A 52-week, Two Arm, Randomized, Open-label, Multicenter Study Assessing the Efficacy and Safety of Two Different Brolucizumab 6 mg Dosing Regimens for Patients With Suboptimal Anatomically Controlled Neovascular Age-related Macular Degeneration
Phase: PHASE4
Conditions: Age-related Macular Degeneration
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development 
[RTH258/brolucizumab] 
Clinical Trial Protocol CRTH258ADE01 / NCT04679935
A 52-week, two arm, randomized, open-label, multicenter 
study assessing the efficacy and safety of two different 
brolucizumab 6 mg dosing regimens for patients with 
suboptimal anatomically controlled neovascular age-
related macular degeneration (FALCON) 
Document type: 
Amended Clinical Trial Protocol 
EUDRACT number: 
2019-004767-53 
Version number: 
02 (clean) 
Clinical trial phase: 
IV 
Release date: 
30-Nov-2022
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 ........................................................................................................................ 4 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 8 
Amendment 2 30-Nov-2022 .............................................................................................. 10 
Amendment 1 18-Nov-2021 .............................................................................................. 12 
Protocol summary .............................................................................................................. 15 
1 
Introduction ....................................................................................................................... 18 
1.1 
Background ............................................................................................................ 18 
1.2 
Purpose .................................................................................................................. 20 
2 
Objectives and endpoints ................................................................................................... 20 
3 
Study design ...................................................................................................................... 21 
4 
Rationale ............................................................................................................................ 24 
4.1 
Rationale for study design ..................................................................................... 24 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 24 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 25 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 25 
4.5 
Risks and benefits .................................................................................................. 25 
5 
Population .......................................................................................................................... 26 
5.1 
Inclusion criteria .................................................................................................... 27 
5.2 
Exclusion criteria ................................................................................................... 27 
6 
Treatment ........................................................................................................................... 30 
6.1 
Study treatment ...................................................................................................... 30 
6.1.1 
Investigational and control drugs .......................................................... 30 
6.1.2 
Additional study treatments .................................................................. 30 
6.1.3 
Treatment arms/group ........................................................................... 30 
6.1.4 
Treatment duration ................................................................................ 31 
6.2 
Other treatment(s) .................................................................................................. 31 
6.2.1 
Concomitant therapy ............................................................................. 31 
6.2.2 
Prohibited medication ........................................................................... 32 
6.2.3 
Rescue medication ................................................................................ 33 
6.3 
Subject numbering, treatment assignment, randomization .................................... 33 
6.3.1 
Subject numbering ................................................................................ 33 
6.3.2 
Treatment assignment, randomization .................................................. 33 

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6.4 
Treatment blinding ................................................................................................ 34 
6.5 
Dose escalation and dose modification.................................................................. 34 
6.6 
Additional treatment guidance ............................................................................... 34 
6.6.1 
Treatment compliance ........................................................................... 34 
6.7 
Preparation and dispensation ................................................................................. 34 
6.7.1 
Handling of study treatment .................................................................. 34 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 35 
7 
Informed consent procedures ............................................................................................ 38 
8 
Visit schedule and assessments ......................................................................................... 39 
8.1 
Screening ............................................................................................................... 42 
8.1.1 
Information to be collected on screening failures ................................. 42 
8.2 
Subject demographics/other baseline characteristics............................................. 42 
8.3 
Efficacy .................................................................................................................. 43 
8.3.1 
Visual acuity.......................................................................................... 43 
8.3.2 
SD-Optical coherence tomography ....................................................... 43 
8.3.3 
Color fundus photography and fluorescein angiography ...................... 44 
8.3.4 
Appropriateness of efficacy assessments .............................................. 44 
8.4 
Safety ..................................................................................................................... 44 
8.4.1 
Laboratory evaluations .......................................................................... 45 
8.4.2 
Pregnancy and assessments of fertility ................................................. 45 
8.4.3 
Ophthalmic examination and imaging .................................................. 46 
8.4.4 
Appropriateness of safety measurements .............................................. 47 
 
 47 
 
 47 
 
 47 
 
 48 
9 
Study discontinuation and completion .............................................................................. 48 
9.1 
Discontinuation ...................................................................................................... 48 
9.1.1 
Discontinuation of study treatment ....................................................... 48 
9.1.2 
Withdrawal of informed consent ........................................................... 50 
9.1.3 
Lost to follow-up ................................................................................... 50 
9.1.4 
Early study termination by the sponsor ................................................. 51 
9.2 
Study completion and post-study treatment .......................................................... 51 
10 Safety monitoring and reporting ........................................................................................ 51 
10.1 
Definition of adverse events and reporting requirements ...................................... 52 
10.1.1 
Adverse events ...................................................................................... 52 
10.1.2 
Serious adverse events .......................................................................... 54 

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10.1.3 
SAE reporting........................................................................................ 54 
10.1.4 
Pregnancy reporting .............................................................................. 55 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 55 
10.2 
Additional Safety Monitoring ................................................................................ 56 
11 Data collection and database management ........................................................................ 56 
11.1 
Data collection ....................................................................................................... 56 
11.2 
Database management and quality control ............................................................ 56 
11.3 
Site monitoring ...................................................................................................... 57 
12 Data analysis and statistical methods ................................................................................ 58 
12.1 
Analysis sets .......................................................................................................... 58 
12.2 
Subject demographics and other baseline characteristics ...................................... 58 
12.3 
Treatments ............................................................................................................. 59 
12.4 
Analysis of the primary endpoint(s) ...................................................................... 59 
12.4.1 
Definition of primary endpoint(s) ......................................................... 59 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 59 
12.4.3 
Handling of missing values/censoring/discontinuations ....................... 59 
12.4.4 
Sensitivity and supportive analyses ...................................................... 60 
12.5 
Analysis of secondary endpoints ........................................................................... 60 
12.5.1 
Efficacy endpoints ................................................................................. 60 
12.5.2 
Safety endpoints .................................................................................... 60 
 
 62 
12.7 
Interim analyses ..................................................................................................... 62 
12.8 
Sample size calculation.......................................................................................... 62 
12.8.1 
Primary endpoint ................................................................................... 62 
13 Ethical considerations and administrative procedures ...................................................... 62 
13.1 
Regulatory and ethical compliance ........................................................................ 62 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 62 
13.3 
Publication of study protocol and results............................................................... 63 
13.4 
Quality Control and Quality Assurance ................................................................. 63 
14 Protocol adherence ............................................................................................................ 63 
14.1 
Protocol amendments............................................................................................. 63 
15 References ......................................................................................................................... 65 
16 Appendices ........................................................................................................................ 66 
 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 20 

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Table 6-1 
Investigational drug ............................................................................... 30 
Table 6-2 
Prohibited medications and procedures ................................................ 32 
Table 8-1 
Assessment schedule ............................................................................. 40 
Table 8-2 
Assessments & Specifications............................................................... 45 
Table 8-3 
Laboratory assessments ......................................................................... 45 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 56 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 22 
Figure 6-1 
Screening and randomization procedure ............................................... 34 
Figure 6-2 
Treatment regimen ................................................................................ 36 
Figure 6-3 
Examples for treatment regimen adjustments ....................................... 37 
 

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List of abbreviations 
 
 
AE 
Adverse Event 
AMD 
Age-related Macular Degeneration 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutic Chemical 
BCVA 
Best Corrected Visual Acuity 
CFP 
Color Fundus Photography 
CMO 
Chief Medical Office 
CNV 
Choroidal Neovascularization 
COVID-19 
Coronavirus Disease 2019 
CRC 
Central Reading Center 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSFT 
Central Subfield Thickness 
CTT 
Clinical Trial Team 
DA 
Disease Activity 
DAA 
Disease Activity Assessment 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report/Record Form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
EOS 
End-of-Study 
EOT 
End-of-Treatment 
eSource 
Electronic Source 
ETDRS 
Early Treatment Diabetic Retinophathy Study 
FA 
Fluorescein Angiography 
FAS 
Full Analysis Set 
FCP 
Fundus-Controlled Perimetry 
FDA 
Food and Drug Administration 
FIR 
First Interpretable Results 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
h 
Hour 
hCG 
Human Chorionic Gonadotropin 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IN 
Investigator Notification 
IOI 
Intraocular Inflammation 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IRF 
Intraretinal Fluid 
IUD 
Intrauterine Device 

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IUS 
Intrauterine System 
IVT 
Intravitreal Injection 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities  
mg 
Milligram(s) 
mL 
Milliliter(s) 
nAMD 
Neovascular Age-related Macular Degeneration 
NIH 
National Institutes of Health 
OCT 
Optical Coherence Tomography 
PD 
Protocol Deviation 
PDT 
Photodynamic Therapy 
PED 
Pigment Epithelial Detachment 
PFS 
Pre-filled Syringe 
PPS 
Per-protocol Set 
PRN 
pro re nata 
PS 
Patient Safety 
PT 
Preferred Term 
q4w 
every 4 weeks 
q6w 
every 6 weeks 
q8w 
every 8 weeks 
q10w 
every 10 weeks 
q12w 
every 12 weeks 
QMS 
Quality Management System 
RAO 
Retinal Artery Occlusion 
RAP 
Retinal Angiomatous Proliferation 
RAS 
Randomized Analysis Set 
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 
Standard Deviation 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SOC 
System Organ Class 
SRF 
Subretinal Fluid 
SUN 
Standardization Uveitis Nomenclature 
sub-RPE 
Sub-Retinal Pigment Epithelium 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T&E 
Treat-and-Extend 
USM 
Urgent Safety Measures 
VA 
Visual Acuity 
VEGF 
Vascular Endothelial Growth Factor 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 
YAG 
Yttrium Aluminum Garnet 

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Glossary of terms 
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 participant 
Clinical Trial Team 
A group of people responsible for the planning, execution and reporting of all clinical 
trial activities. Examples of team members include the Study Lead, Medical Monitor, 
Trial Statistician etc. 
Cohort 
A group of individuals who share a common exposure, experience or characteristic, 
or a group of individuals followed-up or traced over time 
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 
End of the clinical trial 
The end of the clinical trial is defined as the last visit of the last subject (including 
follow-up) 
Enrollment 
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol) 
Estimand 
As defined in the ICH E9(R1) addendum, estimand is a precise description of the 
treatment effect reflecting the clinical question posed by the trial objective. It 
summarizes at a population-level what the outcomes would be in the same 
participants under different treatment conditions being compared. Attributes of an 
estimand include the population, variable (or endpoint) and treatment of interest, as 
well as the specification of how the remaining intercurrent events are addressed and 
a population-level summary for the variable. 
Intercurrent events 
Events occurring after treatment initiation that affect either the interpretation or the 
existence of the measurements associated with the clinical question of interest. 
Investigational drug/ 
treatment 
The drug whose properties are being tested in the study 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy) 
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 
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 
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine the assignments 
in order to reduce bias. 
Randomization number 
A unique identifier assigned to each randomized subject 
Re-screening 
If a participant fails the initial screening and is considered as a Screen Failure, 
he/she can be invited once for a new Screening visit after medical judgment and as 
specified by the protocol 
Screen Failure 
A subject who did not meet one or more criteria that were required for participation 
in the study 
Source Data/Document 
Source data refers to the initial record, document, or primary location from where 
data comes. The data source can be a database, a dataset, a spreadsheet or even 
hard-coded data, such as paper or eSource. 
Start of the clinical trial 
The start of the clinical trial is defined as the signature of the informed consent by 
the first subject 

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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. 
Treatment arm/group  
A treatment arm/group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. 
Variable (or endpoint) 
The variable (or endpoint) to be obtained for each participant that is required to 
address the clinical question. The specification of the variable might include whether 
the participant experiences an intercurrent event. 
Withdrawal of study 
consent (WoC) / 
Opposition to use of 
data / biological 
samples 
Withdrawal of consent from the study occurs when the participant explicitly requests 
to stop use of their data and biological samples (opposition to use data and 
biological samples) AND no longer wishes to receive study treatment, AND does not 
agree to further protocol required assessments. This request should be in writing 
(depending on local regulations) and recorded in the source documentation.  
 
