Conditions: Diabetic Macular Edema
Keywords: Diabetic Macular Edema intravitreal injection brolucizumab aflibercept double-masked
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 360
Healthy volunteers: no

Brief summary:
This was a Phase III, randomized, double-masked, multi-center, active-controlled, two-arm study designed to evaluate the efficacy and safety of brolucizumab 6 mg compared to the active control, aflibercept 2 mg used per authorized label, in subjects with visual impairment due to diabetic macular edema (DME).

Detailed description:
The study included a screening period of up to 2 weeks to assess eligibility, followed by a double-masked treatment period (Day 1 to Week 96). The baseline visit was defined as Day 1/Visit 1, and end of treatment visit as Visit 27 (Week 96). After the last treatment visit, there was a post-treatment follow-up period from Week 96 to Week 100 and an exit visit at Week 100. Subjects were assigned to one of two treatment arms in a 1:1 ratio: brolucizumab 6 mg/0.05 mL (5 loading doses each administered every 6 weeks (q6w) during loading phase then q12w/q8w during maintenance phase with an option to extend treatment interval by 4 weeks during the second year) or aflibercept 2 mg/0.05 mL (5 loading doses each administered every 4 weeks (q4w) during loading phase then q8w during maintenance phase).

Disease activity assessments (DAAs) were conducted by the masked investigator for both treatment arms at Week 32 and Week 36, i.e., 8 and 12 weeks after the end of the loading phase for subjects receiving brolucizumab, and at Week 48, Week 60 and Week 72 (i.e., every 12 weeks). 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 any of the subsequent DAA visits, in which case subjects were switched to a q8w treatment interval until Week 72.

A one-time disease stability assessment was performed by the masked investigator at Week 72 in both treatment arms with the purpose of evaluating the potential for treatment interval extension by 4 weeks. The subjects in the brolucizumab arm who demonstrated disease stability in the one-time assessment at Week 72 under their current assigned treatment regimen (q12w or q8w) were considered for treatment interval extension. To evaluate the adequacy of the individualized q8w, q12w or q16w treatment intervals in the brolucizumab arm, DAAs were performed at every visit from Week 72 up to and including Week 96 (i.e., every 4 weeks) and subjects had their treatment interval modified accordingly. If after Week 72 disease activity had been identified by the masked investigator at a scheduled treatment visit (according to the subject specific treatment schedule q12w or q16w) the subject was assigned to q8w treatment schedule.

Arms:
arm 1: Brolucizumab 6 mg/0.05 mL, 5 loading doses, with subsequent doses per protocol-specified maintenance schedule arm 2: Aflibercept 2 mg/0.05 mL, as labeled, 5 loading doses, with subsequent doses every 8 weeks

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

Protocol document:
Prot_000.pdf: 
Global Clinical Development - General Medicine 
[RTH258/brolucizumab]
Clinical Trial Protocol [CRTH258B2302 / NCT03481660]
A Two-Year, Two-Arm, Randomized, Double-Masked, Multicenter, 
Phase III Study Assessing the Efficacy and Safety of Brolucizumab 
versus Aflibercept in Adult Patients with Visual Impairment due to 
Diabetic Macular Edema (KITE)
Document type:
Amended Protocol Version
EUDRACT number:
2017-003960-11
Version number:
v02 (Clean)
Clinical trial phase:
III 
Document status:
Final
Release date:
11-Jun-2020
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.4 (May 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 11-JUN-2020 .............................................................................................11
Summary of previous amendments ...................................................................................13
Amendment 1 ....................................................................................................................13
Protocol summary..............................................................................................................15
1
Introduction .......................................................................................................................20
1.1
Background............................................................................................................20
1.2
Purpose ..................................................................................................................22
2
Study objectives and endpoints .........................................................................................22
3
Investigational plan ...........................................................................................................24
3.1
Study design...........................................................................................................24
3.2
Rationale for study design .....................................................................................25
3.3
Rationale for dose/regimen, route of administration and duration of treatment....25
3.4
Rationale for choice of comparator .......................................................................26
3.5
Purpose and timing of interim analyses/design adaptations..................................27
3.6
Risks and benefits..................................................................................................27
4
Population..........................................................................................................................27
4.1
Inclusion criteria ....................................................................................................27
4.2
Exclusion criteria...................................................................................................28
5
Treatment...........................................................................................................................30
5.1
Study treatment......................................................................................................30
5.1.1
Investigational and control drugs..........................................................30
5.1.2
Additional treatment..............................................................................31
5.2
Treatment arms......................................................................................................31
5.3
Treatment assignment and randomization.............................................................31
5.4
Treatment masking ................................................................................................32
5.5
Treating the patient................................................................................................33
5.5.1
Patient numbering .................................................................................33
5.5.2
Dispensing the study drug.....................................................................33
5.5.3
Handling of study and additional treatment..........................................33


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5.5.4
Instructions for prescribing and taking study treatment........................34
5.5.5
Permitted dose adjustments and interruptions of study treatment ........38
5.5.6
Rescue medication/procedure ...............................................................38
5.5.7
Concomitant medications and treatments .............................................38
5.5.8
Prohibited medication ...........................................................................39
5.5.9
Emergency breaking of assigned treatment code..................................39
5.6
Study completion and discontinuation...................................................................40
5.6.1
Study completion and post-study treatment..........................................40
5.6.2
Discontinuation of study treatment .......................................................40
5.6.3
Withdrawal of informed consent...........................................................41
5.6.4
Loss to follow-up ..................................................................................41
5.6.5
Early study termination by the sponsor.................................................41
6
Visit schedule and assessments .........................................................................................42
6.1
Information to be collected on screening failures..................................................45
6.2
Patient demographics/other baseline characteristics .............................................45
6.3
Treatment exposure and compliance .....................................................................45
6.4
Efficacy..................................................................................................................46
6.4.1
Visual acuity..........................................................................................46
6.4.2
Optical coherence tomography .............................................................46
6.4.3
Color fundus photography and fluorescein angiography......................46
6.4.4
Appropriateness of efficacy assessments..............................................47
6.5
Safety.....................................................................................................................47
6.5.1
Physical examination ............................................................................47
6.5.2
Vital signs..............................................................................................48
6.5.3
Height and Weight ................................................................................48
6.5.4
Ophthalmic examination.......................................................................48
6.5.5
Laboratory evaluations..........................................................................49
6.5.6
Pregnancy and assessments of fertility .................................................50
6.5.7
Appropriateness of safety measurements..............................................50
6.6
Other assessments..................................................................................................50
6.6.1
Clinical Outcome Assessments (COAs) ...............................................50
6.6.2
Resource utilization...............................................................................51
6.6.3
Pharmacokinetics ..................................................................................51
6.6.4
Anti-drug antibodies (immunogenicity)................................................51
52
6.6.6
Other biomarkers...................................................................................52


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7
Safety monitoring..............................................................................................................52
7.1
Adverse events.......................................................................................................52
7.2
Serious adverse events...........................................................................................54
7.2.1
Definition of SAE .................................................................................54
7.2.2
SAE reporting........................................................................................55
7.3
Liver safety monitoring .........................................................................................55
7.4
Renal safety monitoring.........................................................................................56
7.5
Reporting of study treatment errors.......................................................................57
7.6
Pregnancy reporting...............................................................................................57
8
Data review and database management.............................................................................57
8.1
Site monitoring ......................................................................................................57
8.2
Data collection.......................................................................................................58
8.3
Database management and quality control............................................................58
8.4
Data Monitoring Committee..................................................................................59
8.5
Adjudication Committee........................................................................................59
9
Data analysis......................................................................................................................59
9.1
Analysis sets ..........................................................................................................60
9.2
Patient demographics and other baseline characteristics.......................................61
9.3
Treatments .............................................................................................................61
9.4
Analysis of the primary and first key secondary endpoints...................................61
9.4.1
Primary and first key secondary endpoints ...........................................61
9.4.2
Additional key secondary endpoints .....................................................63
9.4.3
Sensitivity and supportive analyses ......................................................65
9.5
Analysis of secondary endpoints ...........................................................................65
9.5.1
Efficacy endpoints.................................................................................65
9.5.2
Safety endpoints....................................................................................67
9.5.3
Resource utilization...............................................................................68
9.5.4
Pharmacokinetics ..................................................................................68
9.5.5
Biomarkers............................................................................................68
9.5.6
PK/PD ...................................................................................................68
9.5.7
PRO (Patient Reported Outcome).........................................................68
9.5.8
Anti-drug antibodies..............................................................................69
69
69
9.7
Interim analyses.....................................................................................................69
9.8
Sample size calculation..........................................................................................69


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10 Ethical considerations........................................................................................................70
10.1
Regulatory and ethical compliance........................................................................70
10.2
Informed consent procedures.................................................................................70
10.3
Responsibilities of the investigator and IRB/IEC..................................................71
10.4
Publication of study protocol and results...............................................................71
10.5
Quality Control and Quality Assurance.................................................................71
11 Protocol adherence ............................................................................................................71
11.1
Protocol amendments.............................................................................................72
12 References .........................................................................................................................73
13 Appendix 1: Clinically notable laboratory values and vital signs.....................................74
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.....................................................................................................................75
15 Appendix 3: Specific Renal Alert Criteria and Actions....................................................76
List of tables
Table 2-1
Objectives and related endpoints ..........................................................22
Table 5-1
Brolucizumab: Impact of DAA and DSA on treatment schedule.........35
Table 5-2
Prohibited medications / procedures.....................................................39
Table 6-1
Assessment schedule.............................................................................43
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................57
Table 9-1
Primary and supplementary estimands..................................................63
Table 13-1
Clinically notable laboratory values......................................................74
Table 14-1
Liver Event and Laboratory Trigger Definitions ..................................75
Table 15-1
Specific Renal Alert Criteria and Actions.............................................76
List of figures
Figure 3-1
Study design..........................................................................................24
Figure 5-1
Dosing schedule ....................................................................................36


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


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hCG
Human chorionic gonadotropin
HDL
High-density lipoprotein
IB
Investigator Brochure
ICH
International Conference on Harmonization
i.e.
Id est
IEC
Independent Ethics Committee
IOI
Intraocular inflammation
IOP
Intraocular pressure
IN
Investigator notification
IP
Investigational product
IRB
Institutional Review Board
IRF
Intraretinal fluid
IRT
Interactive Response Technology
ITT
Intention-to-treat
IUD
Intrauterine device
IUS
Intrauterine system
IVT
Intravitreal Treatment
kDa
Kilodaltons
LDH
Lactate dehydrogenase
LDL
Low-density lipoprotein
LFT
Liver function test
LOCF
Last observation carried forward
MAR
Missing at random
MedDRA
Medical dictionary for regulatory activities
MMRM
Mixed model for repeated measures
n.a.
Not applicable
nAMD
Neovascular age-related macular degeneration
NEI
National Eye Institute
NIH
National Institutes of Health
NIM
Non-inferiority margin
OCT
Optical coherence tomography
PD
Protocol Deviation
PDR
Proliferative diabetic retinopathy
PFS
Pre-filled syringe
PK
Pharmacokinetic
PPS
Per Protocol Set/Protocol analysis set
PRO
Patient reported outcome
PT
Preferred Term 
QoL
Quality of Life
RBC
Red blood cells
SAE
Serious Adverse Event
SAP
Statistical analysis plan
scFv
single-chain fragment variable


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


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


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


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Amendment 2 11-JUN-2020
Amendment rationale
The main purpose of this amendment is to provide clarification and guidance on safety 
assessments in accordance to the urgent safety measure regarding the post-marketing reports 
with brolucizumab (Beovu®) in the treatment of nAMD, which were identified as retinal 
vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular 
inflammation, that may result in severe vision loss. In addition, the amendment includes the 
modifications due to COVID-19 pandemic.
Changes to the protocol
Protocol sections changed in relation to this emerging safety issue are:

Section 1.1 Background: Information was added to describe a new safety signal from post-
marketing case reports.

Section 5.5.4 Instructions for prescribing and taking study treatment: Additional guidance 
was added to this section emphasizing that if any sign of intraocular inflammation is 
present, an IVT injection must not be performed and patients should be treated for IOI 
according to clinical practice.

Additional examination and assessments included to fully characterize cases of intraocular 
inflammation were made in the following sections:

Table 6-1 Assessment schedule

Section 6.4.3 Color fundus photography and fluorescein angiography

Section 6.5.4 Ophthalmic Examination

Section 6.5.7 Appropriateness of safety measurements
Modifications were made to include importance of Estimands per ICH E9(R1) guidance in the 
following Sections:

Section 9.1 Analysis sets

Section 9.4.1.2 Handling of missing values/censoring/discontinuations

Section 9.4.3 Sensitivity and supportive analyses
Changes were incorporated to address the COVID-19 pandemic in the following sections:

Section 6 Visit Schedule and Assessments

Section 6.5 Safety

Section 6.5.5 Laboratory evaluation

Section 9 Data Analysis

Section 10.2 Informed Consent Procedures
Other changes incorporated in this amendment:

Section 5.1.1 Investigational and control drugs

Section 5.4 Treatment masking: Language was added to clarify unmasked investigator/site 
personnel must not be switched to a masked role at any time after randomization
 


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
Section 5.5.4 Instructions for prescribing and taking study treatment: Language regarding 
the injection procedure was added replacing reference to an applicable manual.

Section 6.5.4 Ophthalmic examination: Clarification on the use of  same method for IOP 
measurement and timing for post-injection IOP measurement

 
 

Section 7.2.2 SAE reporting: Clarification of the SAE reporting period

Section 8.4 Data Monitoring Committee: Data Monitoring Committee was updated to 
program level Data Monitoring Committee.
 

Section 12 References

List of Abbreviations 
Other minor clarifications were made where applicable. Changes to specific sections of the 
protocol are shown in the track changes version of the protocol using strike through red font for 
deletions and red underlined for insertions.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Summary of previous amendments
Amendment 1
Amendment rationale
The main purpose of this amendment is to:

Compile the required changes in Informed Consent Forms with regards the definition of 
“personal data” and “withdrawal of informed consent” in order to incorporate and reflect 
the European Economic Area (EEA) General Data Protection Regulation (GDPR) 
requirements.
In addition, purpose of this amendment is to incorporate changes to the protocol language to 
improve clarity, accuracy and ensure better adherence.

Assessment schedule: The anti-drug antibody schedule in assessment Table 6-1 was 
corrected in line with Section 6.6.4. The appearance of Table 6-1 was adjusted to improve 
clarity.

Inclusion criteria on cut-off value of central subfield retinal thickness:  The inclusion 
criteria no. 5 was revised to allow enrollment of patients with central subfield retinal 
thickness (measured from RPE to ILM inclusively) of ≥320 µm on SD-OCT at screening, 
in lieu of 340 µm in the original protocol.   The revised cut-off  of 320 µm corresponds to 
the highest cut-off for DME on the most common SD-OCT devices, 

Contraception requirement: The contraception requirement was extended from 40 days 
to 3 months after last dose, for consistency with the approved label of comparator in EU 
and US. 

Pharmacokinetics: The pharmacokinetics of aflibercept was removed from testing and 
analysis, as the pharmacokinetics data for aflibercept has been available. Systemic 
brolucizumab concentration will be assessed approximately 24 hours after initial and final 
loading phase doses.
Changes to the protocol
Major changes are made to the protocol in the following sections:

Glossary of terms and Section 5.6.3: Definition of “personal data” was added and 
“withdrawal of study consent (WOC)” was updated.  The framework of analysis on study 
information collected from withdrawn patients was clarified. The definition of “Dosage” 
was updated with more clarity.

Protocol Summary page, Section 2, Section 6.6.3 and Section 9.5.4: The pharmacokinetics 
of aflibercept was removed from testing and analysis. The Pharmacokinetics samples will 
be collected at approximately 24 hours after first dose and the treatment at Week 24.

Section 4.1 Inclusion Criteria and Protocol summary: In inclusion criterion no. 5, central 
subfield retinal thickness cutoff value on SD-OCT was updated from ≥ 340 µm to from ≥ 
320 µm.


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
Section 4.2 Exclusion Criteria no.26 and Section 6.5.6: The duration required for 
contraception after stopping investigational medication was updated from 40 days to 3 
months, and this requirement was moved from the protocol section of exclusion criteria to
the section of assessment of fertility.

Table 6-1 Assessment schedule: The assessment schedule of anti-drug antibodies was 
corrected according to protocol body text Section 6.6.4. Assessment schedule of optional 
assessment 
, 
 
 is clarified. An optional FSH assessment is added for woman with need to 
confirm the reproductive status. Footnote list was updated.

Section 6.6.4 Anti-drug antibodies (immunogenicity): Clarification was made for anti-drug 
antibody measurement. Systemic exposure of brolucizumab/aflibercept will be measured in 
these blood samples concomitantly with ADA levels for interpretation purposes, no 
pharmacokinetic parameters will be determined from brolucizumab/aflibercept sytemic 
exposure which are collected along with ADA.

References: Reference was updated for 3 cited literature references in Section 1.1, and the 
other 2 references which were not required were removed.

List of abbreviations was updated.

Unit of Creatinine was corrected in Appendix 1.
Changes to specific sections of the protocol are shown in the track changes version of the
protocol using strike through red font for deletions and red underlined for insertions.


