A 64-week, Two-arm, Randomized, Double-masked, Multicenter, Phase IIIb Study Assessing the Efficacy and Safety of Brolucizumab 6 mg Compared to Aflibercept 2 mg in a Treat-to-control Regimen in Patients With Neovascular Agerelated Macular Degeneration (TALON)
Phase: PHASE3
Conditions: Age-related Macular Degeneration
Sponsor: Novartis Pharmaceuticals



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Table of contents
Table of contents......................................................................................................2
List of tables ............................................................................................................5
List of figures...........................................................................................................5
List of abbreviations ................................................................................................6
Glossary of terms.....................................................................................................8
Amendment 3 (23-Sep-2021) ................................................................................10
Summary of previous amendments .......................................................................11
Amendment 2 (13-Aug-2021) ...............................................................................11
Amendment 1 (02-Jun-2020).................................................................................14
Protocol summary..................................................................................................16
1
Introduction .......................................................................................................................19
1.1
Background................................................................................................19
1.2
Purpose.......................................................................................................22
2
Objectives and endpoints...................................................................................................22
3
Study design ......................................................................................................................24
4
Rationale............................................................................................................................26
4.1
Rationale for study design .........................................................................26
4.2
Rationale for dose/regimen and duration of treatment ..............................27
4.3
Rationale for choice of control drug..........................................................28
4.4
Purpose and timing of interim analyses.....................................................28
4.5
Risks and benefits ......................................................................................28
5
Population..........................................................................................................................30
5.1
Inclusion criteria ........................................................................................30
5.2
Exclusion criteria .......................................................................................30
6
Treatment...........................................................................................................................33
6.1
Study treatment..........................................................................................33
6.1.1
Investigational and control drugs..........................................................33
6.1.2
Additional study treatments ..................................................................33
6.1.3
Treatment arms/group ...........................................................................33
6.1.4
Treatment duration................................................................................33
6.2
Other treatment(s)......................................................................................34
6.2.1
Concomitant therapy.............................................................................34
6.2.2
Prohibited medication ...........................................................................35
6.2.3
Rescue medication ................................................................................35
6.3
Subject numbering, treatment assignment, randomization........................36
6.3.1
Subject numbering ................................................................................36

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6.3.2
Treatment assignment, randomization ..................................................36
6.4
Treatment blinding.....................................................................................36
6.5
Dose escalation and dose modification......................................................38
6.6
Additional treatment guidance...................................................................38
6.6.1
Treatment compliance...........................................................................38
6.6.2
Emergency breaking of assigned treatment code..................................38
6.7
Preparation and dispensation .....................................................................39
6.7.1
Handling of study treatment..................................................................39
6.7.2
Instruction for prescribing and taking study treatment .........................39
7
Informed consent procedures ............................................................................................43
8
Visit schedule and assessments .........................................................................................43
8.1
Screening ...................................................................................................48
8.1.1
Information to be collected on screening failures.................................48
8.2
Subject demographics/other baseline characteristics.................................48
8.3
Efficacy......................................................................................................49
8.3.1
Visual acuity..........................................................................................49
8.3.2
Optical coherence tomography .............................................................49
8.3.3
Color fundus photography 
......................50
8.3.4
Appropriateness of efficacy assessments..............................................51
8.4
Safety .........................................................................................................51
8.4.1
Vital sign assessments...........................................................................51
8.4.2
Laboratory evaluations..........................................................................52
8.4.3
Pregnancy..............................................................................................52
8.4.4
Ophthalmic examination and imaging ..................................................53
8.4.5
Appropriateness of safety measurements..............................................54
8.5
Additional assessments..............................................................................54
8.5.1
Clinical Outcome Assessments (COAs) ...............................................54
9
Study discontinuation and completion ..............................................................................54
9.1
Discontinuation..........................................................................................54
9.1.1
Discontinuation of study treatment .......................................................55
9.1.2
Withdrawal of informed consent...........................................................56
9.1.3
Lost to follow-up...................................................................................57
9.1.4
Early study termination by the sponsor.................................................57
9.2
Study completion and post-study treatment...............................................57
10 Safety monitoring and reporting........................................................................................57
10.1
Definition of adverse events and reporting requirements..........................58
10.1.1
Adverse events ......................................................................................58

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10.1.2
Serious adverse events ..........................................................................60
10.1.3
SAE reporting........................................................................................61
10.1.4
Pregnancy reporting ..............................................................................61
10.1.5
Reporting of study treatment errors including misuse/abuse................62
10.2
Additional Safety Monitoring....................................................................62
10.2.1
Data Monitoring Committee .................................................................62
11 Data Collection and Database management......................................................................62
11.1
Data collection ...........................................................................................62
11.2
Database management and quality control ................................................63
11.3
Site monitoring ..........................................................................................64
12 Data analysis and statistical methods ................................................................................64
12.1
Analysis sets ..............................................................................................64
12.2
Subject demographics and other baseline characteristics..........................65
12.3
Treatments .................................................................................................65
12.4
Analysis of the primary endpoint(s) ..........................................................65
12.4.1
Definition of primary endpoint(s).........................................................65
12.4.2
Statistical model, hypothesis, and method of analysis..........................66
12.4.3
Handling of missing values/censoring/discontinuations.......................66
12.4.4
Sensitivity and Supportive analyses......................................................71
12.5
Analysis of secondary endpoints ...............................................................72
12.5.1
Efficacy endpoint(s)..............................................................................72
12.5.2
Safety endpoints....................................................................................73
12.5.3
Patient reported outcomes.....................................................................74
.............................................................74
12.7
Interim analyses .........................................................................................74
12.8
Sample size calculation..............................................................................75
12.8.1
Primary endpoint(s)...............................................................................75
13 Ethical considerations and administrative procedures ......................................................76
13.1
Regulatory and ethical compliance............................................................76
13.2
Responsibilities of the investigator and IRB/IEC......................................76
13.3
Publication of study protocol and results...................................................76
13.4
Quality Control and Quality Assurance.....................................................76
14 Protocol adherence ............................................................................................................77
14.1
Protocol amendments.................................................................................77
15 References .........................................................................................................................78
16 Appendices ........................................................................................................................81

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List of tables
Table 2-1
Objectives and related endpoints ..........................................................22
Table 6-1
Investigational and comparator drugs ...................................................33
Table 6-2
Prohibited medications and procedures ................................................35
Table 6-3
Disease activity assessment and treatment occurrence according to 
visit type................................................................................................41
Table 8-1
Assessment Schedule ............................................................................45
Table 8-2
Laboratory Assessments........................................................................52
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................62
Table 12-1
Primary and supportive estimands ........................................................67
Table 12-2
Expected interval distribution for aflibercept 2 mg and 
brolucizumab 6 mg................................................................................75
List of figures
Figure 3-1
Study design..........................................................................................24
Figure 6-1
Treatment regimen ................................................................................40

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List of abbreviations
AE
Adverse event
AESI
Adverse event of special interest
AMD
Age-related Macular Degeneration
ANCOVA
Analysis of covariance
ANOVA
Analysis of Variance
BCVA
Best-corrected visual acuity
CFP
Color Fundus Photography
CFR
Code of Federal Regulation
CMO & PS
Chief Medical Office & Patient Safety
CNV
Choroidal Neovascularization
COVID-19
Coronavirus Disease 2019
CRC
Central Reading Center
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSFT 
Central Subfield Thickness
DA
Disease Activity
DMC
Data Monitoring Committee
EDC
Electronic Data Capture
EOS
End-of-Study
EOT
End-of-Treatment
ETD
Early Treatment Discontinuation
ETDRS
Early Treatment Diabetic Retinopathy Study
FA
Fluorescein Angiography
FAS
Full Analysis Set
FIR
First Interpretable Results
GCP
Good Clinical Practice
IB
Investigator's Brochure
ICH
International Council on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IOI
Intraocular Inflammation
IOP
Intraocular Pressure
IRB
Institutional Review Board
IRF
Intraretinal Fluid
IRT
Interactive Response Technology
IVT
Intravitreal injection
LOCF
Last Observation Carried Forward
MedDRA
Medical dictionary for regulatory activities
nAMD
neovascular Age-related Macular Degeneration
NIH
National Institutes of Health

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PDT
Photodynamic Therapy
PPS
Per-Protocol Set
PFS
Prefilled Syringe
PRN
Pro re nata
PRO
Patient Reported Outcomes
RO
Retinal Vascular Occlusion
RPE
Retinal Pigment Epithelium
RV
Retinal Vasculitis
SAE
Serious adverse event
SAP
Statistical Analysis Plan
scFv
Single-chain antibody fragment
SD-OCT
Spectral Domain Optical Coherence Tomography
SOC
Standard Of Care
SRF
Subretinal Fluid
SUN
Standardization uveitis nomenclature
SUSAR
Suspected Unexpected Serious Adverse Reactions
T&E
Treat-and-Extend
TtC
Treat-to-Control
USM
Urgent Safety Measure
VEGF
Vascular endothelial growth factor
VFQ25
Visual Function Questionnaire 25
YAG
Yttrium aluminum garnet

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Glossary of terms
Assessment
A procedure used to generate data required by the study
Control drug
A study drug used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug.
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day)
Electronic data 
capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used 
to capture data transcribed from paper source forms used at the point of 
care.
Enrollment
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the 
protocol)
Investigational drug
The study drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and 
is synonymous with “investigational new drug” or “test substance”
Investigational 
treatment
All investigational drug(s) whose properties are being tested in the study as 
well as their associated treatment controls. This includes any placebos, any 
active controls, as well as approved drugs used outside of their 
indication/approved dosage or tested in a fixed combination. Investigational 
treatment generally does not include other treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used within approved indication/dosage.
Masked/evaluating 
investigator
For the entire study duration and all study subjects, the masked/evaluating 
investigator is responsible for all aspects of the study (the 
conduct/supervision of all assessments and treatment decisions except the 
injection procedures and the safety assessment following the study drug 
injections).
Medication number 
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an Integration Response Technology (IRT) 
system.
Medication pack 
number
A unique identifier on the label of each drug package in studies that 
dispense study treatment using an IRT system
Patient
An individual with the condition of interest
Period
A subdivision of the study timeline; divides phases into smaller functional 
segments such as screening, baseline, etc.
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment
Screen Failure
A subject who is screened but is not treated or randomized
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 completion
Point/time at which the subject came in for a final evaluation visit or when 
study drug was discontinued whichever is later.
Study drug 
discontinuation
Point/time when subject permanently stops taking study drug for any reason; 
may or may not also be the point/time of premature subject withdrawal.
Study treatment
Any drug administered to the study participants as part of the required study 
procedures; includes investigational drug (s), control(s) or non-
investigational medicinal product(s)
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject and 
should be used to identify the subject throughout the study for all data 
collected, sample labels, etc.
Unmasked/treating 
investigator
For the entire study duration and all study subjects, the treating investigator 
only performs the treatment (injection active/sham) and assesses subject 
safety following the active/sham injections.
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study
Withdrawal of 
consent (WoC)
Withdrawal of consent from the study is defined as when a subject does not 
want to participate in the study any longer, and does not want any further 
visits or assessments, and does not want any further study related contact, 
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Amendment 3 (23-Sep-2021)
Amendment rationale
The purpose of this amendment is to include information on the gender imbalance in the 
reported rates of intraocular inflammation-related adverse events following brolucizumab 
treatment.  
Changes to the protocol

Section 4.5 Risk and benefits: Information added regarding the gender imbalance in the 
reported rates of intraocular inflammation-related adverse events following brolucizumab 
treatment.
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 2 (13-Aug-2021)
Amendment rationale
The main reasons for the protocol amendment are:
(1) To provide clarification and guidance on the early discontinuation of study treatment that is 
required for those subjects who are currently on q4w dosing beyond the first 3 monthly loading 
doses (“loading phase”) or would need q4w dosing beyond the “loading phase” based on the 
investigator’s assessment. This is as per the urgent safety measure dated 27-May-2021 based 
on CTH258AUS04 (MERLIN) Year 1 first interpretable results (FIR) indicating a higher 
frequency of IOI including Retinal Vasculitis (RV), and Retinal Vascular Occlusion (RO) in 
brolucizumab 6 mg q4w when compared to aflibercept 2 mg q4w (IOI: 9.3% vs 4.5% of which 
RV: 0.8% vs 0.0%; RO: 2.0% vs 0.0%, respectively).
(2) Additionally, as per the Urgent Safety Measure dated 10-August-2021, the results of the 
mechanistic study BASICHR0049 identified a causal link with an immune-mediated 
mechanism of the previously identified risk of Retinal vasculitis (RV), and/or Retinal vascular 
occlusion (RO), typically in the presence of IOI. The protocol is hence amended to require 
discontinuation of study treatment in subjects who develop these events. 
(3) Finally, the safety sections were updated throughout the protocol including updating the 
Risks and Benefits section and creating a new section under Safety Monitoring to consolidate 
all the information regarding the risk mitigation into one section in the protocol. Additionally, 
as subjects treated with brolucizumab who experience intraocular inflammation may be at risk 
of developing retinal vasculitis and/or retinal vascular occlusion they should be closely 
monitored and the investigator needs to evaluate the appropriateness of continuing further with 
study treatment when IOI only (without RV and/or RO) is present.
To maintain masking, the new requirements apply to both treatment arms. 
Changes to the protocol
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.
Editorial changes and spelling corrections are done throughout the protocol.
Protocol sections changed in relation to urgent safety measures (USM) are:

Section 1.1 Background: Language was added to indicate that the interval between two 
brolucizumab doses should not be shorter than 8 weeks beyond loading, and that the 
impact on the risk/benefit balance is considered to be low when patients are dosed ≥q8w 
after the loading phase. Clarified that treatment intervals after the initiation phase will 
range from 8 weeks to 16 weeks. In addition, the results of the mechanistic study 
BASICHR0049 of blood samples from nAMD patients exposed to brolucizumab and 
having subsequently developed RV and/or RO were added.

Table 2-1 Objectives and related endpoints: Footnote was added to clarify analysis of 4-
week treatment intervals.

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
Section 3 Study design: Reduced visit window for Week 14 to ±7 days. Clarified that if 
disease activity is observed at Week 14/Week 16, then the study treatment will be 
administered at this visit and the further injections will be discontinued. Clarified the 
difference between study completion as per protocol versus early treatment 
discontinuation. Clarified that only during the loading phase injections should be at least 
21 days apart.

Figure 3-1 Study design: Updated the range for treatment intervals.

Section 3 Study design; Section 4.1 Rationale for study design; Section 6.7.2 Instruction 
for prescribing and taking study treatment: Modified to clarify the shortest treatment 
interval in the TtC phase.

Section 4.2 Rationale for dose/regimen and duration of treatment: Language added to 
provide background of the USM and impact on design.

Section 4.5 Risks and Benefits: Added the three urgent safety measures related to adverse 
events observed in patients treated with brolucizumab from the MERLIN 
(CRTH258AUS04) study, the post marketing reports and the causal link (results of the 
mechanistic study BASICHR0049).

Section 6.1.4 Treatment duration: Guidance added for subjects requiring injections every 4 
weeks. Added a paragraph to clarify that subjects who prematurely discontinue from study 
treatment should continue in the study and should return 4 weeks after last treatment to 
perform assessments for early treatment discontinuation.

Section 6.7.2 Instruction for prescribing and taking study treatment: Text added to show 
the treatment intervals allowed in the maintenance phase, following Week 16. In addition, 
changes made to clarify that subjects who require treatment every 4 weeks beyond the 
loading phase, should be discontinued from study treatment. A paragraph describing 
inspection visits for an interval extension from 4 weeks to 8 weeks was removed because 
this option will no longer apply in the study. Changes also made to update that if RV 
and/or RO is confirmed, subjects should be discontinued from study treatment. If only IOI 
(without RV and/or RO) is confirmed, the subject should be closely monitored and the 
investigator should evaluate the appropriateness of continuing further with study 
treatment. This has also been updated Table 6-3.

Figure 6-1 Treatment regimen: Updated the range for treatment intervals.

Table 6-3 Disease activity assessment and treatment occurrence according to visit type: 
Added newly implemented visit type “ETD”.

Section 8: Visit schedule and assessments: Clarification added for visit windows for 
inspection visit at week 14. Removed a sentence that two consecutive injections should be 
at least 21 days apart as this is no longer applicable since in the maintenance phase, any 
subject who requires treatment every 4 weeks has to be discontinued from study treatment.

