Conditions: Diabetic Macular Edema
Keywords: Diabetic Macular Edema intravitreal injection brolucizumab aflibercept double-masked Diabetic Macular edema (DME) macular edema diabetic retinopathy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 517
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the efficacy and safety of brolucizumab vs. aflibercept in the treatment of patients with visual impairment due to diabetic macular edema (DME).

Detailed description:
This study was designed as a Phase III, multi-center, randomized, double-masked, active controlled, parallel group prospective study to evaluate if brolucizumab 6 mg dosed q4w is safe and effective in the treatment of subjects with visual impairment due to diabetic macular edema (DME). Subjects who met all the inclusion and none of the exclusion criteria were randomized in a 2:1 ratio to one of two treatment arms i.e., brolucizumab 6 mg and aflibercept 2 mg. Only one eye was selected as study eye and treated with study medication.

The study included a screening period of up to 2 weeks to assess eligibility, followed by a double-masked treatment period (Day 1 to Week 48). For all subjects, the last study assessment was performed at the Week 52/end of study (EOS) visit. All subjects had study visits q4w through Week 52. The primary analysis was performed at the EOS visit (Week 52).

To ensure masking was maintained, the investigational site had both masked and unmasked staff to perform the masked and unmasked study assessments/procedures accordingly.

Arms:
arm 1: Brolucizumab 6 mg/0.05 mL every 4 weeks. arm 2: Aflibercept 2mg/0.05 mL every 4 weeks

Interventions: intervention 1: Brolucizumab intervention 2: Aflibercept
Intervention descriptions: intervention 1: Intravitreal injection intervention 2: Intravitreal injection

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.................................................................................................................9
Amendment 1 (08-June-2020)...........................................................................................11
Protocol summary..............................................................................................................13
1
Introduction .......................................................................................................................17
1.1
Background............................................................................................................17
1.2
Purpose ..................................................................................................................19
2
Objectives and endpoints...................................................................................................19
3
Study design ......................................................................................................................20
4
Rationale............................................................................................................................21
4.1
Rationale for study design .....................................................................................21
4.2
Rationale for dose/regimen and duration of treatment ..........................................21
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................22
4.4
Purpose and timing of interim analyses/design adaptations..................................22
4.5
Risks and benefits..................................................................................................22
5
Population..........................................................................................................................23
5.1
Inclusion criteria ....................................................................................................23
5.2
Exclusion criteria...................................................................................................23
6
Treatment...........................................................................................................................26
6.1
Study treatment......................................................................................................26
6.1.1
Investigational and control drugs..........................................................26
6.1.2
Treatment arms/group ...........................................................................26
6.1.3
Treatment duration................................................................................26
6.2
Other treatment(s)..................................................................................................27
6.2.1
Concomitant therapy.............................................................................27
6.2.2
Prohibited medication ...........................................................................27
6.3
Subject numbering, treatment assignment, randomization....................................28
6.3.1
Subject numbering ................................................................................28
6.3.2
Treatment assignment, randomization ..................................................28
6.4
Treatment masking ................................................................................................29
6.5
Dose escalation and dose modification..................................................................30
6.6
Additional treatment guidance...............................................................................30


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6.6.1
Treatment compliance...........................................................................30
6.6.2
Emergency breaking of assigned treatment code..................................30
6.7
Preparation and dispensation.................................................................................31
6.7.1
Handling of study treatment..................................................................31
6.7.2
Instruction for prescribing and taking study treatment .........................31
7
Informed consent procedures ............................................................................................32
8
Visit schedule and assessments .........................................................................................33
8.1
Screening ...............................................................................................................38
8.1.1
Information to be collected on screening failures.................................38
8.2
Subject demographics/other baseline characteristics.............................................38
8.3
Efficacy..................................................................................................................39
8.3.1
Visual Acuity ........................................................................................39
8.3.2
Optical coherence tomography .............................................................39
8.3.3
Color fundus photography and fluorescein angiography......................40
8.3.4
Appropriateness of efficacy assessments..............................................40
8.4
Safety.....................................................................................................................41
8.4.1
Laboratory evaluations..........................................................................41
8.4.2
Pregnancy..............................................................................................42
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
Anti-drug antibodies (immunogenicity)................................................44
9
Study discontinuation and completion ..............................................................................44
9.1
Discontinuation......................................................................................................44
9.1.1
Discontinuation of study treatment .......................................................44
9.1.2
Withdrawal of informed consent...........................................................45
9.1.3
Lost to follow-up...................................................................................46
9.1.4
Early study termination by the sponsor.................................................46
9.2
Study completion and post-study treatment ..........................................................46
10 Safety monitoring and reporting........................................................................................47
10.1
Definition of adverse events and reporting requirements......................................47
10.1.1
Adverse events ......................................................................................47
10.1.2
Serious adverse events ..........................................................................48
10.1.3
SAE reporting........................................................................................49
10.1.4
Pregnancy reporting ..............................................................................50
10.1.5
Reporting of study treatment errors ......................................................50


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10.2
Additional Safety Monitoring................................................................................50
10.2.1
Data Monitoring Committee .................................................................50
11 Data Collection and Database management......................................................................51
11.1
Data collection.......................................................................................................51
11.2
Database management and quality control............................................................51
11.3
Site monitoring ......................................................................................................52
12 Data analysis and statistical methods ................................................................................53
12.1
Analysis sets ..........................................................................................................53
12.2
Subject demographics and other baseline characteristics......................................53
12.3
Treatments .............................................................................................................54
12.4
Analysis of the primary endpoint(s) ......................................................................54
12.4.1
Definition of primary endpoint(s).........................................................54
12.4.2
Statistical model, hypothesis, and method of analysis..........................54
12.4.3
Handling of missing values/censoring/discontinuations.......................56
12.4.4
Sensitivity and Supportive analyses......................................................56
12.5
Analysis of secondary endpoints ...........................................................................57
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................57
12.5.2
Safety endpoints....................................................................................58
12.5.3
Anti-drug antibody................................................................................59
59
12.7
Interim analyses.....................................................................................................60
12.8
Sample size calculation..........................................................................................60
12.8.1
Primary endpoint(s)...............................................................................60
13 Ethical considerations and administrative procedures ......................................................60
13.1
Regulatory and ethical compliance........................................................................60
13.2
Responsibilities of the investigator and IRB/IEC..................................................61
13.3
Publication of study protocol and results...............................................................61
13.4
Quality Control and Quality Assurance.................................................................61
14 Protocol adherence ............................................................................................................61
14.1
Protocol amendments.............................................................................................62
15 References .........................................................................................................................63
16 Appendices ........................................................................................................................65


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List of tables
Table 2-1
Objectives and related endpoints ..........................................................19
Table 6-1
Investigational and control drug............................................................26
Table 6-2
Prohibited medications/procedures.......................................................27
Table 8-1
Assessment Schedule ............................................................................35
Table 8-2
Vital signs assessment...........................................................................41
Table 8-3
Laboratory Assessments........................................................................41
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................50
Table 12-1
Primary and supplementary estimands..................................................55
List of figures
Figure 3-1
Study design..........................................................................................21
Figure 6-1
Dosing schedule ....................................................................................32


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List of abbreviations
ADA
anti-drug antibody
AE
adverse event
ANOVA
analysis of variance
AR
Analysis Restriction
BCVA
Best-corrected visual acuity
CFR
Code of Federal Regulation
CI
confidence interval
CMO
Chief Medical Office
CNV
Choroidal neovascularization
CO
country organization
COVID-19
Coronavirus disease 2019
COA
Clinical Outcome Assessment
CP
Color fundus photography
CRA
Clinical Research Associate
CRC
Central Reading Center
CRO
Contract Research Organization
CSFT
Central subfield thickness 
DM
Diabetes mellitus
DMC
Data Monitoring Committee
DME
Diabetic macular edema
DR
Diabetic retinopathy
DRSS
Diabetic retinopathy severity scale
EC
Ethics committee
eCRF
Electronic Case Report/Record Form
EDC
Electronic Data Capture
EMA
European Medicines Agency
EOS
End of Study
ESI
adverse event of special interest
ETDRS
Early Treatment Diabetic Retinopathy Study
EU
European Union
EudraCT
European Clinical Trials Database
FA
fluorescein angiography
FAS
Full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GCS
Global Clinical Supply
HbA1c
Hemoglobin A1c
hCG
human chorionic gonadotropin
IB
Investigator's Brochure
ICF
informed consent form


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ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IN
Investigator notification
IOI
Intraocular inflammation
IOP
Intraocular pressure
IP
Investigational Product
IRB
Institutional Review Board
IRF
Intraretinal fluid
IRT
Interactive Response Technology
IUD
Intrauterine device
IUS
intrauterine system
IVT
Intravitreal
kDA
kiloDaltons
LOCF
Last observation carried forward
MedDRA
Medical dictionary for regulatory activities
nAb
Neutralizing antibody
nAMD
Neovascular age-related macular degeneration
NIH
National Institutes of Health
NIM
Non-inferiority margin
OCT
Optical coherence tomography
PD
Protocol Deviation
PDR
Proliferative diabetic retinopathy
PFS
Pre-filled syringe
PK
pharmacokinetic(s)
PPS
Per Protocol Set/Protocol analysis set
PS
Patient Safety
q12w
every 12 weeks
q4w
every 4 weeks
q8w
every 8 weeks
QMS
Quality Management System
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
standard deviation
SD-OCT
Spectral domain optical coherence tomography
SMQ
Standardized MedDRA Query


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SOC
System Organ Class
SRF
Subretinal fluid
SUN
Standardization uveitis nomenclature
SUSAR
Suspected Unexpected Serious Adverse Reactions
TFQ
Trial Feedback Questionnaire
US
United States
VA
Visual acuity
VEGF
Vascular endothelial growth factor
WHO
World Health Organization
YAG
yttrium aluminum garnet


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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 blinding of investigational drug, assess internal 
study validity, and/or evaluate comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day)
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
Investigational 
drug/treatment
The drug whose properties are being tested in the study
Masked/evaluating 
investigator
For the entire study duration and all study patients, the masked/evaluating 
investigator is responsible for all aspects of the study (the 
conduct/supervision of all assessments and treatment decisions except the 
injection procedures and the safety assessment following the injection)
Medication pack
number
A unique identifier on the label of each drug package in studies that 
dispense study treatment using an IRT system
Patient ID
A unique number assigned to each patient upon signing the informed 
consent
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and 
will be used in clinical trial database setup and eventually in analysis
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
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 treatment
Any single drug or combination of drugs or intervention administered to the 
subject as part of the required study procedures


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Study treatment 
discontinuation
When the subject permanently stops taking any of the study drug(s) 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.
Unmasked/treating 
investigator
For the entire study duration and all study patients, the treating investigator 
only performs the treatment (injection active) and assesses patient safety 
following the injections
Variable
Information used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints
Visual acuity 
assessor
For the entire study duration and all study patients, the visual acuity 
assessor (which could be a masked/evaluating investigator) performs the 
BCVA assessment and is masked to the assigned treatment
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 data


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Amendment 1 (08-June-2020)
Amendment rationale
The main purpose of this amendment is to provide clarification and guidance on safety 
assessments in accordance to the urgent safety measure regarding the post-marketing reports 
with brolucizumab (Beovu®) in the treatment of nAMD, which were identified as retinal 
vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular 
inflammation, that may result in severe vision loss. In addition, the amendment includes the 
modifications due to COVID-19 pandemic.
Changes to the protocol
Protocol sections changed in relation to this emerging safety issue are:

Section 1.1 Background: Information was added to describe new safety signal from 
post-marketing case reports.

Section 6.7.2 Instructions for prescribing and taking study treatment: Additional guidance 
was added to this section emphasizing that if any sign of intraocular inflammation is present, 
an IVT injection must not be performed and patients should be treated for IOI according to 
clinical practice.

Additional examination and assessments included to fully characterize cases of intraocular 
inflammation were made in the following sections:

Table 8-1 Assessment schedule

Section 8.3.3 Color fundus photography and fluorescein angiography

Section 8.4.3 Ophthalmic Examination

Section 8.4.4 Appropriateness of safety measurements
Changes were incorporated to address the COVID-19 pandemic in the following sections:

Section 6.2.2 Prohibited medication

Section 7 Informed consent procedures

Section 8 Visit Schedule and Assessments

Section 8.4 Safety

Section 8.4.1 Laboratory evaluations

Section 12 Data Analysis and statistical methods
Other changes incorporated in this amendment:

Section 6.1.1 Investigational and control drugs.

Section 6.4
Treatment masking: Language was added to clarify unmasked 
investigator/site personnel must not be switched to a masked role at any time after 
randomization.

Section 8 Visit schedule and assessments: addition of visit windows except for Baseline 
visit.

Section 8.4.3 Ophthalmic examination: clarification on the use of same method for IOP 
measurement and timing for post-injection IOP measurement. 


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
Section 8.5.2 Anti-drug antibodies (immunogenicity).

Section 10.1.3 SAE reporting: clarification of the SAE reporting period.

Section 10.2.1 Data Monitoring Committee: Language was added to introduce program 
level DMC.

Section 12 Analysis sets and statistical methods: Language was adapted to clarify 
primary and supplementary estimands and analyses based on estimands.

Section 15 References

List of Abbreviations
Other minor clarifications were made where applicable. Changes to specific sections of the 
protocol are shown in the track changes version of the protocol using strike through red font for 
deletions and red underlined for insertions.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Protocol summary
Protocol 
number
CRTH258B2305
Full Title
A 12-Month, 2-Arm, Randomized, Double-Masked, Multicenter Phase III Study 
Assessing the Efficacy and Safety of Brolucizumab every 4 weeks versus 
Aflibercept every 4 weeks in Adult Patients with Visual Impairment due to 
Diabetic Macular Edema (KINGFISHER)
Brief title
Efficacy and Safety of Brolucizumab every 4 weeks versus Aflibercept every 4 
weeks in Adult Patients with Visual Impairment Due to Diabetic Macular Edema 
(DME)
Sponsor and 
Clinical Phase
Novartis
Phase III
Investigation 
type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to evaluate the efficacy and safety of brolucizumab 
dosed every 4 weeks versus aflibercept dosed every 4 weeks (q4w) in the 
treatment of patients with visual impairment due to DME.
Primary 
Objective 
To demonstrate that brolucizumab is non-inferior to aflibercept with respect to 
the change in visual acuity from baseline compared to Week 52.
Secondary 
Objectives

To assess the effect of brolucizumab compared with aflibercept with respect 
to anatomical outcomes

To assess the effect of brolucizumab compared with aflibercept with respect 
to visual acuity (VA)

To assess the effect of brolucizumab relative to aflibercept on the status of 
Diabetic Retinopathy (DR)

To assess the safety and tolerability of brolucizumab compared with 
aflibercept

To assess the immunogenicity of brolucizumab
Study design
This study is a multi-center, randomized, double masked, parallel group study in 
subjects with visual impairment due to DME. Subjects who meet all the inclusion 
and none of the exclusion criteria will be randomized in a 2:1 ratio to one of two 
treatment arms

Brolucizumab 6 mg: treatment every 4 weeks up to and including Visit 13 
(Week 48)

Aflibercept 2 mg: treatment every 4 weeks up to and including Visit 13 
(Week 48)
Population
Approximately 619 adult patients will be screened (20% screening failure rate 
expected) so that approximately 495 patients will be randomized in a 2:1 ratio 
(330 in brolucizumab arm, 165 in aflibercept arm, 9% dropout rate expected) in 
approximately 115 centers worldwide. The study duration is 52 weeks, including 
follow-up. The study includes both naive patients and those who previously 
received anti-vascular endothelial growth factor (VEGF) therapies.


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Key Inclusion 
criteria

Signed informed consent must be obtained prior to participation in the study.

Patients ≥ 18 years of age at baseline.

Patients with type 1 or type 2 diabetes mellitus (DM) and Hemoglobin A1c 
(HbA1c) ≤ 12% at screening.

Study eye
Visual impairment due to DME with:

Best-corrected visual acuity (BCVA) score between 73 and 23 letters, 
inclusive, using Early Treatment Diabetic Retinopathy Study (ETDRS) visual 
acuity testing charts at an initial testing distance of 4 meters (approximate 
Snellen equivalent of 20/40 to 20/320) at both screening and baseline.

DME involving the center of the macula, with Central Subfield Thickness 
(CSFT) ≥320 µm on Spectral Domain Optical Coherence Tomography 
(SD-OCT) at screening.
Key Exclusion 
criteria
Ocular conditions

High-risk proliferative diabetic retinopathy (PDR) in the study eye as per 
investigator assessment at both screening and baseline

Concomitant conditions or ocular disorders in the study eye at screening or 
baseline which may, in the opinion of the investigator, confound 
interpretation of study results, compromise visual acuity or require medical 
or surgical intervention during the 12-month study period (eg, structural 
damage of the fovea, vitreous hemorrhage, retinal detachment, 
vitreomacular traction, macular hole, retinal vein/arterial occlusion, 
neovascularization of iris or choroidal neovascularization (CNV) of any 
cause).

Any active intraocular or periocular infection or active intraocular 
inflammation in the either eye at screening or baseline.

