A Multicenter, Randomized, Double-masked Phase 3a Study to Assess Safety and Efficacy of Brolucizumab 6 mg q4 Weeks Compared to Aflibercept 2 mg q4 Weeks in Patients With Neovascular Age-related Macular Degeneration (nAMD) With Persistent Retinal Fluid (MERLIN)
Phase: PHASE3
Conditions: Age-Related Macular Degeneration
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development 
RTH258/Brolucizumab 
Clinical Trial Protocol CRTH258AUS04 / NCT03710564
A multicenter, randomized, double-masked Phase 3a study 
to assess safety and efficacy of brolucizumab 6 mg q4 
weeks compared to aflibercept 2 mg q4 weeks in patients 
with neovascular age-related macular degeneration (nAMD) 
with persistent retinal fluid (MERLIN) 
Document type: 
Amended Protocol Version 
EUDRACT number: 
N/A 
Version number: 
03 (Clean) 
Clinical trial phase: 
IIIa 
Release date: 
11-Jun-2020
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 2.0 (01-Aug-2018) 

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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 9 
Amendment 03 ......................................................................................................................... 11 
Protocol summary .............................................................................................................. 14 
1 
Introduction ....................................................................................................................... 18 
1.1 
Background ............................................................................................................ 18 
1.2 
Purpose .................................................................................................................. 19 
2 
Objectives and endpoints ................................................................................................... 20 
3 
Study design ...................................................................................................................... 21 
4 
Rationale ............................................................................................................................ 22 
4.1 
Rationale for study design ..................................................................................... 22 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 23 
4.3 
Rationale for choice of comparator ....................................................................... 23 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 23 
4.5 
Risks and benefits .................................................................................................. 24 
5 
Population .......................................................................................................................... 24 
5.1 
Inclusion criteria .................................................................................................... 24 
5.2 
Exclusion criteria ................................................................................................... 25 
6 
Treatment ........................................................................................................................... 27 
6.1 
Study treatment ...................................................................................................... 27 
6.1.1 
Investigational and control drugs .......................................................... 27 
6.1.2 
Additional study treatments .................................................................. 28 
6.1.3 
Treatment arms/groups .......................................................................... 28 
6.1.4 
Treatment duration ................................................................................ 28 
6.2 
Other treatment(s) .................................................................................................. 28 
6.2.1 
Concomitant therapy ............................................................................. 28 
6.2.2 
Prohibited medication ........................................................................... 29 
6.3 
Subject numbering, treatment assignment, randomization .................................... 30 
6.3.1 
Subject numbering ................................................................................ 30 
6.3.2 
Treatment assignment, randomization .................................................. 30 
6.4 
Treatment masking ................................................................................................ 31 
6.5 
Dose escalation and dose modification .................................................................. 32 

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6.6 
Additional treatment guidance ............................................................................... 33 
6.6.1 
Treatment compliance ........................................................................... 33 
6.6.2 
Emergency breaking of assigned treatment code .................................. 33 
6.7 
Preparation and dispensation ................................................................................. 33 
6.7.1 
Handling of study treatment and additional treatment .......................... 34 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 34 
7 
Informed consent procedures............................................................................................. 36 
8 
Visit schedule and assessments ......................................................................................... 37 
8.1 
Screening ............................................................................................................... 41 
8.1.1 
Information to be collected on screening failures ................................. 42 
8.2 
Subject demographics/other baseline characteristics ............................................. 42 
8.3 
Efficacy .................................................................................................................. 42 
8.3.1 
Best-Corrected Visual Acuity ............................................................... 43 
8.3.2 
Spectral Domain Optical Coherence Tomography ............................... 43 
 
 43 
8.3.4 
Color fundus photography ..................................................................... 44 
8.3.5 
Fluorescein Angiography ...................................................................... 44 
8.3.6 
Appropriateness of efficacy assessments .............................................. 44 
8.4 
Safety/Tolerability ................................................................................................. 44 
8.4.1 
Laboratory evaluations .......................................................................... 47 
8.4.2 
Pregnancy and assessments of fertility.................................................. 48 
8.4.3 
Appropriateness of safety measurements .............................................. 48 
8.5 
Additional assessments .......................................................................................... 49 
8.5.1 
Clinical Outcome Assessments (COAs) ............................................... 49 
 
 49 
9 
Study discontinuation and completion .............................................................................. 50 
9.1 
Discontinuation ...................................................................................................... 50 
9.1.1 
Discontinuation of study treatment ....................................................... 50 
9.1.2 
Withdrawal of informed consent ........................................................... 50 
9.1.3 
Lost to follow-up ................................................................................... 51 
9.1.4 
Early study termination by the Sponsor ................................................ 51 
9.2 
Study completion and post-study treatment ........................................................... 52 
10 Safety monitoring and reporting ........................................................................................ 52 
10.1 
Definition of adverse events and reporting requirements ...................................... 52 
10.1.1 
Adverse events ...................................................................................... 52 
10.1.2 
Serious adverse events .......................................................................... 54 

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10.1.3 
SAE reporting ........................................................................................ 55 
10.1.4 
Pregnancy reporting .............................................................................. 55 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 55 
10.2 
Additional safety monitoring ................................................................................. 56 
10.2.1 
Liver safety monitoring ......................................................................... 56 
10.2.2 
Renal safety monitoring ........................................................................ 57 
11 Data collection and database management ........................................................................ 57 
11.1 
Data collection ....................................................................................................... 57 
11.2 
Database management and quality control ............................................................ 57 
11.3 
Site monitoring ...................................................................................................... 58 
11.4 
Data Monitoring Committee .................................................................................. 59 
12 Data analysis and statistical methods ................................................................................ 59 
12.1 
Analysis sets .......................................................................................................... 59 
12.2 
Subject demographics and other baseline characteristics ...................................... 60 
12.3 
Treatments ............................................................................................................. 60 
12.4 
Analysis of the primary endpoint ........................................................................... 60 
12.4.1 
Definition of primary endpoint ............................................................. 60 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 60 
12.4.3 
Handling of missing values/censoring/discontinuations ....................... 61 
12.4.4 
Sensitivity and Supportive analyses ...................................................... 61 
12.5 
Analysis of secondary endpoints ........................................................................... 61 
12.5.1 
Efficacy endpoints ................................................................................. 61 
12.5.2 
Safety endpoints .................................................................................... 62 
 