Table 8-1 Assessment schedule: Columns added for early treatment discontinuation visits 
and for assessment visits after start of standard of care, including respective footnotes. In 
addition, footnotes #3 was updated to reflect the requirement to discontinue subjects from 
further treatment in case of disease activity at the inspection visit at Week 14; and a 
clarification was added in footnote #11 with respect to ophthalmic examinations and 
images. Updated the name of the ophthalmic examination where “and imaging” was 
added. Footnotes #12, #13, and #14 added with respect to ETD and EOS assessments.

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
Section 12.8.1 Primary endpoints: Clarification regarding sample size analyses.
Amendment 1 (02-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 new safety signal from 
post-marketing case reports and its impact on the benefit-risk balance.

Section 6.2.2 Prohibited Medication: Restrictions in use of corticosteroids have been removed 
to provide flexibility using systemic steroids for the treatment of AEs at the investigator’s 
discretion.

Section 6.7.2 Instructions for prescribing and taking study treatment: Additional guidance was 
added to this section emphasizing that if any sign of intraocular inflammation 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 added in the following sections:

Table 8-1 Assessment schedule

Section 8.3.3 Color fundus photography 

Section 8.4.4 Ophthalmic Examination

Section 8.4.5 Appropriateness of safety measurements
Changes were incorporated to address the COVID-19 pandemic in the following sections:

Section 5.2 Exclusion Criteria

Section 6.2.2 Prohibited Medication

Section 7 Informed Consent Procedures

Section 8 Visit Schedule and Assessments

Section 8.4 Safety

Section 8.4.2 Laboratory evaluation

Section 12 Data Analysis
Other changes incorporated in this amendment:

Throughout the protocol: the ± 7-day window has been replaced by a ± 14-day window to allow 
for broader visit window to accommodate longer treatment intervals.

Section 3 Study Design: changed to allow the assessments of the baseline visit to be performed 
on two consecutive days

Figure 6-1 Removed the inspection visit during the second consecutive 16-week interval

Section 6.1.1 Study Treatment: Introduced wording to include prefilled syringes in selected 
countries

Section 6.4 Treatment masking: Language was added to clarify unmasked investigator/site 
personnel must not be switched to a masked role at any time after randomization.

Section 6.7.2 Instruction for Prescribing and Taking Study Treatment: Language regarding the 
injection procedure was added replacing reference to an applicable manual. 

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
Section 8.4.3 Pregnancy: Additional serum pregnancy testing was included to confirm positive 
urine testing outcome.

Section 8.4.4 Ophthalmic examination: Added instructions for the patients in case of symptoms 
of inflammation.

Section 10.1.3 SAE Reporting: Clarification of the SAE reporting period

Section 10.2.1 Data Monitoring Committee: Language was added to introduce program level 
Data Monitoring Committee.

Section 12.1 Analysis Sets: Modified to include importance of Estimands per ICH E9(R1) 
guidance.

Section 15 References: Added two references

List of Abbreviations
Minor editorial changes (e.g. typographical mistakes, grammatical changes, rewording) to improve flow 
and consistency have been made throughout the protocol.
Changes to specific sections of the protocol are shown in the track changes version of the protocol using 
strike through red font for deletions and red underlined for insertions.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent Ethics 
Committee (IECs) and Health Authorities.
The changes herein affect the Informed Consent. Sites are required to update and submit for approval 
a revised Informed Consent that takes into account the changes described in this protocol amendment.

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Protocol summary
Protocol 
number
CRTH258A2303
Full Title
A 64-week, two-arm, randomized, double-masked, multi-center, phase IIIb study 
assessing the efficacy and safety of brolucizumab 6 mg compared to aflibercept 
2 mg in a treat-to-control regimen in patients with neovascular age-related 
macular degeneration (TALON)
Brief title
Study assessing the efficacy and safety of brolucizumab vs aflibercept in a treat-
to-control regimen in patients with neovascular age-related macular 
degeneration
Sponsor and 
Clinical Phase
Novartis
Phase IIIb
Investigation 
type
Drug
Study type
Interventional
Purpose and 
rationale
To evaluate the efficacy and safety of brolucizumab used in a Treat-to-Control 
(TtC) regimen for the treatment of patients with neovascular age-related macular 
degeneration (nAMD) with the objective to evaluate the potential to reduce 
treatment frequencies
Primary 
Objective(s) 
To demonstrate that brolucizumab is superior to aflibercept with respect to the 
duration of treatment intervals at Week 32
To demonstrate that brolucizumab is non-inferior to aflibercept with respect to 
average change in best corrected visual acuity (BCVA) from baseline at Weeks 
28 and 32
Secondary 
Objectives
1.
To evaluate the durability of brolucizumab relative to aflibercept
2.
To evaluate the functional outcomes with brolucizumab relative to aflibercept
3.
To evaluate the anatomical outcomes with brolucizumab relative to 
aflibercept
4.
To evaluate the effect of brolucizumab relative to aflibercept on Patient-
Reported Outcomes (PRO)
5.
To assess the safety and tolerability of brolucizumab relative to aflibercept
Study design
The study is a 64-week, randomized, double-masked, multi-center, active-
controlled, two-arm study in patients with nAMD.
Patients will be randomized in a 1:1 ratio to one of the two treatment arms:

Brolucizumab 6 mg: 3 x 4-week injections and one 8-week injection, 
followed by Treat-to-Control treatment from Week 16 up to Week 60/62.

Aflibercept 2 mg: 3 x 4-week injections and one 8-week injection, followed 
by Treat-to-Control treatment from Week 16 up to Week 60/62.
In both treatment arms, treatment intervals after the initiation phase will be either 
8 weeks, 12 weeks, or 16 weeks. More frequent injections, i.e., treatment intervals 
of <8 weeks are not allowed.
Population
Approximately 962 adult patients will be screened (28% screening failure rate 
expected) and approximately 692 (346 per arm) patients will be randomized in a 
1:1 ratio in approximately 200 centers worldwide. The maximum study duration 
for one subject is 66 weeks, including screening and post-treatment follow-up.

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Key Inclusion 
criteria

Signed informed consent must be obtained prior to participation in the study

Male or female patients ≥ 50 years of age at screening who are treatment 
naive

Active choroidal neovascularization (CNV) secondary to age-related macular 
degeneration (AMD) that affects the central subfield, including retinal 
angiomatous proliferation (RAP) with a CNV component, confirmed by 
presence of active leakage from CNV seen by fluorescein angiography (FA) 
(or other imaging modalities) and sequelae of CNV, e.g. pigment epithelial 
detachment (PED), subretinal or sub-retinal pigment epithelium (sub-RPE) 
hemorrhage, blocked fluorescence, macular edema (study eye)

Presence of intraretinal fluid (IRF) or subretinal fluid (SRF) that affects the 
central subfield, as seen by Spectral Domain Optical Coherence 
Tomography (SD-OCT) (study eye)

Best-corrected visual acuity (BCVA) score between 83 and 38 letters, 
inclusive, at an initial testing distance of 4 meters, using Early Treatment 
Diabetic Retinopathy Study (ETDRS) visual acuity charts (approximately 
Snellen equivalent of 20/25 to 20/200) at both screening and baseline visit 
(study eye)
Key Exclusion 
criteria

Concomitant ocular conditions/disorders 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 planned medical or surgical intervention during the first 12-month 
study period, structural damage of the fovea, atrophy or fibrosis at the center 
of the fovea (study eye)

Any active intraocular or periocular infection or active intraocular 
inflammation, at screening or baseline (study eye)

Uncontrolled glaucoma defined as intraocular pressure (IOP) > 25 mmHg on 
medication, or according to investigator’s judgment, at screening or baseline 
(study eye)

Presence of amblyopia, amaurosis or ocular disorders in the fellow eye with 
BCVA < 20/200 at screening (except when due to conditions which can lead 
to improved visual acuity (VA) after surgery, e.g. cataract) 

Ocular treatments: previous treatment with any anti-vascular endothelial 
growth factor (VEGF) drugs or investigational drugs, intraocular or periocular 
steroids, macular laser photocoagulation, photodynamic therapy (PDT), 
vitreoretinal surgery, intraocular surgery (study eye)

Stroke or myocardial infarction during the 6-month period prior to baseline

Systemic anti-VEGF therapy at any time.
Study 
treatment
Brolucizumab 6 mg/0.05 mL
Aflibercept 2 mg/0.05 mL
Efficacy 
assessments
BCVA using ETDRS-like charts
SD-OCT
Color Fundus Photography (CFP)
Fluorescein Angiography (FA)
National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) vision-
related quality of life instrument

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Key safety 
assessments
Monitoring of Adverse Events (AE)
Ophthalmic examinations and imaging
Vital signs
Laboratory assessments (hematology, clinical chemistry, urinalysis)
Pregnancy testing
Data analysis
In order to test the superiority of brolucizumab compared to aflibercept in terms 
of the distribution of the last treatment interval with no disease activity (q4w, 
q8w, and q12w) up to Week 32, a one-sided Wilcoxon test for 2 ordered 
multinomial distribution with type I error of α = 0.025 will be considered.
To test the non-inferiority of brolucizumab compared to aflibercept in terms of 
average BVCA change from baseline at Week 28 and Week 32, a two-sided 95% 
confidence interval for the treatment difference will be derived from an analysis of 
variance (ANOVA) model with treatment arm, baseline BCVA categories and age 
categories as fixed effects. In order to demonstrate non-inferiority with respect to 
average BCVA change from baseline at Week 28 and Week 32, the lower limit of 
the two-sided 95% confidence interval for the treatment difference (brolucizumab 
– aflibercept) must be greater than -4 letters, representing the non-inferiority 
margin. Furthermore, the respective one-sided P-value for BCVA non-inferiority 
assessed at significance level of 0.025 will be provided.
Summary statistics will be presented by treatment arm unless otherwise specified. 
For continuous variables, summary statistics will generally include: n, mean, 
standard deviation, median, minimum and maximum. For categorical variables, 
these will generally include: n and percentage in each category.
The interim database lock for the primary analyses will be conducted when all 
ongoing subjects have completed their Week 32 visit. Subjects will remain in the 
study and will continue to receive masked treatment through the planned study 
duration of 64 weeks, to allow for further evaluation of efficacy and safety.
Additional analyses are planned to evaluate the impact of the coronavirus disease 
2019 (COVID-19) pandemic and the q4w urgent safety measures on the primary 
and selected secondary endpoints.
Key words
Neovascular age-related macular degeneration, anti-VEGF, choroidal 
neovascularization, individualized treatment

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1
Introduction
1.1
Background
Age-related macular degeneration (AMD) is a leading cause of severe vision loss in people, 
affecting 11.6% to 18.5% of individuals between 60 and 69 years old and 31.6% to 45.3% of 
individuals between 80 and 84 years old in North America, Europe, and Oceania 
(Wong et al 2014). Genetic, environmental and health factors play an important role in the 
pathogenesis of the disease.
AMD is classified into 2 clinical subtypes: the non-neovascular (atrophic) or dry form, and the 
neovascular (exudative) or wet form (Ferris et al 1984, Lim et al 2012, Miller 2013). 
Neovascular AMD (nAMD) is characterized by the growth of abnormal new blood vessels 
(neovascularization) under the retinal pigment epithelium (RPE) or sub-retinal space from the 
subjacent choroid, termed choroidal neovascularization (CNV) (Ferris et al 1984). These newly 
formed vessels have an increased likelihood to leak blood and serum, damaging the retina by 
stimulating inflammation and scar tissue formation. This damage to the retina results in 
progressive, 
severe, 
and 
irreversible 
vision 
loss 
(Shah and Del Priore 2007, 
Shah and Del Priore 2009). Without treatment, most affected eyes will have poor central vision 
(20/200) within 12 months (Blinder et al 2003). Although the neovascular form of the disease 
is only present in about 10 % of all AMD cases, it accounted for approximately 90 % of the 
severe vision loss from AMD prior to the introduction of antivascular endothelial growth factor 
(anti-VEGF) treatments (Ferris 1983).
Anti-VEGF in nAMD
Vascular endothelial growth factor (VEGF) has been shown to be elevated in patients with 
nAMD and is thought to play a key role in the neovascularization process (Spilsbury et al 2000). 
The use of intravitreal injection (IVT) pharmacotherapy targeting VEGF has significantly 
improved visual outcomes in patients with nAMD (Bloch et al 2012, Campbell et al 2012). 
Anti-VEGF treatments, such as ranibizumab (Lucentis®) and aflibercept (Eylea®), inhibit 
VEGF signaling pathways and have been shown to halt the growth of neovascular lesions and 
resolve retinal edema. Intravitreal administration of anti-VEGF treatments is the current 
standard of care in nAMD. They have considerably reduced the incidence of blindness and 
severe vision loss and revolutionized outcomes for patients with nAMD (Freund et al 2013, 
Holz et al 2014).
Currently marketed anti-VEGF treatments typically start with a loading phase of 3 monthly 
doses, followed by maintenance dosing, either with fixed (e.g. every 4 or 8 weeks) or 
individualized treatment intervals, based on pro re nata (PRN) or Treat-and-Extend (T&E) 
concepts (Wykoff et al 2018). Although the PRN treatment regimen is able to reduce the 
frequency and overall cost of treatment in nAMD, it remains relatively inconvenient for patients 
because frequent follow-up is still required to ensure comparable visual outcomes to monthly 
dosing (Busbee et al 2013, Holz et al 2015, Li et al 2016, Holz et al 2017, Koh et al 2017).
Treat-and-Extend treatment regimen
Typically, Treat-and-Extend (T&E) treatment regimen includes a loading phase of monthly 
injections, followed by a maintenance phase during which injection interval is progressively 
prolonged if there is no disease activity, primarily determined by optical coherence tomography 

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(OCT) and visual acuity assessment, or shortened if disease recurs. The T&E treatment regimen 
aims at identifying optimal individual injection intervals to minimize the number of injections 
and reduce visit burden while maintaining the vision gains obtained at the end of the loading 
phase during the maintenance phase.
The TREX-AMD, TREND and CANTREAT studies compared a T&E regimen with a 2-week 
interval adjustment after 2 or 3 monthly injections of ranibizumab to monthly ranibizumab 
injections in patients with nAMD. Patients in the T&E regimen arms received on average 2 to 
3 fewer injections than those treated monthly after 1 year, for similar mean BCVA gains and 
comparable safety profile between arms (Wykoff et al 2015, Silva et al 2018, Kertes et al 2019). 
In the first year of the ARIES study (Mitchell et al 2018), nAMD patients received 3 monthly 
injections of aflibercept and another injection 8 weeks thereafter, followed by either a T&E 
regimen with a 2-week adjustment or injections every 8 weeks (q8w). Vision changes from 
Week 16 to Week 52 were comparable for both regimens, with a mean of 0.8 fewer injection 
with the T&E regimen. In the head-to-head RIVAL study, aflibercept and ranibizumab 
administered in an identical T&E regimen based on a 2-week interval adjustment after 3 
monthly injections produced similar visual improvements at 1 year after a mean of 9.7 injections 
in both arms (Gillies et al 2019). Less than 25% of the patients reached the maximal interval of 
12 weeks at 12 months. The Japanese ALTAIR study (Ohji et al 2018) compared two T&E 
regimens of aflibercept using either 2-week or 4-week adjustments, with the treatment intervals 
from 8 weeks to 16 weeks, after 3 monthly injections and another injection 8 weeks thereafter. 
BCVA improved from baseline by 9.0 and 8.4 letters at Week 52, and 7.6 and 6.1 letters at 
Week 96, for the 2-week and 4-week adjustment arms, respectively. About 25 % of patients 
were maintained on a 8-week interval until Week 96, whereas the last interval at Week 96 was 
16 weeks for 41.5% to 46.3% of the patients. The overall safety profile of IVT aflibercept was 
consistent with previous studies.
T&E treatment regimen has been approved in the labels of ranibizumab 0.5 mg (Lucentis®) and 
aflibercept 2 mg (Eylea®) in Europe and many other countries. For instance, Eylea® SmPC 
indicates that after 3 monthly doses and the next dose two months thereafter, the treatment 
interval may be maintained at 2 months or further extended using a T&E dosing regimen by 2-
or 4-weekly increments.
The T&E treatment paradigm has come in a variety of regimens. Whereas most T&E regimens 
entail extending or shortening the injection interval based on absence or presence of disease 
activity, the Treat-to-Control (TtC) regimen emphasizes sustained disease control to determine 
the optimal treatment interval for each patient rather than solely adjusting treatment 
intervals. For instance, it allows patients that may not benefit from treatment interval extension 
to be temporarily or lastingly maintained on a treatment interval. 
While T&E regimens have been associated with a reduction in treatment and visit burdens in 
nAMD, the number of visits remain relatively high for most patients as the average number of 
injections in the studies range from 8 to 10.1 in the first 12 months and from 14.1 to 18.6 in the 
first 2 years (Wykoff et al 2015, DeCroos et al 2017, Wykoff et al 2017, Guymer et al 2018, 
Silva et al 2018, Ohji et al 2018, Gillies et al 2019, Kertes et al 2019). There still is a need for 
highly effective treatments that prolong intervals between injections and further reduce 
treatment burden, while maintaining vision gains.

