Conditions: Diabetic Macular Edema
Keywords: Diabetic Macular edema (DME) Intravitreal injection brolucizumab aflibercept macular edema diabetic retinopathy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 266
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the efficacy and safety of brolucizumab in treatment of Chinese patients with visual impairment due to Diabetic Macular Edema.

Detailed description:
The study is a randomized, double-masked, multi-center, active-controlled, 2-arm study in Chinese patients with Diabetic macular edema (DME). Approximately 335 Chinese patients were planned to be screened (20% screening failure rate expected) and approximately 268 (134 per arm) patients were planned to be randomized in approximately 25 centers.

Patients who met all the inclusion and none of the exclusion criteria were randomized in a 1:1 ratio to one of two treatment arms:

* Brolucizumab 6 mg: 5 × every 6 weeks (q6w) loading then every 12 weeks (q12w) or every 8 weeks (q8w) maintenance
* Aflibercept 2 mg: 5 × every 4 weeks (q4w) loading then q8w maintenance

Disease activity assessments (DAAs) were conducted by the masked investigator for both treatment arms at Weeks 32, 36, and 48. In the brolucizumab arm, subjects who qualified for q12w during this initial q12w interval continued on a q12w treatment frequency unless disease activity was identified at the subsequent DAA visit at Week 48, in which case subjects were switched to a q8w treatment interval until Week 52.

Arms:
arm 1: 5 x every 6 weeks loading then every 12 weeks or every 8 weeks maintenance arm 2: 5 x every 4 weeks loading then every 8 weeks maintenance

Interventions: intervention 1: Brolucizumab intervention 2: Aflibercept
Intervention descriptions: intervention 1: 5 x every 6 weeks loading then every 12 weeks or every 8 weeks maintenance intervention 2: 5 x every 4 weeks loading then every 8 weeks maintenance

Protocol document:
Prot_000.pdf: 
Novartis Research and Development
RTH258
Clinical Trial Protocol CRTH258B2304 / NCT04058067 
A One-Year, Randomized, Double-Masked, Multicenter, 
Phase III, Two-Arm Study Assessing the Efficacy and 
Safety of Brolucizumab versus Aflibercept in Adult Chinese 
Patients with Visual Impairment Due to Diabetic Macular 
Edema (KINGLET)
Document type:
Amended Clinical Trial Protocol
EUDRACT number:
Not applicable
Version number:
02 (Clean)
Clinical Trial Phase:
III
Release date:
08-Oct-2021
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template version 1.0 dated 01-Dec-2017


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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 2 08-Oct-2021...............................................................................................11
Amendment 1 10-Sep-2020...............................................................................................13
Protocol summary..............................................................................................................15
1
Introduction .......................................................................................................................18
1.1
Background............................................................................................................18
1.2
Purpose ..................................................................................................................20
2
Objectives and endpoints...................................................................................................20
3
Study design ......................................................................................................................21
4
Rationale............................................................................................................................23
4.1
Rationale for study design .....................................................................................23
4.2
Rationale for dose/regimen and duration of treatment ..........................................23
4.3
Rationale for choice of comparator .......................................................................24
4.4
Purpose and timing of interim analyses/design adaptations..................................24
4.5
Risks and benefits..................................................................................................24
5
Population..........................................................................................................................25
5.1
Inclusion criteria ....................................................................................................25
5.2
Exclusion criteria...................................................................................................25
6
Treatment...........................................................................................................................28
6.1
Study treatment......................................................................................................28
6.1.1
Investigational and control drugs..........................................................28
6.1.2
Additional study treatments ..................................................................28
6.1.3
Treatment arms/group ...........................................................................28
6.1.4
Treatment duration................................................................................29
6.2
Other treatment(s)..................................................................................................29
6.2.1
Concomitant therapy.............................................................................29
6.2.2
Prohibited medication ...........................................................................29
6.2.3
Rescue medication ................................................................................30
6.3
Subject numbering, treatment assignment, randomization....................................30
6.3.1
Subject numbering ................................................................................30
6.3.2
Treatment assignment, randomization ..................................................31
6.4
Treatment masking ................................................................................................31


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6.5
Dose escalation and dose modification..................................................................33
6.5.1
Dose modifications................................................................................33
6.6
Additional treatment guidance...............................................................................33
6.6.1
Treatment compliance...........................................................................33
6.6.2
Emergency breaking of assigned treatment code..................................33
6.7
Preparation and dispensation.................................................................................34
6.7.1
Handling of study treatment..................................................................34
6.7.2
Instruction for prescribing and taking study treatment .........................35
7
Informed consent procedures ............................................................................................37
8
Visit schedule and assessments .........................................................................................38
8.1
Screening ...............................................................................................................42
8.1.1
Information to be collected on screening failures.................................42
8.2
Subject demographics/other baseline characteristics.............................................42
8.3
Efficacy..................................................................................................................43
8.3.1
Visual acuity..........................................................................................43
8.3.2
Optical coherence tomography .............................................................43
8.3.3
Color fundus photography and fluorescein angiography......................43
8.3.4
Appropriateness of efficacy assessments..............................................44
8.4
Safety.....................................................................................................................44
8.4.1
Laboratory evaluations..........................................................................45
8.4.2
Pregnancy and assessments of fertility .................................................45
8.4.3
Other safety evaluations........................................................................46
8.4.4
Appropriateness of safety measurements..............................................47
8.5
Additional assessments..........................................................................................47
8.5.1
Clinical Outcome Assessments (COAs) ...............................................47
8.5.2
Pharmacokinetics ..................................................................................48
8.5.3
Other Assessments ................................................................................48
9
Study discontinuation and completion ..............................................................................49
9.1
Discontinuation......................................................................................................49
9.1.1
Discontinuation of study treatment .......................................................49
9.1.2
Withdrawal of informed consent/Opposition to use data/biological 
samples..................................................................................................50
9.1.3
Lost to follow-up...................................................................................51
9.1.4
Early study termination by the sponsor.................................................51
9.2
Study completion and post-study treatment ..........................................................51
10 Safety monitoring and reporting........................................................................................51
10.1
Definition of adverse events and reporting requirements......................................51


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10.1.1
Adverse events ......................................................................................51
10.1.2
Serious adverse events ..........................................................................53
10.1.3
SAE reporting........................................................................................54
10.1.4
Pregnancy reporting ..............................................................................55
10.1.5
Reporting of study treatment errors ......................................................55
10.2
Additional Safety Monitoring................................................................................55
10.2.1
Data Monitoring Committee .................................................................55
11 Data Collection and Database management......................................................................55
11.1
Data collection.......................................................................................................55
11.2
Database management and quality control............................................................56
11.3
Site monitoring ......................................................................................................57
12 Data analysis and statistical methods ................................................................................57
12.1
Analysis sets ..........................................................................................................58
12.2
Subject demographics and other baseline characteristics......................................58
12.3
Treatments .............................................................................................................58
12.4
Analysis of the primary endpoint(s) ......................................................................59
12.4.1
Definition of primary endpoint(s).........................................................59
12.4.2
Statistical model, hypothesis, and method of analysis..........................59
12.4.3
Handling of missing values/censoring/discontinuations.......................60
12.4.4
Sensitivity and Supportive analyses......................................................61
12.5
Analysis of secondary endpoints ...........................................................................62
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................62
12.5.2
Safety endpoints....................................................................................64
12.5.3
Pharmacokinetics ..................................................................................65
12.5.4
Patient reported outcomes.....................................................................65
12.5.5
Anti-drug antibodies..............................................................................65
65
12.7
Interim analyses.....................................................................................................66
12.8
Sample size calculation..........................................................................................66
12.8.1
Primary endpoint(s)...............................................................................66
13 Ethical considerations and administrative procedures ......................................................66
13.1
Regulatory and ethical compliance........................................................................66
13.2
Responsibilities of the investigator and IRB/IEC..................................................67
13.3
Publication of study protocol and results...............................................................67
13.4
Quality Control and Quality Assurance.................................................................67
14 Protocol adherence ............................................................................................................67
14.1
Protocol Amendments ...........................................................................................68


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15 References .........................................................................................................................69
16 Appendices ........................................................................................................................70
16.1
Appendix 1: Clinically notable laboratory values .................................................70
List of tables
Table 2-1
Objectives and related endpoints ..........................................................20
Table 6-1
Investigational and control drug............................................................28
Table 6-2
Prohibited medications/procedures.......................................................30
Table 6-3
Masking levels ......................................................................................31
Table 8-1
Assessment Schedule ............................................................................40
Table 8-2
Assessments & Specifications...............................................................45
Table 8-3
Laboratory Assessments........................................................................45
Table 10-1
Guidance for capturing the study treatment errors................................55
Table 12-1
Primary and supplementary estimands..................................................61
Table 16-1
Clinically notable laboratory values......................................................70
List of figures
Figure 3-1
Study design..........................................................................................22
Figure 6-1
Treatment schedule ...............................................................................36


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List of abbreviations
ACR
albumin-creatinine ratio
ADA
anti-drug antibody
AE
adverse event
AMD
age-related macular degeneration
ANOVA
analysis of variance
ARs
analysis restrictions
BCVA
best-corrected visual acuity
BL
Baseline
CFR
Code of Federal Regulation
CMO & 
PS
Chief Medical Office and Patient Safety
CNV
Choroidal neovascularization
COA
Clinical Outcome Assessment
COVID-
19
Coronavirus disease 2019
CRA
Clinical research associate
CRC
Central Reading Center
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSFT
central subfield thickness
CSR
clinical study report
CTT
Clinical Trial Team
DAA
Disease Activity Assessment
DAR
dose administration record
DDE
Direct Data Entry
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 Form
EDC
Electronic Data Capture
EMA
European Medicines Agency
EOS
End of study
EOT
End of treatment
ESI
event of special interest
ETDRS
Early Treatment Diabetic Retinopathy Study
EU
European Union
FA
fluorescein angiography
FAS
Full analysis set
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GCS
Global Clinical Supply


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HbA1c
Hemoglobin A1c
hCG
Human chorionic gonadotropin
HCP
Health care professionals
HRQL
Health-Related Quality of Life
IB
Investigator Brochure
ICF
Informed consent form
ICH
International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human
IEC
Independent Ethics Committee
ILM
inner limiting membrane
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
LFT
Liver function test
LLOQ
lower limit of quantification
LOCF
Last observation carried forward
MAR
missing at random
MD
Medical Doctor
ME
Macular edema
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
MMRM
Mixed model for repeated measures
MoA
Mode of Action
nAMD
Neovascular age-related macular degeneration
NEI
National Eye Institute
NIH
National Institutes of Health
NIM
Non-inferiority margin
OCT
Optical coherence tomography
PCR
protein-creatinine ratio
PD
Protocol Deviation
PDR
Proliferative diabetic retinopathy
PK
pharmacokinetic(s)
PPS
Per Protocol Set/Protocol analysis set
PT
Preferred Term
q12w
every 12 weeks
q4w
every 4 weeks
q6w
every 6 weeks


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q8w
every 8 weeks
QMS
Quality Management System
QoL
Quality of Life
RAO
Retinal Artery Occlusion
RO
Retinal vascular occlusion
RV
Retinal vasculitis
RPE
Retinal Pigment Epithelium
SAE
serious adverse event
SAF
Safety Analysis Set
SAP
Statistical analysis plan
scFv
single-chain fragment variable
SD-OCT
Spectral domain optical coherence tomography
SOC
System Organ Class
SOP
Standard Operation Procedure
SRF
Subretinal fluid
SUN
standardization uveitis nomenclature
SUSAR
Suspected Unexpected Serious Adverse Reactions
USM
Urgent Safety Measures
US
United States
VA
Visual acuity
VEGF
Vascular endothelial growth factor
VFQ-25
Visual Functioning Questionnaire-25
WHO
World Health Organization
WoC
Withdrawal of Consent
YAG 
laser
Yttrium aluminum garnet laser


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Glossary of terms
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
A study drug 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.
Enrollment
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol)
Estimand
As defined in the ICH E9(R1) addendum, estimand is a precise description of 
the treatment effect reflecting the clinical question posed by the trial objective. It 
summarizes at a population-level what the outcomes would be in the same 
participants under different treatment conditions being compared. Attributes of 
an estimand include the population, variable (or endpoint) and treatment of 
interest, as well as the specification of how the remaining intercurrent events 
are addressed and a population-level summary for the variable.
eSource DDE
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines 
source documents and case report forms (eCRFs) into one application, 
allowing for the real time collection of clinical trial information to sponsors and 
other oversight authorities, as appropriate
Investigational drug
The study drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product”.
Masked/evaluating 
investigator
For the entire study duration and all study patients, the masked/evaluating 
investigator is responsible for all aspects of the study (the conduct/supervision 
of all assessments and treatment decisions except the injection procedures and 
the safety assessment following the active/sham injections)
Medication number
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IRT system.
Patient
An individual with the condition of interest
Patient-Reported Outcome 
(PRO)
A measurement based on a report that comes directly from the patient about 
the status of a participant's health condition without amendment or 
interpretation of the patient's report by a clinician or anyone else
Period
A minor subdivision of the study timeline; divides phases into smaller functional 
segments such as screening, baseline, titration, washout, etc.
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
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine the 
assignments in order to reduce bias.
Randomization number
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment
Re-screening
If a participant fails the initial screening and is considered as a Screen Failure, 
he/she can be invited once for a new Screening visit after medical judgment 
and as specified by the protocol
Screen Failure
A subject who is screened but is not treated or randomized
Study completion
Point/time at which the subject came in for a final evaluation visit or when study 
drug was discontinued whichever is later.
Study drug discontinuation
Point/time when subject permanently stops taking study drug for any reason; 
may or may not also be the point/time of premature subject withdrawal.


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Study drug/treatment
Any drug (or combination of drugs) administered to the subject as part of the 
required study procedures; includes investigational drug, active drug run-ins or 
background therapy.
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the defined 
study treatment completion date
Subject
An individual who has consented to participate in this study. The term Subject 
may be used to describe either a healthy volunteer or a patient.
Subject number
A number assigned to each subject who enrolls in the study. When combined 
with the center number, a unique identifier is created for each subject in the 
study.
Unmasked/treating 
investigator
For the entire study duration and all study patients, the treating investigator only 
performs the treatment (injection active/sham) and assesses patient safety 
following the active/sham injections
Variable (or endpoint)
The variable (or endpoint) to be obtained for each participant that is required to 
address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event.
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 study consent 
(WoC)/ Opposition to use of 
data /biological samples
Withdrawal of consent from the study occurs when the participant explicitly 
requests to stop use of their data and biological samples (opposition to use 
data and biological samples) AND no longer wishes to receive study treatment 
AND does not agree to further protocol required assessments. This request 
should be in writing (depending on local regulations) and recorded in the source 
documentation.
Opposition to use data/biological samples occurs in the countries where 
collection and processing of personal data is justified by a different legal reason 
than consent.


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Amendment 2 08-Oct-2021
Amendment rationale 
The main purpose of this amendment is to implement the Urgent Safety Measures (USM) 
described in the 10-Aug-2021 Dear Investigator Letter (DIL) into the study protocol.  The 
USM were implemented for ongoing studies not achieving Last Patient Last Visit (LPLV) by 
11-Aug-2021 and in response to the identification of a causal immune-mediated mechanism 
of the previously identified risk of retinal vasculitis (RV), and/or retinal vascular occlusion 
(RO), typically in the presence of intraocular inflammation (IOI) indicating a requirement to 
discontinue treatment in patients who develop events of RV and/or RO.
This amendment also includes information on gender imbalance on IOI following brolucizumab 
treatment and recommendations on the time window for a study subject to receive the 
COVID-19 vaccine.  
This amendment also includes the changes back to the original protocol in Section 5.2 and 
Section 6.2.2 based on the National Medical Products Administration (NMPA)’s comment 
during the protocol amendment v01 (dated on 10Jun2020) review.
Some other administrative changes have also been incorporated.
Changes to the protocol
Protocol sections changed in relation to this emerging safety measure are:

Section 1.1 Background: Information added to describe Urgent Safety Measures

Section 4.5 Risk and benefits: Information added to describe Urgent Safety Measures and 
additional information on gender imbalance on IOI following brolucizumab treatment

Section 6.7.2 Instruction for administering study treatment: Requirement of treatment 
discontinuation was added if subject developed RV and/or RO, in both arms.

Section 8.4.3 Ophthalmic examination: Requirement of treatment discontinuation was 
added if subject developed RV and/or RO.

Section 9.1.1 Discontinuation of study treatment: Requirement of treatment 
discontinuation was added if subject developed RV and/or RO.

Section 9.1.2 Clarified the definition of Withdrawal of Consent (WoC).
Other changes incorporated in this amendment

Glossary of teams has been updated to the latest template wording

Section 6.2.1.1 Permitted concomitant therapy requiring caution and/or action: added 
recommendations on the time window for a study subject to receive the COVID-19 
vaccine

Section 5.2 and Section 6.2.2: Changes related to the COVID-19 pandemic in Amendment 
1 were reverted back to the original protocol v00 based on the NMPA’s comment on 
Amendment 1.


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
Section 8.5.2 To make consistent with the following wordings (approximately 24 
consented subjects to obtain approximately 12 subjects per treatment arm to maintain 
masking).

Other minor clarifications and corrections were made where applicable.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strikethrough red font for deletions and red underlined for insertions.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation. 
The changes herein affect the Informed Consent.  Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Amendment 1 10-Sep-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 neovascular age-related macular degeneration 
(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 Coronavirus disease 2019 (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 6.2.2 Prohibited medication: Restrictions in use of corticosteroids have been 
removed to provide flexibility using systemic steroids for the treatment of AEs during the 
study period at the investigator’s discretion.

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 (IOI) 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 IOI 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 Other safety evaluations: slit lamp and indirect fundus examination

Section 8.4.4 Appropriateness of safety measurements
Changes were incorporated to address the COVID-19 pandemic in the following sections:

Section 5.2 Exclusion criteria 20

Section 6.2.2 Prohibited medication Table 6-2

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


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Other changes were incorporated in the following sections:

Table 2-1 Objectives and related endpoints: aligned with Section 12.5.1.2.  

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.

Table 8-1 Assessment schedule: The assessment schedule of Visual Function 
Questionnaire-25 was updated from Visit 9 to Visit 10 due to the typographical error in 
previous version.

Section 8.2 Subject demographics/other baseline characteristics: Removed ethnicity since 
it was not collected in the study. 

Section 8.4.3 Other safety evaluations: Clarification of Post-injection IOP measurement 
timing.

Section 8.5.3 Other assessments

Section 10.1.3 SAE reporting: Clarification of the SAE reporting period.