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Protocol summary
Protocol number
RTH258B2302
Full Title
A two-year, two-arm, randomized, double-masked, multicenter, phase III 
study assessing the efficacy and safety of brolucizumab versus aflibercept 
in adult patients with visual impairment due to diabetic macular edema
(KITE)
Brief title
Study of efficacy and safety of brolucizumab vs. aflibercept in patients with 
visual impairment due to diabetic macular edema
Sponsor and Clinical 
Phase
Novartis
Phase III
Investigation type
Drug
Study type
Interventional
Purpose and rationale
This study is designed to evaluate the efficacy and safety of brolucizumab 
in treatment of patients with visual impairment due to diabetic macular 
edema (DME)
Primary Objective(s) 
To demonstrate that brolucizumab
is non-inferior to aflibercept with 
respect to the visual outcome after the first year of treatment 
Secondary Objectives
To assess the efficacy and the ocular and systemic safety of 
brolucizumab:

To demonstrate that brolucizumab is non-inferior to aflibercept with 
respect to visual outcome during the last 3 months of the first year of 
treatment

To estimate the proportion of patients treated at q12w frequency with 
brolucizumab

To estimate the predictive value of the first q12w cycle for 
maintenance of q12w treatment with brolucizumab

To assess the potential to extend treatment intervals for 
brolucizumab patients during the second year of treatment

To evaluate the functional and anatomical outcome with 
brolucizumab relative to aflibercept 

To evaluate the effect of brolucizumab relative to aflibercept on the 
Diabetic Retinopathy status

To assess the safety of brolucizumab relative to aflibercept 

To evaluate the effect of brolucizumab relative to aflibercept on 
patient-reported outcomes (VFQ-25)

To confirm the systemic brolucizumab exposure in patients with 
visual impairment due to diabetic macular edema

To assess the immunogenicity of brolucizumab 
Study design
In this 2-year, randomized, double-masked, multicenter, active controlled 
study consenting patients will participate in a screening period, lasting up 


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to 14 days. Eligible patients will be randomized in a 1:1 ratio to one of the 
two treatment arms:

Brolucizumab 6 mg: 5 x q6w loading then q12w/q8w maintenance
(with option to extend treatment interval during second 
year)

Aflibercept 2 mg:      5 x q4w loading then q8w maintenance
Population
Approximately 356 randomized patients ≥18 years of age with either type 
1 or 2 controlled diabetes mellitus and visual impairment due to diabetic 
macular edema
Key Inclusion criteria
General
1.
Patients must give written informed consent before any study related 
assessments are performed
2.
Patients ≥18 years of age at baseline
3.
Patients with type 1 or type 2 diabetes mellitus and HbA1c of ≤10% 
at screening
4.
Medication for the management of diabetes must have been stable 
within 3 months prior to randomization and is expected to remain 
stable during the course of the study
Study Eye
5.
Visual impairment due to DME with:
BCVA score between 78 and 23 letters, inclusive, using Early 
Treatment Diabetic Retinopathy Study (ETDRS) visual acuity 
testing charts at a testing distance of 4 meters (approximate 
Snellen equivalent of 20/32 to 20/320), at screening and baseline
DME involving the center of the macula, with central subfield 
retinal thickness (measured from RPE to ILM inclusively) of ≥320
µm on SD-OCT at screening
If both eyes are eligible, the eye with the worse visual acuity will be 
selected for study eye. However, the investigator may select the eye 
with better visual acuity, based on medical reasons or local ethical 
requirements.


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Key Exclusion criteria
1.
Previous treatment with any anti-VEGF drugs or investigational drugs 
in the study eye
2.
Active proliferative diabetic retinopathy in the study eye as per the 
investigator
3.
Concomitant conditions or ocular disorders in the study eye at 
screening or baseline which could, in the opinion of the investigator, 
prevent response to study treatment or may confound interpretation 
of study results, compromise visual acuity or require medical or 
surgical intervention during the first 12-month study period (e.g., 
cataract, vitreous hemorrhage, retinal vascular occlusion, retinal 
detachment, macular hole, or choroidal neovascularization of any 
cause)
4.
Any active intraocular or periocular infection or active intraocular 
inflammation (e.g., infectious conjunctivitis, keratitis, scleritis, 
endophthalmitis, infectious blepharitis, uveitis) in study eye at 
screening or baseline
5.
Structural damage of the fovea in the study eye at screening likely to 
preclude improvement in visual acuity following the resolution of 
macular edema, including atrophy of the retinal pigment epithelium, 
subretinal fibrosis, laser scar(s), epiretinal membrane involving fovea 
or organized hard exudate plaques
6.
Uncontrolled glaucoma in the study eye defined as intraocular
pressure (IOP) > 25 mmHg on medication or according to
investigator’s judgment, at screening or baseline
7.
Neovascularization of the iris in the study eye at screening or 
baseline
8.
Evidence of vitreomacular traction in the study eye at screening or 
baseline which, in the opinion of the investigator, affect visual acuity
Study treatment

Brolucizumab 6 mg/0.05 mL

Aflibercept 2 mg/0.05 mL
Key Efficacy 
assessments

BCVA testing using ETDRS chart

Anatomical markers on Spectral Domain Optical Coherence 
Tomography (SD-OCT) and Color Fundus photography

ETDRS DRSS score based on Color Fundus photography
Key safety 
assessments

Adverse events

Standard ophthalmic examination

Intraocular pressure measurement

Vital signs

Blood chemistry/hematology/urinalysis
Other assessments

Visual Function Questionnaire-25 (VFQ-25)

Anti-drug antibody (ADA)

Systemic brolucizumab exposure
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). 


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The FAS includes all randomized patients who receive at least one 
intravitreal (IVT) injection.
Sensitivity analyses will be performed using the per protocol analysis set 
(PPS) and alternative methods of handling missing values and 
descriptive analyses based on observed data only.
Primary and key secondary endpoints:
The primary endpoint is the change from baseline in BCVA at Week 52.
The key secondary efficacy endpoint involved in confirmatory testing is
the change from baseline in BCVA averaged over the period Week 40 to 
Week 52.
Additional key secondary endpoints are proportion of patients maintained 
at q12w up to Week 52 and proportion of patients maintained at q12w up 
to Week 52 within those patients that qualified for q12w at Week 36 (for 
brolucizumab treatment arm only)
Statistical Hypotheses and testing strategy:
The following non-inferiority hypotheses are related to a non-inferiority 
margin 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: B – A     ≤ -4 letters vs.
HA2: B – A    > -4 letters
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; 
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) as factors. Two-sided 95% 
confidence intervals (CI) for the least square means difference 
(brolucizumab - aflibercept) will be presented. Within the specified testing 
procedure, non-inferiority will be established if the lower limit of the 
corresponding 95% CI is greater than -4 letters.
Sample size justification:
A sample size of 160 patients per arm will allow demonstration of non-
inferiority (NIM of 4 ETDRS letters) of brolucizumab 6 mg vs. 
aflibercept 2 mg with respect to the BCVA change from baseline at Week 
52, with 90% power at a one-sided alpha level of 0.025, assuming equal 
means and a common standard deviation of 11 letters. Based on its 
nature it can be assumed that the endpoint ‘change from baseline in 
BCVA averaged over the period Week 40 to Week 52’ will not present a 
higher standard deviation, so that a (local) power of at least 90% can also 
be expected for its non-inferiority claim. 


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To account for a drop-out rate of 10%, a total of 356 (178 per arm) 
patients will need to be randomized.
Key words
Diabetic Macular Edema, intravitreal injection, brolucizumab, aflibercept, 
double-masked


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1
Introduction
1.1
Background
Diabetes mellitus (DM) is the most common endocrine disease in developed countries, with 
prevalence estimates ranging between 2 to 5% of the world population. Diabetic 
retinopathy (DR) and diabetic macular edema (DME) are common microvascular 
complications in patients with diabetes and may have a debilitating impact on visual acuity 
(VA), eventually leading to blindness. DME is a frequent manifestation of DR (Lee et al 2015)
and is the major cause of visual loss in patients with DR.
For anti-VEGF agents like ranibizumab or aflibercept a favorable benefit risk ratio was 
demonstrated with superior efficacy versus the previous standard of care (laser 
photocoagulation) in large Phase 3 programs that consequently led to their approval for the 
treatment of DME (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 standard therapy
The current treatment options for patients with DME are: laser photocoagulation, IVT 
corticosteroids, IVT corticosteroid implants, or IVT anti-VEGF. Due to the efficacy and safety
profile of anti-VEGF therapy, it has become the first-line treatment. Corticosteroids are used as 
a second line treatment and focal / grid laser photocoagulation remains a therapeutic option, but
with a lower expected benefit compared with steroid and anti-VEGF therapy. 
Despite the treatment success of existing anti-VEGFs, there remains a need for further treatment 
options to improve response rate and/or reduce resource use and injection frequency in patients 
with DME (Mitchell et al 2011; Smiddy 2011; Lang et al 2013; Virgili et al 2014; Agarwal et 
al 2015). 
Brolucizumab
Brolucizumab, formerly known as RTH258 and ESBA1008, is a humanized single-chain 
fragment variable (scFv), binding to VEGF-A (i.e. interfering with activation of VEGF-R1 and 
R2 on endothelial cells) with a molecular weight of ~26 kDa that is also being developed for 
the treatment of choroidal neovascularization (CNV) associated with neovascular age-related 
macular degeneration (nAMD). 
The characteristics of brolucizumab allow delivery of a high molar dose via intravitreal 
injection. A 6 mg dose of brolucizumab delivers a molar dose which is approximately 11 and 
22 times higher than aflibercept 2 mg and ranibizumab 0.5 mg, respectively. Higher molar doses 
are expected to lead to longer presence of relevant drug levels in the eye. In addition, a low 
molecular weight and high concentration gradient between the vitreous and the retina may 
increase drug distribution to the target site of action, supporting effective control of anatomical 
disease activity. 
In a single ascending dose Phase I study (C-10-083), the median time until patients fulfilled 
protocol defined criteria for receipt of standard of care treatment was 30 days longer for 
brolucizumab 3 mg (p=0.037) and 6 mg (p=0.036) versus ranibizumab. In a separate repeat 
dosing study (C-12-006) comparing brolucizumab 6 mg (bimonthly [q8w], then quarterly 


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[q12w] administration) against aflibercept (bimonthly administration [q8w]), brolucizumab 
achieved comparable visual outcome during the loading and q8w phase, with a lower number 
of patients requiring additional rescue treatments (5 vs. 10, respectively). Brolucizumab 
demonstrated a trend for greater improvements and more stability in retinal anatomy during the 
4 cycles of q8w dosing (up to Week 40), e.g. simultaneous resolution of intraretinal and 
subretinal fluid which was achieved in 61% of brolucizumab patients versus 35% of aflibercept 
patients at Week 40. 
In the Phase III studies (HAWK, HARRIER), brolucizumab demonstrated non-inferiority to 
aflibercept in mean change in best-corrected visual acuity from baseline to Week 48 in both 
trials. These results were achieved while a majority of patients on brolucizumab 6 mg – 56% in 
HAWK and 51% in HARRIER – were maintained on a q12w dosing interval following the 
loading phase through Week 48. Brolucizumab safety was comparable to aflibercept, with the 
overall incidence of adverse events balanced across all treatment groups in both studies.
Since the initial marketing authorization approval in October 2019 for the treatment of nAMD, 
retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular 
inflammation, have been reported from post-marketing experience with brolucizumab
(Beovu®). Although in some patients the presence of retinal vasculitis and/or retinal vascular 
occlusion have led to severe vision loss, on the overall benefit-risk balance of the product is 
considered to be low and the overall risk/benefit assessment remains positive.
Summary
Ranibizumab, aflibercept and brolucizumab all inhibit the activity of VEGF-A and all have 
demonstrated efficacy in the treatment of patients with nAMD. Both ranibizumab and 
aflibercept have also consistently demonstrated efficacy in the treatment of patients with visual 
impairment due to DME. These findings support the evaluation of brolucizumab in DME 
patients. Furthermore, the profile of brolucizumab in nAMD trials indicates a potential of 
brolucizumab to differentiate versus existing anti-VEGFs on duration of action and anatomical 
efficacy in DME patients:

The higher dose administered with brolucizumab is intended to provide a prolonged 
duration of action compared with ranibizumab and aflibercept 

The positive nAMD study results regarding the q12w/q8w regimen support the 
administration of q6w loading regimen for brolucizumab and q12w/q8w during the 
maintenance phase, extending the total duration of the loading phase whilst also reducing 
the injection burden 

The historical data in DME studies (Schmidt-Erfurth U 2014) suggests the less frequent 
treatment need over time justifying the investigation of longer treatment interval of 16 
weeks during the second year of follow up in this study
The above supports the initiation of a Phase III program consisting of 2 phase III studies,
RTH258B2301 and RTH258B2302, to evaluate the efficacy and safety of brolucizumab in 
treatment of patients with visual impairment due to DME with the intention of evaluating the 
potential to reducing the treatment burden for patients.


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1.2
Purpose
The purpose of this study is to evaluate the efficacy and safety of brolucizumab in treatment of 
patients with visual impairment due to DME.
2
Study objectives and endpoints
For the detailed description of endpoints and their statistical analysis, please refer to Section 
9.4 for primary and key secondary endpoints, Section 9.5 for other secondary 
 
endpoints.
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)
Endpoint(s) for primary objective(s)

To demonstrate that brolucizumab is non-
inferior to aflibercept with respect to the
visual outcome after the first year of 
treatment

Change from baseline in BCVA at 
Week 52
Secondary Objective(s)
Endpoint(s) for secondary objective(s)

To demonstrate that brolucizumab is non-
inferior to aflibercept with respect to visual 
outcome during the last 3 months of the first 
year of treatment

Change from baseline in BCVA 
averaged over a period Week 40 to 
Week 52

To estimate the proportion of patients 
treated at q12w frequency with
brolucizumab 

Proportion of patients maintained 
at q12w up to Weeks 52 & 100

To estimate the predictive value of the first 
q12w cycle for maintenance of q12w
treatment with brolucizumab

Proportion of patients maintained  
at q12w up to Week 52, within 
those patients that qualified for 
q12w at Week 36

Proportion of patients maintained  
at q12w/q16w up to Week 100, 
within those patients that qualified 
for q12w at Week 36

To assess the potential to extend treatment 
intervals for brolucizumab patients during 
the second year of treatment

Proportion of patients maintained 
on q16w up to Week 100 within 
the patients on q12w at Week 68
and on q16w at Week 76

Proportion of patients re-assigned 
and maintained on q12w up to 
Week 100 within the patients on 


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Objective(s)
Endpoint(s)
q8w at Week 68 and on q12w at 
Week 80

Treatment status at Week 100

To evaluate the functional and anatomical 
outcome  with brolucizumab relative to 
aflibercept 

Change from baseline by visit up 
to Week 100 in BCVA and in 
parameters derived from SD-OCT, 
Color fundus photography and
Fluorescein angiography

To evaluate the effect of brolucizumab 
relative to aflibercept on the Diabetic 
Retinopathy status

Change in ETDRS Diabetic 
Retinopathy Severity Scale 
(DRSS) score up to Week 100

To assess the safety of brolucizumab relative 
to aflibercept 

Incidence of Ocular and Non-
ocular AEs, vital signs and
laboratory values up to Week 100

To evaluate the effect of brolucizumab  
relative to aflibercept on patient-reported 
outcomes (VFQ-25)

Change in patient reported 
outcomes (VFQ-25) total and 
subscale scores from baseline up to 
Week 100

To confirm the systemic brolucizumab 
exposure in patients with visual impairment 
due to diabetic macular edema 

Systemic brolucizumab 
concentration approximately 24 
hours after initial and final loading 
phase doses

To assess the immunogenicity of 
brolucizumab over two years of treatment

ADA status at baseline and up to 
Week 100


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3
Investigational plan
3.1
Study design
The study is a randomized, double-masked, multi-center, active-controlled, 2 armed study in 
patients with DME.
Patients who consent and meet all the inclusion and none of the exclusion criteria will be 
screened to evaluate eligibility. After confirmation of eligibility, patients will be randomized in 
a 1:1 ratio to one of two treatment arms:

Brolucizumab 6 mg:              5 x q6w loading then q12w/q8w maintenance (with option 
to extend treatment interval during second year)

Aflibercept 2 mg:              5 x q4w loading then q8w maintenance
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 96
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.
Double-masked treatment period
Randomization
Screening period 
Day 1 to Week 100
Baseline 
Up to 2 weeks
Brolucizumab 6 mg 
Aflibercept 2 mg 


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The baseline visit is defined as Day 1/Visit 1, and end of treatment visit as Visit 27 (Week 96).
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 ±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 study 
visit when the per-protocol assessments took place. In addition, for a given protocol visit, 
assessments can be performed on two consecutive 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 96 to Week 100
For all patients, the last study assessment will be performed at Week 100, at least four weeks
after the last active study treatment in this study.
Patients withdrawn from the study prior to study completion will be asked to return for an early 
discontinuation visit (Visit 28), four weeks (±7 days) following their last study visit (see 
Section 5.6.2).
3.2
Rationale for study design
This study is designed as a multi-center, double-masked, 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 authorized label. Since the treatment schedule is different between 
arms, to ensure masking, the following will apply:

in addition to every 4-week visits for all patients for 2 years, extra visits are scheduled at 
Weeks 6 and 18 for both treatment arms

the patients will receive active/sham injection at each protocol visit except Weeks 20, 28 
and 100 visits (No scheduled treatment for any arm)

Disease activity assessment and disease stability assessment 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.
The patient population will be described in more detail in the Section 4.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
The doses and regimen for brolucizumab and aflibercept are based on the following 
considerations:


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
Based on the Phase III brolucizumab studies in nAMD, brolucizumab 6 and 3 mg doses 
showed comparable efficacy and safety profiles to existing anti-VEGFs with numerical 
advantages related to efficacy for the higher dose. 

Current evidence from large anti-VEGF pivotal studies in DME indicates that in comparison 
to nAMD an extended period of intense treatment (loading regimen) is required to achieve 
maximal BCVA gain. Hence the loading regimen was extended to Week 24 for 
brolucizumab.

The high dose of brolucizumab administered is intended to provide a prolonged duration of 
action. The positive nAMD study results regarding the q12w/q8w regimen in HAWK and 
HARRIER (Phase III clinical trials in nAMD) support q12w/q8w dosing during the 
maintenance phase also for DME in which treatment frequencies in the maintenance phase 
are similar. At the same time, these results support stretching the interval between injections 
in the loading regimen to 6 weeks. Both, extended intervals in the loading regimen and 
q12w/q8w dosing aim at reducing the injection burden. 

Aflibercept is applied as per the current labels in the EU and US.

Based on the Phase III trials HAWK and HARRIER, 12 weekly disease activity assessments 
(DAA) were sufficient to verify whether patients were appropriately treated. Introduction 
of disease activity assessments 8 weeks following treatment (in HARRIER) did not result 
in earlier detection of disease activity attributable to the q12w status. Hence, disease activity 
assessments are scheduled every 12 weeks in this study up to Week 72. From Week 72 
onwards, DAAs will be performed at every visit up to and including Week 96 (i.e. every 4 
weeks). Only assessments at scheduled treatment visits might have an impact on the 
patient’s treatment schedule (see Section 5.5.4).  

In addition to the disease activity assessment, there will be a one-time disease stability 
assessment (DSA) at Week 72. Patients will be assessed by the masked investigator 
regarding the option to extend the current treatment interval by 4 weeks, i.e. to extend 
patients on a q12w treatment schedule to q16w and patients on q8w to q12w. For patients 
that the investigator decides to extend treatment interval, the treatment schedule will be 
adjusted as further detailed in Section 5.5.4. This approach is supported by historical data 
(Schmidt-Erfurth U, 2014) suggesting a reduced treatment need in the second year.
Route of administration is intravitreal injection as for all anti-VEGF treatments currently 
approved for the treatment of DME. Study duration of 2 years (with treatment over 23 months) 
is warranted to assess longer-term efficacy and safety and to assess the q12w/q16w options for 
brolucizumab over time.
3.4
Rationale for choice of comparator
Aflibercept 2 mg q8w is an established SoC option and has been chosen as comparator for this 
study due to the consistency of the approved dose and posology of aflibercept (Eylea®) across 
many countries especially EU and US for the targeted indication as compared to other approved 
anti-VEGF treatments. 