 
 

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Amendment 2 30-Nov-2022  
Amendment rationale from protocol version 01  
The main reasons for the protocol amendment are:  
Due to the slow enrollment the feasibility of this trial has been reconsidered. The first patient 
was recruited in July 2021. So far, only 47 out of 490 anticipated patients (9.6%) could be 
enrolled within 16 months. 
Several actions were taken to improve the recruitment rate: the protocol was amended in 
February 2022 to broaden the inclusion criteria; regular study newsletters, investigator meetings 
and monitor visits to inform the sites, opening of further sites. 
Despite these actions, the sites could not find enough patients matching the inclusion and 
exclusion criteria. Novartis also requested an actual recruitment forecast by the sites which 
confirms that this population cannot be recruited in any reasonable time. In combination with 
the low recruitment rate achieved so far, it is very unlikely that the number of patients required 
to determine the primary endpoint will be enrolled within a reasonable time. Therefore, this 
amendment is driven by feasibility reasons. 
The aim of this amendment is to prematurely discontinue study recruitment due to feasibility 
reasons (slow enrollment) and allow all randomized patients to stay in the study and continue 
their treatment until week 52. Reason for the treatment continuation is that brolucizumab is an 
approved marketed product for the treatment of nAMD in the countries where the study is 
running. Moreover, with continuation in the study, we will be able to collect the full data sets 
for all patients that are already randomized and evaluate the data in a descriptive manner. The 
primary endpoint hypothesis can no longer be addressed, but our goal is to at least provide 
insights on whether pretreated nAMD patients need loading with three monthly brolucizumab 
injections and put the results of our descriptive analysis into context together with current and 
future literature on how to treat patients who had an unsatisfactory response to other anti-VEGF 
treatments. 
The premature discontinuation of recruitment will become effective with approval of this 
protocol amendment by the Institutional Review Board (IRBs)/Independent Ethics Committee 
(IECs) and Health Authorities. From this time point on, no further patients can be recruited, but 
the trial will continue for all already randomized patients. 
Changes to the protocol 
Changes to specific section of the protocol are shown in 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. Other minor 
clarifications and corrections were made where applicable. 
• Protocol summary: The patient number was changed from planned 490 to expected 50 
randomized patients. It was clarified that the primary objective can no longer be addressed 
and all analyses will be performed in a purely descriptive manner due to the reduced sample 
size. Accordingly, the primary objective has been revised from demonstrating non-
inferiority to assessing the difference in BCVA between the two study arms. 

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• Section 1.2 Purpose: The study purpose has been revised since the primary objective cannot 
be analyzed as initially planned. 
• Section 2 Objectives and endpoints: It was clarified that the primary endpoint can no longer 
be addressed and all analyses will be performed in a purely descriptive manner. The primary 
endpoint was changed from demonstrating non-inferiority to evaluate the difference in 
BCVA between the two study arms. 
• Section 3 Study design: The patient number was changed from 490 to approximately 50 
patients which will be randomized in a 1:1 ratio in approximately 33 centers. 
• Section 4.1 Rationale for study design: The study design rationale was updated to reflect 
that the initially planned primary objective can no longer be reached. 
• Section 12.4 Analysis of the primary endpoint: It was clarified that the primary endpoint 
can no longer be addressed and all endpoints will be analyzed in a purely descriptive manner, 
non-inferiority testing will be omitted. No sensitivity or supportive analysis for the primary 
endpoint will be carried out.  
• Section 12.8 Sample size calculation: It was clarified that the initial recruitment number 
cannot be achieved due to the slow recruitment rate and the enrollment will be prematurely 
discontinued when this protocol amendment becomes effective, expecting a total of about 
50 patients to be enrolled. As a consequence, all analyses will be performed in a purely 
descriptive manner. Based on an expected sample size of 25 patients per group, a precision 
in terms of the width of the respective 95% confidence interval for the difference in change 
from baseline of the visual acuity of +/- 7,21 can be achieved.  
 
IRBs/IECs 
A copy of this amended protocol will be submitted 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, which will be updated by the sponsor and 
submitted to the IRB/IEC and Health Authority approval according to local regulations prior to 
implementation.  
 

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Amendment 1 18-Nov-2021  
Amendment rationale  
The main reasons for the protocol amendment are: 
(1) To implement the Urgent Safety Measures (USM) described in the 10-Aug-2021 Dear 
Investigator Letter (DIL) into the study protocol. The USM were implemented for ongoing 
studies not achieving Last Patient Last Visit (LPLV) by 11-Aug-2021 and in response to the 
identification of a causal immune-mediated mechanism of the previously identified risk of 
retinal vasculitis (RV), and/or retinal vascular occlusion (RO), typically in the presence of 
intraocular inflammation (IOI). 
(2) 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. Furthermore, it was 
clarified that treatment intervals of < 8 weeks are not allowed after the initiation phase. 
(3) This amendment also includes information on gender imbalance on IOI following 
brolucizumab treatment and recommendations on the time window for a study subject to receive 
the COVID-19 vaccine.  
(4) The list of inclusion and exclusion criteria has been updated to better reflect the patient 
population in real-world clinical practice. In addition, the criteria for disease activity assessment 
have been clarified. 
Changes to the protocol 
Changes to specific section of the protocol are shown in 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. Other minor 
clarifications and corrections were made where applicable. 
Protocol sections changed in relation to this emerging safety measure are: 
• Section 1.1 Background: Information added to describe the Urgent Safety Measures  
• Section 4.2 Rationale for dose/regimen and duration of treatment: Language added to 
provide background of the USM  
• Section 4.5 Risk and benefits: Information added to describe USM from the MERLIN 
(CRTH258AUS04) study and results of the mechanistic study BASICHR0049 and 
additional information on gender imbalance on IOI following brolucizumab treatment 
• Section 6.1.4 Treatment duration: Guidance added for subjects requiring injections every 
4 weeks and patients with IOI, RV and/or RO 
• Section 8.4 Safety: Guidance for COVID-19 remote assessments was updated to reflect that 
study treatment cannot be administered without an on-site study visit 
• Section 8.4.2 Pregnancy and assessment of fertility: Requirement that treatment must be 
discontinued for pregnant woman was added 

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• Section 8.4.3 Ophthalmic examination: Requirement of treatment discontinuation for 
brolucizumab was added if subject developed IOI, RV and/or RO 
• Section 9.1.1 Discontinuation of study treatment: the following circumstances were added 
and instructions were given for switch to standard of care: 
• Unsatisfactory therapeutic effect, e.g. a subject requires injections more frequently than 
every 8 weeks after the loading phase (week 8, loading arm) or baseline (non-loading 
arm) 
• Subjects develop IOI, RV and/or RO 
• Section 10 Safety monitoring and reporting: Consolidated the requirements for monitoring 
of adverse events. Added the new requirement that if IOI, RV and/or RO is confirmed, 
subjects should be discontinued from study treatment.  
• Section 10.1.3 SAE reporting: Clarified the timing for SAE reporting to Novartis as per 
latest protocol template and extended reporting to 60 days after the last administration of 
study treatment. 
 
Other changes incorporated in this amendment 
• The glossary of terms was updated to the latest template wording 
• Section 1.2 Purpose: the wording to describe the study purpose was updated 
• Section 3 Study Design: the instructions for disease activity assessment and treatment 
regimen adjustment were updated for clarification purposes 
• Section 5.1 Inclusion criteria: The list of inclusion criteria was updated to better reflect the 
patient population in real-world clinical practice. 
• Section 5.2 Exclusion criteria: The list of exclusion criteria was updated to better reflect the 
patient population in real-world clinical practice. 
• Section 6.2.1.1 Permitted concomitant therapy requiring caution and/or action: added 
recommendations on the time window for a study subject to receive the COVID-19 vaccine  
• Section 6.3.2 Treatment assignment, randomization: Figure 6-1 Screening and 
randomization procedure was updated into a colored image.  
• Section 6.7.2 Instruction for prescribing and taking study treatment: the instructions for 
disease activity assessment and treatment regimen adjustment, Figure 6-2 Treatment 
regimen and Figure 6-3 Examples for treatment regimen adjustments were updated for 
clarification purposes 
• Section 8 Visit schedule and assessments: legend of Table 8-1 assessment schedule was 
updated for better comprehensibility 
• Section 9.1.2 Withdrawal of informed consent: Clarified the definition of Withdrawal of 
Consent (WoC) 
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.  

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The changes herein affect the Informed Consent, which will be updated by the sponsor and 
submitted to the IRB/IEC for approval according to local regulations prior to implementation.  

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Protocol summary 
Protocol number 
CRTH258ADE01 
Full Title 
A 52-week, two arm, randomized, open-label, multicenter study assessing the 
efficacy and safety of two different brolucizumab 6 mg dosing regimens for 
patients with suboptimal anatomically controlled neovascular age-related 
macular degeneration (FALCON) 
Brief title 
Study assessing efficacy and safety of two different brolucizumab regimens for 
pretreated patients with neovascular age-related macular degeneration  
Sponsor and 
Clinical Phase 
Novartis Pharma GmbH 
Phase IV 
Investigation 
type 
Drug 
Study type 
Interventional  
Purpose and 
rationale 
This study is designed to evaluate the efficacy and safety of two different 
brolucizumab regimens for pretreated patients with neovascular age-related 
macular degeneration. The study shall provide contributive information as to 
whether nAMD patients who showed an unsatisfactory response to previous 
anti-VEGF treatments (i.e. residual or recurrent fluid despite continuous anti-
VEGF treatment), need loading with three monthly brolucizumab 6 mg injections 
or whether they can immediately receive brolucizumab treatment every 12 
weeks. Our goal is to provide insights to support the medical practice and put 
the results of our descriptive analysis into context together with current and 
future literature on how to initiate treatment for pretreated patients who had an 
unsatisfactory response to other anti-VEGF treatments and to evaluate interval 
prolongation compared to previous treatment. 
Primary 
Objective(s)  
The study will evaluate the difference in BCVA change from baseline for 
brolucizumab 6 mg with one (initial) injection followed by treatment every 12 
weeks as compared to brolucizumab 6 mg with three monthly loading injections 
followed by treatment every 12 weeks. 
 