Section 12 Data analysis and statistical methods: Language was updated 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 in 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.
This amendment is primarily required for patient safety (i.e. necessary to eliminate immediate 
hazards to the trial subjects per ICH GCP 3.3.8). Therefore, the changes related to the emerging 
safety issue will be implemented prior to IRB/IEC and Health Authority approval, however the 
remaining changes will not be implemented until after receipt of IRB/IEC and Health Authority 
approval according to local regulations.
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
RTH258B2304
Full Title
A One-Year, Randomized, Double-Masked, Multicenter, Phase III, Two-Arm Study 
Assessing the Efficacy and Safety of Brolucizumab versus Aflibercept in Adult Chinese 
Patients with Visual Impairment Due to Diabetic Macular Edema (KINGLET)
Brief title
Efficacy and Safety of Brolucizumab versus Aflibercept in Adult Chinese Patients with 
Visual Impairment Due to Diabetic Macular Edema
Sponsor and 
Clinical Phase
Novartis
Phase III
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to evaluate the efficacy and safety of brolucizumab in 
treatment of Chinese patients with visual impairment due to Diabetic Macular Edema 
(DME).
Primary 
Objective(s) 
The primary objective of this study is to demonstrate that brolucizumab is non-inferior to 
aflibercept with respect to the visual outcome after up to one year of treatment
Secondary 
Objectives
1.
To estimate the proportion of patients treated at every 12 weeks (q12w) frequency 
with brolucizumab
2.
To estimate the predictive value of the first q12w cycle for maintenance of q12w 
treatment with brolucizumab
3.
To evaluate the functional and anatomical outcome with brolucizumab relative to 
aflibercept
4.
To evaluate the effect of brolucizumab relative to aflibercept on the Diabetic 
Retinopathy (DR) status
5.
To assess the safety of brolucizumab relative to aflibercept
6.
To evaluate the effect of brolucizumab relative to aflibercept on patient-reported 
outcomes (Visual Functioning Questionnaire-25 (VFQ-25))
7.
To confirm the systemic brolucizumab exposure in a subset of patients
8.
To assess the immunogenicity of brolucizumab over one year of treatment
Study design
The study is a randomized, double-masked, multi-center, active-controlled, 2 armed 
study in Chinese patients with DME.
Patients who meet all the inclusion and none of the exclusion criteria will be randomized 
in a 1:1 ratio to one of two treatment arms:

Brolucizumab 6 mg: 5 x every 6 weeks (q6w) loading then q12w or every 8 weeks 
(q8w) maintenance

Aflibercept 2 mg: 5 x every 4 weeks (q4w) loading then q8w maintenance
Population
The study population will be male and female Chinese patients ≥ 18 years old with 
visual impairment due to DME. Approximately 335 Chinese patients will be screened 
(20% screening failure rate expected) and approximately 268 (134 per arm) patients will 
be randomized in approximately 25 centers.
Key Inclusion 
criteria
1.
Signed informed consent must be obtained prior to participation in the study.
2.
Patients ≥18 years of age at screening
3.
Patients with type 1 or type 2 diabetes mellitus (DM) and Hemoglobin A1c (HbA1c) 
of ≤10% at screening
4.
Medication for the management of diabetes must have been stable within 3 months 
prior to randomization and is expected to remain as stable as medically acceptable 
during the course of the study


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5.
Study Eye
Visual impairment due to DME with:

Best-corrected visual acuity (BCVA) score between 78 and 23 letters, inclusive, 
using ETDRS visual acuity (VA) testing charts at a starting testing distance of 4 
meters (approximate Snellen equivalent of 20/32 to 20/320) at screening and 
baseline

DME involving the center of the macula, with central subfield retinal thickness (e.g. 
measured from retinal pigment epithelium (RPE) to the inner limiting membrane 
(ILM) inclusively) of ≥320 µm on Spectral domain optical coherence tomography 
(SD-OCT) at screening. Eligibility is determined by Investigator’s assessment at 
time of Screening.
If both eyes are eligible, the eye with the worse visual acuity will be selected for study 
eye. However, the investigator may select the eye with better visual acuity, based on 
medical reasons or local ethical requirements.
Key Exclusion 
criteria

Active Proliferative diabetic retinopathy (PDR) in the study eye as per investigator

Concomitant conditions or ocular disorders in the study eye at screening or 
baseline which could, in the opinion of the investigator, prevent response to study 
treatment or may confound interpretation of study results, compromise visual acuity 
or require medical or surgical intervention for the duration of the study (e.g. 
cataract, vitreous hemorrhage, retinal vascular occlusion, retinal detachment, 
macular hole, or choroidal neovascularization (CNV) of any cause)

Any active intraocular or periocular infection or active intraocular inflammation (e.g. 
infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis, 
uveitis) in study eye at screening or baseline

Structural damage of the fovea in the study eye at screening likely to preclude 
improvement in visual acuity following the resolution of macular edema (ME), 
including atrophy of the retinal pigment epithelium, subretinal fibrosis, laser scar(s), 
epiretinal membrane involving fovea or organized hard exudate plaques

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

Neovascularization of the iris in the study eye at screening or baseline

Evidence of vitreomacular traction in the study eye at screening or baseline which 
in the opinion of the investigator, affects visual acuity

Previous treatment with any anti-vascular endothelial growth factor (VEGF) drug or 
investigational drugs in the study eye
Study treatment
Brolucizumab 6 mg/0.05mL
Aflibercept 2 mg/0.05mL
Efficacy 
assessments

BCVA with ETDRS-like chart at 4 meters

Anatomical markers on SD-OCT

ETDRS Diabetic Retinopathy Severity Scale (DRSS) score based on 7-field stereo 
Color Fundus Photography

Vascular leakage evaluation by fluorescein angiography (FA)
Pharmacokinetic 
assessments
Systemic brolucizumab exposure assessment will be performed on approximately 24 
consented patients or approximately 12 patients per treatment arm to maintain 
masking.
Key safety 
assessments

Adverse events (AEs), including AEs of special interest

Physical examination, vital signs

Standard ophthalmic examination (Biomicroscopy (slit lamp examination), 
Intraocular pressure, Indirect ophthalmoscopy)

Hematology/clinical chemistry/urinalysis
Other 
assessments

Patient Reported Outcome: National Eye Institute (NEI) VFQ-25

Pharmacokinetics (PK) of brolucizumab


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
Anti-Drug Antibodies (ADA) of brolucizumab
Data analysis
Primary analysis data set:
The primary data set for efficacy evaluation is the full analysis set (FAS) with missing 
values imputed by last observation carried forward (LOCF). The FAS includes all 
randomized patients who receive at least one intravitreal (IVT) injection.
Sensitivity and supportive analyses will be performed using the per protocol analysis set 
(PPS) and alternative methods of handling missing values.
Primary and key secondary endpoints:
The primary endpoint is the change from baseline in BCVA at Week 52.
The key secondary efficacy endpoint involved in confirmatory testing is average change 
from baseline in BCVA averaged over the period Week 40 to Week 52.
Additional key secondary endpoints are proportion of patients maintained at q12w up to 
Week 52 and proportion of patients maintained at q12w up to Week 52 within those 
patients that qualified for q12w at Week 36 (for brolucizumab treatment arm only)
Statistical Hypotheses and testing strategy:
The following non-inferiority hypotheses are related to a non-inferiority margin (NIM) of 4 
letters:
B = Brolucizumab 6 mg - 5 x q6w loading then q12w/q8w maintenance
A = Aflibercept 2 mg - 5 x q4w loading then q8w maintenance
H01: μB – μA ≤ -4 letters vs. HA1: μB – μA > -4 letters
H02: φB – φA ≤ -4 letters vs. HA2: φB – φA > -4 letters
Where μB and μA are the corresponding unknown true mean changes from baseline in 
BCVA at Week 52; φB and φA are the corresponding unknown true mean changes from 
baseline in BCVA averaged over the period Week 40 to Week 52;
These 2 hypotheses will be tested sequentially in the order of their numbering (HAn, n=1, 
2). Consequently, confirmatory testing of the second hypothesis requires rejection of the 
first null hypothesis. In this setting, each hypothesis will be assessed at a one-sided 
significance level of 0.025, while keeping the global type I error rate at 0.025.
Primary statistical method:
Analysis of variance (ANOVA) models will be used to test the treatment differences 
regarding the endpoints ‘change from baseline in BCVA at Week 52’ and ‘change from 
baseline in BCVA averaged over the period Week 40 to Week 52’. The models will include 
baseline BCVA category (≤65, >65 letters) and age category (<65, ≥65 years) as factors. 
Two-sided 95% confidence intervals (CI) for the least square means difference 
(brolucizumab - aflibercept) will be presented. Within the specified testing procedure, 
non-inferiority will be established if the lower limit of the corresponding 95% CI is greater 
than -4 letters.
Sample size justification:
A sample size of 120 patients per arm will allow to demonstrate a non-inferiority (NIM of 
4 ETDRS letters) of brolucizumab 6 mg vs. aflibercept 2 mg with respect to the BCVA 
change from baseline at Week 52, with 80% power at a one-sided alpha level of 0.025, 
assuming equal means and a common standard deviation of 11 letters. Assuming that 
averaging over the 4 time points will not lead to an increase in the standard deviation a 
power of at least 80% can also be expected for its corresponding non-inferiority claim. 
To account for a drop-out rate of 10%, a total of 268 (134 per arm) patients will need to 
be randomized.
Key words
Diabetic Macular Edema, intravitreal injection, brolucizumab, aflibercept, double-
masked


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1
Introduction
1.1
Background
Diabetes mellitus (DM) is the most common endocrine disease in developed countries, with 
prevalence estimates ranging between 2 to 5% of the world population. Diabetic retinopathy 
(DR) and diabetic macular edema (DME) are common microvascular complications in patients 
with diabetes and may have a debilitating impact on visual acuity (VA), eventually leading to 
blindness. DME is a frequent manifestation of DR (Lee et al 2015) and is the major cause of 
visual loss in patients with DR.
For anti-vascular endothelial growth factor (VEGF) agents like ranibizumab or aflibercept, a 
favorable benefit risk ratio was demonstrated with superior efficacy versus the previous 
standard of care (laser photocoagulation) in large Phase 3 programs that consequently led to 
their approval for the treatment of DME (Ziemssen et al 2017; Korobelnik et al 2014). Anti-
VEGF treatment led to clinically relevant improvements of BCVA, reduction of fluid 
accumulation and decreased severity of diabetic retinopathy.
Current available therapies
The current treatment options for patients with DME are: laser photocoagulation, intravitreal 
(IVT) corticosteroids, IVT corticosteroid implants, or IVT anti-VEGF. Due to the efficacy and 
safety profile of anti-VEGF therapy, it has become the first-line treatment. Corticosteroids are 
used as a second line treatment and focal/grid laser photocoagulation remains a therapeutic 
option, but with a lower expected benefit compared with steroid and anti-VEGF therapy.
Currently available anti-VEGF treatments require frequent regular IVT injections which can be 
burdensome to patients and health care professionals (HCP). Thus, despite the treatment success 
of existing anti-VEGFs, there remains a need for further treatment alternatives to improve 
response rate and/or reduce treatment burden and injection frequency in patients with DME 
(Mitchell et al 2011; Smiddy 2011; Lang et al 2013; Virgili et al 2014; Agarwal et al 2015).
Brolucizumab
Brolucizumab, formerly known as RTH258 and ESBA1008, is a humanized single-chain 
fragment variable (scFv), binding to VEGF-A (i.e. interfering with activation of VEGF-R1 and 
R2 on endothelial cells) with a molecular weight of ~26 Kilodaltons (kDa) that has also being 
developed for the treatment of choroidal neovascularization (CNV) associated with neovascular 
age-related macular degeneration (nAMD).
The characteristics of brolucizumab allow delivery of a high molar dose via intravitreal 
injection. Higher molar doses are expected to lead to longer presence of relevant drug levels in 
the retina. In addition, a low molecular weight and high concentration gradient between the 
vitreous and the retina may increase drug distribution to the target site of action, supporting 
effective control of anatomical disease activity. This could potentially translate into a more 
durable efficacy and a reduced treatment burden (number of injections) for the patient and 
HCP.


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Brolucizumab in nAMD
In a single ascending dose Phase I study (C-10-083), the median time until age-related macular 
degeneration (AMD) patients fulfilled protocol defined criteria for receipt of standard of care 
treatment was 30 days longer for brolucizumab 3 mg (p=0.037) and 6 mg (p=0.036) versus 
ranibizumab. In a separate repeat dosing study (C-12-006) comparing brolucizumab 6 mg 
(every 8 weeks (q8w), then every 12 weeks (q12w) administration) against aflibercept (q8w 
administration), brolucizumab achieved comparable visual outcome during the loading and q8w 
phase, with a lower number of patients requiring additional rescue treatments (5 vs. 10, 
respectively). Brolucizumab demonstrated a trend for greater improvements and more stability 
in retinal anatomy during the 4 cycles of q8w dosing (up to Week 40), e.g. simultaneous 
resolution of intraretinal and subretinal fluid (SRF) which was achieved in 61% of 
brolucizumab patients versus 35% of aflibercept patients at Week 40. In the Phase III studies 
RTH258-C001 (HAWK) and RTH258-C002 (HARRIER), brolucizumab demonstrated non-
inferiority to aflibercept in mean change in best-corrected visual acuity (BCVA) from baseline 
to Week 48 in both trials. These results were achieved while a majority of patients on 
brolucizumab 6 mg – 56% in HAWK and 51% in HARRIER – were maintained on a q12w 
dosing interval following the loading phase through Week 48. Significantly fewer patients on 
brolucizumab had disease activity at Week 16 (head-to-head comparison based on a matching 
dosing regimen) with a relative decrease of 30% (P = 0.0022) versus aflibercept. Significantly 
fewer patients on brolucizumab had intraretinal fluid (IRF) and/or subretinal fluid (SRF), with 
a 35% and 33% reduction relative to aflibercept at Week 16 (P < 0.001 for both) in HAWK and 
HARRIER, respectively, and a 31% and 41% reduction relative to aflibercept at Week 48 in 
HAWK and HARRIER, respectively (P < 0.0001 for both). Brolucizumab 6mg achieved 
superior reductions in central subfield thickness (CSFT) versus aflibercept in both the head-to-
head and maintenance phases (P = 0.0016 and P = 0.0023 at Week 16 and Week 48, respectively, 
in HAWK; P < 0.0001 at both Week 16 and Week 48 in HARRIER). Brolucizumab safety was 
comparable to aflibercept, with the overall incidence of adverse events (AEs) balanced across 
all treatment groups in both studies.
Since the first marketing authorization approval in 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 
post-marketing experience with brolucizumab (Beovu®). Results of the mechanistic study 
BASICHR0049 on blood samples from nAMD patients exposed to brolucizumab and having 
subsequently developed retinal vasculitis and/or retinal vascular occlusion, taken together with 
accumulated data from HAWK, HARRIER and CRTH258AUS04 (MERLIN), regarding the 
association of treatment-emergent immunogenicity and IOI, indicate a causal link between the 
treatment-emergent immune reaction against brolucizumab and the brolucizumab-related 
retinal vasculitis and/or retinal vascular occlusion, typically in the presence of IOI. Considering 
the incidence of these events is uncommon, the overall risk/benefit assessment remains positive.
Summary
Ranibizumab, aflibercept and brolucizumab all inhibit the activity of VEGF-A and both 
ranibizumab and aflibercept have demonstrated efficacy in the treatment of patients with nAMD. 
Both ranibizumab and aflibercept have also consistently demonstrated efficacy in the treatment 
of patients with visual impairment due to DME. These findings support the evaluation of 


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brolucizumab in DME patients. Furthermore, the efficacy profile of brolucizumab in nAMD 
patients indicates a potential of brolucizumab to differentiate versus existing anti-VEGFs on 
duration of action and anatomical efficacy in DME patients:

The longer duration of action is supported by the following outcomes of the phase I and II 
nAMD studies with brolucizumab 6 mg dose: 

Maximum improvements in BCVA and CSFT at Week 4 for ranibizumab versus 
Week 6 for brolucizumab 

Greater CSFT stability during q8w maintenance versus aflibercept: 

Fewer rescue treatments versus aflibercept in q8w phase 

The aforementioned results were confirmed by the nAMD 48-week study results (HAWK 
and HARRIER studies), which demonstrated: 

Visual gains at Week 48 achieved with 56% (HAWK) and 51% (HARRIER) of 
patients treated following a q12w regimen

Superior reduction in CSFT versus aflibercept

The potential for less frequent injections of brolucizumab as compared to aflibercept

Lower proportion of patients with intra- and/or subretinal fluid
These considerations support the initiation of a Phase III program to evaluate the efficacy and 
safety of brolucizumab in treatment of patients with visual impairment due to DME with the 
objective to evaluate the potential to reduce the treatment burden for patients.
1.2
Purpose
The purpose of this study is to evaluate the efficacy and safety of brolucizumab in treatment of 
Chinese patients with visual impairment due to DME.
2
Objectives and endpoints
For the detailed description of endpoints and their statistical analysis, please refer to 
Section 12.4 for primary and key secondary endpoints, Section 12.5 for other secondary 
 
 endpoints.
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To demonstrate that brolucizumab 6mg is 
non-inferior to aflibercept 2mg with respect 
to the visual outcome after up to one year 
of treatment

Change from baseline in BCVA at Week 52

Change from baseline in BCVA averaged over a 3 
month period (from Week 40 to Week 52)
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To estimate the proportion of patients 
treated at q12w frequency with 
brolucizumab

Proportion of patients maintained at q12w up to Week 
52

To estimate the predictive value of the first 
q12w cycle for maintenance of q12w 
treatment with brolucizumab

Proportion of patients maintained at q12w up to Week 
52, within those patients that qualified for q12w at 
Week 36


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Objective(s)
Endpoint(s)

To evaluate the functional and anatomical 
outcome with brolucizumab relative to 
aflibercept

Change from baseline by visit up to Week 52 in BCVA 
and in parameters derived from SD-OCT, Color fundus 
photography and Fluorescein angiography

To evaluate the effect of brolucizumab 
relative to aflibercept on the Diabetic 
Retinopathy status

Change in ETDRS Diabetic Retinopathy Severity Scale 
(DRSS) score up to Week 52

To assess the safety of brolucizumab 
relative to aflibercept 

Continuous incidence of Ocular and Non-ocular AEs, 
vital signs and laboratory values up to Week 52

To evaluate the effect of brolucizumab 
relative to aflibercept on patient-reported 
outcomes (VFQ-25)

Change in patient reported outcomes (VFQ-25) total 
and subscale scores from baseline up to Week 52

To confirm the systemic brolucizumab 
exposure in a subset of patients 

Systemic brolucizumab concentration approximately 
24 hours after initial and final loading phase doses in a 
sub set of patients

To assess the immunogenicity of 
brolucizumab over one year of treatment

Anti-drug antibody status at screening and up to Week 
52 in brolucizumab arm
3
Study design
The study is a randomized, double-masked, multi-center, active-controlled, 2 armed study in 
patients with DME.
Patients who consent will undergo screening assessments to evaluate their eligibility based on 
the inclusion and exclusion criteria. Patients who meet all the inclusion and none of the 
exclusion criteria will be randomized in a 1:1 ratio to one of two treatment arms:

Brolucizumab 6 mg: 5 x q6w loading then q12w or q8w maintenance

Aflibercept 2 mg: 5 x q4w loading then q8w maintenance


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Figure 3-1
Study design
Screening period: Day -14 to Day -1
A screening period of up to 2 weeks will be used to assess eligibility.
One time rescreening of patients is allowed, except for the purpose of capturing new BCVA or 
imaging assessments that previously failed to qualify the patient. As long as testing can be 
repeated within 14 days of the first screening, the other screening assessments do not need to 
be repeated. If rescreening is to occur beyond 14 days from the original screening visit date, 
then all screening procedures must be repeated. Medical judgment should be exercised to ensure 
that treatment of DME is not withheld in order for a patient to participate in the study.
Double masked treatment period: Day 1 to Week 48
After confirmation of eligibility, patients will be randomized in a 1:1 ratio to one of the 
treatment arms.
Only one eye will be selected as study eye and treated with study medication.
The baseline visit is defined as Day 1/Visit 1, and End of treatment (EOT) visit as Visit 15 
(Week 48).
A study visit schedule will be established at the time of randomization for all patients. All efforts 
should be made to adhere to this study visit schedule ±7day window (except Baseline/Day 1 
where no window is allowed). In addition, for a given protocol visit (except Baseline/Day 1), 
assessments can be performed on two consecutive days in which both days must occur within 
the ±7 day window. Treatment is intended to be administered on the day of study visit, or if this 
is not possible, within 3 days after the first day of a study visit when the per-protocol 
assessments took place. For Baseline/Day 1, treatment must be given on the same day of the 
visit. Also, two consecutive injections should be spaced by at least 21 days.
Patients must have confirmed type 1 or type 2 diabetes at screening. Adequate glycemic control 
must be confirmed by an HbA1c level ≤10 % at screening.
Post-treatment follow-up period: Week 48 to Week 52:
For all patients, the last study assessment will be performed at End of Study (EOS) visit (Week 
52), four weeks (±7 days) after the last active study treatment in this study.


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Patients withdrawn from the study prior to study completion will be asked to return for an early 
discontinuation visit (EOS visit), four weeks (±7 days) following their last study treatment 
administration.
4
Rationale
4.1
Rationale for study design
This study is designed as a multi-center, double-masked, 2 arm active controlled prospective 
study to demonstrate the safety and efficacy of brolucizumab 6 mg against the active control, 
aflibercept 2 mg, used per approved label in China. Since the treatment schedule is different 
between arms, to ensure masking, the following will apply:

in addition to every 4-week visits for all patients for 1 year, extra visits are scheduled at 
Weeks 6 and 18 for both treatment arms in order to maintain the double-masking despite 
the different treatment administration schedule between the two treatment arms

the patients will receive active or sham injection at each protocol visit except Weeks 20, 28 
and 52 (No scheduled treatment for any arm)

Disease activity assessment (DAA) will be performed for both arms

to fulfil the double-masking requirement, the investigational site will have masked and 
unmasked staff
Non-inferiority testing related to the primary efficacy parameter BCVA will be based on a 
margin of 4 letters. This non-inferiority margin provides assurance that any proof of non-
inferiority only occurs if the observed treatment differences are of no clinical relevance.
4.2
Rationale for dose/regimen and duration of treatment
The doses and regimen for brolucizumab and aflibercept are based on the following 
considerations:

Brolucizumab is well tolerated at a dose of 6 mg administered at a q4w regimen during the 
loading phase, based on the previous clinical phase III program in which 1088 patients with
nAMD received brolucizumab. The nAMD study results regarding q12w/q8w maintenance 
regimen support stretching the minimum interval between injections to 6 weeks to reduce 
the treatment burden (see Section 1.1 for further details).

Current evidence from large anti-VEGF pivotal studies in DME combined with the evidence 
detailed above supports an extended period of intense treatment (loading regimen) is 
required to achieve maximal BCVA gain. Hence the loading regimen was extended to Week 
24 for brolucizumab.

Route of administration is intravitreal injection as for all anti-VEGF treatments currently 
approved for the treatment of DME and other retinal diseases related to macular edema. The 
intraocular level of anti-VEGF treatments such as brolucizumab would not be sufficient 
following systemic administration to ensure treatment efficacy. Thus, brolucizumab has to 
be injected intravitreally.

Aflibercept is applied as per the current approved label in China.