 63 
 
 63 
12.7 
Interim analyses ..................................................................................................... 64 
12.8 
Sample size calculation .......................................................................................... 64 
12.8.1 
Primary endpoint ................................................................................... 64 
13 Ethical considerations and administrative procedures....................................................... 65 
13.1 
Regulatory and ethical compliance ........................................................................ 65 
13.2 
Responsibilities of the Investigator and IRB/IEC ................................................. 65 
13.3 
Publication of study protocol and results ............................................................... 65 
13.4 
Quality Control and Quality Assurance ................................................................. 65 
14 Protocol adherence ............................................................................................................ 66 
14.1 
Protocol amendments ............................................................................................. 66 
15 References ......................................................................................................................... 67 

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16 Appendices ........................................................................................................................ 69 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs ......................... 69 
16.2 
Appendix 2: Liver event and laboratory trigger definitions and follow-up 
requirements .......................................................................................................... 70 
16.3 
Appendix 3: Specific renal alert criteria and actions and event follow-up ............ 71 
 
 
List of tables 
Table 2-1 
Objectives and related endpoints ........................................................... 20 
Table 6-1 
Investigational and control drugs .......................................................... 27 
Table 6-2 
Prohibited medication ........................................................................... 29 
Table 8-1 
Assessment schedule ............................................................................. 38 
Table 8-2 
Assessments & specifications ............................................................... 44 
Table 8-3 
Laboratory assessments ......................................................................... 48 
Table 10-1 
Guidance for capturing the study treatment errors ................................ 56 
Table 16-1 
Clinically notable laboratory values ...................................................... 69 
Table 16-2 
Liver event and laboratory trigger definitions ....................................... 70 
Table 16-3 
Specific renal alert criteria and actions ................................................. 71 
 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 22 
Figure 6-1 
Dosing schedule .................................................................................... 35 

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List of abbreviations 
 
ACR 
Albumin-Creatinine Ratio 
 
 
AE 
Adverse Event 
A/G 
Albumin/Globulin (ratio) 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AMD 
Age-related Macular Degeneration 
ANOVA 
Analysis of Variance 
Anti-VEGF 
Anti-Vascular Endothelial Growth Factor 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical (classification system) 
BCVA 
Best-Corrected Visual Acuity 
BL 
Baseline 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CFR 
Code of Federal Regulations 
CFP 
Color Fundus Photography 
CI 
Confidence Interval 
cm 
Centimeter(s) 
CMO&PS 
Chief Medical Office and Patient Safety 
CNV 
Choroidal Neovascularization 
CO 
Country Organization 
COA 
Clinical Outcome Assessment 
COVID-19 
Coronavirus disease 2019 
CRC 
Central Reading Center 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSM 
Clinical Site Management 
CST 
Central Subfield Thickness 
CTM 
Clinical Trial Management 
DMC 
Data Monitoring Committee 
DME 
Diabetic Macular Edema 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
EoS 
End of Study 
ESI 
Event(s) of Special Interest 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EU 
European Union 
FA 
Fluorescein Angiography 
FAF 
Fundus Autofluorescence 
FAS 
Full Analysis Set 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl Transferase 
h 
Hour 
HA 
Health Authority 

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HCG 
Human Chorionic Gonadotropin 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IgG 
Immunoglobulin G 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IOI 
Intra-ocular Inflammation 
IOP 
Intra-ocular Pressure 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IRE 
Intra-retinal Edema 
IRF 
Intra-retinal Fluid 
IRT 
Interactive Response Technology 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
IVT 
Intravitreal 
kDa 
kiloDalton 
kg 
kilogram(s) 
LDH 
Lactate Dehydrogenase 
LFT 
Liver Function Test 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram(s) 
mL 
Milliliter(s) 
mm 
Millimeter(s) 
mmHg 
Millimeter(s) Mercury 
nAMD 
Neovascular Age-Related Macular Degeneration 
No. 
Number 
OCT 
Optical Coherence Tomography 
 
 
PCR 
Protein-Creatinine Ratio 
PD 
Protocol Deviation 
 
 
PFS 
Prefilled syringe 
pH 
Potential Hydrogen 
prn 
As needed (from Latin pro re nata) 
PPS 
Per-Protocol Set 
q 
Every (from Latin quaque) 
QMS 
Quality Management System 
RAO 
Retinal Arterial Occlusion 
RAP 
Retinal Angiomatous Proliferation 
RAS 
Randomized Analysis Set 
RBC 
Red Blood Cell(s) 
RPE 
Retinal Pigment Epithelium 

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RVO 
Retinal Vein Occlusion 
SAE 
Serious Adverse Event 
scFv 
Single-chain Variable Fragment 
sCr 
Serum Creatinine 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SOC 
Standard of Care 
SOM 
Site Operations Manual 
SOP 
Standard Operating Procedure 
SRF 
Sub-retinal Fluid 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TFQ 
Trial Feedback Questionnaire 
TBL 
Total Bilirubin 
ULN 
Upper Limit of Normal 
US 
United States 
VA 
Visual Acuity 
VEGF 
Vascular Endothelial Growth Factor 
VEGFR 
Vascular Endothelial Growth Factor Receptor 
w 
Week 
WBC 
White Blood Cell(s) 
WHO 
World Health Organization 
WoC 
Withdrawal of Consent 
YAG 
Yttrium Aluminum Garnet 