As a consequence of Amendment 2, the assumed patient number necessary for 
analysis of the primary objective will not be achieved. Therefore, the primary 
endpoint and all analyses will now be performed in a purely descriptive manner. 
 
With 25 patients per group, a precision in terms of the width of the respective 
95% confidence interval for the difference in change from baseline of the visual 
acuity of +/- 7,21 can be achieved. 
Secondary 
Objectives 
• 
To evaluate treatment interval prolongation compared to previous treatment  
• 
To estimate the proportions of patients maintained at every 12 weeks 
treatment frequency in the two brolucizumab groups  
• 
To evaluate the functional outcomes comparing the two brolucizumab 
groups  
• 
To evaluate the anatomical outcomes comparing the two brolucizumab 
groups  
• 
To evaluate the safety and tolerability of brolucizumab  
Study design 
The study is a 52-week, randomized, open-label, multi-center, two-arm study in 
patients with nAMD. Consenting patients will participate in a screening period, 
lasting up to 14 days. Eligible patients will be randomized in a 1:1 ratio to one of 
the two treatment arms: 

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1. Brolucizumab 6 mg “loading arm”: 3 x 4-weekly initial injections followed 
by an injection every 12 weeks  
2. Brolucizumab 6 mg “non-loading arm”: one initial injection followed by an 
injection every 12 weeks  
 
In both study arms, treatment intervals after the initiation phase will be either 
8 weeks or 12 weeks depending on disease activity status. More frequent 
injections, i.e., treatment intervals of < 8 weeks are not allowed after the initiation 
phase. 
Population 
490 randomized patients ≥50 years of age with visual impairment due to 
neovascular age-related macular degeneration had initially been targeted. 
 
According to Amendment 2 for premature discontinuation of recruitment, the 
planned sample size will not be achieved, expecting a total of approximately 50 
patients to be recruited by the time of approval of Amendment 2. 
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 
• 
Active choroidal neovascularization (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 and sequelae of CNV, e.g. pigment epithelial 
detachment (PED), subretinal or sub-retinal pigment epithelium (sub-RPE) 
hemorrhage, blocked fluorescence, macular edema (intraretinal fluid (IRF) 
and/or subretinal fluid (SRF) and/or sub-retinal pigment epithelium (sub-
RPE) fluid that affects the central subfield, as seen by Spectral Domain 
Optical Coherence Tomography (SD-OCT)) at screening, as confirmed by 
central reading center (study eye). If active CNV according to the above 
explained activity criteria is not detectable in screening image data (no IRF 
and no SRF), presence of residual and/or recurrent fluid (IRF and/or SRF) 
within the last 6 months before baseline visit is also considered eligible. In 
this case, historical images must be submitted for analysis by the central 
reading center. 
• 
Pretreatment with any anti-VEGF drug for a maximum of five years 
(60 months). Patients should have shown functional and/or anatomical 
treatment response to the pretreatment(s), prior to participating in this study. 
• 
The treatment initiation phase with the current anti-VEGF must have been 
completed for at least 6 months with continuous treatment in a ≥ q4w to 
≤ q12w injection interval (±2-day window, i.e. 26 to 86 days inclusive) before 
the baseline visit. At least 4 weeks (minimum 26 days) must have passed 
between the last anti-VEGF pretreatment and baseline. 
• 
BCVA score must be ≤ 83 and ≥ 38 letters at 4 meters starting distance using 
Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity 
charts (approximately Snellen equivalent of 20/25 and 20/200), at both 
screening and baseline 
Key Exclusion 
criteria 
• 
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 
52-week study period, atrophy or fibrosis at the center of the fovea as 
confirmed by central reading center or structural damage of the fovea (study 
eye) 
• 
Treatment with anti-VEGF drugs for > 5 years 

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• 
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 whose surgery 
may improve VA, e.g. cataract) 
• 
Ocular treatments: pretreatment with brolucizumab at any time in the study 
eye, previous treatment with investigational drugs in the last 6 months, 
intraocular or periocular steroids at any time, macular laser photocoagulation 
or photodynamic therapy at any time, peripheral laser photocoagulation 
within 3 months prior to baseline, intraocular surgery within 3 months prior 
to baseline, vitreoretinal surgery at any time, aphakia with the absence of 
posterior capsule (study eye) 
• 
Stroke or myocardial infarction during the 6-month period prior to baseline 
• 
Systemic anti-VEGF therapy during the 3-month period prior to baseline 
Study treatment 
Brolucizumab 6 mg/0.05 mL  
Efficacy 
assessments 
• 
BCVA testing using ETDRS charts, anatomical markers on SD-OCT, Color 
Fundus photography (CFP) and Fluorescein angiography (FA) 
Key safety 
assessments 
• 
Monitoring of adverse events 
• 
Standard ophthalmic examinations and imaging 
• 
Vital signs (blood pressure, heart rate) 
• 
Pregnancy testing  
Other 
assessments  
 
 
 
• 
Whole blood collection via venipuncture 
Data analysis 
The difference of brolucizumab “non-loading” compared to brolucizumab 
“loading” in terms of mean change in BCVA from baseline to mean of visits at 
week 40 to week 52 will be evaluated using descriptive statistics.  
 
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. 
Key words 
Neovascular age-related macular degeneration, anti-VEGF, choroidal 
neovascularization, brolucizumab, loading vs. non-loading 
 
 
 

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1 
Introduction 
1.1 
Background 
Age-related macular degeneration (AMD) is the leading cause of severe vision loss in people 
over the age of 65 in the United States and other Western countries (Rein et al., 2009). The 
neovascular, exudative or wet form of AMD (nAMD) is characterized by the growth of 
abnormal new blood vessels (neovascularization) under the retinal pigment epithelium (RPE) 
from the choroid into the retina (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 which 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).  
Vascular endothelial growth factor (VEGF) was identified to play a key role in the 
neovascularization process (Spilsbury et al., 2000). The use of intravitreal injection 
pharmacotherapy targeting VEGF, such as ranibizumab (Lucentis®) and aflibercept (Eylea®), 
has significantly improved visual outcomes in patients with nAMD (Bloch et al., 2012, 
Campbell et al., 2012) and has been shown to halt the growth of neovascular lesions and resolve 
retinal edema, which raised anti-VEGF treatments to current standard of care in nAMD. 
Brolucizumab 
Brolucizumab is a humanized single-chain antibody fragment (scFv), binding to VEGF-A with 
high affinity. It 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 has a molecular weight of ~26 kDa 
which allows a delivery of a high molar dose via intravitreal injection. A 6 mg dose of 
brolucizumab delivers a molar dose which is approximately 11 and 22 times higher than 
aflibercept 2 mg and ranibizumab 0.5 mg, respectively. Higher molar doses are expected to lead 
to longer presence of relevant drug levels in the eye. In addition, a low molecular weight and 
high concentration gradient between the vitreous and the retina may increase drug distribution 
to the target site of action, supporting effective control of anatomical disease activity and has 
therefore the potential to show superior outcomes.  
Brolucizumab has been approved for treatment of nAMD by more than 70 health authorities 
globally, e.g. the Food and Drug Administration (FDA), the European Medicines Agency 
(EMA) and Swissmedic. It was tested in two large phase 3 trials and found to be efficacious 
and safe when compared to aflibercept in patients with nAMD (HAWK and HARRIER). 
Brolucizumab demonstrated non-inferiority to aflibercept in mean change in best-corrected 
visual acuity (BCVA) from baseline to week 48 in both trials. Treatment of treatment-naive 
patients was started with three monthly brolucizumab injections (loading phase), followed by 
treatment every 12 weeks (q12w). If disease activity was identified during the study, patients 
were assigned to treatment every 8 weeks (q8w) and stayed on the q8w interval until the end of 
study. After one year of treatment, the primary endpoint was met with change of BCVA from 
baseline being non-inferior with more than 50 % of patients (56 % in HAWK, 51 % in 
HARRIER) were being maintained on a q12w dosing interval following the loading phase 
through week 48 in the brolucizumab arm vs. the aflibercept arm (fixed q8w treatment 
frequency). The visual acuity gains observed in the first year were maintained in the second 

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year. In addition, in these phase 3 trials brolucizumab demonstrated superior anatomical 
outcomes vs. aflibercept. Significantly fewer patients on brolucizumab had intraretinal fluid 
(IRF) and/or subretinal fluid (SRF) and brolucizumab achieved superior reductions in central 
subfield thickness (CSFT) versus aflibercept. These superior anatomic outcomes for 
brolucizumab were maintained in the second year. Brolucizumab safety was comparable to 
aflibercept, with the overall incidence of adverse events balanced across all treatment groups in 
both studies. 
 
Since the first marketing authorization approval in October 2019 for the treatment of nAMD, 
adverse events of retinal vasculitis and/or retinal vascular occlusion, that may result in severe 
vision loss and typically in the presence of intraocular inflammation, have been reported from 
post-marketing experience with brolucizumab (Beovu). Results of the mechanistic study 
BASICHR0049 on blood samples from nAMD patients exposed to brolucizumab and having 
subsequently developed retinal vasculitis and/or retinal vascular occlusion, taken together with 
accumulated data from HAWK, HARRIER and MERLIN, regarding 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 (RV) and/or retinal vascular occlusion (RO), 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, MERLIN, 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 
loading phase and when patients who develop RV and/or RO are discontinued from further 
treatment with brolucizumab. 
Current standard therapy regimens 
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).  
In ranibizumab and aflibercept trials, in both interventional (e.g. TREND (Silva et al., 2018), 
ALTAIR (Bayer Vital Gmbh, 2019) and real life studies (prospective non-interventional trials, 
e.g. OCEAN (Voegeler and Mueller, 2017), a number of patients still showed persistent fluid 
when extended to q6w or longer treatment intervals, although initial functional and anatomical 
response after the loading phase (three initial injections) was seen. The German Retina Society 
recommends that switching to another anti-VEGF drug may be considered if an inadequate 
morphological effect is observed after the initial three series or follow-up therapies. In several 
case series it was shown that after a change of the drug, a further visual stabilization could be 
achieved with a simultaneous reduction of the morphological lesion activity criteria 
(Retinologische Gesellschaft, 2014). 

