and discussed in 
the Clinical Study Report.
12.2
Subject demographics and other baseline characteristics
Demographics and baseline characteristics will be summarized with descriptive statistics for 
the FAS by treatment group and overall. Summary statistics for other analysis sets will only be 
generated if these are anticipated to be different given the subset of the subjects included in the 
particular analysis set. 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.
12.3
Treatments
Study treatment
Descriptive summary statistics for exposure to study treatment will be provided for the SAF, 
FAS and PPS populations. For the efficacy analysis sets (FAS and PPS), the cumulative number 
of active and sham IVT injections will be presented by visit for the period baseline to Week 
52/Week 72, including a separate analysis for the loading phases, i.e. up to Week 20 (6 x q4w 
loading), and maintenance phase (Week 24 to Week 52/Week 72). For the SAF, the summary 
will include exposure data up to Week 52/Week 72.


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Prior medication and concomitant therapies
The number and percentage of subjects taking prior medication (any medication taken up to 90 
days prior to screening) or concomitant therapies will be summarized by preferred term 
according to the WHO Drug Reference List dictionary using the SAF and FAS (in case there 
are differences between the two populations). 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. Further details will be provided in the SAP.
12.4
Analysis of the primary endpoint(s)
12.4.1
Definition of primary endpoint(s)
The primary endpoint is the change from baseline in BCVA at Week 24. BCVA will be assessed 
by the masked investigator using ETDRS-like charts at an initial distance of 4 meters.
The primary analysis of the primary endpoint will be based on the FAS.
12.4.2
Statistical model, hypothesis, and method of analysis
The objective related to the primary endpoint is to demonstrate non-inferiority of brolucizumab 
versus aflibercept with respect to change from baseline in BCVA at Week 24, assuming a non-
inferiority margin of 4 ETDRS letters.
Let:
B = Brolucizumab 6 mg - 6 x q4w loading
A = Aflibercept 2 mg - 6 x q4w loading
Consider the following non-inferiority hypotheses related to a non-inferiority margin of 4 
letters:
H0: μB – μA ≤ -4 letters versus HA: μB – μA > -4 letters
where μB and μA are the corresponding unknown true mean changes from baseline in BCVA at 
Week 24 in the brolucizumab and aflibercept arms, respectively.
The primary estimand associated with the above hypothesis is defined as the between-treatment 
difference in change from baseline in BCVA at Week 24, excluding the effect of relevant BRVO 
prohibited/alternative medication(s) applied to the study eye (e.g. alternative anti-VEGF 
treatments for BRVO, laser, intraocular corticosteroids, among others as further detailed in 
Section 6.2.2 and in the SAP). The analysis set for the primary estimand will be the FAS.
Based on the FAS, the above hypotheses will be tested via an analysis of variance (ANOVA) 
model. The model will include treatment, baseline BCVA (≤ 34, 34 - 55, ≥ 55 letters) and age 
category (< 65, ≥ 65) as factors. Additional factors, e.g. ethnicity, may also be included as 
appropriate, as well as interactions between treatment and factors of interest.
The two-sided 95% confidence interval (CI) for the least square mean difference (brolucizumab 
- aflibercept) at Week 24 will be presented. Non-inferiority will be considered established if the 
lower limit of the corresponding 95% CI is greater than -4 letters. The same approach for non-


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inferiority assessment in change from baseline in BCVA at Week 24 will be applied to any 
supplementary estimand.
The primary estimand and supplementary estimand of interest are noted in Table 12-1 below 
together with their key attributes. Sensitivity to the primary estimand will only be explored if 
the proportion of subjects with missing or censored data is deemed large enough so as to 
potentially impact the results from the analyses. The estimands outlined below will be discussed 
in further detail in the SAP.
Table 12-1
Primary and supplementary estimands
Estimand
Estimand 
definition
Analysis set
Use of data after 
discontinuation of study 
treatment due to1:
Statistical 
methods
(Including 
missing data 
strategy)
lack of efficacy 
or safety
any 
other 
reason 
Primary estimand
Difference in 
change from 
baseline in BCVA at 
Week 24 excluding 
the effect of BRVO 
prohibited/
alternative
medication(s)
All 
randomized 
subjects who 
receive at 
least 1 IVT 
injection of 
the 
randomized 
study 
treatment 
(FAS)
Included
Analysis of 
variance (ANOVA) 
model assessed 
at a one-sided 
significance level 
of 0.025, and 
including terms for 
treatment, 
baseline BCVA (≤ 
34, 34 - 55, ≥ 55 
letters) and age 
category (< 65, ≥ 
65), and using 
LOCF imputation 
for 
missing/censored 
data.
Sensitivity to 
primary estimand
Difference in 
change from 
baseline in BCVA at 
Week 24 excluding 
the effect of BRVO 
prohibited/
alternative
medication(s)
All 
randomized 
subjects who 
receive at 
least 1 IVT 
injection of 
the 
randomized 
study 
treatment 
(FAS)
Included
MMRM2 approach 
based on 
observed data 
(assuming data 
missing at 
random), and 
including fixed 
effect terms for 
treatment, visit, 
visit by treatment 
interaction, 
baseline BCVA (≤ 
34, 34 - 55, ≥ 55 
letters) and age 
category (< 65, ≥ 
65)


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Estimand
Estimand 
definition
Analysis set
Use of data after 
discontinuation of study 
treatment due to1:
Statistical 
methods
(Including 
missing data 
strategy)
lack of efficacy 
or safety
any 
other 
reason 
Supplementary
estimand
Difference in 
change from 
baseline in BCVA at 
Week 24 excluding 
the effect of BRVO 
prohibited/
alternative
medication(s) and 
protocol deviations 
as per the definition 
of the PPS
All 
randomized 
subjects who 
adhere to the 
protocol as 
per the 
definition of 
PPS
Included
Not 
included; 
treated 
as 
missing
ANOVA model as 
per the primary 
estimand.
LOCF imputation 
for 
missing/censored 
data
1Note that, for all estimands as applicable, all data captured until the start of prohibited medication or 
alternative medication for ME secondary to RVO after discontinuation from study treatment will be 
included in the analysis.
2 MMRM: Mixed Model Repeated Measures
12.4.3
Handling of missing values/censoring/discontinuations
As stated in the definition of the primary estimand, missing BCVA values will be imputed by 
Last Observation Carried Forward (LOCF) as the primary approach. For subjects with no post-
baseline BCVA value, the baseline value will be carried forward. Data collected after the start 
of alternative BRVO treatments in the study eye (e.g. other anti-VEGF treatment, certain laser 
procedures or intraocular corticosteroids; further details will be discussed in the SAP) will be 
censored.
The LOCF approach is expected to be sensitive to an early study treatment termination/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 as described above (BRVO), 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 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. It is important to note that, in order to facilitate a meaningful 
treatment effect assessment, 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. In the aflibercept Phase III studies COPERNICUS and GALILEO (CRVO) and 
VIBRANT (BRVO) missing BCVA data was imputed based on LOCF.


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12.4.4
Sensitivity and supplementary analyses
Sensitivity and supplementary analyses for the primary endpoint, change from baseline in 
BCVA at Week 24, are specified in terms of sensitivity and supplementary estimands as 
described in Table 12-1 This describes different approaches to deal with intercurrent events 
such as intake of BRVO prohibited/alternative medication in the study eye, or any event leading 
to exclusion from the PPS, and the resulting missing/censored data. The same approaches to 
deal with intercurrent events and/or missing data may be applied to some or all of the secondary 
endpoints as appropriate. For the primary and relevant secondary endpoints, descriptive 
analyses based on observed data only (with and without censoring of data collected after use of 
relevant prohibited/alternative medication for BRVO as described in Section 6.2.2 and further 
detailed in the SAP) may also be produced.
The following subgroup analyses will be explored using the FAS and the statistical model 
described in the primary estimand in Table 12-1:

Age category (< 65, ≥ 65 years)

Sex (male, female)

Baseline BCVA categories (≤ 34, 34 - 55, ≥ 55 letters)

Duration of ME (≤ 3, > 3 months)

Baseline CSFT (< 450, 450 - 650, ≥ 650 μm)

Baseline status of IRF (presence, absence)

Baseline status of SRF (presence, absence)

Region 

Japanese 

Chinese

Rest of World
Further description of the supplementary and sensitivity analyses will be detailed in the SAP.
12.5
Analysis of secondary endpoints
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
Secondary efficacy endpoints based on BCVA:

Change from baseline in BCVA averaged over the period Week 40 to Week 52

Change from baseline in BCVA averaged over the period Week 64 to Week 76

Change from baseline in BCVA by visit up to Week 76

Proportion of study eyes with a gain ≥ 5, 10 and 15 letters in BCVA by visit compared to 
baseline

Proportion of study eyes with a loss ≥ 5, 10 and 15 letters in BCVA by visit compared to 
baseline
Note: subjects 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 effect, e.g. for the 
"≥ 15-letter gain" endpoint, for those subjects with BCVA values at baseline ≥ 70 letters.


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Secondary efficacy endpoints related to anatomy:

Change from baseline in central subfield thickness (CSFT) averaged over the period Week 
40 to Week 52

Change from baseline in CSFT averaged over the period Week 64 to Week 76

Change from baseline in CSFT, by visit up to Week 76

Proportion of study eyes with presence of retinal fluid (intra- and/or subretinal fluid) by 
visit up to Week 76 (derived from SD-OCT, from central reading center)

Proportion of study eyes with a CSFT < 300 µM (derived from SD-OCT, from central 
reading center) by visit up to Week 76
Secondary efficacy endpoints related to treatment frequency:

Number of injections between Week 24 and Week 52

Number of injections between Week 24 and Week 76

Time to first re-treatment between Week 24 and Week 76
12.5.2
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 analysis set, SAF.
Adverse events
The number (and percentage) of subjects with treatment-emergent adverse events (events 
started after the first dose of study medication or events present prior to start of double-masked 
treatment but which increased in severity based on preferred term) will be summarized in the 
following ways:

by treatment, primary system organ class and preferred term

by treatment, primary system organ class, preferred term and maximum severity

by treatment, Standardized MedDRA Query (SMQ) and preferred term
Separate summaries will be provided for study treatment related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation of study treatment 
or the study. In addition, a separate summary for death including on-treatment and post-
treatment deaths will be provided. Separate presentations will be provided related to ocular 
events in the study eye and fellow eye and systemic events. Additional summaries will be 
provided by severity and causality (separately assessed for the injection procedure and the drug).
Subject listings of all adverse events will be provided. Deaths and other serious or clinically 
significant non-fatal adverse events will be listed separately. A subject with multiple adverse 


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events within a primary system organ class is only counted once towards the total of the primary 
system organ class.
An adverse event of special interest (ESI) is one of scientific and medical interest to the Sponsor 
and includes, but is not limited to, the following:

Endophthalmitis

Uveitis: all cases of anterior, posterior, or panuveitis

≥ 30 letter decrease in BCVA compared with Baseline visual acuity

New retinal tear or detachment
The number (and proportion) of subjects with adverse events related to identified and potential 
risks, including ESI, will be summarized by treatment.
Ophthalmic examinations
Pre-injection IOP measurements will be presented descriptively (absolute values and change 
from baseline). Post-injection IOP measurements will be listed.
Vital signs
All vital signs data will be listed by treatment group, subject, and visit and, if ranges are 
available, abnormalities will be flagged with thresholds representing clinical relevant 
abnormality. Summary statistics of absolute and change from baseline data will be provided by 
treatment and visit. Shift tables using the low/normal/high classification will be used to compare 
baseline to the worst on-treatment value.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, subject, and visit, and abnormalities will 
be flagged (using extended normal ranges as provided by the central laboratory) with thresholds 
representing clinical relevant abnormality. Summary statistics of absolute and change from 
baseline data will be provided by treatment and visit. Shift tables using the low/normal/high 
classification will be used to compare baseline to the worst on-treatment value.