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

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, eg, cataract)
Ocular treatments

Use of anti-VEGF therapies, intraocular surgery or laser photocoagulation 
(macular or panretinal) in the study eye during the 3-month period prior to 
baseline

Use of intraocular corticosteroids including dexamethasone intravitreal 
implant (Ozurdex) in the study eye during the 6-month period prior to 
baseline, and use of fluocinolone acetonide intravitreal (IVT) implant (Iluvien) 
at any time prior to baseline

Prior investigational drugs in either eye, vitreoretinal surgery in the study eye 
at any time prior to baseline
Study 
treatment
Brolucizumab 6 mg/0.05 mL
Aflibercept 2 mg/0.05 mL
Efficacy 
assessments

Best-corrected visual acuity using ETDRS-like charts

Spectral-Domain Optical Coherence Tomography (SD-OCT)

7-field stereo Color Fundus Photography (CP)




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Key words
Diabetic Macular Edema, intravitreal injection, brolucizumab, aflibercept, double-
masked


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1
Introduction
1.1
Background
Diabetes mellitus (DM) is the most common endocrine disease in developed countries, with 
prevalence estimates ranging between 2% to 5% of the world population. Diabetic retinopathy 
(DR) and diabetic macular edema (DME) are common microvascular complications in patients 
with diabetes and may have a debilitating impact on visual acuity (VA), eventually leading to 
blindness. DME is a frequent manifestation of DR (Lee et al 2015) and is the major cause of 
vision loss in patients with DR.
Available therapies
The current treatment options for patients with DME are intravitreal (IVT) treatment of anti-
vascular endothelial growth factor (VEGF), corticosteroids, corticosteroid implants, or laser 
photocoagulation. The favorable efficacy and safety profile of anti-VEGF therapies has placed 
these as first-line treatment. Corticosteroids are typically used as a second-line treatment and 
focal/grid laser photocoagulation remains a therapeutic option, but with a lower expected 
benefit compared with steroid and anti-VEGF therapies.
For anti-VEGF agents like ranibizumab or aflibercept, a favorable benefit-risk ratio was 
demonstrated versus the previous standard of care (laser photocoagulation) in large Phase III 
programs 
that 
consequently 
led 
to 
their 
approval 
for 
the 
treatment 
of 
DME (Ziemssen et al 2017; Korobelnik et al 2014). Anti-VEGF treatment led to clinically 
relevant improvements of best-corrected visual acuity (BCVA), resolution of macular edema 
and decreased severity of diabetic retinopathy. However, despite the treatment success of 
existing anti-VEGFs, there remains a need for further treatment options to improve response 
rate and/or reduce use and injection frequency in patients with DME (Virgili et al 2014; 
Agarwal et al 2015; Sivaprasad and Oyetunde 2016). 
Brolucizumab
Brolucizumab, formerly known as RTH258, is a humanized single-chain fragment variable 
(scFv), binding to VEGF-A (ie, interfering with activation of VEGF-R1 and R2 on endothelial 
cells) with a molecular weight of ~26 Kilodaltons (kDa) that is being developed for the 
treatment of neovascular age-related macular degeneration (nAMD), DME, and macular edema 
associated with retinal vein occlusion (RVO).
Development of brolucizumab initially focused on the nAMD indication. In two Phase III 
studies in patients with nAMD, brolucizumab ((3 mg and/or 6 mg) every 8 weeks (q8w)/every 
12 weeks (q12w) after three monthly loading doses) was non-inferior to aflibercept [(2 mg) 
q8w after three monthly loading doses] for the change from baseline in BCVA at Week 48. 
Furthermore, brolucizumab was shown to be long acting, with over 50% of patients maintained 
on a q12w regimen at 48 Weeks. Brolucizumab has been shown to be efficacious and safe for 
use as chronic therapy, and addresses the unmet medical need of enhanced durability and 
reduced treatment and monitoring burden compared with available therapy.
Since the first marketing authorization approval in October 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 


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post-marketing experience with brolucizumab (Beovu®). Considering these events, the overall 
risk/benefit assessment remains positive.
Brolucizumab for diabetic macular edema
Two pivotal, two-year, randomized, double masked, multi-center Phase III studies of 
brolucizumab are ongoing in patients with DME: CRTH258B2301 (KESTREL) and 
CRTH258B2302 (KITE). Based on the positive nAMD results for the q12w/q8w regimen, 
KESTREL and KITE are designed to evaluate the potential of reducing the treatment and 
monitoring burden for patients and caregivers with a q6w loading regimen for brolucizumab 
followed by q12w/q8w maintenance phase compared to aflibercept administered as per current 
label (q4w loading followed by q8w maintenance). 
Although it is important for physicians and patients to optimize and individualize the treatment 
strategy while reducing treatment burden, previous studies with anti-VEGF therapies suggest 
that some patients may need continuous dosing as frequently as every 4 weeks to improve and 
maintain functional and anatomical outcomes.

The two-year results for protocol T comparing multiple anti-VEGF therapies for the 
treatment of DME indicated that some patients required over 11 injections in the first year 
of treatment (Wells et al 2016).

Post-hoc analyses from large anti-VEGF studies in DME identified a subset of patients 
with limited response to initial q4w (monthly) injections who benefitted from continued 
q4w therapy (ie, delayed responders). These patients may need up to one year of intensive 
treatment to obtain comparable outcomes to early responders (Bressler et al 2016; 
Pieramici et al 2016; Pieramici et al 2018).

In the 148-Week results from the VISTA and VIVID studies, although the aflibercept q8w 
regimen provided, on average, comparable visual and anatomical improvements as the 
q4w regimen, the observed fluctuations of central subfield thickness (CSFT) in the q8w 
arm suggest a suboptimal anatomical outcome.
The reasons for individual variability of clinical response and treatment need in DME patients 
observed in clinical trials have been investigated in a number of studies. Although controversial, 
these studies suggest that baseline characteristics such as visual acuity, CSFT, glycated 
hemoglobin (HbA1c), and severity of diabetic retinopathy may affect functional and anatomical 
improvements 
after 
anti-VEGF 
treatment 
(Bansal et al 2015; 
Staurenghi et al 2018; 
Bressler et al 2019). The open-label extension study of the RISE and RIDE trials reported that 
individual treatment need, as measured by injection, frequency, ranges from 0 to 13 in one year 
(Wykoff et al 2016). The authors suggest that duration of diabetes and DME, central foveal 
thickness, area of fluorescein leakage, HbA1c and severity of diabetic retinopathy may be 
related to injection frequency. Recent data from real world evidence studies suggests that DME 
patients tend to receive fewer injections and achieve poorer outcomes in terms of visual acuity 
compared to those patients in the large clinical studies (Ciulla et al 2018).
In conclusion, the available evidence suggests that there is a subset of DME patients who may 
benefit from more frequent anti-VEGF injections to achieve rapid response with optimal 
functional and anatomical outcomes.


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1.2
Purpose
The purpose of this study is to evaluate the efficacy and safety of brolucizumab dosed every 4 
weeks versus aflibercept dosed every 4 weeks in the treatment of patients with visual 
impairment due to DME.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To demonstrate that 
brolucizumab is non-inferior to 
aflibercept with respect to the 
change in visual acuity from 
baseline up to Week 52

Change from baseline in BCVA at Week 52
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To assess the effect of 
brolucizumab compared with 
aflibercept with respect to 
anatomical outcomes

Change from baseline in CSFT at each post-baseline 
visit

Proportion of study eyes with fluid-free macula at 
each post-baseline visit

Proportion of study eyes with absence of 
DME (CSFT < 280 μm) at each post-baseline visit

Time to first fluid-free macula

Time to first absence of DME (CSFT < 280 μm)

To assess the effect of 
brolucizumab compared with 
aflibercept with respect to visual 
acuity

Change from baseline in BCVA at each post-
baseline visit

Proportion of study eyes with gain in BCVA of 
5/10/15 letters or more at each post-baseline visit 
compared to baseline

To assess the effect of
brolucizumab relative to aflibercept 
on the status of Diabetic 
Retinopathy

Change from baseline in ETDRS Diabetic 
Retinopathy Severity Scale (DRSS) score at Week 
12, Week 24 and Week 52

To assess the safety and tolerability 
of brolucizumab compared with 
aflibercept

Incidence of ocular and non-ocular Adverse Events 
(AEs)

To assess the immunogenicity of 
brolucizumab

Anti-drug antibody (ADA) measurement


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3
Study design
This is a multi-center, randomized, double-masked, parallel group study in subjects with visual 
impairment due to DME. 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 2:1 ratio to one of two treatment 
arms:

Brolucizumab 6 mg: treatment every 4 weeks up to and including Visit 13 (Week 48)

Aflibercept 2 mg: treatment every 4 weeks up to and including Visit 13 (Week 48)
Approximately 619 adult patients will be screened (20% screening failure rate expected) so that 
approximately 495 patients will be randomized in a 2:1 ratio (330 in brolucizumab arm, 165 in 
aflibercept arm, 9% dropout rate expected) in approximately 115 centers worldwide. The study 
duration is 52 weeks, including follow-up.
All participants will have study visits every 4 weeks through Week 52. The primary analysis 
will be performed at the End of Study (EOS) visit, Visit 14 (Week 52) (Figure 3-1) (further 
details can be found in Section 5 and Section 8.1).
Screening Period
Patients will be screened for enrollment into the treatment period at the Screening Visit. The 
screening period may last up to 14 days prior to administration of the first dose of study 
treatment, dependent upon confirmation of the patient meeting eligibility criteria.
Treatment Period
Subjects meeting eligibility criteria will enter the treatment period and be randomized in a 2:1 
ratio into one of the two treatment arms at the Baseline visit: brolucizumab 6 mg or aflibercept 
2 mg.
Follow-up period
For all subjects, the last study assessment will be performed at the Week 52/EOS visit (Visit 
14), four weeks after the last study treatment in this study. 
Subjects withdrawn from the study prior to study completion will be asked to return, if possible, 
for an early discontinuation (EOS) visit, four weeks following their last study treatment 
administration.


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Figure 3-1
Study design
  
q4w= every 4 weeks
4
Rationale
4.1
Rationale for study design
This study is designed as a randomized, double-masked, multicenter, active controlled 
prospective study to evaluate if brolucizumab 6 mg dosed q4w is safe and effective in the 
treatment of DME patients.
Based on Food and Drug Administration (FDA)'s Guidance for Industry: Premarketing Risk 
Assessment (FDA 2005) a 2:1 randomization ratio is chosen to ensure that approximately 300 
subjects are randomized into the brolucizumab arm.
To ensure masking is maintained, the investigational site will have both masked and unmasked 
staff to perform the masked and unmasked study assessments/procedures accordingly.
4.2
Rationale for dose/regimen and duration of treatment
The doses and regimen for brolucizumab and aflibercept are based on the following 
considerations:

In the Phase III brolucizumab studies in nAMD CRTH258A2301 (HAWK) and 
CRTH258A2302 (HARRIER), brolucizumab 3 mg and/or 6 mg doses showed efficacy 
and safety profiles comparable to aflibercept with numerical advantages related to efficacy 
for the 6 mg dose.

In the HAWK and HARRIER studies, brolucizumab (6 mg) was well tolerated when 
administered at a q4w regimen during the loading phase (12 weeks).


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
Previous studies suggest that for some DME patients, frequent dosing (ie, q4w) with anti-
VEGF therapy may be necessary to improve and maintain functional and anatomical 
outcomes (see Section 1.1 for details).

Aflibercept is applied as per the current approved label for DME.
Route of administration is via intravitreal injection as for all anti-VEGF therapies currently 
approved for the treatment of DME.
The study duration of approximately 1 year is adequate to assess the efficacy and safety of 
brolucizumab 6 mg dosed in a q4w regimen.
The current study design will provide efficacy and safety data of brolucizumab 6 mg on a q4w 
regimen to enable physicians to treat an individual patient as frequently as needed in order to 
achieve maximum efficacy outcomes.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Aflibercept 2 mg is an established standard of care option in the treatment of DME and has been 
chosen as the comparator for this study due to the approved dose and posology of aflibercept 
(EYLEA®) for the targeted indication. 
4.4
Purpose and timing of interim analyses/design adaptations
Not applicable
4.5
Risks and benefits
The risk to subjects in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring.
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study, and agree that in order 
to participate in the study they must adhere to the contraception requirements outlined in the 
exclusion criteria. If there is any question that the subject will not reliably comply, they should 
not be entered or continue in the study.
Ranibizumab and aflibercept (both approved inhibitors of VEGF-A) have consistently 
demonstrated efficacy in VEGF-driven retinal pathologies, including DME, with benefits 
outweighing the risks. Assuming a corresponding class-effect, it is justified to expect that 
brolucizumab (having the same mode of action (MoA) as ranibizumab and aflibercept) will 
likewise be efficacious and have a similar safety profile in the DME indication. In both Phase 
III studies in nAMD (HAWK, HARRIER), brolucizumab demonstrated non-inferiority to 
aflibercept in mean change from baseline in BCVA at Week 48. The visual acuity gains 
observed in the first year were maintained in the second year.
Overall, brolucizumab was well tolerated in Phase I, II, and III clinical studies in nAMD, with 
an ocular and non-ocular safety profile similar to ranibizumab and aflibercept.
Further details of the known and potential risks and benefits associated with brolucizumab are 
presented in the Investigator’s Brochure (IB).


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5
Population
The study population will consist of male and female patients with type 1 or type 2 diabetes 
mellitus and diagnosed with visual impairment due to DME. Approximately 619 patients are 
expected to be screened (20% screening failure rate expected) with approximately 495 patients 
expected to be randomized at approximately 115 sites. The study will include both patients who 
are naive and patients who previously received anti-VEGF therapy. In addition, this study will 
allow patients with HbA1c ≤ 12% and patients with mild or moderate proliferative diabetic 
retinopathy, characteristics which may be associated with the need for frequent anti-VEGF 
therapy.
5.1
Inclusion criteria
1. Signed informed consent must be obtained prior to participation in the study.
2. Patients ≥18 years of age at baseline.
3. Patients with type 1 or type 2 diabetes mellitus and HbA1c ≤ 12% at screening.
4. Study eye
Visual impairment due to DME with:

BCVA score between 73 and 23 letters, inclusive, using ETDRS visual acuity testing 
charts at an initial testing distance of 4 meters (approximate Snellen equivalent of 
20/40 to 20/320) at both screening and baseline.

DME involving the center of the macula, with CSFT ≥320 µm on SD-OCT 
at screening.
If both eyes are eligible, the eye with the worse visual acuity will be selected for study 
eye. However, the investigator may select the eye with better visual acuity, based on 
medical reasons or local ethical requirements.
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study
Ocular conditions
1. High-risk proliferative diabetic retinopathy (PDR) in the study eye as per investigator 
assessment at both screening and baseline.
2. Concomitant conditions or ocular disorders in the study eye which may, in the opinion of 
the investigator, confound interpretation of study results, compromise visual acuity or 
require medical or surgical intervention during the 12-month study period (eg, structural 
damage of the fovea, vitreous hemorrhage, retinal detachment, vitreomacular traction, 
macular hole, retinal vein/arterial occlusion, neovascularization of iris or choroidal 
neovascularization of any cause) at screening or baseline.
3. Any active intraocular or periocular infection or active intraocular inflammation (eg, 
infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis, uveitis) 
in either eye at screening or baseline.
4. 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


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5. 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, eg, 
cataract)
Ocular treatments
6. Use of anti-VEGF therapies in the study eye during the 3-month period prior to baseline
7. Use of intraocular corticosteroids including dexamethasone intravitreal implant (Ozurdex) 
in the study eye during the 6-month period prior to baseline, and use of fluocinolone 
acetonide intravitreal implant (Iluvien) at any time prior to baseline.
8. Intraocular surgery or laser photocoagulation (macular or panretinal) in the study eye 
during the 3-month period prior to baseline
9. Prior investigational drugs in either eye at any time prior to baseline
10. Vitreoretinal surgery in the study eye at any time prior to baseline
11. Aphakia with the absence of posterior capsule in the study eye
Systemic conditions or treatments
12. Use of systemic corticosteroids for 30 or more consecutive days within 90 days prior to 
baseline, with the exception of low stable doses of corticosteroids (defined as ≤ 10 mg 
prednisolone or equivalent dose used for 90 days or more); Inhaled, nasal or dermal 
steroids are permitted.
13. Stroke or myocardial infarction during the 6-month period prior to baseline
14. End stage renal disease requiring dialysis or renal transplant
15. Systemic anti-VEGF therapy at any time prior to baseline
16. Systemic medications known to be toxic to the lens, retina or optic nerve (eg, 
deferoxamine, chloroquine/hydroxychloroquine, tamoxifen, phenothiazines and 
ethambutol) used during the 6-month period prior to baseline
17. Uncontrolled blood pressure defined as a systolic value ≥180 mmHg or diastolic value 
≥100 mmHg at screening or baseline (In case there is an elevated blood pressure 
measurement, it should be repeated after 20 minutes. If the repeat measurement is 
elevated, then the patient is not eligible to be enrolled into the study).
18. 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
19. 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
20. History of a medical condition (eg, 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
21. 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)


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Other
22. 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
23. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during the study drug administration and for 3 months after stopping the investigational 
medication. Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (eg, 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 childbearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, 
age appropriate history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least 
six weeks before taking study treatment. In the case of oophorectomy alone, only when 
the reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of childbearing 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 
(ICF).


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6
Treatment
6.1
Study treatment
6.1.1
Investigational and control drugs
Table 6-1
Investigational and control drug
Investigational 
Drug
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor (global 
or local)
Brolucizumab 6 
mg/0.05 mL
Solution for 
injection
Intravitreal use
Glass vials or 
pre-filled syringe
Sponsor, global
Comparator 
Drug
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor (global 
or local)
Aflibercept 2 
mg/0.05 mL
Solution for 
injection
Intravitreal use
Glass vials or 
pre-filled syringe
Sponsor, global
Brolucizumab will be provided in a single use, sterile glass vial, or may be provided in prefilled 
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 prefilled 
syringe (in selected countries) containing sufficient Aflibercept to deliver a 2 mg dose when 
administering a volume of 0.05 mL.
Novartis will provide sufficient supplies of brolucizumab and aflibercept for treatment use to 
allow for completion of the study.
6.1.2
Treatment arms/group
Eligible subjects will be randomly assigned at Visit 1/Baseline to one of the following two 
masked treatment arms in a ratio of 2:1.