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For these patients, a presumably more effective and longer lasting anti-VEGF agent like 
brolucizumab may lead to optimized fluid, and disease control i.e. sustained functional and 
anatomical response, respectively; which overall might result in improved patient care (e.g. less 
frequent visits, reduced treatment burden). Often the switch is initiated with a loading phase of 
three monthly doses, as described above for treatment naïve patients. However, a clear 
recommendation and scientific evidence is missing and it is unclear how to optimally initiate 
the change to brolucizumab treatment subsequent to an unsatisfactory anti-VEGF treatment 
response.  
Summary 
Ranibizumab, aflibercept and brolucizumab all inhibit the activity of VEGF-A and all have 
demonstrated efficacy in the treatment of patients with nAMD. However, under ranibizumab 
and aflibercept, a number of patients have still shown persistent fluid when extended to q6w or 
longer treatment intervals. Since brolucizumab showed superior anatomical outcomes and 
longer durability in HAWK & HARRIER, these findings support the evaluation of 
brolucizumab also in pretreated patients.  
1.2 
Purpose 
The purpose of this study is to evaluate the efficacy and safety of two different brolucizumab 
6 mg treatment regimens for pretreated patients with suboptimal anatomically controlled 
nAMD. We aim to evaluate whether nAMD patients who showed an unsatisfactory response to 
previous anti-VEGF treatments (i.e. residual or recurrent fluid despite continuous anti-VEGF 
treatment), can immediately go to a q12w regimen when treatment is initiated with 
brolucizumab 6mg, or need loading with three monthly brolucizumab 6 mg injections. Our goal 
is to provide insights to support the medical practice and put the results of our descriptive 
analysis into context together with current and future literature on how to treat patients who had 
an unsatisfactory response to other anti-VEGF treatments. 
2 
Objectives and endpoints 
As a consequence of Amendment 2, the assumed patient number necessary for analysis of the 
primary objective will not be achieved. Therefore, the primary endpoint and all analyses will 
now be performed in a purely descriptive manner. 
Table 2-1 
Objectives and related endpoints  
Objective(s) 
Endpoint(s) 
Primary Objective(s) 
Endpoint(s) for primary objective(s)  
• 
To evaluate the difference in 
brolucizumab 6 mg with one (initial) 
injection followed by q12w 
maintenance as compared to 
brolucizumab 6 mg with 3x q4w 
loading injections followed by q12w 
maintenance 
• 
Mean change in BCVA from baseline to mean of 
visits at week 40 to week 52  
Secondary Objective(s) 
Endpoint(s) for secondary objective(s) 

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Objective(s) 
Endpoint(s) 
• 
To evaluate treatment interval 
prolongation compared to previous 
treatment  
 
 
 
 
• 
To estimate the proportions of 
patients maintained at q12w treatment 
frequency in the two brolucizumab 
groups  
 
• 
To evaluate the functional outcomes 
comparing the two brolucizumab 
groups  
 
 
 
 
 
 
• 
To evaluate the anatomical outcomes 
comparing the two brolucizumab 
groups  
 
 
• 
To evaluate the safety and tolerability 
of brolucizumab  
• 
Mean treatment interval (overall as well as per 
study group comparing treatment intervals from 
baseline to week 52 in the study vs. 24 weeks to 
baseline prior to enrollment)  
• 
Rate of patients (overall and per group) with 
prolonged interval compared to mean treatment 
interval in last 24 weeks prior to enrollment  
• 
Comparison of proportions of patients maintained 
at a q12w interval at week 52 between the two 
arms  
• 
Distributions of patients at q8w/q12w intervals from 
baseline to week 52  
• 
Average change in BCVA from baseline to 
week 52  
• 
Proportions of patients with BCVA improvements 
of ≥5, ≥ 10, and ≥ 15 letters from baseline to week 
52  
• 
Proportions of patients with BCVA ≥ 69 letters at 
week 52  
• 
Mean change in BCVA from baseline to mean of 
visits at week 16 to week 28  
• 
Change from baseline in CST as assessed by SD-
OCT per visit up to week 52  
• 
Absence of IRF, SRF, and sub-RPE fluid as 
assessed by SD-OCT per visit up to week 52  
• 
Presence of active CNV leakage as assessed by 
fluorescein angiography at week 52  
• 
Incidence of ocular and non-ocular AEs up to 
week 52  
3 
Study design 
This study is a 52-week randomized, open-label, multi-center, two arm study for pretreated 
patients with suboptimal anatomically controlled nAMD. Patients who consent will be screened 
whether they meet all the inclusion and none of the exclusion criteria to evaluate eligibility. 
After confirmation of eligibility, patients will be randomized in a 1:1 ratio to one of the two 
treatment arms: 

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• Brolucizumab 6 mg “loading arm”: 3 x 4-weekly initial injections followed by an 
injection every 12 weeks;  
• Brolucizumab 6 mg “non-loading arm”: one initial injection followed by an injection 
every 12 weeks  
The initial plan was to screen approximately 598 adult patients (18 % screening failure rate 
expected) and randomize approximately 490 patients (245 per arm, 10 % drop-out rate 
expected) in a 1:1 ratio in approximately 65 centers. According to Amendment 2 for premature 
discontinuation of recruitment, the planned sample size will not be achieved, expecting a total 
of approximately 50 patients to be recruited by the time of approval of Amendment 2 (25 per 
arm, in approximately 33 centers). 
The maximum study duration for one subject is 54 weeks, including the screening period and 
post-treatment follow-up. 
There will be three periods in this study (see Figure 3-1 and Figure 6-2): 
• Screening period: from day -14 to baseline 
• Open-label treatment period: from baseline (day 1) to week 48 
• Post-treatment follow-up period: from week 48 to week 52 
 
Figure 3-1 
Study design 
1. Screening period: Day -14 to day -1  
A screening period of up to 2 weeks will be used to assess eligibility.  
One-time rescreening of patients is allowed, except for the purpose of capturing new BCVA or 
imaging assessments that previously failed to qualify the patient. As long as testing can be 
repeated within 14 days of the first screening, the other screening assessments do not need to 
be repeated. If rescreening is to occur beyond 14 days from the original screening visit date, 
then all screening procedures must be repeated. Medical judgment should be exercised to ensure 
that treatment of nAMD is not withheld in order for a patient to participate in the study.  
Up to 2 weeks 
Screening period 
Randomization 
Brolucizumab 6 mg 
„loading“ 
Brolucizumab 6 mg 
„non-loading“ 
Treatment period 
day 1 to week 48 
Up to 2 weeks 
Post-treatment follow up 
week 48 to week 52 
4 weeks 

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2. Open-label treatment period: Day 1 to week 48 
After confirmation of eligibility, patients will be randomized in a 1:1 ratio to one of the 
treatment arms.  
Only one eye will be selected as study eye and treated with study medication. 
The baseline visit is defined as day 1/visit 1, and end of treatment visit as visit 13 (week 48). 
A study visit schedule will be established at the time of randomization for all patients with study 
visits scheduled every 4 weeks. All efforts should be made to adhere to this study visit schedule 
±7-day window. Treatment is intended to be administered on the day of study visit, or if this is 
not possible, within 3 days after the study visit when the per-protocol assessments took place. 
In addition, for a given protocol visit, assessments can be performed in two consecutive days. 
In the “loading arm”, patients will receive three consecutive injections every 4 weeks at 
baseline, weeks 4 and 8, which should be at least 21 days apart, followed by an injection every 
12 weeks. In the “non-loading arm”, patients will receive one initial injection followed by an 
injection every 12 weeks. For both study arms: The assessment of disease activity will be 
performed 8 and 12 weeks after the previous injection. If disease activity is identified by the 
investigator for the first time at any visit after / from week 8 respectively, patients should stay 
on a q12w dosing, if the decline in BCVA is clinically non-significant (BCVA loss ≤ 4 ETDRS 
letters) compared to the previous visit. If after / from week 8, a BCVA-loss of ≥ 5 ETDRS 
letters appears compared to the previous visit or disease activity is identified for a second time 
based on the investigator’s judgment of visual and/or anatomic outcomes and signs of disease 
activity, patients must be assigned to q8w dosing. One attempt of interval re-extension from 
q8w to q12w treatment will be allowed based on the investigator’s judgement if no disease 
activity (DA) is detected during the subsequent visit(s). If the patient shows significant DA at 
any visit after the re-extension attempt, injection intervals will be fixed to q8w until the end of 
the study. The disease activity decision should be based on the BCVA loss criteria (BCVA loss 
≤ 4 ETDRS letters and BCVA-loss of ≥ 5 ETDRS compared to the previous visit) and beyond 
that on investigator’s judgement of visual and/or anatomic outcomes and signs of disease 
activity (e.g. IRF, SRF, hemorrhage, leakage, visual acuity loss over time etc.). 
Patients who require injections more frequently than every 8 weeks after the loading phase 
(week 8, loading arm) or baseline (non-loading arm) will be discontinued from further study 
treatment. 
 
3. Post-treatment follow-up period: Week 48 to week 52  
For all patients, the last study assessment will be performed at week 52.  
Patients withdrawn from the study prior to study completion will be asked to return for an early 
discontinuation visit (EOS / visit 14), four weeks (±7 days) following their last study visit (see 
Section 9). 

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4 
Rationale 
4.1 
Rationale for study design 
This study is designed as a randomized, open-label, multi-center, two-arm parallel study to 
assess the efficacy and safety of two different brolucizumab 6 mg regimen for pretreated 
patients with suboptimal anatomically controlled nAMD.  
The primary efficacy endpoint based on BCVA was chosen to evaluate the benefits of treatment 
in terms of functional outcome. Non-inferiority testing was intended originally related to the 
primary efficacy parameter BCVA change from baseline. However, due to feasibility reasons, 
purely descriptive analyses will be performed. 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.  
The BCVA will be evaluated as the mean change from baseline to mean of visits at week 40 to 
52 due to the fact, that patients will receive injections at different intervals and timepoints. 
Patients in the loading arm on a q12w treatment interval may receive their last injection at week 
44, whereas patient in the non-loading arm on a q12w treatment interval may receive their last 
injection at week 48. Shifting from q12w to a q8w treatment regime will also lead to differences 
in treatment schedule. 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 four time points 12 weeks 
apart will mitigate this potential bias. 
4.2 
Rationale for dose/regimen and duration of treatment 
The dose and different regimens for brolucizumab 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 3 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 maintenance phase to reduce the treatment burden (see Section 1.1). 
• 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). Therefore, the protocol contains the 
note to discontinue subjects from study treatment who require treatment every 4 weeks. 