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Glossary of terms 
Additional treatment 
Medicinal products that may be used during the clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g. any background 
therapy) 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, 
urine, stool, etc. taken from a study subject 
Control drug 
A study drug (active or placebo) used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug 
Cycles 
Number and timing or recommended repetitions of therapy are usually expressed as 
number of days (e.g., q28 days) 
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 (CRFs) which are used to capture data transcribed 
from paper source forms used at the point of care. 
End of the clinical trial 
The end of the clinical trial is defined as the last visit of the last subject or at a later 
point in time as defined by the protocol 
Enrollment 
Point/time of subject entry into the study at which informed consent must be 
obtained 
Investigational drug/ 
treatment 
The drug whose properties are being tested in the study 
Masked/evaluating 
investigator 
For the entire study duration and all study 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 intravitreal [IVT] injections) 
Medication number 
A unique identifier on the label of medication kits 
Mis-randomized 
subjects 
Mis-randomized subjects are those who were not qualified for randomization and 
who did not take study treatment, but have been inadvertently randomized into the 
study 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy) 
Part 
A sub-division of a study used to evaluate specific objectives or contain different 
populations. For example, one study could contain a single dose part and a multiple 
dose part, or a part in subjects with established disease and in those with newly 
diagnosed disease. 
Patient 
An individual with the condition of interest for the study 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) which are 
described in the Protocol. Periods define the study phases and will be used in 
clinical trial database setup and eventually in analysis. 
Personal data 
Subject information collected by the Investigator that is transferred to Novartis for 
the purpose of the clinical trial. This data includes subject identifier information, 
study information and biological samples. 
Premature subject 
withdrawal 
Point/time when the subject exits from the study prior to the planned completion of 
all study drug administration and/or 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 
Screen Failure 
A subject who did not meet one or more criteria that were required for participation 
in the study 

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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. 
Start of the clinical trial 
The start of the clinical trial is defined as the signature of the informed consent by 
the first subject 
Study treatment 
Any single drug or combination of drugs or intervention administered to the subject 
as part of the required study procedures 
Study treatment 
discontinuation 
When the subject permanently stops taking any of the study drug(s) prior to the 
defined study treatment completion date (if any) for any reason; may or may not also 
be the point/time of study discontinuation 
Subject 
A trial participant (can be a healthy volunteer or a patient) 
Subject number 
A unique number assigned to each subject upon signing the informed consent. This 
number is the definitive, unique identifier for the subject and should be used to 
identify the subject throughout the study for all data collected, sample labels, etc. 
Treatment arm/group 
A treatment arm/group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts 
Unmasked/treating 
investigator 
For the entire study duration and all study subjects, the treating investigator only 
performs the IVT injection and assesses patient safety following the IVT injections 
Variable 
A measured value or assessed response that is determined from specific 
assessments and used in data analysis to evaluate the drug being tested in the 
study 
Visual acuity examiner 
For the entire study duration and all study subjects, the visual acuity examiner 
(which could be the masked/evaluating investigator) performs the BCVA 
assessment and is masked to the assigned treatment 
Withdrawal of study 
consent (WoC) 
Withdrawal of consent from the study occurs only when a subject does not want to 
participate in the study any longer and does not allow any further collection of 
personal data 

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IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority approval 
according to local regulations prior to implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
 
Site Operations Manual (SOM)/Operational Manual 
A Site Operations Manual (SOM)/Operational Manual accompanies this protocol, providing 
the operational details for study procedures. Note: The SOM will not be a part of the Clinical 
Study Report. 

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Protocol summary 
Protocol number 
CRTH258AUS04 
Full title 
A multicenter, randomized, double-masked Phase 3a study to assess safety 
and efficacy of brolucizumab 6 mg q4 weeks compared to aflibercept 2 mg q4 
weeks in patients with neovascular age-related macular degeneration 
(nAMD) with persistent retinal fluid (MERLIN) 
Brief title 
Study of safety and efficacy of brolucizumab 6 mg dosed every 4 weeks 
compared to aflibercept 2 mg dosed every 4 weeks in patients with retinal 
fluid despite frequent anti-VEGF injections 
Sponsor and 
Clinical Phase 
Novartis; Phase 3a 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of this study is to compare safety and efficacy of brolucizumab 6 
mg dosed every 4 weeks to aflibercept 2 mg dosed every 4 weeks in those 
nAMD patients with retinal fluid despite frequent anti-VEGF injections 
Primary Objective 
The primary objective of this study is to evaluate whether brolucizumab 6 mg 
dosed every 4 weeks is non-inferior to aflibercept 2 mg dosed every 4 weeks 
in BCVA change from Baseline to Week 52 
Secondary 
Objectives 
1. To assess efficacy of brolucizumab 6 mg dosed every 4 weeks compared 
with aflibercept 2 mg dosed every 4 weeks with respect to visual acuity 
(VA) stabilization or improvement at Week52 and 104 
2. To evaluate anatomic parameters of disease activity and retinal fluid 
status in patients treated with brolucizumab 6 mg dosed every 4 weeks 
compared with aflibercept 2 mg dosed every 4 weeks at Weeks 52 and 
104 
3. To assess safety and tolerability of brolucizumab 6 mg dosed every 4 
weeks compared with aflibercept 2 mg dosed every 4 weeks 
Study design 
This is a multi-center, double-masked, parallel group study with 2 arms 
randomized in a 2:1 (brolucizumab:aflibercept) ratio. 
Total study duration is 104 weeks from Baseline. All participants will have 
study visits every 4 weeks through Week 104. The primary analysis will be 
performed at Week 52. 
Population 
The study population will consist of male and female patients, 50 years or 
older, who have received recent, frequent anti-VEGF treatments for their 
nAMD. Approximately 860 patients will be screened to randomize 513 
patients in approximately 66 centers in the United States. All patients that are 
currently enrolled in the study can continue up to 104 weeks if they consent 
to extend their treatment. 
Key Inclusion 
criteria 
• 
Signed informed consent must be obtained prior to participation in the 
study 
• 
Active CNV lesions secondary to AMD that affect the central subfield 
(including retinal angiomatous proliferation [RAP] lesions with a CNV 
component) and which has associated Intra-retinal Fluid (IRF) or Sub- 
retinal Fluid (SRF) within the central 3 mm subfield in the study eye, 
confirmed by the Central Reading Center (CRC) at Screening 