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Brolucizumab
Brolucizumab (RTH258, formerly known as ESBA1008), is a humanized single-chain antibody 
fragment (scFv) inhibitor of VEGF-A with a molecular weight of ~26 kDa. Brolucizumab 
works by binding to the receptor binding site of the VEGF-A molecule, thereby preventing the 
interaction of VEGF-A with its receptors VEGFR1 and VEGFR2 on the surface of endothelial 
cells (Escher et al 2015). Brolucizumab is designed for ophthalmic use and is administered by 
IVT injection. In this setting, the smaller molecular size of the scFv is expected to have 
advantages over immunoglobulin G antibodies and larger antibody fragments due to the 
delivery of a higher molar dose (i.e. VEGF binding equivalents per mg protein), which may 
prolong the therapeutic effect and enable better tissue penetration at the retina.
In two large Phase III pivotal studies (RTH258-C001 [HAWK] and RTH258-C002 
[HARRIER]), nAMD patients received brolucizumab every 12 weeks (q12w), with the option 
of adjusting to a q8w dosing interval based on disease activity, or aflibercept q8w, after three 
monthly loading doses. Brolucizumab was non-inferior to aflibercept with regards to change 
from Baseline in BCVA at Week 48, with over half of the subjects in the brolucizumab 6 mg 
arm maintained exclusively on the q12w dosing interval (56% in HAWK and 51% in 
HARRIER). The visual acuity gains observed in the first year were maintained in the second 
year. Significantly fewer patients in the brolucizumab 6 mg arm had disease activity at Week 
16 in a head-to-head comparison based on a matching dosing intervals, with a relative decrease 
of 30% (P = 0.0022) versus aflibercept. Significantly fewer patients on brolucizumab had 
intraretinal fluid (IRF) and/or subretinal fluid (SRF), with a 35% and 33% reduction relative to 
aflibercept at Week 16 (P < 0.001 for both) in HAWK and HARRIER, respectively, and a 31% 
and 41% reduction relative to aflibercept at Week 48 in HAWK and HARRIER, respectively 
(P < 0.0001 for both). Brolucizumab 6 mg achieved superior reductions in central subfield 
thickness (CSFT) versus aflibercept in both the matched dosing and maintenance phases 
(P = 0.0016 and P = 0.0023 at Week 16 and Week 48, respectively, in HAWK; P < 0.0001 at 
both Week 16 and Week 48 in HARRIER). These advantages for brolucizumab were 
maintained in the second year. Safety was comparable between the treatment arms over 2 years.
Since the initial marketing authorization approval in Oct-2019 for the treatment of nAMD, 
adverse events of retinal vasculitis and/or retinal vascular occlusion, that may result in severe 
vision loss and typically in the presence of intraocular inflammation, have been reported from 
post-marketing experience with brolucizumab (Beovu®). Results of the mechanistic study 
BASICHR0049 of blood samples from nAMD patients exposed to brolucizumab and having 
subsequently developed Retinal Vasculitis (RV) and/or Retinal Vascular Occlusion (RO), taken 
together with accumulated data of the association of treatment-emergent immunogenicity and 
intraocular inflammation (IOI) indicate a causal link between the treatment-emergent immune 
reaction against brolucizumab and the brolucizumab-related “retinal vasculitis and/or retinal 
vascular occlusion, typically in the presence of IOI”. This finding supports the requirement to 
discontinue treatment with brolucizumab in patients who develop events of RV and/or RO.
In addition, based on the USM (CRTH258AUS04 first interpretable results [FIR]), the interval 
between two brolucizumab doses should not be shorter than 8 weeks beyond the loading phase.
These impacts on the risk/benefit balance of the product are considered to be low and the overall 
risk/benefit assessment remains positive, when patients are dosed at q8w or longer after the 

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loading phase and when patients who develop RV and/or RO are discontinued from further 
treatment with brolucizumab.
Summary
The T&E regimen is an effective approach associated with a reduction in anti-VEGF treatment 
and visit burdens for patients with nAMD. There remains a need for medicines with longer 
therapeutic durability that could support more efficient T&E strategy by enabling faster interval 
extensions, e.g. by 4 weeks, and longer treatment interval, e.g. 16 weeks. The efficacy profile 
of brolucizumab in nAMD patients points to a potential for brolucizumab to be associated with 
longer treatment intervals, and thus fewer visits, than aflibercept in a Treat-to-Control regimen, 
with comparable visual outcomes, based on the following highlights from HAWK and 
HARRIER:

the superior anatomical outcomes vs aflibercept in the matching dose comparison,

the more pronounced reduction in CSFT over time,

the visual outcomes similar to aflibercept over time, with more than 50% of the patients 
on q12w at year 1.
The TALON study intends to complement the current clinical dataset on brolucizumab by 
generating new evidence based on the T&E concept prevalent in the current management of 
patients with nAMD. It will be comparing the efficacy and safety of brolucizumab and 
aflibercept administered in an identical 4-week-adjustment Treat-to-Control regimen with 
treatment intervals from 8 to 16 weeks after the initial three consecutive monthly injections and 
one treatment interval extension by 4 weeks from Week 8 to Week 16 (“initiation phase”). 
Subjects requiring injections every 4 weeks after the initiation phase will be discontinued from 
further study treatment.
1.2
Purpose
The purpose of this study is to demonstrate the superiority of brolucizumab compared with 
aflibercept in terms of durability and the non-inferiority of brolucizumab compared to 
aflibercept in terms of visual outcomes in an identical Treat-to-Control (TtC) regimen in 
patients with neovascular age-related macular degeneration (nAMD).
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To demonstrate that brolucizumab is 
superior to aflibercept with respect to the 
duration of treatment intervals at Week 
32

Distribution of the last interval with no disease 
activity up to Week 32 (if there was disease 
activity, the last interval will be shortened by 4 
weeks, down to a minimum of 4 weeks*) 

To demonstrate that brolucizumab is 
non-inferior to aflibercept with respect to 
average change in BCVA from baseline 
at Weeks 28 and 32

Average change in BCVA from baseline at 
Weeks 28 and 32

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Objective(s)
Endpoint(s)
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To evaluate the durability of 
brolucizumab relative to aflibercept

Distribution of the last interval with no disease 
activity up to Week 64 (if there was disease 
activity, the last interval will be shortened by 4 
weeks down to a minimum of 4 weeks*)

Distribution of the maximal intervals with no 
disease activity up to Week 64

Proportion of patients with no disease activity at 
Weeks 14 and 16

Time from the last loading injection to the first 
visit with no disease activity

To evaluate the functional outcomes with 
brolucizumab relative to aflibercept

Average change in BCVA from baseline at 
Weeks 60 and 64

Occurrence of BCVA improvements of ≥ 10 and 
≥ 15 letters from baseline at Week 32, Week 64, 
and at the last injection visit

Occurrence of BCVA ≥ 69 letters at Week 32, 
at Week 64, and at the last injection visit

To evaluate the anatomical outcomes 
with brolucizumab relative to aflibercept

Average change from baseline in CSFT as 
assessed by SD-OCT at Weeks 28 and 32

Average change from baseline in CSFT as 
assessed by SD-OCT at Weeks 60 and 64

Number of visits with presence of IRF and/or 
SRF, and sub-RPE fluid in the central subfield, 
as assessed by SD-OCT at Weeks 28 and 32

Number of visits with presence of IRF and/or 
SRF, and sub-RPE fluid in the central subfield 
as assessed by SD-OCT at Weeks 60 and 64

To evaluate the effect of brolucizumab 
relative to aflibercept on Patient-
Reported Outcomes (PRO)

Change in Visual Function Questionnnaire-25 
(VFQ-25) total and subscale scores from 
baseline at Weeks 32 and 64

To assess the safety and tolerability of 
brolucizumab relative to aflibercept

Incidence of Ocular and Non-ocular AEs up to 
Week 64
* Subjects who will be assigned to a 4-week interval will be analyzed in the q4w category, but 
discontinued from further study treatment.

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3
Study design
The study is a 64-week randomized, double-masked, multi-center, active-controlled, two-arm 
study in patients with nAMD who have not previously received anti-VEGF treatment.
Patients who consent will undergo screening assessments to evaluate their eligibility based on 
the inclusion and exclusion criteria. Patients who meet all the inclusion and none of the 
exclusion criteria will be randomized in a 1:1 ratio to one of two treatment arms:

Brolucizumab 6 mg: 3 x 4-week injections and one 8-week injection, followed by Treat-
to-Control treatment from Week 16 up to Week 60/62.

Aflibercept 2 mg: 3 x 4-week injections and one 8-week injection, followed by Treat-to-
Control treatment from Week 16 up to Week 60/62.
Approximately 962 adult patients will be screened (28% screening failure rate expected) and 
approximately 692 (346 per arm, 10% drop-out rate expected) patients will be randomized in a 
1:1 ratio in approximately 200 centers worldwide. The maximum study duration for one subject 
is 66 weeks, including screening and post-treatment follow-up.
There will be 3 periods in this study (see Figure 3-1 and Figure 6-1):

Screening period: from Day -14 to Baseline

Double-masked treatment period: from Baseline (Day 1) to Week 60/62

Post-treatment follow-up period: from Week 60/62 to Week 64.
Figure 3-1
Study design
# Week 14 if inspection visit
Depending on visit schedules:
* 62 weeks
** Week 62
Screening period: Day-14 to Day-1

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A screening period of up to 2 weeks will be used to assess eligibility.
One time reassessment 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 nAMD is not withheld in order for a patient to participate in the study.
Patients must have confirmed nAMD at screening.
Double-masked treatment period: Day 1 to Week 60/62
After confirmation of eligibility, patients will be randomized in a 1:1 ratio to one of the two 
treatment arms. A study visit schedule will be established at the time of randomization for all 
patients (Figure 6-1). All efforts should be made to adhere to this study visit schedule within a 
±14day window (±7 days at visit Week 14). For a given protocol visit assessments can be 
performed on two consecutive days, provided both days are within the visit window. Treatment 
is intended to be administered on the day of study visit, or if this is not possible, within 3 days 
after the study visit when the per-protocol assessments will have taken place (except 
Baseline/Day1, in which case study treatment administration should occur within the next 24 
hours). 
The baseline visit is defined as Baseline/Day 1. For all patients, the last potential study 
treatment will be at the Week 60 visit or at the Week 62 visit if the patients will have received 
the study treatment at an odd number of inspection visits (see below). The initiation phase starts 
on Day 1 and ends on Week 16. TtC regimen starts on Week 16 until end of treatment (Week 
60/62).
Patients will receive three consecutive injections every 4 weeks at Baseline, Weeks 4 and 8 
(loading phase), which should be at least 21 days apart. The injection interval will then be 
extended by 4 weeks to a 8-week interval to Week 16. From Week 16, based on investigator’s 
judgment of visual and/or anatomic outcomes, the injection interval can be further extended by 
4 weeks at a time, if there is no disease activity, as provided in the guidance to the investigators, 
e.g. no change in visual acuity and in other signs of the disease (e.g. IRF, SRF, hemorrhage, 
leakage, etc.). If disease activity recurs, the injection interval should be shortened accordingly 
by 4 weeks at a time or to a minimal interval of 8 weeks. The injection interval can also be 
maintained if the investigator deems that the patient will not benefit from injection interval 
extension. Patients who require study treatment every 4 weeks after the initiation phase (Week 
14/Week 16) will be discontinued from further study treatment at the next visit.
At the investigator’s discretion, an inspection visit 6 weeks after the last injection can be 
performed when the injection interval is extended from 4 weeks to 8 weeks, i.e., after the 3rd 
injection at Week 8. If there is no disease activity in the study eye at the inspection visit, as 
assessed by the masked investigator, no treatment is administered at this inspection visit; the 
next visit and injection will take place 2 weeks later, i.e. 8 weeks after the previous study 
treatment. If disease activity is observed by the masked investigator in the study eye at the 
inspection visit at Week 14, the study treatment will be administered by the unmasked 
investigator, and the subject will be discontinued from further study treatment at the next visit. 
Inspection visits 10 weeks and 14 weeks after the last injection can be performed when the 

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injection interval is extended from 8 weeks to 12 weeks, and from 12 weeks to 16 weeks, 
respectively (see Section 6.7.2).
Post-treatment follow-up period: Week 60/62 to Week 64
For all patients completing the study as per protocol, the End-of-Study (EOS) assessment will 
be performed at Week 64 (± 21 days), four weeks (± 14 days) following their last possible study 
treatment administration (Week 60/62).
Subjects withdrawn from the study prior to study completion will be asked to return for an early 
discontinuation (EOS) visit, four weeks (± 14 days) following their last study treatment 
administration (End-of-Treatment, EOT). For early treatment discontinuations (ETD) refer to 
Section 9.1.1.
4
Rationale
4.1
Rationale for study design
This study is designed as a randomized, double-masked, multi-center, active-controlled, two-
arm study to demonstrate the safety and efficacy of brolucizumab 6 mg compared to the active 
comparator, aflibercept, used in an identical Treat-to-Control regimen, a modified Treat-and-
Extend regimen (see Section 1.1).
The anti-VEGFs, e.g. aflibercept and ranibizumab, are the mainstay of treatment for nAMD 
(Schmidt-Erfurth et al 2007; Schmidt-Erfurth et al 2014). Hence, aflibercept will be used as an 
active comparator in the present study.
Co-primary efficacy endpoints based on treatment interval and BCVA were chosen to evaluate 
the benefits of treatment in terms of treatment durability and functional outcome, respectively:

Treatment intervals may be extended, reduced, or maintained, based on the evaluation of 
disease activity by masked investigators. Superiority testing related to the distribution of 
the last interval with no disease activity up to Week 32 will be carried out. If there is 
disease activity during the last interval up to Week 32, the last interval will be shortened 
by 4 weeks down to a minimum of  8 weeks.

The co-primary efficacy endpoint based on BCVA (ETDRS letters, measured at 4 meters) 
will also be assessed by masked personnel. Non-inferiority testing related to the co-
primary efficacy parameter BCVA will be based on a margin of 4 letters. Historically, the 
change from baseline in BCVA at a selected time point is considered appropriate as the 
primary efficacy endpoint in confirmatory nAMD studies, based on the evidence available 
from existing anti-VEGF treatments in nAMD (e.g. ranibizumab, aflibercept). The BCVA 
assessment has its own variability and generally in the clinical practice a change of BCVA 
> 5 letters would be considered as clinically relevant regardless of the underlying disease. 
A non-inferiority margin of 4 letters for the endpoint change from baseline in BCVA is 
well established and considered clinically relevant in the indication of nAMD (FVF4579g 
- HARBOR, RTH258-C001 - HAWK and RTH258-C002 - HARRIER studies) and was 
also applied in diabetic macular edema (CRFB002D2304 - RETAIN study).

The co-primary endpoint will be assessed as average change from baseline in BCVA at 
Week 28/30 and Week 32. In the Treat-to-Control phase, patients will receive injections at 

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different intervals. Patients with longer treatment intervals may receive their last injection 
far earlier before the fixed assessment time point than those with shorter treatment 
intervals. A difference in the time since the last injection between both arms may affect 
BCVA gain and could introduce a bias on BCVA gain if measured at a single fixed 
assessment time point. Averaging change in BCVA from baseline at 2 time points 4 weeks 
apart will mitigate this potential bias.
Masked treatment for approximately 60 weeks of treatment, including 44 weeks of Treat-to-
Control regimen, allows evaluation of the long-term safety and efficacy of brolucizumab 
compared to aflibercept in an identical Treat-to-Control regimen in nAMD.
The following will apply to ensure masking is maintained:

To fulfil the double-masking requirement, the study site will have masked and unmasked 
staff to perform the masked and unmasked study assessments/procedures accordingly.