Brolucizumab 6 mg injected every 4 weeks up to and including Visit 13 (Week 48).

Aflibercept 2 mg injected every 4 weeks up to and including Visit 13 (Week 48).
6.1.3
Treatment duration
The planned total duration of study treatment is 48 weeks with a 4-week follow up period.
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration, and can be initiated by either the subject or the investigator.
Subjects who prematurely discontinue study treatment for any reason except withdrawal of 
consent should continue in the study and carry out the scheduled visits and assessments, at the 
discretion of the subject and investigator.


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6.2
Other treatment(s)
6.2.1
Concomitant therapy
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after the subject is enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the subject was enrolled into the study must be recorded on the appropriate electronic Case 
Report Forms (eCRFs). Each concomitant drug or procedure must be individually assessed 
against all exclusion criteria/prohibited medications and procedures. If in doubt, the investigator 
should contact the Novartis medical monitor before randomizing a subject or allowing a new 
medication to be started. If the subject is already enrolled, contact Novartis to determine if the 
subject should continue participation in the study.
6.2.1.1
Permitted concomitant therapy
Panretinal photocoagulation is permitted at any time during the study as deemed necessary by 
the investigator (eg, when diabetic retinopathy progresses into high risk PDR) and the patient 
can continue the study treatment.
If needed, administration of topical ocular corticosteroids in the study eye is allowed during the 
study. If cataract surgery or yttrium aluminum garnet (YAG) laser is necessary in the study eye, 
it should be scheduled in a way not to disturb the schedule for study treatment.
During the study, if the fellow eye develops visual impairment due to DME or other disease, it 
may also be treated with standard of care at the discretion of the investigator, as well as other 
treatments according to clinical practice. Fellow eye treatment will be captured in the eCRF. 
The fellow eye must be monitored according to routine practice and AEs captured in the eCRF.
6.2.2
Prohibited medication
Use of the treatments displayed in the table below is not allowed after screening.
Table 6-2
Prohibited medications/procedures
Medication / Procedures
Prohibition 
period
Action taken
Study eye
Intra- or periocular corticosteroids (except if needed as 
short term treatment of AE)
Any time
Discontinue study 
treatment (except if for 
treatment of AE)
Anti-VEGF therapy other than assigned study 
treatment
Any time
Discontinue study 
treatment
Laser photocoagulation (focal/grid )
Any time
Continuation of study 
treatment at the 
investigator's discretion
Any investigational drug, biologic or device
Any time
Discontinue study 
treatment


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Medication / Procedures
Prohibition 
period
Action taken
Fellow eye
Investigational treatment
Any time
Continuation of study 
treatment in the study eye 
at the investigator's 
discretion
Systemic
Systemic corticosteroids for 30 or more consecutive 
days (low stable doses of corticosteroids [defined as 
≤10 mg prednisolone or equivalent dose], inhaled, 
nasal, or dermal steroids are permitted)
Any time
Discontinue study 
treatment
Anti-VEGF therapy
Any time
Discontinue study 
treatment
Any investigational drug, biologic or device (with the 
exception of over-the counter vitamins, supplements 
or diets)
Any time
Discontinue study 
treatment
Medications toxic to the lens, retina or optic nerve
(except temporary use for COVID-19 treatment)
Any time
Discontinue study 
treatment
Standard of care or other treatments according to the investigator's practice for DME and other 
diseases in the fellow eye are permitted at any time and must be recorded in the appropriate 
eCRF page.
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 ICF 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 investigational 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 ICF, the subject is assigned to the next 
sequential Subject No. available.
6.3.2
Treatment assignment, randomization
Interactive Response Technology (IRT) will be used for dispensing medication during the 
treatment period, and all screened subjects must be added to IRT.
At Baseline/Day 1, all eligible subjects will be randomized via IRT to one of the treatment arms 
in a ratio of 2:1. The randomization will be stratified by the following baseline BCVA scores: 
≤34 letters read and >34 letters read. The investigator or his/her delegate will contact the IRT 
after confirming 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 
one vial) to be dispensed to the subject.


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The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. The IRT 
provider will produce a subject randomization list 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 end points, the handling of withdrawals, and 
so on. The essential aim of masking, therefore, is to prevent identification of the treatments by 
the investigator, subject, and others associated with the conduct of the study until all such 
opportunities for bias are no longer present.
This study will be double-masked, with subjects randomized to be treated with brolucizumab 
6 mg or aflibercept 2 mg. All masked members of the Study Team will be masked to treatment 
assignments until database lock. Sponsor personnel who have access to treatment codes (eg, 
bioanalysts) will not divulge the codes to subjects, investigators, site staff or other Sponsor 
personnel.
Unmasking of investigators and personnel directly involved in the conduct of the study will 
only occur in case of patient emergencies (Section 6.6.2), and then at the time of the final 
analysis (Section 12), 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 a subject's study treatment is required (eg, in case of Suspected Unexpected 
Serious Adverse Reaction (SUSAR)), an individual investigator will have the ability to unmask 
the treatment assignment for a specific subject. The investigator should notify the Sponsor prior 
to unmasking a subject, if there is sufficient time. Further, the Sponsor must be informed 
whenever the randomization code is broken and be informed about the reasons for unmasking.
Each site must have both masked and unmasked investigators available. The investigator who 
performs the injection will be unmasked to the treatments as will any other site personnel who 
have been delegated responsibility for working with the investigational product (IP). Only the 
masked site personnel and masked investigator perform BCVA, complete ophthalmic 
examination, ophthalmic imaging assessments and administer the Trial Feedback Questionnaire 
(TFQ). Also, the masked investigator/site personnel assess ocular and non-ocular safety 
parameters, and determine causality of AEs for subjects during the course of the study except 
for an event reported immediately following IVT injection. The unmasked investigator/site 
personnel should assess subject safety immediately following injection.


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Once the designated roles are determined, the unmasked investigator/site personnel must not be 
switched at any time after randomization to a masked role. Every effort must be made to limit 
the number of unmasked site 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: 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 investigator 
and unmasked site staff.
Unmasked field monitors will be available to perform study medication accountability and to 
deal with study issues involving the unmasked investigator or unmasked site staff.
An independent, masked review of color fundus photography, fluorescein angiography, 
SD-OCT 
 for patients enrolled in the 
study will be performed at a Central Reading Center (CRC).
6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments are not permitted.
Study treatment can be interrupted if warranted due to an AE.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
Every time the study treatment is to be administered, IRT needs to be accessed by unmasked 
site personnel for the medication (kit) number. The date and time of all study treatment 
injections administered during the study and any deviations from the protocol treatment 
schedule will be captured by the unmasked site personnel or by the unmasked field monitor on 
the appropriate study treatment dispensing form.
Exposure to the study treatment will be based on the number of injections administered. The 
unmasked field monitor will assess compliance with the study treatment at each visit using vial 
counts and information provided by the pharmacist or by the unmasked site personnel.
6.6.2
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a subject, he/she must provide the 
requested subject identifying information and confirm the necessity to break the treatment code 
for the subject. The investigator will then receive details of the investigational drug treatment 
for the specified subject and a fax or email confirming this information. The system will 
automatically inform the Novartis monitor for the site and the study team that the code has been 
broken.


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It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide:

protocol number

study drug name

subject number
In addition, oral and written information to the subject must be provided on how to contact the 
investigator's backup in cases of emergency, or when he/she is unavailable, to ensure that 
unmasking can be performed at any time.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under Section 6.1.1. 
The study medication has a 2-part label (base plus tear-off label). A unique medication number 
is printed on the study medication label. Unmasked site personnel will identify the study drug 
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 site 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 unmasked site personnel have access. Upon receipt, all study treatment must 
be stored according to the instructions specified on the labels and in the Investigator’s Brochure. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Country Organization (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 investigator must maintain an accurate record of the shipment and dispensing of 
study treatment in a drug accountability log. Monitoring of drug accountability will be 
performed by unmasked field monitors during site visits or remotely and at the completion of 
the trial.
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
6.7.2
Instruction for prescribing and taking study treatment
All kits of study treatment assigned by the IRT will be recorded and databased in the IRT system.
Treatment Period
Arm 1: Brolucizumab 6 mg q4 weeks


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Brolucizumab 6 mg will be administered via intravitreal injection every 4 weeks up to and 
including Visit 13 (Week 48) to subjects randomized to the brolucizumab 6 mg q4 week 
treatment arm.
Arm 2: Aflibercept 2 mg q4 weeks
Aflibercept 2 mg will be administered via intravitreal injection every 4 weeks up to and 
including Visit 13 (Week 48) to subjects randomized to the aflibercept 2 mg q4 week treatment 
arm.
Figure 6-1
Dosing schedule
BL=Baseline
Intravitreal injection
The IVT injection will be carried out under controlled, aseptic conditions and antimicrobial 
requirements, per local clinical practice by the unmasked investigator according to the IRT 
randomization/kit assignment.
An 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 is 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.
Every injection administered to the subject will be recorded in the eCRF.
7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), Institutional Review Board/Independent Ethics Committee (IRB/IEC)-
approved informed consent.
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 


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his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (eg, all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use Good Clinical Practice (ICH GCP) guidelines and regulatory 
requirements and is considered appropriate for this study. Any changes to the proposed consent 
form suggested by the investigator must be agreed by Novartis before submission to the 
IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the subject informed consent and should 
be discussed with the subject during the study as needed. Any new information regarding the 
safety profile of the investigational drug that is identified between IB updates will be 
communicated as appropriate, for example, via an investigator notification (IN) or an aggregate 
safety finding. As new information becomes available, informed consent to be updated and 
then must be discussed with the subject.
During the COVID-19 pandemic that may challenge the ability to obtain a standard written 
informed consent due to limits that prevent an on-site visit, the Investigator may conduct the 
informed consent discussion remotely (e.g. telephone, videoconference). Guidance issued by 
local regulatory bodies on this aspect prevail and must be implemented and documented (e.g. 
the presence of an impartial witness, sign/dating separate ICFs by trial participant and person 
obtaining informed consent, etc). Remote informed consent should be appropriately 
documented and confirmed by way of standard informed consent procedures at the earliest 
opportunity when the subject will be back at the trial sites.
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
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. All data must be entered in the eCRF in a timely manner 
(see Section 11.1).
A planned study visit schedule will be established at Baseline/Day 1, randomization (first day 
of treatment), for all subjects. All post-baseline 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).


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Patients must be seen for all visits on the designated day, or as close to it as possible, with a 
minimum of 21 days between treatments.
For a given protocol visit (except for Baseline/Day 1), assessments can be performed on 2
consecutive days.
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.
A ± 7 days visit window is allowed (except for Baseline/Day 1), should the subject be unable 
to return per scheduled visit.
For all visits, efficacy assessments (Section 8.3) and safety assessments (Section 8.4) should be 
performed prior to any administration of study treatment. IOP should be measured pre-IVT and 
post-IVT injection.
Missed or rescheduled visits should not lead to automatic study treatment or study 
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 (EOS) final visit will be performed.
If the COVID-19 pandemic limits or prevents on-site study visits, study treatment could not be 
administered and other study assessments may not be performed. Alternative methods of safety 
monitoring may be implemented. Depending on local regulations, site capabilities and patient’s 
visit status in the study, phone calls or virtual contacts (e.g. teleconsult) can be performed for 
safety follow-up for the duration of the pandemic, until it is safe for the participant to visit the 
site again.


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Table 8-1
Assessment Schedule
Period
Screening
Treatment
Follow up
Visit Name
Screening
Baseline
2
3
4
5
6
7
8
9
10
11
12
13/ 
EOT
14/ EOS
Weeks
-2 to -1
1
4
8
12
16
20
24
28
32
36
40
44
48
52
Informed consent
X
Inclusion / Exclusion 
criteria
X
X
Demography
X
Medical 
history/current 
medical conditions
X
Prior and 
concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood collection for 
anti-drug antibody 
(ADA)
X
X
X
X
X
X
Blood collection for 
study drug systemic 
exposure
X
X
X
X
X
X
Hematology
X
X
X
HbA1C
X
X
X
X
X
Clinical Chemistry
X
X
X
Pregnancy test 
(serum), if applicable
(Section 8.4.2)
X
X
Pregnancy test 
(urine), if applicable
(Section 8.4.2)
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X


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Period
Screening
Treatment
Follow up
Visit Name
Screening
Baseline
2
3
4
5
6
7
8
9
10
11
12
13/ 
EOT
14/ EOS
Weeks
-2 to -1
1
4
8
12
16
20
24
28
32
36
40
44
48
52
Best-corrected visual 
acuity (BCVA) (*both 
eyes where 
indicated)
X*
X
X
X
X
X
X
X*
X
X
X
X
X
X
X*
Intraocular pressure 
(IOP) (*both eyes 
where indicated)
X*
X
X
X
X
X
X
X*
X
X
X
X
X
X
X*
Ophthalmic Exam a,b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Spectral domain 
optical coherence 
tomography (SD-
OCT) (*both eyes 
where indicated)a
X*
X
X
X
X
X
X
X*
X
X
X
X
X
X
X*
Color fundus 
photography (*both 
eyes where 
indicated)a
X*
X
X*
X*
Fluorescein 
angiography (FA) 
both eyes (** at the 
discretion of the 
investigator)a
X
X**
X


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Period
Screening
Treatment
Follow up
Visit Name
Screening
Baseline
2
3
4
5
6
7
8
9
10
11
12
13/ 
EOT
14/ EOS
Weeks
-2 to -1
1
4
8
12
16
20
24
28
32
36
40
44
48
52
Trial feedback 
questionnaire 
(optional)
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug 
administration
X
X
X
X
X
X
X
X
X
X
X
X
X
a Additional ophthalmic examinations and images will be performed in case of any signs of intraocular inflammation
b Ophthalmic exam includes fundus and slit lamp examination. Pupil dilation optional according to local practice


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8.1
Screening
A screening period of up to 2 weeks will be used to assess subject eligibility. The completion 
of assessments for this visit may occur on different days. The screening period starts with the 
first screening procedure (other than signing of the informed consent).
For 
the purpose 
of 
screening, fluorescein angiography 
(FA) 
images 
from 
a 
previous routine evaluation may be used as long as FA was performed within 7 days of the 
screening 
visit 
using 
Central 
Reading 
Center 
(CRC)-certified 
equipment 
and 
technician/investigator.
One-time reevaluation of subjects is allowed during the 14 day screening period to confirm 
eligibility, except for the purpose of capturing new BCVA or imaging assessments that 
previously failed to qualify the subject. Medical judgment should be exercised to ensure that 
treatment of DME 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 informed consent, demographic information, 
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 Serious 
Adverse Events (SAE)s will be monitored 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 characteristic in alignment with eCRF.
The following information will be collected/documented at screening and/or baseline visits as 
relevant (see Table 8-1) for each subject:

Age

Gender

Race/Ethnicity

Type of diabetes

Vital signs

Study eye

Best-corrected visual acuity

Anatomical parameters of the retina

Intraocular pressure

Pregnancy test, if applicable






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8.4
Safety
Safety assessments will include physical examination, vital signs, ophthalmic examinations, 
laboratory evaluation as well as the monitoring and recording of the 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.
Table 8-2
Vital signs assessment
Assessment
Specification
Physical examination
A complete physical examination will include general 
health check according to local clinical practice. The 
examination will be performed at Screening and at EOS 
visit. 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 
(beats per minute). In case there is an elevated blood 
pressure measurement as specified in the exclusion 
criteria, at the screening or baseline visits, the blood 
pressure measurement should be repeated after 20 
minutes. If the repeat measurement is elevated, then 
the patient is not eligible to be enrolled into the study. 
Sitting blood pressure and pulse rate will be collected at 
all visits 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 applicable visits. 
Details on the collection, 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.  
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.


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Test Category
Test Name
HbA1c
Glycosylated Hemoglobin
Chemistry
Serum biochemistry tests:
Serum electrolytes (sodium, potassium, chloride, phosphorus, calcium), 
uric acid, blood urea nitrogen, creatinine, albumin, glucose, total protein, total 
bilirubin and direct bilirubin, serum glutamic oxaloacetic transaminase (SGOT)/ 
aspartate aminotransferase (AST), serum glutamic pyruvic transaminase 
(SGPT)/ alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), 
alkaline phosphatase (ALP) and lactate dehydrogenase (LDH)
Additional chemistry tests:
Lipids panel-triglycerides (TG), low-density lipoproteins (LDL), high-density 
lipoproteins (HDL), total cholesterol (TC)
Urinalysis
Dipstick measurements for specific gravity, pH, protein, glucose, ketones, 
urobilinogen, bilirubin, nitrite, leucocyte, esterase and urine occult blood
8.4.2
Pregnancy
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if necessary according to local requirements. 
Highly effective contraception is required for women of childbearing potential during the study 
drug administration and for 3 months after stopping the study treatment.
A serum pregnancy test will be conducted for all women of childbearing potential to assess 
pregnancy before inclusion into the study at the Screening visit and then at Week 52/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.
8.4.3
Ophthalmic examination
The ophthalmic examination will consist of the following:

Biomicroscopy (slit lamp examination) will be completed at every (scheduled and 
unscheduled) visit by the masked investigator to examine the structures (e.g., eyelids/lashes, 
conjunctiva, cornea, anterior chamber, iris, lens and anterior part of the vitreous) of the 
study eye according to the clinical practice (fellow eye will be examined at the discretion of 
the investigator). The results of the examination of either eye will 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 uveitis nomenclature (SUN) working group grading system (Jabs et 
al 2005). The test results will be recorded in the source documents (e.g., ophthalmic 
examination tool) and captured in the appropriate eCRF as applicable.
Any clinically significant abnormalities deemed by the investigator as adverse event must 
be recorded on the adverse event page of the eCRF (events identified prior to signing 
informed consent should be recorded on the medical history page).