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Study duration of 1 year (with treatment of approximately 12 months) is warranted to assess 
longer-term efficacy and safety and to assess the q12w/q8w options for brolucizumab over time.
4.3
Rationale for choice of comparator
Aflibercept 2 mg q8w is an established standard of care option and has been chosen as 
comparator for this study due to the consistency of the approved dose and posology of 
aflibercept (Eylea®) across many countries especially European Union (EU) and United States 
(US) for the targeted indication as compared to other approved anti-VEGF treatments.
Therefore, using the same study comparator as in global pivotal studies will allow the 
comparison of the results between China and global study populations.
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, and periodic review of safety data 
by an independent Data Monitoring Committee (DMC).
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 (HAWK, HARRIER) in nAMD, brolucizumab demonstrated non-inferiority to 
aflibercept in mean change in BCVA from baseline to Week 48. These results were achieved 
while a majority of patients on brolucizumab 6 mg – 56% in HAWK and 51% in HARRIER –
were maintained on a q12w dosing interval following the loading phase through Week 48, i.e. 
with a reduced treatment frequency compared to aflibercept. 
Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of IOI have been 
reported following brolucizumab injection. These immune mediated adverse events may occur 
following the first intravitreal injection. Discontinuation of study treatment is required in 
subjects who develop these events. In addition, subjects who experience IOI may be at risk of 
developing retinal vasculitis and/or retinal vascular occlusion and should be closely monitored.
Based on clinical studies, IOI related adverse events including retinal vasculitis and retinal 
vascular occlusion, were reported more frequently in female patients treated with brolucizumab 
than male patients (e.g. 5.3% females vs. 3.2% males in HAWK and HARRIER, Novartis data 
on file). 


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Brolucizumab safety was comparable to aflibercept, with the overall incidence of adverse 
events balanced across all treatment groups in both studies when treatment interval is not less 
than every 8 weeks after the first 3 monthly initial doses (loading phase). The risk/benefit 
assessment for brolucizumab remains positive.
The higher intravitreal concentration of brolucizumab (approximately 11-time higher for 6 mg 
brolucizumab vs 2 mg aflibercept) is expected to confer a longer duration of effect in DME that 
will translate into a reduced frequency of injections with a non-inferior efficacy. A reduced 
treatment frequency will provide benefit to patients and caregivers/physicians. Further details 
of the known and potential risks and benefits associated with brolucizumab are presented in the 
Investigator’s Brochure (IB).
5
Population
The study population will be male and female Chinese patients ≥18 years old with visual 
impairment due to DME. Approximately 335 Chinese patients will be screened (20% screening 
failure rate expected) and approximately 268 (134 per arm) patients will be randomized in 
approximately 25 centers.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Signed informed consent must be obtained prior to participation in the study.
2. Patients ≥18 years of age at screening
3. Patients with type 1 or type 2 diabetes mellitus and HbA1c of ≤10% at screening
4. Medication for the management of diabetes must have been stable within 3 months prior to 
randomization and is expected to remain as stable as medically acceptable during the course 
of the study
5. Study Eye
Visual impairment due to DME with:

BCVA score between 78 and 23 letters, inclusive, using ETDRS visual acuity testing 
charts at a starting testing distance of 4 meters (approximate Snellen equivalent of 20/32 
to 20/320) at screening and baseline

DME involving the center of the macula, with central subfield retinal thickness (e.g. 
measured from retinal pigment epithelium (RPE) to the inner limiting membrane (ILM) 
inclusively) of ≥320 µm on SD-OCT at screening. Eligibility is determined by 
Investigator’s assessment at time of 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 concomitant condition/disease
1. Active Proliferative Diabetic Retinopathy in the study eye as per investigator


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2. Concomitant conditions or ocular disorders in the study eye at screening or baseline which 
could, in the opinion of the investigator, prevent response to study treatment or may 
confound interpretation of study results, compromise visual acuity or require medical or 
surgical intervention for the duration of the study (e.g. cataract, vitreous hemorrhage, 
retinal vascular occlusion, retinal detachment, macular hole, or choroidal 
neovascularization of any cause)
3. Any active intraocular or periocular infection or active intraocular inflammation (e.g. 
infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis, uveitis) 
in study eye at screening or baseline
4. Structural damage of the fovea in the study eye at screening likely to preclude 
improvement in visual acuity following the resolution of macular edema, including 
atrophy of the retinal pigment epithelium, subretinal fibrosis, laser scar(s), epiretinal 
membrane involving fovea or organized hard exudate plaques
5. Uncontrolled glaucoma in the study eye defined as intraocular pressure (IOP) > 25 mmHg 
on medication or according to investigator’s judgment at Screening or Baseline
6. Neovascularization of the iris in the study eye at screening or baseline
7. Evidence of vitreomacular traction in the study eye at screening or baseline which in the 
opinion of the investigator, affects visual acuity
8. Presence of amblyopia, amaurosis or ocular disorders with vision <20/200 (35 letters) in 
the fellow eye at screening or baseline
9. History of idiopathic or autoimmune uveitis in the study eye
Ocular treatments
10. Previous treatment with any anti-VEGF drug or investigational drugs in the study eye
11. Use of dexamethasone intravitreal implant (Ozurdex) or fluocinolone acetonide 
intravitreal implant (Iluvien) in study eye at any time. Prior use of other intraocular or 
periocular corticosteroids in the study eye is not an exclusion provided at least 6-month 
wash-out prior to baseline
12. Laser photocoagulation (focal/grid or panretinal) in the study eye during the 3-month 
period prior to baseline
13. Intraocular surgery including Yttrium aluminum garnet laser (YAG laser) in the study eye 
during the 3-month period prior to baseline
14. History of vitreoretinal surgery in study eye
15. Aphakia with the absence of posterior capsule in the study eye
Systemic conditions or treatments
16. Stroke or myocardial infarction during the 6-month period prior to baseline
17. Renal failure requiring dialysis or renal transplant
18. Uncontrolled blood pressure defined as a systolic value ≥160 mmHg or diastolic value 
≥100 mmHg at screening or baseline
19. Systemic anti-VEGF therapy during the 3-month period prior to baseline
20. Systemic medications known to be toxic to the lens, retina or optic nerve (e.g. 
deferoxamine, chloroquine/hydroxychloroquine, tamoxifen, phenothiazines and 
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21. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes, or clinically relevant sensitivity to fluorescein dye as assessed by the 
investigator
22. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless 
of whether there is evidence of local recurrence or metastases
23. History of a medical condition (disease, metabolic dysfunction with exception of type 1 or 
2 diabetes mellitus, physical examination finding, or clinical laboratory finding) that, in 
the judgment of the investigator, would preclude scheduled study visits, completion of the 
study, or a safe administration of investigational product (IP)
24. Use of systemic investigational drugs within 5 half-lives of baseline, [or within 30 
days/until the expected pharmacodynamic effect has returned to baseline], whichever is 
longer (observational clinical studies solely involving over-the-counter vitamins, 
supplements, or diets are not exclusionary)
Other
25. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive human 
chorionic gonadotropin (hCG) pregnancy test
26. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during the study drug administration and for 3 months after study drug discontinuation. 
Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before baseline. In case of 
oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to baseline). For female patients in the 
study, the vasectomized male partner should be the sole partner for that patient

Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS) or other forms of hormonal contraception that have comparable efficacy (failure 
rate <1%), for example hormone vaginal ring or transdermal hormone contraception
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with 
or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case 
of oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow up hormone level assessment is she considered not of child bearing potential.


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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).
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
Solution for 
injection
Intravitreal use
Open label supply in Sterile 
glass vial. Blinding at the 
clinical site by unblinded site 
personnel 
Global
Control Drug
Pharmaceutical 
Dosage Form 
Route of 
Administration
Supply type
Sponsor 
(global or local)
Aflibercept 2 mg
Solution for 
injection
Intravitreal use
Open label supply in Sterile 
glass vial. Blinding at the 
clinical site by unblinded site 
personnel
Global
Brolucizumab is formulated as a sterile solution aseptically filled in a sterile glass vial for single 
use and the content of the vial must not be split.
Brolucizumab study kits will consist of a carton that contains 1 single use, sterile glass vial 
containing brolucizumab 6 mg/0.05 mL.
Aflibercept study kit will consist of a carton that contains 1 single use, sterile glass vial 
containing aflibercept 2 mg/0.05mL.
Sham injections refer to an imitation of an intravitreal injection procedure using an empty sterile 
syringe without a needle. There will be no sham vials.
Novartis will ensure sufficient supplies of brolucizumab and aflibercept for treatment use to 
allow for completion of the study.
6.1.2
Additional study treatments
No other treatment beyond investigational drug and control drug are included in this trial.
6.1.3
Treatment arms/group
At visit 1, subjects will be assigned to one of the following 2 treatment arms in a 1:1 ratio:

Brolucizumab 6 mg: 5 x q6w loading then q12w/q8w maintenance

Aflibercept 2 mg: 5 x q4w loading then q8w maintenance


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6.1.4
Treatment duration
The planned duration of treatment is 12 months (48 weeks). Discontinuation of study treatment 
for a subject occurs when study drug will be stopped earlier than the protocol planned duration, 
and can be initiated by either the subject or the investigator.
6.2
Other treatment(s)
6.2.1
Concomitant therapy
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after signing the study informed consent. All medications, procedures and 
significant non-drug therapies (e.g. blood transfusions) administered after the patient was 
enrolled into the study must be recorded in the appropriate electronic Case Report Form (eCRF) 
page.
Each concomitant drug/procedure must be individually assessed against all exclusion 
criteria/prohibited medication. If in doubt the investigator should contact the Sponsor medical 
monitor before randomizing a subject or allowing a new medication to be started.
6.2.1.1
Permitted concomitant therapy
During the study, if the fellow eye develops visual impairment due to DME or other diseases, 
it may be treated with standard of care at the discretion of the investigator (i.e. treatment of the 
fellow eyes with anti-VEGF medication other than brolucizumab is allowed). Treatment of the 
fellow eye should be scheduled in a way not to disturb the schedule for visits and treatments in 
the study eyes. 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.
In case of development of neovascularization in the study eye during the study, scatter laser 
therapy or panretinal photocoagulation is permitted at any time during the course of the study 
as deemed necessary by the masked investigator. The patient can continue to participate in the 
study and receive study treatment as planned. When laser treatment is performed at the active 
study treatment visit, it should be performed prior to study medication injection.
Topical ocular corticosteroids administered in the study eye are allowed during the study. 
Corticosteroids administered via intra-nasal, inhaled or intra-articular route are also permitted 
during the study.
If cataract surgery is necessary, attempt to schedule cataract surgery ≥ 7 days after the most 
recent study treatment. Study treatment may be resumed ≥ 14 days after cataract surgery, 
assuming an absence of surgical-related complications.
If the subject is planning to receive a COVID-19 vaccine that is authorized by local regulation, 
it is recommended to receive the vaccine at least 7 days before or after the study treatment visit 
including Baseline (Day 1) visit.
6.2.2
Prohibited medication
Use of the treatments displayed in the below table are not allowed after screening.


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Table 6-2
Prohibited medications/procedures
Medications/Procedures
Prohibition 
period
Action taken
Study eye
Intra- or periocular corticosteroids (except if needed as 
short term treatment of AE)
Any time
Discontinue study treatment 
(except if for treatment of AE)
Anti-VEGF therapy other than assigned study 
medication
Any time
Discontinue study treatment
Laser photocoagulation (focal/grid)
Before or at 
Week 32
Continuation of study treatment at 
the investigators discretion
Any investigational drug, biologic or device
Any time
Discontinue study treatment
Vitrectomy and vitreo-retinal surgery
Any time
Discontinue study treatment
Systemic
Anti-VEGF therapy
Any time
Discontinue study treatment
Any investigational drug, biologic or device
Any time
Discontinue study treatment
Medications toxic to the lens, retina or optic nerve
Any time
Discontinue study treatment
Standard of care or other treatments according to the investigators practice for DME and other 
diseases in the fellow eye are permissible at any time and must be recorded in the appropriate 
eCRF page.
Oral, intravenous, intramuscular, or extensive dermal (> 20% total body surface area) 
corticosteroids should not be administered within 5 days prior to study drug administration.
6.2.3
Rescue medication
The study eye, in both treatment groups, identified as needing q8w at a previous visit could 
receive rescue treatments with laser photocoagulation (focal/grid) from week 36 onwards if 
macular edema (ME) worsening results in a ≥10-letter loss at 2 consecutive visits or ≥15-letter 
at 1 visit best previous measurement, with BCVA not better than baseline. When applicable, 
patients could receive both laser photocoagulation and active study treatment as scheduled at 
the same visit. Patients can continue with the study treatment.
Panretinal photocoagulation is permitted during the study as deemed necessary by the 
investigator, and the subject can continue the study.
In case the investigator deems it in the best interest of the subject to receive treatment in the 
study eye, aside from laser, which is prohibited by this protocol, instructions provided in Table 
6-2 should be followed.
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (4 digit number for Center No. as assigned by Novartis to the investigative site) with a 
sequential subject number suffixed to it (3 digit number for Subject No.), so that each subject 


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is numbered uniquely across the entire database. Upon signing the informed consent form, the 
subject is assigned to the next sequential Subject No. available.
Subjects who have been screen failures but are rescreened (see Section 8.1) will be assigned a 
new Subject No.
6.3.2
Treatment assignment, randomization
At baseline visit, all eligible subjects will be randomized via Interactive Response Technology 
(IRT) to one of the treatment arms, in a ratio of 1:1. Stratification for systemic exposure 
sampling will be considered.
The unmasked investigator or her/his delegate will contact the IRT, after receiving confirmation 
from the masked investigator that the subject fulfills all the inclusion and none of the exclusion 
criteria. The IRT will assign a randomization number to the subject, which will link the subject 
to a treatment arm.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of subject numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms. A separate medication list will be produced 
by or under the responsibility of Novartis Global Clinical Supply (GCS) using a validated 
system that automates the random assignment of medication numbers.
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Group.
6.4
Treatment masking
Table 6-3
Masking levels
Time or Event
Role
Randomization list 
generated
Treatment allocation & 
dosing
Safety event (single 
subject unmasked)
Patients
M
M
M
Site staff1
M
M
M
Unmasked site staff (see 
text for details)
M
U
U
Global Clinical Supply 
and Randomization 
Office
U
U
U
Unmasked sponsor staff 
(see text for details)
M
U
U
Statistician/statistical 
programmer/ data 
analysts
M
M
M
Independent committees 
used for assessing 
interim results
U
U
U
All other sponsor staff not 
identified above
M
M
M


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Time or Event
Role
Randomization list 
generated
Treatment allocation & 
dosing
Safety event (single 
subject unmasked)
M: Remains masked
U: Can be unmasked
1 In the event of a medical emergency or an AE during the study where the knowledge of subject treatment is 
required (e.g. in case of suspected unexpected serious adverse reactions (SUSAR)), an individual investigator 
will have the ability to unmask the treatment assignment for a specific subject.
The intent of masking is to limit the occurrence of conscious and unconscious bias in the 
conduct and interpretation of the clinical study. Bias could arise from the influence that the 
knowledge of a specific treatment assignment may have on the recruitment and allocation of 
subjects, their subsequent care, the assessment of endpoints, the handling of withdrawals, and 
so on. The essential aim of masking, therefore, is to prevent identification of the treatments by 
the investigator, subject, and others associated with the conduct of the study until all such 
opportunities for bias have passed.
This study will be double-masked, with subjects randomized to be treated with brolucizumab 6 
mg or aflibercept 2 mg. All members of the Sponsor team will be masked to treatment 
assignments while the study is in progress. In addition, the biostatistician who is directly 
involved in the conduct of the study (i.e. involved in patient level discussions or direct 
interaction with sites) will remain masked to treatment assignments while the study is in 
progress. Sponsor personnel who have access to treatment codes (e.g. bioanalysts) will not 
divulge the codes to subjects, investigators, site staff or Sponsor.
Unmasking of investigators and personnel directly involved in the conduct of the study will 
only occur in the case of patient emergencies (see Section 6.6.2), and then at the time of the 
final analysis (see 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 subject treatment is required (e.g. in case of SUSAR), an individual investigator 
will have the ability to unmask the treatment assignment for a specific subject. The investigator 
should notify the Sponsor prior to unmasking a subject, if there is sufficient time. Further, the 
Sponsor must be informed whenever the randomization code is broken and be informed about 
the reasons for unmasking.
Each site must have both masked and unmasked investigators available. The investigator who 
performs the injection will be unmasked to the treatments as will any other site personnel who 
have been delegated responsibility for working with the IP. The unmasked site personnel and 
unmasked injecting investigator must not perform BCVA, complete ophthalmic examination, 
disease activity assessments or administer the VFQ-25. Also, the unmasked site personnel and 
unmasked injecting physician must not perform assessment of any ocular or non-ocular safety 
parameters, or assess causality AEs for subjects during the course of the study except an event 
reported immediately following IVT injection.
The unmasked investigator/site personnel should, however, assess subject safety immediately 
following injection. Once the designated roles are determined, the unmasked investigator/site 
personnel must not be switched at any time after randomization to masked role. Every effort 
must be made to limit the number of unmasked study personnel to ensure the integrity of this 
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Treatment masking of individual subjects will remain intact until the final database lock has 
occurred by ensuring: Randomization data are kept strictly confidential until the time of
unmasking and will not be accessible by anyone else involved in the study except the 
unmasked/treating investigator. During and after database lock, the masked personnel and 
patients will remain masked to the treatment assignment until the conclusion of the study.
Unmasked monitors will be available to perform study medication accountability and to deal 
with study issues involving the unmasked investigator or unmasked site staff.
An independent, masked review of fundus photography, fluorescein angiography and optical 
coherence tomography (OCT) images for patients enrolled in the study will be performed at a 
Central Reading Center (CRC).
6.5
Dose escalation and dose modification
6.5.1
Dose modifications
Deviations to mandatory dose interruptions during the loading phase and/or dose modifications 
during the whole study are not allowed.
Interruption of study treatment is allowed if warranted by 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 
study 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 study personnel or by unmasked field monitor on 
the appropriate study treatment dispensing form.
Exposure to the study treatment will be based on the number of injections administered. 
Compliance with the study treatment will be assessed by the unmasked field monitor at each 
visit using vial counts and information provided by the pharmacist or by the unmasked study 
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 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-masking 
can be performed at any time.
The appropriate personnel from the site and sponsor will assess whether study treatment should 
be discontinued for any subject whose treatment code has been broken for any reason.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section.
For brolucizumab, the study medication has a 2-part label (base plus tear-off label). A unique 
medication number is printed on each part of this label, which corresponds to one of the 
treatment arms. Unmasked study personnel will identify the study medication kits to dispense 
to the subject by contacting the IRT and obtaining the medication number(s). Immediately 
before dispensing the medication kit to the subject, unmasked site personnel will detach the 
outer part of the label from the packaging and affix it to the source document.
6.7.1
Handling of study treatment
Study treatment must be received by a designated unmasked person at the study site, handled 
and stored safely and properly and kept in a secured location to which only the unmasked 
investigator and designated site personnel have access. Upon receipt, all study treatment must 
be 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 CO Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number.
The unmasked study personnel must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Monitoring of drug accountability will be 
performed by unmasked monitors during site visits or remotely and at the completion of the 
trial. Subjects will be asked to return all unused study treatment and packaging at the end of the 
study or at the time of discontinuation of study treatment.
At the conclusion of the study, and as appropriate during the course of the study, the unmasked 
study personnel will return all unused study treatment, packaging, drug labels, and a copy of 
the completed drug accountability log to the unmasked Novartis monitor or to the Novartis 
address provided in the investigator folder at each site.


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6.7.2
Instruction for prescribing and taking study treatment
All kits of study treatment assigned by the IRT will be recorded/databased in the IRT.
There will be two treatment phases for IVT injections with different timing for brolucizumab 
and aflibercept treatment arms:
Loading Phase
Brolucizumab: In the loading phase, treatment with brolucizumab will occur every 6 weeks for 
five (5) consecutive injections (baseline (BL), Weeks 6, 12, 18 and 24). To preserve the masking, 
the patients assigned to this regimen will receive sham injection on Weeks 4, 8 and 16.
Aflibercept: In the loading phase, treatment with aflibercept will occur every 4 weeks for five 
(5) consecutive injections (BL, Weeks 4, 8, 12 and 16). To preserve the masking, the patients 
assigned to aflibercept Arm will receive sham injection on Weeks 6 and 18.
Maintenance Phase
The treatment intervals during the maintenance phase will be as follows:
Brolucizumab 6 mg:

From Week 24 onwards, patients will be scheduled to receive one injection of 
brolucizumab 6 mg every 12 weeks. At Weeks 32 and 36, DAA (Disease Activity 
Assessment) will be performed. If, however, Disease Activity is identified by the 
evaluating/masked investigator at Weeks 32 or 36, the patient will be assigned to receive 
treatment every 8 weeks (see Evaluation of Disease Activity below). DAA will be 
performed at Week 36 independently from the outcome of DAA performed at Week 32. 
An additional DAA will be performed at Week 48 to document the adequacy of the q12w 
treatment schedule at the end of the study (without having impact on the patient’s 
treatment schedule).
Aflibercept 2 mg:

From Week 16 onwards, patients will receive one injection of aflibercept 2 mg every 8 
weeks (first injection after Week 16 to be given at Week 24) until Week 48 visit. DAAs 
will be conducted by the evaluating/masked investigator for masking purposes and will 
not influence the treatment interval.