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• The route of administration is an intravitreal injection as for all anti-VEGF treatments 
currently approved for the treatment of nAMD. 
• Study duration of 52 weeks allows for one initial injection followed by four complete 
12-week intervals to evaluate effect of non-loading on long-term efficacy and safety. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Not applicable. 
4.4 
Purpose and timing of interim analyses/design adaptations 
Not applicable. No formal interim analysis will be performed.  
4.5 
Risks and benefits 
Ranibizumab and aflibercept (both approved inhibitors of VEGF-A) have consistently 
demonstrated efficacy in VEGF-driven retinal pathologies, including nAMD, with benefits 
outweighing the risks and are considered standard of care for treatment of nAMD patients. 
In both phase 3 studies (HAWK and 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 and 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. This might 
translate into greater durability and longer injection intervals for brolucizumab 6 mg, with non-
inferior efficacy. The potential superior anatomical results and 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). 
Since until now only treatment-naive patients have been investigated with brolucizumab 6.0 mg 
treatment, this study will give insights on treatment response in pretreated patients. With the 
presumed longer lasting efficacy of brolucizumab the treatment burden also for pretreated 
patients might be reduced.  
 
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 8.4.3 and Section 10. 
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 

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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. 
Intravitreal injections, including those with brolucizumab, have been associated with 
endophthalmitis and retinal detachments. Acute intraocular pressure (IOP) increases have also 
been reported.  
Intraocular inflammation, including retinal vasculitis and/or retinal vascular occlusion may 
occur following the first intravitreal injection with brolucizumab and at any time of treatment. 
These events were observed more frequently early on during treatment.  
 
  
Patients with a medical history of intraocular inflammation and/or retinal vascular occlusion in 
the year prior to treatment with brolucizumab are at risk of developing retinal vasculitis and/or 
retinal vascular occlusion and should be closely monitored. 
In patients developing intraocular inflammation (IOI), including retinal vasculitis and/or retinal 
vascular occlusion, treatment with brolucizumab in the FALCON study should be discontinued 
and the events should be promptly managed.  
In addition, based on USM (CRTH258AUS04 FIR), the brolucizumab dosing interval should 
not be less than 8 weeks beyond the loading period. 
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). A higher 
incidence was also observed in Japanese patients. 
Overall, brolucizumab was well tolerated in clinical studies with nAMD subjects when 
treatment interval is not less than every 8 weeks after the first 3 monthly initial doses (loading 
phase). The risk/benefit profile for brolucizumab remains positive. 
5 
Population 
The study population will be male and female patients ≥50 years old diagnosed with active 
choroidal neovascularization (CNV) secondary to AMD, treated previously for this disease and 
able to comply with study or follow-up procedures. 
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. 

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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. Before enrollment, morphological eligibility 
must be confirmed by the central reading center as part of the screening period. 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 choroidal neovascularization (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 and 
sequelae of CNV, e.g. pigment epithelial detachment (PED), subretinal or sub-retinal 
pigment epithelium (sub-RPE) hemorrhage, blocked fluorescence, macular edema 
(intraretinal fluid (IRF) and/or subretinal fluid (SRF) and/or sub-retinal pigment epithelium 
(sub-RPE) fluid that affects the central subfield, as seen by SD-OCT) at screening as 
confirmed by central reading center. If active CNV according to the above explained activity 
criteria is not detectable in screening image data (no IRF and no SRF), presence of residual 
and/or recurrent fluid (IRF and / or SRF) within the last 6 months before baseline visit is 
also considered eligible. In this case, historical images must be submitted for analysis by 
the central reading center. 
4. Pretreatment with any anti-VEGF drug for a maximum of five years (60 months). Patients 
should have shown functional and/or anatomical treatment response to the pretreatment(s), 
prior to participating in this study. 
5. The treatment initiation phase with the current anti-VEGF must have been completed for at 
least 6 months with continuous treatment in a ≥ q4w to ≤ q12w injection interval (±2-day 
window, i.e., 26 to 86 days inclusive) before the baseline visit. At least 4 weeks (minimum 
26 days) must have passed between the last anti-VEGF pretreatment and baseline. 
6. BCVA score must be ≤ 83 and ≥ 38 letters at 4 meters starting distance using Early 
Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity charts (approximately 
Snellen equivalent of 20/25 and 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 52-week study period (e.g. structural 
damage of the fovea, vitreous hemorrhage, retinal vein occlusion, retinal detachment, 
macular hole, choroidal neovascularization unrelated to age-related macular 
degeneration, diabetic retinopathy (except mild non-proliferative) and diabetic macular 
edema). 

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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. 
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 confirmed by 
central reading center. 
6. The total area of fibrosis or subretinal blood affecting the foveal center point comprising 
≥ 50% of the lesion area as well as chronic cystic lesions in the study eye as confirmed 
by central reading center. 
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. Treatment with any anti-VEGF drug for > 5 years in the study eye. 
9. Pretreatment with brolucizumab at any time in the study eye. 
10. Previous treatment with investigational drugs in the last 6 months in the study eye. 
11. Previous use of intraocular or periocular steroids (non-topical) in study eye.  
12. Macular laser photocoagulation (focal/grid) or photodynamic therapy in the study eye 
at any time prior to baseline and peripheral laser photocoagulation in the study eye 
within 3 months prior to baseline. 
13. Intraocular surgery in the study eye within 3 months prior to baseline. 
14. Vitreoretinal surgery in the study eye at any time prior to baseline. 
15. Aphakia with the absence of posterior capsule in the study eye. 
Systemic conditions or treatments: 
16. Stroke or myocardial infarction during the 6-month period prior to baseline. 
17. End stage renal disease requiring dialysis or renal transplant. 
18. Uncontrolled blood pressure defined as a systolic value ≥ 160 mmHg or diastolic value 
≥ 100 mmHg at screening or baseline. (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). 
19. Systemic anti-VEGF therapy during the 3-month period prior to baseline.  

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20. Systemic medications known to be toxic to the lens, retina or optic nerve (e.g. 
deferoxamine, chloroquine/hydroxychloroquine, tamoxifen, phenothiazines and 
ethambutol) used during the 6‑month period prior to baseline except temporary use for 
Coronavirus SARS-CoV-2 (COVID-19) treatment. 
21. 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. 
22. History of malignancy of any organ system (other than localized basal cell carcinoma 
of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, 
regardless of whether there is evidence of local recurrence or metastases. 
23. History of a medical condition (e.g. metabolic dysfunction disease with exception of 
controlled 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. 
Other:  
24. Patients on an investigational drug, biologic, or participated in a device study shorter 
than 5 half lives of the respective investigational drug, or < 30 days, or until the expected 
pharmacological effect has returned to baseline, whichever is longer. 
25. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
human chorionic gonadotropin (hCG) pregnancy test. 
26. Women of 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. 

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In case of use of oral contraception, women should have been stable on the same pill for 
a minimum of 3 months before taking study treatment. 
Women are considered post-menopausal and not of child-bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at 
least six weeks ago. In the case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment is she 
considered not of child-bearing potential. 
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 drug 
Investigational Drug 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply 
Type 
Sponsor 
(global or 
local) 
Brolucizumab / 
RTH258 120mg/ml 
Solution for injection 
Intravitreal use 
pre-filled 
syringe 
local 
The investigational treatment used in this study is brolucizumab 6 mg/0.05 mL. Brolucizumab 
is formulated as a sterile solution aseptically filled in a sterile syringe for single use containing 
sufficient brolucizumab to deliver a 6 mg dose when administering a volume of 0.05 mL. The 
content of the study drug pre-filled syringe must not be split. Brolucizumab will be packed 
according to local legal requirements.  
The storage conditions will be described on the package and follow the current 
recommendations of the manufacturer. Study medication should not be stored together with 
commercial brolucizumab to avoid mix up.  
The sponsor will ensure sufficient supplies of brolucizumab for treatment use to allow for 
completion of the study. 
6.1.2 
Additional study treatments 
No other treatment beyond investigational drug are 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: 

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• Brolucizumab 6 mg “loading arm”: 3 x 4-weekly initial injections followed by an 
injection every 12 weeks (q12w maintenance) 
• Brolucizumab 6 mg “non-loading arm”: one initial injection followed by an injection 
every 12 weeks (q12w maintenance) 
6.1.4 
Treatment duration 
The planned duration of treatment is maximum 48 weeks and determined by the treatment arm 
and q12w/q8w maintenance, respectively. 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. 
Study treatment will also be discontinued for patients who require injections more frequently 
than every 8 weeks after the loading phase (week 8, loading arm) or baseline (non-loading arm). 
In patients developing intraocular inflammation, including retinal vasculitis and/or retinal 
vascular occlusion, treatment with brolucizumab in the FALCON study should be discontinued 
and the events should be promptly managed. 
Subjects who prematurely discontinue study treatment for any reason except for withdrawal of 
consent should continue in the study and carry out the scheduled visits and assessments, at the 
discretion of the subject and investigator. 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
The investigator must instruct the subject to notify the study site about any new medications the 
subject takes after signing the study informed consent. 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 in the appropriate Case Report 
Forms.  
Each concomitant drug/procedure must be individually assessed against all exclusion 
criteria/prohibited medication. If in doubt the investigator should contact the sponsor before 
randomizing a subject or allowing a new medication to be started. If the subject is already 
enrolled, contact the sponsor 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 
Fellow eye 
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.  
Study eye 

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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 and cannot 
be postponed until end of study, 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 perfomed ≥ 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 time 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. 
6.2.2 
Prohibited medication 
Use of the treatments displayed in the below table (Table 6-2) are not allowed after screening. 
Table 6-2 
Prohibited medications and procedures 
Medication/Procedures 
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, nanosecond 
laser or focal laser photocoagulation 
with involvement of the macular 
area 
Anytime 
PD documentation and 
continuation of study treatment 
at the investigators discretion  
Any investigational drug, biologics 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 
 
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.  

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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. 
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., three digits), 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 (Center No., four digits) (as assigned by the sponsor to the investigative 
site) with a sequential subject number suffixed to it, 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.  
Once assigned to a patient, the patient number will not be reused for another patient. Subjects 
who have been screen failures but are rescreened (see Section 8.1) will be assigned a new 
Subject No. if rescreening occurs beyond 14 days from the original screening date. 
If the patient fails to be randomized for any reason, the reason for not being randomized will be 
entered on the Screening Log, and the Demography eCRF should be completed. 
6.3.2 
Treatment assignment, randomization 
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 
randomization list will be produced by or under the responsibility of the sponsor using a 
validated system that automates the random assignment of treatment arms to randomization 
numbers in the specified ratio. Randomization codes will be assigned by the eCRF. The 
randomization codes should be requested only after receiving the positive feedback from the 
reading center (via the eCRF) and central lab (female patients, if applicable) that the patient in 
screening is eligible to be included in the study as described in Figure 6-1.  
Randomization codes and data about all study drug injected to the patient’s eye will be tracked 
in the eCRF. 