Intraocular pressure (IOP) will be assessed in the study eye, pre- and post-IVT injection, 
at every scheduled visit. In the fellow eye, IOP will be assessed at Screening, Week 24, and 
Week 52/EOS visits. The values recorded in mmHg will be entered into the eCRF for either 




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data about the patient's disease, symptoms or adverse events, and therefore will not be 
considered trial data.
8.5.2
Anti-drug antibodies (immunogenicity)
Anti-brolucizumab antibodies, anti-drug antibodies, (ADAs) assessment will be performed at 
Screening, Weeks 4, 12, 24, 36, and 52/EOS visits in subjects treated with brolucizumab only. 
However, in order to maintain masking, collection of blood samples for ADA assessment will 
be performed in both treatment arms. In case of intraocular inflammation (eg, uveitis) 
diagnosed and reported as an AE at a scheduled visit (without ADA sampling) or at an 
unscheduled visit, an additional ADA sample will be collected. Concentrations of free 
brolucizumab will be determined at the same timepoints as the determination of ADA 
status/titer. These data will be used for interpretation of the ADA data. No pharmacokinetic 
(PK) parameters will be determined from brolucizumab systemic exposure. Additional 
pharmacodynamic assessment (e.g. systemic VEGF) may be conducted on the samples. 
Samples collected from subjects assigned to aflibercept treatment will not be assayed for ADA 
nor for systemic drug concentration.
At all applicable visits, blood draws should take place prior to the IVT injection. A standardized 
procedure for the collection, processing, storage and shipment of these blood samples is 
provided by the central laboratory. Further details on sample collection, numbering, processing 
and shipment can be found in the central laboratory manual.
9
Study discontinuation and completion
9.1
Discontinuation
The investigator should discontinue study treatment for a given subject and/or withdraw the 
subject from study if, on balance, he/she believes that continuation would be detrimental to the 
subject's well-being.
A subject will be considered to have completed the study when the subject has completed the 
last visit planned in the protocol (see Table 8-1).
The investigator and/or referring physician will recommend the appropriate follow-up medical 
care, if needed, for all subjects who are prematurely withdrawn from the study.
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration and can be initiated by either the subject or the investigator.
The investigator must discontinue study treatment for a given subject if he/she believes that 
continuation would negatively impact the subject's well-being.
Study treatment must be discontinued under the following circumstances

Subject/guardian decision

Pregnancy (see Section 8.4.2 and Section 10.1.4)

Use of prohibited treatment (see Section 6.2.2)


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
Any situation in which study participation might result in a safety risk to the subject

Following emergency unmasking
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information.
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see 'Withdrawal of Informed Consent' Section 9.1.2). Where possible, they 
should return for the assessments indicated in the Assessment Schedule. If they fail to return 
for these assessments for unknown reasons, every effort (eg, telephone, e-mail, letter) should 
be made to contact the subject/pre-designated contact as specified in the lost to follow-up 
section, Section 9.1.3. This contact should preferably be done according to the study visit 
schedule.
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule. In this 
scenario, after study treatment discontinuation, at a minimum the following data should be 
collected at clinic visits or via telephone/email contact:

New / concomitant treatments

Adverse Events / Serious Adverse Events
The investigator must contact the IRT to register the subject’s discontinuation from study 
treatment.
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code section (Section 6.6.2).
9.1.1.1
Replacement policy
Subjects who started treatment but prematurely discontinued study treatment and/or the 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 (eg, 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.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.


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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 the time of withdrawal) according to applicable 
law.
For United States (US): 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 Europe (EU) and Rest of World (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, eg, dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety. Should early termination be 
necessary, subjects must be seen as soon as possible and treated as a prematurely withdrawn 
subject. The investigator may be informed of additional procedures to be followed in order to 
ensure that adequate consideration is given to the protection of the subject’s interests. The 
investigator or sponsor depending on the local regulation will be responsible for informing 
IRBs/IECs of the early termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last 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 may receive standard of care if needed.


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10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (eg, any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a 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 subjects and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through 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 (ie, 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 cohorts, not on a single subject
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. action taken regarding with study treatment
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

No action taken (eg, further observation only)

[Investigational] treatment interrupted/withdrawn


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
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 the 
medical history of the subject.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (eg, continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the IB.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease.
10.1.2
Serious adverse events
An SAE is defined as any adverse event (appearance of [or worsening of any pre-existing]) 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of 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


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
constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, eg, 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.
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 
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 and 
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 


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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. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded and reported by the investigator to the Novartis CMO&PS. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the 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 (European Medicines Agency (EMA) definition).
Misuse/abuse is not applicable to this study as IVT injection is performed by the investigator.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate eCRF irrespective of whether or not associated with an AE/SAE and reported 
to Novartis Safety only if associated with an SAE.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
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.
10.2
Additional Safety Monitoring
10.2.1
Data Monitoring Committee


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The RTH258 program level Data Monitoring Committee (DMC) will monitor ocular safety. 
DMC will function independently of all other individuals associated with the conduct of this 
clinical trial, including the site investigators participating in the study. 
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.
11
Data Collection and Database management
11.1
Data collection
All data should 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 (Code of Federal Regulation) 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 (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
11.2
Database management and quality control
Novartis personnel (or designated Contract Research Organization (CRO)) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated 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 processed 
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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 laboratories.
Randomization codes and data about all study treatment (s) dispensed to the subject will be 
tracked using an IRT. The system will be supplied by a vendor, who will also manage the 
database. The data will be sent electronically to Novartis (or a designated CRO) at specific 
timelines.
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 (PDs) 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 or at an investigator’s meeting, a Novartis (or 
delegated CRO) representative will review the protocol and data capture requirements (ie, 
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 masked 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 
as well as the progress of enrollment. The unmasked field monitor will ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitors during these visits. Continuous remote 
monitoring of each site’s data may be performed by the field monitors or a centralized Novartis 
(or delegated CRO) 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, 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 
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12
Data analysis and statistical methods
The primary safety and efficacy analysis will be based on the Week 52 data, ie, all data up to 
and including Week 52. This analysis will be performed once all subjects complete their Week 
52/EOS visit or terminate the study before Week 52. Summary statistics will be presented by 
treatment group unless otherwise specified. For continuous variables, summary statistics will 
generally include: n, mean, standard deviation (SD), median, quartiles, minimum and maximum. 
For categorical variables, this will generally include: n, frequency and percentage in each 
category. 
Additional analysis  may be also conducted to evaluate the impact of COVID-19 pandemic.
Further technical details and discussions of the statistical considerations will be provided in the 
Statistical Analysis Plan (SAP). Any data analysis carried out independently by the investigator 
should be submitted to Novartis before publication or presentation.
12.1
Analysis sets
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 
randomization by the investigator and given a randomization number. Subjects will be analyzed 
according to the treatment assigned to them at randomization.
The Full Analysis Set (FAS) comprises all randomized subjects who receive at least one 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 one 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 48.
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 52 including, for eg, lack of compliance 
(including missed treatments and treatment misallocation), missing data, prohibited 
concomitant medications, 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 final database lock at Week 52 the relevant protocol deviations will be identified at 
the subject level in the database. After the database lock, analysis restrictions will be derived in 
the analysis database. Censoring applied in relation to the specific PDs/ARs will be specified 
as well.
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 


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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 if these are different. The cumulative number of IVT injections will 
be presented for the period baseline to Week 48, by treatment arm. For the safety analysis set, 
summary statistics will include exposure data up to Week 52.
Prior medication and concomitant therapies
The number and percentage of patients taking prior medication or concomitant therapies will 
be summarized by preferred term according to the WHO Drug Reference List dictionary using 
the Safety Set and FAS (in case there are differences between those two). The concomitant 
therapies (medications and procedures) will include all therapies received after start of study 
including those already started prior to the start of the study treatment.
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 52. BCVA will be assessed 
by the masked investigator using ETDRS-like charts at an initial testing distance of 4 meters as 
described in Section 8.3.1.
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 the change from baseline in BCVA at Week 52, assuming a 
non-inferiority margin of 4 ETDRS letters (see Section 12.8 for details on the rationale for the 
non-inferiority margin).
Let:
B = Brolucizumab 6 mg
A = Aflibercept 2 mg
Consider the following non-inferiority hypotheses related to a non-inferiority margin of 4 
letters:
H0: μB – μA ≤ -4 letters vs HA: μB – μA > -4 letters,
where μB and μA represent the unknown true mean change from baseline in BCVA at Week 52 
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 52,excluding the effect of relevant DME 
prohibited medication(s) applied to the study eye (eg, alternative anti-VEGF treatments for 
DME, as further detailed in Section 6.2.2 and in the SAP). The analysis set for the primary 
estimand will be the FAS.


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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 letters) and age category 
(< 65, ≥ 65) as factors. Additional factors 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 52 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-inferiority assessment in change from baseline in BCVA at Week 52 will be 
applied to any supplementary estimand.
The primary estimand and other supplementary estimands of interest are described 
in Table 12-1 below, together with their key attributes, and 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 toa:
Statistical methods 
(Including missing 
data strategy)
use of DME 
prohibited 
medication
any other 
reason 
Primary 
estimand
Difference in 
change from 
baseline in 
BCVA at 
Week 52 
excluding the 
effect of DME 
prohibited 
medication(s)
All 
randomized 
subjects who 
receive at 
least 1 IVT 
injection of 
the 
randomized 
study 
treatment 
(FAS)
Not included; 
treated as 
missing
Included
Analysis of variance 
(ANOVA) model 
assessed at a 
two-sided significance 
level of 0.05, and 
including terms for 
treatment, baseline 
BCVA (≤ 34, > 34
letters) and age 
category (< 65, ≥ 65), 
and using last 
observation carried 
forward (LOCF) 
imputation/replacement
for missing/censored 
data.
Supplemen
tary
estimand
Difference in 
change from 
baseline in 
BCVA at 
Week 52 
excluding the 
effect of DME 
rescue 
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
Not included; 
treated as 
missing
Not 
included; 
treated as 
missing
ANOVA model as per 
the primary estimand.
LOCF 
imputation/replacement
for missing/censored 
data


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a) Note that, for all estimands as applicable, all data captured until the start of rescue medication will 
be included in the analysis. 
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 certain alternative DME treatments in the study eye (eg, other anti-VEGF treatment) will be 
censored (further details will be discussed in the SAP).
The LOCF approach is expected to be sensitive to an early study treatment 
discontinuation/study discontinuation 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, data collected after the start of such a 
treatment would be censored. LOCF will then be based on the last BCVA value prior to the 
start of this treatment, again expecting that this value would reflect the negative BCVA outcome 
under study treatment that led to the use of alternative treatment for DME. In case of missing 
data due to lack of safety/tolerability with impairment of the visual function of the study eye, 
the LOCF method would also provide a sensitive approach to capture such an unfavorable 
outcome.
In case of missing data occurring independently of the response to study treatment, the LOCF 
approach assumes stability which seems to be adequate for this population based on historical 
data both for maintenance treatment phase (ie, stabilization of BCVA) and also in case of the 
absence of any treatment effect, with an average natural disease progression in terms of BCVA 
of only 1-2-letter loss over 1 year. In case of an early study discontinuation within the first 6 
months of treatment, the LOCF method will likely result in a conservative estimate of the 
BCVA measure within each arm, potentially underestimating the true outcome.
LOCF is an established method within the assessment of efficacy of anti-VEGF treatments in 
terms of BCVA outcome. Non-inferiority studies should follow the main design features 
(primary variables, the dose of the active comparator, eligibility criteria, etc) as the previously 
conducted superiority trials in which the active comparator demonstrated clinically relevant 
efficacy. The primary endpoint in the aflibercept phase III studies VIVID and VISTA was the 
change from baseline in BCVA at Week 52, with missing data imputed based on LOCF. Based 
on those studies, the percentage of missing data regarding BCVA is not considered critical 
(<10%) which limits the impact of the missing data imputation method.
Other methods of handling missing or confounded data within sensitivity analyses will be 
performed, as detailed in the SAP.
12.4.4
Sensitivity and Supportive analyses
Sensitivity and supportive analyses for the primary endpoint, change from baseline in BCVA 
at Week 52, are specified in terms of sensitivity and supportive estimands as described in 
Table 12-1. This describes different approaches to deal with intercurrent events such as intake 
of prohibited DME 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. 


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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 medication 
for DME as described in Section 6.2.2 and further details in the SAP) may also be produced.
The following subgroup analyses may be explored using the FAS and the statistical model 
described in the primary estimand in Table 12-1:

Age category (< 65, ≥ 65 years)

Gender (male, female)

Diabetes type (Type 1, Type 2)

Baseline HbA1c (< 7.5, ≥ 7.5%)

Baseline BCVA categories (≤ 34, > 34 letters)

Duration of DME (≤ 3, >3-<12, ≥ 12 months)

DME type (focal, diffuse) as per CRC

Baseline CSFT (< 450, ≥450 - <650, ≥ 650 μm)

Baseline status of Intraretinal fluid (IRF) (presence, absence)

Baseline status of Subretinal fluid (SRF) (presence, absence)

Baseline status of DRSS score (<61, ≥ 61)
Further description of all the supportive 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 related to anatomy:

Change from baseline in central subfield thickness (CSFT) at each post-baseline visit

Proportion of study eyes with fluid-free macula at each post-baseline visit: 

Proportion of study eyes with absence of SRF 

Proportion of study eyes with absence of IRF 

Proportion of study eyes with simultaneous absence of SRF and IRF at each post-
baseline visit

Proportion of study eyes with absence of DME (CSFT < 280 μm) at each post-baseline 
visit

Time to first fluid-free macula:

Time to first absence of SRF

Time to first absence of IRF

Time to first simultaneous absence of SRF and IRF

Time to first absence of DME (CSFT < 280 μm)
Secondary efficacy endpoints based on BCVA:

Change from baseline in BCVA at each post-baseline visit

Proportion of study eyes with gain in BCVA of 5/10/15 letters or more at each post-
baseline visit compared to baseline


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Note: subjects with BCVA value of 84 letters or more at a post-baseline visit will be considered 
as responders for this endpoint. This is to account for a ceiling effect, for example, for the "15 
letters or more" endpoint, for those subjects with BCVA values at baseline ≥ 70 letters.
Secondary efficacy endpoints related to status of Diabetic Retinopathy:

Change from baseline in ETDRS Diabetic Retinopathy Severity Scale (DRSS) score at 
Week 12, Week 24, and Week 52
Details regarding the analysis of secondary endpoints will be described in the SAP.
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, maximum severity and outcome

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. Separate presentations will be provided related to ocular events in the study eye 
and fellow eye and non-ocular events. Additional summaries will be provided by severity, 
causality (separately assessed for the injection procedure and the drug) and outcome. Subject 
listings of all adverse events will be provided. Deaths and other serious or clinically significant 
non-fatal adverse events will be listed separately. A subject with multiple adverse events of 
same preferred term or within a primary system organ class is only counted once towards the 
total of the preferred term or 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


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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.
12.5.3
Anti-drug antibody
Assessment of ADAs (screening and confirmatory assay followed by titer and neutralizing 
antibody (nAb) for confirmed positive samples) will be performed at Screening, Weeks 4, 12, 
24, 36, and 52/EOS visits in subjects randomized to treatment with brolucizumab. However, 
in order to maintain masking, collection of blood samples for ADA assessment will be 
performed in both treatment arms. In case of intraocular inflammation (eg, uveitis) diagnosed 
and reported as an AE at a scheduled visit (with no ADA sampling) or at an unscheduled 
visit, an additional ADA sample will be collected.
The number and percent of subjects according to their ADA status ( including negative, positive 
without boost, treatment-induced, treatment-boosted, persistent and transient) will be presented. 
Subject listings of all ADA titer values and the corresponding free brolucizumab concentration 
will be presented for all subjects in the brolucizumab arm.
Further details of the ADA analyses will be described in the SAP.