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Figure 6-1
Treatment schedule
DAA: Disease Activity Assessment
Evaluation of Disease Activity:
The concept of the brolucizumab q12w/q8w regimen is to allocate patients according to their 
individual treatment needs to either a q12w or a q8w treatment schedule. The initial schedule is 
q12w and a patient will remain on q12w as long as the masked investigator does not identify 
DME disease activity which in his opinion requires more frequent anti-VEGF treatment. 
However, the DAA and the decision by the investigator to adjust the treatment frequency only 
occur in pre-specified DAA-visits. To ensure identification of patients with higher treatment 
need early on, a closer monitoring of patients’ individual treatment need will take place during 
the first q12w treatment interval with DAAs at Week 32 and 36 (i.e. for brolucizumab patients, 
8 and 12 weeks after the last loading injection).
The assessment of the disease activity is at the discretion of the masked investigator and should 
be made based on changes in vision and anatomical parameters with reference to the patients’ 
disease status at the time of Week 28. The outcome of this assessment will be captured as:

‘q8w-need’: identified disease activity which according to the masked investigator 
requires more frequent anti-VEGF treatment, e.g.: ≥5 letters loss in BCVA (compared to 
Week 28) which - based on anatomical parameters – is attributable to DME disease 
activity.

‘no q8w-need’: otherwise (no signs of disease activity)
If DAA reveals a need for more frequent treatment in brolucizumab patients, they will be 
assigned to receive brolucizumab injections at q8w intervals thereafter, up to the end of the 
study. Aflibercept patients will receive maintenance treatment every 8 weeks, regardless of the 
outcome of the Disease Activity Assessment as per approved regimen. Only assessments at 
scheduled treatment visits might have an impact on the patient’s treatment schedule.


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Missing DAA:
A patient who misses Week 32 (Visit 11) will undergo the disease activity assessment at Week 
36 (Visit 12) as he/she would have done if the visit had not been missed. If, however, a patient 
misses the DAA planned on Week 36 visit, then the patient (brolucizumab arm only) will be 
assumed to have had a ‘q8w-need’ at this missed visit and will be assigned to a q8w schedule 
at the next visit (i.e. at the next visit the patient will receive an active injection) up to study exit. 
The IRT system will make the necessary changes once the missed visit is registered. If a patient 
misses the DAA planned on Week 48 (Visit 15) visit then the patient (brolucizumab arm only) 
will be assumed to have had a ‘q8w-need’ at this missed visit.
If a patient misses Week 28 (Visit 10), then the Week 24 (Visit 9) values should be applied as 
the reference for disease activity assessments.
Masking:
In order to maintain masking, the assessment of disease activity is conducted on all patients. 
The assessment of the masked/evaluating investigator will be passed to the unmasked/treating 
investigator or delegate in order to obtain the applicable treatment, active or sham, as assigned 
by IRT depending on the treatment arm and the actual treatment frequency as described above.
At all applicable visits from Week 4 to Week 48, inclusive (with exception of Weeks 20 and 28 
where no treatment is scheduled), a sham treatment will be performed to maintain patient 
masking. For the sham treatment the tip of an injection syringe (the hub without a needle) will 
be used.
IVT injection procedure:
The IVT injection procedure for brolucizumab and aflibercept, including aseptic and 
antimicrobial requirements, will be performed according to local clinical practice. The sham 
injection should mimic an IVT injection including the aseptic and antimicrobial requirements. 
The tip of the sham injection syringe (the hub without a needle) will be placed on the eye for 
the approximate amount of time it would take to perform an IVT injection. IVT injection will 
be performed by the unmasked investigator.
IVT injection is contraindicated in patients with active ocular or periocular infections and in 
patients with active intraocular inflammation (IOI); therefore, the investigators must verify that 
these conditions are not present in the study eye prior to every injection.
If any signs of intraocular inflammation are present, then an IVT injection must not be 
performed. Additional ophthalmic examination and imaging should be performed to evaluate 
IOI (see Section 8.4.3).
If IOI is confirmed, subjects should be treated for IOI according to clinical practice and 
closely monitored since they may be at risk of developing retinal vasculitis and/or retinal 
vascular occlusion. If subject develops retinal vasculitis and/or retinal vascular occlusion 
based on the investigator’s evaluation, the study treatment must be discontinued.
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 (IRB)/Independent Ethics Committee (IEC)-
approved informed consent.


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If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). 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 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 Investigator's Brochure (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.
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 for 3 months after 
stopping the investigational medication 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/sponsor after 
IRB/IEC approval.
Subjects might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience.
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 subject and person 
obtaining informed consent, etc.). Remote informed consent should be appropriately 
documented and confirmed by way of standard informed consent procedures at the earliest 
opportunity when the subject will be back at the trial sites.
8
Visit schedule and assessments
The Assessment Schedule (Table 8-1) lists all of the assessments and indicates with an “X”, the 
visits when they are performed. All data obtained from these assessments must be supported in 
the patients' source documentation.


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Patients must be seen for all visits on the designated day, or as close to it as possible. Missed or 
rescheduled visits should not lead to automatic discontinuation. Patients who prematurely 
discontinue the study for any reason should be scheduled for a visit as soon as possible, at which 
time all of the assessments listed for the final visit will be performed.
If the COVID-19 pandemic limits or prevents on-site study visits, study treatment could not be 
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 subject to visit the site 
again.


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Table 8-1
Assessment Schedule
Period
Screening
Treatment
Follow-up Period
Visit Name
Screening 
/ Visit 0
Baseline 
/ Visit 1
1b
2
3
4
5
6
7
8
9
9b
10
11
12
13
14
15/EOT2
16 / EOS3
Days
-14 to -1
1
2
29
43
57
85 113 127 141
169
169 
+1
197 225 253 281 309
337
365
Weeks
-2 to -1
1
1
4
6
8
12
16
18
20
24
24
28
32
36
40
44
48
52
Demography
X
Informed consent4
X
Medical history/current medical 
conditions
X
Physical Examination5
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion / Exclusion criteria
X
X
Visual Function Questionnaire-25
X
X
X
Vital Signs
X6
X6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test (serum)7
X
X
Pregnancy test (urine)7
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetics Informed 
Consent
X
Anti-drug antibody (ADA) blood 
collection
X
X
X
X
X
X
PK blood collection8
X
X
Hematology
X
X
Clinical Chemistry
X
X
X
X
X
Urinalysis
X
X
X
Best corrected visual acuity
X9
X9
X
X
X
X
X
X
X
X
X9
X
X
X
X
X
X9
Intraocular Pressure (IOP)
X9
X
X
X
X
X
X
X
X
X
X9
X
X
X
X
X
X9
Ophthalmic Exam1, 10
X9
X
X
X
X
X
X
X
X
X
X9
X
X
X
X
X
X9


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Period
Screening
Treatment
Follow-up Period
Visit Name
Screening 
/ Visit 0
Baseline 
/ Visit 1
1b
2
3
4
5
6
7
8
9
9b
10
11
12
13
14
15/EOT2
16 / EOS3
Days
-14 to -1
1
2
29
43
57
85 113 127 141
169
169 
+1
197 225 253 281 309
337
365
Weeks
-2 to -1
1
1
4
6
8
12
16
18
20
24
24
28
32
36
40
44
48
52
Spectral Domain Optical Coherence
Tomography1
X9
X
X
X
X
X
X
X
X
X
X9
X
X
X
X
X
X9
Color fundus photo (7-field) 1
X9
X
X9
Fluoroscein angiography1
X9
X
X9
Disease activity assessment
X
X
X
Contact IRT
X
X12
X
X
X
X
X
X
X
X
X
X
X
X
Study drug or sham administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X Assessment to be recorded in the clinical database or received electronically from a vendor
1 Additional ophthalmic examinations and images will be performed in case of any signs of intraocular inflammation.
2 EOT: End of treatment
3 End of Study (EOS): All exit procedures should be followed, regardless of when the patient exits the study. Visit should be at least 4 weeks from last dose of study 
treatment. Patient report outcome (PRO) will not be administered on EOS if different from Week 52 visit.
4 Must be signed/dated prior to performing any study procedures
5 At Visit 1, significant findings present prior to the study start (or known to being started before) must be recorded in the relevant Medical History; and any changes 
during the study which meet the definition of an Adverse Event must be recorded as an Adverse Event
6 In case there is an elevated blood pressure measurement as specified in the exclusion criteria, at 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.
7 Women of childbearing potential only
8 If PK Consent was provided
9 Both eyes
10 Includes fundus and slit lamp examination according to local practice.
 
12 Patients will be randomized to brolucizumab 6 mg/50 µL or aflibercept 2 mg/50 µL


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8.1
Screening
Screening
A screening period of up to 2 weeks will be used to assess eligibility.
One time rescreening of patients is allowed, except for the purpose of capturing new BCVA or 
imaging assessments that previously failed to qualify the patient. As long as testing can be 
repeated within 14 days of the first screening, the other screening assessments do not need to 
be repeated. If rescreening is to occur beyond 14 days from the original screening visit date, 
then all screening procedures must be repeated. Medical judgment should be exercised to ensure 
that treatment of DME is not withheld in order for a patient to participate in the study.
8.1.1
Information to be collected on screening failures
Subjects who sign an informed consent form and 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 Case Report Form (CRF). The demographic information, informed 
consent, Inclusion/Exclusion, and Disposition CRF 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 Section 10.1.3). Adverse events that are not SAEs will be followed by the 
investigator and collected only in the source data. If the subject fails to be randomized, the IRT 
must be notified within 2 days of the screen fail that the subject was not randomized.
Subjects who are randomized and fail to start treatment, e.g. subjects randomized in error, will 
be considered an early terminator. The reason for early termination should be recorded on the 
appropriate CRF.
8.2
Subject demographics/other baseline characteristics
The following information will be collected/documented at screening/baseline visit for each 
patient:

Age

Gender

Race

Type of diabetes

Vital signs

Study eye

Best corrected visual acuity

Macular edema characteristics

Intraocular pressure

HbA1c and other laboratory test results

Concomitant medications

Medical history/current medical conditions


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Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
8.3
Efficacy
The following tests will be performed to assess activity of brolucizumab and aflibercept on 
visual function, retinal structure and leakage:

Best-corrected visual acuity with ETDRS-like chart at 4 meters

Anatomical markers on Spectral Domain Optical Coherence Tomography

ETDRS DRSS score based on 7-field stereo Color Fundus Photography

Vascular leakage evaluation by fluorescein angiography
All efficacy assessments should be performed prior to any administration of study treatment 
and/or rescue medication.
8.3.1
Visual acuity
Visual acuity will be assessed at every study visit using best correction determined from 
protocol refraction (BCVA). BCVA measurements will be taken in a sitting position using 
ETDRS–like visual acuity testing charts. The details of the procedure and training materials are 
provided in the applicable manual. Certification of the assessment procedures and assessors will 
occur prior to any evaluation of study subjects.
8.3.2
Optical coherence tomography
Spectral domain optical coherence tomography (SD-OCT) will be assessed in the study eye at 
every study visit and in both eyes at Screening, Week 28 and Week 52 (EOS) visits.
These assessments will be performed by trained technician or investigator at the sites and should 
be performed prior to any study drug administration. Certification of the equipment and 
examiners at each investigative site will occur prior to evaluation of study subjects. Masked 
investigators will evaluate the SD-OCT to assess the status of disease activity. The SD-OCT 
machine used for an individual subject should not change for the duration of the study.
The images will be reviewed by a CRC to ensure a standardized evaluation. For further 
procedural details, the investigator should refer to applicable manual provided by the CRC.
8.3.3
Color fundus photography and fluorescein angiography
Color fundus photography and fluorescein angiography will be performed in the study eye at 
Week 28 visit, and in both eyes at Screening and Week 52 (EOS) visits. In case of premature 
termination there is no need to repeat the color fundus photography and fluorescein angiography 
if there was color fundus photography and fluorescein angiography within the previous 12 


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weeks, except if there is significant worsening of DME disease, in the opinion of the 
investigator.
These assessments will be performed by a trained technician at the sites and should be 
performed prior to any study drug administration. Certification of the equipment and examiners 
at each investigative site will occur prior to evaluation of study subjects. The images will be 
reviewed by a CRC to ensure a standardized evaluation. Grading for DRSS will be performed 
at the CRC. For further procedural details, the investigator should refer to applicable manual 
provided by the CRC.
Additional images will be taken in case of any signs of intraocular inflammation. OCT, Color 
fundus photography and fluorescein angiography (preferably, 
 or with peripheral 
sweeps) should be performed for safety evaluation as described in Section 8.4.3.
8.3.4
Appropriateness of efficacy assessments
BCVA as a measure of retinal function as well as SD-OCT images to analyze anatomical 
changes are standard assessments to monitor DME and potential treatment effects in routine 
practice and clinical trials. Likewise established is FA that helps classifying the type of macular 
edema and is used to assess vascular leakage. ETDRS DRSS assessed via color fundus 
photography is standardized evaluation on the severity of diabetic retinopathy. This grading 
informs about the severity of the diabetic retinopathy underlying the macular edema. It was 
shown that anti-VEGF can improve the severity of the retinopathy the implications for the 
course of the edema and its treatment are currently being investigated. 
8.4
Safety
Safety assessments will include physical examination, vital signs, height and weight, 
ophthalmic examinations, laboratory evaluation as well as monitoring and recording type, 
frequency, and severity for all AEs.
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, Section 10.1.1 refers to the AE section.
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.


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Table 8-2
Assessments & Specifications
Assessment
Specification
Physical examination
A routine physical examination will be performed at screening and at EOS visit and 
include the examination of general appearance (e.g. skin, neck, lymph nodes, 
extremities, vascular and neurological).
Information for all physical examinations will be included in the source documentation 
at the study site. Clinically relevant findings that are present prior to signing informed 
consent must be included in the eCRF capturing Medical History. Significant findings 
made after signing informed consent which meet the definition of an Adverse Event 
must be recorded on the appropriate AE eCRF page.
Vital signs
Sitting blood pressure and pulse rate will be collected at all visits before treatment 
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. If the repeat 
measurement is elevated, then the patient is not eligible to be enrolled into the study.
On days when study drug is administered, vital signs will be measured before
administration of study medication. The results will be recorded in the eCRF.
Height and weight
Height and weight will be measured at the screening visit only as part of the physical 
examination. Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram 
(kg), in indoor clothing but without shoes) will be measured at screening only. 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 collections, shipment of the samples and reporting of the results by the central 
laboratory are provided to investigators in the central laboratory manual.
Clinically notable laboratory values are defined in Table 16-1 of Appendix 1.
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.
Clinical Chemistry

Glycosylated hemoglobin (HbA1c)

Serum biochemistry tests
Serum electrolytes (sodium, potassium, chloride, phosphorus, calcium), uric acid, urea 
nitrogen, creatinine, albumin, glucose, total protein, total bilirubin and direct bilirubin, 
SGOT (AST), SGPT (ALT), GGT, alkaline phosphatase, and LDH

Additional chemistry tests: Lipids panel (TG, LDL, HDL, TC)
Urinalysis
Dipstick measurements for specific gravity, pH, protein, glucose, ketones, bilirubin, 
nitrite, leucocyte and urine occult blood.
8.4.2
Pregnancy and assessments of fertility
High effective contraception is required for women of childbearing potential during the study 
drug administration and for 3 months after stopping the investigational medication.


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Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child 
bearing potential must also be available as source documentation in the following cases:
1. Surgical bilateral oophorectomy without a hysterectomy
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile.
In the absence of the above medical documentation, Follicle Stimulating Hormone (FSH) 
testing is required of any female subject, regardless of reported reproductive/menopausal status 
at screening/baseline.
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements.
A serum pregnancy test will be conducted for all women of childbearing potential to assess 
pregnancy before inclusion into the study at screening visit and then at Week 52 (EOS) visit. 
During study, monthly urine pregnancy testing will be performed and results captured in the 
source documents
8.4.3
Other safety evaluations
The ophthalmic examination will consist of the following:

Biomicroscopy (slit lamp examination) will be completed at every (scheduled and 
unscheduled) visit to examine the anterior segment structures (e.g., eyelids/lashes, 
conjunctiva, cornea, anterior chamber, iris, lens and anterior part of the vitreous) of the 
study eye (fellow eye will be examined only at Screening, Week 28, Week 52 (EOS) and 
on discretion of the investigator). The outcome of the examination will be recorded in the 
source documents.
Slit lamp examination must be carefully performed before each study treatment. If there 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 should be recorded in the adverse event page of the 
eCRF (events identified at the time prior to signing the ICF should be recorded in the 
medical history page).

Intraocular pressure will be assessed in the study eye, pre-dose and post-dose at every 
scheduled visit. In the fellow eye, IOP will be assessed at screening, Week 28, and Week 
52 (EOS). The values recorded in mmHg will be entered into the eCRF. Treatment and close 
monitoring of IOP should be performed by the masked investigator for any non-transient 
elevation in intraocular pressure (≥25 mmHg). Intravitreal procedure is not recommended 
unless normalization of the IOP has been achieved. Post-dose IOP should be assessed within 
60 minutes after every IVT/Sham injection and if ≥25 mmHg, the assessment should be 
repeated until the IOP comes back to normal. Any clinically significant abnormalities 
deemed by the investigator as adverse event, should be recorded on the adverse event page 
of the eCRF (events identified at the time prior to signing the ICF should be recorded on the 
medical history page).


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
Posterior segment (indirect fundus) examination will be conducted by the masked 
investigator at the screening visit for both eyes. An examination of the peripheral retina 
must also be conducted to ensure that the intravitreal injection can safely be performed. 
Posterior segment examination must be performed carefully before each study treatment. 
The results of the examination including any abnormalities (e.g. vitreous cells/haze, retinal 
tear/detachment, hemorrhage and vascular occlusion, vasculitis, etc.) should be recorded in 
the source documents. If there are any signs of IOI, vitreous cells and haze should be 
assessed using National Institutes of Health (NIH) grading system (Nussenblatt et al., 1985). 
The outcome of the examination will be documented in the source document (e.g., 
ophthalmic examination tool) and appropriate eCRF page as applicable. Any clinically 
significant abnormalities of either eye should be recorded in the medical/ocular history page 
prior to signing the ICF and in the adverse event page of the eCRF for any findings identified 
after signing the ICF. 

Instruct the patient to contact the site for any changes in vision or any symptoms of 
inflammation between scheduled visits. Every effort should be made to bring the subject 
for immediate examination. When IOI, retinal vasculitis, and/or Retinal Artery Occlusion 
(RAO) is present or suspected during a visit, investigators must perform thorough 
ophthalmic examination, and will conduct OCT, fluorescein angiography and color fundus 
photography (preferably 
 with peripheral sweeps). These additional 
assessments will be documented in the source and appropriate eCRF pages as applicable. 
The images are requested to be uploaded onto the CRC portal. If subject develops retinal 
vasculitis and/or retinal vascular occlusion based on the investigator’s evaluation, the study 
treatment must be discontinued. In addition, as some of the subjects who experience IOI 
may be at the risk of developing retinal vasculitis and/or retinal vascular occlusion, the 
subject should be closely monitored and managed according to clinical practice.
8.4.4
Appropriateness of safety measurements
The safety assessments selected are standard for this indication and patient population. If there 
are any signs of IOI, additional assessment will be performed as described in Section 8.4.3.
8.5
Additional assessments
Additional assessments that will be performed:

Patient Reported Outcome: National Eye Institute (NEI) VFQ-25

Pharmacokinetics (PK) of brolucizumab

Anti-Drug Antibodies (ADA) of brolucizumab
8.5.1
Clinical Outcome Assessments (COAs)
The impact of brolucizumab on the subject visual function will also be assessed by a visual 
function questionnaire using the National Eye Institute VFQ-25 which is a validated instrument 
that has been used in many studies of subjects with DME. The NEI VFQ-25 was developed to 
address the need to measure a patient's subjective assessment of vision-related Quality of Life 
(QoL) (Mangione et al 2001). This is part of the 51-item NEI-VFQ which was developed based 
on feedback from subjects to measure vision-targeted functioning and the impact of vision 
problems on Health-Related Quality of Life (HRQL) across a number of common eye 


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conditions. This allowed the developers to identify the content areas and aspects of visual 
disability that were most important and relevant to AMD patients. In addition to its use in 
measuring the treatment effect on vision-related function in AMD patients, the NEI VFQ-25 
has been used to measure treatment benefits in subjects with DME (Klein et al 2001).
At baseline, Weeks 28, and 52, the NEI VFQ-25 will be completed and captured by masked site 
staff on behalf of the subjects, at sites where local language versions are available, validated, 
and approved by the IEC/IRB. All these questionnaires should be completed before completing 
any other study procedures of the visit. The time of the day that the questionnaire was completed 
must be recorded in the subject's source documents. Answers to NEI VFQ-25 will be captured 
electronically independently from the eCRF (in a dedicated database). The subject's answer to 
the interview questions will be reviewed and examined by masked site staff and recorded in the 
source documents.
A detailed training manual relating to the administrative procedures of the questionnaires will 
be provided to the sites.
Completed questionnaires will be reviewed and examined by the masked/evaluating 
investigator, before the clinical examination, for responses that may indicate potential AE or 
SAE. If AEs or SAEs are confirmed, then the physician must record the events as per 
instructions given in Section 10.1.1 and Section 10.1.2 of the protocol.
8.5.2
Pharmacokinetics
Serum PK samples will be collected on approximately 24 consented patients to obtain 
approximately 12 patients in brolucizumab arm for systemic exposure assessment (around 12 
patients per treatment arm to maintain masking, samples from patients who received aflibercept 
will not be analyzed). Serum samples will be taken at 2 time points:

Approximately 24 hours after the first dose at Baseline

Approximately 24 hours after the treatment at Week 24
Further details on sample collection, numbering, processing and shipment can be found in the 
central laboratory manual.
8.5.3
Other Assessments
Anti-drug antibodies (immunogenicity):
Anti-drug antibodies (ADAs) assessment will be done at screening, Weeks 4, 12, 24, 36 and 52 
(EOS) visit in subjects treated with brolucizumab only (collection of ADA samples will be done 
in both treatment arms to maintain masking, samples from subjects in aflibercept arm will not 
be analyzed). Systemic exposure of brolucizumab will be measured concomitantly with ADA 
levels for interpretation purposes only. Blood draws should take place prior to the 
injection/sham. A standardized procedure for the collection, processing, storage and shipment 
of these blood samples is provided by the central laboratory. Further details on sample 
collection, numbering, processing and shipment can be found in the central laboratory manual.
Additional pharmacodynamic assessment may be conducted on the samples wherever permitted 
by local regulation.