Disease activity assessment and decision on next treatment interval will be made by the 
masked investigator for both arms and at each visit during the Treat-to-Control phase, 
including Week 16 (or the first optional inspection visit Week 14, at the discretion of the 
masked investigator).
4.2
Rationale for dose/regimen and duration of treatment
The dose and regimen for brolucizumab and aflibercept are based on the following 
considerations:

Brolucizumab is well tolerated at a dose of 6 mg administered three times every four 
weeks during the loading phase, based on the previous clinical Phase III program in which 
1088 subjects with nAMD received brolucizumab (RTH258-C001 - HAWK and RTH258-
C002 - HARRIER). The nAMD study results regarding q12w/q8w maintenance dosing 
interval support stretching the interval between injections during the Treat-to-Control 
phase to reduce the treatment burden (see Section 1.1).

Current evidence from large ranibizumab studies in nAMD (CRF002A2411 - TREND, 
CRF002ACA06 - CAN-TREAT, CRF002AAU15 - FLUID, CRF002AAU17 - RIVAL 
studies) indicates that the Treat-and-Extend regimen is an efficient regimen which is 
clinically comparable to monthly injections in improving visual acuity while reducing the 
number of visits and treatments (see Section 1.1).

In the aforementioned studies, Treat-and-Extend regimens with treatment intervals 
between 4 and 12 weeks were found to be effective and safe. Recently, treatment intervals 
were extended to the maximum interval of 16 weeks as early as Week 40 for some 
Japanese patients with nAMD treated with aflibercept 2 mg in a Treat-and-Extend 
regimen where treatment intervals could be every 4-week adjusted based on disease 
activity, following 3 consecutive 4-week injections and a 8-week injection 
(Ohji et al 2018). There is no evidence yet about the safety and efficacy of intervals longer 
than 12 weeks with brolucizumab. However, one could expect that patients could also be 
effectively and safely injected with brolucizumab 6 mg at 16-week intervals, as 
brolucizumab 6 mg dosed q12w/q8w was superior to aflibercept 2 mg dosed q8w in terms 
of fluid control and suppression of disease activity as seen in RTH258-C001 - HAWK and 
RTH258-C002 - HARRIER.

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
CRTH258AUS04 (MERLIN) is a two-year, multicenter, randomized, double masked, 
Phase IIIa study evaluating brolucizumab 6 mg q4w versus aflibercept 2 mg q4w in 
patients with nAMD with persistent fluid.  Review of the 52-week FIR led to an urgent 
safety communication based on an increased incidence of intraocular inflammation (IOI) 
and related adverse events including retinal vasculitis (RV), and retinal vascular occlusion 
(RO) in patients with q4w dosing with brolucizumab beyond the “loading phase”. IOI 
including RV, and RO were reported at a higher frequency in brolucizumab 6 mg q4w 
when compared to aflibercept 2 mg q4w (IOI: 9.3% vs 4.5% of which RV: 0.8% vs 0.0%; 
RO: 2.0% vs 0.0%, respectively). Accordingly, the CRTH258A2303 protocol is being 
amended to discontinue subjects from study treatment who require treatment every 
4 weeks.

The route of administration is an intravitreal injection as for all anti-VEGF treatments 
currently approved for the treatment of nAMD.
Study duration of 64 weeks allows for two complete 16-week intervals to assess long-term 
efficacy and safety of this Treat-to-Control regimen.
4.3
Rationale for choice of control drug
Aflibercept 2 mg (Eylea®) is an established standard of care for nAMD and has been chosen as 
an active comparator that is approved across many countries.
4.4
Purpose and timing of interim analyses
The primary analysis will be conducted when all ongoing subjects have completed their Week 
32 visit. Subjects will remain in the study and will continue to receive masked treatment through 
the planned study duration of 64 weeks, to allow for further evaluation of efficacy and safety.
Treatment masking of individual subjects will remain in effect for all subjects, masked 
investigators and selected staff from the Sponsor who have access to the patient data and have 
contact with investigators until the final database lock has occurred.
4.5
Risks and benefits
The risk to subjects in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring described in Section 6.7.2, 
Section 8.4.4 and Section 10.
Adverse events (AEs) of retinal vasculitis and/or retinal vascular occlusion have occurred since 
the Oct-2019 marketing authorization approval for brolucizumab (Beovu®) in the treatment of 
nAMD. These AEs may result in severe vision loss and typically in the presence of intraocular 
inflammation. Based on clinical studies, IOI related adverse events, including retinal vasculitis 
and retinal vascular occlusion, were reported more frequently in female patients treated with 
brolucizumab than male patients (e.g. 5.3% females vs. 3.2% males in HAWK and HARRIER).
Results of the mechanistic study BASICHR0049 of blood samples from nAMD patients 
exposed to brolucizumab and having subsequently developed Retinal Vasculitis (RV) and/or 
Retinal Vascular Occlusion (RO) taken together with accumulated data of the association of 
treatment-emergent immunogenicity and intraocular inflammation (IOI) indicate a causal link 
between the treatment-emergent immune reaction against brolucizumab and the brolucizumab-

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related “retinal vasculitis and/or retinal vascular occlusion, typically in the presence of IOI”. 
This finding supports the requirement to discontinue treatment with brolucizumab in patients 
who develop events of RV and/or RO.
In addition, based on USM (CRTH258AUS04 FIR), the brolucizumab dosing interval should 
not be less than 8 weeks beyond the loading period.
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study, and agree that in order 
to participate in the study they must adhere to the contraception requirements outlined in the 
exclusion criteria. If there is any question that the subject will not reliably comply, they should 
not be entered or continue in the study.
Aflibercept, an approved inhibitor of VEGF-A, has consistently demonstrated efficacy in 
VEGF-driven retinal pathologies, including nAMD, with benefits outweighing the risks.
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 subjects 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 lower probability of disease activity after the head-to-head comparison at Week 16, the 
greater reduction in CSFT through Week 48, the lower proportion of patients with SRF and/or 
IRF at the majority of visits through Week 48 for brolucizumab 6 mg versus aflibercept 2 mg 
in HAWK and HARRIER are anticipated to confer a longer duration of effect that will translate 
into greater durability and longer injection intervals for brolucizumab 6 mg, with non-inferior 
efficacy. A reduced treatment and monitoring visit frequency will provide benefit to subjects 
and caregivers/physicians. Further details of the known and potential risks and benefits 
associated with brolucizumab are presented in the Investigator’s Brochure (IB).

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5
Population
The study population will be male and female patients ≥ 50 years old diagnosed with active 
choroidal neovascularization (CNV) secondary to AMD, not treated previously for this disease 
and able to comply with study or follow-up procedures.
Assuming a 28% screen failure rate, approximately 962 adult patients will be screened and 
approximately 692 (346 per arm, 10% dropout rate expected) patients will be randomized in a 
1:1 ratio in approximately 200 centers worldwide.
If both eyes are eligible as per the inclusion and exclusion criteria described below, the eye with 
the worse visual acuity should be selected for study eye, unless the investigator deems it more 
appropriate to select the eye with better visual acuity, based on medical reasons or local ethical 
requirements.
5.1
Inclusion criteria
The investigator will assess the eligibility of the patient and the study eye at the screening visit 
and confirm eligibility prior to randomization. Subjects eligible for inclusion in this study must 
meet all of the following criteria:
1. Signed informed consent must be obtained prior to participation in the study.
2. Male or female patients, ≥ 50 years of age at screening.
Study Eye:
3. Active CNV secondary to AMD that affects the central subfield, including retinal 
angiomatous proliferation (RAP) with a CNV component, confirmed by presence of active 
leakage from CNV seen by fluorescein angiography (or other imaging modalities) and 
sequelae of CNV, e.g. pigment epithelial detachment (PED), subretinal or sub-retinal 
pigment epithelium (sub-RPE) hemorrhage, blocked fluorescence, macular edema.
4. Presence of intraretinal fluid (IRF) or subretinal fluid (SRF) that affects the central subfield, 
as seen by SD-OCT.
5. BCVA score must be ≤ 83 and ≥ 38 letters at an initial distance of 4 meters starting distance 
using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity charts 
(approximately Snellen equivalent of 20/25 to 20/200), at both screening and baseline.
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
Ocular conditions:
1. Concomitant conditions or ocular disorders in the study eye at screening or baseline which 
could, in the opinion of the investigator, prevent response to study treatment or may 
confound interpretation of study results, compromise visual acuity or require planned 
medical or surgical intervention during the first 12-month study period.
2. Any active intraocular or periocular infection or active intraocular inflammation (e.g. 
infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis, uveitis) 
in study eye at screening or baseline.
3. Uncontrolled glaucoma in the study eye defined as intraocular pressure (IOP) > 25 mmHg 
on medication, or according to investigator’s judgment, at screening or baseline.

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4. Presence of amblyopia, amaurosis or ocular disorders in the fellow eye with BCVA 
< 20/200 at screening (except when due to conditions whose surgery may improve VA, e.g. 
cataract).
5. Atrophy or fibrosis involving the center of the fovea in the study eye, as assessed by color 
fundus photography.
6. The total area of fibrosis or subretinal blood affecting the foveal center point comprising 
≥50% of the lesion area in the study eye.
7. Structural damage within 0.5 disc diameter of the center of the macula in the study eye, e.g. 
vitreomacular traction, epiretinal membrane, scar, laser burn, at the time of screening that 
in the investigator’s opinion could preclude visual function improvement with treatment.
Ocular treatments:
8. Previous treatment with any anti-VEGF drugs or investigational drugs in the study eye at 
any time prior to baseline.
9. Previous use of intraocular or periocular steroids in study eye within the 6-month period 
prior to baseline.
10. Macular laser photocoagulation (focal/grid) or photodynamic therapy (PDT) in the study 
eye at any time prior to baseline and peripheral laser photocoagulation in the study eye 
within 3 months prior to baseline.
11. Intraocular surgery in the study eye within 3 months prior to baseline.
12. Vitreoretinal surgery in the study eye at any time prior to baseline.
13. Aphakia with the absence of posterior capsule in the study eye.
Systemic conditions or treatments:
14. Stroke or myocardial infarction during the 6-month period prior to baseline.
15. End stage renal disease requiring dialysis or renal transplant.
16. Uncontrolled blood pressure defined as a systolic value ≥ 160 mmHg or diastolic value 
≥100 mmHg at screening or baseline. (In case there is an elevated blood pressure 
measurement, it should be repeated after 20 minutes. If the repeat measurement is elevated, 
then the patient is not eligible to be enrolled into the study).
17. Systemic anti-VEGF therapy at any time.
18. Systemic medications known to be toxic to the lens, retina or optic nerve (e.g. deferoxamine, 
chloroquine/hydroxychloroquine, tamoxifen, phenothiazines and ethambutol) used during 
the 6month period prior to baseline except temporary use for COVID-19 treatment.
19. History of hypersensitivity to any of the study drugs or their excipients or to drugs of similar 
classes, or clinically relevant sensitivity to fluorescein dye as assessed by the investigator.
20. 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.
21. History of a medical condition (e.g. metabolic dysfunction disease with exception of type 1 
or 2 diabetes mellitus, physical examination finding, or clinical laboratory finding) that, in 
the judgment of the investigator, would preclude scheduled study visits, completion of the 
study, or a safe administration of investigational product.

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22. Use of systemic investigational drugs within 5 half-lives of baseline or within 30 days/until 
the expected pharmacodynamic effect has returned to baseline, whichever is longer; or 
longer if required by local regulations (observational clinical studies solely involving over-
the-counter vitamins, supplements, or diets are not exclusionary).
Other:
23. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive human 
chorionic gonadotropin (hCG) pregnancy test.
24. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
the study drug administration and for 3 months after stopping the investigational medication. 
Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject

Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), 
or other forms of hormonal contraception that have comparable efficacy (failure rate 
< 1%), for example hormone vaginal ring or transdermal hormone contraception.
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child-bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks 
before taking study treatment. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child-bearing potential.
If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the informed consent form.

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6
Treatment
6.1
Study treatment
6.1.1 Investigational and control drugs
Table 6-1
Investigational and comparator drugs
Investigational/ 
Comparator 
Drug
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor
Brolucizumab 6 
mg (RTH258 6 
mg/0.05 mL)
Solution for 
injection
Intravitreal use
Glass vials or 
pre-filled syringe
Global
Aflibercept 2 
mg/0.05 mL
Solution for 
injection
Intravitreal use
Glass vials or 
pre-filled syringe
Global
Brolucizumab will be provided in a single use, sterile glass vial, or may be provided in 
prefilled syringe (PFS) (in selected countries), containing sufficient brolucizumab to deliver a 
6 mg dose when administering a volume of 0.05 mL.
Aflibercept will be provided in a single use, sterile glass vial, or may be provided in prefilled 
syringe (in selected countries) containing sufficient aflibercept to deliver a 2 mg dose when 
administering a volume of 0.05 mL.
The content of the study drug vials must not be split.
Novartis will ensure sufficient supplies of brolucizumab and aflibercept for treatment use to 
allow for completion of the study.
6.1.2 Additional study treatments
No other treatment beyond investigational drug and control drug is included in this trial.
6.1.3 Treatment arms/group
Eligible subjects will be randomly assigned at Baseline to one of the following two treatment 
arms in a 1:1 ratio:

Brolucizumab 6 mg: 3 x 4-week injections and one 8-week injection, followed by Treat-
to-Control treatment from Week 16 up to Week 60/62

Aflibercept 2 mg: 3 x 4-week injections and one 8-week injection, followed by Treat-to-
Control treatment from Week 16 up to Week 60/62
6.1.4 Treatment duration
The planned duration of treatment is 60 weeks (62 weeks for the patients who may have 
received study treatment at an odd number of inspection visits). Discontinuation of study 
treatment for a subject occurs when study drug is stopped earlier than the protocol planned 
duration and can be initiated by either the subject or the investigator.
After the initiation phase (Week 14/Week 16), study treatment will also be discontinued for 
patients who require injections every 4 weeks. 

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If retinal vasculitis, and/or retinal vascular occlusion is confirmed, subjects must be 
discontinued from study treatment. 
Subjects who prematurely discontinue study treatment for any reason, except for withdrawal of 
consent, should continue in the study. Subjects should return 4 weeks after last study treatment 
to perform the assessments for early treatment discontinuation (ETD). Please refer to Table 8-
1.
6.2
Other treatment(s)
6.2.1 Concomitant therapy
The investigator must instruct the subject to notify the study site about any new medications the 
subject takes after enrollment in the study. All medications, procedures and significant non-
drug therapies (including physical therapy and blood transfusions) administered after the 
subject was enrolled into the study must be recorded on the appropriate Electronic Case Report 
Forms (eCRFs).
Each concomitant medication must be individually assessed against all exclusion 
criteria/prohibited medication. If in doubt, the investigator should contact the Novartis medical 
monitor before randomizing a subject or allowing a new medication to be started. If the subject 
is already enrolled, contact Novartis to determine if the subject should continue to take study 
treatment or should discontinue study treatment but still continue participation in the study.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
During the study, standard of care or other treatments according to the investigator's practice 
for nAMD and other diseases in the fellow eye are permitted at any time and must be recorded 
in the appropriate eCRF page. Treatment of the fellow eye must be scheduled in a way not to 
disturb the schedule for visits and treatments in the study eye. The fellow eye must be monitored 
according to routine practice and adverse events (AEs) captured in the eCRF.
Administration of topical ocular corticosteroids in the study eye is allowed during the study. 
Corticosteroids administered via intra-nasal, inhaled, intra-articular or non-extensive dermal 
route (< 20% total body surface area) are also permitted during the study. For other routes of 
corticosteroid administration, refer to Section 6.2.2.
If cataract surgery is necessary, attempt to schedule cataract surgery ≥ 7 days after the most 
recent study treatment. Study treatment may be resumed ≥ 14 days after cataract surgery, 
assuming an absence of surgically related complications.
If yttrium aluminum garnet (YAG) laser is necessary, it should be performed ≥ 7 days prior to 
the scheduled study visit.
Ideally, while adhering to the visit schedule specified in the protocol, study drug should be 
administered at least 7 days before or after SARS-CoV-2 vaccinations. This will allow to 
separate potential drug-drug interactions and side effects caused by vaccination. This 7-day 
time window would also be recommended for the first study treatment at the Baseline visit.