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12.7
Interim analyses
Not applicable.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
The primary objective is to demonstrate non-inferiority of brolucizumab versus aflibercept with 
respect to the change from baseline in BCVA at Week 52.
The fixed-margin method is used to derive an appropriate non-inferiority margin (NIM) for this 
study (FDA 2016). Results from a meta-analysis of the phase III studies VIVID and VISTA 
comparing monthly aflibercept 2 mg vs laser in patients with DME suggest a pooled mean 
treatment effect of 10.8 letters (95% CI, [8.0, 13.6]) favoring aflibercept in the change from 
baseline in BCVA at Week 52. The smallest effect of aflibercept vs laser is defined as the lower 
limit of the 95% CI for the pooled mean BCVA, ie, an effect of 8.0 letters. The NIM is then set 
as the value which preserves 50% of this effect, ie, the NIM is set to 4 letters. This non-
inferiority margin provides assurance that any proof of non-inferiority only occurs if the effect 
of brolucizumab is superior to that of laser, and the observed treatment difference to aflibercept 
is of no clinical relevance.
Subjects will be randomized to the brolucizumab and aflibercept arms in a ratio of 2:1. A total 
sample size of 357 subjects (238 on the brolucizumab arm vs 119 on the aflibercept arm) will 
allow assessment of non-inferiority (using a NIM of 4 letters) of brolucizumab 6 mg versus 
aflibercept 2 mg with respect to the change from baseline in BCVA at Week 52. Assuming 
equal means and a common standard deviation of 11 letters, for a NIM of 4 letters and a 
twosided alpha level of 0.05, there is 90% power to reject the null hypothesis that 
brolucizumab is inferior to aflibercept. To ensure that at least 300 patients are treated with 
brolucizumab 6 mg on a fixed q4w regimen, the total sample size will be increased to 450 
subjects total (300 on the brolucizumab arm vs 150 on the aflibercept arm). This results in a 
statistical power for assessing non-inferiority of 95%.
Given the planned unequal sample size of 300 vs 150, there is a higher probability that 
infrequent AEs will occur in the brolucizumab arm than in the aflibercept arm in this study. For 
example, for an AE with a probability of occurrence of 0.01, the probabilities of observing at 
least one event are 95% and 78% for the brolucizumab and aflibercept arms, respectively, using 
a Binomial distribution.
To account for a dropout rate of 9%, a total of approximately 495 subjects (330 on the 
brolucizumab arm vs 165 on the aflibercept arm) 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 International Conference on Harmonisation (ICH) Harmonized Tripartite Guidelines 
for Good Clinical Practice, with applicable local regulations (including European Directive 


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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 (eg, 
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 European Clinical Trials Database (EudraCT). In addition, after study completion 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (eg, 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 as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal standard operation manuals, 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 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, 


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other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be implemented.
14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


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15
References
References are available upon request
Agarwal A, Sarwar S, Sepah YJ, et al (2015) What have we learnt about the management of 
diabetic macular edema in the antivascular endothelial growth factor and corticosteroid era? 
Curr Opin Ophthalmol; 26(3):177-83.
Bansal AS, Khurana RN, Wieland MR, et al (2015) Influence of Glycosylated Hemoglobin on 
the Efficacy of Ranibizumab for Diabetic Macular Edema: A Post Hoc Analysis of the 
RIDE/RISE Trials. Ophthalmology; 122(8):1573-9.
Bressler SB, Ayala AR, Bressler NM, et al (2016) Persistent Macular Thickening After 
Ranibizumab Treatment for Diabetic Macular Edema With Vision Impairment. JAMA 
Ophthalmol; 123(6):278-85.
Bressler SB, Odia I, Maguire MG, et al (2019) Factors Associated With Visual Acuity and 
Central Subfield Thickness Changes When Treating Diabetic Macular Edema With 
Anti-Vascular Endothelial Growth Factor Therapy: An Exploratory Analysis of the Protocol T 
Randomized Clinical Trial. AMA Ophthalmol; 1:6786.
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, 
US Food and Drug Administration (2005) Guidance for Industry: Premarketing risk 
assessment.
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, 
US Food and Drug Administration (2016) Guidance for industry: Non-inferiority clinical
trials to establish effectiveness.
Ciulla TA, Bracha P, Pollack J, et al (2018) Real-world outcomes of anti-vascular endothelial 
growth factor therapy in diabetic macular edema in the United States. Ophthalmol Retina; 1-9.
Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature (SUN) 
Working Group (2005) Standardization of uveitis nomenclature for reporting clinical data. 
Results of the First International Workshop. Am J Ophthalmol. 2005 Sep;140(3):509-16.
Korobelnik JF, Do DV, Schmidt-Erfurth U, et al (2014) Intravitreal aflibercept for diabetic 
macular edema. Ophthalmology; 121(11):2247-54.
Lee R, Wong TY, Sabanayagam C (2015) Epidemiology of diabetic retinopathy, diabetic 
macular edema and related vision loss. Eye Vis (Lond); 215(17):1-25.
Nussenblatt RB, Palestine AG, Chan CC, et al (1985) Standardization of vitreal inflammatory 
activity in intermediate and posterior uveitis. Ophthalmology; 92(4):467-71
Pieramici D, Singh RP, Gibson A, et al (2018) Outcomes of diabetic macular edema eyes with 
limited early response in the VISTA and VIVID studies. Ophthalmol Retina; 2(6): 558-66.
Pieramici DJ, Wang PW, Ding B, et al (2016) Visual and Anatomic Outcomes in Patients 
with Diabetic Macular Edema with Limited Initial Anatomic Response to Ranibizumab in 
RIDE and RISE. Ophthalmology; 123(6):1345-50.


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Sivaprasad S, Oyetunde S (2016) Impact of injection therapy on retinal patients with diabetic 
macular edema or retinal vein occlusion. Clin Ophthalmol; 10:939-46.
Staurenghi G, Feltgen N, Arnold JJ, et al (2018) Impact of baseline Diabetic Retinopathy 
Severity Scale scores on visual outcomes in the VIVID-DME and VISTA-DME studies. Br J 
Ophthalmol; 102:954-58.
Virgili G, Parravano M, Menchini F, et al (2014) Cost-effectiveness of treatments for diabetic 
macular oedema: should we pay more attention to the appraisal and reporting of economic 
evaluations? Br J Ophthalmol: 98(4):421-2.
Wells JA, Glassman AR, Ayala AR, et al (2016) Aflibercept, Bevacizumab, or Ranibizumab 
for Diabetic Macular Edema: Two-Year Results from a Comparative Effectiveness 
Randomized Clinical Trial. Ophthalmology; 123(6):1351-9.
Wykoff CC, Elman MJ, Regillo CD, et al (2016) Predictors of Diabetic Macular Edema 
Treatment Frequency with Ranibizumab During the Open-Label Extension of the RIDE and 
RISE Trials. Ophthalmology; 123(8):716-21.
Ziemssen F, Cruess A, Dunger-Baldauf C, et al (2017) Ranibizumab in Diabetic Macular 
Oedema - A Benefit-risk Analysis of Ranibizumab 0.5 mg PRN Versus Laser Treatment. 
Eur Endocrinol; 13(2):91-98.


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16
Appendices
Not applicable.

SAP_001.pdf: 


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Document History – Changes compared to previous final version of SAP
Date
Time point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)
28-
November
-2019
Prior to DB 
lock
Creation of first
version
N/A
NA
12-April-
2021
Prior to DB 
lock
Creation of 
amendment 1
Update definitions of end of 
treatment and unscheduled 
visit to make them clearer
Update analysis restriction and 
estimand related statement
Add subgroup of interest 
baseline BCVA categories
≤65, >65 letters; Change 
subgroup of interest baseline 
status of DRSS score to 12-
point scale
Add analyses to cover potential 
impact of the COVID-19 
pandemic
Add the summary tables of 
medical history and 
prior/concomitant medications, 
as per the protocol
Add clarifications for the 
definition of primary and 
supplementary estimands
Change baseline BCVA 
category factor to ≤ 65, > 65 
letters In the ANOVA model
Add loss in BCVA in secondary 
efficacy endpoints
Update testing strategy to add 
confirmatory testing on efficacy 
endpoints
Add handling of censoring for 
safety analyses
Section 2.1.1
Section 2.2
Section 2.2.1
Sections 2.3.1, 
2.5.4.2, 2.5.4.3, 
2.6.2, 2.6.2.1, 
2.7.1
Sections 2.3.3, 
2.4.2
Sections 2.5, 
2.5.4.1, 2.5.4.2
Sections 2.5.2, 
2.6.2.1
Section 2.6.1
Section 2.6.2.3
Section 2.7


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Date
Time point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)
Add details on the 
determination of AESIs
Add section regarding BCVA 
loss and additional imaging 
parameters for subjects with 
AESI in the study eye
Remove patient profile plot, 
add NAb analysis
Update Table 5-1, Table 5-3
Correct minor issues in the first 
version
Section 2.7.1.1
Sections
2.7.4.2, 2.7.4.3
Section 2.9
Sections 5.3, 
5.5


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Table of contents
Table of contents .................................................................................................................4
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................8
1.1
Study design.............................................................................................................8
1.2
Study objectives and endpoints ...............................................................................9
2
Statistical methods.............................................................................................................10
2.1
Data analysis general information .........................................................................10
2.1.1
General definitions................................................................................10
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
Demographics and baseline characteristics...........................................13
2.3.3
Medical history......................................................................................14
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................14
2.4.1
Study treatment exposure......................................................................14
2.4.2
Prior medication and concomitant therapies.........................................14
2.5
Analysis of the primary objective..........................................................................15
2.5.1
Primary endpoint...................................................................................15
2.5.2
Statistical hypothesis, model, and method of analysis..........................15
2.5.3
Handling of missing values/censoring/discontinuations.......................17
2.5.4
Sensitivity and Supportive analyses......................................................18
2.6
Analysis of secondary efficacy endpoints .............................................................20
2.6.1
Secondary efficacy endpoints ...............................................................20
2.6.2
Statistical hypothesis, model, and method of analysis..........................21
2.6.3
Handling of missing values/censoring/discontinuations.......................26
2.7
Safety analyses.......................................................................................................26
2.7.1
Adverse events (AEs)............................................................................26
2.7.2
Deaths....................................................................................................28
2.7.3
Laboratory data .....................................................................................28
2.7.4
Other safety data ...................................................................................29
2.8
Pharmacokinetic endpoints....................................................................................30
2.9
Anti-drug antibodies..............................................................................................30
.31
31


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2.11
Interim analysis......................................................................................................31
3
Sample size calculation .....................................................................................................31
4
Change to protocol specified analyses ..............................................................................32
5
Appendix ...........................................................................................................................33
5.1
Imputation rules.....................................................................................................33
5.1.1
Study drug.............................................................................................33
5.1.2
AE date imputation ...............................................................................33
5.1.3
Concomitant medication date imputation .............................................35
5.1.4
Medical history date of diagnosis imputation.......................................36
5.2
AEs coding/severity...............................................................................................37
5.3
Laboratory parameters and vital signs derivations ................................................37
5.4
Statistical models...................................................................................................38
5.4.1
Primary analysis....................................................................................38
5.4.2
Other secondary efficacy analysis.........................................................38
5.5
Rule of exclusion criteria of analysis sets..............................................................39
5.6
Censoring rules for analysis...................................................................................41
6
Reference...........................................................................................................................42


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List of abbreviations
ADA
Anti-Drug Antibody
AE
Adverse Event
AESI
Adverse Event of Special Interest
ANOVA
Analysis of variance
AR
Analysis restrictions
AR
First-order Autoregressive
BCVA
Best Corrected Visual Acuity
CI
Confidence interval
CF
Color Fundus
COVID-19
Coronavirus Disease 2019
CS
Compound Symmetry
CSFT
Central subfield thickness (average thickness of circular 1mm area centered around fovea 
measured from RPE to ILM, inclusively)
CSR
Clinical Study Report
CRC
Central Reading Center
DBL
Database Lock
DME
Diabetic Macular Edema
DRSS
Diabetic Retinopathy Severity Scale
EDTRS
Early Treatment Diabetic Retinopathy Study
EOS
End of Study
EOT
End of Treatment
FA
Fluorescein angiography
FAS
Full Analysis Set
HbA1c
Glycated hemoglobin
hCG
human chorionic gonadotropin
IOP
Intraocular Pressure
IRF
Intraretinal Fluid
IVT
Intravitreal Treatment
KM
Kaplan Meier
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
MMRM
Mixed Model for Repeated Measures
NAb
Neutralizing Antibody
NIM
Non-Inferiority Margin
OCT
Optical Coherence Tomography
PD
Protocol Deviation
PDS
Programming Datasets Specification
PPS
Per Protocol Set
PT
Preferred Term
RAS
Randomized Set


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SAE
Serious Adverse Event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SD-OCT
Spectral Domain Optical Coherence Tomography
SE
Standard Error
SOC
System Organ Class
SRF
Subretinal fluid
TEAE
Treatment-Emergent Adverse Event
TOEP
Toeplitz
ULN
Upper Limit of Normal
VA
Visual Acuity
VC
Variance Components
VEGF
Vascular Endothelial Growth Factor
WHO
World Health Organization


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1
Introduction
The purpose of this Statistical Analysis Plan (SAP) is to describe the implementation of 
statistical analysis planned in the study protocol, and to provide detailed statistical methods that 
will be used for the Clinical Study Report (CSR) of study CRTH258B2305.
Data will be analyzed according to the data analysis Section 12 of the study protocol which will 
be available in Appendix 16.1.1 of the CSR. Important information is given in the following 
sections and details will be provided, as applicable, in Appendix 16.1.9 of the CSR.
The SAP will be finalized before the database lock (DBL) for the primary analysis at Week 52. 
Any changes to the SAP after approval will be documented.
The following document was referenced while writing this SAP:
CRTH258B2305 Clinical Trial Protocol Final version 00 dated 26-Mar-2019
1.1
Study design
This is a multi-center, randomized, double-masked, parallel group study in subjects with 
visual impairment due to DME to demonstrate the safety and efficacy of brolucizumab 6 mg 
q4w against the active control aflibercept 2 mg q4w. Subjects who meet all the inclusion and 
none of the exclusion criteria will be randomized in a 2:1 ratio to one of two treatment arms:

Brolucizumab 6 mg: treatment every 4 weeks up to and including Visit 13 (Week 48)

Aflibercept 2 mg: treatment every 4 weeks up to and including Visit 13 (Week 48)
Approximately 619 adult patients will be screened (20% screening failure rate expected) so that 
approximately 495 patients will be randomized in a 2:1 ratio (330 in brolucizumab arm, 165 in 
aflibercept arm, 9% dropout rate expected) in approximately 115 centers worldwide. The study 
duration is 52 weeks, including follow-up.
All participants will have study visits every 4 weeks through Week 52. The primary analysis
will be performed at the End of Study (EOS) visit, Visit 14 (Week 52) (Figure 1-1).
Figure 1-1
Study design




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2
Statistical methods
2.1
Data analysis general information
The statistical analysis will be performed by Novartis using SAS Version 9.4 or above.  
Continuous variables will be summarized using the number of observations, mean, standard 
deviation, standard errors (SE), median, quartiles, minimum and maximum values. Categorical 
variables will be summarized with number of observations, the number of observations for each 
category and the corresponding percent. Where appropriate, 2-sided  95% confidence intervals 
(CIs) for point estimates of the mean or proportion will be provided unless otherwise specified. 
Point estimates, 95% CIs of treatment differences will be provided as appropriate unless 
otherwise specified.
2.1.1
General definitions
Study treatment
Study treatment, or study drug, refers to both Brolucizumab 6mg and Aflibercept 2mg IVT 
injections.
Study day
Day 1 is defined as the date of first dose of study drug (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 mapping
The end of study date is the date when a subject completes or discontinues the study. 


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For reporting data by visit in outputs, the end of study visit will be allocated to the actual 
(reported) visit number. If end of study date is not on a scheduled visit, then the end of study 
visit will be allocated, based on study day, to the closest future scheduled study visit.
End of treatment day mapping
The “Date of Last Exposure” is the date of the last study treatment on or prior to the end of 
treatment (EoT) date.
For reporting data by visit in outputs, the EoT date will be allocated to the actual (reported) visit 
number. If EoT date is not on a scheduled visit, then the EoT date will be allocated, based on 
study day, to the closest future scheduled study visit.
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 maximum change from baseline. Unscheduled visits will not 
be included in analyses with mixed model for repeated measures (MMRM).
Given unscheduled visits are not active treatment visits, IOP measurements at unscheduled 
visits are not considered as pre-injection IOP measurements, hence will not be used to identify 
subjects with pre-injection IOP >30 mmHg.
Missing and implausible dates
The general approach to handling missing dates is shown in Section 5.1.
2.2
Analysis sets
The All Enrolled set includes all subjects who signed informed consent. This analysis set will 
be used to summarize subject disposition.
The Randomized Set (RAS) will consist of all randomized subjects. Subjects are considered 
randomized when they had been deemed eligible for randomization by the investigator and 
given a randomization number. Subjects will be analyzed according to the treatment assigned 
to at randomization.
The 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. Following the intent-to-treat principle, subjects will be analyzed according 
to the treatment assigned to at randomization.
Supportive analyses of the primary endpoint will include analysis using the Per Protocol Set
(PPS). PPS is a subset of the FAS and will exclude or censor subjects with important protocol 
deviations (PDs) and analysis restrictions (ARs) that are expected to majorly affect the validity 
of the assessment of efficacy and/or safety at Week 52 including for e.g. lack of compliance 
(including missed treatments and treatment misallocation), missing data, prohibited 
concomitant medication and deviation from inclusion/exclusion criteria. Confounded data or 
discontinuation from treatment due to lack of efficacy and/or safety do not constitute a reason 
for exclusion from the PPS. 