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12.5.4
Patient reported outcomes
The VFQ-25 questionnaires will be scored at baseline and Week 24, 52 and 76 visits. Absolute 
and changes from baseline in VFQ-25 scores will be calculated and summarized descriptively.
Further details on the scoring algorithm and analysis will be provided in the SAP.
12.5.5
Anti-drug antibody
Collection of blood for ADA assessment will be done at screening, Week 4, 12, 24, 36, 52 and 
76 visits prior to the injection/sham, 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.
 
 
Subject listings of all ADA titer 
values will be presented for all subjects.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
A sample size of 230 subjects per arm will allow assessment of non-inferiority (using a non-
inferiority margin, NIM, of 4 ETDRS letters) of brolucizumab 6 mg versus aflibercept 2 mg
with respect to the change from baseline in BCVA at Week 24. Assuming equal means and a 
common standard deviation of 12 letters, for a NIM of 4 letters and a onesided alpha level of 
0.025, there is 94% power to reject the null hypothesis that brolucizumab 6 mg is inferior to 
aflibercept 2 mg.


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To account for a drop-out rate of 10%, a total of approximately 500 (250 per arm) subjects will 
need to be randomized.
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g. 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as Clinicaltrials.gov and 
as required in EudraCT. In addition, upon study completion and finalization of the study report 
the results of this trial will be submitted for publication and posted in a publicly accessible 
database of clinical trial results, such as the Novartis clinical trial results website and all required 
Health Authority websites (e.g. Clinicaltrials.gov, EudraCT, etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures (SOPs) as well as applicable global/local GCP regulations and ICH 
Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.


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


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15
References
References are available upon request
(1984) Argon laser photocoagulation for macular edema in branch vein occlusion. The Branch 
Vein Occlusion Study Group. Am J. Ophthalmol p 271-82.
Aiello LP, Avery RL, Arrigg PG, et al (1994) Vascular endothelial growth factor in ocular 
fluid of patients with diabetic retinopathy and other retinal disorders. N. Engl. J. Med. p. 
1480-7.
Brown DM, Campochiaro PA, Singh RP, et al (2010) Ranibizumab for macular edema 
following central retinal vein occlusion: six-month primary end point results of a phase III 
study. Ophthalmology p 1124-1133.e1.
Campochiaro PA, Choy DF, Do DV, et al (2009) Monitoring ocular drug therapy by analysis 
of aqueous samples. Ophthalmology p 2158-64.
Campochiaro PA, Heier JS, Feiner L, et al (2010) Ranibizumab for macular edema following 
branch retinal vein occlusion: six-month primary end point results of a phase III study. 
Ophthalmology p 1102-1112.e1.
Clark WL, Boyer DS, Heier JS, et al (2016) Intravitreal Aflibercept for Macular Edema 
Following Branch Retinal Vein Occlusion: 52-Week Results of the VIBRANT Study. 
Ophthalmology p 330-6.
Cugati S, Wang JJ, Rochtchina E, et al (2006) Ten-year incidence of retinal vein occlusion in 
an older population: the Blue Mountains Eye Study. Arch. Ophthalmol p 726-32.
Finkelstein D (1986) Argon laser photocoagulation for macular edema in branch vein 
occlusion. Ophthalmology p 975-7.
Haller JA, Bandello F, Belfort R, et al (2010) Randomized, sham-controlled trial of 
dexamethasone intravitreal implant in patients with macular edema due to retinal vein 
occlusion. Ophthalmology p 1134-1146.e3.
Jabs DA, Nussenblatt RB, Rosenbaum JT (2005) Standardization of uveitis nomenclature for 
reporting clinical data. Results of the first international workshop. Am. J. Ophthalmol; 140(3): 
p 509-16.
Klein R, Klein BE, Moss SE, et al (2000) The epidemiology of retinal vein occlusion: the 
Beaver Dam Eye Study. Trans Am Ophthalmol Soc p 133-41; discussion p 141-3.
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 p 733-40.
Klein R, Moss SE, Meuer SM, et al (2008) The 15-year cumulative incidence of retinal vein 
occlusion: the Beaver Dam Eye Study. Arch. Ophthalmol p 513-8.
Mangione CM, Lee PP, Gutierrez PR, et al (2001) Development of the 25-item National Eye 
Institute Visual Function Questionnaire. Arch. Ophthalmol p 1050-8.


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Nussenblatt RB, Palestine AG, Chan CC, et al (1985) Standardization of vitreal inflammatory 
activity in intermediate and posterior uveitis. Ophthalmology; 92(4): p 467-71.
Pielen A, Clark WL, Boyer DS, et al (2017) Integrated results from the COPERNICUS and 
GALILEO studies. Clin Ophthalmol p 1533-1540.
Pulido JS, Flaxel CJ, Adelman RA, et al (2016) Retinal Vein Occlusions Preferred Practice 
Pattern® Guidelines. Ophthalmology p P182-208.
Rabena MD, Pieramici DJ, Castellarin AA, et al (2007) Intravitreal bevacizumab (Avastin) in 
the treatment of macular edema secondary to branch retinal vein occlusion. Retina 
(Philadelphia, Pa.) p 419-25.
Sivaprasad S, Amoaku WM, Hykin P, et al (2015) The Royal College of Ophthalmologists 
Guidelines on retinal vein occlusions: executive summary. Eye (Lond) p 1633-8.
Varma R, Bressler NM, Suñer I, et al (2012) Improved vision-related function after 
ranibizumab for macular edema after retinal vein occlusion: results from the BRAVO and 
CRUISE trials. Ophthalmology p 2108-18.


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16
Appendices
16.1
Appendix 1: Clinically notable laboratory values
Table 16-1
Clinically notable laboratory values
Panel/Test
Type
Gender/
Age
Conve
ntional 
Unit
Conve
ntional 
Low
Conve
ntional 
High
SI Unit
SI 
Low
SI 
High
Non-
numeric
Clinical 
Chemistry/ 
Calcium
alert
All
mg/dL
6.1
12.9
mmol/L
1.52
3.22
-
Clinical 
Chemistry/ 
Creatinine
reference
All
mg/dL
0.7
1.4
µmol/L
62
124
-
Clinical 
Chemistry/ 
Glucose 
(non fasting)
alert
All
mg/dL
40
450
mmol/L
2.22
24.98
-
Clinical 
Chemistry/ 
Potassium
alert
All
mEq/L
2.8
6.3
mmol/L
2.8
6.3
-
Clinical 
Chemistry/
Sodium
alert
All
mEq/L
117
160
mmol/L
117
160
-
hCG
alert
All
-
-
-
-
-
-
Negative, 
inconclus
ive
Hematology/ 
Hematocrit
alert
All
%
18
60
%
18
60
-
Hematology/ 
Hemoglobin
alert
All
g/dL
8
22
g/L
80
220
-
Hematology/ 
Platelet
alert
All
K/cu 
mm
30
900
x109/L
30
900
-
Hematology/ 
WBC
alert
All
K/cu 
mm
2
25
x109/L
2
25
-

SAP_001.pdf: 


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SAP 
 
CRTH258C2301 & C2302  
 
 
Document History – Changes compared to previous final version of SAP 
 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
10-
Sep-
2021 
Prior 
to 
DB 
lock 
Creation of 
final 
version 
N/A - First version 
NA 
 


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CRTH258C2301 & C2302  
 
Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 7 
1.1 
Study design ............................................................................................................ 7 
1.2 
Study objectives and endpoints ............................................................................... 8 
2 
Statistical methods ............................................................................................................... 9 
2.1 
Data analysis general information ........................................................................... 9 
2.1.1 
General definitions .................................................................................. 9 
2.2 
Analysis sets .......................................................................................................... 11 
2.2.1 
Subgroups of interest............................................................................. 12 
2.3 
Subject disposition, demographics and other baseline characteristics .................. 12 
2.3.1 
Subject disposition ................................................................................ 12 
2.3.2 
Demographic characteristics ................................................................. 13 
2.3.3 
Ocular baseline characteristics .............................................................. 13 
2.3.4 
Medical history...................................................................................... 14 
2.4 
Treatments (study treatment concomitant therapies, compliance) ........................ 14 
2.4.1 
Study treatment/compliance .................................................................. 14 
2.4.2 
Prior, concomitant medications or surgical/medical procedures .......... 14 
2.5 
Analysis of the primary endpoint .......................................................................... 15 
2.5.1 
Primary Estimand .................................................................................. 15 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 16 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 16 
2.5.4 
Supportive analyses ............................................................................... 17 
2.6 
Analysis of selected secondary endpoints ............................................................. 19 
2.6.1 
Selected secondary endpoint ................................................................. 19 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 19 
2.6.3 
Handling of missing values/censoring/discontinuations ....................... 21 
2.7 
Analysis of secondary efficacy endpoints ............................................................. 22 
2.7.1 
Secondary endpoints ............................................................................. 22 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 22 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 23 
2.8 
Safety analyses....................................................................................................... 23 
2.8.1 
Adverse events (AEs) ............................................................................ 24 
2.8.2 
Deaths .................................................................................................... 26 
2.8.3 
Laboratory data ..................................................................................... 26 


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2.8.4 
Other safety data ................................................................................... 26 
2.9 
Pharmacokinetic endpoints .................................................................................... 27 
2.10 
Anti-drug antibody ................................................................................................ 28 
2.11 
Subject-reported outcomes .................................................................................... 29 
 
 30 
 
 30 
 
 30 
2.13 
Interim analysis ...................................................................................................... 31 
3 
Sample size calculation ..................................................................................................... 31 
4 
Change to protocol specified analyses .............................................................................. 31 
5 
Appendix ........................................................................................................................... 32 
5.1 
Imputation rules ..................................................................................................... 32 
5.1.1 
Study drug ............................................................................................. 32 
5.1.2 
AE date imputation ............................................................................... 33 
5.1.3 
Concomitant medication and therapies and procedures date 
imputation ............................................................................................. 34 
5.1.4 
Medical history date of Primary diagnosis imputation ......................... 36 
5.1.5 
Concomitant therapies and procedures date imputation ....................... 36 
5.2 
AEs coding/grading ............................................................................................... 36 
5.3 
Laboratory parameters derivations ........................................................................ 36 
5.4 
Clinically notable vital signs ................................................................................. 37 
5.5 
Statistical models ................................................................................................... 37 
5.5.1 
Primary analysis .................................................................................... 37 
5.5.2 
Other analysis ........................................................................................ 38 
5.6 
Rule of exclusion criteria of analysis sets.............................................................. 39 
5.7 
Definition for discontinuation from treatment due to lack of efficacy or safety ... 40 
5.8 
Subgroup analysis to evaluate the impact of COVID-19 pandemic ...................... 41 
6 
Reference ........................................................................................................................... 41 