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6.2.2 Prohibited medication
Use of the treatments displayed in the below table are not allowed after screening.
Table 6-2
Prohibited medications and procedures
Medication/Procedure
Prohibition period
Action taken
Study Eye
Any periocular injection or 
intraocular administration of 
corticosteroids (except if 
needed as short-term treatment 
of AE)
Anytime
Discontinue study treatment 
(except if for treatment of AE)
Anti-VEGF therapy other than 
assigned study medication
Anytime
Discontinue study treatment
Panretinal laser, PDT laser, or 
focal laser photocoagulation 
with involvement of the macular 
area
Anytime
Discontinue study treatment
Any investigational drug, 
biologic or device
Anytime
Discontinue study treatment
Systemic
Anti-VEGF treatment
Anytime
Discontinue study treatment
Any investigational drug, 
biologic or device
Anytime
Discontinue study treatment
Medications known to be toxic 
to the lens, retina or optic 
nerve, including ethambutol, 
chloroquine/hydroxychoroquine
, deferoxamine, phenothiazines 
and tamoxifen (except 
temporary use for COVID-19 
treatment)
Anytime
Discontinue study treatment
In the fellow eye, treatment with investigational product (drug, biologic or device) is prohibited. 
Any marketed medication used to treat the fellow eye should be recorded in the appropriate 
eCRF page.
6.2.3 Rescue medication
There will be no rescue medication for nAMD in the study eye.
In case of lack of efficacy with investigational drug for nAMD and if the investigator deems it 
is in the best interest of the patient to receive prohibited treatment (Section 6.2.2) in the study 
eye, the investigator should follow the instructions for study treatment discontinuation or study 
discontinuation provided in Section 9.

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6.3
Subject numbering, treatment assignment, randomization
6.3.1 Subject numbering
Each subject is identified in the study by a Subject Number (Subject No.) that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (4 digit number for Center No. as assigned by Novartis to the investigative site) with a 
sequential subject number suffixed to it (3 digit number for Subject No.), so that each subject 
is numbered uniquely across the entire database. Upon signing the informed consent form, the 
subject is assigned to the next sequential Subject No. available in the electronic data capture 
(EDC) system.
Subjects who have been screen failures but are rescreened (see Section 8.1) will be assigned a 
new Subject No. 
6.3.2 Treatment assignment, randomization
All screened subjects must be added to the Interactive Response Technology (IRT) system. At 
the Baseline Visit/Day 1 all eligible subjects will be randomized via IRT to 1 of the treatment 
arms in a ratio of 1:1.
The unmasked investigator or his/her delegate will contact the IRT after receiving confirmation 
from the masked investigator that the subject fulfills all the inclusion/exclusion criteria. The 
IRT will assign a randomization number to the subject, which will be used to link the subject 
to a treatment arm and will specify a unique medication number for the study treatment 
packages (each containing 1 vial) to be dispensed to the subject. The randomization number 
will not be communicated to subject or site users.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 
randomization list will be produced using a validated system that automates the random 
assignment of subject numbers to randomization numbers. These randomization numbers are 
linked to the different treatment arms, which in turn are linked to medication numbers. A 
separate medication list will be produced by or under the responsibility of Novartis Global 
Clinical Supply using a validated system that automates the random assignment of medication 
numbers to packs containing the study treatment.
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office.
6.4
Treatment blinding
The intent of masking is to limit the occurrence of conscious and unconscious bias in the 
conduct and interpretation of the clinical study. Bias could arise from the influence that the 
knowledge of a specific treatment assignment may have on the recruitment and allocation of 
subjects, their subsequent care, the assessment of endpoints, the handling of withdrawals, and 
so on. The essential aim of masking, therefore, is to prevent identification of the treatments by 
the investigator, subject, and others associated with the conduct of the study until all such 
opportunities for bias are no longer present.

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This study will be double-masked, with subjects randomized to be treated with 
brolucizumab 6 mg or aflibercept 2 mg. The sponsor clinical study team will be masked to 
treatment assignments until the Week 32 Interim Database Lock for the primary analysis and 
will be unmasked once the Week 32 Interim Database Lock for primary endpoints is reached. 
However, masking to the original treatment assignment will be maintained at the site level 
(patients, masked study site personnel, masked monitors) until the end of the study.
Unmasking of investigators and site personnel directly involved in the conduct of the study will 
only occur in case of subject emergencies (see Section 6.6.2), and then at the time of the final 
analysis, at the conclusion of the study (see Section 4.4 and Section 11.2).
In the event of a medical emergency or an adverse event (AE) during the study where the 
knowledge of subject treatment is required (e.g. in case of Suspected Unexpected Serious 
Adverse Reaction (SUSAR)), an investigator will have the ability to unmask the treatment 
assignment for a specific subject. The investigator should notify the Sponsor prior to unmasking 
a subject, if there is sufficient time. Further, the Sponsor must be informed whenever the 
randomization code is broken and be informed about the reasons for unmasking.
Each site must have both masked and unmasked investigators available. The investigator who 
performs the injection will be unmasked to the treatments as will any other site personnel who 
have been delegated responsibility for working with the investigational product. The unmasked 
site personnel and unmasked injecting investigator must not perform BCVA assessments, 
complete ophthalmic examination, disease stability assessments or administer the National Eye 
Institute Visual Function Questionnaire-25 (NEI VFQ-25). Also, the unmasked site personnel 
and unmasked injecting physician must not perform assessment of any ocular or non-ocular 
safety parameters, or assess causality of AEs for subjects during the course of the study.
The unmasked investigator/site personnel should, however, assess the subject's functional 
vision (e.g. finger counting) and may perform other safety assessments as needed immediately 
following injection.
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 database lock has occurred 
by ensuring that randomization data are kept strictly confidential until the time of unmasking 
and will not be accessible by anyone else involved in the study except the unmasked/treating 
investigator. During and after Database Locks at Week 32 and Week 64, the masked personnel 
at site and subjects will remain masked to the treatment assignment until the conclusion of the 
study.
Unmasked monitors will be available to perform study medication accountability and to deal 
with study issues involving the unmasked investigator or unmasked site staff.
An 
independent, 
masked 
review 
of color fundus 
photography (CFP), 
 
 images collected at pre-defined 
time-points (see Section 8.3.2 and Section 8.3.3) for subjects enrolled in the study will be 
performed at a Central Reading Center (CRC).

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6.5
Dose escalation and dose modification
No study treatment dose modification is allowed.
Deviations to dose intervals during the initiation phase and/or dose adjustments during the 
whole study are not allowed.
Interruption of study treatment is allowed if warranted by an AE.
6.6
Additional treatment guidance
6.6.1 Treatment compliance
IRT needs to be accessed by unmasked study personnel at every visit. Registration of all visits 
in the IRT system is necessary and when treatment is warranted, IRT will provide a medication 
(kit) number to administer the assigned investigational product to the subject. The date and time 
of all study treatment injections administered during the study and any deviations from the 
protocol treatment schedule will be captured by the unmasked study personnel or by unmasked 
field monitor on the appropriate study treatment dispensing form.
Exposure to the study treatment will be based on the number of injections administered. 
Compliance with the study treatment will be assessed by the unmasked field monitor at each 
visit using vial counts and information provided by the pharmacist or by the unmasked study 
personnel.
6.6.2 Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when required to in order to treat the subject 
safely. Most often, study treatment discontinuation and knowledge of the possible treatment 
assignments are sufficient to treat a study subject who presents with an emergency condition. 
Emergency treatment code breaks are performed using the IRT. When the investigator contacts 
the IRT system to break a treatment code for a subject, he/she must provide the requested 
subject identifying information and confirm the necessity to break the treatment code for the 
subject. The investigator will then receive details of the investigational drug treatment for the 
specified subject and a fax or email confirming this information. The system will automatically 
inform the Novartis monitor for the site and the study team that the code has been broken. If the 
treatment code needs to be broken in the interest of subject 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/code break cards at any time in case of emergency. 
The investigator will provide:

protocol number

name (if available)

subject number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that unmasking 
can be performed at any time.

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The appropriate personnel from the site and Sponsor will assess whether study treatment should 
be discontinued for any subject whose treatment code has been broken for any reason.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section (Section 6.1.1). For both brolucizumab and aflibercept, the study drug 
packaging has a 2-part label (base plus tear-off label). A unique medication number is printed 
on each part of this label, which corresponds to one of the treatment arms. Unmasked study 
personnel will identify the study medication kits to dispense to the subject by contacting the 
IRT and obtaining the medication number(s). Immediately before dispensing the medication kit 
to the subject, unmasked study personnel will detach the outer part of the label from the 
packaging and affix it to the source document (Drug Label Form) for that subject's unique 
subject number.
6.7.1 Handling of study treatment
Study treatment must be received by a designated unmasked person at the study site, handled 
and stored safely and properly and kept in a secured location to which only the unmasked 
investigator and designated site personnel have access. Upon receipt, all study treatment must 
be registered in the IRT system and stored according to the instructions specified on the labels 
and in the IB. Clinical supplies are to be dispensed only in accordance with the protocol. 
Technical complaints are to be reported to the respective Novartis Country Organization 
Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number.
The unmasked study personnel must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Monitoring of drug accountability will be 
performed by unmasked monitors during site visits or remotely and at the completion of the 
trial.
At the conclusion of the study, and as appropriate during the course of the study, the unmasked 
study personnel will return all unused study treatment, packaging, drug labels, and a copy of 
the completed drug accountability log to the unmasked Novartis monitor or to the Novartis 
address provided in the investigator folder at each site.
6.7.2 Instruction for prescribing and taking study treatment
All kits of study treatment assigned by the IRT will be recorded/databased in the IRT system
There will be two treatment phases (see Figure 6-1).

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Figure 6-1
Treatment regimen
# The treatment interval can also be maintained if the investigator deems that the patient will not 
benefit from treatment interval extension
* Week 62, depending on visit schedule
Initiation Phase
In the initiation phase, treatment with either brolucizumab 6 mg or aflibercept 2 mg will occur 
every 4 weeks for 3 consecutive injections (baseline, Weeks 4 and 8). The injection interval 
will then be extended by 4 weeks to Week 16. 
At the investigator’s discretion, an inspection visit at Week 14, i.e. 6 weeks after the 3rd 
injection, can be performed. If there is no disease activity in the study eye at Week 14 as 
assessed by the masked investigator, no treatment will be administered at the inspection 
visit; the next visit and treatment will take place at Week 16. If disease activity is observed by 
the masked investigator in the study eye at Week 14, the study treatment will be administered 
by the unmasked investigator, and the subject will be discontinued from further study treatment 
at the next visit.
Treat-to-Control (TtC) Phase
The TtC phase starts at Week 16 and is defined as follows:

Following Week 16, treatment intervals will be either 8 weeks, 12 weeks, or 16 weeks. A 
subject must be discontinued from further study treatment if treatment is required more
frequently, i.e., every 4 weeks.

The assessment of disease activity is performed at each visit by the masked investigator.

Based on investigator’s judgment of visual and/or anatomic outcomes, the treatment 
interval can be extended by 4 weeks at a time, if there is no disease activity, i.e. no change 
in visual acuity and in other signs of the disease (e.g. IRF, SRF, hemorrhage, leakage, 
etc.).

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
If disease activity recurs, the interval should be shortened accordingly by 4 weeks at a 
time or to a minimal interval of 8 weeks.

The treatment interval can also be maintained if the investigator deems that the patient 
will not benefit from treatment interval extension.

Inspection visits 10 weeks after the last injection can be performed at the investigator's 
discretion when the injection interval is extended from 8 weeks to 12 weeks. If there is no 
disease activity in the study eye at the inspection visit as assessed by the masked 
investigator, the study treatment will not be administered; the next visit and injection will 
take place 2 weeks later, i.e. 12 weeks after the previous study treatment. If disease 
activity is observed by the masked investigator in the study eye at the inspection visit, the 
study treatment will be administered by the unmasked investigator; the injection interval 
will be reduced to 8 weeks and the next injection visit will be 8 weeks after the inspection 
visit.

Similarly, inspection visits 14 weeks after the last injection can be performed at the 
investigator's discretion when the injection interval is extended from 12 weeks to 16 
weeks, respectively. If there is no disease activity in the study eye at the inspection visit as 
assessed by the masked investigator, the study treatment will not be administered; the next 
visit and injection will take place 2 weeks later, i.e. 16 weeks after the previous study 
treatment. If disease activity is observed by the masked investigator in the study eye at the 
inspection visit, the study treatment will be administered by the unmasked investigator; 
the injection interval will be reduced to 12 weeks and the next injection visit will be 12 
weeks after the inspection visit.

Regardless of treatment administration, Week 28, Week 32, and Week 60 visits are 
mandatory. Patients who will receive study treatment at an inspection visit may also have 
a study visit at Week 30 or 62; for these patients, the Week 30 or 62 visit will take place in 
lieu of the visit at Week 28 or 60 (unless this visit is inspection visits), respectively.

The last potential study treatment may be administered at the Week 60 visit (or at the 
Week 62 visit for the patients who will have received study treatment at an odd number of 
inspection visits).

A disease activity assessment will also be performed at the Week 64/EOS visit; however, 
no study treatment will be administered.
The different types of visits occurring through the study are summarized in Table 6-3 with a 
description of when disease activity assessment and treatment take place.
Table 6-3
Disease activity assessment and treatment occurrence according to 
visit type
Type
Study Period or 
Phase
Disease Activity 
Assessment
Treatment
Screening visit
Screening
Yes
No
Baseline (Day 1) visit
Initiation phase
Yes
Yes
Week 4 and 8 visits
Initiation phase
No
Yes
Treatment visits
Treat-to-Control phase
Yes
Yes

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Type
Study Period or 
Phase
Disease Activity 
Assessment
Treatment
Inspection visits 
(optional)
Treat-to-Control phase
Yes
Based on DA, as per 
the masked 
investigator's judgment
Week 28/30*, 32, and 
60/62* visits
Treat-to-Control phase
Yes
Only if a treatment was 
planned at the visit
ETD visit, and EOS 
visit (Week 64) 
Follow-up
Yes
No
* depending on visit schedule
Brolucizumab or aflibercept should be administered in the study eye on the day of the study 
visit or, if this is not possible, within 3 days after the occurrence of the study visit (except for 
Baseline/Day 1, in which case study treatment administration should occur within the next 24 
hours) or no later than within the visit window (±14 days) as described in Section 3 and 
Section 8. When assessments and treatments take place on the same day, treatment must occur 
after completion of the efficacy assessments described in Section 8.3 and pre-injection safety 
measures (tonometry, slit lamp and fundus examinations) described in Section 8.4.4. If study 
visit assessments and the corresponding treatment occur on separate days, a repeat safety check-
up should be performed prior to treatment of the eye and results documented in the source 
documents. If any safety concern arises related to the study eye that, in the opinion of the 
investigator, may be further impacted by the study treatment or injection procedure, treatment 
needs to be cancelled. IVT injection is contraindicated in subjects with active intraocular or 
periocular infections and in subjects with active intraocular inflammation; therefore, the 
investigators must verify that these conditions are not present in the study eye prior to every 
injection. Any adverse events must be recorded in the eCRF.
If any signs of intraocular inflammation is present, then an IVT injection must not be performed. 
Additional ophthalmic examination and imaging should be performed to evaluate IOI (see 
Section 8.4.4).
If retinal vasculitis, and/or retinal vascular occlusion is confirmed, subjects should be 
discontinued from study treatment. In addition, subjects who experience IOI only (without RV 
and/or RO) may be at risk of developing retinal vasculitis and/or retinal vascular occlusion and 
should be closely monitored and the investigator should evaluate the appropriateness of 
continuing further with study treatment. 
The assessment of the masked/evaluating investigator will be passed to the unmasked/treating 
investigator or delegate in order to be entered in the IRT system. The IVT injection procedure 
for brolucizumab and aflibercept including aseptic and antimicrobial requirements, will be 
performed according to local clinical practice. IVT injection will be performed by the unmasked 
investigator. All kits of study treatment assigned by the IRT will be recorded in the IRT system.
Every effort should be made to ensure that the subject adheres to the visit/treatment schedule.