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• 
Total area of CNV (including both classic and occult components) must 
comprise >50 % of the total lesion area in the study eye, confirmed by 
CRC at Screening 
• 
Received first anti-VEGF injection for nAMD in the study eye a 
minimum of 9 months prior to Screening 
• 
If first anti-VEGF injection for nAMD in the study eye received ≤36 
months prior to Screening: BCVA ≥55 letters (approximate Snellen 
equivalent 20/80), inclusive, in the study eye at Screening and 
Baseline using Early Treatment Diabetic Retinopathy Study (ETDRS) 
testing; If first anti-VEGF injection for nAMD in the study eye received 
>36 months prior to Screening: BCVA ≥65 letters (approximate 
Snellen equivalent 20/50), in the study eye at Screening and Baseline 
using ETDRS testing 
• 
Received at least 7 anti-VEGF injections in immediate prior 9 months; 
with the last two injections having been licensed anti-VEGF (aflibercept 
or ranibizumab) 
• 
Demonstrated nAMD fluid improvement or partial response with anti- 
VEGF therapy as determined by Investigator 
• 
Patients must have persistent IRF and/or SRF at Screening and 
Baseline as determined by Investigator 
Key Exclusion 
criteria 
• 
Any active intra-ocular or peri-ocular infection or active intra-ocular 
inflammation 
(e.g. 
infectious 
conjunctivitis, 
keratitis, 
scleritis, 
endophthalmitis, infectious blepharitis) in either eye at Screening and 
Baseline 
• 
Total area of fibrosis ≥ 50 % of the total lesion in the study eye, 
confirmed by CRC at Screening 
• 
Fovea of the study eye must not be affected by sub-retinal fibrosis or 
geographic atrophy by clinical exam and OCT, confirmed by CRC at 
Screening 
• 
Sub-retinal blood affecting the foveal center point and/or ≥ 50 % of the 
lesion of the study eye, confirmed by CRC at Screening 
• 
History or evidence of the following in the study eye: 
o 
Intra-ocular or refractive surgery within the 90 day period prior 
to Screening 
o 
Previous penetrating keratoplasty, vitrectomy or ocular 
radiation 
o 
Previous panretinal photocoagulation 
o 
Previous treatment with verteporfin photodynamic therapy 
o 
Previous submacular surgery, other surgical intervention or 
laser treatment for AMD 
o 
Uncontrolled glaucoma defined as intra-ocular pressure (IOP) 
>25 mmHg on medication or according to Investigator’s 
judgment at Screening or Baseline 

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o 
Aphakia and/or absence of the posterior capsule at Screening 
or Baseline. Yttrium Aluminum Garnet (YAG) laser posterior 
capsulotomy secondary to uncomplicated cataract extraction 
with posterior intraocular lens implantation is allowed when 
>30 days from screening. 
o 
Intra- or peri-ocular use of corticosteroids during the 6 month 
period prior to Baseline 
o 
Use of topical ocular corticosteroids for 30 or more 
consecutive days within the 90 days prior to Screening 
• 
Participation in an investigational drug, biologic, or device study within 
30 days or the duration of 5 half-lives of the IP (whichever is longer) 
prior to first dose Note: observational clinical studies solely involving 
over-the-counter vitamins, supplements, or diets are not exclusionary 
• 
Pregnant or nursing (lactating) women and women of childbearing 
potential, defined as all women physiologically capable of becoming 
pregnant, unless they are using highly effective methods of 
contraception while taking study treatment and for 3 months after 
stopping medication 
Study treatment 
• 
Brolucizumab 6 mg 
• 
Aflibercept 2 mg 
Efficacy 
assessments 
• 
BCVA 
• 
Spectral domain optical coherence tomography 
 
 
• 
Color fundus photography 
• 
Fluorescein angiography 
Key safety 
assessments 
• 
Ophthalmic examination (IOP, slit-lamp, and fundus exam) 
• 
Fundus autofluorescence 
• 
Color Fundus Photography (preferably wide-field or with peripheral 
sweeps) 
• 
Post-injection assessment 
• 
Treatment emergent AEs, including AEs of special interest 
Other 
assessments 
 
 
 
 
• 
Vascular Endothelial Growth Factor (VEGF) 
Data analysis 
Primary analysis data set: 
The primary efficacy analysis will be performed using FAS. 
The primary presentation of efficacy results will use Last-Observation-Carried- 
Forward (LOCF) approach for the imputation of missing values. All non- 
missing post-Baseline values including assessments done at unscheduled 
visits will be used when implementing the LOCF imputation. Baseline values 
will not be carried forward. 