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List of abbreviations 
ADA 
Anti-drug antibody 
AE 
Adverse Event 
ANOVA 
Analysis of variance 
ATC 
Anatomical Therapeutic Classification 
ATE 
Arterial Thromboembolic Event 
BCVA 
Best Corrected Visual Acuity 
BLQ 
Below the Limit of Quantification 
BRVO 
Branch retinal vein occlusion 
CF 
Color Fundus photography 
CFT 
Central foveal thickness 
CI 
Confidence interval 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case Report Form 
CRVO 
Central retinal vein occlusion 
CSFT 
Central subfield thickness (average thickness of circular 1mm area centered 
around fovea measured from RPE to ILM, inclusively) 
CSR 
Clinical Study Report 
DBL 
Database lock 
DMC 
Data Monitoring Committee 
DSA 
Disease stability assessment 
eCRS 
Electronic case retrieval strategy 
EoS 
End of Study 
EoT 
End of Treatment 
ETDRS 
Early treatment diabetic retinopathy study 
FA 
Fluorescein angiography 
FAS 
Full analysis set 
HRVO 
Hemiretinal vein occlusion 
IFT 
Individualized flexible treatment 
IOP 
Intraocular Pressure 
IRT 
Interactive Response Technology 
IRF 
Intraretinal fluid 
ISFT 
Inner subfield thickness 
IVT 
Intravitreal 
KM 
Kaplan Meier 
LLOQ 
Lower Limit of Quantification 
LOCF 
Last observation carried forward 
MAR 
Missing at random 
ME 
Macular Edema 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
MH 
Medical History 
mL 
Millilitres 


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MMRM 
Mixed model for repeated measures 
 
 
NEI 
National Eye Institute 
OCT 
Optical Coherence Tomography 
PD 
Protocol Deviation 
PPS 
Per protocol set 
PT 
Preferred Term 
q4w 
Every 4 weeks 
RAS 
Randomized analysis set 
RoW 
Rest of World 
SAE 
Serious Adverse Event 
SAF 
Safety analysis set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical analysis system 
SD 
Standard deviation 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SE 
Standard Error 
SOC 
System Organ Class 
SRF 
Subretinal fluid 
TEAE 
Treatment-Emergent Adverse Event 
VA 
Visual acuity 
VEGF 
Vascular endothelial growth factor 
VFQ-25 
Visual Functioning Questionnaire-25 
WCF 
Wide-field color fundus photography 
WFA 
Wide-field fluorescein angiography 
WHO 
World Health Organization 
 




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Figure 1-1 
Study design 
 
*Loading phase; IFT: Individualized flexible treatment 
 
1.2 
Study objectives and endpoints 
The primary endpoint is at Week 24. The primary, secondary, 
 objectives and the 
corresponding endpoints planned on the protocol are listed in Table 1-1. A subset of the 
secondary objectives are considered in the testing strategy and details will be provided in section 
2.6. 
Table 1-1 
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 
change in best-corrected visual acuity 
(BCVA) from baseline up to Month 6 
• 
Change from baseline in BCVA at Week 24 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To assess the effect of brolucizumab as 
compared to aflibercept on best-corrected 
visual acuity (BCVA) 
• 
Change from baseline in BCVA averaged over Week 40 
to Week 52 and Week 64 to Week 76 
• 
Change from baseline in BCVA by visit up to Week 76 
• 
Proportion of study eyes with a gain ≥ 5, 10 and 15 
letters in BCVA by visit compared to baseline 
• 
Proportion of study eyes with a loss ≥ 5, 10 and 15 
letters in BCVA by visit compared to baseline 
• 
To evaluate the anatomical outcome with 
brolucizumab relative to aflibercept 
• 
Change from baseline in central subfield thickness 
(CSFT) averaged over Week 40 to Week 52 and Week 
64 to Week 76 
• 
Change from baseline in CSFT by visit up to Week 76 
• 
Proportion of study eyes with presence of retinal fluid 
(intra- and/or subretinal fluid) by visit up to Week 76  




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Study day 
Day 1 is defined as the date of first dose of study treatment (Brolucizumab or Aflibercept). 
Study day is defined as the number of days since the date of first dose of study treatment (Day 1).  
Therefore, for a particular date, study day will be calculated as follows: 
• for dates on or after the date of first administration of study treatment:  
Study day = Assessment date – Date of first dose of study treatment + 1; 
• for dates prior to the date of first administration of study treatment: 
Study day = Assessment date – Date of first dose of study treatment. 
Baseline 
The baseline value is defined as the last assessment performed prior to administration of the 
first dose of study treatment.  
All data collected after first study treatment are defined as post-baseline.  
End of study/end of treatment day mapping 
The EoS date is the date when a patient completes or discontinues the study, i.e., the 
“Disposition Event Date” from the “disposition” case report form (CRF) for study disposition. 
The end of treatment (EoT) date is the date when a patient completes or discontinues the study 
treatment, i.e., the “Disposition Event Date” from the “disposition” CRF for treatment 
disposition.  
The “Date of Last Exposure” (from “Study treatment” CRF form) is the date of the last study 
treatment or sham injection on or prior to the EoT date.  
For reporting data by visit in outputs, the EoS/EoT date will be allocated to the actual (reported) 
visit number. If EoS/EoT date is not on a scheduled visit, then the EoS/EoT date will be 
allocated, based on study day, to the future unattended study visit. The target day for Week X 
visit is calculated as 7X+1. 
Unscheduled visits 
Data collected at unscheduled visits will not be used in ‘by-visit’ tabulations or graphs, but 
will be included in analyses based on all post-baseline values such as last observation carried 
forward (LOCF) imputation, and summary of maximum decrease/increase from baseline or 
abnormal findings during the study for pre-specified endpoints. These data will not be used in 
analyses with mixed model for repeated measures (MMRM). 
All data collected at unscheduled visits will be included in listings. 
Missing and imputable dates 
The general approach to handling missing dates is described in Section 5.1. 
OCT reading result for “Cannot Grade” 
For subgroup definition or model factors based on the endpoints related to presence of fluids at 
baseline, if baseline visit is reported as “Cannot Grade”, then it will be considered as “Absent”. 


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If post-baseline visit is reported as “Cannot Grade”, then it will be considered as missing where 
the endpoint is treated as a binary variable. 
Prohibited therapy, Rescue therapy, and Alternative treatment for ME secondary to RVO 
The prohibited medication/procedures are defined in the protocol ([section 6.2.2]). The 
application of such medications captured as PD (i.e., COMD01, prohibited medication and/or 
procedure with impact on efficacy and/or safety) during the study treatment period will be 
considered as an intercurrent event for efficacy analysis. 
The rescue therapy is the application of macular laser photocoagulation on or after Week 24 
and before the EoT. 
The alternative treatment for ME secondary to RVO refers to the application of the treatments 
specified on the table below to the study eye. It is only applicable to treatment started on or 
after the discontinuation from study treatment date. The use of alternative treatment will not be 
captured as a PD but may be considered as an intercurrent event. 
Table 2-1 
Potential alternative treatment for ME secondary to RVO in the study 
eye 
• 
Ranibizumab (Lucentis) 
• 
Aflibercept (Eylea)  
• 
Bevacizumab (Avastin, off-label use)  
• 
Laser photocoagulation 
• 
Steroids: 
o 
Dexamethasone (Ozurdex) 
o Fluocinolone acetonide (Iluvien) 
o Triamcinolone (off-label use) 
 
2.2 
Analysis sets 
Subject exclusion rules for each analysis set based on the specific protocol deviations (PDs) 
will be specified in Section 5.6. Before the DBL, the relevant PDs will be identified and entered 
in the database. 
All-Enrolled Analysis Set: The All-enrolled Analysis Set includes all subjects who signed 
informed consent and are assigned subject numbers. 
Randomized Analysis Set (RAS) consists of all randomized subjects. Subjects are considered 
randomized when they have been given a randomization number, except for misrandomized 
subjects. An accidental or premature randomization of a subject without providing study 
medication is considered as a misrandomized subject. Subjects will be analyzed according to 
the treatment assigned to at randomization. The RAS will be used for the summaries of subject 
disposition, protocol deviation, demographics, baseline characteristics, and medical history data. 


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Full Analysis Set (FAS) includes all randomized subjects 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. Subjects in the FAS will be analyzed according to the treatment assigned to at 
randomization. The FAS will be used for all efficacy analyses, unless otherwise specified. 
Per Protocol Set (PPS) is a subset of the FAS and will exclude subjects or data points with pre-
specified PDs and other non-PD related criteria that are expected to majorly affect the validity 
of the assessment of the primary endpoint at Week 24. PPS will be used in supportive analyses 
of the primary endpoint.  
Safety Analysis Set (SAF) includes all subjects who receive at least one IVT injection. Subjects 
in the SAF will be analyzed according to the actual treatment received during the study. If a 
subject received both study treatments accidentally during the study, he/she will be analyzed 
according to the treatment to which he/she was exposed for longer in duration during the study 
treatment period. The SAF will be used for all safety analyses, including concomitant 
medication/surgical and medical procedures, treatment exposure, as well as anti-drug antibody 
(ADA) status. 
2.2.1 
Subgroups of interest 
Subgroup analyses are conducted to assess consistency of the treatment effect among the 
subgroups and will not apply multiplicity adjustments. The following subgroups will be 
evaluated for the primary endpoint of change from baseline in BCVA at Week 24: 
• Age category (< 65, ≥ 65 years) 
• Sex (male, female, undifferentiated, unknown) 
• Baseline BCVA categories (≤ 34, ≥ 35 - ≤ 55, ≥ 56 letters) 
• Duration of ME (≤ 3, > 3 months) 
• Baseline CSFT (< 450, ≥ 450 - ≤ 650, > 650 μm) 
• Baseline status of intraretinal fluid (IRF) (presence, absence) 
• Baseline status of subretinal fluid (SRF) (presence, absence) 
• Region (Japanese, Chinese, Rest of World) 
• Impact to COVID-19 (with impact, without impact) up to Week 24  (defined in Section 
5.8) 
2.3 
Subject disposition, demographics and other baseline 
characteristics 
No inferential testing on the differences in subject disposition, demographics and other baseline 
characteristics between treatment arms will be performed. 
2.3.1 
Subject disposition 
The number and percentage of subjects who were screened but not randomized will be 
summarized based on All-enrolled Analysis Set. The rescreened subjects will only be counted 
once and based on the final disposition status. The reasons for screen failures will also be listed. 
The following disposition status will be summarized based on the RAS: 


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• The number and percentage of subjects who receive study treatment and who complete 
the study treatment 
• The number and percentage of subjects who complete the study 
• The number and percentage of subjects who discontinue from study treatment as well 
as the primary reason for discontinuation on or prior to Week 24, Week 52, and Week 
72 (EoT)  
• The number and percentage of subjects who discontinue from the study as well as the 
primary reason for discontinuation on or prior to Week 24, Week 52, and Week 76 (EoS)  
In addition, listings of subjects who discontinue from the study and/or treatment along with the 
primary reason and the study day of discontinuation will be provided by treatment.  
The number and percentage of subjects in each analysis set will be presented by treatment group 
for the RAS. In addition, PDs and non-PD events (if applicable) that lead to subject exclusion 
from PPS will be summarized by deviation category, deviation terms and treatment for the RAS. 
Number and percentage of subjects with PDs will be presented by deviation category and 
treatment. Due to the COVID-19 pandemic, higher number PDs are expected. To evaluate the 
PDs that occurred due to COVID-19, the number and percentage of subjects with PDs that 
occurred due to COVID-19 outbreak will also be provided by deviation category and treatment. 
A listing of all PDs will be provided by treatment and subject including the information if the 
PD leads to the subject exclusion from an analysis set and the relationship to COVID-19 if the 
PD is due to COVID-19.  
2.3.2 
Demographic characteristics 
Demographic characteristics, including gender, race, ethnicity, age, age categories (<65 and ≥ 
65 years) and region will be summarized with descriptive statistics for the RAS by treatment 
and overall.  
Demographic characteristics will also be summarized by the following subgroups: 
• COVID-19 impacted and non-impacted up to Week 24 (defined in Section 5.8) 
• COVID-19 impacted and non-impacted up to Week 76  
2.3.3 
Ocular baseline characteristics 
The summary of baseline ocular characteristics will be provided by treatment group using the 
RAS for the study eye and listed separately for the study eye and the fellow eye.  
Ocular baseline characteristics include: 
• The study eye selection (left eye, i.e., OS or right eye, i.e., OD)  
• The number and percentage of patients with macular edema secondary to hemiretinal 
vein occlusion (HRVO) in  the RAVEN study 
• Time (months) since the primary diagnosis of macular edema secondary to BRVO or 
CRVO/HRVO as continuous variable and categories (≤ 3, > 3 months) 