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7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), Institutional Review Board/Independent Ethics Committee (IRB/IEC)-
approved informed consent.
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol) and collecting any study-relevant information. The 
process of obtaining informed consent must be documented in the subject source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the International Council on Harmonization Good Clinical Practice (ICH 
GCP) guidelines and regulatory requirements and is considered appropriate for this study. Any 
changes to the proposed consent form suggested by the investigator must be agreed by Novartis 
before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the subject informed consent and should 
be discussed with the subject during the study as needed. Any new information regarding the 
safety profile of the investigational drug that is identified between IB updates will be 
communicated as appropriate, for example, via an Investigator Notification (IN) or an aggregate 
safety finding. As new information becomes available, informed consent to be updated and then 
must be discussed with the subject.
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
During the COVID-19 pandemic that may challenge the ability to obtain a standard written 
informed consent due to limits that prevent an on-site visit, the Investigator may conduct 
the informed consent discussion remotely (e.g. telephone, videoconference). Guidance 
issued by local regulatory bodies on this aspect prevail and must be implemented and 
documented (e.g. the presence of an impartial witness, sign/dating separate ICFs by trial 
participant and person obtaining informed consent, etc.). Remote informed consent should 
be appropriately documented and confirmed by way of standard informed consent 
procedures at the earliest opportunity when the subject will be back at the trial sites.
8
Visit schedule and assessments
The Assessment Schedule (Table 8-1) lists all of the assessments and indicates with an “X” the 
visits when they are performed. All data obtained from these assessments must be supported in 
the subject’s source documentation. All data must be entered in the eCRF in a timely 

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manner (see Section 11.1). The assessments indicated with an “S” to be recorded in the source 
documentation only.
A planned study visit schedule will be established at Baseline/Day 1, randomization (first day 
of treatment) for all subjects. All post-baseline and/or subsequent scheduled visits will be 
calculated based on the Day 1 visit date. During the TtC phase, from Week 16 to Week 60/62, 
the treatment visit intervals will be determined by the masked investigator, based on the patient's 
disease activity (see Section 6.7.2). All efforts should be made to adhere to all scheduled visits 
and assessments as outlined in the assessment schedule (Table 8-1).
A ± 14-day visit window is allowed, except for Baseline/Day 1, the inspection visit at Week 14 
(± 7-day visit window), and the Week 64 visit (± 21-day visit window), should the subject be 
unable to return per scheduled visit. All efforts should be made to revert back to the planned 
visit schedule taking into consideration the restrictions on the minimum treatment interval for 
the study medications (brolucizumab or aflibercept).
For a given protocol visit assessments can be performed on 2 consecutive days in which both 
days must occur within the visit window.
Treatment is intended to be administered on the day of study visit, or if this is not possible, 
within 3 days after the study visit at which the per-protocol assessments took place (except 
Baseline/Day 1, in which case study treatment administration should occur within the next 24 
hours). For all visits, efficacy assessments (Section 8.3) and safety assessments (Section 8.4) 
should be performed prior to any administration of study treatment.
Missed or rescheduled visits should not lead to automatic discontinuation. Subjects who 
prematurely discontinue the study for any reason should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for the EOS final visit will be performed.
If the COVID-19 pandemic limits or prevents on-site study visits, study treatment could not be 
administered and other study assessments may not be performed. Alternative methods of safety 
monitoring may be implemented. Depending on local regulations, site capabilities and patient’s 
visit status in the study, phone calls or virtual contacts (e.g. teleconsult) can be performed for 
safety follow-up for the duration of the pandemic, until it is safe for the participant to visit the 
site again.

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Table 8-1
Assessment Schedule
Period
Screening
Initiation phase
Treat-to-Control phase
Follow-up
Visit Name
Screening
Baseline 
Visit 1
W4
W8
W162
n3
W284
W32
n3
W60/EOT5
ETD12
W64/EOS13 m14
Visit Numbers1
1
100
110
120
130
140
150
160
170
180
190
190
Weeks
-2 to -1
1
4
8
16
18 to 26
28
32
34 to 58
60
64
Informed consent
X
Inclusion / 
Exclusion criteria
X
X
Demography
X
Medical 
history/current 
medical 
conditions
X
Prior/concomitant 
medication
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test6
S
S
S
S
S
S
S
S
S
S
S
S
Vital Signs7
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
Clinical chemistry
X
X
X
X
Urinalysis
X
X
X
X
VFQ-25
X
X
X
X
BCVA score 
(ETDRS)
X
X
X
X
X
X
X
X
X
X
X
X
X
Intraocular 
Pressure (IOP)
X
X
X
X
X
X
X
X
X
X
X
X
SD-OCT11
X
X
X
X
X
X
X
X
X
X
X
X
CFP11
X
X
X
X

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Period
Screening
Initiation phase
Treat-to-Control phase
Follow-up
Visit Name
Screening
Baseline 
Visit 1
W4
W8
W162
n3
W284
W32
n3
W60/EOT5
ETD12
W64/EOS13 m14
Visit Numbers1
1
100
110
120
130
140
150
160
170
180
190
190
Weeks
-2 to -1
1
4
8
16
18 to 26
28
32
34 to 58
60
64
Randomization
X
Disease activity 
assessment
X
X
X
X
X
X
X
X
Contact IRT
X
X
X
X
X
X
X
X
X
X
X
X
Ophthalmic 
examination and 
imaging 9,11
S
S
S
S
S
S
S
S
S
S
S
S
Study drug or 
comparator IVT
X
X
X
X
X
X10
X10
X
X10
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 Visit structure given for internal programming purpose only
2 The number of weeks between visits will vary depending on the disease stability and length of intervals between injections as determined by disease activity 
assessment. Study treatment at the optional inspection visits (6 weeks after the last injection when the interval is extended from 4 weeks to 8 weeks, 10 weeks after the 
last injection when the interval is extended from 8 weeks to 12 weeks, and 14 weeks from the last injection when the interval is extended from 12 weeks to 16 weeks) is 
at the discretion of the investigator based on disease activity assessment.
3 At the investigator’s discretion, an inspection visit may be performed at Week 14. If there is no disease activity in the study eye at Week 14, the next visit and treatment 
will take place at Week 16. If disease activity is observed in the study eye, the study treatment will be administered and the subject will be discontinued from further study 
treatment. 
4 Patients may have a study visit at Week 30; in this case, the Week 30 visit will take place in lieu of the Week 28 visit, unless the Week 28 visit is an inspection visit. 
5 Week 60 is the last visit when study treatment may be administered. End-of-Treatment visit will take place on Week 62 in lieu of Week 60 for the patients who have a 
study visit on Week 62, unless the Week 60 visit is an inspection visit.  
6 A serum pregnancy test must be performed on all women of child-bearing potential at screening and Week 64/EOS.  Additional urine tests should be performed prior to 
each IVT.
7 Vital signs include sitting blood pressure and pulse rate.
9 May include visual acuity check, slit lamp examination, fundus examination, optic nerve perfusion, and tonometry, for safety assessment before and after IVT.
10 Study treatments on the mandatory Week 28/30, Week 32, and Week 60/62 visits only if required based on treatment interval.
11 Additional ophthalmic examinations and images will be performed in case of any signs of intraocular inflammation, retinal vasculitis, and/or retinal vascular occlusion.

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Period
Screening
Initiation phase
Treat-to-Control phase
Follow-up
Visit Name
Screening
Baseline 
Visit 1
W4
W8
W162
n3
W284
W32
n3
W60/EOT5
ETD12
W64/EOS13 m14
Visit Numbers1
1
100
110
120
130
140
150
160
170
180
190
190
Weeks
-2 to -1
1
4
8
16
18 to 26
28
32
34 to 58
60
64
12 ETD: Early treatment discontinuation applies to subjects who discontinue early from study treatment and continue in the study. The assessments should be performed 
4 weeks after the last injection of study drug. This can occur at any time point.
13 The week 64 EOS assessments only apply to subjects who completed the study per protocol. The assessments are not required for subjects who have undergone ETD 
assessments and continued in the study without study treatment.
14 For subjects who continue in the study after ETD and up to Week 64 (end of study) while subject is on standard of care. Additional safety assessments and imaging 
can also be performed if required, as per investigators discretion. In addition, after ETD, subjects are not required to attend the mandatory visits at Week 28/Week 32, 
and Week 60/Week 62. The last visit should be at week 64. This can occur at any time point.

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
Laboratory test results

VFQ-25 questionnaire

Concomitant medications

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.
8.3
Efficacy
The following assessments will be performed to evaluate the effect of brolucizumab and 
aflibercept on visual function, retinal structure and vascular leakage:

Best-corrected visual acuity with ETDRS-like charts at an initial testing distance of 4 
meters

Anatomical retinal evaluation of SD-OCT images

Color Fundus Photography 
All efficacy assessments should be performed prior to any administration of study treatment 
and/or rescue medication.
8.3.1 Visual acuity
Visual acuity will be assessed in the study eye at every study visit and in the fellow eye at the 
screening, Week 32 and Week 64/EOS visits using best correction determined from protocol 
refraction (BCVA). BCVA measurements will be taken in a sitting position using ETDRS–like 
visual acuity testing charts at an initial testing distance of 4 meters. The details of the refraction 
technique and VA testing, as well as training material, are provided in the applicable manual. 
Certification of the assessment procedures and assessors will occur prior to any evaluation of 
study subjects.
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.
8.3.2 Optical coherence tomography
Spectral Domain Optical Coherence Tomography (SD-OCT) images will be obtained and 
assessed in the study eye at every study visit and in the fellow eye at the screening, Week 32 
and Week 64/EOS visits. Only SD-OCT machines can be used (i.e. no time-domain nor swept-
source OCT).
These assessments will be performed by a trained technician or investigator at the sites and 
should be performed after BCVA assessment and prior to any study drug administration. 
Masked investigators will evaluate the SD-OCT images to assess the status of disease stability. 
The SD-OCT machine used for an individual subject should not change for the duration of the 
study.

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baseline visits, the blood pressure measurement should be repeated after 20 minutes. If the 
repeat measurement is elevated as specified in the exclusion criteria, then the subject is not 
eligible to be enrolled into the study.
On days when study drug is administered, vital signs will be measured before administration 
of study medication. The results will be recorded in the eCRF.
8.4.2 Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected at screening, Week 32, 
ETD, and Week 64/EOS visits. Details on the collections, shipment of the samples and reporting 
of the results by the central laboratory are provided to investigators in the central laboratory 
manual.
Clinically significant abnormalities must be recorded in the relevant section of the medical 
history, current medical conditions or adverse event eCRF page as appropriate.
If the COVID-19 pandemic limits or prevents on-site study visits, the collection of samples may 
be modified by Novartis if applicable and if modified, will be communicated to the Investigator. 
Table 8-2
Laboratory Assessments
Test Category
Test Name
Hematology
Hematocrit, hemoglobin, red blood cell (RBC) count, white blood cell 
(WBC) count with differential (absolute and percentage of neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils), and quantitative 
platelet count
Clinical chemistry
Serum biochemistry tests
Serum electrolytes (sodium, potassium, chloride, phosphorus, calcium, 
magnesium), uric acid, urea nitrogen, creatinine, albumin, glucose, total 
protein, total bilirubin and direct bilirubin, serum glutamic oxaloacetic 
transaminase (SGOT)/ aspartate aminotransferase (AST), serum glutamic 
pyruvic transaminase (SGPT)/ alanine aminotransferase (ALT), gamma-
glutamyl transferase (GGT), alkaline phosphatase (ALP) and lactate 
dehydrogenase (LDH)
Additional chemistry tests: Lipids panel - triglycerides (TG), low-density 
lipoproteins (LDL), high-density lipoproteins (HDL), total cholesterol (TC)
Urinalysis
Dipstick measurements for specific gravity, pH, protein, glucose, ketones, 
bilirubin, nitrite, leucocyte and urine occult blood
8.4.3 Pregnancy
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements.
Highly effective contraception is required for women of child-bearing potential during the study 
drug administration and for 3 months after stopping the investigational and comparator
medications.
A serum pregnancy test will be conducted for all women of child-bearing potential to assess 
pregnancy before inclusion into the study at Screening visit, and then at Week 64/EOS visit. 
During the study, urine pregnancy testing will be performed at visits when serum pregnancy 
testing will not be conducted  If a urine test is positive after inclusion in the study, a serum 

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pregnancy test must be performed for confirmation; if the serum test is positive, the subject 
should discontinue study medication. Results of all pregnancy testing must be available as 
source documentation.
8.4.4 Ophthalmic examination and imaging
The ophthalmic exam will consist of the following:

Intraocular pressure (IOP) will be assessed in the study eye, pre-dose and post-dose at 
every scheduled visit. The same method of tonometry has to be used through the whole 
study. In the fellow eye, IOP will be assessed at screening, Week 32 and Week 64/EOS visit. 
The values recorded in mmHg for either eye 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 injection is not recommended 
unless normalization of the IOP has been achieved. Post-dose IOP should be assessed within 
60 minutes after injection and if ≥25 mmHg, assessment should be repeated until back to 
normal. Monitoring of optic nerve head perfusion after injection may be appropriate, at the 
discretion of the investigator and/or according to local requirements/practices. Results of 
these procedures will be recorded as appropriate in the source documents, and if the findings 
constitute an AE, it should be recorded in the eCRF.

Anterior biomicroscopy (slit lamp examination) will be completed at every (scheduled 
and unscheduled) visit to examine the anterior segment structures (e.g. eyelids/lashes, 
conjunctiva, cornea, anterior chamber, iris, lens and anterior part of the vitreous) of the 
study eye (fellow eye will be examined at screening and on discretion of the investigator). 
The outcome of the examination will be recorded in the source documents.
Slit lamp examination must be carefully performed before each study treatment. If there 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.

Posterior segment (indirect fundus) examination will be conducted by the investigator at 
the screening visit for both eyes. An examination of the peripheral retina must also be 
conducted to ensure that the intravitreal injection can safely be performed. 
Posterior segment examination must be performed carefully before each study treatment. 
The results of the examination including any abnormalities (e.g. vitreous cells/haze, retinal 
tear/detachment, hemorrhage and vascular occlusion, vasculitis, etc.) should be recorded in 
the source documents. If there are any signs of IOI, vitreous cells and haze should be 
assessed using National Institutes of Health (NIH) grading system (Nussenblatt et al.1985).
The outcome of the examination will be documented in the source document (e.g.
ophthalmic examination tool) and appropriate eCRF page as applicable. 
Pupil dilation for slit lamp examination and indirect ophthalmoscopy is optional according to 
local practices.
Clinically significant abnormal findings (as judged by the masked investigator) from slit lamp 
or ophthalmoscopy observations should be recorded as an AE in the eCRF.
Instruct the patient to contact the site for any changes in vision or any symptoms of 
inflammation between scheduled visits. Every effort should be made to bring the subject for 
immediate examination. 

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Imaging: When IOI, retinal vasculitis, and/or RO (Retinal Vascular Occlusion) is present or 
suspected during a visit, investigators must perform thorough ophthalmic examination, and will 
conduct 
 color fundus photography (preferably wide-field or 
with peripheral sweeps). These additional assessments will be documented in the source and 
appropriate eCRF pages as applicable. The images are requested to be uploaded onto the CRC 
portal.
8.4.5 Appropriateness of safety measurements
The safety assessments selected are standard for this indication/subject population.
If there are any signs of IOI, additional assessments will be performed as described in 
Section 8.4.4.
8.5
Additional assessments
8.5.1 Clinical Outcome Assessments (COAs)
8.5.1.1
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 nAMD. The VFQ-25 was developed to address the 
need to measure a patient’s subjective assessment of vision-related Quality of Life 
(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 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. At baseline and Weeks 32 and 64, 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 for responses that may indicate potential AE or SAE, which 
should be confirmed and recorded into eCRF based on the judgement of the evaluating 
investigator (see Section 10.1.1 and Section 10.1.2 of the protocol).
9
Study discontinuation and completion
9.1
Discontinuation
The investigator should discontinue study treatment for a given subject and/or withdraw the 
subject from the study if, on balance, he/she believes that continuation would be detrimental to 
the subject’s well-being.
A subject will be considered to have completed the study when the subject has completed the 
last visit planned in the protocol.