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Primary endpoint: 
The primary endpoint is the change in BCVA from Baseline to Week 52 or the 
last BCVA obtained before discontinuation from the study, whichever occurs 
first. 
Primary statistical method: 
Difference in means (brolucizumab q4 week dosing minus aflibercept q4 week 
dosing), calculated based on analysis of variance (ANOVA) model with the 
primary efficacy endpoint as the response variable, treatment, Baseline BCVA 
categories (<=70 >=71 letters), immediate prior treatment (aflibercept or 
ranibizumab) and time since first anti-VEGF injection (≤36 months, >36 
months), and age categories (<75, >=75 years) as factors and its two-sided 
95% confidence interval (CI) will be calculated for the primary efficacy analysis. 
Baseline BCVA is defined as the last measurement on or prior to Baseline visit. 
A non-inferiority of brolucizumab 6 mg dosed every 4 weeks to aflibercept 2 
mg dosed every 4 weeks will be established if the lower limit of the 95 % CI 
mentioned above is greater than -4 letters (corresponding to the non-inferiority 
margin of 4 letters). 
Sample size justification: 
The primary efficacy variable is change in BCVA from Baseline. The primary 
analysis time point is Week 52. 
As suggested by the US regulatory authority, a non-inferiority margin of 4 
letters is considered a clinically acceptable difference of brolucizumab 6 mg 
dosed every 4 weeks compared to aflibercept 2 mg dosed every 4 weeks in a 
previously treated population and will be utilized in this study. 
In SAVE study (Brown 2013) of ranibizumab (n=87), a standard deviation of 
6.4 letters for the change in BCVA from Baseline was observed at Month 3. In 
ASSESS study (Singh 2015) (n=26), a standard deviation of 9.2 letters was 
obtained at Month 12. In this study, a standard deviation of 10 letters for the 
change in BCVA from Baseline to Week 52 in pre-treated patients is assumed. 
To meet US regulatory authority recommendation for safety assessment, 
data for brolucizumab 6 mg dosed every 4 weeks from at least 300 subjects 
with 12-month exposure are required. Thus, 450 subjects will be needed with 
a 2:1 ratio to brolucizumab 6 mg q4 weeks (300 subjects) and aflibercept 2 
mg q4 weeks (150 subjects). This sample size is sufficient to demonstrate 
non-inferiority (margin = 4 letters) of brolucizumab 6 mg q4 weeks versus 
aflibercept 2 mg q4 weeks with respect to BCVA change from Baseline to 
Week 52 at a two-sided alpha level of 0.05 with a power of approximately 
97% assuming equal efficacy and a common standard deviation of 10 letters. 
To account for a dropout rate of 12%, a total of 513 subjects (342 subjects to 
the brolucizumab 6 mg q4w arm and 171 to the aflibercept 2 mg q4w arm) 
will be randomized. The nQuery Advisor 7.0 was used for the above sample 
size calculations. 
Key words 
Neovascular age-related macular degeneration; nAMD; intravitreal injection; 
IVT; anti-VEGF; brolucizumab; aflibercept; EYLEA; double-masked; MERLIN 

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1 
Introduction 
1.1 
Background 
Age-related macular degeneration (AMD) is the leading cause of severe vision loss in people, 
affecting 10 – 13 % of individuals over the age of 65 in North America, Europe, and Australia 
(Kawasaki 2010, Rein 2009, Smith 2001). 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 1984, Lim 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 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 2007, Shah 2009). Without treatment, most affected eyes will 
have poor central vision (20/200) within 12 months (Blinder 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 anti- 
vascular endothelial growth factor (anti-VEGF) treatments (Ferris 1983, Sommer 1991, Wong 
2008). 
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 2000). 
The use of intravitreal (IVT) pharmacotherapy targeting VEGF has significantly improved 
visual outcomes in patients with nAMD (Bloch 2012, Campbell 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. 
Brolucizumab (RTH258, formerly known as ESBA1008), is a humanized single-chain variable 
fragment (scFv) inhibitor of VEGF with a molecular weight of ~26 kDa. Brolucizumab is an 
inhibitor of VEGF-A and 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. 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 IgG 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 3 pivotal studies (CRTH258A2301 [HAWK] and CRTH258A2302 
[HARRIER]), brolucizumab was non-inferior to aflibercept in best-corrected visual acuity 
(BCVA) change from Baseline at Week 48, with over half the subjects in the brolucizumab arm 
maintained exclusively on a q12 week dosing interval after 3 monthly (i.e. every 4 weeks) 
loading doses. Safety was comparable between the treatment arms. 

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In nAMD, there is well known individual variability in clinical response to anti-VEGF agents- 
underlying factors including genetics, VEGF expression, lesion size, type and maturity may 
influence treatment response and frequency (Muether 2013, Stewart 2015). 
In the United States, the Food and Drug Administration has approved monthly and pro re nata 
(prn) dosing regimens for aflibercept and ranibizumab for the treatment of nAMD, which 
provides flexibility to treat patients according to their individual needs. 
Retina specialists strive to individualize treatment strategies to prevent CNV recurrence; 
however, currently the causes of variability in anti-VEGF treatment need in nAMD patients are 
not well understood, nor is there an accepted biomarker to identify the required anti-VEGF 
treatment frequency in individual patients. Despite attempts to maximize and individualize 
therapy, retinal fluid may persist, potentially limiting visual outcomes (Wykoff 2014, Jaffe 
2016). In the pivotal studies of aflibercept, 28 – 36 % of subjects receiving bi-monthly 
aflibercept injections demonstrated residual intra-retinal edema (IRE) and/or sub-retinal fluid 
(SRF) following one year of treatment (Heier 2012). A post-hoc analysis of the VIEW data set 
showed that monthly dosing with aflibercept led to better fluid resolution in all compartments 
(Waldstein 2016) and in those subjects with early persistent fluid, monthly dosing of aflibercept 
led to improved BCVA gains at one year (Jaffe 2016). 
In the two phase 3 studies of brolucizumab in treatment-naïve patients with nAMD, 8 weeks 
after the loading phase (i.e. Week 16) 30 % and 34 % of brolucizumab subjects had SRF/intra- 
retinal fluid (IRF) present compared to 45 % and 52 % of subjects in the aflibercept arm. By 
Week 48, following a q12/q8 week dosing regimen, 26 % and 31 % of brolucizumab subjects 
continued to have retinal fluid compared to 44 % and 45 % of q8 week aflibercept-treated 
subjects. These data suggest that a subset of patients may achieve additional visual acuity gains 
combined with further fluid resolution with more frequent dosing of brolucizumab. 
Since the first marketing authorization approval of brolucizumab in October 2019 for the 
treatment of nAMD, adverse events of retinal vasculitis and/or retinal vascular occlusion, that 
my result in severe vision loss and typically in the presence of intraocular inflammation, have 
been reported from post-marketing experience with brolucizumab (Beovu). Considering these 
events, the overall risk/benefit assessment remains positive. 
 