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9
Study discontinuation and completion
9.1
Discontinuation
The investigator should discontinue study treatment for a given patient and/or withdraw the 
patient from study if, on balance, he/she believes that continuation would be detrimental to the 
patient’s well-being.
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol.
The investigator and/or referring physician will recommend the appropriate follow-up medical 
care, if needed, for all patients who are prematurely withdrawn from the study.
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:

Patient/guardian decision

Pregnancy

Use of prohibited treatment as per recommendations in the prohibited treatment section

Any situation in which study participation might result in a safety risk to the patient

Subject develops a retinal vasculitis and/or retinal vascular occlusion 

Unsatisfactory therapeutic effect

Patient's condition no longer requiring study treatment
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 withdraw of informed consent Section 9.1.2). Where possible, they should 
return for the assessments indicated in the assessment schedule until the EOS visit. If they 
fail to return for these assessments for unknown reasons, every effort (e.g. telephone, e-mail, 
letter) should be made to contact the subject/pre-designated contact as specified in the lost to 
follow-up section. This contact should preferably be done according to the study visit schedule.
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

new / concomitant treatments


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
adverse events/Serious Adverse Events
The investigator must also 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 6.6.2.
9.1.1.1
Replacement policy
Discontinued subjects will not be replaced.
9.1.2
Withdrawal of informed consent/Opposition to use data/biological 
samples
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent/opposition to use data/biological samples occurs only when a subject:

Explicitly requests to stop use of their biological samples and/or data (opposition to use 
subject’s data and biological samples)
and

No longer wishes to receive study treatment
and

Does not want any further visits or assessments (including further study-related contacts)
This request should be in writing (depending on local regulations) and recorded in the source 
documentation.
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Where consent to the use of Personal and Coded Data is not required in a certain country's legal 
framework, the participant therefore cannot withdraw consent. However, they still retain the 
right to object to the further collection or use of their Personal Data.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table (Table 8-1).
Novartis will continue to keep and use all research results (data) that have already been collected 
for the study evaluation, including processing of biological samples that has already started at 
time of consent withdrawal/opposition. No new Personal Data (including biological samples) 
will be collected following withdrawal of consent/opposition.


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For China: All biological samples not yet analyzed at the time of withdrawal will no longer be 
used, unless permitted by applicable law. They will be stored according to applicable legal 
requirements.
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination:

Unexpected, significant, or unacceptable safety risk to subjects enrolled in the study

Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data

Discontinuation of study drug development
In taking the decision to terminate, Novartis will always consider the subject welfare and safety. 
Should early termination be necessary, subjects must be seen as soon as possible and treated as 
a prematurely withdrawn subject. The investigator may be informed of additional procedures 
to be followed in order to ensure that adequate consideration is given to the protection of the 
subject’s interests. The investigator or sponsor depending on local regulation will be responsible 
for informing IRBs/IECs of the early termination of the trial.
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. 
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.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.


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The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Adverse events must be recorded in the Adverse Events CRF 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 intraocular injection procedure. If the event is 
due to lack of efficacy or progression of underlying illness (i.e. progression of the study 
indication) the assessment of causality will usually be ‘Not suspected’. The rationale for 
this guidance is that the symptoms of a lack of efficacy or progression of underlying illness 
are not caused by the trial drug, they happen in spite of its administration and/or both lack 
of efficacy and progression of underlying disease can only be evaluated meaningfully by an 
analysis of 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:

Dose not changed

Drug interrupted/withdrawn

Concomitant medication or non-drug therapy given

Patient hospitalized/patient's hospitalization prolonged (see Section 10.1.2 for definition 
of SAE)
6. its outcome:  
a. not recovered/not resolved;
b. recovered/resolved;
c. recovered/resolved with sequelae; 
d. fatal;
e. unknown.


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Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 30 days following the last 
administration of study treatment.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. Continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator Brochure (IB).
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease. Investigators have the responsibility for managing the safety of 
individual subjects and identifying adverse events. Clinically notable laboratory values and 
other test abnormalities are included in Appendix 1.
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent


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
social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the subject or may require 
medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines).
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
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 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 30 day period after the last study visit should only be reported 
to Novartis Safety if the investigator suspects a causal relationship to study treatment.


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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 Chief Medical 
Office and Patient Safety (CMO & PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment with 
any pregnancy outcome. Any SAE experienced during pregnancy must be reported.
10.1.5
Reporting of study treatment errors
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE.
Table 10-1
Guidance for capturing the study treatment errors
Treatment error type
Document in Dose 
Administration (DAR) 
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
The RTH258 program level Data Monitoring Committee (DMC) will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will assess at defined intervals the progress 
of a clinical trial, safety data, and critical efficacy variables and recommend to the sponsor 
whether to continue, modify or terminate a trial.
Specific details regarding composition, responsibilities, data monitoring and meeting frequency, 
and documentation of DMC reports, minutes, and recommendations will be described in a 
separate charter that is established between the sponsor and the DMC.
11
Data Collection and Database management
11.1
Data collection
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 Code of Federal Regulation (CFR) Part 11 


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requirements, Investigator site staff will not be given access to the Electronic Data Capture 
(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 will be 
processed centrally by the Central Reading Center and the results will be sent electronically to 
Novartis.
The data management staff will perform a reconciliation of the data entered on the eCRF versus 
what is received from the central reading center and central labs. At a minimum, this 
reconciliation will include header reconciliation, visit window checks, duplicate record checks, 
out of range checks as defined by the Clinical Trial Team (CTT) and checks to address missing 
reading center data and missing central lab data.
Randomization codes and data about all study treatment(s) dispensed to the subject will be 
tracked using an Interactive Response Technology (IRT). The system will be supplied by a 
vendor, who will also manage the database. The data will be sent electronically to Novartis (or 
a designated CRO) 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 


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analysis. Any changes to the database after that time can only be made after written agreement 
by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit and/or at an investigator’s meeting, a Novartis 
(or delegated CRO) representative will review the protocol and data capture requirements (i.e. 
eSource direct data entry (DDE) or eCRFs) with the investigators and their staff. During the 
study, Novartis employs several methods of ensuring protocol and GCP compliance and the 
quality/integrity of the sites’ data. The field monitor will visit the site to check the completeness 
of subject records, the accuracy of data capture / data entry, the adherence to the protocol and 
to Good Clinical Practice, the progress of enrollment, and to ensure that study treatment is being 
stored, dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits. Continuous remote monitoring of each 
site’s data may be performed by a centralized Novartis (or delegated CRO) Clinical research 
associate (CRA) organization. Additionally, a central analytics organization may analyze data 
& identify risks & trends for site operational parameters, and provide reports to Novartis clinical 
teams to assist with trial oversight.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, retinal images, and the results of any other tests or assessments. 
All information on CRFs 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 CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed.
12
Data analysis and statistical methods
The primary safety and efficacy analysis will be based on the Week 52 data, i.e. all data up to 
and including 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, 
median, quartiles, minimum, and maximum. For categorical variables, this will generally 
include: n, frequency and percentage in each category.
Further technical details and discussions of the statistical considerations will be provided in the 
statistical analysis plan (SAP).
Any data analysis carried out independently by the investigator should be submitted to Novartis 
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Additional analysis populations may be defined and sensitivity analyses may be conducted to 
evaluate the impact of COVID-19 pandemic.
12.1
Analysis sets
The Randomized Set will consist of all randomized patients. Patients are considered 
randomized when they had been deemed eligible for randomization by the investigator and 
given a randomization number. Patients will be analyzed according to the treatment assigned to 
at randomization.
The Full Analysis Set (FAS) will include all randomized patients who receive at least one IVT 
injection of the study treatment. The full analysis set will serve as the primary analysis set for 
all efficacy analyses. Following the intent-to-treat principle, patients will be analyzed according 
to the treatment assigned to at randomization.
Supportive analyses of the primary and key secondary endpoints will include analysis using the 
Per Protocol Set (PPS). PPS is a subset of the FAS and will exclude patients with protocol 
deviations (PDs) and analysis restrictions (ARs) that are expected to majorly affect the validity 
of the assessment of efficacy at Week 52 including for e.g. lack of compliance (including missed 
treatments and treatment misallocation), missing data, prohibited concomitant medication and 
deviation from inclusion/exclusion criteria. Confounded data or discontinuation from treatment 
due to lack of efficacy and/or safety do not constitute a reason for exclusion from the PPS.
Before the Week 52 database lock the relevant protocol deviations will be identified at the 
patient level in the database. After the Week 52 database lock, analysis restrictions will be 
derived in the analysis database. Censoring applied in relation to the specific PDs / ARs will be 
specified as well.
The FAS will be the analysis set for the primary estimand as defined in Table 12-1. However, 
when assessing the robustness of the overall efficacy conclusions, considerations will be given 
to the analysis based on the primary estimand using FAS and the supplementary estimand (see 
Table 12-1) 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 patients who receive at least one IVT injection 
of the study drug. Patients in the safety analysis set will be analyzed according to the treatment 
arm from which they received majority of treatments up to and including Week 48.
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.
Relevant medical history/current medical conditions will be tabulated by system organ class 
(SOC) and preferred term (PT) of the MedDRA dictionary for the FAS.Other relevant baseline 
information will be listed and summarized with descriptive statistics as appropriate.
12.3
Treatments
Study treatment


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Descriptive statistics for exposure to study treatment will be provided for the Safety set, FAS 
and PPS. For the efficacy analysis sets (FAS and PPS), the number of active and sham IVT 
injections will be presented by visit and cumulatively for the period baseline to Week 48, 
including separate analysis for the loading phases, i.e. up to Week 16 (last treatment of the 
5*q4w loading of aflibercept) and up to Week 24 (last treatment of 5*q6w loading of 
brolucizumab), and maintenance phase. For the safety analysis set, summary will include 
exposure data up to Week 52.
Prior medication and concomitant therapies
The number and percentage of patients taking prior medication or concomitant therapies will 
be summarized by preferred term according to the WHO Drug Reference List dictionary using 
the Safety Set and FAS (in case there are differences between those two). The concomitant 
therapies (medications and procedures) will include all therapies received after start of study 
treatment including those already started prior to the start of study treatment.
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.
The first key secondary endpoint is average change in BCVA from baseline over the period 
Week 40 through Week 52. For each patient, this endpoint is defined as the average of the 
changes from baseline to Weeks 40, 44, 48 and 52. The motivation for the choice of this 
endpoint is that, averaging the BCVA values over Week 40 to Week 52 will account for both 
random fluctuations and potential trough and peak values during the different treatment cycles. 
During the period Week 40 to Week 52, aflibercept and brolucizumab patients on q8w will have 
two assessments 4 weeks after the last dose, and two assessments 8 weeks after the last dose. 
Brolucizumab patients on a q12w regimen will have two assessments 4 weeks after the last dose, 
one assessment 8 weeks after the last dose, and one assessment 12 weeks after the last dose.
The primary analysis of the primary and first key secondary endpoints will be based on the FAS.
12.4.2
Statistical model, hypothesis, and method of analysis
The objective related to the primary and first key secondary endpoints is to demonstrate non-
inferiority of brolucizumab to aflibercept with respect to change from baseline in BCVA, 
considering a margin of 4 ETDRS letters.
Let:
B = Brolucizumab 6 mg - 5 x q6w loading then q12w/q8w maintenance
A = Aflibercept 2 mg - 5 x q4w loading then q8w maintenance
The following non-inferiority hypotheses are related to a non-inferiority margin of 4 letters:
H01: μB – μA ≤ -4 letters vs. HA1: μB – μA > -4 letters
H02: φB – φA ≤ -4 letters vs. HA2: φB – φA > -4 letters


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where μB and μA are the corresponding unknown true mean changes from baseline in BCVA at 
Week 52; φB and φA are the corresponding unknown true mean changes from baseline in BCVA 
averaged over the period Week 40 to Week 52;
Based on the FAS, the above hypotheses will be tested via an analysis of variance (ANOVA) 
model. The model will include treatment, baseline BCVA (≤65, >65 letters) and age category 
(<65, ≥65 years) as factors. Two-sided 95% confidence interval (CI) for the least square means 
difference (brolucizumab - aflibercept) will be presented. Non-inferiority will be considered 
established if the lower limit of the corresponding 95% CI is greater than -4 letters.
These two hypotheses will be tested sequentially in the order of their numbering (HAn, n=1, 2). 
Consequently, confirmatory testing of the second hypothesis requires rejection of the first null 
hypothesis.
In this setting, each hypothesis will be assessed at a one-sided significance level of 0.025, while 
keeping the global type I error rate at 0.025.
12.4.3
Handling of missing values/censoring/discontinuations
Missing BCVA values will be imputed by LOCF (Last Observation Carried Forward) as a 
primary approach. For patients with no post-baseline BCVA value, the baseline value will be 
carried forward. Data collected after start of alternative DME treatment in the study eye (e.g. 
other anti-VEGF treatment, laser or intraocular corticosteroids, as further detailed in the SAP) 
will be censored for the primary analysis.
From an estimand perspective, the main focus is to adequately reflect in the analysis 
unfavorable study outcome related to the treatment (e.g. lack of efficacy, safety problems).
The LOCF approach is expected to be sensitive to an early study termination due to lack of 
efficacy assuming that such lack of efficacy is reflected in the last observed BCVA 
measurement. In case of the use of alternative treatment for the underlying disease (DME), data 
collected after the start of such a treatment would be censored. LOCF will then be based on the 
last value prior to the start of this treatment, again expecting that this value would reflect the 
negative BCVA outcome under study treatment. In case of missing data due to lack of 
safety/tolerability with impairment of the function of the study eye the LOCF method would 
also provide a sensitive approach to capture such an unfavorable outcome.
In case of missing data occurring independently of the response to study treatment, the LOCF 
approach assumes stability which seems to be adequate based on historical data both for the 
maintenance treatment phase (i.e. stabilization of BCVA) and also in case of the absence of any 
treatment effect with an average natural disease progression in terms of BCVA of only 1-2-
letter loss over 1 year. In case of an early study termination during the loading phase, the LOCF 
method will result in a conservative estimate potentially underestimating the true outcome.
LOCF is an established method within the assessment of efficacy of anti-VEGF treatments in 
terms of BCVA outcome. Non-inferiority studies should follow the main design features 
(primary variables, the dose of the active comparator, eligibility criteria, etc.) as the previously 
conducted superiority trials in which the active comparator demonstrated clinically relevant 
efficacy. The primary endpoint in aflibercept Phase III studies VIVID and VISTA was the 
BCVA change from Baseline to Week 52 with missing data imputed based on LOCF. Based on 


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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 SAP.
Table 12-1
Primary and supplementary estimands
Estimand
Estimand definition
Analysis 
set
Statistical methods (Including strategy for 
imputation of missing/censored data)
Primary 
estimand
Difference in change from 
baseline in BCVA at Week 52 
excluding the effect of 
switching to alternative DME 
medication in the study eye
FAS
Analysis of variance (ANOVA) model 
including terms for treatment, baseline BCVA 
(≤65, >65 letters) and age category (<65, 
≥65 years), and using LOCF 
imputation/replacement for missing/censored 
data.
Supplementary 
estimand
Difference in change from 
baseline in BCVA at Week 52 
for patients adhering to the 
protocol as per the PPS 
definition
PPS
ANOVA model as per the primary estimand.
LOCF imputation/replacement for 
missing/censored data
12.4.4
Sensitivity and Supportive analyses
Sensitivity and supportive analyses will be performed for primary and the first key secondary 
endpoints related to BCVA using the per protocol analysis set (PPS), alternative methods of 
handling missing values (Section 12.4.3) and descriptive analyses based on observed data only 
(with and without censoring of data collected after use of alternative treatment for DME in the 
study eye, e.g. other anti-VEGF treatment, laser, intraocular corticosteroids, as further detailed 
in the SAP).
The following subgroup analyses will be conducted in FAS applying the primary analysis 
approach as specified above:

Age category (<65, ≥65 years)

Gender (male, female)

Diabetes type (Type 1, Type 2)

Baseline HbA1c (<7.5, ≥7.5%)

Baseline BCVA categories (≤65, >65 letters)

Duration of DME (≤3, >3-<12, ≥12 months)

DME type (focal, diffuse) as per CRC

Baseline CSFT (<450, ≥450-<650, ≥650 µm)

Baseline status of IRF (presence, absence)

Baseline status of SRF (presence, absence)
Further description of the additional analyses will be detailed in the SAP.


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12.5
Analysis of secondary endpoints
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
12.5.1.1 Additional key secondary endpoints
Additional key secondary endpoints are:

Proportion of patients maintained at q12w up to Week 52 (for brolucizumab treatment arm 
only)

Proportion of patients maintained at q12w up to Week 52, within those patients that 
qualified for q12w at Week 36 (for brolucizumab treatment arm only)
The estimate for the proportion of patients with a positive q12w treatment status at Week 52 
will be derived from Kaplan Meier time-to-event analyses for the event ‘first q8w-need’ 
applying a ‘q8w-need’ allocation in case of missing or confounded data attributable to lack of 
efficacy and/or lack of safety.
The proportion of patients with a positive q12w treatment status at Week 52 will be derived 
considering the q8w-need (reflecting duration of effect) and potential limitations in terms of 
efficacy and safety:

Patients will need to have the status of ‘q8w need = no’ at Weeks 32, 36 and 48 unless the 
‘q8w need = yes’ is confounded by reasons other than lack of efficacy and/or safety (see 
censoring details below)

Potential limitations in terms of efficacy and safety will be addressed by considering 
patients – even without an explicit ‘q8w need = yes’ – as having a negative q12w status in 
case any of the following confounding factors is attributable to lack of efficacy and/or lack 
of safety of the study treatment (assessed based on a masked medical review): early 
treatment/study discontinuation, use of forbidden concomitant medications/procedures 
and/or other deviation from treatment schedule (e.g. due to a missed visit/treatment). The 
corresponding q8w need will be allocated to the next disease activity assessment visit 
following the occurrence of such a confounding factor
In case missing or confounded data regarding the q12w treatment status are attributable to 
reasons other than lack of efficacy and/or safety, the patient is censored within the q12w 
treatment status analysis according to the following specifications:

Early treatment/study discontinuation: censoring at the last valid disease activity assessment

Single missed visit with a relevant disease activity assessment: censoring at the last valid 
disease activity assessment prior to the missed visit

Prohibited concomitant medications/procedures: censoring at the last valid disease activity 
assessment prior to the corresponding application

Discrepancy between disease activity assessment by investigator and the actual treatment 
received: censoring at the corresponding visit

Other treatment allocations/applications deviating from the concept of ‘treatment allocation 
according to disease activity’: censoring at the last valid disease activity assessment
The details regarding handling of missing values and discontinuations including the timing of 
censoring within the time-to-event analyses for the event ‘first q8w-need’ are specified above.


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From an estimand perspective, the assessment of failing study completion according to protocol 
due to lack of efficacy/safety is considered adequately represented by a negative q12w-status.
Alternative methods of handling missing or confounded data within sensitivity analyses will 
include an approach with 'q8w-need' allocation only in case of missing or confounded data 
attributable to lack of efficacy and an 'as observed' approach, i.e. an analysis without 'q8w-need' 
allocation.
Sensitivity analyses will be performed for additional key secondary endpoints using the per 
protocol analysis set (PPS), alternative methods of handling missing values (described above) 
and descriptive analyses based on observed data only (with and without censoring of data 
collected after use of alternative treatment for DME in the study eye, e.g. other anti-VEGF 
treatment, laser, intraocular corticosteroids, as further detailed in the SAP).
12.5.1.2 Other secondary endpoints
Summary statistics will be presented by treatment group using the FAS. For continuous 
variables, summary statistics will generally include: n, mean, standard deviation, median, 
quartiles, minimum, and maximum. For categorical variables, this will generally include: n, 
frequency and percentage in each category.
Further technical details and discussions of the statistical considerations will be provided in the 
SAP.
Secondary efficacy endpoints based on BCVA:

Change from baseline in BCVA at each visit up to Week 52

Average change from baseline in BCVA over the period Week 4 to Week 52.