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3.5
Purpose and timing of interim analyses/design adaptations
The primary analysis will be conducted when all ongoing patients have completed their Week 
52 visit. A second analysis may be performed by locking the Week 76 data in case of regulatory 
request for supplemental data to be submitted during the review period.
Patients will remain in the study and will continue to receive masked treatment through the 
planned duration (100 weeks) to allow for further masked evaluation of efficacy and safety. 
Treatment masking of individual patients will remain intact for all patients, investigators and 
selected staff from the Sponsor who have contact with patients or investigators or those who 
are involved in the direct conduct of the study until the final database lock has occurred.
3.6
Risks and benefits
Ranibizumab and aflibercept (both approved inhibitors of VEGF-A) have consistently 
demonstrated efficacy in VEGF-driven retinal pathologies, including DME, with benefits 
outweighing the risks. Assuming a corresponding class-effect, it is justified to expect that 
brolucizumab (having the same 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. Brolucizumab safety 
was comparable to aflibercept, with the overall incidence of adverse events balanced across all 
treatment groups in both studies.
The higher intravitreal dose of brolucizumab (11-times molar excess for 6 mg vs. 2 mg 
aflibercept) is expected to similarly (to nAMD) confer a longer duration of effect in DME that 
will translate into a reduced frequency of injections with non-inferior efficacy. A reduced 
treatment frequency will provide benefit to patients and caregivers/physicians. Further details 
of the known and potential risks and benefits associated with brolucizumab are presented in the
Investigator’s Brochure.
4
Population
The study population will be male and female patients ≥18 years old with visual impairment 
due to DME. Approximately 450 patients will be screened (20% screening failure rate expected) 
and 356 (178 per arm) patients will be randomized in approximately 80 centers worldwide. 
4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1.
Written informed consent must be obtained before any assessment is performed. 
2.
Patients ≥18 years of age at baseline
3.
Patients with type 1 or type 2 diabetes mellitus and HbA1c of ≤10% at screening. 


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4.
Medication for the management of diabetes must have been stable within 3 months prior
to randomization and is expected to remain stable during the course of the study
Study Eye
5.
Visual impairment due to DME with:
•
BCVA score between 78 and 23 letters, inclusive, using ETDRS visual acuity testing 
charts at a testing distance of 4 meters (approximate Snellen equivalent of 20/32 
to 20/320) at screening and baseline
•
DME involving the center of the macula, with central subfield retinal thickness 
(measured from RPE to ILM inclusively) of ≥320 µm on SD-OCT at screening
If both eyes are eligible, the eye with the worse visual acuity will be selected for study eye. 
However, the investigator may select the eye with better visual acuity, based on medical reasons 
or local ethical requirements.
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients:
1. Active Proliferative diabetic retinopathy in the study eye as per investigator
2. Concomitant conditions or ocular disorders in the study eye at screening or baseline  
which could, in the opinion of the investigator, prevent response to study treatment or 
may confound interpretation of study results, compromise visual acuity or require 
medical or surgical intervention during the first 12-month study period (e.g., cataract, 
vitreous hemorrhage, retinal vascular occlusion, retinal detachment, macular hole, or 
choroidal neovascularization of any cause)
3. Any active intraocular or periocular infection or active intraocular inflammation 
(e.g., infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis, 
uveitis) in study eye at screening or baseline
4. Structural damage of the fovea in the study eye at screening likely to preclude 
improvement in visual acuity following the resolution of macular edema, including 
atrophy of the retinal pigment epithelium, subretinal fibrosis, laser scar(s), epiretinal 
membrane involving fovea or organized hard exudate plaques
5. Uncontrolled glaucoma in the study eye defined as intraocular pressure (IOP) > 25 
mmHg on medication or according to investigator’s judgment at Screening or Baseline
6. Neovascularization of the iris in the study eye at screening or baseline 
7. Evidence of vitreomacular traction in the study eye at screening or baseline which in the 
opinion of the investigator, affects visual acuity
8. Presence of amblyopia, amaurosis or ocular disorders with vision <20/200 (35 letters)
in the fellow eye at screening or baseline
9. History of idiopathic or autoimmune uveitis in the study eye


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Ocular treatments
10. Previous treatment with any anti-VEGF drugs or investigational drugs in the study eye
11. Use of dexamethasone intravitreal implant (Ozurdex) or fluocinolone acetonide 
intravitreal implant (Iluvien) in study eye at any time. Prior use of other intraocular or 
periocular corticosteroids in the study eye is not an exclusion provided at least 6-month 
wash-out prior to baseline
12. Laser photocoagulation (focal/grid or panretinal) in the study eye during the 3-month 
period prior to baseline 
13. Intraocular surgery including 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 
ethambutol) used during the 6-month period prior to baseline 
21. History of hypersensitivity to any of the study drugs or its excipients or to drugs of 
similar chemical classes, or clinically relevant sensitivity to fluorescein dye as assessed 
by the investigator
22. History of malignancy of any organ system (other than localized basal cell carcinoma 
of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, 
regardless of whether there is evidence of local recurrence or metastases
23. History of a medical condition (disease, metabolic dysfunction with exception of type 1 
or 2 diabetes mellitus, physical examination finding, or clinical laboratory finding) that, 
in the judgment of the investigator, would preclude scheduled study visits, completion 
of the study, or a safe administration of investigational product
24. Use of systemic investigational drugs within 5 half-lives of baseline, [or within 30 days 
/until the expected pharmacodynamic effect has returned to baseline], whichever is 
longer (observational clinical studies solely involving over-the-counter vitamins, 
supplements, or diets are not exclusionary)
Other


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25. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
hCG pregnancy test
26. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during the study. Highly effective contraception methods include:
•
Total abstinence (when this is in line with the preferred and usual lifestyle 
of the patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception
•
Female sterilization (have had surgical bilateral oophorectomy with or 
without hysterectomy) or tubal ligation at least six weeks before baseline. In 
case of oophorectomy alone, only when the reproductive status of the woman 
has been confirmed by follow up hormone level assessment
•
Male sterilization (at least 6 months prior to baseline). For female patients in 
the study, the vasectomized male partner should be the sole partner for that 
patient
•
Use of oral (estrogen and progesterone), injected or implanted hormonal 
methods of contraception or placement of an intrauterine device (IUD) or 
intrauterine system (IUS) or other forms of hormonal contraception that have 
comparable efficacy (failure rate <1%), for example hormone vaginal ring 
or transdermal hormone contraception
In case of use of oral contraception woman should have been stable on the same pill for 
a minimum of 3 months before taking investigational drug.
In case local regulations deviate from the contraception methods listed above, local 
regulations apply and will be described in the ICF.
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at 
least six weeks ago. In the case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment is she 
considered not of child bearing potential.
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
The investigational treatment used in this study is:

Brolucizumab 6 mg/0.05 mL


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The control treatment is:

Aflibercept 2 mg/0.05 mL
Brolucizumab is formulated as a sterile solution aseptically filled in a sterile glass vial for single 
use or in a prefilled syringe (PFS) in selected countries and the content of the vial must not be 
split.
Brolucizumab study kits will consist of a carton that contains 1 single use, sterile glass vial or
in a prefilled syringe (PFS) in selected countries, containing sufficient brolucizumab to deliver 
to brolucizumab 6 mg/0.05 mL.
Aflibercept will be provided in a single use, sterile glass vial, or may be provided in a prefilled 
syringe in selected countries containing sufficient Aflibercept to deliver a 2 mg dose when 
administering a volume of 0.05 mL.
Sham injections refer to an imitation of an intravitreal injection procedure using an empty sterile 
syringe without a needle. There will be no empty sham vial.
Novartis will ensure sufficient supplies of brolucizumab and aflibercept for treatment use to 
allow for completion of the study.
5.1.2
Additional treatment
No additional treatment beyond investigational drug and control drug are included in this trial.
5.2
Treatment arms
Brolucizumab 6 mg/0.05 mL
5 x q6w loading then q12w/q8w maintenance
(with option to extend treatment interval during second year)
Aflibercept 2 mg/0.05 mL                        5 x q4w loading then q8w maintenance
5.3
Treatment assignment and randomization 
At baseline visit, all eligible patients will be randomized via Interactive Response Technology 
(IRT) to one of the treatment arms, in a ratio of 1:1. Stratification for systemic exposure
sampling will be considered.
The investigator or her/his delegate will contact the IRT, after it was confirmed that the patient 
fulfills all the inclusion and none of the exclusion criteria. The IRT will assign a randomization 
number to the patient, which will link the patient to a treatment arm.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of patient numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms. A separate medication list will be produced 
by or under the responsibility of Novartis Drug Supply Management using a validated system 
that automates the random assignment of medication numbers.
The randomization scheme for patients will be reviewed and approved by a member of the 
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5.4
Treatment masking
The intent of masking is to limit the occurrence of conscious and unconscious bias in the 
conduct and interpretation of the clinical study. Bias could arise from the influence that the 
knowledge of a specific treatment assignment may have on the recruitment and allocation of 
subjects, their subsequent care, the assessment of end points, the handling of withdrawals, and 
so on. The essential aim of masking, therefore, is to prevent identification of the treatments by 
the investigator, subject, and others associated with the conduct of the study until all such 
opportunities for bias have passed.
This study will be double-masked, with subjects randomized to be treated with brolucizumab 6 
mg or aflibercept 2 mg. All members of the Sponsor Study team will be masked to treatment 
assignments until all randomized patients complete Week 52 visit or terminate the study prior 
to Week 52. Sponsor personnel who have access to treatment codes will not divulge the codes 
to subjects, investigators, site staff or Sponsor.
Unmasking of investigators and site personnel directly involved in the conduct of the study will 
only occur in the case of patient emergencies (see Section 5.6), and then at the time of the final 
analysis (see Section 3.5), at the conclusion of the study.
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 
masked study. 
Treatment masking of individual subjects will remain intact until the final database lock has 
occurred by ensuring: Randomization data are kept strictly confidential until the time of 
unmasking and will not be accessible by anyone else involved in the study except the 
unmasked/treating investigator. During and after database lock at Week 52 and Week 100, the 
masked personnel and patients will remain masked to the treatment assignment until the 
conclusion of the study. 


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Unmasked monitors will be available to perform study medication accountability and to deal 
with study issues involving the unmasked investigator or unmasked site staff.
An independent, masked review of fundus photography, fluorescein angiography and optical 
coherence tomography (OCT) images for patients enrolled in the study will be performed at a 
CRC.
5.5
Treating the patient 
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
5.5.1
Patient numbering
Upon signing the informed consent form, the patient is assigned the next sequential number 
available in electronic data capture (EDC) system. The investigator or her/his staff will contact 
the IRT and provide the requested identifying information for the patient to register them into 
the IRT. Once assigned to a patient, the patient number will not be reused for another patient. 
If the patient fails to be randomized for any reason, the IRT must be notified within 2 days that 
the patient was not randomized. The reason for not being randomized will be entered on the 
Screening Log, and the Demography eCRF should be completed.
5.5.2
Dispensing the study drug
Each study site will be supplied with study drug.
For brolucizumab, the study drug packaging has a 2-part label. A unique medication number is 
printed on each part of this label. Investigator staff will identify the study drug package(s) to 
dispense to the patient by contacting the IRT and obtaining the medication number(s). 
Immediately before treating the patient, investigator staff will detach the outer part of the label 
from the packaging and affix it to the source document (Drug Label Form) for that patient’s 
unique patient number.
5.5.3
Handling of study and additional treatment
5.5.3.1
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the unmasked investigator and 
designees have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels. Clinical supplies are to be dispensed only in accordance 
with the protocol. Technical complaints are to be reported to the respective Novartis CPO 
Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the patient except for the medication number.
The unmasked investigator must maintain an accurate record of the shipment and dispensing of 
study treatment in a drug accountability log. Monitoring of drug accountability will be 


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performed by unmasked monitors during site visits or remotely and at the completion of the 
trial. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
5.5.3.2
Handling of additional treatment 
Not applicable.
5.5.4
Instructions for prescribing and taking study treatment
All kits of study treatment assigned by the IRT will be recorded/databased in the IRT.
There will be two treatment phases for IVT injections with different timing for brolucizumab
and aflibercept treatment arms: 
Loading Phase
Brolucizumab: In the loading phase, treatment with brolucizumab will occur every 6 weeks for 
five (5) consecutive injections (BL, Weeks 6, 12, 18 and 24). To preserve the masking, the 
patients assigned to this regimen will receive sham injection on Weeks 4, 8 and 16.
Aflibercept: In the loading phase, treatment with aflibercept will occur every 4 weeks for five 
(5) consecutive injections (BL, Weeks 4, 8, 12 and 16). To preserve the masking, the patients 
assigned to aflibercept Arm will receive sham injection on Weeks 6 and 18.
Maintenance Phase
The treatment 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. If, however, Disease Activity is identified by 
the evaluating/masked investigator, the patient will be assigned to receive treatment 
every 8 weeks (see Evaluation of Disease Activity below). An additional DAA will 
be performed at Week 96 to document the adequacy of the q12w treatment schedule 
at the end of the 2 year follow-up (without having impact on the patient’s treatment 
schedule)

At Week 72 based on Disease Stability Assessment (see Assessment of Disease 
Stability below) by the evaluating/masked investigator there will be the option to 
extend the treatment interval by 4 Weeks, i.e. patients on q12w treatment schedule 
at Week 72 can be assigned to q16w and patients on q8w can be assigned to q12w.
If however after Week 72 disease activity is identified by the evaluating/masked 
investigator at a scheduled treatment visit (according to the patient specific treatment 
schedule q12w or q16w) the patient will be assigned to q8w treatment schedule (see 
Table 5-1 below)


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Remark: In order to allow for adjustment in the treatment schedule at each 
scheduled q12w/q16w treatment visit, starting at week 76, DAAs must be performed 
at each visit up to and including Week 96.  The disease activity assessment will be 
entered in to the IRT. Only if disease activity is identified at q12w/q16w treatment 
visits, the IRT system will adjust the treatment interval to q8w.
Table 5-1
Brolucizumab: Impact of DAA and DSA on treatment schedule
Time 
period
Treatment 
schedule 
before 
Week 72
Week 72 
DSA
Treatment 
schedule 
after week 
72
DAA visits with the option to 
adjust to q8w = Scheduled 
q12w/q16w treatment 
visits (Implementation via IRT)
DAA visits 
without the option to 
adjust to q8w 
(IRT entry without 
impact on treatment 
schedule)
Week 
24 to 
Week 
72
q12w
n.a.
n.a.
Week 32*, Week 36, Week 48, Week 
60, Week 72
n.a.
As of 
Week 
76
q12w
Interval 
extension 
q16w 
Week 76, Week 92**
Week 80, Week 84, 
Week 88, Week 96
No 
interval 
extension 
q12w
Week 84, Week 96**
Week 76, Week 80, 
Week 88, Week 92
q8w 
Interval 
extension 
q12w
If last treatment at 
Week 64
Week 76, 
Week 88**
Week 80, Week 84, 
Week 92, Week 96
If last treatment at 
Week 68
Week 80, 
Week 92**
Week 76, Week 84, 
Week 88, Week 96
No 
Interval 
extension
q8w
n.a.
n.a.
* No scheduled treatment but DAA with option to adjust to q8w
** On these visits, the need of q8w is captured without further brolucizumab treatment
Aflibercept 2 mg:

From Week 16 onwards, patients will receive one injection of aflibercept 2 mg every 
8 weeks (first injection after Week 16 to be given at Week 24) until Week 96 visit. 
DAAs and DSA will be conducted by the evaluating/masked investigator for 
masking purposes and will not influence the treatment interval.


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Figure 5-1
Dosing schedule
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 assessments 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). 
After this first q12w treatment interval DAAs will take place together with the scheduled 
q12w /q16w treatment visits (see Table 5-1).
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 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
If DAA reveals a need for more frequent treatment the patient will be assigned to receive 
injections q8w thereafter, up to the end of the study or up to a treatment interval extension based 
on the stability assessment at Week 72. 
Missing DAA assessments:
A patient who misses Week 32 will undergo the disease activity assessment at Week 36 as 
he/she would have done if the visit had not been missed. If, however, a patient misses any 
of the following disease activity assessment visits:

Before Week 72: Week 36, Week 48 or Week 60 

After Week 72: a visit with a DAA relevant for treatment adjustment to q8w (see 
above)


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then the patient (brolucizumab patients 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 or up to a treatment interval 
extension based on the stability assessment at Week 72. The IRT system will make the 
necessary changes once the missed visit is registered.
The handling and consequences of a missed Week 72 visit is addressed below in the section 
‘Assessment of Disease Stability’.
If a patient misses Week 28, then the Week 24 values should be applied as the reference 
for disease activity assessments.
Assessment of Disease Stability:
At Week 72 patients will be assessed by the masked investigator regarding the option to extend 
the current treatment interval by 4 weeks, i.e. to extend a q12w treatment schedule to q16w and 
q8w to q12w.
Based on the general concept that an extension of the treatment interval should only be 
considered for patients having shown sufficient disease stability under the current treatment 
schedule, the masked investigator will assess at Week 72 whether in his opinion a 4-week 
extension of the treatment interval is adequate. The outcome of this assessment will be captured 
as:

‘Extension of treatment interval’: according to the masked investigator there is sufficient 
disease stability to justify an extension of the treatment interval by 4 weeks, e.g. patient 
showed no disease activity during the last 2 DAAs, at Week 60 and Week 72.

‘No extension of treatment interval’: otherwise 
Patients not identified by the masked investigator for an extension of their treatment intervals 
will continue with their latest treatment frequency considering adjustments according to DAAs.
Details regarding the impact of the DSA on the treatment schedule are described in Table 5-1.
Missing DSA assessment:
Patients who miss Week 72 visit, i.e. missing the corresponding DAA and DSA, will be 
allocated by IRT according to the DAA of Week 76:

In case of no disease activity at Week 76 the treatment schedule will be done in 
line with an ‘extension of the treatment interval’.

In case of disease activity at Week 76 the patient will receive treatment at this 
visit and will continue on q8w until the end of the study.  
Masking:
In order to maintain masking, the assessment of disease activity and disease stability 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 be entered in the IRT and obtain 
the applicable treatment, active or sham, as assigned by IRT depending on the treatment arm 
and the actual treatment frequency as described above.