1.2 
Purpose 
Brolucizumab has not been studied in a long-term dosing regimen more frequently than every 
8 weeks in patients with nAMD. Data related to a q4w dosing frequency is limited to a three- 
month loading phase. 
This study will provide 104 -week data evaluating the safety and efficacy of a monthly (i.e. 
every 4 weeks) brolucizumab treatment regimen in prior-treated patients with nAMD as 
compared to monthly aflibercept. Patients to be enrolled into this study have recently shown 
response to anti-VEGF treatment while requiring frequent injections (e.g., on average every 4 
– 5 weeks) to stabilize their CNV activity. 
Subjects may be eligible to continue into an extension study in order to receive treatment with 
brolucizumab (a) after completing the 104 -week double-masked treatment period, (b) upon 
meeting all inclusion/exclusion criteria for the extension study, and (c) based on Investigator’s 

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judgment that the subject is expected to benefit from treatment with brolucizumab. The 
objective of the extension study is to assess safety and efficacy of brolucizumab for an extended 
period. 
 
 
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 evaluate whether brolucizumab 6 mg 
dosed every 4 weeks is non-inferior at 
Week 52 to aflibercept 2 mg dosed every 
4 weeks 
• 
Change in BCVA from Baseline to Week 52 
 
Secondary Objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To assess efficacy of brolucizumab 6 mg 
dosed every 4 weeks compared with 
aflibercept 2 mg dosed every 4 weeks with 
respect to visual acuity (VA) stabilization 
or improvement at weeks 52 and 104 
• 
To evaluate anatomic parameters of 
disease activity and retinal fluid status in 
patients treated with brolucizumab 6 mg 
dosed every 4 weeks compared with 
aflibercept 2 mg dosed every 4 weeks 
• 
To assess safety and tolerability of 
brolucizumab 6 mg dosed every 4 weeks 
compared with aflibercept 2 mg dosed 
every 4 weeks 
Efficacy Endpoints 
• 
VA stabilization or improvement at Week 52 and Week 
104 
• 
Loss in BCVA of 5/10/15 letters or more from Baseline to 
post-baseline visit 
• 
Gain in BCVA of 5/10/15 letters or more from Baseline to 
post-baseline visit 
• 
Change in central subfield thickness (CST) from 
Baseline to post-baseline visit 
• 
Absence of IRF and/or SRF at post-baseline visit 
• 
Absence of sub-RPE fluid at post-baseline visit in 
patients with sub-RPE fluid at Baseline 
• 
Fluid free status- no IRF, SRF or sub-RPE fluid at post- 
baseline treatment visit 
• 
Time to first dry retina (no IRF or SRF) 
• 
Time to sustained dry retina (no IRF or SRF at ≥ 2 
consecutive visits) 
Additional Endpoints 
 
 
 
 
Safety and Tolerability Endpoints 
• 
Incidence of treatment-emergent Adverse Events (AEs) 
• 
Treatment-emergent changes in ocular and systemic 
parameters 
 
 
 

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Objective(s) 
Endpoint(s) 
 
 
 
 
 
3 
Study design 
This is a multi-center, randomized, double-masked, parallel group study. This study has 2 
masked arms where patients will be randomized with a 2:1 (brolucizumab:aflibercept) ratio. 
All participants will have study visits every 4 weeks through Week 104 If a patient had 
discontinued in the first year (prior to week 52) they are not eligible to return into the study. 
The primary analysis of efficacy and safety data will be performed at Visit 14 (Week 52) (Figure 
3-1). 
Screening Period 
Patients will be screened for enrollment into the double-masked treatment period at the 
Screening Visit. The screening period may last up to 14 days prior to administration of the first 
dose of study treatment, dependent upon confirmation of the patient meeting eligibility criteria. 
Screening must occur between 21 and 31 days from the patient’s last Standard of Care (SOC) 
anti-VEGF injection. 
Including the Screening Period, the total study duration for a patient may be up to 106 weeks. 
Double-Masked Treatment Period 
Subjects meeting eligibility criteria will enter the treatment period and be randomized into one 
of the following 2 masked treatment arms at the Baseline visit: 
Masked Arm 1: Brolucizumab 6 mg q4 weeks 
Brolucizumab 6 mg will be injected every 4 weeks up to and including Visit 26 (Week 
100 ). 
Masked Arm 2: Aflibercept 2 mg q4 weeks 
Aflibercept 2 mg will be injected every 4 weeks up to and including Visit 26 (Week 
100 ). 
The first dose of masked study treatment must be administered between 28 and 38 days from 
the subject’s last SOC anti-VEGF injection. 
The primary endpoint will be evaluated at, Visit 14 (Week 52). 

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Figure 3-1 
Study design 
 
 
 
 
Subjects may be eligible to continue into an extension study in order to receive treatment with 
brolucizumab (a) after completing the 104 -week double-masked treatment period, (b) upon 
meeting all inclusion/exclusion criteria for the extension study, and (c) based on Investigator’s 
judgment that the subject is expected to benefit from treatment with brolucizumab. The 
objective of the extension study is to assess safety and efficacy of brolucizumab for an extended 
period. 
 