Average change from baseline in BCVA over the period Week 20 to Week 52 and Week 28 
to Week 52

Gain in BCVA of ≥5, ≥10 and ≥15 ETDRS letters from baseline to each post-baseline visit
Note: Patients with BCVA value of 84 letters or more at a post-baseline visit will be considered 
as responders for the corresponding endpoint. This is to account for a ceiling effect, e.g. for the’ 
≥15-letter gain’ endpoint, for those patients with BCVA values at baseline ≥ 70 letters.

Time to achieve gain of ≥5, ≥10 and ≥15 ETDRS letters from baseline (or reaching a score 
of 84 or more)

Loss in BCVA of ≥5, ≥10 and ≥15 ETDRS letters from baseline to each post-baseline visit

Absolute BCVA ≥73 ETDRS letters at each post-baseline visit
Secondary efficacy endpoints related to dosing regimen:

q8w treatment need status assessed at Week 32

Treatment status at Week 52
Secondary efficacy endpoints related to anatomy:

Change from baseline in central subfield thickness (CSFT, as determined by SD-OCT from 
the CRC) at each assessment visit

Average change in CSFT from baseline over the period Week 40 through Week 52

Average change in CSFT from baseline over the period Week 4 to Week 52


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
Patient status regarding normal CSFT (<280 microns) at each assessment visit

Proportion of patients with presence of SRF, IRF and simultaneous absence of SRF and IRF 
at each assessment visit

Proportion of patients with presence of leakage on FA at Weeks 52
Secondary efficacy endpoints related to the status of Diabetic Retinopathy:

Patient status regarding a ≥2- and ≥3-step improvement or worsening from baseline in the 
ETDRS Diabetic Retinopathy Severity Scale (DRSS) score at each assessment visit

Incidence of progression to PDR as assessed by ETDRS-DRSS score of at least 61 by Week 
52
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 Set.
Adverse events
A treatment-emergent adverse event is defined as any adverse event that develops after 
initiation of the study treatment or any event already present that worsens following exposure 
to the study treatment. Only treatment-emergent adverse events will be presented in the 
summary tables.
Adverse events will be coded using the MedDRA dictionary and presented by system organ 
class (SOC) and preferred term (PT). Treatment-emergent AEs will be analyzed based on the
number and percentage of patients with at least one AE in the category of interest. Separate 
presentations will be provided related to ocular events in the study eye and fellow eye and 
systemic events. Additional summaries will be provided by severity and causality (separately 
assessed for the injection procedure and the drug). Serious adverse events and adverse events 
leading to discontinuation of study treatment will also be summarized separately.
Patient listings of all adverse events will be provided. Deaths and other serious or clinically 
significant non-fatal adverse events will be listed separately.
An adverse event of special interest (ESI) is one of scientific and medical interest to the Sponsor 
and include, 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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The number (and proportion) of subjects with adverse events related to identified and potential 
risks, including ESI, will be summarized by treatment.
Ophthalmic examinations
Pre-injection IOP measurements will be presented descriptively (absolute values and change 
from baseline). Post-injection IOP measurements will be listed.
Laboratory tests, vital signs, and special tests
Laboratory data and vital signs will be summarized by presenting shift tables using extended 
normal ranges (as provided by the central laboratory) with thresholds representing clinical 
relevant abnormality and by presenting descriptive statistics of raw data and change from 
baseline. Values outside the extended normal range will be listed by patient and treatment arm 
and flagged in data listings.
12.5.3
Pharmacokinetics
Serum concentration data of brolucizumab will be listed by patient, and visit/sampling time 
point. Pharmacokinetic parameters will not be calculated. For purposes of calculating mean 
concentration values at each time point a value equal to one-half the lower limit of 
quantification (LLOQ) will be used for any individual subject whose determined concentration 
value is below the limit of quantitation. If a majority of patients at any time point/group are 
found to be below the limit of quantitation or if the calculated mean concentration value is 
below the nominal limit of quantitation then the resultant mean concentration will instead be 
reported as below the limit of quantitation. Descriptive statistics of the concentration values at 
each time point will include arithmetic and geometric means, SD, median, minimum and 
maximum, as appropriate.
12.5.4
Patient reported outcomes
The NEI VFQ-25 questionnaires will be scored (total and subscale scores) at Baseline and 
Weeks 28 and 52. Absolute scores and the absolute changes from Baseline will be calculated 
and summarized descriptively.
Further details on the scoring algorithm and analysis will be provided in the SAP.
12.5.5
Anti-drug antibodies
Collection of blood for ADA assessment will be done at Screening and weeks 4, 12, 24, 36, 52 
(end of study visit, EOS) visit prior to the injection/sham.


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12.7
Interim analyses
Interim analyses are not planned in this study.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
A sample size of 120 patients per arm will allow to demonstrate a non-inferiority (NIM of 4 
ETDRS letters) of brolucizumab 6 mg vs. aflibercept 2 mg with respect to the BCVA change 
from baseline at Week 52, with 80% power at a one-sided alpha level of 0.025, assuming equal 
means and a common standard deviation of 11 letters. Assuming that averaging over the 4 time 
points will not lead to an increase in the standard deviation a power of at least 80% can also be 
expected for its corresponding non-inferiority claim. 
To account for a drop-out rate of 10%, a total of 268 (134 per arm) patients will need to be 
randomized.
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.


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13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g. 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov. 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.
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 SOPs, and are performed according to written Novartis processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.


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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 p. 177-83.
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; 40(3)  p. 509-16
Klein R, Moss SE, Klein BE, et al (2001) The NEI-VFQ-25 in people with long-term type 1 
diabetes mellitus: the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Arch. 
Ophthalmol. p. 733-40.
Korobelnik JF, Do DV, Schmidt-Erfurth U, et al (2014) Intravitreal aflibercept for diabetic 
macular edema. Ophthalmology p. 2247-54.
Lang GE, Berta A, Eldem BM, et al (2013) Two-year safety and efficacy of ranibizumab 0.5 
mg in diabetic macular edema: interim analysis of the RESTORE extension study. 
Ophthalmology p. 2004-12.
Lee R, Wong TY, Sabanayagam C (2015) Epidemiology of diabetic retinopathy, diabetic 
macular edema and related vision loss. Eye Vis (Lond) p. 17.
Mangione CM, Lee PP, Gutierrez PR, et al (2001) Development of the 25-item National Eye 
Institute Visual Function Questionnaire. Arch. Ophthalmol. p. 1050-8.
Mitchell P, Bandello F, Schmidt-Erfurth U, et al (2011) The RESTORE study: ranibizumab 
monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. 
Ophthalmology p. 615-25.
Nussenblatt RB, Palestine AG, Chan CC, et al (1985) Standardization of vitreal inflammatory 
activity in intermediate and posterior uveitis. Ophthalmology; 92(4) p. 467-71
Smiddy WE (2011) Economic considerations of macular edema therapies. Ophthalmology p. 
1827-33.
Virgili G, Parravano M, Menchini F, et al (2014) Cost-effectiveness of treatments for diabetic 
macular oedema: should we pay more attention to the appraisal and reporting of economic 
evaluations? Br J Ophthalmol p. 421-2.
Ziemssen F, Cruess A, Dunger-Baldauf C, et al (2017) Ranibizumab in Diabetic Macular 
Oedema - A Benefit-risk Analysis of Ranibizumab 0.5 mg PRN Versus Laser Treatment. Eur 
Endocrinol p. 91-98.


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

SAP_001.pdf: 
Novartis 
Restricted 
Page 1 
SAP Amendment 1 
CRTH258B2304 
Clinical Development 
RTH258/Brolucizumab 
CRTH258B2304 / NCT04058067   
A One-Year, Randomized, Double-Masked, Multicenter, 
Phase III, Two-Arm Study Assessing the Efficacy and 
Safety of Brolucizumab versus Aflibercept in Adult Chinese 
Patients with Visual Impairment Due to Diabetic Macular 
Edema (KINGLET) 
Statistical Analysis Plan (SAP) 
Document type: 
SAP Documentation 
Document status: 
Final Amendment V1.0 
Release date: 
16-Feb-2023
Number of pages: 
4645 
Property of Novartis 
Restricted 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Document History – Changes compared to previous final version of SAP 


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SAP Amendment 1 
 
CRTH258B2304 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
17-
Jan-
2020 
Prior 
to DB 
lock 
Creation of 
first version 
N/A 
NA 
16-
Feb-
2023 
Prior 
to DB 
lock 
Creation of 
amendment 
1 
Clarify primary and supplementary 
estimands and analyses based on 
estimands 
 
Add analyses of impact of the COVID-19 
pandemic 
 
 
 
Modify table of alternative DME treatment 
 
 
Update DRSS original scale definition and 
analysis method 
 
Add confirmatory testing related to 
additional secondary efficacy endpoints 
 
Add SRF/IRF status classification 
 
Add listing for imaging parameters 
 
Combine outputs of PK endpoints with 
ADA endpoints  
 
Modify titer value threshold, and add 
analyses of ADA endpoints 
 
Update listing of “change to protocol 
specified analyses” 
 
Update statistical methods for proportion 
variables 
 
Update rules of exclusion and censoring of 
analysis 
Sections 2.1, 
2.5.1, 2.5.2, 2.5.4 
 
 
Sections 2.2.1, 
2.3.1, 2.5.4.3, 
2.6.4, 2.7.2.1, 
2.8.1 
 
Section 2.5.3 
 
 
 
Section 2.7.2.2 
 
 
Section 2.7.2.3 
  
 
Section 2.7.3 
 
Section 2.8.4.4 
 
Sections 2.9, 2.10 
 
 
Section 2.10 
 
 
Section 4 
 
Section 5.4.2.2 
 
 
 
Sections 5.5, 5.6 


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Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 7 
1.1 
Study design............................................................................................................. 7 
1.2 
Study objectives and endpoints ............................................................................... 8 
2 
Statistical methods ............................................................................................................... 9 
2.1 
Data analysis general information ........................................................................... 9 
2.1.1 
General definitions ................................................................................ 10 
2.2 
Analysis sets .......................................................................................................... 11 
2.2.1 
Subgroups of interest............................................................................. 11 
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...................................................................................... 13 
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 and first key secondary endpoints ........................................... 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 the additional key secondary objectives ............................................. 20 
2.6.1 
Additional key secondary endpoints ..................................................... 20 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 20 
2.6.3 
Handling of missing values/censoring/discontinuations ....................... 21 
2.6.4 
Supportive analyses ............................................................................... 21 
2.7 
Analysis of secondary efficacy objectives ............................................................. 22 
2.7.1 
Secondary efficacy endpoints ............................................................... 22 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 23 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 28 
2.8 
Safety analyses....................................................................................................... 29 
2.8.1 
Adverse events (AEs) ............................................................................ 29 
2.8.2 
Deaths .................................................................................................... 31 
2.8.3 
Laboratory data ..................................................................................... 31 
2.8.4 
Other safety data ................................................................................... 31 


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2.9 
Pharmacokinetic endpoints .................................................................................... 32 
2.10 
Anti-drug antibodies .............................................................................................. 32 
2.11 
Subject-reported outcomes .................................................................................... 33 
 
 35 
 
 35 
2.13 
Interim analysis ...................................................................................................... 35 
3 
Sample size calculation ..................................................................................................... 35 
4 
Change to protocol specified analyses .............................................................................. 35 
5 
Appendix ........................................................................................................................... 36 
5.1 
Imputation rules ..................................................................................................... 36 
5.1.1 
Study drug ............................................................................................. 36 
5.1.2 
AE date imputation ............................................................................... 36 
5.1.3 
Concomitant medication date imputation ............................................. 38 
5.1.4 
Medical history date of diagnosis imputation ....................................... 39 
5.2 
AEs coding/severity ............................................................................................... 39 
5.3 
Laboratory parameters and vital signs derivations ................................................ 40 
5.4 
Statistical models ................................................................................................... 40 
5.4.1 
Primary and first key secondary analysis .............................................. 40 
5.4.2 
Other secondary efficacy analysis ......................................................... 41 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 42 
5.6 
Censoring rules for analysis................................................................................... 44 


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List of abbreviations 
ADA 
Anti-drug antibody 
AE 
Adverse Event 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
AR 
Analysis restrictions 
ATC 
Anatomical Therapeutic Classification 
BCVA 
Best Corrected Visual Acuity 
CI 
CM 
Confidence interval 
Concomitant Medication 
cm 
Centimeter 
CF 
Color Fundus 
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 
DMC 
Data Monitoring Committee  
DME 
DR 
Diabetic Macular Edema 
Diabetic Retinopathy 
DRSS 
Diabetic Retinopathy Severity Scale 
eCRF 
Electronic Case Report Form 
EDTRS 
Early Treatment Diabetic Retinopathy Study 
IOP 
Intraocular Pressure 
IRT 
Interactive Response Technology 
IRF 
Intraretinal fluid 
IVT 
Intravitreal 
KM 
LLOQ 
LSM 
Kaplan Meier 
Lower Limit of Quantification 
Least Square Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
mL 
NPDR 
Milliliters 
Non-Proliferative Diabetic Retinopathy 
OCT 
Optical Coherence Tomography 
PD 
PDR 
Protocol Deviation 
Proliferative Diabetic Retinopathy 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SE 
Standard Error 
SOC 
System Organ Class 


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SRF 
Subretinal fluid 
ULN 
Upper Limit of Normal 
q1 
25th percentile 
q3 
75th percentile 
q4w 
Every 4 weeks 
q6w 
Every 6 weeks 
q8w 
Every 8 weeks 
q12w 
Every 12 weeks 
SRF 
Subretinal fluid 
TEAE 
Treatment-Emergent Adverse Event 
TFLs 
Tables, Figures, Listings 
VA 
Visual acuity 
VFQ-25 
Visual Functioning Questionnaire-25 
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 CRTH258B2304. 
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). Any changes to the SAP after 
approval will be documented. 
The following document archived in CREDI was referenced while writing this SAP: 
CRTH258B2304-v02--protocol dated 14-Oct-2021 
1.1 
Study design 
This is a randomized, double-masked, multi-center, active-controlled, 2-armed study in patients 
with diabetic macular edema (DME) to evaluate the safety and efficacy of brolucizumab 6 mg 
against the active control aflibercept 2 mg. 
Approximately 335 Chinese patients will be screened (20% screening failure rate expected) and 
approximately 268 patients will be randomized in a 1:1 ratio in one of the following treatment 
arms: 
• Brolucizumab 6mg: 5 × q6w loading then q12w/q8w maintenance 
• Aflibercept 2mg: 5 × q4w loading then q8w maintenance 
At baseline visit, all eligible patients will be randomized via Interactive Response Technology 
(IRT) to one of the treatment arms, stratified by systemic exposure sampling status (serum PK 
sample consented vs. not consented). This stratification is only for the purpose of ensuring 
approximately half of PK sample consented patients would be randomized to Brolucizumab 6 
mg treatment arm. 
Since the treatment schedule is different for each arm the following will be applied to ensure 
masking: 
• In addition to every 4-week visits for all patients, extra visits are scheduled at Weeks 6 
and 18 for both treatment arms 
• The patients will receive active/sham injection at each protocol visit except weeks 20, 
28 and 52 visits (no scheduled treatment for either arm) 
• Disease activity assessment will be performed for both arms. 
• To fulfil the double-masking requirement, the investigational site will have masked and 
unmasked staff. 


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Figure 1-1 
Study design 
 
There will be two treatment phases for intravitreal (IVT) injections with different timing for 
brolucizumab and aflibercept treatment arms: 
Loading Phase: 
Brolucizumab 6 mg: In the loading phase, treatment with brolucizumab will occur every 6 
weeks for five (5) consecutive injections (Baseline, Weeks 6, 12, 18 and 24). To preserve the 
masking, the patients assigned to this regimen will receive sham injection on Weeks 4, 8 and 
16. 
Aflibercept 2 mg: In the loading phase, treatment with aflibercept will occur every 4 weeks for 
five (5) consecutive injections (Baseline, Weeks 4, 8, 12 and 16). To preserve the masking, the 
patients assigned to this regimen will receive sham injection on Weeks 6 and 18. 
Maintenance Phase: 
Brolucizumab 6 mg: From Week 24 onwards, patients will be scheduled to receive one 
injection of brolucizumab 6 mg every 12 weeks. If, however, disease activity is identified by 
the evaluating/masked investigator at Weeks 32 or 36, the patient will be assigned to receive 
injection of brolucizumab 6 mg every 8 weeks (please refer to protocol for ‘Evaluation of 
Disease Activity’). A disease activity assessment will also be performed at Week 48 but will 
not be entered into IRT and will have no effect on the subject’s treatment schedule. 
Aflibercept 2 mg: From Week 16 onwards, patients will receive one injection of aflibercept 2 
mg every 8 weeks (first injection after Week 16 to be given at Week 24) until Week 48 visit. 
Disease activity assessments will be conducted by the evaluating/masked investigator for 
masking purposes and will not influence the treatment interval. 
The primary safety and efficacy analysis will be based on the data up to and including Week 
52.  
1.2 
Study objectives and endpoints 
Study objectives and related endpoints are described in Table 1-1 below. 


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Table 1-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To demonstrate that brolucizumab 6 mg is 
non-inferior to aflibercept 2 mg with respect 
to the visual outcome after up to one year 
of treatment 
• 
Change from baseline in BCVA at Week 52 
• 
Change from baseline in BCVA averaged over a 3 
month period (from Week 40 to Week 52) 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To estimate the proportion of patients 
treated at q12w frequency with 
brolucizumab 
• 
Proportion of patients maintained at q12w up to Week 
52 
• 
To estimate the predictive value of the first 
q12w cycle for maintenance of q12w 
treatment with brolucizumab 
• 
Proportion of patients maintained at q12w up to Week 
52, within those patients that qualified for q12w at 
Week 36 
• 
To evaluate the functional and anatomical 
outcome with brolucizumab relative to 
aflibercept 
• 
Change from baseline by visit up to Week 52 in BCVA 
and in parameters derived from SD-OCT, Color fundus 
photography and Fluorescein angiography 
• 
To evaluate the effect of brolucizumab 
relative to aflibercept on the Diabetic 
Retinopathy status 
• 
Change in ETDRS Diabetic Retinopathy Severity Scale 
(DRSS) score up to Week 52 
• 
To assess the safety of brolucizumab 
relative to aflibercept  
• 
Incidence of Ocular and Non-ocular AEs, vital signs 
and laboratory values up to Week 52 
• 
To evaluate the effect of brolucizumab 
relative to aflibercept on patient-reported 
outcomes (VFQ-25) 
• 
Change in patient reported outcomes (VFQ-25) total 
and subscale scores from baseline up to Week 52 
• 
To confirm the systemic brolucizumab 
exposure in a subset of patients   
• 
Systemic brolucizumab concentration approximately 
24 hours after initial and final loading phase doses in a 
subset of patients 
• 
To assess the immunogenicity of 
brolucizumab over one year of treatment 
• 
Anti-drug antibody status at screening and up to Week 
52 in brolucizumab arm 
 
2 
Statistical methods 
2.1 
Data analysis general information 
The primary safety and efficacy analysis will be based on the data up to and including Week 
52, once all subjects completed or discontinued from the study. 
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. 


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Point estimates, 95% CIs of treatment differences will be provided as appropriate unless 
otherwise specified. 
2.1.1 
General definitions  
Study drug and study treatment 
Study drug refers to both Brolucizumab 6 mg and Aflibercept 2 mg IVT injections. 
Study treatment refers to study drug or sham injections. 
Study day 
Day 1 is defined as the date of first administration of study treatment. 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 day mapping 
The end of study date is the date when a subject completes or discontinues the study.  
For reporting data by visit in outputs, the end of study visit will be allocated to the actual 
(reported) visit. 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 end of treatment day/date of last exposure is the date of the last study treatment. 
For reporting data by visit in outputs, the end of treatment date will be allocated to the actual 
(reported) visit number. If end of treatment date is not on a scheduled visit, then the end of 
treatment 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 summary of maximum letter loss in BCVA from baseline. 
These data will not be used in analyses with mixed model for repeated measures (MMRM). 
Moreover, given unscheduled visits will not be active treatment visits, IOP measurements at 
unscheduled visits will not be considered as pre-injection IOP measurements, hence will not be 
used to identify subjects with pre-injection IOP >30 mmHg. 