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The investigator and/or referring physician will recommend the appropriate follow-up medical 
care, if needed, for all subjects who are prematurely withdrawn from the study.
9.1.1 Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration, and can be initiated by either the subject or the investigator.
The investigator must discontinue study treatment for a given subject if he/she believes that 
continuation would negatively impact the subject's well-being.
Study treatment must be discontinued under the following circumstances:

Subject requires treatment on a q4w interval after the initiation phase (Week 14/Week16), 
i.e., after the three monthly injections at Baseline, Week 4, and Week 8, followed by the 
first interval extension

Subject develops retinal vasculitis and/or retinal vascular occlusion 

Subject/guardian decision

Pregnancy (see Section 8.4.3 and Section 10.1.4)

Use of prohibited treatment (see Section 6.2.2)

Any situation in which continuation with study treatment might result in a safety risk to 
the subject

Following emergency unmasking (see Section 6.6.2).
If premature discontinuation of study treatment occurs, the following should be done as 
appropriate:

The investigator must contact the IRT to register the subject’s discontinuation from study 
treatment.

The investigator should make a reasonable effort to understand and document the primary 
reason for the subject’s premature discontinuation of study treatment using the appropriate 
eCRF page.

Subjects who prematurely discontinue study treatment for any reason, except for 
withdrawal of consent (refer to Section 9.1.2), should continue in the study. Subjects 
should return 4 weeks after last study treatment to perform the assessments for early 
treatment discontinuation (ETD). Please refer to Table 8-1.

After these assessments are performed, patient can be switched to standard of care (SOC) 
anti-VEGF IVT as per investigators discretion. IVT injection is contraindicated in subjects 
with active intraocular or periocular infections and in subjects with active intraocular 
inflammation; therefore, the investigators must verify that these conditions are not present 
in the study eye prior to every injection. 

After premature study treatment discontinuation, at a minimum till week 64, in 
abbreviated visits, the following data should be collected at clinic visits or via 
telephone/email contact: 

New/concomitant treatments

Adverse events/Serious Adverse Events

BCVA 

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Additional safety assessments and imaging can be performed if required, as per 
investigator’s discretion.
•
Dosing of SOC and follow-up visits as per investigators discretion. Subjects are not 
required to attend the mandatory visits at Week 28/Week 32 and Week 60/Week 62.

Subjects who decide not to participate in the study further should NOT be considered 
withdrawn from the study, UNLESS they withdraw their consent (see Section 9.1.2). 
Where possible, subjects should return for the EOS visit assessments to be performed 
as scheduled in Table 8-1. EOS visit assessments on Table 8-1 do not need to be repeated 
at week 64 for patients on standard of care as they would have been performed as ETD 
assessment prior to standard of care switch. 

If a subject fails to return for study visits without stating an intention to discontinue or 
withdraw, the investigator must show "due diligence" by documenting in the source 
documents steps taken to contact the subject, e.g. dates of telephone calls, registered 
letters, etc. A subject should not be considered as lost to follow-up until due diligence has 
been completed (see Section 9.1.3). If the subject cannot or is unwilling to return at any 
visit(s), the site staff should maintain regular telephone contact with the subject, or with a 
person pre-designated by the subject. This telephone contact should preferably be done 
according to the study visit schedule.
In the event that premature study treatment discontinuation occurs because treatment code has 
been broken, please refer to Section 6.6.2.
9.1.1.1
Replacement policy
Subjects who started treatment but prematurely discontinued treatment and/or study will not be 
replaced.
9.1.2 Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data.
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that
would have been collected at subsequent visits will be considered missing.
The investigator must contact the IRT to register the subject's withdrawal of consent.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table (Table 8-1).

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Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until the time of withdrawal) according to applicable 
law.
For the United States of America: All biological samples not yet analyzed at the time of 
withdrawal may still be used for further testing/analysis in accordance with the terms of this 
protocol and of the informed consent form.
For the European Union and the Rest of the World: All biological samples not yet analyzed 
at the time of withdrawal will no longer be used, unless permitted by applicable law. They will 
be stored according to applicable legal requirements.
9.1.3 Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc.
A subject should not be considered as lost to follow-up until due diligence has been completed.
9.1.4 Early study termination by the sponsor
The study can be terminated by Novartis at any time. Reasons for early termination may 
include:

Unexpected, significant, or unacceptable safety risk to subjects enrolled in the study

Discontinuation of study drug development

Practical reasons, including slow enrollment

Regulatory or medical reasons
In taking the decision to terminate, Novartis will always consider the subject welfare and safety. 
Should early termination be necessary, subjects must be seen as soon as possible and treated as 
a prematurely withdrawn subject. The investigator may be informed of additional procedures 
to be followed in order to ensure that adequate consideration is given to the protection of the 
subject’s interests. The investigator or Sponsor depending on local regulation will be 
responsible for informing IRBs/IECs of the early termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes their EOS visit, and any repeat 
assessments associated with this visit have been documented and followed-up appropriately by 
the Investigator, or in the event of an early study termination decision, the date of that decision.
After study completion the subject may receive standard of care or other treatments, at the 
discretion of the investigator and/or referring physician, if needed.
10
Safety monitoring and reporting
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For adverse events of special interest, intraocular inflammation, including retinal vasculitis 
and/or retinal vascular occlusion please ensure compliance with the following:

Instruct the patient to contact the site for any changes in vision or any symptoms of 
inflammation between scheduled visits (refer to the optional patient brochure). Every 
effort should be made to bring the subject for immediate examination. 

Close patient monitoring and thorough examination of the eye should be done to detect 
potential signs of inflammation (Section 8.4.4).

When IOI, retinal vasculitis, and/or retinal vascular occlusion is present or suspected 
during a visit, investigators must perform thorough ophthalmic examination, and will 
conduct 
 color fundus photography (preferably wide-
field or with peripheral sweeps). The images are requested to be uploaded onto the CRC 
portal.

If any signs of intraocular inflammation is present, an IVT injection must not be 
performed. Therefore investigators must verify that these conditions are not present in the 
study eye prior to every injection. 

Subjects who experience intraocular inflammation only (without RV and/or RO) may be 
at risk of developing retinal vasculitis and/or retinal vascular occlusion and should be 
closely monitored. The investigator should carefully evaluate the appropriateness of 
continuing further with study treatment.

If retinal vasculitis and/or retinal vascular occlusion is confirmed, subjects should be 
discontinued from study treatment. 

Participants should be treated for these events promptly according to clinical practice.
For additional information related to safety assessments refer to Section 6.7.2 and Section 8.4.4
10.1
Definition of adverse events and reporting requirements
10.1.1 Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign (including abnormal laboratory findings), symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events may also be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.

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Adverse events must be recorded in the Adverse Events eCRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information (as far as possible) 
(if the event is serious refer to Section 10.1.2):
a) the severity grade

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
b) its relationship to the study treatment or the ocular injection procedure. If the event is due 
to lack of efficacy or progression of underlying illness (i.e. progression of the study 
indication) the assessment of causality will usually be ‘Not suspected’. The rationale for 
this guidance is that the symptoms of a lack of efficacy or progression of underlying illness 
are not caused by the trial drug, they happen in spite of its administration and/or both lack 
of efficacy and progression of underlying disease can only be evaluated meaningfully by an 
analysis of treatment arms, not on a single subject
c) its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported
d) whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
e) action taken with the study treatment. All adverse events must be treated appropriately. 
Treatment may include one or more of the following:

no action taken (e.g. further observation only)

(investigational) treatment interrupted/withdrawn

concomitant medication or non-drug therapy given

subject hospitalized/subject's hospitalization prolonged (see Section 10.1.2 for definition 
of SAE)
f) its outcome:

not recovered/not resolved;

recovered/resolved;

recovered/resolved with sequelae;

fatal or unknown.
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued until 30 days (safety follow-up) after the last 
administration of study treatment (EOT).
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 

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visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the IB.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease. Investigators have the responsibility for managing the safety of 
individual subjects and identifying adverse events.
10.1.2 Serious adverse events
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 

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considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines).
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.
10.1.3 SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis safety immediately, without undue delay, under no circumstances later than within 24 
hours of learning of its occurrence. Detailed instructions regarding the submission process and 
requirements are to be found in the investigator folder provided to each site.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a Chief Medical Office & Patient 
Safety (CMO & PS) Department associate may urgently require further information from the 
investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 30 day period after the last study visit should only be reported 
to Novartis Safety if the investigator suspects a causal relationship to study treatment.
10.1.4 Pregnancy reporting
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence (female participants only).
The pregnancy (for female participants) should be followed up to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications.

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Pregnancy should be recorded and reported by the investigator to the Novartis CMO & PS 
Department. Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to brolucizumab (investigational treatment) and/or 
aflibercept with any pregnancy outcome.
Any SAE experienced during pregnancy must be reported.
10.1.5 Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (European Medicines Agency definition).
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the dose administration record in the eCRF and in the Dispensing Log at the study site, 
irrespective of whether or not associated with an AE/SAE and reported to Safety only if 
associated with an SAE.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dose 
Administration (DAR) 
eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes (only data and 
time of injection)
No
Only if associated with 
an SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections (Section 10.1.1, Section 10.1.2 and Section 10.1.3).
10.2
Additional Safety Monitoring
10.2.1 Data Monitoring Committee  
The RTH258 program level Data Monitoring Committee (DMC) will monitor ocular safety. 
DMC will function independently of all other individuals associated with the conduct of this 
clinical 
trial, 
including 
the 
site 
investigators 
participating 
in 
the 
study.
Specific details regarding composition, responsibilities, data monitoring and meeting frequency, 
and documentation of DMC reports, minutes, and recommendations will be described in a 
separate charter that is established between the sponsor and the DMC.
11
Data Collection and Database management
11.1
Data collection
Designated masked investigator staff will enter the data required by the protocol into the 
Electronic Case Report Forms (eCRF). The eCRFs have been built using fully validated secure 
web-enabled software that conforms to 21 CFR Part 11 requirements. Investigator site staff will 
not be given access to the EDC system until they have been trained. Automatic validation 
programs check for data discrepancies in the eCRFs, allow modification and/or verification of 
the entered data by the investigator staff.

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The investigator/designee is responsible for assuring that the data (entered into eCRF) is 
complete, accurate, and that entry and updates are performed in a timely manner. The 
investigator must certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigative site.
All data must be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
11.2
Database management and quality control
Novartis (or designated CRO) personnel will review the data entered by investigative staff for 
completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigative site via the EDC system. Designated masked investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical (ATC) classification system. Medical history/current medical conditions 
and adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis. Color fundus photographs, 
 will be 
processed centrally by the Central Reading Center and the results will be sent electronically to 
Novartis. VFQ-25 data will be processed centrally by a designated vendor and the results will 
be sent electronically to Novartis. The Data management staff will review data received from 
the central reading center and central labs. Data Review will be done for data structure and data 
completeness / accuracy as defined in Vendor Data Transfer Specifications.
Randomization codes and data about all study treatments dispensed to the subject and all dosage 
changes will be tracked and managed using an Interactive Response Technology (IRT). The 
system will be supplied by a vendor who will also manage the database. The IRT data will be 
sent electronically to Novartis.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis.
The occurrence of relevant protocol deviations will be determined at Week 32 before the Interim 
Database Lock for the primary analysis and at the conclusion of the study. Once all the 
necessary actions have been completed and the database has been declared to be complete and 
accurate, it will be locked and the treatment codes will be unmasked and made available for 
data analysis. However, masking to the original treatment assignment will be maintained at the 
site level (patients, masked study site personnel, masked monitors) after the Week 32 Interim 
Database Lock until the end of the study (see Section 6.4). Any changes to the database after 
that time can only be made after written agreement by Novartis development management.

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11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis (or 
designated CRO) representative will review the protocol and data capture requirements (i.e. 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of subject records, the accuracy 
of data capture / data entry, the adherence to the protocol and to GCP, the progress of enrollment, 
and to ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits. Continuous remote monitoring of each site’s data may be performed by a centralized 
Novartis (or designated CRO) Clinical Research Associates organization. Additionally, a 
central analytics organization may analyze data, identify risks & trends for site operational 
parameters, and provide reports to Novartis clinical teams to assist with trial oversight.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, retinal images (CFP, 
), and the results of any other tests 
or assessments. All information on eCRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed.
12
Data analysis and statistical methods
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
In addition to the statistical methods outlined below, further details will be described in the 
Statistical Analysis Plan (SAP).
Additional analysesare planned to evaluate the impact of COVID-19 pandemic and the urgent 
safety measures.
12.1
Analysis sets
The Randomized Analysis Set consists of all randomized subjects.
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned 
by randomization. According to the intent to treat principle, subjects will be analyzed according 
to the treatment they have been assigned to during the randomization procedure.
The Safety Set includes all subjects who received at least one dose of study treatment. Subjects 
will be analyzed according to the study treatment received  where treatment received is defined 

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as the randomized treatment if the subject took at least one dose of that treatment or the first 
treatment received if the randomized treatment was never received.
The Per-Protocol Set (PPS) is a subset of subjects of the Full Analysis Set with protocol 
deviation with impact. The list of protocol deviations criteria will be provided in a separate 
document.
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 
estimands (refer to Table 12-1) using PPS, i.e. similar conclusions on non-inferiority based on 
both estimands are expected. Inconsistencies in the results will be examined and discussed in 
the CSR.
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment arm for the FAS and Safety set.
Categorical data will be presented as frequencies and percentages. For continuous data, n, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented (when applicable).
Relevant medical histories and current medical conditions at baseline will be summarized 
separately by system organ class and preferred term, by treatment arm.
The last available assessment on or prior to randomization (assignment of study treatments, i.e. 
brolucizumab/aflibercept) is taken as “baseline” assessment.
12.3
Treatments
The Safety set will be used for the analyses below.
The extent of exposure to study treatments as number of injections from baseline to Week 64 
will be descriptively summarized by treatment arm. Furthermore, number of subjects at each 
injection category (e.g. 1 injection, 2 injections, etc.) from baseline to Week 64 by treatment 
arm will be provided. All collected injection data will be listed.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment arm.
12.4
Analysis of the primary endpoint(s)
The primary objective of this study is:

To demonstrate that brolucizumab is superior to aflibercept with respect to the duration of 
treatment intervals at Week 32; AND

To demonstrate that brolucizumab is non-inferior to aflibercept with respect to average 
change in BCVA from baseline at Weeks 28 and 32.
12.4.1 Definition of primary endpoint(s)
The co-primary endpoint of this study is:

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
Distribution (proportion of patients) of last interval with no disease activity up to Week 32 
(if there was disease activity, the last interval will be shortened by 4 weeks, down to a 
minimum of 4 weeks); AND

Average change in BCVA from baseline at Week 28 and Week 32.
Both criteria in the co-primary endpoint must be met to satisfy the primary objective of this 
study.
12.4.2 Statistical model, hypothesis, and method of analysis
To test the superiority of brolucizumab vs aflibercept in terms of the distribution of the last 
interval with no disease activity (q4w, q8w, and q12w) up to Week 32, a one-sided Wilcoxon 
test for 2 ordered multinomial distribution with type I error of α = 0.025 will be considered. 
Specifically, the Wilcoxon test will assess the following hypothesis:
H0: brolucizumab and aflibercept interval distributions are equal, vs
H1: brolucizumab interval distribution is stochastically larger than aflibercept interval 
distribution.
The number (%) of patients in q4w, q8w, and q12w at Week 32 together with the respective P-
value of the Wilcoxon test will be provided. The Wilcoxon test statistic is equivalent to the 
score statistic for testing global treatment difference in interval distributions from the 
proportional odds cumulative logistic model (Natarajan et al 2012).
To test the non-inferiority of brolucizumab compared to aflibercept in terms of average change 
in BCVA from baseline at Week 28 and Week 32, a two-sided 95% confidence interval for the 
treatment difference will be derived from an analysis of variance (ANOVA) model with 
treatment arm, baseline BCVA categories and age categories as fixed effects. The baseline 
BCVA and age categories will be specified in the SAP. In order to demonstrate non-inferiority 
of average change in BCVA from baseline at Week 28 and Week 32, the lower limit of the two-
sided 95% confidence interval for the treatment difference (brolucizumab – aflibercept) must 
be greater than -4 letters representing the non-inferiority margin. Furthermore, the respective 
one-sided P-value for non-inferiority in terms of change in BCVA assessed at significance level 
of 0.025 will be provided.
Upon significance of both non-inferiority of average change in BCVA from baseline at Week 
28 and Week 32 and superiority of distribution of the last interval without disease activity up 
to Week 32, the primary objectives of this study will be satisfied.
The FAS will be used as primary population to analyze the co-primary endpoints.
12.4.3 Handling of missing values/censoring/discontinuations
The imputation of missing data will be handled by defining the estimand framework. The 
primary estimands are described by the following four attributes:
1. The target population is defined by the study inclusion and exclusion criteria. The 
protocol defines the use of allowed concomitant medications for this target population, as 
well as medications which are prohibited.
2. The co-primary variable 1 is proportion of patients in q4w, q8w, and q12w intervals 
(interval distribution) at last interval with no disease activity up to Week 32 (if there was 