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Before the database lock the relevant important protocol deviations will be identified at the 
subject level in the database. After the database lock, analysis restrictions will be derived in the 
analysis database. Censoring applied in relation to the specific PDs / ARs (i.e. non PDs) will be 
specified as well.
The FAS will be the analysis set for the primary estimand as defined in Table 2-1. However,
when assessing the robustness of the overall efficacy conclusions, considerations will be given
to the analysis based on the primary estimand using FAS and the supplementary estimand (see
Table 2-1) using PPS, i.e., similar conclusions on non-inferiority based on both estimands are
expected. Inconsistencies in key efficacy study results between the FAS and PPS will be
examined and discussed in the clinical study report (CSR).
The Safety Analysis Set (SAF) will include all subjects who receive at least one study drug 
IVT injection. Subjects in the safety analysis set will be analyzed according to the treatment 
arm from which they received majority of treatments up to and including Week 48.
Before the database lock, the relevant important protocol deviations will be identified as 
specified in Section 5.6. The corresponding identifications at the subject level including data 
exclusion from PPS and censoring will be captured in the database. Analysis Restrictions (non
protocol deviations) will be identified by programming (as specified in the programming
specification document) independently to the treatment arm.
Rules of exclusion criteria of analysis sets are in Appendix Section 5.5.
2.2.1
Subgroups of interest
The subgroups of interest are specified below:

Age category (<65, ≥65 years)

Gender (male, female)

Diabetes type (Type 1, Type 2)

Baseline HbA1c (<7.5, ≥7.5%)

Baseline BCVA categories (≤34, >34 letters; ≤65, >65 letters)

Duration of DME (≤3, >3-<12, ≥12 months)

DME type (focal, diffuse as per central reading center (CRC)

Baseline central subfield thickness (CSFT) (< 450, ≥ 450 - <650, ≥650 µm)

Baseline status of intraretinal fluid (IRF) (presence, absence)

Baseline status of subretinal fluid (SRF) (presence, absence)

Baseline status of DRSS 12-point scale (≤6, ≥7)
Subgroup analysis will be performed for the primary efficacy variable only, using the primary 
analysis approach. More details can be found in Section 2.5.4.
2.3
Subject disposition, demographics and other 
baseline characteristics
2.3.1
Subject disposition
The following summaries will be included in the disposition table considering all enrolled 
subjects: Number and percent of subjects who are enrolled into the study, treated, complete the 


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study, discontinue the study (including reasons for discontinuation) and discontinue from study 
treatment (including reasons for discontinuation). 
The number and percent of subjects who discontinue the study and who discontinue treatment 
will be presented by study visit. The number and percent of subjects treated by site will be 
presented. A listing of subjects who discontinue from the study and/or treatment early will be 
provided by treatment arm. The listing will identify the visits completed and when the study or 
treatment was discontinued including the corresponding reasons.
Subjects who sign an informed consent form and who are subsequently found to be ineligible
prior to randomization will be considered a screen failure. Screen failure information will not 
be summarized and only listed.
Number and percent of subjects who were excluded (i.e. not evaluable) from each of the SAF, 
FAS, and PPS will be presented using the randomized analysis set. A listing of subjects along 
with the analysis set that they were excluded from and the corresponding reasons will also be 
presented.
Number and percent of subjects with important protocol deviations (PD) and analysis 
restrictions (AR) will be presented by treatment arm and deviation/restriction category. Due to 
the COVID-19 pandemic, higher number of 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 arm. A listing 
of all ARs and PDs will be provided by treatment arm and subject, including the information if 
the AR/PD leads to the subject exclusion from an analysis set. The relationship to COVID-19
will be flagged for PDs in the listing.
2.3.2
Demographics and baseline characteristics
Demographics and baseline characteristics will be summarized with descriptive statistics for 
the FAS by treatment arm and overall. Demographics characteristics will include age, gender, 
race, ethnicity. The summary of baseline ocular characteristics will be presented for the study 
eye only and listed separately for the study eye and the fellow eye.
Ocular baseline characteristics include:

Study eye selection (left eye OS or right eye OD),

Diabetes type (type 1, type 2),

Duration of DME since the primary diagnosis as continuous variable and using 
categories (≤ 3, >3-<12, ≥12 months), 

Macular edema type (focal, diffuse) as per CRC,

Baseline BCVA as continuous variable and using categories (≤34, >34 letters; ≤65, >65 
letters),

Baseline HbA1c as continuous variable and using categories (<7.5, ≥7.5%), 

Baseline CSFT (<450, ≥450-<650, ≥650 µm),

Baseline status of IRF (presence, absence),

Baseline status of SRF (presence, absence),

Baseline ETDRS DRSS score using categories (12-point scale, as defined in Table 2-4).

Prior anti-VEGF treatment (study eye) (yes, no)


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Duration of DME since diagnosis (months) will be derived as [(first dose date –diagnosis start 
date + 1)/(365.25/12)]. In case of partial dates, the imputation rule is specified in Section 5.1.4.
Other relevant baseline information will be listed and summarized with descriptive statistics as 
appropriate. 
No tests for differences in demographics and baseline characteristics between treatment arms 
will be performed. Potential related differences will be assessed based on clinical relevance.
2.3.3
Medical history
Medical history and current medical conditions will be summarized and listed for ocular (study 
eye) and non-ocular events.
2.4
Treatments (study treatment, rescue medication, 
concomitant therapies, compliance)
2.4.1
Study treatment exposure
Extent of exposure to study treatment is calculated as the number of IVT injections received. 
Descriptive statistics for exposure to study treatment will be provided for the Safety set.
The following summaries will be presented:

Overall number of treatments cumulatively

Treatment exposure by visit: The number and percent of subjects who received IVT 
injections, missed a treatment and missed visits will be presented by visit
Exposure data will be listed for each treatment arm.
2.4.2
Prior medication and concomitant therapies
Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment. Concomitant therapies are defined as medications and procedures received after the 
start of study treatment including those already started prior to the start of the study treatment.
Prior and concomitant medications will be coded according to the WHO Drug Reference List 
dictionary, with Anatomical Therapeutic Classification (ATC) class and preferred term.
Ocular and non-ocular prior and concomitant medications will be summarized and listed by 
ATC class and preferred term (PT) for each treatment arm. Ocular medications will be listed 
for the study eye and the fellow eye separately.
Ocular concomitant non-drug therapies and procedures will be summarized for the study eye 
only. Both ocular and non-ocular concomitant non-drug therapies and procedures will be listed.
Prior anti-VEGF medications will be summarized by ATC class and preferred term for systemic, 
for the study eye by treatment arm. Concomitant anti-VEGF medications will be summarized 
by ATC class and preferred term for systemic, for the study eye and the fellow eye separately
by treatment arm.


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In the summary tables, data collected after the subject discontinued study treatment and started 
alternative DME treatment in the study eye will be censored (from the day the subject started 
alternative DME treatment onwards).
2.5
Analysis of the primary objective
2.5.1
Primary endpoint
The primary endpoint is the change from baseline in BCVA at Week 52 in the study eye.
The primary analysis of the primary endpoint will be based on the FAS with last observation 
carried forward (LOCF) imputation of missing BCVA values. 
The primary estimand for the primary endpoint includes the following components:

Population: Subjects with visual impairment due to DME as per the inclusion/exclusion
criteria

Endpoint: The primary endpoint is the change from baseline in BCVA at Week 52.
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 as follows:

Study discontinuation due to any reason: data imputed with LOCF

Treatment discontinuation due to any reason: use all the data

Data after the start of alternative DME treatment will be censored

Summary measure: Difference in the change from baseline in BCVA at Week 52 
between brolucizumab and aflibercept treatment arms
2.5.2
Statistical hypothesis, model, and method of analysis
The objective related to the primary endpoint is to demonstrate non-inferiority of brolucizumab 
to aflibercept with respect to change from baseline in BCVA, considering a margin of 4 ETDRS 
letters.
Let: 
B = Brolucizumab 6 mg
A = Aflibercept 2 mg  
Consider the following non-inferiority hypotheses related to a non-inferiority margin of 4 letters: 
H0: μB – μA
≤ -4 letters
vs.
HA: μB – μA
> -4 letters
where μB and μA are the corresponding unknown true mean changes from baseline in BCVA at 
Week 52 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 52, excluding the effect of relevant DME


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prohibited medication(s) applied to the study eye (eg, alternative anti-VEGF treatments for
DME, as further detailed in protocol Section 6.2.2). The analysis set for the primary estimand 
will be the FAS.
Based on the FAS, the above hypothesis will be tested via an analysis of variance (ANOVA) 
model. The model will include treatment, baseline BCVA (≤65, >65 letters) and age category 
(<65, ≥65) as factors. Additional factors may also be included as appropriate, as well as 
interactions between treatment and factors of interest.
Two-sided 95% confidence interval (CI) for the least square means difference (brolucizumab -
aflibercept) will be presented. Non-inferiority will be considered established if the lower limit 
of the corresponding 95% CI is greater than -4 letters. P-value for treatment comparison (2-
sided) and p-value for non-inferiority (4 letter margin) (1-sided) will be presented. The same 
approach for non-inferiority assessment in change from baseline in BCVA at Week 52 will be 
applied to any supplementary estimand.
The primary estimand and other supplementary estimands are described in Table 2-1 below, 
together with their key attributes. 
Table 2-1
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)
use of 
alternative 
DME 
treatment
any other 
reason 
Primary 
estimand
Difference in change 
from 
baseline 
in 
BCVA at Week 52 
excluding the effect 
of 
switching 
to
alternative 
DME
medication in the 
study eye
FAS
Not included; 
treated 
as 
missing
Included
Analysis of variance (ANOVA) 
model assessed at a two-sided 
significance level of 0.05, and
including terms for treatment, 
baseline BCVA (≤ 65, > 65
letters) and age category (< 65, ≥ 
65), and using last observation 
carried 
forward 
(LOCF) 
imputation/replacement
for 
missing/censored data.
Suppleme
ntary
Estimand 
A
Difference in change 
from
baseline 
in 
BCVA at Week 52 
for subjects adhering 
to the protocol as per 
the PPS definition
PPS
Not included;
treated as
missing
Not
Included; 
treated 
as 
missing
at 
subject
level2
ANOVA model as per the primary 
estimand. 
LOCF 
imputation/replacement
for missing/censored data
Suppleme
ntary 
estimand 
B
Difference in change 
from 
baseline 
in 
BCVA at Week 52 
including the effect 
of 
switching 
to 
alternative 
DME 
medication in the 
study eye
FAS
Included
Included
ANOVA model as per the primary 
estimand.
LOCF imputation for missing 
data.
No censoring of data after start of 
alternative DME treatment for the 
study eye


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1 Note that, for all estimands as applicable, all data captured until the start of alternative DME treatment will be 
included in the analysis; 
2 For additional information on data handling related to intercurrent events, see Section 5.5 and Section 5.6.
2.5.3
Handling of missing values/censoring/discontinuations
As stated in the definition of the primary estimand, missing BCVA values will be imputed by 
LOCF as a primary approach. Observed values from both scheduled and unscheduled visits will 
be used for the LOCF imputation. For subjects with no post-baseline BCVA value, the baseline 
value will be carried forward.
For subjects who discontinue treatment but continue in the study, data collected after start of 
alternative DME treatment in the study eye (see Table 2-2) will be censored for the primary 
analysis. Censored data will be replaced using LOCF with the last observation prior to the start 
of alternative DME treatment in the study eye.
Table 2-2
Potential alternative DME treatment in the study eye

Ranibizumab

Aflibercept

Bevacizumab (off-label use) 

Laser photocoagulation, previous standard of care still being used as mono- or combination 
therapy with anti-VEGF; 

Intraocularly administered Steroids:
o
Dexamethasone
o
Fluocinolone acetonide 
From an estimand perspective, the main focus is to adequately reflect in the analysis 
unfavorable study outcome related to the treatment (e.g. lack of efficacy, safety problems).
The LOCF approach is expected to be sensitive to an early study termination due to lack of 
efficacy assuming that such lack of efficacy is reflected in the last observed BCVA 
measurement. In case of the use of alternative treatment for the underlying disease (DME), data 
collected after the start of such a treatment would be censored. LOCF will then be based on the 
last value prior to the start of this treatment, again expecting that this value would reflect the 
negative BCVA outcome under study treatment. In case of missing data due to lack of 
safety/tolerability with impairment of the function of the study eye the LOCF method would 
also provide a sensitive approach to capture such an unfavorable outcome.
In case of missing data occurring independently of the response to study treatment, the LOCF 
approach assumes stability which seems to be adequate based on historical data both for the 
maintenance treatment phase (i.e. stabilization of BCVA) and also in case of the absence of any 
treatment effect with an average natural disease progression in terms of BCVA of only 1-2-
letter loss over 1 year. In case of an early study discontinuation within the first 6 months of 
treatment, the LOCF method will likely result in a conservative estimate of the BCVA measure 
within each arm, potentially underestimating the true outcome.


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LOCF is an established method within the assessment of efficacy of anti-VEGF treatments in 
terms of BCVA outcome. Non-inferiority studies should follow the main design features 
(primary variables, the dose of the active comparator, eligibility criteria, etc.) as the previously 
conducted superiority trials in which the active comparator demonstrated clinically relevant 
efficacy. The primary endpoint in aflibercept Phase III studies VIVID and VISTA was the 
BCVA change from Baseline to Week 52 with missing data imputed based on LOCF. Based on 
those studies, the percentage of missing data regarding BCVA is not considered critical (<10%) 
which limits the impact of the missing data imputation method.
2.5.4
Sensitivity and Supportive analyses
2.5.4.1
Sensitivity analysis on the primary estimand
Sensitivity to the statistical model and imputation assumptions from the primary estimand will
be considered, using the primary analysis set (FAS) only.
An alternative method of handling missing/censored values as described below may be
considered to assess the robustness of the hypothesis testing resulting from the primary analysis
described in Section 2.5.2:

Mixed model for repeated measures (MMRM) assuming missing at random (MAR) with 
observed data (including censoring for alternative DME treatment in the study eye). The 
MMRM will include treatment, visit, baseline BCVA category, age category and 
treatment by visit interactions as fixed-effect terms and visit as a repeated measure. An 
unstructured covariance matrix will be used to model the within-subject error. For the 
MMRM analysis:

The treatment difference at Week 52 will be estimated using the LSM and 95% CI.

If an MMRM model with 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), first-order autoregressive (AR) 
and Toeplitz (TOEP), variance components (VC).
In this analysis, data collected after the switch to alternative DME treatment in the study eye 
will be censored.
Other sensitivity analyses on the primary estimand might be considered, such as tipping point
analysis or multiple imputation by chained equations (MICE) method.
2.5.4.2
Supportive analysis using a supplementary estimand
Supplementary estimand on the PPS:
The target population, the primary endpoint, the treatment of interest and the summary measure 
of the supplementary estimand are the same as for the primary estimand. The handling of the 
intercurrent events for the supplementary estimand can be found in Table 5-6 for the PPS 
population.
The supportive analysis on this supplementary estimand will apply the same LOCF/ANOVA 
method as for the primary estimand. 
Supplementary estimand on the FAS:


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The target population, the primary endpoint, the treatment of interest and the summary measure 
of the supplementary estimand are the same as for the primary estimand. However, data after 
start of alternative DME treatment in the study eye will be included in the analysis (see Table 
2-1).
Supplementary estimand to assess the impact of COVID-19:
Another supplementary estimand might be defined to assess the impact of intercurrent events 
associated with study treatment discontinuation due to COVID-19 on the study conclusions. 
For subjects who discontinue study treatment due to COVID-19 but continue in the study, data 
collected after the treatment discontinuation will be censored for the analysis. Censored data 
will be replaced using LOCF with the last observation collected prior to the study treatment 
discontinuation. This analysis will be conducted on the FAS if at least 5% of subjects 
discontinued treatment due to COVID-19.
2.5.4.3
Summary statistics and subgroup analysis
Summary statistics:

Descriptive statistics of BCVA primary endpoint will use observed data and primary 
analysis set (FAS), with and without censoring data after use of alternative treatment for 
DME in the study eye.
Subgroup analyses will be conducted to assess the consistency of treatment effect across 
various subgroups described in Section 2.2.1. They will be conducted using the framework for 
the primary estimand only (FAS with censoring of data collected after use of alternative DME 
treatment in the study eye, and missing/censored values imputed using LOCF):

Subgroup analyses will be conducted using the same model and analysis strategies 
described for the primary analysis but fitted by category of each of the subgroups. 
Subgroup variables that are used as fixed effects in the model will be removed from the 
model statement for the subgroup analysis.

Subgroup analysis results will be presented using forest plots.
Subgroup analyses to evaluate impact of COVID-19 pandemic:
As per internal guidance, a sensitivity analysis related to the exposure of subjects to COVID-
19 will be conducted.
Impacted subjects to COVID-19 pandemic are defined as subjects who:

missed at least one injection due to COVID-19

or discontinued study treatment due to COVID-19

or were reported COVID-19 infection (including suspected as per PTs in PDS).
Non-impacted subjects to COVID-19 are defined as subjects who:

did not miss any injection due to COVID-19

and did not discontinue study treatment due to COVID-19

and were not reported COVID-19 infection (including suspected as per PTs in PDS).
Subgroup analyses will be conducted using the same model and analysis strategies described 
for the primary endpoint in the impacted and non-impacted subgroups. In addition, 


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demographics and baseline characteristics will be summarized for impacted and non-impacted 
subjects.
2.6
Analysis of secondary efficacy endpoints
2.6.1
Secondary efficacy endpoints
Secondary efficacy endpoints related to BCVA, anatomy or status of diabetic retinopathy are 
listed below. 
Secondary efficacy endpoints based on BCVA:

Change from baseline in BCVA at each post-baseline visit

Proportion of study eyes with gain in BCVA of 5/10/15 letters or more at each post-baseline 
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 this endpoint. This is to account for a ceiling effect, for 
example, for the "≥15-letter gain" endpoint, for those subjects with BCVA values at baseline 
≥ 70 letters.

Proportion of study eyes with a loss in BCVA of ≥5, ≥10 and ≥15 ETDRS letters from 
baseline to each post-baseline visit
Secondary efficacy endpoints related to anatomy:

Change from baseline in central subfield thickness (CSFT, as determined by SD-OCT from 
the central reading center) at each post-baseline visit

Proportion of study eyes with fluid-free macula at each post-baseline visit:

Proportion of study eyes with absence of subretinal fluid (SRF)

Proportion of study eyes with absence of Intraretinal fluid (IRF)

Proportion of study eyes with simultaneous absence of SRF and IRF at each post 
baseline visit
Note: proportion of fluid-free macula will be based on the full population of FAS.