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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 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 and key secondary endpoints will include analysis using the 
Per Protocol Set (PPS). PPS is a subset of the FAS and will exclude 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, e.g. lack of compliance 
(including missed treatments and treatment misallocation), missing data, prohibited 
concomitant medication and deviation from inclusion/exclusion criteria. Confounded data or 
discontinuation from treatment due to lack of efficacy and/or safety do not constitute a reason 
for exclusion from the PPS.  
Before the 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.  
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. 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 study treatments. 
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: 


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• Age category (<65, ≥65 years) 
• Gender (male, female) 
• Diabetes type (Type 1, Type 2) 
• Baseline HbA1c (<7.5, ≥7.5%) 
• Baseline BCVA categories (≤65, >65 letters) 
• Duration of DME since the primary diagnosis (≤ 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) in the central subfield 1 mm area (presence, 
absence) 
• Baseline status of subretinal fluid (SRF) in the central subfield 1 mm area (presence, 
absence) 
Subgroup analysis will be performed for the primary and key secondary efficacy endpoints only, 
(as defined in Section 2.5.1 and Section 2.6.1), using the primary analysis approach. More 
details can be found in Section 2.5.4 and Section 2.6.2. 
Additionally, analyses of the impact of COVID-19 pandemic in subjects will be conducted. 
Impacted subjects are defined as subjects who: 
• Miss at least one visit due to COVID-19  
• Or discontinue study/study treatment due to COVID-19 
• Or report COVID-19 infection (including suspected as per PTs in the PDS) 
Subgroup analyses will be conducted using the same model described for the primary endpoint 
and selective secondary endpoints in the impacted and non-impacted subgroups. Details can be 
found in Section 2.5.4, Section 2.6.4, Section 2.7.2 and Section 2.8.1. Demographics and 
baseline characteristics will be summarized for impacted and non-impacted subjects. 
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 
study, discontinue the study prior to Week 52 (including reasons for discontinuation) and 
discontinue from study treatment prior to Week 48 (including reasons for discontinuation).  
The number and percent of subjects who discontinue the study and who discontinue study 
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. 


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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 PDs and ARs 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 occur due to COVID-19, the number and percentage of 
subjects with PDs that occur due to COVID-19 will also be provided by deviation category, 
relationship to COVID-19 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 and the relationship to COVID-19. 
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, age 
category (< 65, ≥ 65 years), gender and race. 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),  
• 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 (≤65, >65 letters, and ≤60,  
≥61 - ≤69, ≥70 letters), 
• Baseline CSFT (<450, ≥450 - <650, ≥650 µm), 
• Baseline status of IRF in the central subfield 1 mm area (presence, absence), 
• Baseline status of SRF in the central subfield 1mm area (presence, absence), 
• Baseline ETDRS DRSS 12-point scale using categories (as defined in Table 2-4). 
Other baseline characteristics include: 
• Diabetes type (type 1, type 2), 
• Baseline HbA1c as continuous variable and using categories (<7.5, ≥7.5%),  
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. 


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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 study treatment 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 for baseline to Week 48/end of treatment including separate 
analysis for the loading phases, i.e. up to Week 16 (last treatment of the 5xq4w loading of 
aflibercept) and up to Week 24 (last treatment of 5xq6w loading of brolucizumab), and 
maintenance phase, using the following categories: active and sham IVT injections, active 
only, sham only 
• Treatment exposure by visit: The number and percent of subjects who received active IVT 
injections, sham injections, missed a treatment (active and sham) and missed visits will be 
presented by treatment arm and visit 
• Frequency of all observed dosing patterns from baseline to Week 52, differentiating 
between active and sham treatments, missed study treatments and wrong study treatments  
• Brolucizumab q12w/q8w allocation by visit from Week 32 onwards: Number and percent 
of subjects on q12w and q8w at each visit, including number of subjects who switched from 
q12w to q8w 
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 medications are defined as medications 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 for each treatment arm. Ocular medications will be listed for the 
study eye and the fellow eye separately. Anti-VEGF medications will be summarized by ATC 
class and preferred term for systemic route, for the study eye and the fellow eye separately by 
treatment arm. 
Ocular concomitant non-drug therapies and procedures will be summarized for the study eye 
only. Both ocular and non-ocular concomitant significant non-drug therapies and procedures 
will be listed. 
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). 


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2.5 
Analysis of the primary objective 
2.5.1 
Primary and first key secondary endpoints 
The primary endpoint is the change from baseline in BCVA at Week 52 in the study eye. 
The first key secondary endpoint is average change in BCVA from baseline over the period 
Week 40 through Week 52 in the study eye. For each subject, this endpoint is defined as the 
average of the changes from baseline to Weeks 40, 44, 48 and 52.  
The motivation for the choice of this endpoint is that averaging the BCVA values over Week 
40 to Week 52 will account for both random fluctuations and potential trough and peak values 
during the different treatment cycles.  
The primary analysis of the primary and first key secondary endpoints will be based on the FAS 
with last observation carried forward (LOCF) imputation of missing or censored 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 assessor 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 intercurrent events as follows:  
o Study discontinuation due to any reason: data imputed with LOCF 
o Treatment discontinuation due to any reason: use all the data 
o Data after the start of alternative DME treatment will be censored and replaced 
using LOCF  
• 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 and first key secondary endpoints is to demonstrate non-
inferiority of brolucizumab to aflibercept with respect to change from baseline in BCVA, 
considering a margin of 4 ETDRS letters. 
Let:  
B = Brolucizumab 6 mg 
- 5 x q6w loading then q12w/q8w maintenance 
A = Aflibercept 2 mg    
- 5 x q4w loading then q8w maintenance 
The following non-inferiority hypotheses are related to a non-inferiority margin of 4 letters:  
 
H01: μB – μA 
≤ -4 letters 
vs. 
HA1: μB – μA 
> -4 letters 
 
H02: B – A 
≤ -4 letters 
vs. 
HA2: B – A 
> -4 letters 


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where μB and μA are the corresponding unknown true mean changes from baseline in BCVA at 
Week 52; B and A are the corresponding unknown true mean changes from baseline in BCVA 
averaged over the period Week 40 to Week 52;  
Based on the FAS, the above hypotheses will be tested via an analysis of variance (ANOVA) 
model. The model will include treatment, baseline BCVA (≤65, >65 letters) and age category 
(<65, ≥65 years) as factors. Two-sided 95% confidence interval (CI) for the least square means 
(LSM) 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 two hypotheses will be tested sequentially (HAn, n=1, 2), i.e. confirmatory testing of the 
second hypothesis requires rejection of the first null hypothesis.  
In this setting, each hypothesis will be assessed at a one-sided significance level of 0.025, while 
keeping the global type I error rate at 0.025. 
The primary estimand and other supplementary estimands of interest are described in Table 2-
1 below, together with their key attributes. The same approach for non-inferiority assessment 
in change from baseline in BCVA at Week 52 and average change from baseline in BCVA over 
the period Week 40 through Week 52 will be applied to any supplementary estimand. 
Table 2-1 
Primary and supplementary estimands 
Estimand 
Estimand 
definition 
Analys
is 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 
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 
level 
ANOVA model as per the 
primary estimand.  
LOCF imputation/replacement 
for missing/censored data 


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Estimand 
Estimand 
definition 
Analys
is 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  
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 
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 
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 switching 
to 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 by the last observation collected prior to 
the start of alternative DME treatment in the study eye. Detailed alternative DME treatments 
will be listed in the Programming Data Specifications (PDS) documentation. 
Table 2-2 
Alternative DME treatment in the study eye 
• 
Ranibizumab 
• 
Aflibercept  
• 
Bevacizumab (off-label use) 
• 
Conbercept 
• 
Laser photocoagulation, previous standard of care still being used as mono- or combination 
therapy with anti-VEGF;  
• 
Intraocularly/periocularly administered steroids: 
o 
Dexamethasone 
o 
Fluocinolone acetonide 
o 
Triamcinolone acetonide 
o 
Other intraocular/periocular steroids 
From an estimand perspective, the main focus is to adequately reflect in the analysis 
unfavorable study outcome related to the treatment (e.g. lack of efficacy, safety problems). 


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The LOCF approach is expected to be sensitive to an early study termination due to lack of 
efficacy assuming that such lack of efficacy is reflected in the last observed BCVA 
measurement. In case of the use of alternative treatment for the underlying disease (DME), data 
collected after the start of such a treatment would be censored. LOCF will then be based on the 
last value prior to the start of this treatment, again expecting that this value would reflect the 
unfavorable 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 loss of only 1-
2 letters over 1 year. In case of an early study termination during the loading phase, the LOCF 
method will result in a conservative estimate potentially underestimating the true outcome.  
LOCF is an established method within the assessment of efficacy of anti-VEGF treatments in 
terms of BCVA outcome. Non-inferiority studies should follow the main design features 
(primary variables, the dose of the active comparator, eligibility criteria, etc.) as the previously 
conducted superiority trials in which the active comparator demonstrated clinically relevant 
efficacy. The primary endpoint in aflibercept Phase III studies VIVID and VISTA was the 
BCVA change from Baseline 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. 
2.5.4 
Sensitivity and Supportive analyses 
2.5.4.1 
Sensitivity analyses 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 values such as below will be considered to assess 
the robustness of the hypothesis testing resulting from the primary analysis: 
Mixed model for repeated measures (MMRM) assuming missing at random (MAR) with 
observed data (including censoring of BCVA values collected after the start of alternative DME 
treatment). The MMRM will include treatment, visit, baseline BCVA category, age category 
and treatment by visit interaction as fixed-effect terms and visit as a repeated measure. An 
unstructured covariance matrix will be used to model the within-subject error. For the MMRM 
analysis: 
• The treatment difference brolucizumab - aflibercept at Week 52 will be estimated using 
the LSM and 95% CI. 
• For the endpoint of average change from Baseline over the period Week 40 through 
Week 52, a SAS code using the ESTIMATE statement in PROC MIXED will be 
provided in the programming specification document to obtain the LS mean estimate 
and 95% CI for the corresponding treatment difference. 
• 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 


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is reached: compound symmetry (CS), first-order autoregressive (AR) and Toeplitz 
(TOEP), and 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. Different from 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 the supplementary estimand will apply the same LOCF/ANOVA 
method as for the primary estimand. 
Supplementary estimand on the FAS: 
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). 
2.5.4.3 
Summary statistics and subgroup analysis 
Summary statistics: 
• Descriptive statistics of BCVA primary and first key secondary endpoints will use 
observed data and primary analysis set (FAS), with and without censoring data after use 
of alternative DME treatment 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, including in the impacted and non-impacted 
subgroups defined 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 and first key secondary analyses 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. 
• In case of analyses on subgroups with extremely imbalanced sample sizes, the subgroup 
levels can either be combined, if appropriate, or the extremely small subgroup will be 
excluded while fitting the analysis model.   
• The point estimate and 95% CI for the between treatment difference for each subgroup 
will be presented using forest plots. 


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2.6 
Analysis of the additional key secondary objectives 
2.6.1 
Additional key secondary endpoints 
Additional key secondary endpoints are: 
• Proportion of subjects maintained at q12w up to Week 52 (for brolucizumab treatment arm 
only) 
• Proportion of subjects maintained at q12w up to Week 52, within those subjects that 
qualified for q12w at Week 36  (for brolucizumab treatment arm only) 
2.6.2 
Statistical hypothesis, model, and method of analysis 
No hypothesis will be tested for the additional key secondary efficacy endpoints.  
The primary analysis approach described below (efficacy/safety approach) will be conducted 
using the FAS.  
The estimate for the proportion of subjects with a positive q12w treatment status will be derived 
from Kaplan Meier (KM) time-to-event analyses for the event ‘first q8w-need’ imputing a 
‘q8w-need’ allocation in case of missing or confounded data attributable to lack of efficacy 
and/or lack of safety.  
The proportion of subjects with a positive q12w treatment status will be derived as follows 
requiring ‘sufficient duration of effect’ (as assessed by q8w-need) together with ‘sufficient 
efficacy and safety’: 
• For the ‘sufficient duration of effect’ requirement, subjects will need to have the status of 
‘q8w-need = no’ at Weeks 32, 36 and 48 unless the ‘q8w-need = yes’ is confounded by 
reasons other than lack of efficacy and/or safety (see censoring details below) 
• The requirement regarding ‘sufficient efficacy and safety’ will be addressed by considering 
subjects – even without an explicit ‘q8w-need = yes’ – as having a negative q12w status in 
case any of the following confounding factors is attributable to lack of efficacy and/or lack 
of safety of the study treatment: early treatment/study discontinuation, missed DAA. The 
q8w-need assessment will be imputed as “Yes” at the DAA visit following early 
treatment/study discontinuation due to lack of efficacy and/or lack of safety of the study 
treatment (applies to both missing and non-missing DAAs) 
In case missing or confounded data regarding the q12w treatment status are attributable to 
reasons other than lack of efficacy and/or safety, the subject is censored within the q12w 
treatment status analysis according to the following specifications: 
• Early treatment/study discontinuation: censoring at the last valid DAA visit  on or prior to 
treatment/study discontinuation 
• Single missed visit with a relevant DAA: censoring at the last valid DAA prior to the missed 
visit. 
• Prohibited concomitant medications/procedures: censoring at the last valid DAA prior to 
the corresponding application 


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• Discrepancy between DAA by investigator and the actual treatment received: censoring at 
the corresponding visit 
• Other treatment allocations/applications deviating from the concept of ‘treatment allocation 
according to disease activity’: censoring at the last valid DAA at or prior to the deviating 
visit. 
Censoring rules related to the q12w treatment status analysis are described in Section 5.5. 
The proportion of subjects with a positive q12w treatment status at Week 52 will be presented 
together with a two-sided 95% confidence interval (see Section 5.4.2.3). 
The outcome of the Kaplan Meier analyses will be presented graphically by the estimated q12w-
probability over time, i.e. at each DAA-visit. 
While for the analysis of the overall q12w proportion, all subjects in the FAS will be considered, 
the analysis of the proportion of subjects maintained at q12w up to Week 52, within those 
subjects that qualified for q12w at Week 36 is based on the subset of FAS subjects with no 
identified q8w-need at Week 32 and Week 36. For this subset of subjects a valid Week 36 DAA 
is required, while missing the Week 32 assessment is considered as no q8w-need. 
2.6.3 
Handling of missing values/censoring/discontinuations 
The details regarding handling of missing values and discontinuations, including the timing of 
censoring for the time-to-event analyses of ‘first q8w-need’, are specified in the previous 
section.  
Remark: Subjects without any valid DAA are considered censored at baseline for the overall 
q12w-proportion and for the analysis of the predictive value of the first q12w cycle. 
From an estimand perspective, the assessment of failing study completion according to protocol 
due to lack of efficacy/safety is considered adequately represented by a negative q12w-status.  
2.6.4 
Supportive analyses 
Supportive analysis will be performed on the FAS using alternative methods of handling 
missing or confounded data: 
• ‘Efficacy only’ approach: approach with ‘q8w-need’ allocation only in case the reason 
for a missing or confounded q12w status was attributable to lack of efficacy of the study 
treatment. In case of a corresponding safety reason the subject was censored at the last 
valid DAA.  
• ‘As observed’ approach: analysis without ‘q8w-need’ allocation. 
Additionally, analysis described in Section 2.6.2 conducted on FAS will be repeated on PPS to 
assess the consistency of the assessments of the q12w proportions when looking only at those 
subjects who adhere to the protocol. 
Subgroup analyses will be conducted as well to assess the consistency of the assessment of the 
q12w proportions across various subgroups described in Section 2.2.1, considering the FAS 
only and the efficacy/safety approach only. 
In addition, subgroup analyses will be conducted for the additional key secondary endpoints in 
the impacted and non-impacted subgroups defined in Section 2.2.1. 


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2.7 
Analysis of secondary efficacy objectives 
2.7.1 
Secondary efficacy endpoints 
Secondary efficacy endpoints related to BCVA, dosing regimen, anatomy or status of diabetic 
retinopathy are listed below. 
 
Secondary efficacy endpoints based on BCVA: 
• Change from baseline in BCVA at each visit up to Week 52 
• Average change from baseline in BCVA over the period Week 4 to Week 52. For each 
subject this endpoint is derived as the average of the changes from baseline at each post-
baseline visit between Week 4 and Week 52.  
• Average change from baseline in BCVA over the period Week 20 to Week 52 and Week 28 
to Week 52. For each subject those endpoints are derived as the average of the changes from 
baseline at each post-baseline visit between Week 20 and Week 52, and between Week 28 
and Week 52. 
• Number and percentage of subjects with a gain in BCVA of ≥5, ≥10 and ≥15 ETDRS letters 
from baseline to each post-baseline visit 
Note: Subjects with BCVA value of 84 letters or more at a post-baseline visit will be 
considered as responders for the corresponding endpoint. This is to account for a ceiling 
effect, e.g. for the’ ≥15-letter gain’ endpoint, for those subjects with BCVA values at 
baseline ≥ 70 letters. 
• Time to achieve gain of ≥5, ≥10 and ≥15 ETDRS letters from baseline (or reaching a score 
of 84 or more) 
• Number and percentage of subjects with a loss in BCVA of ≥5, ≥10 and ≥15 ETDRS letters 
from baseline to each post-baseline visit 
• Number and percentage of subjects with an absolute BCVA ≥73 ETDRS letters at each 
post-baseline visit  
Secondary efficacy endpoints related to dosing regimen: 
• Number and percent of subjects with q8w treatment need status assessed at Week 32  
• Treatment status at Week 52 
Secondary efficacy endpoints related to anatomy: 
• Change from baseline in central subfield thickness (CSFT, as determined by SD-OCT from 
the central reading center) at each assessment visit 
• Average change in CSFT from baseline over the period Week 40 through Week 52. For 
each subject this endpoint is derived as the average of the changes from baseline at Weeks 
40, 44, 48, 52. 
• Average change in CSFT from baseline over the period Week 4 to Week 52 
• Subject status regarding normal CSFT (<280 microns) at each assessment visit 


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• Proportion of subjects with presence of SRF, IRF and proportion of subjects with presence 
of SRF and/or IRF in the central subfield 1 mm area at each assessment visit 
• Proportion of subjects with presence of leakage on fluorescein angiography (FA) at Week 
52 
Secondary efficacy endpoints related to the status of Diabetic Retinopathy (see Section 
2.7.2.1): 
• Proportion of subjects with ≥2- and ≥3-step improvement or worsening from baseline in the 
ETDRS DRSS  at each assessment visit 
• Incidence of progression to proliferative diabetic retinopathy (PDR) as assessed by ETDRS 
DRSS original scale ≥61 by Week 52 among non-PDR subjects at screening 
2.7.2 
Statistical hypothesis, model, and method of analysis 
2.7.2.1 
General analysis specifications for secondary efficacy endpoints 
No hypothesis will be tested for the secondary efficacy endpoints listed in the above Section 
2.7.1 besides testings specified in Section 2.7.2.3.  
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 2.7.3. 
Continuous endpoints: 
The continuous secondary endpoints related to BCVA and CSFT will be analyzed using 
ANOVA models.  The LSM estimates for each treatment and for the treatment difference 
(brolucizumab – aflibercept), including 95% CIs for treatment difference, will be presented. 
For the ANOVA analysis of BCVA-related endpoints, baseline BCVA categories (≤65, >65 
letters) and age categories (<65, ≥65 years) will be considered as class variables. For the 
ANOVA analysis of CSFT, baseline CSFT categories (<450, ≥450 - <650, ≥650 µm) will be 
used instead of baseline BCVA categories as a class variable.  
The line plot on LSM (±SE) by visit will also be provided for each treatment arm. 
Binary endpoints: 
For binary endpoints, frequency tables (count and percentage) will be provided by visit. In 
addition, proportions and treatment differences in proportions along with 95% CIs will be 
presented for each time point using a logistic regression with treatment, the corresponding 
baseline status (similar to the ones specified for the ANOVA models) and age category as fixed 
effects.   
Bar chart will be plotted by visit and treatment arm.  
Time-to-event endpoints: 
The time to achieve gain of ≥5, (respectively ≥10 and ≥15) ETDRS letters from baseline (or 
reaching a score of 84 or more) will be analyzed using KM analysis. KM estimates on percent 
of subjects who achieve gain will be presented together with 95% CI by treatment and visit. 
The median time (95% CI) to gain will also be constructed by treatment arm. KM curves 


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presenting the cumulative probability of subjects with gain of ≥5, (respectively ≥10 and ≥15) 
ETDRS letters from baseline will be provided by treatment arm.   
The impact of COVID-19 pandemic on the following secondary endpoints will be assessed with 
subgroup analysis of impacted and non-impacted subjects defined in Section 2.2.1: 
• Average change in CSFT from baseline over the period Week 40 through Week 52 
• Change from baseline in CSFT at each assessment visit 
• Proportion of subjects with ≥2-step improvement or worsening from baseline in the 
ETDRS DRSS 12-point scale at each assessment visit 
• Treatment status at Week 52 
2.7.2.2 
ETDRS DRSS 
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 at each assessment visit 
• Incidence of progression to PDR as assessed by ETDRS-DRSS of at least 61 by Week 52 
(among non-PDR subjects at screening) 
Those endpoints will be derived from the ETDRS-DRSS assessed by the central reading center 
based on color fundus (CF) photography images in the study eye at screening, Week 28, and 
end of study visit or premature discontinuation visit. 
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 
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: NA, No images received) that are not related to 
an evaluable DR severity level will be handled as missing.  