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• Baseline best corrected visual acuity (BCVA) as continuous variable and categories (≤ 
34, 35 - 55, ≥ 56 letters)  
• Baseline anatomical and retinal pathology outcomes:   
o central subfield thickness (CSFT, µm) as continuous variable and categories (< 
450, 450 - 650, > 650 μm) 
o The presence of IRF in the central subfield (present, absent, cannot grade) 
o The presence of SRF in the central subfield (present, absent, cannot grade) 
o The presence of IRF or SRF in the central subfield (present, absent, cannot 
grade) 
o The presence of macular capillary non-perfusion  
Duration of macular edema secondary to BRVO or CRVO/HRVO since diagnosis (months) 
will be derived as [(first dose date – diagnosis date + 1)/365.25X12]. In case of partial dates, 
the imputation rule is specified in Section  5.1.4. 
Baseline disease characteristics will also be summarized by the following subgroups: 
• COVID-19 impacted and non-impacted up to Week 24 (defined in Section 5.8) 
• COVID-19 impacted and non-impacted up to Week 76  
2.3.4 
Medical history 
Any condition entered on the Medical History (MH) CRF, and any surgical and medical 
procedures taken and stopped prior to first dose of study treatment entered on the Therapies and 
Procedures (PR) CRF, will be coded using the MedDRA dictionary. Relevant medical history 
and current medical conditions will be summarized for ocular (study eye) and non-ocular events 
for the RAS. Listing will also be provided. 
2.4 
Treatments (study treatment concomitant therapies, compliance) 
2.4.1 
Study treatment/compliance 
For each subject, the extent of exposure to study treatment is estimated as the total number of 
intravitreal (IVT) injections of study treatment received. The summary of the total number of 
IVT injections will be provided by treatment and time period as follows: from first dose up to 
the end of the loading phase (i.e., Week 20), from first dose up to Week 52, and from first dose 
up to the EoT for the Safety Set.  
Exposure data and disease stability assessment (DSA) will be listed by visit for both treatment 
arms. 
2.4.2 
Prior, concomitant medications or surgical/medical procedures  
Prior medications are defined as therapies taken and stopped prior to first dose of study 
treatment. Concomitant medications/surgical and medical procedures are defined as therapies 
received after the start of study treatment including those already started prior to the initiation 
of the study treatment. Medications/surgical and medical procedures will be categorized into 


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one (and only one) of the above classes based on recorded or imputed start and end dates. When 
incomplete or missing, dates will be imputed according to Section 5.1.3. 
Prior and concomitant medication will be coded according to the WHO Drug Reference List 
dictionary, 
with 
Anatomical 
Therapeutic 
Classification 
(ATC) 
class 
4 
(i.e., 
Therapeutic/Pharmacological subgroup), if missing, the next higher level of ATC class will be 
used, and preferred term (PT). Ocular on the study eye and non-ocular prior and concomitant 
medications will be summarized by ATC class and PT for each treatment arm.  
Concomitant surgical and medical procedures will be coded using the MedDRA dictionary and 
summarized by system organ class (SOC) and PT for the study eye. 
The following listings will be provided for prior and concomitant medications as well as 
surgical and medical procedures for the Safety Set: 
• Ocular and non-ocular prior and concomitant medications, concomitant surgical and 
medical procedures 
• Alternative treatment for ME secondary to RVO on the study eye 
Concomitant anti-VEGF medications will be summarized for the Safety Set by ATC class and 
preferred term for non-ocular route, the study eye and the fellow eye separately. Alternative 
treatment for ME secondary to RVO on the study eye on/after treatment discontinuation will be 
summarized by preferred term. 
2.5 
Analysis of the primary endpoint 
This is a non-inferiority study. Non-inferiority will be considered established if the lower limit 
of the corresponding 95% CI for the estimated between group difference (brolucizumab vs. 
aflibercept) on change from baseline in BCVA at Week 24 is greater than -4 letters. Two-sided 
P-value for treatment comparison and one-sided p-value for non-inferiority testing will be 
provided.   
2.5.1 
Primary Estimand 
The primary estimand for the primary endpoint includes the following components: 
Population: Subjects with visual impairment due to ME secondary to BRVO/CRVO.  
Endpoint: The primary endpoint is the change from baseline in BCVA at Week 24. BCVA will 
be assessed by the masked investigator using ETDRS-like charts at an initial distance of 4 
meters.  
Treatment of interest: The randomized study treatment (brolucizumab or aflibercept).  
The handling of the remaining intercurrent events:  
• Treatment discontinuation for any reason: ignore (treatment policy strategy) 
• Data after the start of PD COMD01 (prohibited medication and/or procedure with 
impact on efficacy and/or safety) or alternative medication will be censored  
Summary measure: Difference in the change from baseline in BCVA at Week 24 between 
brolucizumab and aflibercept treatment groups. 


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2.5.2 
Statistical hypothesis, model, and method of analysis 
The objective related to the primary endpoint is to demonstrate non-inferiority of brolucizumab 
versus aflibercept with respect to the change from baseline in BCVA at Week 24, assuming a 
non-inferiority margin of 4 ETDRS letters. 
Let: 
B = Brolucizumab 6 mg - 6 x q4w loading 
A = Aflibercept 2 mg - 6 x q4w loading 
Consider the following non-inferiority hypotheses related to a non-inferiority margin of 4 letters: 
H0: μB – μA ≤ -4 letters versus HA: μB – μA > -4 letters 
where μB and μA are the corresponding unknown true mean changes from baseline in BCVA  at 
Week 24 in the brolucizumab and aflibercept arms, respectively. 
The primary hypothesis will be tested via an analysis of variance (ANOVA) model based on 
the FAS. The ANOVA model will include treatment, baseline BCVA (≤ 34, 35 - 55, ≥ 56 letters) 
and age category (< 65, ≥ 65 years) as factors. The least square mean and two-sided 95% 
confidence interval (CI) for change from baseline in BCVA at Week 24 for each treatment arm 
as well as the difference (brolucizumab vs. aflibercept) will be presented.  Descriptive analyses 
based on observed data will be provided for the FAS population. 
2.5.3 
Handling of missing values/censoring/discontinuations 
The handling of the intercurrent events for the primary estimand is as below: 
• Treatment discontinuation for any reason: ignore (treatment policy strategy) 
• Data after the start of PD COMD01 (prohibited medication and/or procedure with 
impact on efficacy and/or safety) or alternative medication will be censored  
As stated in Table 2-2, missing and censored BCVA values will be imputed by LOCF as the 
primary approach for the primary estimand. Observed values from both scheduled and 
unscheduled post-baseline visits will be used for the LOCF imputation. For subjects with no 
post-baseline BCVA value, the baseline value will be carried forward.  
From an estimand perspective, the main focus on defining the primary estimand is to adequately 
reflect in the analysis unfavorable study outcomes related to the treatment (e.g., lack of efficacy, 
safety events). Data after the application of prohibited medications/procedures or alternative 
treatment for ME secondary to RVO will be censored. LOCF will then be based on the last 
value prior to the start of such treatment, expecting that this value would reflect the negative 
BCVA outcome under study treatment. 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 before or at the time of the early study termination. In 
case of early study termination 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.  


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LOCF is an established method within the assessment of efficacy of anti-VEGF treatments in 
terms of BCVA outcome. It is important to note that, in order to facilitate a meaningful 
treatment effect assessment, 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. In the aflibercept Phase III studies COPERNICUS and GALILEO (CRVO) and 
VIBRANT (BRVO) missing BCVA data was imputed based on LOCF. 
The major reason for missing BCVA assessment at Week 24 is discontinuation from study due 
to early study termination and this will result in data missing completely at random. The BCVA 
change from baseline is increasing very fast in the first several months then stabilized without 
much change. The application of LOCF is assuming the treatment effect at Week 24 is the same 
as the time when a patient discontinued from the study before Week 24, which may introduce 
an under- or overestimate of the between group difference if the BCVA improvement is 
responding slower or faster for brolucizumab compared to aflibercept early in the study. To 
consider the trajectory of the BCVA response to study treatment up to Week 24, the sensitivity 
analyses using Mixed Model Repeated Measure (MMRM) specified in Section 2.5.4.1 will be 
evaluated along with the primary method. 
2.5.4 
Supportive analyses 
Sensitivity and supportive analyses for the primary endpoint, i.e., change from baseline in 
BCVA at Week 24, are planned and specified in Table 2-2.  
The same approach for non-inferiority assessment in change from baseline in BCVA at Week 
24 will be applied to sensitivity analysis and supplementary estimand. When assessing the 
robustness of the non-inferiority conclusions, considerations will be given to the analysis based 
on the primary estimand using FAS and the analysis based on the supplementary estimand using 
PPS, i.e., similar conclusions on non-inferiority based on both estimands are expected. 
Inconsistencies in the results will be examined and discussed in the CSR. 
Table 2-2 
Primary and supplementary estimands 
Estimand 
Analysis 
set 
Analysis 
Statistical methods 
(including missing/censored data strategy) 
Primary  
FAS 
Primary analysis 
ANOVA model including terms for treatment, baseline 
BCVA ≤ 34, 35 - 55, ≥ 56 letters) and age category (< 
65, ≥ 65 years). Using LOCF imputation for 
missing/censored data. 
Sensitivity analysis 
 
MMRM including fixed effect terms for treatment, visit, 
visit by treatment interaction, baseline BCVA (≤ 34, 35 - 
55, ≥ 56  letters) and age category (< 65, ≥ 65 years) 
assuming an unstructured covariance matrix, no 
imputation on missing/censored data. 
Supplementary 
PPS 
Supportive analysis 
ANOVA model including terms for treatment, baseline 
BCVA ≤ 34, 35 - 55, ≥ 56  letters) and age category (< 
65, ≥ 65 years). Using LOCF imputation for 
missing/censored data. 
 


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2.5.4.1 
Sensitivity analyses on the primary estimand 
The primary analysis on the primary estimand using LOCF to impute missing/censored data 
based on the assumption that the effect of the initially randomized treatment at the intake of the 
prohibited medications/procedures or alternative treatment for ME secondary to RVO remains 
constant to the end of the loading phase.   
The sensitivity analysis to the LOCF/ANOVA method on the primary estimand is using 
MMRM, a model-based method assuming data missing at random (MAR). It is assessing the 
treatment effect of the initially randomized treatments assuming all subjects remained on the 
randomized treatment throughout the study. The MMRM will include treatment, visit (treated 
as a categorical variable), baseline BCVA category, age category and treatment by visit 
interaction as fixed-effect terms, and visit as a repeated measure. An unstructured covariance 
matrix will be used to model the within-subject error. If the MMRM model assuming 
unstructured covariance matrix does not converge, a more restricted covariance matrix can be 
considered in the following order until convergence is reached: compound symmetry (CS), 
Toeplitz (TOEP), and first-order autoregressive (AR).  
Other methods for data imputation may be explored if the proportion of subjects with missing 
or censored data is deemed large enough so as to potentially impact the results from the primary 
analysis.  
2.5.4.2 
Supportive analysis using a supplementary estimand 
The primary endpoint, the treatment of interest and the summary measure of the supplementary 
estimand are the same as for the primary estimand. Different from the primary estimand, the 
target population includes subjects with visual impairment due to ME secondary to 
BRVO/CRVO, and with no major protocol deviation or with low treatment compliance during 
loading phase. The details for subject exclusion from PPS can be found in section 5.6 for the 
PPS population. The handling of the intercurrent events for the supplementary estimand is as 
below: 
• Treatment discontinuation due to lack of efficacy or safety: ignore  
• Data after the treatment discontinuation due to other reasons will be censored 
• Data after the start of PD COMD01 (prohibited medication and/or procedure with 
impact on efficacy and/or safety) or alternative medication will be censored 
• Data collected on/after the start of PD of OTH01 (Any other protocol deviation with 
impact on efficacy and/or safety) will be censored  
The supportive analysis on the supplementary estimand will apply the same LOCF/ANOVA 
method as for the primary estimand.  
2.5.4.3 
Subgroup analysis 
The subgroup analyses (subgroups defined in Section 2.2.1) will be explored using the FAS and 
the same ANOVA model as described for the primary endpoint fitted by category of each 
subgroup. Subgroup variables that are used as fixed effects in the model will be removed from 
the model statement for subgroup analysis.  