Proportion of subject with status regarding normal CSFT thickness (<280 microns) at each 
post-baseline visit

Time to first fluid-free macula:

Time to first absence of SRF

Time to first absence of IRF

Time to first absence of SRF and IRF

Time to first absence of DME (CSFT < 280 microns)
Note: time to first fluid-free macula should be based on the subset of FAS population with 
fluid present at baseline.


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Secondary efficacy endpoints related to the status of Diabetic Retinopathy (see Section 
2.6.2.1):

Change from baseline in ETDRS Diabetic Retinopathy Severity Scale (DRSS) score at 
Week 12, Week 24, and Week 52: subject status regarding a ≥2- and ≥3-step improvement 
or worsening from baseline in the ETDRS DRSS score at each assessment visit
2.6.2
Statistical hypothesis, model, and method of analysis
2.6.2.1
General analysis specifications for secondary efficacy endpoints
No hypothesis will be tested for the secondary efficacy endpoints listed in the above Section 
2.6.1.
These endpoints will be summarized and presented descriptively, based on the FAS with LOCF 
imputation for missing or censored data if not otherwise specified. Details on data handling 
such as missing values are described in Section 2.6.3.
The impact of COVID-19 pandemic on CSFT will be assessed with the subgroup analyses of 
impacted/non-impacted subjects, as defined in Section 2.5.4.3.
Continuous endpoints:
The continuous secondary endpoints related to BCVA and CSFT will be analyzed using 
ANOVA models including terms for treatment, baseline value categories (BCVA: ≤ 65, > 65
letters; CSFT: <450, 450-650, ≥650 µm) and age category (< 65, ≥ 65).  The estimates of least 
square means for each treatment and for the treatment differences brolucizumab – aflibercept,
including 95% CIs for the treatment differences, will be presented. For the ANOVA analysis of 
CSFT, baseline CSFT categories will be used instead of baseline BCVA as a class variable. 
The line plot on LSMean (±SE) by visit will also be provided for each treatment arm.
Categorical variables:
For binary endpoints, frequency tables (count and proportion) will be provided by time point. 
In addition, proportions and treatment differences in proportions along with 95% CIs will be 
presented for each visit using a logistic regression with treatment, the corresponding baseline 
status (similar to the ones specified for the ANOVA models) and age categories as fixed effects.  
Bar chart will be plotted by visit and treatment arm. 
Time-to event variables:
The time to event variables will be analyzed using KM analysis. KM estimates on percent of 
subjects achieving event together with 95% CI will be presented by visit. The median time (95% 
CI) to event will also be constructed by treatment arm. KM curves presenting the cumulative 
probability of subjects achieving event from baseline will be provided by treatment arm. Time 
to event variables will be analyzed by Cox proportional hazard model, adjusted for treatment, 
age category and the corresponding baseline value category. The estimated hazard ratio with 
95% Wald confidence interval will be obtained.


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2.6.2.2
ETDRS DRSS Score
Definition of Endpoints
The following categories of change from baseline in diabetic retinopathy (DR) status will be 
analyzed:

Subject status regarding a ≥2- and ≥3-step improvement or worsening from baseline in the 
ETDRS DRSS score at each assessment visit
Those endpoints will be derived from the ETDRS-DRSS score assessed by the central reading 
center based on color fundus photography (CP) images in the study eye at screening, Weeks 12, 
24, 52 and exit/premature discontinuation visit. The DRSS in analysis will be from either 
standard field or the masked DRSS 
.
When the ETDRS-DR severities are evaluable, they will be categorized using the following 
scores: 
Table 2-3
Definition of DRSS: original scale
DRSS scale
Definition
10
DR absent
20
Microaneurysms only
35
Mild non-proliferative diabetic retinopathy (NPDR)
43
Moderate NPDR
47
Moderately severe NPDR
53
Severe NPDR
60
Full/partial panretinal photocoagulation or local photocoagulation 
for new vessel
61
Mild PDR
65
Moderate PDR
71
High-Risk PDR
75
Very high risk PDR
81
Advanced PDR
85
Very advanced PDR
Other recorded DRSS values (code 98: Indeterminable due to missing images, 99:  
Indeterminable due to upgradable images, 00: No images received) that are not related to an 
evaluable DR severity level will be handled as missing. Study eyes treated with panretinal 
photocoagulation or local photocoagulation prior to baseline or during the study period will be 
coded with score 60 or greater. The improvement or worsening of DRSS in those eyes during 
study will not truly reflect the treatment effect, so they will be excluded from the DRSS analysis.
All DRSS values except 60 will be converted into a 12-point scale as defined in Table 2-4.
Table 2-4
Definition of DRSS: 12-point scale
12-point scale
Definition
Original DRSS
1
DR absent
10
2
DR questionable, microaneurysms only
20


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12-point scale
Definition
Original DRSS
3
Mild NPDR
35
4
Moderate NPDR
43
5
Moderately severe NPDR
47
6
Severe NPDR
53
7
Mild PDR
61
8
Moderate PDR
65
9
High-Risk PDR
71
10
Very high-Risk PDR
75
11
Advanced PDR
81
12
Very advanced PDR
85
DR= diabetic retinopathy, DRSS= diabetic retinopathy severity score, NPDR= non-proliferative diabetic 
retinopathy, PDR= proliferative diabetic retinopathy.
Table 2-5 and Table 2-6 describe the definition of a 2-step and a 3-step change, respectively, 
for each (non-missing) baseline and post-baseline ETDRS based on the 12-point scale, as 
defined below:

≥2-step improvement: DRSS (12-point scale) at the visit – DRSS (12-point scale) at baseline 
≤-2

≥3-step improvement: DRSS (12-point scale) at the visit – DRSS (12-point scale) at baseline 
≤-3

≥2-step worsening: DRSS (12-point scale) at the visit – DRSS (12-point scale) at baseline 
≥2

≥3-step worsening: DRSS (12-point scale) at the visit – DRSS (12-point scale) at baseline 
≥3
Table 2-5
Definition of 2-step change in DRSS on the 12-point scale
Baseline
Post-baseline
≥2-step improvement
No change or change 
<2 steps
≥2-step worsening
1
-
1, 2
3 or higher
2
-
1, 2 or 3
4 or higher
3
1
2, 3, or 4
5 or higher
4
1 or 2
3, 4, or 5
6 or higher
5
3 or lower
4, 5, or 6
7 or higher
6
4 or lower
5, 6, or 7
8 or higher
7
5 or lower
6, 7, or 8
9 or higher
8
6 or lower
7, 8, or 9
10 or higher
9
7 or lower
8, 9, or 10
11 or 12
10
8 or lower
9, 10, or 11
12
11
9 or lower
10, 11, or 12
-
12
10 or lower
11, 12
-


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Table 2-6
Definition of 3-step change in DRSS on the 12-point scale
Baseline
Post-baseline
≥3-step improvement
No change or change 
<3 steps
≥3-step worsening
1
-
1, 2 or 3
4 or higher
2
-
1, 2, 3 or 4
5 or higher
3
-
1, 2, 3, 4 or 5
6 or higher
4
1
2, 3, 4, 5 or 6
7 or higher
5
1 or 2
3, 4, 5, 6 or 7
8 or higher
6
3 or lower
4, 5, 6, 7 or 8
9 or higher
7
4 or lower
5, 6, 7, 8 or 9
10 or higher
8
5 or lower
6, 7, 8, 9 or 10
11 or 12
9
6 or lower
7, 8, 9, 10 or 11
12
10
7 or lower
8 or higher
-
11
8 or lower
9 or higher
-
12
9 or lower
10 or higher
-
Analysis method
All DRSS analyses will be based on the 12-point scale shown in Table 2-4. 
Proportions of subjects with ≥2- and ≥3-step improvement or worsening from baseline will be 
summarized using the FAS by assessment visit, except for study eyes which were treated with 
panretinal photocoagulation or local photocoagulation prior to baseline or during the study 
period.
Bar chart will be plotted by assessment visit and treatment arm.
For the proportions of subjects with ≥2-step change from baseline at Week 52 (and similarly 
for  ≥3-step change), the 95% confidence intervals (CIs) for the proportions in each treatment 
arm, the difference in proportions between treatment arms and the 95% CI for the difference
will be presented for each visit using a logistic regression with treatment, the corresponding 
baseline status (similar to the ones specified for the ANOVA models) and age categories as 
fixed effects.
The impact of COVID-19 pandemic on the proportion of subjects with ≥2-step improvement or 
worsening from baseline will be assessed with the subgroup analyses of impacted/non-impacted 
subjects.
2.6.2.3
Confirmatory testing related to additional secondary efficacy 
endpoints
Confirmatory hypothesis testing for additional secondary endpoints will be performed in case 
the proof of non-inferiority related to BCVA is successful for the hypothesis of primary 
endpoint specified in section 2.5.2 (corresponding to H1 in Figure 2-1).
The additional hypotheses are linked to the endpoints below:


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
H2. DRSS ≥2-step change from baseline at Week 52 (non-inferior for proportion of 
subjects in brolucizumab 6 mg vs aflibercept 2 mg with non-inferior margin 10%)

H3. Absence of SRF and IRF in the study eye at Week 52 (superior for proportion of 
subjects in brolucizumab 6 mg vs aflibercept 2 mg)

H4. Change from baseline in CSFT at Week 52 in the study eye (superior in reduction of
the CSFT change from baseline in brolucizumab 6 mg vs aflibercept 2 mg)

H5. Change from baseline in BCVA at Week 52 in the study eye (superior in reduction of
the BCVA change from baseline in brolucizumab 6 mg vs aflibercept 2 mg)
Figure 2-1
Multiple testing strategy
          
-
Hypotheses H1,..., H5 are represented by circles with the initial significance levels. The arrow 
represents the direction in which the significance level is propagated throughout the graph and 
the number in the square box represents the proportion of the propagated significance level.
All the tests are performed at the level resulting from the graphical procedure. If a tested null 
hypothesis is rejected at the local significance level assigned to this null hypotheses, the alpha 
is passed on to other null hypotheses as per the graph.
As described in Section 2.5.2, the primary hypothesis will be tested. 
If the primary hypothesis is rejected at a one-sided significance level of 0.025, the entire alpha 
will be distributed to the null hypothesis related to the non-inferiority testing of H2.
If H2 is rejected at a one-sided significance level of 0.025, the entire alpha will be distributed 
between the null hypotheses related to the superiority testing of H3 (50% of 0.025 = 0.0125), 
and H4 (50% of 0.025 = 0.0125). 
The family-wise type I error rate will be controlled at the one-sided 2.5% level across the 
tested null hypotheses using the closed testing procedure specified by Figure 2-1 using the 
graphical method of Bretz, et al. (Bretz, et al 2009).


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The basis for these tests will be the FAS with LOCF imputation/replacement of 
missing/censored data. For subjects who discontinue study treatment but continued in the study, 
data collected after the switch to alternative DME treatment in the study eye will be censored.
2.6.3
Handling of missing values/censoring/discontinuations
Missing data for all the secondary efficacy endpoints will be imputed using the LOCF method 
unless specified otherwise. 
For the LOCF method, missing data will be imputed by the value of the last available non-
missing post-baseline observation. For subjects who discontinue treatment but continue in the 
study, data collected after start of alternative DME treatment in the study eye will be censored 
for the analysis. Censored data will be replaced by the last available observation prior to the 
start of alternative DME treatment in the study eye.
Missing baseline values will not be imputed. For subjects with no post-baseline values 
(scheduled or unscheduled), the baseline value will be carried forward, as a conservative 
approach.
For endpoints related to presence of fluids, if baseline visit is reported as ”Cannot Grade”, then 
it will be considered as ”Absent”; If post-baseline visit is reported as ”Cannot Grade”, then it 
will be considered as missing and LOCF method for imputation will be applied. If unplanned 
visit is reported as “Cannot Grade”, no imputation will be applied.
2.7
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

Imaging parameters
There are no formal safety hypotheses in this study. All safety analyses will be performed using 
the Safety Set.
Except for imputation of partial dates for AEs, no imputations were performed for missing 
values in the safety analyses.
In all summary tables, unless otherwise specified (e.g. for AE tables), data collected after the
subject discontinued study treatment and started alternative DME treatment in the study eye
will be censored (data on the day the subject started alternative DME treatment will be included).
2.7.1
Adverse events (AEs)
A treatment-emergent adverse event (TEAE) is defined as any adverse event that develops after 
initiation of the study treatment or any event already present that worsens following exposure 


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to the study treatment. Only treatment-emergent adverse events will be presented in the 
summary tables.
Adverse events will be coded using the MedDRA dictionary and presented by system organ 
class (SOC) and preferred term (PT). Treatment-emergent AEs will be analyzed based on the 
number and percentage of subjects with at least one AE in the category of interest. 
The number (and proportion) of subjects with TEAE will be summarized in the following ways:
Table 2-7
TEAE summary
TEAE summary
AE categories
Ocular AE 
in the 
study eye
Ocular AE 
in the fellow 
eye
Non-
ocular 
AE
AEs by primary SOC and PT
Y#
Y#
AEs by primary SOC and PT (including events with onset date after 
start of alternative DME treatment)
Y
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
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
SAEs by SOC and PT 
Y#
Y#
SAEs by SOC and PT (including events with onset date after start of 
alternative DME treatment)
Y
Y
Y
SAEs related to study treatment by SOC and PT
Y
Y
SAEs related to injection procedure by SOC and PT
Y
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.
In all summary tables listed above, unless otherwise specified, data collected starting from
alternative DME treatment after discontinuation of study treatment will be censored. 
If an AE started on the same day as the start of alternative DME treatment for a subject, the AE
will be excluded from the summary table, unless this AE led to study drug withdrawal (in such
a case, the AE would be included in the analysis).
Subject listings of all adverse events will be provided. Deaths and SAEs (i.e., other serious or 
clinically significant non-fatal adverse events) will be listed separately.
The MedDRA version used for reporting the AEs will be described in a footnote.


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2.7.1.1
Adverse events of special interest / grouping of AEs
Incidence of adverse events of special interest (AESI) may be tabulated by treatment. 
AESIs and other safety topics of interest will be identified via the RTH258 electronic case 
retrieval strategy (eCRS). The eCRS that is current at the time the database lock will be used 
and AESIs and other safety topics of interest will be identified where the flag Core Safety Topic 
Risk (SP) = ‘Y’.
2.7.1.2
Adverse event reporting for clinical trial safety disclosure 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on TEAEs 
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 system organ class and 
preferred term on the safety set population. Ocular TEAEs for the study eye and for the fellow 
eye will be considered separately.
If for a 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 (respectively 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.
2.7.2
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.
2.7.3
Laboratory data
Laboratory data will be presented graphically using boxplots of absolute change from baseline 
values by treatment arm and visit. No summary by visit tables will be provided.
A summary table with counts and percentage of subjects satisfying the criteria representing 
clinically relevant abnormality given in Section 5.3 at any visit will be presented. A listing for 
subjects satisfying at least one criterion in Table 5-1 at any visit will also be presented.


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2.7.4
Other safety data
2.7.4.1
Ophthalmic examinations
Descriptive summaries of pre-injection change from baseline in intraocular pressure (IOP)
values for the study eye will be presented graphically at each study visit by treatment arm, 
considering line plots of the mean change in IOP values with error bars representing ± SE. The 
x-axis will be study visit and the y-axis will be the change from Baseline value. No summary 
by visit tables will be provided.
The number and percentage of subjects with pre-injection IOP >30 mmHg at any planned visit 
will be summarized. 
Post-injection IOP are to be assessed within 60 minutes after injection and if ≥25 mmHg, 
assessment should be repeated until back to normal. Summary tables with counts and percentage 
of subjects with an IOP increase of ≥10, ≥20 mmHg from pre-injection to post-injection at any 
visit for the study eye will be presented. 
A summary table with counts and percentage of subjects with observed pre-injection IOP >21
mmHg in 3 consecutive scheduled visits will be presented. A visit with missing pre-injection 
IOP is considered to meet the > 21 mmHg criterion if the preceding and the following visits 
meet the criterion that pre-injection IOP > 21 mmHg. For example, if schedule visit X has 
missing pre-injection IOP and pre-injection IOP >21mmHg is observed for both visit X-1 and 
X+1, the subject is considered to meet the criteria at visit X as well.
A listing for subjects with any post-injection IOP increase of ≥10mmHg from pre-injection IOP 
and a listing of subjects with any IOP > 30mmHg will be presented.
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.  
2.7.4.2
Loss in BCVA
The number and percentage of subjects with a loss in BCVA ≥15, ≥30 letters (study eye) from 
baseline to the last visit, and maximum loss at any visit will be presented. 
BCVA data (study eye) for subjects presenting loss in BCVA ≥15 letters from baseline at any 
post-baseline visit will be listed.
2.7.4.3
Vital signs
A summary table with counts and percentage of subjects satisfying the criteria given in Table
5-2 of the Section 5.3 to at least one visit will be presented. A listing for subjects satisfying at 
least one criterion in Table 5-2 will also be presented.
A line plot of mean change from baseline in the vital sign parameter by study visit and treatment 
with error bars representing ±1 standard error will be presented. The x-axis will be study visit 
and the y-axis will be the mean change from baseline value.