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At all applicable visits from Week 4 to Week 96, inclusive (with exception of Weeks 20 and 28 
where no treatment is scheduled), a sham treatment will be performed to maintain patient 
masking. For the sham treatment the tip of an injection syringe (the hub without a needle) will 
be used.
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 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 is present, then an IVT injection must not be performed. 
Additional ophthalmic examination and imaging should be performed to evaluate IOI (see 
Section 6.5.4).
If IOI is confirmed, subjects should be treated for IOI according to clinical practice.
5.5.5
Permitted dose adjustments and interruptions of study treatment 
Treatment dose adjustments and/or interruptions are not permitted unless interruptions are 
warranted by an AE.
5.5.6
Rescue medication/procedure
The study eye, in both treatment groups, identified as needing q8w at a previous visit could 
receive rescue treatments with laser photocoagulation from week 36 onward if DME worsened 
causing a ≥10-letter loss at 2 consecutive visits or ≥15-letter at 1 visit best previous 
measurement, with BCVA not better than baseline. When applicable, patients could receive 
both laser photocoagulation and active study treatment as scheduled at the same visit. Patients 
can continue with the study treatment. 
Pan retinal photocoagulation is permitted at any time during the study as deemed necessary by 
the investigator, and the patient can continue the study.
In case the investigator deems it in the best interest of the patient to receive treatment in the 
study eye, aside from laser, which is prohibited by this protocol, instructions provided in Table 
5-2 should be followed.
5.5.7
Concomitant medications and treatments
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after signing the study informed consent. All medications, procedures and 
significant non-drug therapies (e.g. blood transfusions) administered after the patient was 
enrolled into the study must be recorded in the appropriate eCRF page.


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Each concomitant drug/procedure must be individually assessed against all exclusion 
criteria/prohibited medication. If in doubt the investigator should contact the Sponsor medical 
monitor before randomizing a patient or allowing a new medication to be started.
5.5.8
Prohibited medication
Table 5-2 becomes effective with screening.
Table 5-2
Prohibited medications / procedures
Medication / Procedures 
Prohibition period
Action taken
Study eye
Intra- or periocular 
corticosteroids (except if 
needed as short term 
treatment of AE) 
Any time
Discontinue study treatment
(except if for treatment of AE)
Anti-VEGF therapy other than 
assigned study medication
Any time
Discontinue study treatment
Laser photocoagulation 
(focal/grid )
Prior or at the time of first 
identification of DAA 
Continuation of study 
treatment at the investigators 
discretion 
Systemic
Anti-VEGF therapy
Any time
Discontinue study treatment
Any investigational drug, 
biologic or device 
Any time
Discontinue study treatment
Standard of care or other treatments according to the investigators practice for DME and other 
diseases in the fellow eye are permitted at any time and must be recorded in the appropriate
eCRF page.
5.5.9
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a patient, he/she must provide the 
requested patient identifying information and confirm the necessity to break the treatment code 
for the patient. The investigator will then receive details of the investigational drug treatment 
for the specified patient and a fax or email confirming this information. The system will 
automatically inform the Novartis monitor for the site and the Study Team that the code has 
been broken.
If the treatment code needs to be broken in the interest of patient safety, the investigator is 
encouraged to contact an appropriate Sponsor representative prior to unmasking if there is 
sufficient time.
It is the unmasked or masked investigator’s responsibility to ensure that there is a dependable 
procedure in place to allow access to the IRT at any time in case of emergency. The investigator 
will provide:

protocol number


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
study drug name (if available)

patient number
In addition, oral and written information to the patient must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. 
The appropriate personnel from the site and Sponsor will assess whether study treatment should 
be discontinued for any patient whose treatment code has been broken for any reason.
5.6
Study completion and discontinuation 
The investigator should discontinue study treatment for a given patient and/or withdraw the 
patient from study if, on balance, he/she believes that continuation would be detrimental to the 
patient’s well-being.
5.6.1
Study completion and post-study treatment 
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol.
The investigator and/or referring physician will recommend the appropriate follow-up medical 
care, if needed, for all patients who are prematurely withdrawn from the study.
5.6.2
Discontinuation of study treatment 
Discontinuation of study treatment for a patient occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by either the patient or the investigator. 
The investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation.
Study treatment must be discontinued under the following circumstances: 

Patient wish 

Pregnancy (see Section 6.5.7 and Section 7.6)

Use of prohibited treatment as per recommendations in Table 5-2

Any situation in which study participation might result in a safety risk to the patient

Unsatisfactory therapeutic effect

Patient’s condition no longer requiring study treatment
If discontinuation of study treatment occurs, the patient should NOT be considered withdrawn 
from the study. The investigator must determine the primary reason for the patient’s premature 
discontinuation of study treatment and record this information on the appropriate eCRF page. 
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.
If study drug discontinuation occurs because treatment code has been broken, please refer to 
Section 5.5.9.


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5.6.3
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject: 

Does not want to participate in the study anymore, and 

Does not allow further collection of personal data 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the patient’s decision to withdraw his/her consent and 
record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
assessment Table 6-1.
Discontinued patients will not be replaced.
Novartis/sponsor will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until their time of withdrawal) according to 
applicable law. 
All biological samples not yet analyzed at the time of withdrawal will no longer be used, unless 
permitted by applicable law. They will be stored according to applicable legal requirements. 
5.6.4
Loss to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the patient, e.g. dates of telephone 
calls, registered letters, etc. 
5.6.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the patient 
must be seen as soon as possible and treated as a prematurely discontinued patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator will 
be responsible for informing the Institutional Review Board/Independent Ethics Committee 
(IRBs/IECs) of the early termination of the trial.


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6
Visit schedule and assessments
Table 6-1 lists all scheduled study visits and indicates with an “x” when a specific assessment 
is to be performed.
Patients must be seen for all visits on the designated day, or as close to it as possible. Missed or 
rescheduled visits should not lead to automatic discontinuation. Patients who prematurely 
discontinue the study for any reason should be scheduled for a visit as soon as possible, at which 
time all of the assessments listed for the final visit will be performed. 
If the COVID-19 pandemic limits or prevents on-site study visits, study treatment could not be 
administered and other study assessments may not be performed. Alternative methods of safety 
monitoring providing continuing care may be implemented. Depending on local regulations, 
site capabilities and patient’s visit status in the study, phone calls or virtual contacts (e.g. 
teleconsult) can be performed for safety follow-up for the duration of the pandemic, until it is 
safe for the participant to visit the site again.


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Table 6-1
Assessment schedule
Visit
Screening
1
Baseline
1b
2
3
4
5
6
7
8
9
9b
10
11
12
13
Week
Up to
2 weeks
Day 1
Day 2
4
6
8
12
16
18
20
24
24+1 day
28
32
36
40
Informed Consenta
X
Demographics
X
Medical History
X
Physical Examinationb
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion/Exclusion Criteria
X
Xd
Visual Function Questionnaire-25
X
X
FSHl
Xl
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum β-hCG Pregnancy teste
X
Urine Pregnancy Teste
X
X
X
X
X
X
X
X
X
X
X
Chemistry/Hematology/Urinalysis
X
X
Xf
Xf
Blood Sample: Anti-Drug Antibodies
X
X
X
X
X
Blood Sample: Pharmacokineticsj
X
X
Best-Corrected Visual Acuity
Xg
X
X
X
X
X
X
X
X
X
Xg
X
X
X
Intraocular pressure
Xg
X
X
X
X
X
X
X
X
X
Xg
X
X
X
Ophthalmic Examh,m
Xg
X
X
X
X
X
X
X
X
X
Xg
X
X
X
Spectral Domain Optical Coherence 
Tomographym
Xg
X
X
X
X
X
X
X
X
X
X
X
X
X
Color Fundus Photography
Fluorescein Angiographym
Xg
X
Disease Activity Assessment
X
X
Contact IRT
X
Xi
X
X
X
X
X
X
X
X
X
X
Treatment
X
X
X
X
X
X
X
X
X
X
X


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


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6.1
Information to be collected on screening failures
All patients who have signed informed consent but not entered into the next period will have 
the study completion eCRF pages for the screening period, demographics, inclusion/exclusion, 
and serious adverse event (SAE) data collected. Adverse events that are not SAEs will be 
followed by the investigator and collected only in the source data.
6.2
Patient demographics/other baseline characteristics
The following information will be collected/documented at screening/baseline visit for each 
patient:

Date of birth, age

Gender

Race/Ethnicity

Type of diabetes

Vital signs

Study eye

Visual acuity

Macular edema characteristics

Intraocular pressure

HbA1c and other laboratory test results

Concomitant medications

Past medical history and current medical conditions
Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature
6.3
Treatment exposure and compliance
Every time the study treatment is to be administered, IRT needs to be accessed for the 
medication (kit) number. The date and time of all study treatment injections administered during 
the study and any deviations from the protocol treatment schedule will be captured by the 
unmasked investigator staff or by unmasked field monitor on the appropriate study treatment 
dispensing form.
Exposure to the study treatment will be based on the number of injections administered. 
Compliance with the study treatment will be assessed by the unmasked field monitor at each 
visit using vial counts and information provided by the pharmacist or by the investigator.


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6.4
Efficacy
The following tests will be performed to assess activity of brolucizumab and aflibercept on 
visual function, retinal structure and leakage:

Best-corrected visual acuity with ETDRS-like chart at an initial testing distance of 4 meters

Anatomical markers on Optical Coherence Tomography

ETDRS DRSS score based on 7-field stereo Color Fundus Photography

Vascular leakage evaluation by Fluorescein Angiography
6.4.1
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 patients.
Subjects at sites in some Asian countries will undergo BCVA testing using numerical charts 
rather than letter charts. Therefore, all references in the protocol to changes in letters read will 
be changes in numbers in these countries.
6.4.2
Optical coherence tomography
Optical Coherence Tomography (OCT) will be assessed in the study eye at every study visit 
and in both eyes at Screening, Week 52 and exit/premature discontinuation visit.
These assessments will be performed by trained technician or investigator at the sites and should 
be performed prior to any study drug administration. Evaluating investigators will evaluate the 
OCT to assess the status of disease activity. The OCT machine used for an individual patient 
should not change for the duration of the study.
In addition to the standard OCT assessment, as optional assessment at sites that have the 
applicable equipment, OCT angiography should be done at baseline, Week 28, Week 52, Week 
76 and exit/premature discontinuation visit in the study eye. If OCT angiography will be 
performed, it must be done for a given patient from baseline. If OCT angiography was not 
performed at baseline, then it should not be introduced at later visits.
The images will be reviewed by a central reading center to ensure a standardized evaluation. 
For further procedural details, the investigator should refer to applicable manual provided by 
the Central Reading Center.
6.4.3
Color fundus photography and fluorescein angiography
Color fundus photography and fluorescein angiography will be performed in the study eye at 
Screening, Weeks 28, 52, 76 and exit/premature discontinuation visit, and in both eyes at 
Screening, Week 52 and exit/premature discontinuation visit. 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 weeks, 
except if there is significant worsening of DME disease, in the opinion of the investigator. 


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These assessments will be performed by a trained technician at the sites. The images will be 
reviewed by a Central Reading Center to ensure a standardized evaluation. Grading for DRSS 
will be performed at the CRC. For further procedural details the investigator should refer to the 
Study Operations Manual provided by the Central Reading Center.
Additional images will be taken in case of any signs of intraocular inflammation. Optical 
Coherence Tomography, color fundus photography and fluorescein angiography (
 
 or with peripheral sweeps) should be performed for safety evaluation as described in 
Section 6.5.4.
6.4.4
Appropriateness of efficacy assessments 
BCVA as a measure of retinal function and 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 is a recent addition to the tests conducted in 
clinical trials. 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.
6.5
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.
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.
6.5.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. The examination will be performed at screening and at 
the end of the study, exit/premature discontinuation. 
Information for all physical examinations must 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 first 


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administration of investigational drug which meet the definition of an Adverse Event must be 
recorded on the appropriate AE eCRF page.
6.5.2
Vital signs
Sitting blood pressure and heart 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 after 20 minutes. If the repeat measurement is elevated, then the patient is not eligible 
to be enrolled into the study.
On days when study drug is administered, vital signs will be measured before administration of 
study medication. The results will be recorded in the eCRF. 
6.5.3
Height and Weight
Height and weight will be measured at the screening visit only. 
Height in centimeters (cm) and body weight (to the nearest kilogram (kg), in indoor clothing 
but without shoes) will be measured at screening only. The results will be recorded in the eCRF.
6.5.4
Ophthalmic examination
The ophthalmic exam will consist of the following:

Anterior biomicroscopy (slit lamp examination) will be completed at every (scheduled 
and unscheduled) visit to examine the anterior segment structures (e.g., eyelids/lashes, 
conjunctiva, cornea, anterior chamber, iris, lens and anterior part of the vitreous) of the 
study eye. (fellow eye will be examined only at screening and on discretion of the 
investigator). The test results will be recorded in the source documents only. 
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 on the adverse event page of the 
eCRF (events identified pre-Baseline should be recorded on the medical history page) 

Intraocular pressure will be assessed in the study eye, pre-dose and post-dose at every 
scheduled visit. In the fellow eye IOP will be assessed at Screening, Weeks 28, 52, 76 and 
exit/premature discontinuation. The values recorded in mmHg will be entered into the eCRF.
Treatment and close monitoring of IOP should be performed by the investigator for any 
non-transient elevation in intraocular pressure (≥25 mmHg).  Intravitreal procedure is not 
recommended unless normalization of the IOP has been achieved. Post dose IOP should be 
assessed after every IVT injection, within 60 minutes after injection and if ≥25 mmHg, 
assessment should be repeated until back to normal.


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Any clinically significant abnormalities should be recorded on the adverse event page of the 
eCRF (events identified pre-Baseline should be recorded on the medical history page).

Posterior segment (indirect fundus) examination will be conducted by the investigator at 
the screening visit for both eyes. An examination of the peripheral retina must also be 
conducted to ensure that the intravitreal injection can safely be performed. 
Posterior segment examination must be performed carefully before each study treatment.
The results of the examination should be recorded including any abnormalities (e.g. vitreous 
cells/haze, retinal tear/detachment, hemorrhage and vascular occlusion, vasculitis, etc.) 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 will be recorded on the medical/ocular 
history page before Baseline and on the adverse event page of the eCRF for any findings 
identified after Baseline. 
Instruct the patient to contact the site for any changes in vision or any symptoms of 
inflammation between scheduled visits. Every effort should be made to bring the subject for 
immediate examination. When IOI, retinal vasculitis, and/or retinal artery occlusion is present 
or suspected during a visit, investigators must perform thorough ophthalmic examination, and
conduct OCT, fluorescein angiography and color fundus photography (
 
with peripheral sweeps). These additional assessments will be documented in the source and 
appropriate eCRF pages as applicable. The images are requested to be uploaded onto the CRC 
portal.
6.5.5
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected at applicable visits. 
Details on the collections, shipment of the samples and reporting of the results by the central 
laboratory are provided to investigators in the laboratory manual. 
If the COVID-19 pandemic limits or prevents on-site study visits, the collection of samples may 
be modified by Novartis, if applicable and if modified, will be communicated to the Investigator.
6.5.5.1
Hematology
Hematocrit, hemoglobin, red blood cell (RBC) count, white blood cell (WBC) count with 
differential (absolute and percentage of neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils), and quantitative platelet count.
6.5.5.2
Clinical chemistry

Glycosylated hemoglobin (HbA1c)

Serum biochemistry tests


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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)
6.5.5.3
Urinalysis
Dipstick measurements for specific gravity, pH, protein, glucose, ketones, urobilinogen, 
bilirubin, nitrite, leucocyte, esterase and urine occult blood.
6.5.6
Pregnancy and assessments of fertility
High effective contraception is required for woman of childbearing potential during the study
and for 3 months after stopping the investigational medication.
All pre-menopausal women who are not surgically sterile will have pregnancy testing.
Additional pregnancy testing might be performed if requested by local requirements.
If no sufficient profile to support the reproductive status of female patients, a FSH (Follicle 
Stimulating Hormone) test can be conducted for female patients at Screening visit only to 
confirm the child bearing potential.
A serum pregnancy test will be conducted for all women of childbearing potential to assess 
pregnancy before inclusion into the study at screening visit and then at Week 52 and exit visits. 
During study, monthly pregnancy testing will be performed and results captured in the source 
documents. 
6.5.7
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population. If there are
any signs of IOI, additional assessment will be performed as described in Section 6.5.4.
6.6
Other assessments
Additional assessments that will be performed:

Patient Reported Outcome: NEI VFQ-25

Pharmacokinetics of brolucizumab

Anti-Drug Antibodies
6.6.1
Clinical Outcome Assessments (COAs)
6.6.1.1
Clinician Reported Outcomes (ClinRO)
Not applicable.


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6.6.1.2
Patient Reported Outcomes (PRO)
The impact of brolucizumab on patient visual function will also be assessed by a visual function 
questionnaire using the National Eye Institute VFQ-25 which is a validated instrument that has 
been used in many studies of patients with DME. The VFQ-25 was developed to address the 
need to measure a patient’s subjective assessment of vision-related QoL (Mangione, et al., 
2001). This is part of the 51-item NEI-VFQ which was developed based on feedback from 
patients to measure vision-targeted functioning and the impact of vision problems on 
Health-Related Quality of Life (HRQL) across a number of common eye conditions. This 
allowed the developers to identify the content areas and aspects of visual disability that were 
most important and relevant to AMD patients. In addition to its use in measuring the treatment 
effect on vision-related function in AMD patients, the VFQ-25 has been used to measure 
treatment benefits in patients with DME (Klein et al., 2001).
At baseline and Weeks 28, 52, 76 and 100, the VFQ-25 will be completed and captured by 
masked site staff on behalf of the patients, at sites where local language versions are available, 
validated, and approved by the IEC/IRB. All these questionnaires should be completed before 
patients see the study physician where applicable.
A detailed training manual relating to the administrative procedures of the questionnaires will 
be provided to the sites.
Completed questionnaires will be reviewed and examined by the masked/evaluating 
investigator, before the clinical examination, for responses that may indicate potential AE or 
SAE. If AEs or SAEs are confirmed, then the physician must record the events as per 
instructions given in Section 7.1 and Section 7.2 of the protocol.
6.6.2
Resource utilization
Data for Healthcare Resource Allocation will not be collected for this study.
6.6.3
Pharmacokinetics
Systemic brolucizumab exposure assessment will be performed on around 48 consented patients
(around 24 patients per treatment arm to maintain masking). Serum samples will be taken at 2 
time points:

Approximately 24 hours after the first dose

Approximately 24 hours after the treatment at Week 24
Further details on sample collection, numbering, processing and shipment can be found in the 
laboratory manual.
6.6.4
Anti-drug antibodies (immunogenicity)
Collection of blood for ADA assessment will be done at Screening, Weeks 4, 12, 24, 36, 52, 76 
and exit/premature discontinuation. Systemic exposure of brolucizumab will also be measured 
in these blood samples concomitantly with ADA levels for interpretation purposes, no 
pharmacokinetic parameters will be determined from brolucizumab systemic exposure which 
are collected along with ADA.