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In case of analyses on subgroups with extremely imbalanced sample sizes, the subgroup levels 
can either be combined, if appropriate, or the extremely small subgroup will be excluded while 
fitting the analysis model.  The point estimate and 95% CI for the between treatment difference 
for each subgroup will be presented using forest plots.  
The COVID-19 related subgroups based on the impact from first treatment up to Week 24 will 
be included for the analysis of the primary endpoint (subgroups defined in Section 5.8).  
2.6 
Analysis of selected secondary endpoints 
The inferential testing on selected secondary endpoints specified in this section will be 
performed if the null hypothesis of the primary endpoint is rejected. 
2.6.1 
Selected secondary endpoint 
The selected secondary endpoints are: 
1. Proportion of subjects with confirmed disease stability at Week 24 
2. Proportion of subjects with retinal fluid in the central subfield (i.e., with IRF and/or SRF) 
at Week 24  
3. CSFT change from baseline at Week 24 
4. Time to recurrence after Week 20 and up to Week 76 
2.6.2 
Statistical hypothesis, model, and method of analysis 
The hypotheses on the selected secondary endpoints will be tested hierarchically in the order 
specified in Section 2.6.1. Within this hierarchical testing approach the testing of a given 
hypothesis requires rejection of all preceding null hypothesis with a significance level of 0.05. 
This testing procedure controls the overall two-sided type-I error rate to less than 0.05 within 
study. 
2.6.2.1 
Disease stability at Week 24  
The null hypothesis is that there is no difference in the proportion of subjects who achieved 
disease stability at Week 24. Superiority of brolucizumab over aflibercept will be concluded if 
there is an increase in proportion of subjects (i.e., rate difference>0) achieving disease stability 
at Week 24 in the brolucizumab arm compared with the aflibercept arm and the two-sided p-
value for the between-treatment comparison is less than 0.05. The confirmatory analysis will 
be conducted on FAS population.  
The confirmatory analysis of the proportion of subjects with disease stability at Week 24 will 
be done based on the FAS using a logistic regression model for response rate (95% CI) in each 
treatment group. The model will be adjusted by treatment, baseline BCVA categories, baseline 
CSFT categories and age categories as fixed effects. The rate difference (95% CI) and p-value 
for between group comparison will be provided using the marginal standardization method.  
2.6.2.2 
Subjects with IRF and/or SRF in the central subfield at Week 24 
The null hypothesis is that there is no difference in the proportion of subjects free of retinal 
fluid (i.e., no IRF or SRF) in the central subfield  at Week 24. Superiority of brolucizumab over 


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aflibercept will be concluded if higher proportion of subjects are free of retinal fluid at Week 
24 in the brolucizumab arm compared with the aflibercept arm and the two-sided p-value for 
the between-treatment comparison is less than 0.05. The confirmatory analysis will be 
conducted on FAS population. 
The confirmatory analysis of the proportion of subjects free of retinal fluid at Week 24 will be 
done based on the FAS using a logistic regression model for the mean response rate and 95% 
CI in each treatment group. The model will be adjusted by treatment, baseline fluid status, and 
age categories as fixed effects. Marginal standardization method will be used to calculate the 
rate difference (95% CI) and p-value for between group comparison.  
2.6.2.3 
CSFT change from baseline at Week 24 
The null hypothesis is that there is no difference in the mean CSFT change from baseline at 
Week 24. Superiority of brolucizumab over aflibercept will be concluded if the reduction at 
Week 24 is higher in the brolucizumab arm compared with the aflibercept arm and the two-
sided p-value for the between-treatment comparison is less than 0.05. The confirmatory analysis 
will be conducted on FAS population. 
The confirmatory analysis of CSFT change from baseline at Week 24 will be done on the FAS 
using ANOVA model. The model will be adjusted by treatment, baseline CSFT categories, and 
age categories as fixed effects. The least square mean by treatment and two-sided 95% CI in 
each treatment group, their difference (95% CI) and p-value for between group comparison will 
be presented.  
2.6.2.4 
Time to recurrence after Week 20 and up to Week 76 
The null hypothesis is that there is no difference in the time to recurrence after Week 20 and up 
to Week 76. Superiority of brolucizumab over aflibercept will be concluded if there is a 
reduction in risk (estimated hazard ratio from Cox-model < 1) between the brolucizumab arm 
and the aflibercept arm, and the two-sided p-value for the between-treatment comparison is less 
than 0.05. The confirmatory analysis will be conducted on FAS population.  
A recurrence is defined as the need for injection according to the DSA. A subject is considered 
to have recurrence if showing the lack of disease stability after Week 20 and up to Week 76. 
For subjects with recurrence after the Week 20 visit, time-to-event is calculated as (first time 
with the lack of disease stability – the injection date on Week 20 visit + 1). For subjects without 
recurrence after Week 20, the censoring time will be calculated as (last visit with DSA 
assessment – the injection date on Week 20 visit + 1). If a subject had a missed injection at 
Week 20 visit, the visit date of Week 20 will be used for time calculation. If a subject had a 
missing Week 20 visit, the targeted visit day, i.e. day 141, will be used for time calculation. If 
a subject did not have any DSA after Week 20 then the subject will be censored at Week 20 
visit. 
The confirmatory analysis of the time to recurrence will be analyzed for FAS subjects excluding 
those who discontinue from study treatment on or before Week 20. Kaplan Meier (KM) 
estimates on percent of subjects with recurrence, together with 95% CI, will be presented for 
Week 52 and Week 76 visits. The median time (and 95% CI) to recurrence will also be 
constructed by treatment arm. KM curves presenting the cumulative probability of first injection 


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on or after Week 20 will be provided by treatment arm. A cox proportional hazards model 
adjusted for treatment, baseline BCVA categories, baseline CSFT categories, and age categories 
will be used for the hazard ratio (95% CI) estimate and the p-value for the between-treatment 
comparison. 
2.6.3 
Handling of missing values/censoring/discontinuations 
2.6.3.1 
Disease stability at Week 24 
The handling of the intercurrent events for this endpoint is as below: 
• With no disease stability at Week 24 if with PD COMD01 (prohibited medication and/or 
procedure with impact on efficacy and/or safety) on or before Week 24 
• With no disease stability at Week 24 if treatment discontinuation due to lack of efficacy 
or safety on or before Week 24 
No data imputation will be applied.  
2.6.3.2 
Subjects with IRF and/or SRF at Week 24 
The handling of the intercurrent events for this endpoint is as below: 
• Treatment discontinuation for any reason: ignore (treatment policy strategy) 
• Data after the start of PD COMD01 (prohibited medication and/or procedure with 
impact on efficacy and/or safety) or alternative medication will be censored  
Same as for the primary endpoint, missing and censored IRF and/or SRF values will be imputed 
by LOCF.  
2.6.3.3 
CSFT change from baseline at Week 24 
The handling of the intercurrent events for this endpoint is as below: 
• Treatment discontinuation for any reason: ignore (treatment policy strategy) 
• Data after the start of PD COMD01 (prohibited medication and/or procedure with 
impact on efficacy and/or safety) or alternative medication will be censored  
Missing and censored CSFT values will be imputed by LOCF. 
2.6.3.4 
Time to recurrence after Week 20 and up to Week 76 
The handling of the intercurrent events for this endpoint is as below: 
• Showing the lack of disease stability at the time of treatment discontinuation due to lack 
of efficacy or safety  
• Showing the lack of disease stability at the start of PD COMD01, or rescue therapy  
No data imputation will be applied. 


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2.7 
Analysis of secondary efficacy endpoints 
2.7.1 
Secondary endpoints 
Secondary efficacy endpoints based on BCVA: 
• Change from baseline in BCVA averaged over Week 40 to Week 52 and Week 64 to 
Week 76 
• Change from baseline in BCVA by visit up to Week 76 
• Proportion of study eyes with a gain ≥ 5, 10 and 15 letters in BCVA by visit compared 
to baseline.  
Note: Subjects with BCVA value of 84 letters or more at a postbaseline visit will be 
considered as responders for the corresponding endpoint. This is to account for a 
ceiling effect, e.g. for the’ ≥15-letter gain’ endpoint, for those subjects with BCVA 
values at baseline >=70 letters 
• Proportion of study eyes with a loss ≥ 5, 10 and 15 letters in BCVA by visit compared 
to baseline 
Secondary efficacy endpoints related to anatomy: 
• Change from baseline in central subfield thickness (CSFT) averaged over Week 40 to 
Week 52 and Week 64 to Week 76  
• Change from baseline in CSFT by visit up to Week 76  
• Proportion of study eyes with presence of retinal fluid (intraretinal fluid, subretinal 
fluid, intra- or subretinal fluid) by visit up to Week 76 
• Proportion of study eyes with a CSFT < 300 μm by visit up to Week 76 
Secondary efficacy endpoints related to treatment frequency: 
• Number of injections between Week 24 and Week 52 and between Week 24 and Week 
72 
Secondary efficacy endpoints related to patient reported outcomes: 
• Change from baseline in patient reported outcomes (NEI VFQ-25) at Week 24, Week 
52 and Week 76 
2.7.2 
Statistical hypothesis, model, and method of analysis 
No hypotheses will be tested for the secondary efficacy endpoints listed in 2.7.1. Between group 
difference may be estimated along with the corresponding 95% CI and nominal p-value. Unless 
otherwise specified, all the analyses will be based on the FAS.  
Continuous endpoints: 
The following continuous endpoints will be analyzed using ANOVA models on data with 
LOCF imputation up to Week 24.  The estimates of least square means for each treatment arm 
and for the treatment differences, including 95% CIs, as well as nominal p-value will be 
presented. The line plot on LSMean (±SE) by visit up to Week 24 will also be provided for each 


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treatment arm. Summary statistics will also be provided by visit up to end of study based on 
observed data without data imputation 
• BCVA change from baseline: ANOVA models similar to the one specified for the 
primary endpoint will be used.   
• CSFT change from baseline: the ANOVA model will be adjusted by treatment, age 
category, and baseline CSFT category.   
For other continuous endpoints, summary statistics will be provided by visit up to end of study 
based on observed data without data imputation. 
Categorical variables: 
For binary endpoints, frequency tables (count and proportion) will be provided by time point 
based on observed data in FAS. The following categorical endpoint will be analyzed using 
logistic regression with LOCF imputation by visit up to Week 24. The model will be adjusted 
by treatment, baseline fluid status, and age categories as fixed effects to calculate the mean 
response rate and 95% CI in each treatment group. The rate difference (95% CI) and p-value 
for between group comparison will be provided using the marginal standardization method.  
• Proportion of study eyes with presence of retinal fluid (intraretinal fluid, subretinal 
fluid, intra- or subretinal fluid)  
Count variables: 
For endpoints on number of injections, the distribution of total number of injections observed 
between Week 24 and Week 52 and between Week 24 and Week 72 will be summarized in the 
subset of patients who are on study treatment at Week 52 and the subset of patients who 
completed the study treatment, respectively. No data censoring will be applied for this endpoints.  
2.7.3 
Handling of missing values/censoring/discontinuations 
Where not specified, the same data censoring rules applied for the primary (Section 2.5) and 
selected secondary endpoints (Section 2.6) will be followed for the secondary endpoints with 
similar data type. 
2.8 
Safety analyses 
Safety endpoints are based on the variables from safety assessments which include: 
• Extent of exposure (see Section 2.4.1) 
• Adverse events 
• Ophthalmic examinations 
• Vital signs 
• Laboratory results 
There are no formal safety hypotheses in this study. All safety analyses will be descriptive and 
performed based on observed data using the SAF. According to the definition of the SAF, 
subjects will be grouped by the actual treatment received.  