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All DRSS values 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 
Microaneurysms only 
20 
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 


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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 
- 
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. 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% CIs for the proportions in each treatment arm, the difference in 
proportions between treatment arms and the 95% CI for the difference will be calculated using 
a logistic regression with treatment, the corresponding baseline DRSS (score ≤43, ≥47 from the 


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original scale or ≤4, ≥5 from the 12-level scale) and age categories (<65, ≥65 years) as fixed 
effects. 
The proportion of subjects who progress to PDR, as assessed by DRSS 12-point scale ≥7 by 
Week 52, will be summarized among the subset of non-PDR subjects at screening (DRSS 12-
point scale < 7). 
2.7.2.3 
Confirmatory testing related to additional secondary efficacy 
endpoints 
Confirmatory hypothesis testing for additional secondary endpoints will be performed in case 
non-inferiority related to BCVA is claimed for the hypotheses of primary endpoint and first key 
secondary endpoint specified in section 2.5.1 (corresponding to H1 and H2 in Figure 2-1). 
The additional hypotheses are linked to the endpoints below: 
• H3. Proportion of subjects with ETDRS DRSS ≥ 2-step improvement in the study eye from 
baseline by Week 52 (non-inferior for proportion of subjects in brolucizumab 6 mg vs 
aflibercept 2 mg with non-inferior margin 10%)  
• H4. Proportion of subjects with presence of fluid (SRF and/or IRF) in the study eye at Week 
52 (superior in proportion of subjects with absence of SRF and IRF in brolucizumab 6 mg 
vs aflibercept 2 mg)  
• H5. Average change in CSFT from baseline over the period Week 40 through Week 52 in 
the study eye (superior in reduction of the CSFT 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 initial proportion of significance level 
assigned. 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. 


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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 hypothesis, the alpha 
is passed on to other null hypotheses as per the graph.  
As described in Section 2.5.2, the primary hypothesis and first key secondary hypothesis will 
be tested sequentially.  
If the primary hypothesis (H1) and first key secondary hypothesis (H2) are rejected sequentially 
at a one-sided significance level of 0.025, then H3, H4 and H5 will be tested sequentially in the 
order of their numbering, i.e., confirmatory testing of the third, fourth, or fifth hypothesis 
requires rejection of the preceding null hypothesis, at a one-sided significance level of 0.025. 
 The family-wise type I error rate will be controlled at the one-sided 2.5% level. 
The basis for these tests will be the FAS. 
2.7.3 
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 imputed 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. 
Table 2-7 describes definition of presence of SRF/IRF: 
Table 2-7 
Definition of presence/absence status of SRF and IRF 
IRF/SRF presence in 
6mm field 
IRF/SRF presence within 1mm 
central subfield 
Presence/absence status of 
SRF/IRF 
Definite 
Yes 
Present 
Definite 
No 
Absent 
Absent 
Not Applicable 
Absent 
Cannot Grade 
Not Applicable 
Baseline: Absent 
Post-baseline: Missing 
Not Applicable 
 
Missing 
For endpoints related to presence of SRF and/or IRF, if post-baseline visit is reported as 
“Missing”, LOCF method for imputation will be applied. 
For the presence of leakage on FA, if baseline visit is reported as “Cannot Grade” or “Not 
Applicable”, then it will be considered as missing; if post-baseline visit is reported as “Cannot 
Grade” or “Not Applicable”, then it will be considered as missing and LOCF method for 
imputation will be applied. 


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2.8 
Safety analyses 
Safety endpoints are based on the variables from safety assessments which include: 
• Extent of exposure (see Section 2.4.1) 
• Adverse events 
• Ophthalmic examinations 
• Vital signs 
• Laboratory results 
• Loss in BCVA 
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 will be performed for missing 
values in the safety analyses. 
In all summary tables, unless otherwise specified, 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). 
2.8.1 
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 
to the study treatment. Only TEAEs 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). TEAEs 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 TEAEs will be summarized in the following ways: 
Table 2-8 
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 


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TEAE summary 
AE categories 
Ocular AE 
in the 
study eye 
Ocular AE 
in the 
fellow eye 
Non-
ocular 
AE 
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 and non-impacted subjects to COVID-19 as defined 
in Section 2.2.1 
In all summary tables listed above, unless otherwise specified, data collected after the subject 
discontinued study treatment and started alternative DME treatment in the study eye 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 will be listed separately. 
The MedDRA version used for reporting the AEs will be described in a footnote. 
2.8.1.1 
Adverse events of special interest / grouping of AEs 
Incidence of adverse events of special interest will be tabulated by treatment arm. 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 of 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’.  
2.8.1.2 
Adverse event reporting for clinical trial safety disclosure  
For the legal requirements of ClinicalTrials.gov, two required tables on TEAEs which are not 
serious adverse events with an incidence greater than 2% and on  treatment emergent AEs and 
SAEs suspected to be related to study treatment will be provided by SOC and PT on the safety 
set. Ocular TEAEs for study eye and fellow eye will be considered separately. 
If for the same subject, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE 


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For occurrence, the presence of at least one SAE (respectively  non-SAE) has to be checked in 
a block e.g., among AEs in a ≤ 1 day gap block, if at least one SAE is occurring, then one 
occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
2.8.2 
Deaths 
A summary of treatment emergent deaths will be presented by primary SOC and PT.  
All deaths recorded in the clinical database will be listed. 
2.8.3 
Laboratory data 
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. 
2.8.4 
Other safety data 
2.8.4.1 
Ophthalmic examinations 
Intraocular pressure (IOP) values summarized and listed in safety analyses refer to assessments 
for study eye. IOP assessed in fellow eye will only be presented if deemed by the investigator 
as adverse event. 
Descriptive summaries of pre-injection IOP change from baseline 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 visit will be 
summarized.  
Post-injection IOP will 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 listing for subjects with post-injection IOP increase 
of ≥10 mmHg from pre-injection IOP at any visit will be presented. 
A summary table with counts and percentages of subjects with observed pre-injection IOP ≥ 
21mmHg 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 scheduled visit X has missing pre-injection IOP and pre-injection IOP ≥ 21 mmHg 
is observed for both visits X-1 and X+1, the subject is considered to meet the criteria at visit X 
as well. 
A listing of subjects with any IOP > 30 mmHg will be presented. 


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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. 
2.8.4.2 
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. 
2.8.4.3 
Vital signs 
A summary table with counts and percentages of subjects satisfying the criteria given in Table 
5-2 of the Section 5.3 at any 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 each vital sign parameter by study visit and 
treatment with error bars representing ±SE will be presented. The x-axis will be study visit and 
the y-axis will be the mean change from baseline value. 
2.8.4.4 
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. 
2.9 
Pharmacokinetic endpoints   
Serum concentration of brolucizumab will be assessed in around 12 subjects in brolucizumab 
arm at Day 2 and Week 24, both approximately 24 hours after dosing.  
At each time point, one-half the lower limit of quantification (LLOQ) will be used for analysis 
when a subject has a determined concentration value below the LLOQ. If a majority of subjects 
at any time point are below the LLOQ or if the calculated mean concentration value is below 
the nominal LLOQ then the resultant mean concentration will be reported as below the LLOQ 
instead. 
2.10 
Anti-drug antibodies 
Collection of blood for ADA assessment for brolucizumab treatment arm will be done at 
Screening, Weeks 4, 12, 24 and 36 prior to the injection/sham, and at exit/premature 
discontinuation. 
 
 
 
 
 
 
 
 
 
 


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In addition, tabulations will be presented for ADA titer values by ADA assessment visit for the 
brolucizumab arm.  
 
 
The line plots showing the BCVA change from baseline up to Week 52 for the study eye 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 generated. 
The summary tables of the incidence of AESIs by ADA status (pre-existing, integrated status 
up to Week 52) will be presented. 
Subject listings of all ADA titer values 
 will be presented for all subjects in the 
brolucizumab arm. Samples collected at unscheduled visits will not be part of the analysis. 
Systemic exposure of brolucizumab will be measured concomitantly with ADA levels for 
interpretation purposes, no pharmacokinetic parameters will be determined from brolucizumab 
systemic exposure. In addition, systemic brolucizumab exposure assessment will be performed 
in a subset of consented subjects at 2 time points, approximately 24 hours after the first dose 
and approximately 24 hours after the treatment at Week 24. Systemic exposure data will be 
summarized and listed. 
2.11 
Subject-reported outcomes 
The Visual Function Questionnaires (VFQ-25) will be scored (total and subscale scores) at 
Baseline, Week 28 and Week 52 visits. Absolute scores and the absolute changes from baseline 
will be calculated and summarized descriptively using the FAS.  
Further details on the scoring algorithm and analysis are provided below. 
Each subscale score has a range of 0 to 100 inclusive and will be calculated from the re-scaled 
raw data as described in Table 2-9. A missing response will not be re-scaled (except for the 
response to question 15c, see below, which will be re-set to 0 if the response to question 15b is 
1). 
The answers to questions will be re-scaled as follows to calculate the composite and subscale 
scores. 


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Table 2-9 
Rescaling of VFQ-25 questions 
Answer to 
question 
Rescaling for  
questions 1, 3, 4 
and 15c 
Rescaling for 
question 2 
Rescaling for 
questions 5-14, 
16 and 16a 
Rescaling for 
questions 17-25 
1 
100 
100 
100 
0 
2 
75 
80 
75 
25 
3 
50 
60 
50 
50 
4 
25 
40 
25 
75 
5 
0 
20 
0 
100 
6 
N/A 
0 
N/A* 
N/A 
Note: * Response choice "6" indicates that the person does not perform the activity because of non-vision related problems. If 
this choice is selected, the item is coded as "missing”. Subscales will be calculated where at least one of the (re-scaled) questions 
contributing to that subscale is non-missing, and otherwise set to missing. 
• Note that the answer to question 15c will subsequently be adjusted based on the answer 
to question 15b. 
o If the answer to 15b is 1 then the answer to 15c will be re-set to 0. 
o If the answer to 15b is 2 or 3 then the answer to 15c will be re-set to missing  
The VFQ subscales and their corresponding questions are shown in Table 2-10. 
Table 2-10 
Questions contributing to VFQ subscales 
Subscale 
Questions 
General vision 
2 
Ocular pain 
4 and 19 
Near activities 
5, 6 and 7 
Distance activities 
8, 9 and 14 
Social functioning 
11 and 13 
Mental health 
3, 21, 22 and 25 
Role difficulties 
17 and 18 
Dependency 
20, 23 and 24 
Driving 
15c, 16 and 16a 
Color vision 
12 
Peripheral vision 
10 
Subscales will be calculated where at least one of the (re-scaled) questions contributing to that 
subscale is non-missing, and otherwise set to missing. 
The composite score is the average of the 11 subscales shown in Table 2-10. It will be set to 
missing if at least six of the subscales are missing. 
The general health score is the re-scaled answer to question 1. 
Descriptive summary statistics for change from baseline to post baseline VFQ assessments will 
be presented using the FAS for the composite and subscale scores. Mean changes from baseline 
to each post baseline VFQ assessments visits will be compared between the brolucizumab arm 
and the aflibercept arm. Appropriate statistical methods (e.g. ANCOVA model with treatment 
as a fixed effect factor and corresponding baseline value of the endpoint in the model) will be 


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used for treatment group comparison. Additionally, descriptive statistics will also be presented 
for the general health score.   
The VFQ-25 composite score and subscale scores will not be listed. 
2.13 
Interim analysis 
Not applicable. 
3 
Sample size calculation 
A sample size of 120 subjects per arm will allow to demonstrate a non-inferiority (NIM of 4 
ETDRS letters) of brolucizumab 6 mg vs. aflibercept 2 mg with respect to the BCVA change 
from baseline at Week 52, with 80% power at a one-sided alpha level of 0.025, assuming equal 
means and a common standard deviation of 11 letters. Assuming that averaging over the 4 time 
points will not lead to an increase in the standard deviation, a power of at least 80% can also be 
expected for its corresponding non-inferiority claim.  
To account for a drop-out rate of 10%, a total of 268 (134 per arm) subjects will need to be 
randomized. 
4 
Change to protocol specified analyses 
There is no change to the protocol specified analysis in terms of endpoints. 
Some changes compared to the protocol specified analyses are made in the current statistical 
analysis plan: 


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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 
Descriptive statistics for exposure to study 
treatment will be provided for the Safety set. 
 
12.3 
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). 
 Ocular and non-ocular prior and concomitant 
medications will be summarized and listed by 
ATC class and preferred term for the Safety set.  
 
12.5.2 
Laboratory data and vital signs will be 
summarized by presenting shift tables 
using extended normal ranges (as 
provided by the central laboratory) 
with thresholds representing clinical 
relevant 
abnormality 
and 
by 
presenting descriptive statistics of raw 
data and change from baseline. 
Values outside the extended normal 
range will be listed by patient and 
treatment arm and flagged in data 
listings. 
No summary by visit tables will be provided. 
A summary table with counts and percentage of 
subjects satisfying the criteria representing 
clinically relevant abnormalities 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 below. 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). 
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. 


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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 concomitant medication (CM) start date year value is missing, the imputed CM start 
date is set to one day prior to treatment start date. 
2. If the CM start date year value is less than the treatment start date year value, the CM 
started before treatment. Therefore: 
a. If the CM month is missing, the imputed CM start date is set to the mid-year point 
(01JulYYYY). 
b. Else if the CM month is not missing, the imputed CM start date is set to the mid-month 
point (15MONYYYY). 
3. If the CM start date year value is greater than the treatment start date year value, the CM 
started after treatment. Therefore: 
a. If the CM month is missing, the imputed CM start date is set to the year start point 
(01JanYYYY). 
b. Else if the CM month is not missing, the imputed CM start date is set to the month start 
point (01MONYYYY). 
4. If the CM start date year value is equal to the treatment start date year value: 


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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 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 
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 is assessed by investigators according to the following:  


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• 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 
 
Hemoglobin 
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 
5.4 
Statistical models 
5.4.1 
Primary and first key secondary analysis 
The primary endpoint (change from baseline in BCVA at Week 52) and first key secondary 
endpoint (average change from baseline in BCVA over the period Week 40 through Week 52) 
will be analyzed using ANOVA models. 
 
Analysis of Variance (ANOVA) 
The following ANOVA model will be used for the primary and first key secondary efficacy 
endpoints: 
<change from Baseline in BCVA at Week 52> <average change from Baseline in BCVA from 
Week 40 to Week 52> = intercept + treatment + Baseline BCVA category + age category + 
error. 
For the above analysis, the data structure is one record per subject.  


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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 and first 
key secondary efficacy variables: 
<change from Baseline in BCVA> = 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 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 
ANCOVA model for continuous variables 
The continuous efficacy variable (such as VQF-25 score change from baseline) will be analyzed 
using an ANCOVA model adjusted for treatment, age category, and the corresponding baseline 
VFQ-25 score. 
The SAS Proc MIXED will be used to perform the ANCOVA 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 covariates if necessary.  
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. 
• 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 
KM estimate for time to event variables 
Within the brolucizumab treatment arm, the proportion of subjects maintained at q12w up to 
Week 52 will be estimated from Kaplan Meier time-to-event analyses for the event ‘ first q8w-
need’ applying event allocations (in case of lack of efficacy and/or lack of safety) and censoring 
as described in Section 2.6.2.  
A corresponding 95% CI will be derived from the LOGLOG transformation, using SAS Proc 
Lifetest, with CONFTYPE = LOGLOG. 


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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 
Subject less than 18 years of age at 
screening 
Exclude from PP analysis 
M_INCL03_Diabetes 
eligibility criteria 
Subjects without diabetes mellitus or 
HbA1c of more than 10% at screening or 
insufficient diabetes management at 
screening or baseline 
Exclude from PP analysis  
P_INCL04_No visual 
impairment (study eye) 
Study Eye: no visual impairment due to 
DME as per BCVA or CSFT criteria 
Exclude from PP analysis 
M_EXCL01_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_EXCL03_Confounding 
treatment study eye with 
impact 
Study Eye: Confounding concomitant 
medications or procedures with impact 
Exclude from PP analysis 
M_EXCL06_Systemic 
cond/trt with impact 
Systemic: Confounding systemic conditions 
(including Blood Pressure) 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 during loading 
phase 
Under-treatment during loading phase; 
missed active treatment (not due to any 
safety event) 
Exclude from PP analysis 
M_TRT03_Over treatment 
Over treatment, received active when 
schedule was for sham /no treatment 
Exclude from PP analysis  
M_TRT04_Under-
treatment after loading 
phase 
Under-treatment after loading phase; 
missed active treatment  (not due to any 
safety event) 
Exclude from PP analysis if any 
missed active treatment between 
W40 and W48 inclusive, or if at 
least 2 missed consecutive active 
doses (not due to safety); 
Otherwise include in all analysis 
M_OTH01_Other PD with 
impact 
Any other protocol deviation with impact on 
the efficacy assessments or safety of the 
subject 
Exclude from PP analysis  
M_COMD01_Prohibited trt 
with impact 
Prohibited  medication and/or procedure  
as per protocol with impact on efficacy 
and/or safety 
Exclude from PP analysis 
P_WITH01_Treatment but 
consent withdrawn 
Subject withdrew consent but continued to 
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 


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PD (e.g. early study terminations, early treatment discontinuations, missing DAA or BCVA 
assessments). 
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 analyses 
AR_EST_02 
Early study termination due to lack of safety 
2 
Include in all analyses 
AR_EST_03 
Early study termination due to reasons other than lack of 
efficacy/safety 
0 
Exclude from PP analysis 
if before week 40.  
Otherwise include in all 
analyses 
AR_ETD_01 
Early study treatment termination due to lack of efficacy 
1 
Include in all analyses 
AR_ETD_02 
Early study treatment termination due to lack of safety 
2 
Include in all analyses 
AR_ETD_03 
Early treatment termination due to reasons other than 
lack of efficacy/safety 
0 
Exclude from PP analysis 
if before week 40.  
Otherwise include in all 
analyses 
AR_MD_01 
No valid BCVA assessment between W40 and W52  
0 
Exclude from PP analysis 
AR_MD_02 
Missing DAA due to lack of safety 
2 
Include in all analyses 
AR_MD_03 
Missing DAA due to reasons other than lack of safety 
0 
Include in all analyses 
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: 
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 
RAN 
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 


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Analysis 
Set 
PD ID that may cause subjects to be excluded 
Non-PD (AR) ID that cause subjects to 
be excluded 
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_INCL04_No visual impairment (study eye), 
M_EXCL01_Condition with impact study eye,  
M_EXCL03_Confounding treatment study eye with 
impact,  
M_EXCL06_Systemic cond/trt with impact, 
M_TRT01_Wrong IP administered,  
M_TRT02_Under-treatment during loading phase, 
M_TRT03_Over treatment,  
M_TRT04_Under-treatment after loading phase,  
M_OTH01_Other PD with impact, 
M_COMD01_Prohibited trt with impact, 
P_WITH01_Treatment but consent withdrawn 
Not in the FAS 
AR_EST_03, 
AR_ETD_03, 
AR_MD_01 
5.6 
Censoring rules for analysis 
PDs and ARs that are considered to be critical for the subject evaluability regarding the primary 
and key secondary endpoints are described in Section 5.5. 
The focus of the ARs is the identification of censoring related to the analysis of BCVA and 
q12w proportion as derived from DAA and described in Section 2.6.2. Censoring is only applied 
in case the underlying reason for a confounded DAA is assessed as ‘0’. Censoring of BCVA 
and DAA applies both to FAS and PPS. 
Table 5-6 summarizes the concepts of censoring for the key parameters BCVA and q12w-status/ 
DAA applied to the two efficacy analysis sets, FAS and PPS, as well as the details for the timing 
of censoring for BCVA and DAA. 
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 and DAA 
Analysis Set 
Censoring concept for BCVA 
Censoring concept for DAA 
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. 
M_TRT01_Wrong_IP_administered: censoring at the 
last valid DAA visit at or prior to the PD visit 
M_TRT02_Under-treatment during loading phase: 
censoring at baseline 
M_TRT03_Over treatment: censoring at the last valid 
DAA visit at or prior to the PD visit 


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M_TRT04_Under-treatment 
after 
loading 
phase: 
censoring at the last valid DAA visit at or prior to the 
PD visit 
M_COMD01_Prohibited trt with impact: censoring at 
the last valid DAA prior to the start of the prohibited 
medication or procedure 
AR_ETD_03: censoring at the last valid DAA visit at or 
prior to the PD visit 
AR_EST_03: censoring at the last valid DAA visit at or 
prior to the PD visit 
AR_MD_03: censoring at the last valid DAA prior to the 
missed visit 
Remark: The primary analysis of the q12w proportion 
as derived from DAA and described in section 2.6.2 
applies censoring in case the underlying DAA is 
considered to be confounded by reasons other than 
lack of efficacy and/or safety. Based on the underlying 
time-to-‘first-q8w-need’ analysis, all information up to 
and including the censoring time-point contribute to the 
evaluation of the q12w status. 
 
Censoring: subjects are considered to no longer 
be under risk for a q8w-need identification at later 
visits. 
 
Censoring at baseline if above PD/AR occurred prior 
to Week 32. 
Censoring at Week 52 visit if subjects completed Week 
52 without above PD/AR 
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) 
Similar to FAS