4 
Rationale 
4.1 
Rationale for study design 
This multicenter study is designed to evaluate whether brolucizumab 6 mg dosed every 4 weeks 
is safe and effective in nAMD patients with persistent fluid. To support efficacy assessments, 
anatomic parameters of disease activity and retinal fluid status change from Baseline will be 
evaluated. 
 
The inclusion criteria aim to identify a population of patients diagnosed with nAMD that have 
received recent, frequent anti-VEGF injections with a positive response to treatment and have 

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residual intra- and/or sub-retinal fluid. In order to demonstrate potential clinical benefit of more 
frequent dosing, patients with good vision will be included; this patient population has not been 
previously studied with brolucizumab and is described in more detail in Section 5 below. 
 
4.2 
Rationale for dose/regimen and duration of treatment 
While there is well known variability in treatment need amongst nAMD patients, the underlying 
causes are unknown and there is no accepted biomarker to identify the required anti-VEGF 
treatment frequency in individual patients. Monthly dosing of aflibercept has been shown to 
improve fluid resolution and BCVA gains compared to bi-monthly dosing in a subgroup of 
nAMD patients with persistent retinal fluid (Jaffe 2016). 
Analysis of data up to Week 96 from the CRTH258A2301 and CRTH258A2302 studies 
demonstrated non-inferiority in BCVA for brolucizumab 6 mg dosed q12/q8 weeks compared 
to aflibercept dosed q8 weeks in naïve nAMD patients. The current study will evaluate whether 
brolucizumab 6 mg dosed every 4 weeks is non-inferior to aflibercept 2 mg dosed every 4 weeks 
in change in BCVA in patients with retinal fluid despite frequent anti-VEGF injections. 
A data gap exists in understanding the long term impact of monthly treatment in patients with 
persistent retinal fluid. Increasing the study duration to 104 weeks will generate supporting 
efficacy and safety data for an extended period for brolucizumab 6 mg dosed q4 weeks 
compared to aflibercept 2 mg dosed q4 weeks in patients with nAMD and persistent retinal 
fluid. 
The primary analysis of efficacy and safety data will be performed at Week 52 (visit 14) In a 
study of monthly aflibercept, BCVA gains have been observed from Week 12 to Week 52, 
indicating that an efficacy assessment may be made at this time-point (Jaffe 2016). 
 
4.3 
Rationale for choice of comparator 
Aflibercept 2 mg is an established standard of care option in treatment of nAMD and has been 
chosen as comparator for this study due to the approved dose and posology of aflibercept 
(EYLEA®) in the US for the targeted indication. 
 
4.4 
Purpose and timing of interim analyses/design adaptations 
There will be one interim analysis after the last patient completes his/her Week 52 (primary 
analysis time point) visit. 
The presentation of tables, listings, and figures will include data up to patients’ date of Week 
52 visit (inclusive). For adverse events and concomitant medications, Week 52 data including 
30 days after patients’ last IP administration at Week 48 will be included. All available data for 
patients discontinuing the study prior to Week 52 will be included in the interim analysis. 
This interim analysis will be the primary analysis. There will be no hypothesis testing at Week 
104. Therefore, no adjustment of the statistical significant level will be made for the primary 
hypothesis testing at Week 52. 

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4.5 
Risks and benefits 
Brolucizumab is an inhibitor of VEGF with a mechanism of action similar to ranibizumab with 
a smaller molecular size (~26 kDa and ~48 kDa, respectively). 
Analysis of data up to Week 48 from the CRTH258A2301 and CRTH258A2302 studies 
demonstrated non-inferiority in BCVA for brolucizumab dosed q12/q8 weeks compared to 
aflibercept in naïve nAMD patients. Ocular and non-ocular (systemic) adverse events were 
comparable between the two groups. 
Patients in both treatment groups experienced robust visual gains; however, there may be a 
subgroup of patients that require more frequent anti-VEGF injections and would benefit 
clinically from a monthly (q4 week) dosing schedule of brolucizumab. This effect has also been 
seen in the analyses of aflibercept studies, specifically in patients with unresolved fluid. 
Monthly dosing of aflibercept in this sub-population improved both BCVA and anatomical 
endpoints compared to q8 week aflibercept. Monthly treatment with brolucizumab may provide 
similar benefit. 
There is an unmet medical need for patients with remaining retinal fluid despite a q8 week 
brolucizumab treatment regimen. Brolucizumab has not been studied in a dosing regimen more 
frequently than every 8 weeks in patients with nAMD. This study will evaluate whether 
brolucizumab 6 mg dosed every 4 weeks is non-inferior (as measured by BCVA gains) to 
aflibercept 2 mg dosed every 4 weeks. 
Women of childbearing 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. 
Further details of the known and potential risks and benefits associated with brolucizumab are 
presented in the Investigator’s Brochure (IB). 
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. 
 
5 
Population 
The study population will consist of male and female patients. Approximately 860 patients are 
expected to be screened with 513 patients to be randomized at approximately 66 sites in the 
United States. Patients who will consent will be extended in the study to continue until 104 
weeks. If a patient had discontinued in the first year (prior to week 52) they are not eligible to 
return to the study. 
 