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The safety analyses will include all treatment-emergent data, i.e., data from first dose of study 
treatment until the EoS. Sensitivity analyses including all data from first dose of study treatment 
until the start of an alternative treatment for ME secondary to RVO will also be conducted if 
specified in the section for the relevant endpoint analysis. 
2.8.1 
Adverse events (AEs) 
A treatment-emergent adverse event (TEAE) is defined as any adverse event that develops or 
any event already present that worsens on or after the first study treatment date  
Adverse events will be coded using the MedDRA dictionary and presented by system organ 
class (SOC) and preferred term (PT). The MedDRA version used for reporting the study will 
be described in a footnote on AE related outputs.  
The number (and percentage) of subjects with TEAE will be summarized by treatment and 
presented by the SOCs in alphabetical order and the PTs in descending incidence in the 
brolucizumab treatment arm and then in the aflibercept treatment arm. A subject with multiple 
adverse events within a given category is only counted once for summary purposes. Ocular and 
non-ocular (systemic) AEs will be presented separately; ocular AEs will be presented by study 
eye and fellow eye separately. AE summaries specified in the table below will be provided. 
Subject listings of all adverse events will be provided. Deaths and SAE (i.e., other serious or 
clinically significant non-fatal adverse events) will be listed separately.  
Table 2-3 
AE summary 
TEAE summary 
AE categories 
Ocular 
AE in the 
study eye 
Ocular AE 
in the 
fellow eye 
Non-
ocular 
AE 
AEs by SOC and PT  
Y# 
Y 
Y# 
AEs by SOC and PT (excluding data after the use of 
alternative treatment for ME secondary to RVO on the 
study eye after discontinuation from study treatment) 
Y 
 
Y 
Frequent AEs by PT┼  
Y 
 
Y 
AEs by maximum severity, SOC and PT  
Y 
 
Y 
AEs related to study treatment by SOC and PT 
Y 
 
Y 
AEs related to injection procedure by SOC and PT 
Y 
 
 
AEs leading to permanent discontinuation of study 
treatment by SOC and PT 
Y 
 
Y 
AEs leading to temporary interruption of study treatment 
by SOC and PT 
Y 
 
Y 
AEs leading to discontinuation from the study by SOC and 
PT 
Y 
 
Y 


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TEAE summary 
AE categories 
Ocular 
AE in the 
study eye 
Ocular AE 
in the 
fellow eye 
Non-
ocular 
AE 
SAEs by SOC and PT  
Y# 
Y 
Y# 
SAEs by SOC and PT (excluding data after the use of 
alternative treatment for ME secondary to RVO on the 
study eye after discontinuation from study treatment) 
Y 
 
Y 
SAEs related to study treatment by SOC and PT 
Y 
 
Y 
SAEs related to injection procedure by SOC and PT 
Y 
 
 
┼≥ 2 % (or other cutting point as appropriate) in any treatment group for a given PT. 
#Including separate summary tables for impacted/non-impacted subjects to COVID-19 by end 
of the study as defined in Section 5.8. 
 
2.8.1.1 
Adverse events of special interest/grouping of AEs 
An adverse event of special interest (AESI) is the one of scientific and medical interest. The 
AESI for analysis includes, but not limited to: 
• Endophthalmitis 
• Intraocular Inflammation (excluding infective or viral nature and including retinal 
vasculitis) 
• Retinal vascular occlusion  
Incidence of AESI in the study eye will be tabulated by treatment arm. Listing for AESIs will  
also be provided. 
AESIs will be identified via the RTH258 electronic case retrieval strategy (eCRS). The eCRS 
that is current at the time of the database lock will be used and AESIs will be identified where 
the flag Core Safety Topic Risk (SP) = ‘Y’. 
2.8.1.2 
Other safety topics of interest 
Other safety topics of interest includes, but not limited to, the following Ocular AEs in the study 
eye or non-ocular AEs: 
• Arterial thromboembolic events 
• Hypertension 
• Intraocular pressure increased transient 
• Non-ocular haemorrhage 
• Retinal detachment and retinal tear 
• Venous thromboembolic events 


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Incidence of other safety topics of interest will be tabulated by treatment arm. Listing will also 
be provided. Other safety topics of interest will be identified via the RTH258 eCRS where the 
flag Core Safety Topic Risk (SP) = ‘Y’. 
2.8.1.3 
Adverse event reporting for clinical trial safety disclosure  
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on TEAEs 
(pooled with ocular and non-ocular AEs) which are not serious adverse events with an incidence 
greater than 5%, and on TEAEs and SAEs suspected to be related to study treatment will be 
provided by SOC and PT based on the SAF. 
If, for the same subject, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE (resp. non SAE) has to be checked in a block 
e.g., among AE's in a ≤ 1 day gap block, if at least one SAE is occurring, then one occurrence 
is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
2.8.2 
Deaths 
A summary of treatment-emergent deaths will be presented by primary SOC and PT. 
All deaths recorded in the clinical database will be listed.  
2.8.3 
Laboratory data 
Chemistry and hematology laboratory parameters will be presented graphically using boxplots 
of change from baseline values by treatment arm and visit. No summary by visit tables will be 
provided. 
A summary on counts and percentages of subjects with laboratory assessment meeting the pre-
specified clinically relevant abnormality criteria (Section 5.3) at any post-treatment visit will 
be presented. A listing of laboratory assessments for subjects meeting at least one abnormal 
criterion will also be provided. 
2.8.4 
Other safety data 
2.8.4.1 
Ophthalmic Examinations  
The ophthalmic examinations will be summarized for the study eye only. 
Descriptive summaries of change from baseline in pre-injection IOP values will be presented 
graphically by visit and treatment, considering line plots of the mean change in IOP values with 


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error bars representing ± SE. The x-axis will be the study visit and the y-axis will be the change 
from baseline value. No summary by visit tables will be provided. 
The counts and percentages of the following findings will be summarized: 
• Subjects with treatment-emergent pre-injection IOP >30 mmHg at any visit  
• Subjects with post-injection IOP >30 mmHg at any visit  
• Subjects with an increase of ≥10, ≥20 mmHg from pre-injection to post-injection IOP 
at any visit. 
• Subjects with treatment-emergent pre-injection IOP ≥21 mmHg in 3 consecutive 
scheduled visits. A scheduled visit with missing pre-injection IOP is considered to meet 
the ≥21 mmHg criterion if the preceding and the following scheduled visits have pre-
injection IOP ≥21 mmHg. For example, if scheduled visit X has missing pre-injection 
IOP and pre-injection IOP ≥21 mmHg for both scheduled visits X-1 and X+1, the 
subject is considered to meet the criteria. 
A listing of all IOP assessments for subjects with at least one of the above findings on the study 
eye will be provided.  
The abnormal findings via slit-lamp and indirect fundus examinations deemed as clinically 
significant by the investigator and reported as AE/SAE will be included in the safety analysis 
on AE/SAE.  
Imaging parameters related to intraocular inflammation including retinal vasculitis and retinal 
vascular occlusion except for retinal vein occlusion in the study eye will be summarized by 
baseline, up to visit 7, after visit 7 to end of study, and for post-baseline up to end of study. 
When more than one grading result is available for a subject within a time period, the maximum 
level of sign will be used. These imaging parameters will be summarized by AESI status for 
baseline and post-baseline up to end of study. The parameters will be listed for subjects with 
AESI and subjects with imaging parameter present at any study visit.  
2.8.4.2 
Vital signs 
A line plot of mean change from baseline with error bars representing ± SE for each vital sign 
parameter will be provided by visit and treatment.   
The number and percentage of subjects with at least one assessment meeting the abnormal 
criteria specified on Section 5.4 will be presented. A listing of all vital sign assessments for 
subjects with at least one abnormal finding will also be presented. 
2.8.4.3 
Vision loss 
A listing of subjects with BCVA loss of 15 letters or more from baseline will be provided for 
the SAF.  
2.9 
Pharmacokinetic endpoints   
No pharmacokinetic parameters will be assessed. 


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2.10 
Anti-drug antibody 
ADA assessment will be done for subjects from the brolucizumab arm at screening, Week 4, 
12, 24, 36, 52 and 76 (or premature EoS) visits prior to the injection/sham. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
   
 
 
 
Subject listing of all ADA titer values and 
 will be presented for all subjects from the 
brolucizumab arm. Samples collected at unscheduled visits will not be part of the analysis. 
 
 
 
 
Systemic exposure of brolucizumab will be measured concomitantly with ADA levels for 
interpretation purposes and no pharmacokinetic parameters will be determined from 
brolucizumab systemic exposure.  Systemic exposure data will be summarized and listed. 


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2.11 
Subject-reported outcomes 
The VFQ-25 questionnaires will be scored (composite and sub-scale scores) at Baseline and 
Weeks 24, 52 and 76 visits.  
The statistical analysis method is provided in section 2.7.2. Absolute scores and the changes 
from baseline will be calculated and summarized descriptively based on observed data using 
the FAS. 
The details on the scoring algorithm and analysis are provided in this section. Each sub-scale 
score has a range of 0 to 100 inclusive and will be calculated from the re-scaled raw data as 
described in Table 2-4. A missing response will not be re-scaled (except for the response to 
question 15c, see below, which will be re-set to 0 if the response to question 15b is 1). 
The answers to questions will be re-scaled as follows to calculate the total and subscale scores. 
Table 2-4 
Rescaling of VFQ-25 questions 
Answer to question 
Rescaling 
for  
questions 
1, 3, 4 and 
15c 
Rescaling for question 2 
Rescaling 
for 
questions 
5-14, 16 
and 16a 
Rescaling 
for 
questions 
17-25 
1 
100 
100 
100 
0 
2 
75 
80 
75 
25 
3 
50 
60 
50 
50 
4 
25 
40 
25 
75 
5 
0 
20 
0 
100 
6 
N/A 
0 
N/A* 
N/A 
*Response choice "6" indicates that the person does not perform the activity because of non-vision 
related problems. If this choice is selected, the item is coded as "missing”. Subscales will be 
calculated where at least one of the (re-scaled) questions contributing to that subscale is non-
missing, otherwise set to missing. 
Note that the answer to question 15c will subsequently be adjusted based on the answer to 
question 15b: 
• If the answer to 15b is 1 then the answer to 15c will be re-set to 0. 
• If the answer to 15b is 2 or 3 then the answer to 15c will be re-set to missing  
The general health rating is the re-scaled answer to question 1. 
Response choice "6" indicates that the person does not perform the activity because of non-
vision related problems. If this choice is selected, the item is coded as "missing”. Subscales will 
be calculated where at least one of the (re-scaled) questions contributing to that subscale is non-
missing, otherwise set to missing. 
The sub-scales (excluding the general health question) and corresponding questions are shown 
in Table 2-5. 