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2.7.4.4
Imaging parameters
Pre-defined imaging parameters in the study eye associated with intraocular inflammation 
and/or retinal vascular occlusion as assessed by the CRC will be listed per visit for all subjects, 
along with AESI flag. No summary table will be provided.
2.8
Pharmacokinetic endpoints
Not Applicable.
2.9
Anti-drug antibodies
Collection of blood for ADA assessment for brolucizumab will be done at Screening, Weeks 4, 
12, 24, 36, and 52 prior to the injection, and at exit/premature discontinuation.
ADA status is defined using the following criteria:

ADA negative:
- ADA negative at all time points (pre-dose and post-dose)
- ADA negative at pre-dose and no titer values above 40 at all other time points
- ADA titer of 40 at pre-dose but negative at all other time points

ADA positive without boost:
- ADA positive at pre-dose, post-dose titer values do not increase from pre-dose by 
more than 3-fold (1 dilution) at any time point

Induced:
- ADA negative at pre-dose, post-dose titer value of 120 or more increase

Boosted:
- ADA positive at pre-dose, post-dose titer values increase from pre-dose by more 
than 3-fold (1 dilution) at any time point
The number and percent of subjects according to their integrated ADA status (ADA negative, 
ADA positive without boost, induced, boosted) will be presented for the brolucizumab
treatment arm.
In addition, tabulations by treatment arm will be presented for ADA titer pattern. Subject
listings of all ADA titer values will be presented for all subjects. 
Systemic exposure of brolucizumab will be measured concomitantly with ADA levels for 
interpretation purposes, no pharmacokinetic parameters will be determined from brolucizumab 
systemic exposure. Systemic exposure data will be summarized and listed.
The number and percentage of subjects with positive neutralizing antibody (NAb) will be 
summarized by ADA assessment visit for subjects with ADA titer values (ADA positive).
Subject listings of all ADA titer values and NAb status will be presented for all subjects in the 
brolucizumab arms. Samples collected at unscheduled visits will not be part of the analysis.
In addition to the planned analyses, figures showing the BCVA change from baseline up to 
Week 52 by ADA status (pre-existing and integrated status up to Week 52) and NAb status 
(pre-existing and integrated status up to Week 52) will be added. Summary tables of the 


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incidence of AESIs by ADA status (pre-existing and integrated status up to Week 52) will also
be added.
2.11
Interim analysis
There will be no interim analysis in this study.
3
Sample size calculation
The fixed-margin method is used to derive an appropriate non-inferiority margin (NIM) for this 
study (FDA 2016). Results from a meta-analysis of the phase III studies VIVID and VISTA 
comparing monthly aflibercept 2 mg vs laser in subjects with DME suggest a pooled mean 
treatment effect of 10.8 letters (95% CI, [8.0, 13.6]) favoring aflibercept in the change from 
baseline in BCVA at Week 52. The smallest effect of aflibercept vs laser is defined as the lower 
limit of the 95% CI for the pooled mean BCVA, ie, an effect of 8.0 letters. The NIM is then set 
as the value which preserves 50% of this effect, ie, the NIM is set to 4 letters. This noninferiority 
margin provides assurance that any proof of non-inferiority only occurs if the effect of 
brolucizumab is superior to that of laser, and the observed treatment difference to aflibercept is 
of no clinical relevance.
Subjects will be randomized to the brolucizumab and aflibercept arms in a ratio of 2:1. A total 
sample size of 357 subjects (238 on the brolucizumab arm vs 119 on the aflibercept arm) will 
allow assessment of non-inferiority (using a NIM of 4 letters) of brolucizumab 6 mg versus 
aflibercept 2 mg with respect to the change from baseline in BCVA at Week 52. Assuming 
equal means and a common standard deviation of 11 letters, for a NIM of 4 letters and a two-
sided alpha level of 0.05, there is 90% power to reject the null hypothesis that brolucizumab is 


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inferior to aflibercept. To ensure that at least 300 subjects are treated with brolucizumab 6 mg 
on a fixed q4w regimen, the total sample size will be increased to 450 subjects (300 on the 
brolucizumab arm vs 150 on the aflibercept arm). This results in a statistical power for assessing 
non-inferiority of 95%.
Given the planned unequal sample size of 300 vs 150, there is a higher probability that 
infrequent AEs will occur in the brolucizumab arm than in the aflibercept arm in this study. For 
example, for an AE with a probability of occurrence of 0.01, the probabilities of observing at 
least one event are 95% and 78% for the brolucizumab and aflibercept arms, respectively, using 
a Binomial distribution. 
To account for a dropout rate of 9%, a total of approximately 495 subjects (330 on the 
brolucizumab arm vs 165 on the aflibercept arm) will need to be randomized.
4
Change to protocol specified analyses
There is no change to the protocol specified analysis in terms of endpoints.
Confirmatory hypothesis testing in relation to additional secondary endpoints is introduced in 
Section 2.6.2.3. Some changes compared to the protocol specified analyses are considered in 
the current statistical analysis plan before finalization in order to implement the Novartis 
internal process on SAP simplification (LEAN):
Protocol 
section
Protocol wording
Change in the SAP
12.3
Descriptive statistics for exposure to 
study treatment will be provided for 
the safety set, FAS and PPS if these 
are different
Descriptive statistics for exposure to study 
treatment will be provided for the Safety set.
12.4.2
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 letters) and 
age category (< 65, ≥ 65) as factors. 
Additional 
factors 
may 
also 
be 
included as appropriate, as well as 
interactions between treatment and 
factors of interest.
In the ANOVA model, baseline BCVA category 
factor is changed to ≤ 65, > 65 letters.
12.5.2
Adverse event of special interest 
(ESI)
AESI 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
AESI
AESIs and other safety topics of interest will be 
identified via the RTH258 electronic case 
retrieval strategy (eCRS).


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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.
Vital signs
A summary table with counts and percentage of 
subjects satisfying the criteria given in Table 5-
2 of the Section 5.3 to at least one visit will be 
presented. A listing for subjects satisfying at 
least one criterion in Table 5-2 will also be 
presented.
A line plot of mean change from baseline in the 
vital sign parameter by study visit and treatment 
with error bars representing ±1 standard error 
will be presented. The x-axis will be study visit 
and the y-axis will be the mean change from 
baseline value.
Laboratory data will be presented graphically 
using boxplots of absolute change from 
baseline values by treatment arm and visit. No 
summary by visit tables will be provided.
A summary table with counts and percentage of 
subjects satisfying the criteria representing 
clinically relevant abnormality given in Section 
5.3 at any visit will be presented. A listing for 
subjects satisfying at least one criterion in Table 
5-1 at any visit will also be presented.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
No imputation will be made to the start date and end date of study treatment.
5.1.2
AE date imputation
5.1.2.1
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


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MON MISSING
MON < TRTM
MON = TRTM
MON > TRTM
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:
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.
5.1.2.2
AE end date imputation
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).


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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.
5.1.3
Concomitant medication date imputation
5.1.3.1
Concomitant medication start date
In order to classify a medication as prior and prior/concomitant, it may be necessary to impute 
the start date.
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


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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
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.
5.1.3.2
Concomitant medication (CM) end date imputation
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 earliest 
of the (treatment end date, 31DECYYYY, date of death).
3. If the CM end date day is missing, the imputed end date should be set to the earliest of the
(treatment end date, last day of the month, date of death).
4. 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.
5.1.4
Medical history date of 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.
1. If DIAG year < treatment start date year 
a.
and DIAG month is missing, the imputed DIAG date is set to the mid-year point 
(01JULYYYY)
b. else if DIAG month is not missing, the imputed DIAG date is set to the mid-
month point (15MONYYYY)
2. If DIAG year = treatment start date year
a.
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


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b. else if DIAG month < treatment start month, the imputed DIAG date is set to the 
midmonth point (15MON YYYY)
c.
else if DIAG month > treatment start month => data error
3. If DIAG year > treatment start date year => data error
5.2
AEs coding/severity
AEs are coded using the MedDRA terminology. 
AEs severity are assessed by investigators according to the following: 

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
5.3
Laboratory parameters and vital signs derivations
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
NA
>3xULN
Glucose
mg/dL
< 40
> 450
mmol/L
< 2.2
> 25.0
Potassium
mEq/L
< 2.8
> 6.2
mmol/L
< 2.8
> 6.2
Sodium
mEq/L
< 120
> 160
mmol/L
< 120
> 160
HCG
Negative, 
inconclusive
Hematocrit
%
< 20
> 60
V/V
< 0.20
> 0.60
Hemaglobin
g/dL
< 6.0
> 20.0
g/L
< 60
> 200
Platelet
X10E3/uL
< 50
> 999
X10E9/L
< 50
> 999
WBC
X10E3/uL
< 2.0
> 35.0
X10E9/L
< 2.0
> 35.0
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


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5.4
Statistical models
In the sample SAS code, the terms in the brackets are for demonstration purpose and to be 
adjusted according to the real data set and variable names.
5.4.1
Primary analysis
The primary endpoint (change from baseline in BCVA at Week 52) will be analyzed using 
ANOVA and MMRM models.
Analysis of Variance (ANOVA)
The following ANOVA model will be used for the primary endpoint:
<change from Baseline in BCVA at Week 52>  = intercept + treatment + Baseline BCVA 
category + age category + error.
For the above analysis, the data structure is one record per subject. 
The SAS Proc MIXED will be used to perform the ANOVA analyses.
Mixed Model Repeated Measures (MMRM)
The following MMRM model will be used for the supportive analysis of the primary efficacy 
variable:
<change from Baseline in BCVA at Week 52> = intercept + treatment + Baseline BCVA 
category + age category + visit + treatment*visit + error.
The SAS Proc MIXED will be used to perform the MMRM analyses.
Note: For the above 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.
5.4.2
Other secondary efficacy analysis
5.4.2.1
ANOVA model for continuous variables
The continuous efficacy variable (such as CSFT change from baseline at Week 52) will be 
analyzed using an ANOVA model adjusted for treatment, age category, and the corresponding 
baseline value category.
The SAS Proc MIXED will be used to perform the ANOVA analyses
5.4.2.2
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, on the FAS. 
The SAS Proc LOGISTIC will be used. 
Note:

For the above analyses, the data structure is one record per subject and visit. The least 
square mean estimates obtained from the above model are for the log-odds ratios.


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
The estimated difference in proportions and the corresponding 95% confidence intervals 
will be obtained by applying the bootstrap method. The pseudo SAS code to derive the 
treatment difference and 95% CI from the least square mean output of the fitted model 
will be provided in the programming specification document.

For superiority tests, p-values (if applicable) will be obtained from odds ratio test in 
logistic model. For non-inferiority tests, p-values (if applicable) will be obtained by 
applying the bootstrap method.
5.4.2.3
Cox and KM estimate for time to event variables
Time to event parameters will be analyzed by Cox proportional hazard model, adjusted for 
treatment, age category and the corresponding baseline value category. The estimated hazard 
ratio with 95% Wald confidence interval will be obtained. SAS Proc Phreg will be used to 
perform the Cox model.
The median time and 95% CI will be derived from KM method, using SAS Proc Lifetest.
5.5
Rule of exclusion criteria of analysis sets 
Important protocol deviations are defined in the Protocol Deviations Requirements Document.  
Table 5-3 includes the important protocol deviations which lead to exclusion of a subject from 
one or more analysis sets. 
Table 5-3
Important protocol deviations leading to exclusion from analysis
Deviation ID
Description of Deviation
Exclusion in Analyses
M_INCL01_ICF not 
obtained
Written informed consent not obtained
Exclude from all analysis
P_INCL02_Age less than 
18 yrs
Patient less than 18 years of age at baseline
Exclude from PP analysis
M_INCL03_Diabetes 
eligibility criteria
Patients without diabetes mellitus or HbA1c of more 
than 12% at screening
Exclude from PP analysis 
P_INCL04a_No visual 
impairment study eye
Study Eye: no visual impairment due to DME as per 
BCVA criteria
Exclude from PP analysis
M_INCL04b_No visual 
impairment study eye
Study Eye: no visual impairment due to DME as per 
CSFT criteria
Exclude from PP analysis
M_EXCL08_ condition with 
impact study eye
Study Eye: Confounding ocular concomitant 
conditions or ocular disorders with impact on 
efficacy and/or safety
Exclude from PP analysis
M_EXCL10_Confounding 
treatment study eye
Study Eye: Confounding concomitant medications 
or procedures
Exclude from PP analysis
M_EXCL11_Confounding 
systemic condition/trt with 
impact
Systemic: confounding systemic conditions or 
systemic treatments with impact on efficacy and/or 
safety
Exclude from PP analysis
M_TRT01_Wrong IP 
administered
Wrong IP administered during the study
Exclude from PP analysis
M_TRT02_Under-
treatment 
Under-treatment: Missed 2 doses (not due to any 
safety event)
Exclude from PP analysis
M_TRT03_Over treatment
Over treatment: 3 doses < 41 days
Exclude from PP analysis 
M_OTH01_Other PD with 
impact
Any other protocol deviation with impact on efficacy  
and/or safety 
Exclude from PP analysis 


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Deviation ID
Description of Deviation
Exclusion in Analyses
M_OTH03_T EXC IP
Administered IP that underwent a temperature 
excursion
Exclude from PP analysis
P_WITH01_Treatment but 
consent withdrawn
Subject withdrew consent but continue in the study 
and receive study medication
Exclude from PP analysis
Table 5-4 lists the non-protocol deviations (analysis restrictions) that may lead to exclusion 
from per-protocol analysis. Analysis restrictions (ARs) address limitations in the evaluability 
which result from missing or confounded data with underlying background not qualifying as a 
PD (e.g. early study terminations, early treatment discontinuations, missing visits / missed 
treatments).
Rules of determination of ARs by programming will be specified in the programming Data 
Specifications (PDS) documentation.
Table 5-4
Non-protocol deviations (analysis restrictions)
AR ID
Description of AR
Category 
of reason
Exclusion in Analyses
AR_EST_01
Early study termination due to lack of efficacy
1
Include in all analysis
AR_EST_02
Early study termination due to safety
2
Include in all analysis
AR_EST_03
Early study termination due to reasons other than lack of 
efficacy/safety before or at week 48
0
Exclude from PP analysis
AR_ETD_01
Early study treatment termination due to lack of efficacy
1
Include in all analysis
AR_ETD_02
Early study treatment termination due to safety
2
Include in all analysis
AR_ETD_03
Early treatment termination due to reasons other than lack 
of efficacy/safety before or at week 48
0
Exclude from PP analysis
Subject evaluability is based on two components:

Exclusion from an analysis set 

Censoring of specific data points from an analysis (see Section 5.6).
The consequence of an AR on the evaluability depends on the underlying reason, while three
different categories of reason are considered:

Lack of efficacy of the study treatment (=1)

Lack of safety / tolerability of the study treatment (=2)

Other (=0)
Remark: Based on the concept of PD’s, their underlying reason will always be ‘0’.
As a general rule, ARs with a reason of 1 or 2 do not lead to an exclusion from any analysis set,
as a potential link between exclusion reason and treatment would constitute a source for 
systematic bias.
Table 5-5 describes subject classification with regards to analysis sets:


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Table 5-5
Subject classification
Analysis 
Set
PD ID that may cause subjects to be excluded
Non-PD (AR) ID that cause subjects to 
be excluded
RAS
M_INCL01_ICF not obtained
Not Randomized
FAS
M_INCL01_ICF not obtained
Not in the RAN,
Did not receive at least one study injection
SAF
M_INCL01_ICF not obtained
Did not receive at least one study injection
PPS
M_INCL01_ICF not obtained,
P_INCL02_Age less than 18 yrs, 
M_INCL03_Diabetes eligibility criteria, 
P_INCL04a_No visual impairment study eye,
M_INCL04b_No visual impairment study eye,
M_EXCL08_ condition with impact study eye, 
M_EXCL10_Confounding treatment study eye, 
M_EXCL11_systemic condition/trt with impact
M_TRT01_Wrong IP administered, 
M_TRT02_Under-treatment, 
M_TRT03_Over treatment, 
M_OTH01_other PD With Impact,
P_WITH01_Treatment but consent withdrawn,
M_OTH03_T EXC IP
Not in the FAS,
AR_EST_03,
AR_ETD_03
5.6
Censoring rules for analysis
Protocol deviations (PDs) and analysis restrictions (ARs) that are considered to be critical for 
the subject evaluability regarding the primary endpoint are described in Section 5.5.
Table 5-6 summarizes the concepts of censoring for the key parameter BCVA applied to the 
two efficacy analysis sets, FAS and PPS, as well as the details for the timing of censoring for 
BCVA.
In case a subject has multiple PDs/ARs with impact on subject’s evaluability the following rules
are applied:

A subject is excluded from an analysis set if at least one PD or AR with this consequence 
was identified (see Table 5-5). This rule is built on the concept of the medical assessment
of the ‘reason’ which considers the reason of an earlier event to potentially also be the
reason for following PDs or ARs.

In case of multiple censoring time points censoring will be performed at the earliest.
Table 5-6
Censoring concepts for BCVA
Analysis Set
Censoring concept for BCVA
FAS
Censoring of BCVA data after switch to alternative DME treatment in the study eye: 
imputation using the last observation collected prior to the start of alternative DME treatment 
(see section 2.5.3)
No other censoring related to PDs or ARs.
PPS
Censoring of BCVA data after switch to alternative DME treatment in the study eye: 
imputation using the last observation collected prior to the start of alternative DME treatment 
(see section 2.5.3)


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Analysis Set
Censoring concept for BCVA
M_COMD01_Prohibitedtrt with impact: censor at the last observation collected prior to the 
start of the prohibited medication or procedure, imputation using the last observation 
collected prior to the start of prohibited medication or procedure
6
Reference
Bretz F, Maurer W, Brannath W, et al (2009) A graphical approach to sequentially rejective 
multiple test procedures. Statistics in Medicine; 28(4): 586-604.