5.1 
Inclusion criteria 
Subjects eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study 
2. Subjects must be 50 years of age or older at Screening 

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3. Active CNV lesions secondary to AMD that affect the central subfield (including retinal 
angiomatous proliferation [RAP] lesions with a CNV component) and which has 
associated IRF or SRF within the central 3 mm subfield in the study eye, confirmed by the 
Central Reading Center (CRC) at Screening 
4. Total area of CNV (including both classic and occult components) must comprise > 50 % 
of the total lesion area in the study eye, confirmed by CRC at Screening 
5. Received first anti-VEGF injection for nAMD in the study eye a minimum of 9 months 
prior to Screening 
6. If first anti-VEGF injection for nAMD in the study eye received ≤ 36 months prior to 
Screening: BCVA ≥ 55 letters (approximate Snellen equivalent 20/80), inclusive, in the 
study eye at Screening and Baseline using Early Treatment Diabetic Retinopathy Study 
(ETDRS) testing; If first anti-VEGF injection for nAMD in the study eye received > 36 
months prior to Screening: BCVA ≥ 65 letters (approximate Snellen equivalent 20/50), in 
the study eye at Screening and Baseline using ETDRS testing 
7. Received at least 7 anti-VEGF injections in immediate prior 9 months; with the last two 
injections having been licensed anti-VEGF (aflibercept or ranibizumab) 
8. Demonstrated nAMD fluid improvement or partial response with anti-VEGF therapy as 
determined by Investigator 
9. Patients must have persistent IRF and/or SRF at Screening and Baseline as determined by 
Investigator 
 
5.2 
Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in this study. 
1. Any active intra-ocular or peri-ocular infection or active intra-ocular inflammation (e.g. 
infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis) in 
either eye at Screening and Baseline 
2. Total area of fibrosis ≥ 50 % of the total lesion in the study eye, confirmed by CRC at 
Screening 
3. Fovea of the study eye must not be affected by sub-retinal fibrosis or geographic atrophy 
by clinical exam and Optical Coherence Tomography (OCT), confirmed by CRC at 
Screening 
4. Sub-retinal blood affecting the foveal center point and/or ≥ 50 % of the lesion of the study 
eye, confirmed by CRC at Screening 
5. Any history or evidence of a concurrent intra-ocular condition in the study eye, including 
retinal diseases other than nAMD, that, in the judgment of the Investigator, could either 
require medical or surgical intervention during the course of the study to prevent or treat 
visual loss that might result from that condition or that limits the potential to gain visual 
acuity upon treatment with the Investigational Product (IP) 
6. Any current or history of macular or retinal disease other than wet AMD provided they 
reduce visual acuity or may confound assessment of the macula (e.g. diabetic macular 
edema (DME), retinal vein occlusion (RVO), pathologic myopia, uveitis, angioid streaks, 
ocular histoplasmosis, retinal detachment, epiretinal membrane that induces retinal striae 

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within 1 mm of the foveal center, macular hole, central serous chorioretinopathy, 
polypoidal vasculopathy) 
7. RPE rip/tear in the study eye at Screening or Baseline 
8. Current vitreous hemorrhage that limits visualization of the fundus or potential for visual 
acuity improvement in the opinion of the Investigator 
9. History or evidence of the following in the study eye*: 
a. Intra-ocular or refractive surgery within the 90 day period prior to Screening 
b. Previous penetrating keratoplasty, vitrectomy or ocular radiation 
c. Previous panretinal photocoagulation 
d. Previous treatment with verteporfin photodynamic therapy 
e. Previous submacular surgery, other surgical intervention or laser treatment for AMD 
f. Uncontrolled glaucoma defined as intra-ocular pressure (IOP) >25 mmHg on 
medication or according to Investigator’s judgment at Screening or Baseline 
g. Aphakia and/or absence of the posterior capsule at Screening or Baseline Yttrium 
Aluminum Garnet (YAG) laser posterior capsulotomy secondary to uncomplicated 
cataract extraction with posterior introccular lens implantation is allowed when >30 
days from screening 
h. Intra- or peri-ocular use of corticosteroids during the 6 month period prior to Baseline 
i. Use of topical ocular corticosteroids for 30 or more consecutive days within the 90 
day period prior to Screening 
Note: concomitant treatment with brolucizumab in the fellow eye during the study is 
prohibited 
*In cases where both eyes are eligible, the eye with the worse BCVA at Baseline will 
be selected as the study eye. If both eyes have the same BCVA, it is recommended to 
select the right eye as the study eye. 
10. Use of systemic corticosteroids for 30 or more consecutive days within 90 days prior to 
Baseline, with the exception of low stable doses of corticosteroids (defined as ≤ 10 mg 
prednisolone or equivalent dose used for 90 days or more); Inhaled, nasal or dermal 
steroids are permitted 
11. History of a medical condition (disease, metabolic dysfunction, 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 IP 
12. History of hypersensitivity to any component of the test article or control article, or 
clinically relevant sensitivity to fluorescein dye as assessed by the Investigator 
13. Participation in an investigational drug, biologic, or device study within 30 days or the 
duration of 5 half-lives of the IP (whichever is longer) prior to first dose 
Note: observational clinical studies solely involving over-the-counter vitamins, 
supplements, or diets are not exclusionary 
14. Systemic anti-VEGF therapy within the 90 day period prior to Screening 
15. Stroke or myocardial infarction in the 90 day period prior to Screening 
16. Uncontrolled blood pressure defined as a systolic value ≥160 mmHg or diastolic value 
≥100 mmHg at Screening 

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17. Pregnant or nursing (lactating) women and women of childbearing potential, defined as all 
women physiologically capable of becoming pregnant, unless they are using highly 
effective methods of contraception while taking study treatment and for 3 months after 
stopping medication. Highly effective contraception methods include: 
a. 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 
b. 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 
c. 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 
d. Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS), or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1 %), for example hormone vaginal ring or transdermal hormone 
contraception 
In case of use of oral contraception, women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
Women are considered post-menopausal and not of childbearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with 
or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks ago. In the 
case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of childbearing 
potential. 
If local regulations deviate from the contraception methods listed above to prevent pregnancy, 
local regulations apply and will be described in the informed consent form (ICF). 
 
6 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational and control drugs 
 
Table 6-1 
Investigational and control drugs 
Investigational/ 
Control Drug 
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply 
Type 
Sponsor 
(global or 
local) 
Brolucizumab 6 
mg/0.05 mL 
Solution for injection 
Intravitreal use 
Masked; 
vials/or PFS 
Sponsor local