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Table 2-5 
Questions by sub-scales contributing to VFQ composite score 
Sub-scale 
Questions 
General vision 
2 
Ocular pain 
4 and 19 
Near activities 
5, 6 and 7 
Distance activities 
8, 9 and 14 
Social functioning 
11 and 13 
Mental health 
3, 21, 22 and 25 
Role difficulties 
17 and 18 
Dependency 
20, 23 and 24 
Driving 
15c, 16 and 16a 
Color vision 
12 
Peripheral vision 
10 
The composite score is the average of the 11 sub-scales shown in Table 2-5. It will be set to 
missing if at least six of the subscales are missing. The change from baseline of rescaled 
composite score and sub-scale scores will be derived based on the changes in the individual 
items scores and then averaged for the sub-scale score. 




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Protocol 
section 
Protocol wording 
Change in the SAP 
RAS. No summary table will 
be produced. 
12.3 
Descriptive summary statistics for 
exposure to study treatment will 
be provided for the SAF, FAS 
and PPS 
Descriptive 
statistics 
for
exposure to study treatment 
will be provided for the SAF. 
 
12.3 
The number and percentage of 
subjects taking prior medication 
or concomitant therapies will 
be summarized using the SAF 
and FAS (in case there are 
differences between those two). 
Ocular and non-ocular prior 
and 
concomitant
medications will be listed. 
Anti-VEGF medications will 
be 
summarized 
for 
the
safety 
set. 
No 
other
summary 
table 
will 
be
produced.  
12.4.4 
The categories for subgroups of: 
Sex: male, female 
Baseline BCVA: ≤34, 34-55,≥55 
letters 
Baseline CSFT: <450, 450-650, 
≥650 µm 
The 
categories 
for
subgroups of: 
Sex: male, female,  
Baseline BCVA: ≤34, 35-55, 
≥ 56  letters 
Baseline CSFT: <450, 450-
650, >650 µm 
12.5.1 
Secondary 
efficacy 
endpoints 
related to treatment frequency: 
• 
Number 
of 
injections 
between Week 24 and 
Week 76 
• 
Time to first re-treatment 
between Week 24 and 
Week 76 
Secondary 
efficacy
endpoints 
related 
to
treatment frequency: 
• 
Number 
of
injections between
Week 24 and Week 
72 
• 
Time to recurrence 
after Week 20 and 
up to Week 76 
General 
Analysis restriction is used to 
specify how the intercurrent event 
is handled 
Analysis restriction is not 
used and the handling of 
intercurrent event will be
specified 
under 
the
Estimand framework 
12.5.2 
 
AESI is updated 
 
 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
Missing or partial dates are not allowed, therefore, no imputation will be made to the start date 
and end date of study treatment. 


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5.1.2 
AE date imputation 
For the start and end dates of the adverse event records, when incomplete or missing, dates will 
be imputed according to Novartis standards as described below. 
5.1.2.1 
AE end date imputation 
Incomplete or missing AE end date will be dealt with in the following way:  
1. If the AE end date month is missing, the imputed end date should be set to the earliest of 
the ( 31DECYYYY, date of death). 
2. If the AE end date day is missing, the imputed end date should be set to the earliest of the 
(last day of the month, date of death). 
3. If AE year is missing or AE is ongoing, the end date will not be imputed. 
4. If the imputed AE end date is less than the existing AE start date then use AE start date as 
AE end date. 
5.1.2.2 
AE start date imputation 
The following table explains the notation used in the logic matrix. Please note that completely 
missing start dates will not be imputed. 
 
 
Day  
Month 
Year 
Partial Adverse Event Start Date 
Not used 
MON 
YYYY 
Treatment Start Date 
Not used 
TRTM 
TRTY 
The following matrix explains the logic behind the imputation. 
 
MON MISSING 
MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY 
MISSING 
(1) No convention 
(1) No convention 
(1) No convention 
(1) No convention 
YYYY < TRTY 
(2.a) Before 
Treatment Start  
(2.b) Before 
Treatment Start  
(2.b) Before 
Treatment Start  
(2.b) Before 
Treatment Start  
YYYY = TRTY 
(4.a) Uncertain 
(4.b) Before 
Treatment Start 
(4.c) Uncertain 
(4.c) After 
Treatment Start 
YYYY > TRTY 
(3.a) After 
Treatment Start 
(3.b) After 
Treatment Start 
(3.b) After 
Treatment Start 
(3.b) After 
Treatment Start 
Before imputing AE start date, find the AE start reference date. 
1. If the (imputed) AE end date is complete and the (imputed) AE end date < treatment 
start date then AE start reference date = min (informed consent date, earliest visit date). 
2. Else AE start reference date = treatment start date 
Impute AE start date - 
1. If the AE start date year value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the AE year value is missing, the imputed AE start date is set 
to NULL. 
 
2. If the AE start date year value is less than the treatment start date year value, the AE 
started before treatment. Therefore: 


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a. If AE month is missing, the imputed AE start date is set to the mid-year point 
(01JulYYYY). 
b. Else if AE month is not missing, the imputed AE start date is set to the mid-month 
point (15MONYYYY). 
 
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment. Therefore: 
a. If the AE month is missing, the imputed AE start date is set to the year start point 
(01JanYYYY). 
b. Else if the AE month is not missing, the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day). 
 
4. If the AE start date year value is equal to the treatment start date year value: 
a. And the AE month is missing the imputed AE start date is set to the AE reference 
start date + 1 day. 
b. Else if the AE month is less than the treatment start month, the imputed AE start 
date is set to the mid-month point (15MONYYYY). 
c. Else if the AE month is equal to the treatment start date month or greater than the 
treatment start date month, the imputed AE start date is set to the later of (month 
start point (01MONYYYY), AE start reference date + 1 day). 
If complete (imputed) AE end date is available and the imputed AE start date is greater than the 
(imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end date. 
5.1.3 
Concomitant medication and therapies and procedures date 
imputation 
For the start and end dates of the concomitant medication records, when incomplete or missing, 
dates will be imputed according to Novartis standards as described below. The same data 
imputation rules will be applied for therapies and procedures. 
5.1.3.1 
Concomitant medication end date imputation 
Incomplete or missing end date will be dealt with in the following way 
1. If the CM end date year value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the CM end year value is missing or ongoing, the imputed CM 
end date is set to NULL. 
2. Else, if the CM end date month is missing, the imputed end date should be set to the last day 
of the year or set to the end of study date if it falls in the same year. 
3. If the CM end date day is missing, the imputed end date should be set to the last day of the 
month or set to the end of study date if it falls in the same year and month. 
If the imputed CM end date is less than the existing CM start date, use the CM start date as the 
imputed CM end date. 


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5.1.3.2 
Concomitant medication start date imputation 
Completely missing start dates will be set to one day prior to treatment start date. As a 
conservative approach, such treatments will be classified as prior and concomitant (and 
summarized for each output). 
Concomitant treatments with partial start dates will have the date or dates imputed. 
The following table explains the notation used in the logic matrix 
 
Day  
Month 
Year 
Partial CMD Start Date 
Not used 
MON 
YYYY 
Treatment Start Date 
Not used 
TRTM 
TRTY 
The following matrix explains the logic behind the imputation. 
 
 
MON MISSING 
MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY 
MISSING 
(1) Uncertain 
(1) Uncertain 
(1) Uncertain 
(1) Uncertain 
YYYY < TRTY 
(2.a) Before 
Treatment Start  
(2.b) Before 
Treatment Start  
(2.b) Before 
Treatment Start  
(2.b) Before 
Treatment Start  
YYYY = TRTY 
(4.a) Uncertain 
(4.b) Before 
Treatment Start 
(4.a) Uncertain 
(4.c) After 
Treatment Start 
YYYY > TRTY 
(3.a) After 
Treatment Start 
(3.b) After 
Treatment Start 
(3.b) After 
Treatment Start 
(3.b) After 
Treatment Start 
 
1. If the CM start date year value is missing, the imputed CM start date is set to one day prior 
to treatment start date. 
2. If the CM start date year value is less than the treatment start date year value, the CM 
started before treatment. Therefore: 
a. If the CM month is missing, the imputed CM start date is set to the mid-year point 
(01JulYYYY). 
b. Else if the CM month is not missing, the imputed CM start date is set to the mid-month 
point (15MONYYYY). 
 
3. If the CM start date year value is greater than the treatment start date year value, the CM 
started after treatment. Therefore: 
a. If the CM month is missing, the imputed CM start date is set to the year start point 
(01JanYYYY). 
b. Else if the CM month is not missing, the imputed CM start date is set to the month 
start point (01MONYYYY). 
4. If the CM start date year value is equal to the treatment start date year value: 
a. And the CM month is missing or the CM month is equal to the treatment start date 
month, then the imputed CM start date is set to one day prior to treatment start date. 
b. Else if the CM month is less than the treatment start date month, the imputed CM start 


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date is set to the mid-month point (15MONYYYY). 
c. Else if the CM month is greater than the treatment start date month, the imputed CM 
start date is set to the month start point (01MONYYYY). 
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM end 
date. 
5.1.4 
Medical history date of Primary diagnosis imputation 
Completely missing dates and partially missing end dates will not be imputed. Partial dates of 
diagnosis will be compared to the treatment start date. 
• If DIAG year < treatment start date year and DIAG month is missing, the imputed DIAG date 
is set to the mid-year point (01JULYYYY) 
• else if DIAG month is not missing, the imputed DIAG date is set to the mid-month point 
(15MONYYYY) 
• If DIAG year = treatment start date year 
• and (DIAG month is missing OR DIAG month is equal to treatment start month), the imputed 
DIAG date is set to one day before treatment start date 
• else if DIAG month < treatment start month, the imputed DIAG date is set to the midmonth 
point (15MON YYYY) 
• else if DIAG month > treatment start month => data error 
• If DIAG year > treatment start date year => data error 
5.1.5 
Concomitant therapies and procedures date imputation 
The missing dates will be imputed using the same rule as for the concomitant medication. 
5.2 
AEs coding/grading 
AEs are coded using the MedDRA terminology. The latest version of MedDRA will be used 
and will be specified on the footnote of relevant output. 
AEs severity are assessed by investigators and captured on the AE CRF based on three levels: 
mild, moderate, and severe. 
5.3 
Laboratory parameters derivations 
No laboratory parameters need to be derived. All laboratory parameters will be analyzed 
directly based on the assessments provided by central lab. For observations below the limit of 
quantification (BLQ), a value of one half of the lower limit of quantification (LLOQ) will be 
used for summary. 
The clinically notable laboratory values to be used for the two studies are listed below.  
Table 5-1  
Clinically notable laboratory values 
Test 
Conventional 
Units 
Critical 
Low 
Critical 
High 
Standard 
Units 
Critical 
Low 
Critical 
High 
Non-
numeric 
Calcium 
mg/dL 
< 6.0 
> 13.0 
mmol/L 
< 1.50 
> 3.25 
 
Creatinine 
mg/dL 
NA 
>5.0  
umol/L 
NA 
>442  
 


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Test 
Conventional 
Units 
Critical 
Low 
Critical 
High 
Standard 
Units 
Critical 
Low 
Critical 
High 
Non-
numeric 
Glucose 
mg/dL 
< 40 
> 500 
mmol/L 
< 2.22 
> 27.75 
 