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Blood draws should take place prior to the injection/sham. A standardized procedure for the 
collection, processing, storage and shipment of these blood samples is provided by the central 
laboratory. Further details on sample collection, numbering, processing and shipment can be 
found in the Central Laboratory Manual.
Additional pharmacodynamic assessment (e.g. systemic VEGF) may be conducted on the 
samples.
6.6.6
Other biomarkers 
Not applicable.
7
Safety monitoring
7.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation patient after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.
The occurrence of adverse events must be sought by non-directive questioning of the patient at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the patient during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.


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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 patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. As a general guidance, alert ranges for laboratory and 
other test abnormalities are included in Appendix 1.
Adverse events must be recorded in the appropriate eCRF capturing AEs under the signs, 
symptoms or diagnosis associated with them, accompanied by the following information:

the severity AE grade

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

its relationship to:

the study drug 

the ocular injection procedure

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported

whether it constitutes a serious adverse event (SAE - See Section 7.2 for definition of 
SAE) and which seriousness criteria have been met.

action taken regarding [investigational] treatment 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 

no action taken (e.g. further observation only) 

[investigational] treatment interrupted/withdrawn

concomitant medication or non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition of 
SAE)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent, and assessment must be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions required 
to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the investigator Brochure (IB). This information will be included in the patient 


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informed consent and should be discussed with the patient during the study as needed. Any new 
information regarding the safety profile of the medicinal product that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator Notification or 
an Aggregate Safety Finding. New information might require an update to the informed consent 
and has then to be discussed with the patient.
The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the investigator’s 
source documents; however, if the AE meets the criteria of an SAE, it must be reported to 
Novartis.
7.2
Serious adverse events 
7.2.1
Definition of SAE 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)]
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes)

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 


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dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (please refer to Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
7.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days following the last study visit must be reported to 
Novartis safety within 24 hours of learning of its occurrence. Any SAEs experienced after the 
30 day period following the last study visit should only be reported to Novartis safety if the 
investigator suspects a causal relationship to study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to each specific 
component of study treatment, (if study treatment consists of several components) complete the 
SAE Report Form in English, and submit the completed form within 24 hours to Novartis. 
Detailed instructions regarding the submission process and requirements for signature are to be 
found in the investigator folder provided to each site. 
Follow-up information is submitted as instructed in the investigator folder. Each re-occurrence, 
complication, or progression of the original event must be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not, and 
whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment a Drug Safety and Epidemiology 
Department associate may urgently require further information from the investigator for health 
authority reporting. Novartis may need to issue an investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries.
Note: SAEs must be reported to Novartis within 24 hours of the investigator learning of its 
occurrence/receiving follow-up information.
7.3
Liver safety monitoring
To ensure patient safety and to ensure that a full data package is collected to best understand 
events of liver dysfunction that emerge during the course of this study, a standardized process 


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for evaluation of liver events has to be followed. This may involve referral of the patient to a 
suitable internal medicine physician.
This additional investigation is triggered by liver function test abnormalities and/or adverse 
events (irrespective of whether classified/reported as (S)AE and irrespective of investigator 
suspected causality).
Please refer to Table 14-1 in Appendix 2 as guidance for complete definitions of liver laboratory 
triggers and liver events.
Every liver laboratory test abnormality trigger or liver event as defined in Table 14-1 of 
Appendix 2 should be followed up by the investigator or designated personal at the trial site or 
a suitable internal medicine MD as summarized below.
For the liver laboratory test abnormality trigger, please use the guidance below:

If the elevation is confirmed as clinically significant, close observation of the patient will 
be initiated, including consideration of treatment interruption if deemed appropriate. This 
observation may be conducted by the investigator or through referral of the patient to a 
suitable internal medicine MD.
For the liver adverse events, consider referral of the patient to a suitable internal medicine MD 
and the guidance below:

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications)

An investigation of the liver event which needs to be followed until resolution.

If meeting SAE criteria, the event must be reported as per Section 7.2.2
All follow-up information, additional procedures performed and test results must be collected 
and documented at the study site.
7.4
Renal safety monitoring 
The following two categories of abnormal renal laboratory values have to be considered as 
guidance during the course of the study:

Serum event:

confirmed (after ≥24h) increase in serum creatinine of ≥25% compared to baseline 
during normal hydration status

Urine event

new onset (≥1+) proteinuria; confirmed by doubling in the urinary albumin-creatinine 
ratio (ACR) or urinary protein-creatinine ratio (PCR) (if applicable)

new onset (≥1+), hematuria or glycosuria 


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Every renal laboratory trigger or renal event as defined in Table 15-1 in Appendix 3 as guidance 
and to  be followed up by the investigator or designated personnel at the trial site as summarized 
in Appendix 3. 
For the renal adverse events, consider referral of the patient to a suitable internal medicine 
physician. All follow-up information, additional procedures performed and test results must be 
collected and documented at the study site.
7.5
Reporting of study treatment errors 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (EMA definition).
Misuse/ abuse is not applicable to this study as IVT injection is performed by the investigator.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the Dosing CRF (date and time of the injection) and in the Dispensing Log at the Study site, 
irrespective of whether or not associated with an AE/SAE and reported to Safety only if 
associated with an SAE. 
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error 
type
Document in CRF
(Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes (only date and 
time of injection)
No
Only if associated with an 
SAE
7.6
Pregnancy reporting
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
8
Data review and database management 
8.1
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 


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eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of patient records, the accuracy 
of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis CRA organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis Clinical Teams to assist with trial oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
patient's file. [Data not requiring a separate written record will be defined before study start and 
will be recorded directly on the eCRFs.] The investigator must also keep the original informed 
consent form signed by the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be useed for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed.
8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRFs) using fully validated secure web-enabled software that conforms 
to US CFR 21 Part 11 requirements. Designated investigator site staff will not be given access 
to the system until they have been trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site. 
8.3
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff is required to respond 
promptly to queries and to make any necessary changes to the data. 


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Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The data will be sent electronically 
to Novartis (or a designated CRO).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.  The 
code break functionality will remain available until study shut down or upon request of Novartis. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unmasked and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
Development management.
8.4
Data Monitoring Committee
An independent program level Data Monitoring Committee (DMC) is established to monitor 
the safety of the trial participants, to ensure that the trial is being conducted with the highest 
scientific and ethical standards, and make appropriate recommendations based on the data seen.
The DMC charter will include the DMC membership and responsibilities, the timing of DMC 
meetings, the content of the analysis report for the DMC meetings, and the communications 
with the Sponsor. The DMC will only make recommendations for changes in study conduct.
8.5
Adjudication Committee
Not required.
9
Data analysis
The primary safety and efficacy analysis will be based on the Week 52 data, i.e. all data up to 
and including Week 52. This analysis will be performed once all patients completed their Week 


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52 visits or terminated the study before Week 52, while patients continue to receive masked 
treatment through the planned study duration of 100 Weeks. The analysis of the data collected 
after the Week 52 visit will be performed once all patients completed or discontinued from the 
study.
Summary statistics will be presented by treatment group unless otherwise specified. For 
continuous variables, summary statistics will generally include: n, mean, standard deviation, 
median, quartiles, minimum, and maximum. For categorical variables, this will generally 
include: n, frequency and percentage in each category.
Additional analysis may be also conducted to evaluate the impact of COVID-19 pandemic.
Further technical details and discussions of the statistical considerations will be provided in the 
SAP.
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
9.1
Analysis sets 
The Randomized Set will consist of all randomized patients. Patients are considered 
randomized when they had been deemed eligible for randomization by the investigator and 
given a randomization number. Patients will be analyzed according to the treatment assigned to 
at randomization.
The Full Analysis Set (FAS) includes all randomized patients who receive at least one IVT 
injection of the study treatment. The full analysis set will serve as the primary analysis set for 
all efficacy analyses. Following the intent-to-treat principle, patients will be analyzed according 
to the treatment assigned to at randomization.
Supportive analyses of the primary and secondary endpoints will include analysis using the Per 
Protocol Set (PPS). PPS is a subset of the FAS and will exclude patients with protocol 
deviations (PDs) and analysis restrictions (ARs) that are expected to majorly affect the validity 
of the assessment of efficacy at Week 52 including for e.g. lack of compliance (including missed 
treatments and treatment misallocation), missing data, prohibited concomitant medication and 
deviation from inclusion/exclusion criteria. Confounded data or discontinuation from treatment 
due to lack of efficacy and/or safety do not constitute a reason for exclusion from the PPS. 
Before the Week 52 database lock the relevant protocol deviations will be identified at the 
patient level in the database. After the Week 52 database lock, analysis restrictions will be 
derived in the analysis database. Censoring applied in relation to the specific PDs / ARs will be 
specified as well.  
The FAS will be the analysis set for the primary estimand as defined in Table 9-1. However, 
when assessing the robustness of the overall efficacy conclusions, considerations will be given 
to the analysis based on the primary estimand using FAS and the supplementary estimand (see
Table 9-1) using PPS, i.e., similar conclusions on non-inferiority based on both estimands are 
expected. Inconsistencies in key efficacy study results between the FAS and PPS will be 
examined and discussed in the clinical study report (CSR).


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


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The primary analysis of the primary and first key secondary endpoints will be based on the FAS. 
9.4.1.1
Statistical model, hypotheses, and method of analysis
The objective related to the primary and first key secondary endpoints is to demonstrate non-
inferiority of brolucizumab to aflibercept with respect to change from baseline in BCVA, 
considering a margin of 4 ETDRS letters.
Let: 
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
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) 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.
9.4.1.2
Handling of missing values/censoring/discontinuations
Missing BCVA values will be imputed by LOCF (Last Observation Carried Forward) as a 
primary approach. For patients with no post-baseline BCVA value, the baseline value will be 
carried forward. Data collected after start of alternative DME treatment in the study eye (e.g. 
other anti-VEGF treatment, laser or intraocular corticosteroids, as further detailed in the SAP) 
will be censored for the primary analysis. 
From an estimand perspective, the main focus is to adequately reflect in the analysis 
unfavorable study outcome related to the treatment (e.g. lack of efficacy, safety problems).
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 


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


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9.4.2.1
Statistical model, hypotheses, and method of analysis
The estimate for the proportion of patients with a positive q12w treatment status at Week 52 
will be derived from Kaplan Meier time-to-event analyses for the event ‘first q8w-need’ 
applying a ‘q8w-need’ allocation in case of missing or confounded data attributable to lack of 
efficacy and/or lack of safety.
The proportion of patients with a positive q12w treatment status at Week 52 will be derived 
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
9.4.2.2
Handling of missing values/censoring/discontinuations
The details regarding handling of missing values and discontinuations including the timing of 
censoring within the time-to-event analyses for the event ‘first q8w-need’ are specified above. 
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. 


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Alternative methods of handling missing or confounded data within sensitivity analyses will 
include an approach with ‘q8w-need’ allocation only in case of missing or confounded data 
attributable to lack of efficacy and an ‘as observed’ approach, i.e. an analysis without ‘q8w-
need’ allocation.
9.4.3
Sensitivity and supportive analyses 
Sensitivity analyses will be performed for primary and all key secondary endpoints using the 
per protocol analysis set (PPS), alternative methods of handling missing values (Section 9.4.1.2
and Section 9.4.2.2) and descriptive analyses based on observed data only (with and without 
censoring of data collected after use of alternative treatment for DME in the study eye, e.g. 
other anti-VEGF treatment, laser, intraocular corticosteroids, as further detailed in the SAP).
The following subgroup analyses will be conducted in FAS applying the primary analysis 
approach as specified above:

Age category (<65, ≥65 years)

Gender (male, female)

Diabetes type (Type 1, Type 2)

Baseline HbA1c (<7.5, ≥7.5%)

Baseline BCVA categories (≤65, >65 letters)

Duration of DME (≤3, >3-<12, ≥12 months)

DME type (focal, diffuse) as per CRC 

Baseline CSFT  (<450, ≥450-<650, ≥650 µm)

Baseline status of IRF (presence, absence)

Baseline status of SRF (presence, absence)
Further description of the supportive analyses will be detailed in the SAP.
9.5
Analysis of secondary endpoints
9.5.1
Efficacy endpoints
Secondary efficacy endpoints based on BCVA:

Change from baseline in BCVA at each visit up to Week 100

Average change from baseline in BCVA over the period Week 88 to Week 100. 

Average change from baseline in BCVA over the period Week 4 to Week 52/100. 

Average change from baseline in BCVA over the period Week 20 to Week 52/100 and 
Week 28 to Week 52/100.

Gain in BCVA of ≥5,≥10 and ≥15 ETDRS letters from baseline to each post-baseline visit
Note: Patients with BCVA value of 84 letters or more at a post-baseline visit will be 
considered as responders for the corresponding endpoint. This is to account for a ceiling 
effect, e.g. for the’ ≥15-letter gain’ endpoint, for those patients with BCVA values at 
baseline ≥ 70 letters.


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
Time to achieve gain of ≥5, ≥10 and ≥15 ETDRS letters from baseline (or reaching a score 
of 84 or more)

Loss in BCVA of ≥5, ≥10 and ≥15 ETDRS letters from baseline to each post-baseline visit

Absolute BCVA ≥73 ETDRS letters at each post-baseline visit 
Secondary efficacy endpoints related to dosing regimen:

Proportion of patients maintained at q12w up to Week 64 (after three q12w- treatment 
intervals)  

Proportion of patients maintained at q12w up to Week 64 (after three q12w- treatment 
intervals), within those patients that qualified for q12w at Week 36 (for 
brolucizumab treatment arm only)

Proportion of patients maintained at q12w/q16w up to Week 100, within those patients that 
qualified for q12w at Week 36 (for brolucizumab treatment arm only)

q8w treatment need status assessed at Week 32

Proportion of patients maintained on q16w up to Week 100 within the patients on q12w at 
Week 68 and on q16w at Week 76

Proportion of patients re-assigned and maintained on q12w up to Week 100 within the 
patients on q8w at Week 68 and on q12w at Week 80

Treatment status at Week 100
Secondary efficacy endpoints related to anatomy:

Change from baseline in central subfield thickness (CSFT, as determined by SD-OCT from 
the central reading center) at each assessment visit

Average change in CSFT from baseline over the period Week 40 through Week 52 / Week 
88 through Week 100

Average change in CSFT from baseline over the period Week 4 to Week 52 / 96

Patient status regarding normal CSFT thickness (<280 microns) at each assessment visit

Proportion of patients with presence of SRF, IRF and simultaneous absence of SRF and IRF 
at each assessment visit

Proportion of patients with presence of leakage on FA at Weeks 52 and 100
Secondary efficacy endpoints related to the status of Diabetic Retinopathy:

Patient status regarding a ≥2- and ≥3-step improvement or worsening from baseline in the 
ETDRS Diabetic Retinopathy Severity Scale (DRSS) score at each assessment visit

Incidence of progression to PDR as assessed by ETDRS-DRSS score of at least 61 by Week 
52 and Week 100


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


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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.
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.
9.5.3
Resource utilization 
Not applicable
9.5.4
Pharmacokinetics 
Serum concentration data of brolucizumab will be listed by treatment, 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 quantitation (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.  
9.5.5
Biomarkers 
Not applicable
9.5.6
PK/PD 
Not applicable
9.5.7
PRO (Patient Reported Outcome)
The VFQ-25 questionnaires will be scored (total and subscale scores) at Baseline and Weeks 
28, 52, 76 and 100 visits. 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.


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9.5.8
Anti-drug antibodies
Collection of blood for ADA assessment will be done at Screening, Weeks 4, 12, 24, 36, 52, 76 
prior to the injection/sham, and exit/premature discontinuation.
 
 
 
 
 
 
 
 
 
 
 
 
 
9.7
Interim analyses
The analysis based on the Week 52 data will be the primary efficacy analysis for this study. The 
database including all Week 52 data will be locked once all active patients have completed the 
Week 52 visit or terminated the study prior to Week 52. A second planned analysis may be 
performed by locking the Week 76 data in case of regulatory request of supplemental data to 
be submitted during the review period.
9.8
Sample size calculation
A sample size of 160 patients per arm will allow to demonstrate a non-inferiority (NIM of 4 
ETDRS letters) of brolucizumab 6 mg vs. aflibercept 2 mg with respect to the BCVA change 
from baseline at Week 52, with 90% 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 90% can also be 
expected for its corresponding non-inferiority claim. 
To account for a drop-out rate of 10%, a total of 356 (178 per arm) patients will need to be 
randomized.


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10
Ethical considerations
10.1
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 Japanese 
Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the 
Declaration of Helsinki.
10.2
Informed consent procedures
Eligible patients may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent, or, if applicable after such consent 
has been provided by a legally acceptable representative(s) of the patient. 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 patient source documents. 
For trials using an Electronic Informed Consent system where a date/timestamp is automatically 
generated, the system-generated date/timestamp is sufficient; additional input of the date at the 
time of consent is not required by the patient. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guideline and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC approval.
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 requirement for the duration of 
the study and for 3 months after stopping the investigational medication. If there is any question 
that the patient will not reliably comply, they must not be entered in the study.
 
 
 
 
 
During the COVID-19 pandemic that may challenge the ability to obtain a standard written 
informed consent due to limits that prevent an on-site visit, the Investigator may conduct 
the informed consent discussion remotely (e.g. telephone, videoconference). Guidance 
issued by local regulatory bodies on this aspect prevail and must be implemented and 
documented (e.g. the presence of an impartial witness, sign/dating separate ICFs by trial 
participant and person obtaining informed consent, etc). Remote informed consent should 


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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. 
10.3
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
informed consent form, consent form updates, patient recruitment procedures (e.g., 
advertisements) and any other written information to be provided to patients. Prior to study start, 
the investigator is required to sign a protocol signature page confirming his/her agreement to 
conduct the study in accordance with these documents and all of the instructions and procedures 
found in this protocol and to give access to all relevant data and records to Novartis monitors, 
auditors, Novartis Quality Assurance representatives, designated agents of Novartis, IRBs/IECs, 
and regulatory authorities as required. If an inspection of the clinical site is requested by a 
regulatory authority, the investigator must inform Novartis immediately that this request has 
been made.
10.4
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results.
10.5
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance, a group independent from those involved in 
conducting, monitoring or performing quality control of the clinical trial. The clinical audit 
process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
11
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction, data, information, observation 
would be incidentally collected, the investigator shall immediately disclose it to Novartis and 


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not use it for any purpose other than the study, except for the appropriate monitoring on study 
participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 
11.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate hazard 
to patients may be implemented immediately provided the health authorities are subsequently 
notified by protocol amendment and the reviewing IRB/IEC is notified. Notwithstanding the 
need for approval of formal protocol amendments, the investigator is expected to take any 
immediate action required for the safety of any patient included in this study, even if this action 
represents a deviation from the protocol. In such cases, the reporting requirements identified in 
Section 7 Safety Monitoring must be followed.