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Figure 6-1 
Screening and randomization procedure 
 
6.4 
Treatment blinding 
Treatment will be open to subjects, investigator staff, persons performing the assessments, and 
the clinical trial team (CTT). The central reading center (CRC) will be blind to the identity of 
the treatment from the time of randomization until database lock.  
6.5 
Dose escalation and dose modification 
No study treatment dose modification is allowed. 
Deviations from 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  
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 investigator staff or by 
the 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 field monitor at each visit using 
medication counts and information provided by the investigator / study personnel. 
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).  
6.7.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 

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site personnel have access. Upon receipt, all study treatment must be 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 
CPO Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment. 
The 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 
the 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 study 
personnel will return all unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site. 
6.7.2 
Instruction for prescribing and taking study treatment 
There will be two different treatment regimens (see Figure 6-2) for IVT injections with different 
timing for brolucizumab “loading” and “non-loading” treatment arms: 
• Brolucizumab 6 mg “loading”: Treatment with brolucizumab will be initiated with 
three loading injections every 4 weeks for three consecutive injections (baseline, 
weeks 4 and 8). From week 8 onwards, patients will be scheduled to receive one 
injection of brolucizumab 6 mg every 12 weeks.  
• Brolucizumab 6 mg “non-loading”: Treatment with brolucizumab will be initiated 
with one single injection (baseline). From baseline onwards, patients will be 
scheduled to receive one injection of brolucizumab 6 mg every 12 weeks.  
For both study arms:  
• The assessment of disease activity will be performed 8 and 12 weeks after the previous 
injection. 
• If disease activity is identified by the investigator for the first time at any visit after / 
from week 8 respectively, patients should stay on a q12w dosing, if the decline in BCVA 
is clinically non-significant (BCVA loss ≤ 4 ETDRS letters) compared to the previous 
visit.  
• If after / from week 8, a BCVA-loss of ≥ 5 ETDRS letters appears compared to the 
previous visit or disease activity is identified for a second time based on the 
investigator’s judgement of visual and/or anatomic outcomes and signs of disease 
activity*, patients must be assigned to q8w dosing.  
• One attempt of re-extension to q12w will be allowed based on the investigator’s 
judgement if no disease activity (DA) is detected during the subsequent visit(s).  
• If the patient shows significant DA after the re-extension attempt, injection intervals 
will be fixed to q8w until the end of the study 

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• *The disease activity decision should be based on the BCVA loss criterium (BCVA loss 
≥ 5 ETDRS letters or ≤ 4 ETDRS letters compared to the previous visit) and beyond 
that on investigator’s judgment of visual and/or anatomic outcomes and signs of disease 
activity (e.g. IRF, SRF, hemorrhage, leakage, visual acuity loss over time etc.). 
 
 
 
Figure 6-2 
Treatment regimen 
Evaluation of Disease Activity (DA): 
The concept of the brolucizumab q12w/q8w regimen is to allocate patients according to their 
individual treatment needs to either a q12w or a q8w treatment schedule. The initial schedule is 
q12w and a patient will remain on q12w as long as the investigator does not identify nAMD 
disease activity which in his opinion requires more frequent anti-VEGF treatment (BCVA-loss 
of ≥ 5 ETDRS letters compared to the previous visit or disease activity is identified for a second 
time based on the investigator’s judgement of visual and/or anatomic outcomes).  
In case of BCVA-loss of ≥ 5 ETDRS letters compared to the previous visit, the patient must be 
switched to a q8w regimen. Beyond the BCVA loss criteria, the assessment of the DA is at the 
discretion of the investigator and should be made based on changes in vision and anatomical 
parameters (e.g. IRF, SRF, hemorrhage, leakage, vision loss over time etc.) with reference to 
the patients’ disease status. Figure 6-3 shows three examples for regimen adjustments for the 
loading arm (examples 1-3) and non-loading arm (examples 4-6), respectively.  

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Figure 6-3 
Examples for treatment regimen adjustments 
Brolucizumab 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 or no later than within the visit 
window (±7 days) as described in Section 3 and Section 8. Every effort should be made to 
ensure that the subject adheres to the visit/treatment schedule. 
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 8.4.3. If study 
visit assessments and the corresponding treatment occur on separate days, a repeat safety 
checkup 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.  
Brolucizumab administration 
The IVT injection procedure for brolucizumab including aseptic and antimicrobial requirements, 
will be performed according to local clinical practice. IVT injection is contraindicated in 

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patients with active ocular or periocular infections and in patients with active intraocular 
inflammation (IOI); therefore, the investigators must verify that these conditions are not present 
in the study eye prior to every injection. Any adverse events must be recorded in the eCRF.  
If any signs of intraocular inflammation are present, then an IVT injection must not be 
performed. Additional ophthalmic examination and imaging should be performed to evaluate 
IOI (see Section 8.4.3). 
In patients developing intraocular inflammation, including retinal vasculitis and/or retinal 
vascular occlusion, treatment with brolucizumab in the FALCON study should be discontinued 
and the events should be promptly managed. 
7 
Informed consent procedures 
Eligible subjects may only be included in the study after signing Institutional Review 
Board/Independent Ethics Committee (IRB/IEC)-approved informed consent. 
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 Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification 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 for the duration 
of the study and for 3 months after stopping the investigational medication. 
If there is any question that the patient will not reliably comply, they must not be entered in the 
study. 
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 

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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 the assessments when they are performed 
(indicated with an “X”). All data obtained from these assessments must be supported in the 
subject’s source documentation. All data must be entered in the eCRF in a timely manner (see 
Section 11.1). 
Subjects should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1). All post-baseline and/or subsequent scheduled visits will be calculated based on 
the day 1 visit date. From baseline on, patients will visit the site every 4 weeks. From baseline 
(non-loading arm) or week 8 (loading arm) to week 52, the treatment intervals will be set to 
q12w / q8w by the 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 ± 7-day visit window is allowed, except for baseline/day1 and the week 52 visit (± 21-day 
visit window), should the subject be unable to return per scheduled visit. For a given protocol 
visit, assessments can be performed on two consecutive days in which both days must occur 
within the ± 7-day 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. 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 final visit will be performed. At this 
final visit, all dispensed investigational product should be reconciled, and the adverse event and 
concomitant medications recorded on the CRF.  
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 
Visit Name 
Screening 
Baseline 
Treatment Period (w) 
Comment 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 / 
EOS 
Week (w) / Day (d) 
-2w to -1d 
Day 1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
b = bilateral 
 
* = assessment of disease activity 
will be performed 8 and 12 weeks 
after the previous injection 
 
1 = if disease activity is identified by 
the investigator for the first time, 
patients will stay on a q12w dosing, 
if the decline in BCVA is clinically 
non-significant (BCVA loss ≤ 4 
ETDRS letters). If renewed disease 
activity is identified or BCVA-loss of 
≥ 5 ETDRS letters appears, patients 
will be assigned to q8w dosing. One 
attempt to re-extension to q12w will 
be allowed based on the 
investigator’s judgement if no 
disease activity is detected during 
the subsequent visit(s). If the patient 
shows significant DA after the re-
extension attempt, injection intervals 
will be fixed at q8w until the end of 
the study (see Section 6.7.2) 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/ current medical 
conditions / nAMD history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection RTH258 – 1 initial 
injection in non-loading arm1 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Injection RTH258 – 3 initial 
injections in loading arm1 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Prior/Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum β-hCG Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Best-Corrected Visual Acuity 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xb 
Intraocular pressure (IOP) 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xb 
Ophthalmic Exam2 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xb 
SD-OCT2  
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xb 
Color Fundus Photography2 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xb 
Fluorescein Angiography2  
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xb 
Disease Activity Assessment 
 
 
 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 

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Visit Name 
Screening 
Baseline 
Treatment Period (w) 
Comment 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 / 
EOS 
Week (w) / Day (d) 
-2w to -1d 
Day 1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
2 = 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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8.1 
Screening 
A screening period of up to 2 weeks will be used to assess eligibility.  
For the purpose of screening, fluorescein angiography (FA) images from a previous routine 
evaluation may be used as long as FA was performed within 7 days of the screening visit using 
CRC-certified equipment and technician/investigator. 
One-time rescreening of patients is allowed, except for the purpose of capturing new BCVA or 
imaging assessments that previously failed to qualify the patient. As long as testing can be 
repeated within 14 days of the first screening, the other screening assessments do not need to 
be repeated. If rescreening is to occur beyond 14 days from the original screening visit date, 
then the subject must be reconsented and 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.  
8.1.1 
Information to be collected on screening failures 
Subjects who sign an informed consent form and subsequently found to be ineligible prior to 
randomization will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate eCRF page. The demographic information, informed consent, and 
inclusion/exclusion pages must also be completed for screen failure subjects. No other data will 
be entered into the clinical database for subjects who are screen failures, unless the subject 
experienced a serious adverse event during the screening phase (see Section 10.1.3 for reporting 
details). SAE data, informed consent, and inclusion/exclusion data are recorded on the eCRF. 
Adverse events that are not SAEs will be followed by the investigator and collected only in the 
source data.  
Subjects who are randomized and fail to start treatment, e.g. subjects randomized in error, will 
be considered an early terminator. The reason for early termination should be recorded on the 
appropriate eCRF.  
8.2 
Subject demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with eCRF. 
The following information will be collected/documented at screening/baseline visit for each 
randomized subject: 
• Year of birth/ age 
• Gender 
• Race  
• Vital signs 
• Study eye 
• Visual acuity 
• Choroidal neovascularization characteristics 

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• Intraocular pressure 
• Ophthalmic examinations 
• Retinal imaging 
• Laboratory test results (pregnancy test) 
• Prior/concomitant medications; anti-VEGF pretreatment (24 weeks to baseline prior to 
enrollment) 
• Medical history (including possible underlying inflammation and autoimmune disease), 
nAMD history and current medication 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 tests will be performed to evaluate the effect of brolucizumab on visual function 
retinal structure and vascular leakage: 
• Best-corrected visual acuity with ETDRS-like charts at 4 meters 
• Anatomical retinal evaluation of SD-OCT images 
• Color Fundus Photography and vascular leakage evaluation by Fluorescein angiography 
All efficacy assessments should be performed prior to any administration of study treatment 
and/or rescue medication. 
8.3.1 
Visual acuity 
Visual acuity will be assessed in the study eye at every study visit and in the fellow eye at the 
screening and week 52/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 materials, are provided in the applicable manual. 
Certification of the assessment procedures and assessors will occur prior to any evaluation of 
study patients. 
8.3.2 
SD-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 and week 52 
/ EOS visits. The central reading center (CRC) will check screening images (SD-OCT, FP, FA) 
for eligibility of patients within 72 hours of image upload. Only after patients are deemed 
eligible by the CRC, they may be randomized if all other in/exclusion criteria are met. 
SD-OCT assessments will be performed by trained technician or investigator at the sites and 
should be performed after BCVA assessment and prior to any study drug administration. The 
investigator will evaluate the SD-OCT images to assess the status of disease activity. The SD-
OCT machine used for an individual patient should not change for the duration of the study. 