Magnesium 
mg/dL 
< 0.7  
> 6.1 
mmol/L 
< 0.30  
> 2.50  
 
Magnesium 
mEq/L 
< 0.6  
> 5.0 
mmol/L 
< 0.30  
> 2.50  
 
Phosphate 
(Phosphorus) 
mg/dL 
< 1.0 
N/A 
mmol/L 
< 0.32  
N/A 
 
Potassium 
mEq/L 
< 2.8 
> 6.5 
mmol/L 
< 2.8 
> 6.5 
 
Sodium 
mEq/L 
< 120 
> 160 
mmol/L 
< 120 
> 160 
 
HCG 
 
 
 
 
 
 
Positive 
Hematocrit 
% 
< 20 
> 60 
V/V 
< 0.20 
> 0.60 
 
Hemoglobin 
g/dL 
< 6.0 
> 20.0 
g/L 
< 60 
> 200 
 
Platelet 
X10E3/uL 
< 50 
> 999 
X10E9/L 
< 50 
> 999 
 
WBC 
X10E3/uL 
< 2.00 
NA 
X10E9/L 
< 2.00 
NA 
 
5.4 
Clinically notable vital signs  
Clinically notable vital sign values to be used for the two studies are listed below. 
Table 5-2 
Clinically notable vital signs 
Variable 
Category 
Critical values 
Systolic blood 
pressure (mmHg) 
High 
Either >180 with an increase from baseline >30 or >200 
absolute 
Low 
Either <90 with a decrease from baseline >30 or 
<75 absolute 
Diastolic blood 
pressure (mmHg) 
High 
Either >105 with an increase from baseline >20 or >115 
absolute 
Low 
Either <50 with a decrease from baseline > 20 or 
<40 absolute 
Pulse rate (bpm) 
High 
Either >120 with an increase from baseline of >25 or > 130 
absolute 
Low 
Either <50 with a decrease from baseline >30 or 
<40 absolute 
 
5.5 
Statistical models 
5.5.1 
Primary analysis 
The primary endpoint (change from baseline in BCVA at Week 24) will be analyzed using 
ANOVA model on data with LOCF as the primary method. The MMRM on observed data will 
be used as the sensitivity analysis.  
 
Analysis of Variance (ANOVA) 
The following ANOVA model will be used for the primary endpoint.  
change from Baseline in BCVA at Week 24= intercept + treatment + Baseline BCVA category 
+ age category + error. 


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The SAS procedure MIXED will be used to perform the ANOVA. The LSmean and two-sided 
95% CI for Change from baseline in BCVA within each treatment arms will be estimated using 
the LSMEAN statement; the LSmean, two-sided 95% CI, and the two-sided p-value on the 
between group difference will be obtained by adding the DIFF option under the LSMEAN 
statement. The one-sided p-value for non-inferiority is calculated as the probability on 
observing the between group difference when the between group difference is less than -4 and 
can be calculated under the assumption of T-distribution: 
PNI=(1-probt((between group difference+4)/stderr,df)) 
For the above analysis, the data structure is one record per subject.  
 
Mixed Model Repeated Measures (MMRM) 
The following MMRM model will be used for the supportive analysis of the primary 
endpoint: 
change from Baseline in BCVA= intercept + treatment + Baseline BCVA category + age 
category + visit + treatment*visit + error. 
 
The SAS procedure MIXED will be used to perform the MMRM. For the MMRM analysis, the 
data structure is one record per FAS subject per scheduled visit. The data will include all 
subjects and have records for all scheduled visits, regardless of whether the assessment was 
missed or not at a given visit. Missing values will NOT be imputed using LOCF. Instead, the 
value will be passed to the model as missing. 
5.5.2 
Other analysis 
5.5.2.1 
Logistic regression for proportion variables 
The binary efficacy variables will be analyzed using the logistic regression model adjusted for 
treatment, age category, corresponding baseline variables, and other corresponding covariates 
if necessary.  
Logistic regression is a model for prediction of the probability of occurrence of an event. It can 
be used to analyze the dichotomous response data while adjusting for one or more covariates. 
Usually, Logistic regression analyzes binomially distributed data of form  
Yi ~ B (ni, pi), for i=1,…,n. 
The logits of the unknown binomial probabilities (i.e., the logarithms of the odds) are modeled 
as a linear function of the Xi. log ቀ
𝑝𝑝𝑖𝑖
1−𝑝𝑝𝑖𝑖ቁ= 𝛽𝛽0 + 𝛽𝛽1𝑥𝑥1,𝑖𝑖+ ⋯+ 𝛽𝛽𝑘𝑘𝑥𝑥𝑘𝑘,𝑖𝑖 
The LOGISTIC procedure in SAS will be used. The data structure is one record per subject. 
The estimated difference in proportions, the corresponding 95% CIs, and p-value will be 
obtained based on the marginal standardization method. This method uses the same fitted 
logistic model, but involves using the model to predict, for each subject in the study, the mean 
outcome assuming assignment to each particular treatment group in turn, assuming each 
subject’s observed values for the baseline CSFT categories and age categories.  Averaging these 
predictions for each treatment group provides the estimate of the mean response rate for each 
treatment group. Then the difference will be derived based on the estimated mean response rates 
comparing brolucizumab arm vs. aflibercept arm. 


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The method will be implemented using SAS macro %margins. 
5.5.2.2 
Survival analysis for time to event variables 
Log-rank test will be used to compare the survival distributions of two treatment groups for 
variable of time to recurrence.  
The log-rank test statistic compares estimates of the hazard functions of the two groups at each 
observed event time. It is constructed by computing the observed and expected number of 
events in one of the groups at each observed event time and then adding these to obtain an 
overall summary across all time points where there is an event. The lifetest procedure in SAS 
will be used. The data structure is one record per subject.  
Cox proportional hazards model is to estimate the effect parameter(s) without any consideration 
of the hazard function assuming the proportional hazards assumption holds. The proportional 
hazards assumption is the assumption that effect parameters multiply hazard at any time. The 
effect parameter(s) estimated by any proportional hazards model can be reported as hazard 
ratios. The phreg procedure in SAS will be used. 
Estimation of 95% confidence intervals 
Approximate 95% CIs will be generated at selected time-points, the (Kaplan and Meier 1958) 
estimates of the proportion of subjects experiencing a specific event. Details of such confidence 
intervals are displayed in Table 5-3. 
Table 5-3 
Confidence Interval calculations 
Approximate Confidence Interval (CI) 
Lower Limit 
Upper Limit 
x% CI for the Kaplan-Meier estimate KM 
KM - cx*SE 
KM + cx*SE 
Notation: SE  =  estimated standard error of KM; 
                            estimation of standard error uses Greenwood’s formula, 
                 cx    = Φ-1(½ + x/200), where Φ is the normal distribution function. 
Examples: for x = 95, cx = Φ-1(0.975) = 1.95996; for x = 97.5, cx = Φ-1(0.9875) = 2.24140 
5.6 
Rule of exclusion criteria of analysis sets  
Subject exclusion and data censoring from the analysis sets is based on protocol deviation and 
non-protocol deviation criteria including analysis restrictions.  
The important PDs that will lead to exclusion of a subject from a corresponding analysis set is 
provided in the following table 
Table 5-4 
Important protocol deviations leading to exclusion from analysis sets 
Deviation 
ID 
Description of Deviation 
Exclusion in Analysis sets 
INCL01 
Written informed consent not obtained 
Excluded from all analysis sets  
INCL03 
Patients without visual impairment due to macular 
edema secondary to RVO diagnosed <6 months prior 
to screening (study eye) 
Excluded from PPS  


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Deviation 
ID 
Description of Deviation 
Exclusion in Analysis sets 
INCL04 
Study Eye: BCVA score outside limits defined in 
protocol, at screening and baseline 
Excluded from PPS  
EXCL01 
Study eye: confounding ocular concomitant 
conditions or ocular disorders with impact on 
efficacy and/or safety 
Excluded from PPS  
EXCL03 
Study Eye: Confounding concomitant medications or 
procedures 
Excluded from PPS  
EXCL04 
Systemic: Confounding systemic conditions or 
systemic treatments with impact on efficacy and/or 
safety 
Excluded from PPS 
The following table is the summary on the subject classification for each analysis set based on 
the presence of PDs and non-PD criteria. 
Table 5-5 
Subject Classification 
Analysis Set 
PD ID that causes 
subjects to be excluded 
Non-PD criteria that cause  
subjects to be excluded 
RAS 
INCL01 
Not randomized, misrandomized 
FAS 
INCL01 
Not in RAS 
Subjects without any study treatment 
PPS 
As listed in Table 5-4  
Not in FAS;   
Under treatment (missing >1 injections) up to 
Week 20 (no injection due to adverse event or 
discontinuation from study due to lack of 
efficacy/safety is not considered as missed dose)   
No valid BCVA assessment (after all data 
censoring rules are applied) at Week 16, 20, or 
24 
SAF 
INCL01 
Subjects without any study treatment 
5.7 
Definition for discontinuation from treatment due to lack of 
efficacy or safety 
Discontinuation from study treatment due to lack of efficacy/safety will be identified if the 
primary reason for discontinuation is “Progressive disease” or “Adverse event”. As 
discontinuation due to lack of efficacy is handled the same as lack of safety, no additional rule 
will be used to separate lack of efficacy versus lack of safety.  


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5.8 
Subgroup analysis to evaluate the impact of COVID-19 pandemic 
Based on the internal guidance, sensitivity analysis related to the impact of subjects to COVID-
19 will be conducted.  
Impacted subjects to COVID-19 up to Week X (X can be 24 or 76) are defined as subjects who: 
• were exposed to COVID-19 as per the definition below, 
• and missed at least one study treatment or visit up to and including Week X due to 
COVID-19. 
Non-impacted subjects to COVID-19 up to Week X are defined as subjects who: 
• were not exposed to COVID-19 as per the below definition,  
• or were exposed to COVID-19 but did not miss any study treatment or visit up to and 
including Week X due to COVID-19. 
The exposure to COVID-19 are based on start and end dates by geographical areas: 
Region/Country 
Start Date 
End Date 
China 
01-Jan-2020 
End date has not yet been defined 
South Korea 
20-Feb-2020 
End date has not yet been defined 
Japan 
21-Feb-2020 
End date has not yet been defined 
Italy 
23-Feb-2020 
End date has not yet been defined 
Rest of the World 
01-Mar-2020 
End date has not yet been defined 
Non-exposed subjects to COVID-19 up to Week X (X can be 24 or 76) are defined as subjects 
who: 
• completed Week X visit prior to the pandemic start date, 
• or withdrew study prior to the pandemic start date, 
Exposed subjects to COVID-19 up to Week X are defined as subjects who: 
• did not complete Week X visit prior to the pandemic start date (while remaining in the 
study at the time of the pandemic start date), 
• or withdrew the study on or after the pandemic start date, 
6 
Reference 
Brown DM, Heier JS, et al (2013) Intravitreal Aflibercept Injection for Macular Edema 
Secondary to Central Retinal Vein Occlusion: 1-Year Results From the Phase 3 
COPERNICUS Study. Am J Ophthalmol 2013;155:429–437. 
Clark WL, Boyer DS, et al (2013) Intravitreal Aflibercept for Macular Edema Following 
Branch Retinal Vein Occlusion: 52-week Results of the VIBRANT Study. Ophthalmology 
2016;123:330-336. 


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Korobelnik JF, Holz FG, et al (2014) Intravitreal Aflibercept Injection for Macular Edema 
Resulting from Central Retinal Vein Occlusion: One-Year Results of the Phase 3 GALILEO 
Study. Ophthalmology 2014;121:202-208