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12
References 
References are available upon request.
Agarwal A, Sarwar S, Sepah YJ, Nguyen QD (2005) What have we learnt about the 
management of diabetic macular edema in the antivascular endothelial growth factor and 
corticosteroid era? Current Opinion in Ophthalmology; 26(3):177-183.
Jabs DA, Nussenblatt RB, Rosenbaum JT (2005) Standardization of Uveitis Nomenclature 
(SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. 
Results of the First International Workshop. Am J Ophthalmol; 140(3):509-16.
Klein R, Moss SE, Klein BE, Gutierrez P, Mangione CM (2001). The NEI-VFQ-25 in People 
With Long-term Type 1 Diabetes Mellitus: The Wisconsin Epidemiologic Study of Diabetic 
Retinopathy. Arch Ophthalmol.; 119(5):733-40.
Korobelnik JF, Do DV, Schmidt-Erfurth U, Boyer DS, Holz FG, Heier JS et al (2014)
Intravitreal aflibercept for diabetic macular edema.  Ophthalmology; 121(11):2247-54. 
Lang GE, Berta A, Eldem BM, Simader C, Sharp D, Holz FG et al (2013) Two-year safety 
and efficacy of ranibizumab 0.5 mg in diabetic macular edema: Interim analysis of the 
RESTORE extension study. Ophthalmology; 120(10):2004-12.
Lee R, Wong TY, Sabanayagam C (2015) Epidemiology of diabetic retinopathy, diabetic
macular edema and related vision loss. Eye Vis (Lond) ; 17.
Mangione CM, Lee PP, Guiterrez PR, Spitzer K, Berry S, Hays RD et al (2001) Development 
of the 25-Item National Eye Institute Visual Function Questionnaire. Arch Ophthalmol.;
119(7):1050-8.
Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, et al
(2011) The RESTORE study: Ranibizumab monotherapy or combined with laser versus laser 
monotherapy for diabetic macular edema. Ophthalmology; 118(4):615-25.
Nussenblatt RB, Palestine AG, Chan CC, Roberge F (1985) Standardization of vitreal 
inflammatory activity in intermediate and posterior uveitis. Ophthalmology; 92(4):467-
71.Schmidt-Erfurth U, Lang GE, Holz FG, Schlingemann RO, Lanzetta P, Massin P, Gerstner 
O, Bouazza AS, Shen H, Osborne A, Mitchell P et al (2014) Three-year outcomes of 
individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE 
extension study. Ophthamology; 121(5): 1045-1053.
Smiddy WE (2011) Economic considerations of macular edema therapies. Ophthalmology;
118(9):1827–33.
Virgili G, Parravano M, Menchini F, Brunetti M (2004) Cost-effectiveness of treatments for 
diabetic macular oedema: should we pay more attention to the appraisal and reporting of 
economic evaluations? Br J Ophthalmol.; 98(4):421-2.
Ziemssen F, Cruess A, Dunger-Baldauf C, Margaron P, Snow H, Strain WD (2017)
Ranibizumab in Diabetic Macular Oedema - A Benefit-risk Analysis of Ranibizumab 0.5 mg 
PRN Versus Laser Treatment. Eur Endocrinol.; 13(2):91-8. 


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13
Appendix 1: Clinically notable laboratory values and vital 
signs 
Table 13-1
Clinically notable laboratory values
Panel/Test 
Type 
Gender
/Age
Conventi
onal Unit 
Conventi
onal Low
Conventi
onal 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
referenc
e
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
x10^9/L
30
900
Hematology/ 
WBC
alert
All
K/cu 
mm
2
25
x10^9/L
2
25


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


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

SAP_001.pdf: 
Novartis
For business use only
Page 1
SAP
CRTH258B2302
Clinical Development
RTH258/Brolucizumab
CRTH258B2302 / NCT03481660
A Two-Year, Two-Arm, Randomized, Double-Masked, 
Multicenter, Phase III Study Assessing the Efficacy and 
Safety of Brolucizumab versus Aflibercept in Adult Patients 
with Visual Impairment due to Diabetic Macular Edema
(KITE)
Statistical Analysis Plan (SAP)
Author:
, Statistician
Document type:
SAP Documentation
Document status:
Amendment V1.1 – clean version
Release date:
17-Aug-2020
Number of pages:
48
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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SAP
CRTH258B2302
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section 
impacted 
(Current)
15-
Oct-
2019
Prior 
to 
DB 
lock
Creation of 
first version
N/A
NA
17-
Aug-
2020
Prior 
to 
DB 
lock
Creation of 
amendment 
1 
Add analyses to cover potential impact of 
COVID-19 pandemic
Update testing strategy to add confirmatory 
testing on efficacy endpoints
Correct minor issues in the first version 
Sections 2.3.1, 
2.5.4.2, 2.5.4.3, 
2.6.4, 2.7.2.2, 
2.8.1
Section 2.7.2.1


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CRTH258B2302
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 ...............................................................................9
2
Statistical methods.............................................................................................................10
2.1
Data analysis general information .........................................................................10
2.1.1
General definitions................................................................................11
2.2
Analysis sets ..........................................................................................................12
2.2.1
Subgroups of interest.............................................................................13
2.3
Patient disposition, demographics and other baseline characteristics ...................13
2.3.1
Patient disposition.................................................................................13
2.3.2
Demographics and baseline characteristics...........................................14
2.3.3
Medical history......................................................................................14
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................14
2.4.1
Study treatment exposure......................................................................14
2.4.2
Prior and concomitant medications.......................................................15
2.5
Analysis of the primary and first key secondary endpoints...................................16
2.5.1
Primary and first key secondary endpoints ...........................................16
2.5.2
Statistical hypothesis, model, and method of analysis..........................16
2.5.3
Handling of missing values/censoring/discontinuations.......................17
2.5.4
Sensitivity and Supportive analyses......................................................19
2.6
Analysis of additional key secondary endpoints ...................................................21
2.6.1
Additional key secondary endpoints .....................................................21
2.6.2
Statistical hypothesis, model, and method of analysis..........................21
2.6.3
Handling of missing values/censoring/discontinuations.......................22
2.6.4
Supportive analyses...............................................................................22
2.7
Analysis of secondary efficacy endpoints .............................................................23
2.7.1
Secondary efficacy endpoints ...............................................................23
2.7.2
Statistical hypothesis, model, and method of analysis..........................25
2.7.3
Handling of missing values/censoring/discontinuations.......................29
2.8
Safety analyses.......................................................................................................29
2.8.1
Adverse events (AEs)............................................................................30
2.8.2
Deaths....................................................................................................32
2.8.3
Laboratory data .....................................................................................32


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SAP
CRTH258B2302
2.8.4
Other safety data ...................................................................................32
2.9
Pharmacokinetic endpoints....................................................................................33
2.10
Anti-drug antibodies..............................................................................................33
2.11
Patient-reported outcomes .....................................................................................34
35
35
36
2.13
Interim analysis......................................................................................................36
3
Sample size calculation .....................................................................................................36
4
Change to protocol specified analyses ..............................................................................36
5
Appendix ...........................................................................................................................37
5.1
Imputation rules.....................................................................................................37
5.1.1
Study drug.............................................................................................37
5.1.2
AE date imputation ...............................................................................37
5.1.3
Concomitant medication date imputation .............................................39
5.1.4
Medical history date of diagnosis imputation.......................................40
5.2
AEs coding/severity...............................................................................................41
5.3
Laboratory parameters and vital signs derivations ................................................41
5.4
Statistical models...................................................................................................42
5.4.1
Primary and first key secondary analysis..............................................42
5.4.2
Other secondary efficacy analysis.........................................................42
5.5
Rule of exclusion criteria of analysis sets..............................................................43
5.6
Censoring rules for analysis...................................................................................45


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CRTH258B2302
List of abbreviations
ADA
Anti-drug antibody
AE
Adverse Event
ALP
Alkaline Phosphate
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
ANOVA
Analysis of Variance
AR
Analysis Restrictions
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Classification
BCVA
Best Corrected Visual Acuity
CI
Confidence Interval
cm
Centimeter
CF
Color Fundus
COVID-19
Coronavirus Disease 2019
CSFT
Central Subfield Thickness
CSFTns
Central Subfield Thickness-neurosensory retina
CSR
Clinical Study Report
CRS
Case Retrieval Strategy
CRC
Central Reading Center
DBL
Database Lock
DMC
Data Monitoring Committee 
DME
Diabetic Macular Edema
DRSS
Diabetic Retinopathy Severity Scale
eCRF
Electronic Case Report Form
eCRS
Electronic Case Retrieval Strategy
ETDRS
Early Treatment Diabetic Retinopathy Study
EoT
End of Treatment
FA
Fluorescein angiography
IA
Interim Analysis
IOP
Intraocular Pressure
IRT
Interactive Response Technology
IRF
Intraretinal Fluid
IVT
Intravitreal Treatment
kg
Kilogram
KM
Kaplan Meier
LSM
Least Square Means
MedDRA
Medical Dictionary for Regulatory Activities
MICE
Multiple Imputation by Chained Wquations
MMRM
Mixed Model for Repeated Measures
mg
Milligrams
mL
Millilitres
OCT
Optical Coherence Tomography


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SAP
CRTH258B2302
PD
Protocol Deviation
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
ULN
Upper Limit of Normal
q1
25th Percentile
q3
75th Percentile
q4w
Every 4 Weeks
q6w
Every 6 Weeks
q8w
Every 8 Weeks
q12w
q16w
Every 12 Weeks
Every 16 Weeks
SRF
Subretinal Fluid
TBL
Total Bilirubin
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 analyses planned in the study protocol, and to provide detailed statistical methods that 
will be used for the Clinical Study Report (CSR) of study CRTH258B2302.
Data will be analyzed according to the data analysis Section 9 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 additional details will be provided, as applicable, in Appendix 16.1.9 of the CSR.
The SAP will be finalized before the interim database lock (DBL) for the primary analysis at 
Week 52. Any changes to the SAP after approval will be documented.
The following document was referenced while writing this SAP:
CRTH258B2302 Clinical Trial Protocol Final version 02 dated 11-June-2020
1.1
Study design
This is a randomized, double-masked, multi-center, active-controlled 2-arm 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 450 patients will be screened in order to randomize a total of approximately 356 
patients (178 per arm) in a 1:1 ratio in one of the two treatment arms:

Brolucizumab 6mg: 5 × q6w loading then q12w/q8w maintenance (with option to 
extend treatment interval during second year)

Aflibercept 2mg: 5 × q4w loading then q8w maintenance
At the baseline visit, all eligible patients will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. Stratification for systemic exposure sampling
will be considered.
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 for 2 years, 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 at Weeks 
20, 28 and 100 visits (no scheduled treatment for any arm)

Disease activity assessment and disease stability 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 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, 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 (Baseline, Weeks 4, 8, 12 and 16). To preserve the masking, the 
patients assigned to aflibercept arm will receive sham injection on Weeks 6 and 18.
Maintenance Phase:
The treatment interval during the maintenance phase will be as follows:
Brolucizumab 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, the patient will be assigned to receive treatment every 8 
weeks (please refer to protocol for ‘Evaluation of Disease Activity’). A disease activity 
assessment will also be performed at Week 96 to document the adequacy of the q12w treatment 
schedule at the end of the 2 year follow-up but will not be entered into IRT and will have no 
effect 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 96 visit. 
Disease activity assessments will be conducted by the evaluating/masked investigator for 
masking purposes and will not influence the treatment interval.
The primary analysis will be based on the Week 52 data, i.e. all data up to and including Week 
52 (see Section 2.1). 


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Patients will remain in the study and will continue to receive masked treatment through the 
planned duration (100 weeks) to allow for further masked evaluation of efficacy and safety. 
Treatment masking of individual patients will remain intact for all patients, investigators and 
selected staff from the Sponsor who have contact with patients or investigators or those who 
are involved in the direct conduct of the study until the final database lock has occurred.
1.2
Study objectives and endpoints
Study objectives and related endpoints are described in Table 1-1 below.
Table 1-1
Objectives and related endpoints
Objective
Endpoint
Primary
To demonstrate that brolucizumab is noninferior to 
aflibercept with respect to the visual outcome after 
the first year of treatment
Change from baseline in best-corrected visual 
acuity (BCVA) at Week 52
Secondary
To demonstrate that brolucizumab is noninferior to 
aflibercept with respect to visual outcome during 
the last 3 months of the first year of treatment
Change from baseline in BCVA averaged 
over a period Week 40 to Week 52
To estimate the proportion of patients treated at 
q12w frequency with brolucizumab
Proportion of patients maintained at q12w up 
to Weeks 52 & 100
To estimate the predictive value of the first q12w 
cycle for maintenance of q12w treatment with 
brolucizumab
Proportion of patients maintained at q12w up 
to Week 52, within those patients that 
qualified for q12w at Week 36
Proportion of patients maintained  at 
q12w/q16w up to Week 100, within those 
patients that qualified for q12w at Week 36
To assess the potential to extend treatment 
intervals for brolucizumab patients during the 
second year of treatment
Proportion of patients maintained on q16w up 
to Week 100 within the patients on q12w at 
Week 68 and on q16w at Week 76
Proportion of patients re-assigned and 
maintained on q12w up to Week 100 within 
the patients on q8w at Week 68 and on q12w 
at Week 80
Treatment status at Week 100
To evaluate the functional and anatomical outcome 
with brolucizumab relative to aflibercept
Change from baseline by visit up to Week 100 
in BCVA and in parameters derived from SD-
OCT, Color fundus photography and 
Fluorescein angiography
To evaluate the effect of brolucizumab relative to 
aflibercept on the Diabetic Retinopathy status
Change in ETDRS Diabetic Retinopathy 
Severity Scale (DRSS) score up to Week 100
To assess the safety and tolerability of 
brolucizumab relative to aflibercept
Incidence of Ocular and Non-ocular AEs, vital 
signs and laboratory values up to Week 100
To evaluate the effect of brolucizumab relative to 
aflibercept on patient-reported outcomes (VFQ-25)
Change in patient reported outcomes (VFQ-
25) total and subscale scores from baseline 
up to Week 100


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Objective
Endpoint
To confirm the systemic brolucizumab exposure in 
patients with visual impairment due to diabetic 
macular edema
Systemic brolucizumab concentration 
approximately 24 hours after initial and final 
loading phase doses
To assess the immunogenicity of brolucizumab 
over two years of treatment
ADA status at baseline and up to Week 100
2
Statistical methods
2.1
Data analysis general information
The primary safety and efficacy analysis will be based on the Week 52 data, i.e. all data up to 
and including Week 52. The analysis of the data collected after Week 52 visit will be performed 
once all patients completed or discontinued from the study.
A second planned interim analysis may be performed by locking the Week 76 data in case of 
regulatory request of supplemental data to be submitted during the review period. 
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. For the treatment difference 
brolucizumab – aflibercept, point estimates, 95% CIs will be provided as appropriate unless 
otherwise specified.
All the analyses listed in the SAP that correspond to data collected during the 2nd year of the 
study (post-Week 52) will be part of the end of study (year-2) CSR only. For the year-2 CSR, 
efficacy endpoints specific to the first year, i.e, up to the Week 52 visit (e.g., the change from 
baseline in BCVA averaged over Week 40 to Week 52) will not be analyzed and reported again; 
analyses by visit and assessments based on cumulative data (e.g., incidence of AEs) will include 
data from baseline up to the end of study. 


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2.1.1
General definitions
Study drug and study treatment
Study drug refers to both brolucizumab 6mg and aflibercept 2mg IVT injections.
Study treatment refers to study drug or sham injections.
Study day
Day 1 is defined as the date of first dose of study drug (brolucizumab or aflibercept). Study day 
is defined as the number of days relative to 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 patient 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 number. If end of study date is not on a scheduled visit, then the end of study 
visit will be allocated, based on study day, to the closest future scheduled study visit.
End of treatment day mapping
The “Date of Last Exposure” is the date of the last study treatment (from “exposure” CRF form) 
is the date of the last study treatment on or prior to the end of study treatment (EoT) date.
For reporting data by visit in outputs, the EoT visit will be allocated to the actual (reported) 
visit number. If EoT date is not on a scheduled visit, then the EoT visit 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, average BCVA change from baseline over a given period, 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). 
All data collected at unscheduled visits will be included in listings.
Missing and implausible dates


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The general approach to handling missing dates is shown in Section 5.1.
2.2
Analysis sets
The All Enrolled set includes all patients who signed informed consent. This analysis set will 
be used to summarize patient disposition.
The Randomized Set will consist of all randomized patients. Patients are considered 
randomized when they have been deemed eligible for randomization by the investigator and 
given a randomization number. Patients will be analyzed according to the treatment assigned to 
at randomization.
The Full Analysis Set (FAS) includes all randomized patients who receive at least one IVT 
injection of the study treatment. The full analysis set will serve as the primary analysis set for 
all efficacy analyses. Patients will be analyzed according to the treatment assigned to at 
randomization.
Supportive analyses of the primary and key secondary endpoints will include analyses using the 
Per Protocol Set (PPS). PPS is a subset of the FAS and will exclude or censor patients with 
important protocol deviations (PDs) and analysis restrictions (ARs) that are expected to majorly 
affect the validity of the assessment of efficacy and/or safety at Week 52, including for e.g. lack 
of compliance (including missed treatments and treatment misallocation), missing data, 
prohibited concomitant medication and deviations
from inclusion/exclusion criteria. 
Confounded data or discontinuation from study treatment due to lack of efficacy and/or safety 
do not constitute a reason for exclusion from the PPS. 
Before the Week 52 database lock the relevant protocol deviations will be identified at the 
patient level in the database. After the Week 52 database lock, analysis restrictions will be 
derived in the analysis database. Censoring applied in relation to the specific PDs / ARs will be 
specified as well.
The FAS will be the analysis set for the primary estimand as defined in Table 9-1. However, 
when assessing the robustness of the overall efficacy conclusions, considerations will be given 
to the analysis based on the primary estimand using FAS and the supplementary estimand (see 
Table 2-1) using PPS, i.e., similar conclusions on non-inferiority based on both estimands are 
expected. Inconsistencies in key efficacy study results between the FAS and PPS will be 
examined and discussed in the clinical study report (CSR).
The Safety Analysis Set (SAF) will include all patients who receive at least one IVT injection. 
Patients in the safety analysis set will be analyzed according to the treatment arm from which 
they received majority of treatments up to and including Week 48.
Prior to locking the database for the primary analysis at Week 52 and breaking the masked 
treatment assignment code, the relevant important protocol deviations will be identified as 
specified in Section 5.6. The corresponding identifications at the patient 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.