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disease activity, the last interval will be shortened by 4 weeks, down to a minimum of 8 
weeks). The co-primary variable 2 is average of change in BCVA from baseline at Week 
28 and Week 32.
3. The intercurrent event describes how events that occur after randomization are captured 
when assessing the co-primary variables. Post-randomization events of interest in this 
study are assessed as: 
1. Discontinuation of study treatments
2. Treatment interruption
4. The summary measures are the P-values of the hypothesis testings to demonstrate 
superiority of brolucizumab compared to aflibercept in terms of interval distribution at 
Week 32 as per the co-primary variable 1 AND to demonstrate non-inferiority of 
brolucizumab compared to aflibercept with respect to average of change in BCVA from 
baseline at Week 28 and Week 32, as per the co-primary variable 2.
The primary estimands and other supportive estimands of interest are described in Table 12-1
below, together with their key attributes. The estimands outlined below will be discussed in 
further detail in the SAP.
Table 12-1
Primary and supportive estimands
Estimand
Estimand 
definition
Analysis set, 
data included 
in the 
analyses
Use of data after intercurrent 
event (missing data 
imputation techniques)
Statistical 
methods
Discontinuati
on of study 
treatments
Treatment 
interruption
Primary 
estimand 1 
(interval 
distribution)
Proportion of 
patients in 
q4w, q8w, 
q12w intervals 
at the last 
treatment 
interval with 
no disease 
activity 
assessed at 
Week 32
FAS
Before Week 
16 (initiation 
phase): q4w
From Week 
16 included 
(TtC phase): 
last interval 
with no 
disease 
activity (if 
there was 
disease 
activity, the 
last interval 
will be 
shortened by 
4 weeks, 
down to a 
minimum of 4 
weeks)
*Last interval 
with no 
disease 
activity (if 
there was 
disease 
activity, the 
last interval 
will be 
shortened by 
4 weeks, 
down to a 
minimum of 4 
weeks)
Superiority 
testing using a 
one-sided 
Wilcoxon test

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Estimand
Estimand 
definition
Analysis set, 
data included 
in the 
analyses
Use of data after intercurrent 
event (missing data 
imputation techniques)
Statistical 
methods
Discontinuati
on of study 
treatments
Treatment 
interruption
Primary 
estimand 2 
(change in 
BCVA)
Average 
BCVA change 
from baseline 
at Week 28 
and Week 32
FAS, 
FAS data 
collected until 
the participant 
discontinued 
study 
treatment and 
started 
alternative 
treatment(s), 
will be 
included. 
BCVA scores 
collected after 
subjects 
discontinued 
early from 
study 
treatment will 
not be 
analyzed
LOCF
LOCF
Analysis of 
variance 
(ANOVA) 
model 
including 
terms for 
treatment arm 
(factor), 
baseline 
BCVA 
categories 
and age 
categories
Supportive 
estimand 1 
(interval 
distribution)
Proportion of 
patients in 
q4w, q8w, 
q12w intervals 
at the last 
treatment 
interval with 
no disease 
activity 
assessed at 
Week 32; 
excluding 
patients with 
protocol 
deviations 
with impact as 
per definition 
of PPS
PPS**
Before Week 
16 (initiation 
phase): q4w
From Week 
16 included 
(TtC phase): 
last interval 
with no 
disease 
activity (if 
there was 
disease 
activity, the 
last interval 
will be 
shortened by 
4 weeks, 
down to a 
minimum of 4 
weeks)
*Last interval 
with no 
disease 
activity (if 
there was 
disease 
activity, the 
last interval 
will be 
shortened by 
4 weeks, 
down to a 
minimum of 4 
weeks)
Superiority 
testing using a 
one-sided 
Wilcoxon test

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Estimand
Estimand 
definition
Analysis set, 
data included 
in the 
analyses
Use of data after intercurrent 
event (missing data 
imputation techniques)
Statistical 
methods
Discontinuati
on of study 
treatments
Treatment 
interruption
Supportive 
estimand 2 
(change in 
BCVA)
Average 
BCVA change 
from baseline 
at Week 28 
and Week 32; 
excluding 
patients with 
protocol 
deviations 
with impact as 
per definition 
of PPS
PPS**
PPS** data 
collected until 
the participant 
discontinued 
study 
treatment and 
started 
alternative 
treatment(s), 
will be 
included. 
BCVA scores 
collected after 
subjects 
discontinued 
early from 
study 
treatment will 
not be 
analyzed
LOCF
LOCF
Analysis of 
variance 
(ANOVA) 
model 
including 
terms for 
treatment arm 
(factor), 
baseline 
BCVA 
categories 
and age 
categories
Sensitivity to 
primary 
estimand 1 
(interval 
distribution)
Proportion of 
patients in 
(q4w, q8w, 
q12w) at the 
last treatment 
interval with 
no disease 
activity 
assessed at 
Week 32
FAS
Before Week 
16 (initiation 
phase): q4w
From Week 
16 included 
(TtC phase): 
last interval 
with no 
disease 
activity (if 
there was 
disease 
activity, the 
last interval 
will be 
shortened by 
4 weeks, 
down to a 
minimum of 4 
weeks)
*Last interval 
with no 
disease 
activity (if 
there was 
disease 
activity, the 
last interval 
will be 
shortened by 
4 weeks, 
down to a 
minimum of 4 
weeks)
Cumulative 
logistic model 
with the 
proportional 
odds 
assumption

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Estimand
Estimand 
definition
Analysis set, 
data included 
in the 
analyses
Use of data after intercurrent 
event (missing data 
imputation techniques)
Statistical 
methods
Discontinuati
on of study 
treatments
Treatment 
interruption
Sensitivity to 
primary 
estimand 2 
(change in 
BCVA)
Average 
BCVA change 
from baseline 
at Week 28 
and Week 32
FAS, FAS
data collected 
until the 
participant 
discontinued 
study 
treatment and 
started 
alternative 
treatment(s), 
will be 
included. 
BCVA scores 
collected after 
subjects 
discontinued 
early from 
study 
treatment will 
not be 
analyzed
LOCF
LOCF
Analysis of 
covariance 
(ANCOVA) 
model 
including 
terms for 
treatment arm 
(factor), 
baseline 
BCVA (as 
continuous 
variable) and 
age (as 
continuous 
variable)
Sensitivity to 
primary 
estimand 2 
(proportion in 
q12w)
Proportion of 
patients in 
q12w at the 
last treatment 
interval with 
no disease 
activity 
assessed at 
Week 32
FAS
Before Week 
16 (initiation 
phase): q4w; 
From Week 
16 included 
(TtC phase): 
last interval 
with no 
disease 
activity (if 
there was 
disease 
activity, the 
last interval 
will be 
shortened by 
4 weeks, 
down to a 
minimum of 4 
weeks)
*Last interval 
with no 
disease 
activity (if 
there was 
disease 
activity, the 
last interval 
will be 
shortened by 
4 weeks, 
down to a 
minimum of 4 
weeks)
Logistic model

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Estimand
Estimand 
definition
Analysis set, 
data included 
in the 
analyses
Use of data after intercurrent 
event (missing data 
imputation techniques)
Statistical 
methods
Discontinuati
on of study 
treatments
Treatment 
interruption
Sensitivity to 
primary 
estimand 3 
(proportion in 
q12w)
Proportion of 
patients in 
q12w at the 
last interval 
with no 
disease 
activity 
assessed at 
Week 32
PPS**
Before Week 
16 (initiation 
phase): q4w; 
From Week 
16 included 
(TtC phase): 
last interval 
with no 
disease 
activity (if 
there was 
disease 
activity, the 
last interval 
will be 
shortened by 
4 weeks, 
down to a 
minimum of 4 
weeks)
Last interval 
with no 
disease 
activity (if 
there was 
disease 
activity, the 
last interval 
will be 
shortened by 
4 weeks, 
down to a 
minimum of 4 
weeks)
Logistic model
LOCF: Last Observation Carried Forward
*: If the duration of the last interval falls within the following ranges of [q4w, q8w) or [q8w, q12w) or ≥ 
q12w then the floor value of these ranges i.e. q4w, q8w, or q12w, respectively, will be used for 
imputation.
**: Patients who take prohibited concomitant medication are already excluded from PPS as taking 
prohibited medication is considered a protocol deviation with impact.
12.4.4 Sensitivity and Supportive analyses
Sensitivity analyses
As a sensitivity analysis for the superiority of brolucizumab compared to aflibercept with 
respect to the last interval distribution with no disease activity (q4w, q8w, and q12w) at Week 
32 using a parametric method, a cumulative logistic model with consideration of the 
proportional odds assumption will be performed based on FAS (Table 12-1). The point estimate 
of the odds ratio of making response at or below any category of interval distribution between 
aflibercept and brolucizumab obtained from the model, the respective 95% confidence interval 
of the odds ratio and the P-value of the treatment effect in this model using the likelihood ratio 
test assessed at one-sided significance level of 0.025 will also be provided. In case the 
proportional odds assumption test is significant, the non-proportional odds assumption might 
be considered.
As a sensitivity analysis for the non-inferiority of brolucizumab compared to aflibercept with 
respect to average change in BCVA from baseline at Week 28 and Week 32, analysis of 
covariance (ANCOVA) including independent variables of treatment arm (factor), age 

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(continuous variable) and baseline BCVA (continuous variable) will be provided (Table 12-1). 
Other covariates may also be specified in the SAP.
Supportive analyses
As a supportive analysis, the analysis of the co-primary endpoints will be repeated based on 
PPS (Table 12-1).
All aforementioned missing data handling approaches will be applied for this supportive 
analysis too.
Sensitivity estimand in exposed and non-exposed to the urgent safety measures: As a 
sensitivity analysis for the superiority of brolucizumab compared to aflibercept with respect to 
the last interval distribution with no disease activity at Week 32, the proportion of subjects with 
12-week intervals as the last interval with no disease activity at Week 32 is compared before 
and after the urgent safety measures were introduced. The analyses are performed in FAS and 
PPS based on the Binomial test of proportions and the logistic regression model with 
adjustments for the baseline age and BCVA.
12.5
Analysis of secondary endpoints
12.5.1 Efficacy endpoint(s)
The secondary efficacy objectives and endpoints of this study are as follows:
To evaluate the durability of brolucizumab relative to aflibercept

Distribution of the last interval with no disease activity up to Week 64 (if there was 
disease activity, the last interval will be shortened by 4 weeks, down to a minimum of 4 
weeks) will be provided.

Distribution of the maximal interval with no disease activity up to Week 64 will be 
provided.

Number (%) of patients with no disease activity at Weeks 14 and 16 will be provided. In 
addition, 95% CI will also be provided.

Time from last loading injection to first visit with no disease activity will be descriptively 
summarized and Kaplan-Meier plots per treatment arm will be provided.
The FAS will be used to analyze durability outcomes.
To evaluate the functional outcomes of brolucizumab relative to aflibercept

Summary statistics of average change in BCVA from baseline at Week 60 and Week 64 
per treatment arm will be provided.

Number (%) of patients with occurrence of BCVA improvements of ≥ 10, and ≥ 15 letters 
from baseline at Week 32, Week 64 and the last injection visit per treatment arm will be 
provided.

Number (%) of patients with occurrence of BCVA ≥ 69 letters at Week 32, Week 64 and 
the last injection visit per treatment arm will be provided.
The FAS will be used to analyze functional outcomes.
To evaluate the anatomical outcomes with brolucizumab relative to aflibercept

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
Average change in CSFT from baseline as assessed by SD-OCT at Weeks 28 and 32 per 
treatment arm will be provided.

Average change in CSFT from baseline as assessed by SD-OCT at Weeks 60 and 64 per 
treatment arm will be provided.

Number (%) of patients with presence of IRF and/or SRF and sub-RPE fluid in the central 
subfield, as assessed by SD-OCT at Weeks 28 and 32, by number of visits (0, 1, 2 visits) 
per treatment arm will be provided.

Number (%) of patients with presence of IRF and/or, SRF, and sub-RPE fluid in the 
central subfield, as assessed by SD-OCT at Weeks 60 and 64, by number of visits (0, 1, 2 
visits) per treatment arm will be provided.
The FAS will be used to analyze anatomical outcomes.
12.5.2 Safety endpoints
The safety set will be used for all safety analyses.
The secondary safety objective and endpoint of this study is as follows:
To assess the safety and tolerability of brolucizumab relative to aflibercept

Incidence of ocular and non-ocular AEs up to Week 64 per treatment arm will be 
provided.
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment arm.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death will be provided. In particular, 
summary tables for adverse events of special interest (AESIs) will summarize only on-treatment 
events, with a start date during the on-treatment period. A separate summary table will be 
provided for AEs of study eye, fellow eye and non-ocular AEs.
The on-treatment period lasts from the date of first administration of study treatment to 30 days 
after the last administration of study treatment (EOT) or EOS whichever is the latest.
Adverse events
All information obtained on adverse events will be displayed by treatment arm and subject. All 
collected AEs will be listed.
The number (%) of subjects with treatment emergent adverse events (events started after the 
first dose of study medication or events present prior to start of double-masked treatment but 
increased in severity based on preferred term) will be summarized in the following ways:

by treatment, primary system organ class and preferred term.

by treatment, primary system organ class, preferred term and maximum severity.
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, AESIs, and adverse events leading to discontinuation.
The number (%) of subjects with adverse events of special interest will be summarized by 
treatment, primary system organ class and preferred term.

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12.8
Sample size calculation
12.8.1 Primary endpoint(s)
The sample size calculation is based on the co-primary endpoint of the distribution of the last 
interval with no disease activity up to Week 32 and average change in BCVA from baseline at 
Weeks 28 and 32 using the following assumptions derived from the HAWK and HARRIER 
studies. The sample size analyses were performed before the urgent safety measures were 
introduced.

expected interval distribution for aflibercept 2 mg and brolucizumab 6 mg (Table 12-2)
Table 12-2
Expected interval distribution for aflibercept 2 mg and brolucizumab 
6 mg
Treatment
4w
8w
12w
Aflibercept
20%
35%
45%
Brolucizumab
13%
32%
55%

common standard deviation of change in BCVA from baseline of 13 letters for both 
brolucizumab and aflibercept.
In order to calculate the sample size for the co-primary endpoint of:
1. Superiority of brolucizumab over aflibercept in terms of interval distribution; AND
2. Non-inferiority of brolucizumab compared to aflibercept in terms of average change in 
BCVA from baseline at Week 28 and Week 32.
Two one-sided tests each with α = 0.025 and power of 80% are conducted.
For superiority of the interval distribution, a one-sided Wilcoxon test for comparing two ordered 
multinomial populations (H0: brolucizumab and aflibercept interval distribution are equal, vs 
H1: brolucizumab interval distribution is larger than aflibercept interval distribution) is 
performed which results in a sample size of 622 patients.
Secondly, for non-inferiority of average change in BCVA from baseline, a one-sided T-test 
assuming equal means with non-inferiority margin of 4 letters and a common standard deviation 
of 13 letters is performed which provides a sample size of 334 patients.
As in this co-primary endpoint, both superiority in terms of interval distribution and non-
inferiority in terms of change in BCVA from baseline must be met, the maximum sample size 
of two hypothesis testings, i.e. 622, is considered. With the sample size of 622 patients, an 
overall power of 77.5% for the co-primary endpoint is obtained (97% re-calculated power for 
non-inferiority in terms of BCVA).
Finally, to take into account loss to follow-up of 10%, the required sample size of the study will 
be 692 patients, who will be randomized to each treatment arm in a 1:1 ratio (346 patients in 
each treatment arm).
The sample size calculations were performed using StatXact 9.0 and PASS 11.

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

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

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15
References
References are available upon request
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Holz FG, Tadayoni R, Beatty S, et al (2015) Multi-country real-life experience of anti-
vascular endothelial growth factor therapy for wet age-related macular degeneration. Br J 
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Koh A, Lanzetta P, Lee WK, et al (2017) Recommended Guidelines for Use of Intravitreal 
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Appendices
Not applicable.