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The images will be reviewed by a CRC to ensure a standardized evaluation. For further 
procedural details the investigator should refer to the applicable manual provided by the CRC. 
8.3.3 
Color fundus photography and fluorescein angiography 
Color fundus photography (CFP) and fluorescein angiography (FA) will be performed in both 
eyes at the screening and week 52/EOS visits. CFP and FA may be performed at other visits at 
the investigator’s discretion. For the purpose of screening, FA images from a previous routine 
evaluation may be used as long as FA was performed within 7 days of the screening visit using 
CRC-certified equipment and technician/investigator. In case of premature discontinuation 
from the study, there is no need to repeat the CFP and FA if there was a CFP and FA performed 
within the previous 12 weeks, except if there is significant disease worsening, in the opinion of 
the investigator. 
These assessments will be performed by trained personnel at the sites. The images will be 
reviewed by a CRC to ensure a standardized evaluation. For further procedural details the 
investigator should refer to the applicable manual provided by the CRC. 
Additional images will be taken in case of any signs of intraocular inflammation. OCT, color 
fundus photography and fluorescein angiography (preferably wide-field or with peripheral 
sweeps) should be performed for safety evaluation as described in Section 8.4.3. 
8.3.4 
Appropriateness of efficacy assessments 
The use of BCVA as a measure of retinal function as well as SD-OCT images to analyze 
anatomical changes are standard assessments in this indication and are required for a 
comparative evaluation of this trial with the existing evidence from previous trials. 
Color fundus photography (CFP) is used to inspect retinal pathology.  
Fluorescein angiography (FA) is also an established procedure that helps to classify the type of 
lesion and is used to assess vascular leakage. 
8.4 
Safety 
Safety assessments will include vital signs, ophthalmic examinations and imaging, and 
laboratory evaluation (pregnancy testing) as wells as monitoring and recording type, frequency, 
and severity for all AEs. 
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 participants to visit the 
site again. 

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Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.  
For details on monitoring, assessment and management of adverse events of inflammation, 
retinal vasculitis and/or retinal vascular occlusion, refer to Section 10. For details on AE 
collection and reporting, refer to Section 10.1. 
Table 8-2 
Assessments & Specifications  
Assessment 
Specification 
Vital signs 
Vital signs include assessment of blood pressure (systolic and diastolic pressure in 
mmHg, sitting position) and pulse (beats per minute) and will be collected at all visits. 
In case there is an elevated blood pressure measurement as specified in the 
exclusion criteria, at the screening and 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. 
Height 
and 
weight 
Height in centimeters (cm) and body weight (to the nearest kilogram (kg), in indoor 
clothing but without shoes) will be measured at screening only. The results will be 
recorded in the eCRF. 
 
8.4.1 
Laboratory evaluations 
No specific mandatory laboratory evaluations for safety assessment will be performed except 
serum pregnancy testing (see Section 8.4.2 for details). Details on the collection, shipment of the 
samples for pregnancy testing and reporting of the results by the central laboratory are provided to 
investigators in the laboratory manual. 
If the COVID-19 pandemic limits or prevents on-site study visits, the collection of samples may 
be modified by Novartis if applicable and if modified, will be communicated to the Investigator. 
Table 8-3 
Laboratory assessments 
Test Category 
Test Name 
Pregnancy test 
Serum pregnancy test will be performed at screening, Urine pregnancy 
test will be performed at all other visits (Section 8.4.2) 
 
8.4.2 
Pregnancy and assessments of fertility 
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 medication. 
A serum pregnancy test will be conducted for all women of child-bearing potential to assess 
pregnancy before inclusion into the study at the screening visit. If the serum pregnancy test is 
inconclusive, the leftover sample will be used to conduct a FSH (Follicle Stimulating Hormone) 
test to confirm the child-bearing potential. 

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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 
pregnancy test must be performed for confirmation; if the serum test is positive, the subject 
must discontinue study treatment with brolucizumab. Results of all pregnancy testing must be 
available as source documentation. 
8.4.3 
Ophthalmic examination and imaging 
The ophthalmic exam will consist of the following:  
• Intraocular pressure will be assessed in the study eye, pre-dose and post-dose and 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 and week 52 / EOS visits. 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 intraocular inflammation (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 after pupil dilation 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 recommended. 

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Clinically significant abnormalities of either eye will be recorded on the medical/ocular history 
page before baseline and on the adverse event page of the eCRF for any findings identified after 
baseline.  
Instruct the patient to contact the site for any changes in vision or any symptoms of 
inflammation between scheduled visits. Every effort should be made to bring the subject for 
immediate examination.  
Imaging: When intraocular inflammation, retinal vasculitis, and/or retinal artery occlusion 
(RAO) is present or suspected during a visit, investigators must perform thorough ophthalmic 
examination, and will conduct OCT, fluorescein angiography and color fundus photography 
(preferably 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. In patients developing intraocular inflammation, including 
retinal vasculitis and/or retinal vascular occlusion, treatment with brolucizumab in the 
FALCON study should be discontinued and the events should be promptly managed.  
8.4.4 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/subject population.  
If there are any signs of IOI, additional assessment will be performed as described in 
Section 8.4.3. 

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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. 
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. 

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The investigator must discontinue study treatment for a given patient if, he/she believes that 
continuation would negatively impact the subject's well-being. 
Study treatment must be discontinued under the following circumstances:  
• Subject decision 
• Pregnancy (see Section 8.4.2 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 
• Unsatisfactory therapeutic effect, e.g. a subject requires injections more frequently than 
every 8 weeks after the loading phase (week 8, loading arm) or baseline (non-loading arm). 
• Subjects develop intraocular inflammation, retinal vasculitis and/or retinal vascular 
occlusion 
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information on 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 with all the scheduled visits and 
assessments (except disease stability assessment, administration of study treatment, post-
injection assessment and adherence to prohibited medication list) until EOS. These patients can 
be switched to standard of care anti-VEGF IVT as per investigator’s discretion. Any 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. 
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. 
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. 
After premature study treatment discontinuation, at a minimum, in abbreviated visits, the 
following data should be collected at clinic visits or via telephone/email contact: 
• New/concomitant treatments 
• Adverse events/Serious Adverse Events 
• BCVA 

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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 
Withdrawal of consent/opposition to use data/biological samples occurs when a participant: 
• Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples) 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts) 
This request should be in writing (depending on local regulations) and recorded in the source 
documentation. 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their 
consent/opposition to use data/biological samples and record this information. 
Where consent to the use of Personal and Coded Data is not required in a certain country's legal 
framework, the participant therefore cannot withdraw consent. However, they still retain the 
right to object to the further collection or use of their Personal Data. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/opposition to use data/biological samples should be made as detailed in the assessment 
table (refer to Section 8).  
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation, including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition. 
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. 

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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 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 sponsor (as applicable by local law) will be responsible for informing 
IRBs/IECs of the early termination of the trial. 
9.2 
Study completion and post-study treatment 
Study completion for an individual patient is defined as when the patient finishes his/her study 
completion / 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 
Subjects should be closely monitored for adverse events. 
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 immediately for any changes in vision or any 
symptoms of inflammation independently of scheduled visits (refer to the optional patient 
brochure). Every effort should be made to bring the subject for immediate (< 12 hours) 
examination including on weekends and public holidays. 
• Close patient monitoring and thorough examination of the eye should be done to detect 
potential signs of inflammation (Section 8.4.3). 
• Patients with a medical history of intraocular inflammation and/or retinal vascular occlusion 
in the year prior to treatment with brolucizumab are at risk of developing retinal vasculitis 
and/or retinal vascular occlusion and should be closely monitored. 
• When IOI, retinal vasculitis, and/or retinal vascular occlusion is present or suspected during 
any visit, investigators must perform thorough dilated pupil ophthalmic examination, and 
will conduct OCT, fluorescein angiography and color fundus photography (preferably wide-
field or with peripheral sweeps). The images are requested to be uploaded onto the CRC 
portal.  

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• If any signs of intraocular inflammation are 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. 
• In patients developing intraocular inflammation, including retinal vasculitis and/or retinal 
vascular occlusion, treatment with brolucizumab in the FALCON study should be 
discontinued and the events should be promptly managed. 
For additional information related to safety assessments refer to Section 6.7.2 and Section 8.4.3.  
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 also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings,  or other 
assessments. 
Adverse events must be recorded in the appropriate eCRF capturing AEs under the signs, 
symptoms or diagnosis associated with them, accompanied by the following information (as far 
as possible) (if the event is serious refer to Section 10.1.2): 
a) the severity AE grade 
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
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 

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d) whether it constitutes a serious adverse event (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  
• patient hospitalized/patient’s hospitalization prolonged (see Section 10.1.2 for 
definition of SAE) 
f) its outcome: 
• not recovered / not resolved; 
• recovered / resolved; 
• recovering / resolving 
• resolved / resolved with sequelae; 
• fatal or unknown 
g) localization (study eye, fellow eye, systemic) 
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 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
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. 

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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 
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 the last study visit or 60 days after the last administration 

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of study treatment whichever is later must be reported to Novartis safety immediately, without 
undue delay, but under no circumstances later than within 24 hours of obtaining knowledge of 
the events. Detailed instructions regarding the submission process and requirements are to be 
found in the investigator folder provided to each site. Following this study period, SAEs 
considered by the investigator to be causal related to study treatment should be reported to 
Novartis safety. 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 
immediately, without undue delay, but under no circumstances later than 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 Novartis Patient Safety 
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. 
10.1.4 
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded and reported by the investigator to the Novartis Patient Safety. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the investigational treatment 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, patient or 
consumer (European Medicines Agency (EMA) definition). 
Misuse/ abuse of the study drug by the patient is not applicable to this study as IVT injection is 
performed by the investigator. 
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the dose administration record in the eCRF and in the Dispensing Log at the study site, 

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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 Dosing 
CRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes (date and time of 
injection) 
Only if associated 
with an AE 
Only if associated 
with an SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections (Section 10.1.1, Section 10.1.2 and Section 10.1.3). 
10.2 
Additional Safety Monitoring 
Not applicable. 
11 
Data collection and database management 
11.1 
Data collection 
Designated 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. 
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 investigational site. 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control 
Novartis personnel (or designated CRO) 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 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications 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 

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events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
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 
randomization list will be produced by or under the responsibility of the sponsor using a 
validated system that automates the random assignment of treatment arms to randomization 
numbers in the specified ratio. Randomization codes will be assigned by the eCRF. 
Randomization codes and data about all study drug dispensed to the patient will be tracked in 
the eCRFs. 
The occurrence of relevant protocol deviations will be determined. Once all the necessary 
actions have been completed and the database has been declared to be complete and accurate, 
it will be locked. Any changes to the database after that time can only be made after written 
agreement by Novartis development management. 
Laboratory samples and images (Color fundus photographs, fluorescein angiograms, and SD-
OCT images) will be processed centrally and the results will be sent electronically to Novartis 
(or a designated CRO). 
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. 
eCRF) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of subject records, the accuracy 
of data capture/data entry, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis (or 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, FA, SD-OCT), and the results of any other 
tests or assessments. All information on CRFs must be traceable to these source documents in 
the subject’s file. The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 

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study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed. 
12 
Data analysis and statistical methods 
The primary safety and efficacy analysis will be conducted on all subject data at the time the 
trial ends. This analysis will be performed once all patients completed their final visits or 
terminated the study prematurely. 
In addition to the statistical methods outlined below, further details will be described in the 
Statistical Analysis Plan (SAP). 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.  
Additional analysis may be also conducted to evaluate the impact of COVID-19 pandemic. 
12.1 
Analysis sets 
The Randomized Analysis Set (RAS) consists of all randomized subjects.  
The Full Analysis Set (FAS) comprises all subjects who receive at least one IVT injection of 
the study treatment. The FAS will serve as the primary analysis set for all efficacy analyses. 
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 
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.  
Relevant protocol deviations and their potential impact on the analysis will be assessed and 
adequately documented / processed before database lock. 
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, 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 history and current medical conditions at baseline will be summarized 
separately by system organ class (SOC) and preferred term, by treatment arm.  
Other relevant baseline information will be listed and summarized with descriptive statistics as 
appropriate.  