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2.2.1
Subgroups of interest
The subgroups of interest are specified below:

Age category (<65, ≥65 years)

Gender (male, female)

Diabetes type (Type 1, Type 2)

Baseline HbA1c (<7.5, ≥7.5%)

Baseline BCVA categories (≤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) (presence, absence)

Baseline status of subretinal fluid (SRF) (presence, absence)
Subgroup analyses will be performed for the primary and key secondary efficacy variables 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.
2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
The following summaries will be included in the disposition table considering all enrolled 
patients: number and percent of patients who are enrolled into the study, treated, complete the 
study (Week 52/Week 100), discontinue the study (prior to or at Week 52/Week 100)  (including 
reasons for discontinuation) and discontinue from study treatment (prior to or at Week 52/Week 
96) (including reasons for discontinuation). 
The number and percent of patients who discontinue the study and who discontinue study 
treatment will be presented by study visit. The number and percent of patients treated by site 
will be presented.
A listing of patients 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.
Patients 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 but only listed.
Number and percent of patients 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 patients along 
with the analysis set that they were excluded from and the corresponding reasons will also be 
presented.
Number and percent of patients with important protocol deviations (PD) and analysis 
restrictions (AR) will be presented by treatment arm and deviation/restriction category. Due to 
the COVID-19 pandemic, higher number of PDs are expected. To evaluate the PDs that 


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occurred due to COVID-19, the number and percentage of patients with PDs that occurred due 
to COVID-19 outbreak 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, gender, 
race, and ethnicity. The summary of baseline ocular characteristics will be presented for the 
study eye only and listed separately for the study eye and the fellow eye.
Ocular baseline characteristics include:

Study eye selection (left eye OS or right eye OD),

Diabetes type (Type 1, Type 2),

Duration of DME since the primary diagnosis as a 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, 
≥60-≤70, >70 letters),

Baseline HbA1c as continuous variable and using categories (<7.5, ≥7.5%), 

Baseline CSFT (<450, ≥450-<650, ≥650 µm),

Baseline status of IRF (presence, absence),

Baseline status of SRF (presence, absence),

Baseline ETDRS DRSS score using categories (12-level scale, see Table 2-4).
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 differences will be assessed based on clinical relevance.
2.3.3
Medical history
Medical history and current medical conditions will be summarized and listed for ocular (study 
eye) and non-ocular events. 
2.4
Treatments (study treatment, rescue medication, 
concomitant therapies, compliance)
2.4.1
Study treatment exposure
Extent of exposure to study treatment is calculated as the number of study treatment injections 
received. 
Descriptive statistics for exposure to study treatment will be provided for the Safety set.


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The following summaries will be presented:

Overall number of treatments cumulatively for the period baseline to Week 48/52 (Week 
96) 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 patients 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 (Week 100),
differentiating between active and sham treatments, missed study treatments and wrong
study treatments 

Brolucizumab treatment allocation by visit from Week 32 onwards: number and percent of 
patients on q12w and q8w at each visit, including number of patients switched from q12w
to q8w. In the year-2 analysis, number and percent of patients on q16w, and switching from 
one regimen to another (e.g. from q12w/q16w to q8w, from q8w to q12w and from q12w 
to q16w) will be presented as well.
Exposure data will be listed for both treatment arm.
2.4.2
Prior and concomitant medications 
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 by treatment arm. Ocular medications will be listed for the study 
eye and the fellow eye separately.
Anti-VEGF medications will be summarized by ATC class and preferred term for systemic
route, the study eye and the fellow eye separately by treatment arm. 
Ocular concomitant significant 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 and first key secondary 
endpoints
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
(ETDRS letters).
The first key secondary endpoint is the average change from baseline in BCVA over the period 
Week 40 through Week 52 in the study eye. 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 (q8w and q12w). 
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: 


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H01: μB – μA     ≤ -4 letters     vs.
HA1: μB – μA    > -4 letters
H02: B – A     ≤ -4 letters    vs.
HA2: B – A    > -4 letters
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 mean
(LSM) difference (brolucizumab - aflibercept) will be presented in letters. 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.
These two alternative hypotheses will be tested sequentially in the order of their numbering 
(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
Analysis 
set
Statistical methods (Including strategy for 
imputation/replacement of missing/censored
data)
Primary 
estimand
Difference in change from 
baseline in BCVA at Week 
52 excluding the effect of 
switching to alternative 
DME medication in the 
study eye
FAS
Analysis of variance (ANOVA) model including 
terms for treatment, baseline BCVA (≤65, >65 
letters) and age category (<65, ≥65 years), and 
using LOCF imputation/replacement for 
missing/censored data.
Supplementary
estimand
Difference in change from 
baseline in BCVA at Week 
52 for patients adhering to 
the protocol as per the 
PPS definition
PPS
ANOVA model as per the primary estimand.
LOCF imputation/replacement for 
missing/censored data
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 patients with 
no post-baseline BCVA value, the baseline value will be carried forward. 
For patients who discontinue study treatment but continue in the study, data collected after the 
switch to alternative DME treatment in the study eye (see Table 2-2) will be censored for the 


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primary analysis. Censored data will be replaced using LOCF with the last observation collected 
prior to the start of alternative DME treatment in the study eye.
Table 2-2
Potential alternative DME treatment in the study eye

Ranibizumab

Aflibercept 

Bevacizumab (off-label use) 

Laser photocoagulation, previous standard of care still being used as mono- or combination 
therapy with anti-VEGF

Intraocularly administered steroids:
o
Dexamethasone
o
Fluocinolone acetonide
From an estimand perspective, the main focus is to adequately reflect in the analysis 
unfavorable study outcomes 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 occurring 
independently of the response to study treatment, 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 
those studies, the percentage of missing data regarding BCVA is not considered critical (<10%) 
which limits the impact of the missing data imputation method.


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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) 
using observed data only (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-patient 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 LSM estimate and 95% CI for the corresponding treatment difference.

If an MMRM model with an unstructured covariance matrix does not converge, 
a more restricted covariance matrix can be considered in the following order 
until convergence is reached: compound symmetry (CS), first-order 
autoregressive (AR), 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 to assess the impact of COVID-19:
Another supplementary estimand might be defined to consider study treatment discontinuation 
due to COVID-19. For patients who discontinue study treatment due to COVID-19 but continue 
in the study, data collected after the treatment discontinuation will be censored for the analysis. 
Censored data will be replaced using LOCF with the last observation collected prior to the study 


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treatment discontinuation. This analysis will be conducted on the FAS if at least 5% of subjects 
discontinued treatment due to COVID-19.
2.5.4.3
Summary statistics and subgroup analysis
Summary statistics:

Descriptive statistics of BCVA primary 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 of interest as described in Section 2.2.1. They will be conducted using the
framework for the primary estimand only (FAS with censoring of data collected after use of 
alternative DME treatment in the study eye, and missing/censored values imputed/replaced 
using LOCF):

Subgroup analyses will be conducted using the same model and analysis strategies 
described for the primary and first key secondary endpoints 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.
Impact of COVID-19 pandemic:
As per internal guidance, a sensitivity analysis related to the exposure of subjects to COVID-
19 will be conducted. The definition of start and end dates by geographical areas to be used for 
the sensitivity analysis are as indicated below:
Region/Country 
Start Date 
End Date 
China 
01-Jan-2020 
End date has not yet been defined 
South Korea 
20-Feb-2020 
End date has not yet been defined 
Japan 
21-Feb-2020 
End date has not yet been defined 
Italy 
23-Feb-2020 
End date has not yet been defined 
Rest of the World 
01-Mar-2020 
End dates have not yet been defined
Non-exposed subjects to COVID-19 are defined as subjects who:

completed Week 52 visit prior to pandemic start date,

or withdrew study prior to pandemic start date,

or withdrew treatment and started alternative DME treatment prior to pandemic start 
date.
Exposed subjects to COVID-19 are therefore defined as subjects who:

did not complete Week 52 visit prior to pandemic start date (while remaining in the 
study at the time of pandemic start date), 

or withdrew study on or after pandemic start date,


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
or withdrew treatment and started alternative DME treatment on or after pandemic start 
date.
Subgroup analyses will be conducted using the same model and analysis strategies described 
for the primary and first key secondary endpoints in the exposed and non-exposed subgroups. 
Demographics and baseline characteristics will be summarized for exposed and non-exposed 
subjects. 
2.6
Analysis of additional key secondary endpoints
2.6.1
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)
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 patients with a positive q12w treatment status will be derived 
from Kaplan-Meier (KM) 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 subjects with a positive q12w treatment status will be derived as follows 
according to the ‘sufficient efficacy and safety’ approach:

The q8w-need assessment is 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 patient is censored within the q12w 
treatment status analysis according to the specifications provided below:

Early treatment/study discontinuation: censoring at the last valid DAA visit while on 
treatment/study

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 patients with a positive q12w treatment status at Week 52 will be presented 
together with two-sided 95% confidence intervals (see Section 5.4.2.3).
The outcome of the Kaplan-Meier analysis 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 patients in the FAS will be considered, 
the analysis of the proportion of patients maintained at q12w up to Week 52, within those 
patients that qualified for q12w at Week 36, is based on the subset of FAS patients with no 
identified q8w-need at Week 32 and Week 36. For this subset of patients 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 within the time-to-event analyses for the event ‘first q8w-need’, are specified in the
previous section. 
Remark: Patients 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 impact of failing study completion according to the protocol 
due to lack of efficacy/safety is considered adequately reflected by a negative q12w-status. 
2.6.4
Supportive analyses
Supportive analyses 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 is attributable to lack of efficacy of the study 
treatment. In case of a corresponding safety reason the patient is censored at the last 
valid DAA.

‘As observed’ approach: analysis without ‘q8w-need’ allocation.
Additionally, analyses described in Section 2.6.2 conducted using the FAS will be repeated 
using the PPS to assess the consistency of the assessment of the q12w proportions when looking 
only at those patients 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.  It will include assessment of the impact of COVID-


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19 pandemic with the subgroup analysis of exposed and non-exposed subjects as defined in 
Section 2.5.4.3.
In addition, analysis will be repeated using the FAS and the efficacy/safety approach only, after
excluding subjects whose DAA assessment has been impacted by COVID-19 (e.g., DAA not 
performed due to COVID-19 site impact).
2.7
Analysis of secondary efficacy endpoints
2.7.1
Secondary efficacy endpoints
Secondary efficacy endpoints related to BCVA, dosing regimen, anatomy or status of diabetic 
retinopathy are listed below. All endpoints that consider data from post-Week 52 visits will not 
be part of the primary analysis at Week 52. These endpoints will only be analyzed in the year-
2 CSR (Week 100).
Secondary efficacy endpoints based on BCVA:

Change from baseline in BCVA at each visit up to Week 100

Average change from baseline in BCVA over the period Week 88 to Week 100 (year-2 
analysis only). For each patient this endpoint is derived as the average of the changes from 
baseline to Weeks 88, 92, 96, 100. 

Average change from baseline in BCVA over the period Week 4 to Week 52/100. For each 
patient this endpoint is derived as the average of the changes from baseline to each post-
baseline visit between Week 4 and Week 52/100. 

Average change from baseline in BCVA over the period Week 20 to Week 52/100 and 
Week 28 to Week 52/100. For each patient those endpoints are derived as the average of the 
changes from baseline to each post-baseline visit between Week 20 and Week 52/100, and 
between Week 28 and Week 52/100.

Number and percentage of patients with a 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 in BCVA of ≥5, ≥10 and ≥15 ETDRS letters from baseline (or reaching 
a score of 84 or more)

Number and percentage of patients with a loss in BCVA of ≥5, ≥10 and ≥15 ETDRS letters 
from baseline to each post-baseline visit

Number and percentage of patients with an absolute BCVA ≥73 ETDRS letters at each post-
baseline visit 


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Secondary efficacy endpoints related to dosing regimen:

Proportion of patients maintained at q12w up to Week 64 (after three q12w treatment 
intervals) and 100 (for brolucizumab treatment arm only). This endpoint will only be 
assessed in the year-2 analysis (Week 100), using the KM method as described for the key 
secondary endpoint at Week 52 (Section 2.6.2)

Proportion of patients maintained at q12w up to Week 64 (after three q12w treatment 
intervals), within those patients that qualified for q12w at Week 36 (for 
brolucizumab treatment arm only). This endpoint will only be assessed in the year-2 
analysis (Week 100), using the KM method as described for the key secondary endpoint at 
Week 52 (Section 2.6.2)

Proportion of patients maintained at q12w/q16w up to Week 100, within those patients that 
qualified for q12w at Week 36 (for brolucizumab treatment arm only). This endpoint will 
only be assessed in the year-2 analysis, using the KM method as described for the key 
secondary endpoint at Week 52 (Section 2.6.2)

Number and percent of patients with q8w treatment need status assessed at Week 32 

Proportion of patients maintained on q16w up to Week 100 within the patients on q12w at 
Week 68 and on q16w at Week 76. This endpoint will only be assessed in the year-2 analysis 
(Week 100) using the KM method as described for the key secondary endpoint at Week 52 
(Section 2.6.2)

Proportion of patients re-assigned and maintained on q12w up to Week 100 within the 
patients on q8w at Week 68 and on q12w at Week 80. This endpoint will only be assessed 
in the year-2 analysis (Week 100) 

Treatment status at Week 100. This endpoint will only be assessed in the year-2 analysis 
(Week 100)
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 from baseline in CSFT over the period Week 40 through Week 52. For 
each patient this endpoint is derived as the average of the changes from baseline to Weeks 
40, 44, 48, 52. Then the same will be derived over the period Week 88 through Week 100, 
considering the average of the changes from baseline to Weeks 88, 92, 96, 100. This 
endpoint will only be assessed in the year-2 analysis (Week 100).

Average change from baseline in CSFT over the period Week 4 to Week 52/100

Proportion of patients with normal CSFT thickness (<280 microns) at each assessment visit

Proportion of patients with presence of SRF, IRF and simultaneous absence of SRF and IRF 
at each assessment visit

Proportion of patients with presence of leakage on FA at Weeks 52 and 100


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Secondary efficacy endpoints related to the status of Diabetic Retinopathy (see Section 
2.7.2.1):

Proportion of patients with 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 proliferative diabetic retinopathy (PDR) as assessed by ETDRS-
DRSS score ≥61 by Week 52 and Week 100, among non-PDR patients at screening
2.7.2
Statistical hypothesis, model, and method of analysis
2.7.2.1
Confirmatory testing related to additional secondary efficacy 
endpoints
Confirmatory hypothesis testing for additional secondary endpoints will be performed in case 
the proof of non-inferiority related to BCVA is successful for the two hypotheses specified 
above (Section 2.5.2) for the primary and first key secondary endpoints.
The additional efficacy hypotheses are linked to the below endpoints:

A. Average change from baseline in CSFT over the period Week 40 through Week 52 in 
the study eye

B. Average change from baseline in BCVA over the period Week 40 through Week 52 in 
the study eye

C. Fluid-status ‘yes/no’ in the study eye at Week 52 (no= absence of SRF and IRF)
All tests will be one-sided tests for superiority of brolucizumab vs aflibercept, i.e.,

for greater reductions in the CSFT change from baseline (ANOVA as specified in Section 
2.7.2.2) with brolucizumab

for greater gains in the BCVA change from baseline (ANOVA as specified in Section 
2.7.2.2) with brolucizumab

for a higher proportion of subjects with absence of fluid (logistic regression as specified in 
Section 2.7.2.2) with brolucizumab
The basis for these tests for superiority will be the FAS with LOCF imputation of missing or 
censored data.
The alternative hypotheses will be tested hierarchically in the order A, then B, then C, i.e., 
confirmatory testing of the hypothesis requires rejection of the previous 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.
2.7.2.2
General analysis specifications for secondary efficacy endpoints
All secondary efficacy endpoints listed in the above Section 2.7.1 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.


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The impact of COVID-19 pandemic on CSFT will be assessed with the subgroup analysis of 
exposed and non-exposed subjects as defined in Section 2.5.4.3.
Continuous endpoints:
The continuous secondary endpoints related to BCVA and CSFT will be analyzed using 
ANOVA models. The estimates of least square means for each treatment and for the treatment 
differences brolucizumab – aflibercept, including 95% CIs for the treatment differences, will 
be presented. 
For the ANOVA analysis of BCVA-related endpoints, baseline BCVA (≤65, >65 letters) and 
age category (<65, ≥65) will be considered as a class variable. For the ANOVA analysis of 
CSFT, baseline CSFT categories (<450, ≥450-<650, ≥650 µm) will be used instead of baseline 
BCVA as a class variable. 
The line plot on LSM (± SE) by visit will also be provided for both treatment arm.
Categorical variables:
For binary endpoints, frequency tables (count and percentage) will be provided by time point. 
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 categories as 
fixed effects.  
Bar chart will be plotted by visit and treatment arm. 
Time-to event variables:
Time-to-event variables such as the time to achieve gain in BCVA of ≥5 (respectively ≥10 and 
≥15) letters from baseline (or reaching a score of 84 or more) will be analyzed using KM 
analysis. KM estimates on percent of patients who achieve gain, together with 95% CI will be 
presented by visit. The median time (95% CI) to gain will also be constructed by treatment arm. 
KM curves presenting the cumulative probability of patients with gain of ≥5 (respectively ≥10 
and ≥15) letters from baseline will be provided by treatment arm.  
2.7.2.3
ETDRS DRSS Score
Definition of Endpoints
The following categories of change from baseline in diabetic retinopathy (DR) status will be 
analyzed:

Patient status regarding a ≥2- and ≥3-step improvement or worsening from baseline in the 
ETDRS DRSS score at each assessment visit

Incidence of progression to PDR as assessed by ETDRS-DRSS score of at least 61 by 
Week 52 and Week 100 (among non-PDR subjects at screening)
Those endpoints will be derived from the ETDRS-DRSS score assessed by the central reading 
center based on colour fundus (CF) photography images in the study eye at screening, Weeks 
28, 52, 76 and exit/premature discontinuation visit.


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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: No images received) that are not related to an 
evaluable DR severity level will be handled as missing. 
All DRSS values will be converted into a 12-level scale as defined in Table 2-4.
Table 2-4
Definition of DRSS: 12-level scale
12-level 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-level scale, as 
defined below:


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
≥2-step improvement: DRSS (12-level scale) at the visit – DRSS (12-level scale) at baseline 
≤-2

≥3-step improvement: DRSS (12-level scale) at the visit – DRSS (12-level scale) at baseline 
≤-3

≥2-step worsening: DRSS (12-level scale) at the visit – DRSS (12-level scale) at baseline 
≥2

≥3-step worsening: DRSS (12-level scale) at the visit – DRSS (12-level scale) at baseline 
≥3
Table 2-5
Definition of 2-step change in DRSS on the 12-level 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-level 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
-


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Analysis method
All DRSS analyses will be based on the 12-level scale shown in Table 2-4.
Proportions of patients 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 patients with ≥2-step change from baseline at Week 52 (and similarly 
for  ≥3-step change), the 95% confidence intervals (CIs) for the proportions in both 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 original scale or ≤4, ≥5 from the 12-level scale) and age categories
(<65, ≥65 years) as fixed effects. 
The proportion of patients who progress to PDR, as assessed by ETDRS-DRSS score ≥61 by 
Week 52 and Week 100, will be summarized among the subset of non-PDR patients at screening 
(ETDRS-DRSS score < 61 at screening).
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 patients who discontinue treatment but continue in the 
study, data collected after the 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 patients with no post-baseline values 
(scheduled or unscheduled), the baseline value will be carried forward, as a conservative 
approach.
For endpoints related to presence of SRF and/or IRF, if baseline visit is reported as ”Cannot 
Grade”, then it will be considered as ”Absent”; if post-baseline visit is reported as ”Cannot 
Grade”, then it will be considered as missing and LOCF method for imputation will be applied.
For the presence of leakage on FA, if baseline visit is reported as ”Cannot Grade”, then it will 
be considered as missing; if post-baseline visit is reported as ”Cannot Grade”, then it will be 
considered as missing and LOCF method for imputation will be applied.
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


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
Laboratory results
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 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. 
The number (and proportion) of patients with TEAEs will be summarized at each analysis 
timepoint (Week 52, Week 100) in the following ways:
Table 2-7
TEAE summary
TEAE summary
AE categories
Ocular AE 
in the 
study eye
Ocular AE 
in the 
fellow eye
Non-
ocular 
AE
AEs by primary SOC and PT
Y#
Y#
AEs by primary SOC and PT (including events with onset date 
after start of alternative DME treatment)
Y
Y
Y
Frequent AEs by PT┼
Y
Y
AEs by maximum severity, SOC and PT 
Y
Y
AEs related to study treatment by SOC and PT
Y
Y
AEs related to injection procedure by SOC and PT
Y
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


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TEAE summary
AE categories
Ocular AE 
in the 
study eye
Ocular AE 
in the 
fellow eye
Non-
ocular 
AE
SAEs related to injection procedure by SOC and PT
Y
┼≥2 % (or other cutting point as appropriate) in any treatment group for a given PT. 
# including separate summary table for exposed and non-exposed subjects to COVID-19 as defined in 
Section 2.5.4.3
In all summary tables listed above, unless otherwise specified, data collected after the patient 
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).
Patient listings of all adverse events will be provided. Deaths and SAEs (i.e., other serious or 
clinically significant non-fatal adverse events) will be listed separately.
The MedDRA version used for reporting the AEs will be described in a footnote.
2.8.1.1
Adverse events of special interest / grouping of AEs
Incidence of adverse events of special interest (AESI) will be tabulated by treatment arm.
AESIs will be identified via the RTH258 electronic case retrieval strategy (eCRS). The eCRS 
that is current at the time the database lock will be used and AESIs 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 and EudraCT, two required tables on TEAEs 
which are not serious adverse events with an incidence greater than 5% and on TEAEs and 
SAEs suspected to be related to study treatment will be provided by system organ class and 
preferred term on the safety set population.
If for the same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE (respectively non-SAE) has to be checked in 
a block e.g., among 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.


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This analysis will be part of the end of study (year-2) CSR only.
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 patients satisfying the criteria representing 
clinically relevant abnormalities given in Section 5.3 at any visit will be presented. A listing for 
patients 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
Descriptive summaries of pre-injection change from baseline in intraocular pressure (IOP)
values for the study eye will be presented graphically at each study visit by treatment arm, 
considering line plots of the mean change in IOP values with error bars representing ± SE. The 
x-axis will be study visit and the y-axis will be the change from Baseline value. No summary 
by visit tables will be provided.
The number and percentage of patients with pre-injection IOP >30 mmHg at any visit will be 
summarized. 
Post-injection IOP is to be assessed approximately 30-60 minutes after injection and if ≥25 
mmHg, the assessment should be repeated until back to normal. Summary tables with counts
and percentage of patients with an IOP increase of ≥10, ≥20 mmHg from pre-injection to post-
injection at any visit for the study eye will be presented. 
A summary table with counts and percentage of patients with observed pre-injection IOP ≥ 
21mmHg at 3 consecutive scheduled visits will be presented. 
A visit with missing pre-injection IOP is considered to meet the ≥ 21mmHg criterion if the 
preceeding and the following visits meet the criterion that pre-injection IOP ≥ 21mmHg. For 
example, if schedule visit X has missing pre-injection IOP and pre-injection IOP ≥ 21mmHg is 
observed for both visit X-1 and X+1, the patient is considered to meet the criteria at visit X as 
well.
A listing for patients with any post-injection IOP increase of ≥10mmHg from pre-injection IOP 
and a listing of patients with any IOP > 30mmHg will be presented.
The abnormal findings via slit-lamp and indirect fundus examinations deemed as clinically 
significant by the investigator and reported as AE/SAE will be included in the safety analysis 
on AE/SAE. 


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2.8.4.2
Loss in BCVA
The number and percentage of patients with a loss in BCVA ≥15, ≥30 letters (study eye) from 
baseline to each visit, to the last visit, and maximum loss at any visit will be presented. 
BCVA data (study eye) for patients 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 percentage of patients satisfying the criteria given in Table
5-2 of the Section 5.3 at least one visit will be presented. A listing for patients satisfying at least 
one criterion in Table 5-2 will also be presented.
A line plot of mean change from baseline in the vital sign parameter by study visit and treatment
arm with error bars representing ±1 standard error will be presented. The x-axis will be study 
visit and the y-axis will be the mean change from baseline value.
2.9
Pharmacokinetic endpoints
Not Applicable.
2.10
Anti-drug antibodies
Collection of blood for ADA assessment for brolucizumab will be done at Screening, Weeks 4, 
12, 24, 36, 52, and 76 prior to the injection/sham, and at exit/premature discontinuation.
 
 
 
 
In addition, tabulations will be presented for ADA titer by ADA assessment visit for the 
brolucizumab arm. 
 


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Subject listings of all ADA titer values 
 will be presented for all subjects in the 
brolucizumab arm. Samples collected at unscheduled visits will not 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 approximately 24 consented patients 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
Patient-reported outcomes
The Visual Function Questionnaires (VFQ-25) will be scored (total and subscale scores) at 
Baseline and Weeks 28, 52, 76 and 100 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 2-8. A missing response will not be re-scaled (except for the 
response to question 15c, see below, which will be re-set to 0 if the response to question 15b is 
1).
The answers to questions will be re-scaled as follows to calculate the total and subscale scores.
Table 2-8
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 general health rating is the re-scaled answer to question 1.
The scales and corresponding questions are shown in Table 2-9.


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Table 2-9
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
The composite score is the average of the 11 subscales shown in Table 2-9. It will be set to
missing if at least six of the subscales are missing.
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 arms 
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 
used for treatment group comparisons. Additionally, descriptive statistics will also be presented 
for the general health score. All analyses will be performed on the subscales values. 
The VFQ-25 composite score and subscale scores will not be listed.


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2.13
Interim analysis
The analysis based on the Week 52 data will be the primary efficacy and safety analysis for this 
study. The database includes all data up to Week 52 from all patients who have completed the 
Week 52 visit or terminated the study prior to (or at) Week 52. 
A second planned analysis may be performed by locking the Week 76 data in case of regulatory 
request of supplemental data to be submitted during the review period.
3
Sample size calculation
A sample size of 160 patients per arm will allow to demonstrate a non-inferiority (NIM of 4 
ETDRS letters) of brolucizumab 6 mg vs. aflibercept 2 mg with respect to the BCVA change 
from baseline at Week 52, with 90% 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 90% can also be 
expected for its corresponding non-inferiority claim. 
To account for a drop-out rate of 10%, a total of 356 (178 per arm) patients will need to be 
randomized.
4
Change to protocol specified analyses
There is no change to the protocol specified analyses in terms of endpoints.
Confirmatory hypothesis testing in relation to additional secondary endpoints is introduced in 
Section 2.7.2.1.
Some changes compared to the protocol specified analyses are considered in the current
statistical analysis plan before finalization in order to implement the Novartis internal process 
on SAP simplification (LEAN):


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Protocol 
section
Protocol wording
Change in the SAP
9.2
Demographics 
and 
baseline  
characteristics will be summarized 
with descriptive statistics for all 
analysis sets by treatment group and 
overall.
Demographics and baseline characteristics will 
be summarized with descriptive statistics for the 
FAS by treatment arm and overall.
9.3
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.
9.5.2
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 
patients satisfying the criteria representing 
clinically relevant abnormalities at any visit will 
be presented. A listing for patients 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.


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MON MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY
MISSING
(1) No convention
(1) No convention
(1) No convention
(1) No convention
YYYY < TRTY
(2.a) Before 
Treatment Start 
(2.b) Before 
Treatment Start 
(2.b) Before 
Treatment Start 
(2.b) Before 
Treatment Start 
YYYY = TRTY
(4.a) Uncertain
(4.b) Before 
Treatment Start
(4.c) Uncertain
(4.c) After 
Treatment Start
YYYY > TRTY
(3.a) After 
Treatment Start
(3.b) After 
Treatment Start
(3.b) After 
Treatment Start
(3.b) After 
Treatment Start
Before imputing AE start date, find the AE start reference date.
1. If the (imputed) AE end date is complete and the (imputed) AE end date < treatment
start date then AE start reference date = min (informed consent date, earliest visit date).
2. Else AE start reference date = treatment start date
Impute AE start date -
1. If the AE start date year value is missing, the date uncertainty is too high to impute a
rational date. Therefore, if the AE year value is missing, the imputed AE start date is set
to NULL.
2. If the AE start date year value is less than the treatment start date year value, the AE
started before treatment. Therefore:
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.


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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.
4. If the imputed AE end date is less than the existing AE start date then use AE start date as 
AE end date.
5.1.3
Concomitant medication date imputation
5.1.3.1
Concomitant medication start date
In order to classify a medication as prior and prior/concomitant, it may be necessary to impute 
the start date.
Completely missing start dates will be set to one day prior to treatment start date. As a 
conservative approach, such treatments will be classified as prior and concomitant (and 
summarized for each output).
Concomitant treatments with partial start dates will have the date or dates imputed.
The following table explains the notation used in the logic matrix
Day 
Month
Year
Partial CMD Start Date
Not used
MON
YYYY
Treatment Start Date
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY
MISSING
(1) Uncertain
(1) Uncertain
(1) Uncertain
(1) Uncertain
YYYY < TRTY
(2.a) Before 
Treatment Start 
(2.b) Before 
Treatment Start 
(2.b) Before 
Treatment Start 
(2.b) Before 
Treatment Start 
YYYY = TRTY
(4.a) Uncertain
(4.b) Before 
Treatment Start
(4.a) Uncertain
(4.c) After 
Treatment Start
YYYY > TRTY
(3.a) After 
Treatment Start
(3.b) After 
Treatment Start
(3.b) After 
Treatment Start
(3.b) After 
Treatment Start
1. If the CM start date year value is missing, the imputed CM start date is set to one day prior
to treatment start date.
2. If the CM start date year value is less than the treatment start date year value, the CM
started before treatment. Therefore:
a. If the CM month is missing, the imputed CM start date is set to the mid-year point
(01JulYYYY).
b. Else if the CM month is not missing, the imputed CM start date is set to the mid-month


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point (15MONYYYY).
3. If the CM start date year value is greater than the treatment start date year value, the CM
started after treatment. Therefore:
a. If the CM month is missing, the imputed CM start date is set to the year start point
(01JanYYYY).
b. Else if the CM month is not missing, the imputed CM start date is set to the month
start point (01MONYYYY).
4. If the CM start date year value is equal to the treatment start date year value:
a. And the CM month is missing or the CM month is equal to the treatment start date
month, then the imputed CM start date is set to one day prior to treatment start date.
b. Else if the CM month is less than the treatment start date month, the imputed CM start
date is set to the mid-month point (15MONYYYY).
c. Else if the CM month is greater than the treatment start date month, the imputed CM
start date is set to the month start point (01MONYYYY).
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM end 
date.
5.1.3.2
Concomitant medication (CM) end date imputation
1. If the CM end date year value is missing, the date uncertainty is too high to impute a rational 
date. Therefore, if the CM end year value is missing or ongoing, the imputed CM end date is 
set to NULL.
2. Else, if the CM end date month is missing, the imputed end date should be set to the earliest 
of the (treatment end date, 31DECYYYY, date of death).
3. If the CM end date day is missing, the imputed end date should be set to the earliest of the
(treatment end date, last day of the month, date of death).
4. If the imputed CM end date is less than the existing CM start date, use the CM start date as 
the imputed CM end date.
5.1.4
Medical history date of diagnosis imputation
Completely missing dates and partially missing end dates will not be imputed. Partial dates of 
diagnosis will be compared to the treatment start date.
1. If DIAG year < treatment start date year 
a.
and DIAG month is missing, the imputed DIAG date is set to the mid-year point 
(01JULYYYY)
b. else if DIAG month is not missing, the imputed DIAG date is set to the mid-
month point (15MONYYYY)
2. If DIAG year = treatment start date year


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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: 

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-
nemeric
Calcium
mg/dL
< 6.0
> 13.0
mmol/L
< 1.50
> 3.25
Creatinine
NA
>3xULN 
Glucose
mg/dL
< 40
> 450
mmol/L
< 2.2
> 25.0
Potassium
mEq/L
< 2.8
> 6.2
mmol/L
< 2.8
> 6.2
Sodium
mEq/L
< 120
> 160
mmol/L
< 120
> 160
HCG
Negative, 
inconclusive
Hematocrit
%
< 20
> 60
V/V
< 0.20
> 0.60
Hemaglobin
g/dL
< 6.0
> 20.0
g/L
< 60
> 200
Platelet
X10E3/uL
< 50
> 999
X10E9/L
< 50
> 999
WBC
X10E3/uL
< 2.0
> 35.0
X10E9/L
< 2.0
> 35.0
Table 5-2
Clinically notable vital signs
Variable
Category
Critical values
Systolic blood
pressure (mmHg)
High
Either >180 with an increase from baseline >30 or >200 absolute
Low
Either <90 with a decrease from baseline >30 or <75 absolute
Diastolic blood
pressure (mmHg)
High
Either >105 with an increase from baseline >20 or >115 absolute
Low
Either <50 with a decrease from baseline > 20 or <40 absolute
Pulse rate (bpm)
High
Either >120 with an increase from baseline of >25 or > 130 absolute
Low
Either <50 with a decrease from baseline >30 or <40 absolute


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5.4
Statistical models
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.
The ANOVA and MMRM models will be fitted for RTH258 6mg vs Aflibercept 2mg.
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 patient. 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 at Week 52> <average change from Baseline in BCVA from
Week 40 to Week 52> = intercept + treatment + Baseline BCVA category + age category +
visit + treatment*visit + error.
The SAS Proc MIXED will be used to perform the MMRM analyses.
Note: For the above MMRM analysis, the data structure is one record per FAS patient per
scheduled visit. The data will include all patients 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 variables (such as VQF-25 score change from baseline) will be 
analyzed using an ANCOVA model adjusted for treatment, age category, and the corresponding 
baseline VQF-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, 
using the FAS. 
The SAS Proc LOGISTIC will be used. 


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Note:

For the above analyses, the data structure is one record per patient 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.
5.4.2.3
KM estimate for time to event variables
Within the brolucizumab treatment arm, the proportion of patients 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.
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 patient from 
one or more analysis sets for the Week 52 analysis:
Table 5-3
Important protocol deviations leading to exclusion from analyses
Deviation ID
Description of Deviation
Exclusion in Analyses
M_INCL01_ICF not 
obtained
Written informed consent not obtained
Exclude from all analyses
P_INCL02_Age less than 
18 yrs
Patient less than 18 years of age at 
baseline
Exclude from PP analysis
M_INCL03_Diabetes 
eligibility criteria
Patients without diabetes mellitus or HbA1c 
of more than 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_Confounding 
condition in study eye
Study Eye: Confounding ocular 
concomitant conditions or ocular disorders
Exclude from PP analysis
M_EXCL02_Confounding 
concomitant medications or 
procedures in study eye
Study Eye: Confounding concomitant 
medications or procedures
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 


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Deviation ID
Description of Deviation
Exclusion in Analyses
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 between W40 and 
W48 inclusive, or if at least 2 
missed consecutive active doses
(not due to safety); Otherwise 
include in all analyses
M_OTH01_Masking 
process not followed
Masking process not followed as per 
protocol with impact on data integrity
Exclude from PP analysis
M_OTH02_Any other PD
Any other protocol deviation with impact on 
the efficacy assessments or safety of the 
patient
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 
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 study 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 Week 40 and Week 
52
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
Patient 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:


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
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 patient classification with regards to analysis sets:
Table 5-5
Patient classification
Analysis 
Set
PD ID that may cause patients to be excluded
Non-PD (AR) ID that cause patients 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
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_Confounding condition in study eye, 
M_EXCL02_Confounding concomitant medications or 
procedures in study eye, 
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_Masking process not followed,
M_OTH02_Any other PD,
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
Protocol deviations (PDs) and analysis restrictions (ARs) that are considered to be critical for 
the patient 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 for DAA is 
only applied in case the underlying reason for a confounded DAA is assessed as ‘0’. Censoring 
of BCVA and DAA applies both to the year-1 analysis and year-2 analysis for the FAS, and 
only to the year-1 analysis for the 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.


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In case a patient has multiple PDs/ARs with impact on patient’s evaluability the following rules 
are applied:

A patient 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.


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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
M_TRT04_Under-treatment after loading phase: censoring at the last valid DAA visit at 
or prior to the PD visit
M_COMD01_Prohibited medication or procedure: 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: patients 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


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M_COMD01_Prohibited medication or procedure: censor at 
the last observation collected prior to the start of the 
prohibited medication or procedure, imputation using the 
last observation collected prior to the start of prohibited 
medication or procedure