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12.3 
Treatments 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. 
The duration of exposure to the investigational drug as number of injections from baseline to 
EOS/week 52 will be summarized by means of descriptive statistics using the safety set. 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 group. 
12.4 
Analysis of the primary endpoint(s) 
The primary objective of this study is to evaluate descriptively the difference of brolucizumab 
6 mg with one (initial) injection followed by q12w maintenance and brolucizumab 6 mg with 
3x q4w loading injections followed by q12w maintenance with respect to the change in BCVA 
from baseline to mean of visits at week 40 to week 52. 
12.4.1 
Definition of primary endpoint(s)  
The analysis of the primary endpoint will be based on the following estimand: 
The population will be male and female patients ≥50 years old diagnosed with active choroidal 
neovascularization (CNV) secondary to AMD and treated previously for this disease, who will 
be switched to brolucizumab at baseline. 
Variable of interest: primary endpoint is the change in BCVA from baseline to mean of visits 
at week 40 to week 52; irrespective of adherence to treatment, i.e. the treatment policy. 
Intervention effect: effect of brolucizumab "non-loading arm" versus " loading arm" after 52 
weeks regardless of adherence to randomized treatment. 
Summary measure: Difference in means 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The analysis of the primary endpoint will be perfomed in a purely descriptive manner and non-
inferiority testing will be omitted. To evaluate the outcome in terms of mean change in BCVA 
from baseline to mean of visits at week 40 through week 52, a two-sided 95% confidence 
interval for the treatment difference will be derived from a mixed model with repeated measures 
(MMRM) model with factors treatment arm, baseline BCVA and age. Details will be specified 
in the respective SAP.  
The FAS will be used to analyze the primary endpoint. 
12.4.3 
Handling of missing values/censoring/discontinuations 
As a primary approach, retrieved data will be included, irrespective of intercurrent events such 
as prohibited medication or treatment interruption or discontinuation (treatment policy, 
difference in all randomized patients). Details will be specified in the respective SAP. For 

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statistical analyses of continuous parameters, missing data in case of lost to follow-up will be 
accounted for in a mixed model for repeated measures (MMRM) assuming data after loss to 
follow-up are missing at random (MAR), and assuming almost all data will be retrieved. Thus, 
every effort must be made to follow-up on patients after treatment discontinuation up to end of 
study. 
12.4.4 
Sensitivity and supportive analyses 
Not applicable. 
12.5 
Analysis of secondary endpoints 
12.5.1 
Efficacy endpoints 
The secondary efficacy objectives and endpoints of this study are listed in Table 2-1. 
Secondary endpoints will be analyzed using adequate descriptive statistics.  
For continuous variables, summary statistics will generally include: n, mean, standard deviation, 
median, minimum and maximum. Treatment group comparisons may include confidence 
intervals and group differences together with the respective confidence intervals. 
The secondary endpoint "Mean change in BCVA from baseline to mean of visits week 16 to 
week 28" will be analyzed analogous to the primary endpoint analysis. 
For categorical variables, these will generally include: n and percentage in each category.  
Rates and percentages will be presented for binary variables. 
For the endpoints "rate of patients (overall and per group) with prolonged interval compared to 
mean treatment interval in last -24 weeks prior to enrollment" and "proportions of patients 
maintained at a q12w interval at week 52" a logistic regression model will be fitted. 
12.5.2 
Safety endpoints 
The secondary safety objective and endpoint of this study is as follows: 
To evaluate the safety and tolerability of brolucizumab  
• Incidence of ocular and non-ocular AEs up to week 52  
There are no formal safety hypotheses in this study. For all safety analyses, the safety set will 
be used. All listings and tables will be presented by treatment arm. 
Safety endpoints are based on the variables from safety assessments which include: 
• Extent of exposure 
• Adverse events 
• Ophthalmic examinations 

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• Vital signs 
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 including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). 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 
A treatment-emergent adverse event is defined as any adverse event that develops after 
initiation of the study treatment or any event already present that worsens following exposure 
to the study treatment. Only treatment-emergent adverse events will be presented in the 
summary tables. 
All information obtained on adverse events will be displayed by treatment arm and subject.  
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 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. 
• by treatment, standardized MedDRA Query (SMQ) and preferred term. 
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation. 
Adverse events will be coded using the MedDRA dictionary and presented by system organ 
class (SOC) and preferred term (PT). Treatment-emergent AEs will be analyzed based on the 
number and percentage of patients with at least one AE in the category of interest. Separate 
presentations will be provided related to ocular events in the study eye and fellow eye and 
systemic events. Additional summaries will be provided by severity and causality (separately 
assessed for the injection procedure and the drug). Serious adverse events and adverse events 
leading to discontinuation of study treatment will also be summarized separately. 
Ophthalmic examinations 
Pre-injection IOP measurements will be presented descriptively (absolute values and change 
from baseline). Post-injection IOP measurements will be listed.  
Vital signs 
All vital signs data will be listed by treatment group, subject, and visit/time and if ranges are 
available, abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time. 

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12.7 
Interim analyses 
Not applicable.  
12.8 
Sample size calculation 
12.8.1 
Primary endpoint 
Due to feasibility reasons, resulting in a substantial delay in recruitment, as described above, 
with Amendment 2 the recruitment will be prematurely discontinued. A final number of 
approximately 50 patients is expected to be recruited by the time of approval of the amendment. 
As a consequence, all analyses will be performed and interpreted in a purely descriptive manner. 
Based on an expected sample size of 25 patients per group, and an assumed common standard 
deviation of 13 letters, a precision in terms of the width of the respective 95% confidence 
interval for the difference in change from baseline of the visual acuity of +/- 7,21 can be 
achieved. Taking into account the current number of patients of (for 23 patients per group), the 
precision in terms of the half width of the 95% confidence interval would be 7,51.  
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
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. 

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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.). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances, including 
incidental collection, is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
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. 

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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 
 
Bayer Vital GmbH (2019) Fachinformation - Eylea® 40 mg/ml Injektionslösung in einer 
Durchstechflasche.  
Blinder, K. J., Bradley, S., Bressler, N. M., et al. (2003) Effect of lesion size, visual acuity, and 
lesion composition on visual acuity change with and without verteporfin therapy for 
choroidal neovascularization secondary to age-related macular degeneration: TAP and 
VIP report no. 1. Am J Ophthalmol; 136:407-18. 
Bloch, S. B., Larsen, M. & Munch, I. C. (2012) Incidence of legal blindness from age-related 
macular degeneration in denmark: year 2000 to 2010. Am J Ophthalmol; 153:209-13 e2. 
Campbell, J. P., Bressler, S. B. & Bressler, N. M. (2012) Impact of availability of anti-vascular 
endothelial growth factor therapy on visual impairment and blindness due to 
neovascular age-related macular degeneration. Arch Ophthalmol; 130:794-5. 
Escher, D., Schmidt, A., Steiner, P., et al. (2015) Single-chain antibody fragments in 
ophthalmology. Euretina;  
Ferris, F. L., 3rd, Fine, S. L. & Hyman, L. (1984) Age-related macular degeneration and 
blindness due to neovascular maculopathy. Arch Ophthalmol; 102:1640-2. 
Jabs, D. A., Nussenblatt, R. B., Rosenbaum, J. T., et al. (2005) Standardization of uveitis 
nomenclature for reporting clinical data. Results of the First International Workshop. 
Am J Ophthalmol; 140:509-16. 
Nussenblatt, R. B., Palestine, A. G., Chan, C. C., et al. (1985) Standardization of vitreal 
inflammatory activity in intermediate and posterior uveitis. Ophthalmology; 92:467-71. 
Rein, D. B., Wittenborn, J. S., Zhang, X., et al. (2009) Forecasting age-related macular 
degeneration through the year 2050: the potential impact of new treatments. Arch 
Ophthalmol; 127:533-40. 
Retinologische Gesellschaft, D. O. G., Berufsverband der Augenärzte Deutschlands (2014) Die 
Anti-VEGF-Therapie bei der neovaskulären altersabhängigen Makuladegeneration: 
Therapeutische Strategien.  
Shah, A. R. & Del Priore, L. V. (2007) Progressive visual loss in subfoveal exudation in age-
related macular degeneration: a meta-analysis using Lineweaver-Burke plots. Am J 
Ophthalmol; 143:83-89. 
Shah, A. R. & Del Priore, L. V. (2009) Natural history of predominantly classic, minimally 
classic, and occult subgroups in exudative age-related macular degeneration. 
Ophthalmology; 116:1901-7. 
Silva, R., Berta, A., Larsen, M., et al. (2018) Treat-and-Extend versus Monthly Regimen in 
Neovascular Age-Related Macular Degeneration: Results with Ranibizumab from the 
TREND Study. Ophthalmology; 125:57-65. 
Spilsbury, K., Garrett, K. L., Shen, W. Y., et al. (2000) Overexpression of vascular endothelial 
growth factor (VEGF) in the retinal pigment epithelium leads to the development of 
choroidal neovascularization. Am J Pathol; 157:135-44. 
Voegeler, J. & Mueller, D. (2017) Non-interventional Final Study Report CRFB002ADE18: 
OCEAN - Observation of treatment patterns with Lucentis and real life ophthalmic 
monitoring, including optional OCT in approved indications.  

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Wykoff, C. C., Clark, W. L., Nielsen, J. S., et al. (2018) Optimizing Anti-VEGF Treatment 
Outcomes for Patients with Neovascular Age-Related Macular Degeneration. J Manag 
Care Spec Pharm; 24:S3-S15. 
 
16 
Appendices 
Not applicable.