Conditions: Neovascular Age-related Macular Degeneration
Keywords: Neovascular age-related macular degeneration anti-VEGF brolucizumab choroidal neovascularization multimodal imaging biomarkers fluid resolution Macular degeneration age-related macular degeneration (ARMD) vision loss macula damage retina damage dry macular degeneration wet macular degeneration AMD
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 122
Healthy volunteers: no

Brief summary:
The purpose of this study was to identify innovative early imaging parameters as predictors of the long-term clinical response to brolucizumab in terms of fluid resolution in patients with wet Age-related Macular Degeneration (wAMD) to evaluate their potential in supporting the choice of treatment regimen (q12w or q8w).

Detailed description:
The study was a one-year, open-label, single arm, multicenter, phase IV study in patients with wAMD. The study planned to enroll approximately 263 (male and female) patients aged 50 years or older with untreated active subfoveal choroidal neovascularization (CNV) secondary to wAMD in the study eye from approximately 30 centers in Italy. The duration of the study treatment for enrolled patients was a maximum of 48 weeks, consisting of 8 weeks of three monthly loading doses and 40 weeks of maintenance regimen period (q8w or q12w) according to disease activity assessment.

Arms:
arm 1: Participants received 3 monthly ocular injections followed by a q12w or q8w maintenance phase based on patient's disease activity (DA).

Interventions: intervention 1: Brolucizumab
Intervention descriptions: intervention 1: 120 mg/ml solution for intravitreal injection

Protocol document:
Prot_000.pdf: 
Novartis Research and Development 
RTH258/Brolucizumab 
Clinical Trial Protocol CRTH258AIT04 / NCT04774926
One year, single arm, open label, multicenter, phase IV 
study using multimodal imaging to guide disease activity 
assessment through innovative early predictive anatomical 
biomarkers of fluid resolution in wAMD patients treated 
with brolucizumab– IMAGINE study 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2020-002452-20 
Version number: 
02 (Track changes) 
Clinical Trial Phase:   Phase IV 
Release date: 
11-Nov-2021
Property of Novartis  
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 8 
Amendment 1 11-Nov-2021 .............................................................................................. 10 
Change1 to the original protocol (v00 11-May-2020) ...................................................... 12 
Protocol summary .............................................................................................................. 14 
1 
Introduction ....................................................................................................................... 18 
1.1 
Background ............................................................................................................ 18 
1.2 
Purpose .................................................................................................................. 22 
2 
Objectives and endpoints ................................................................................................... 22 
2.1 
Primary estimands ................................................................................................. 23 
2.2 
Secondary estimands ............................................................................................. 24 
3 
Study design ...................................................................................................................... 24 
4 
Rationale ............................................................................................................................ 26 
4.1 
Rationale for study design ..................................................................................... 26 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 28 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 28 
4.4 
Purpose and timing of interim analyses ................................................................. 28 
4.5 
Risks and benefits .................................................................................................. 28 
5 
Study Population ............................................................................................................... 29 
5.1 
Inclusion criteria .................................................................................................... 30 
5.2 
Exclusion criteria ................................................................................................... 30 
6 
Treatment ........................................................................................................................... 33 
6.1 
Study treatment ...................................................................................................... 33 
6.1.1 
Investigational drug ............................................................................... 33 
6.1.2 
Additional study treatments .................................................................. 33 
6.1.3 
Treatment arms/group ........................................................................... 33 
6.2 
Other treatment(s) .................................................................................................. 33 
6.2.1 
Concomitant therapy ............................................................................. 33 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action ........... 34 
6.2.2 
Prohibited medication ........................................................................... 34 
6.2.3 
Rescue medication ................................................................................ 35 
6.3 
Participant numbering, treatment assignment, randomization .............................. 35 


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6.3.1 
Participant numbering ........................................................................... 35 
6.3.2 
Treatment assignment, randomization .................................................. 36 
6.4 
Treatment blinding................................................................................................. 36 
6.5 
Dose escalation and dose modification.................................................................. 36 
6.6 
Additional treatment guidance ............................................................................... 36 
6.6.1 
Treatment compliance ........................................................................... 36 
6.7 
Preparation and dispensation ................................................................................. 37 
6.7.1 
Handling of study treatment .................................................................. 37 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 37 
7 
Informed consent procedures ............................................................................................ 39 
8 
Visit schedule and assessments ......................................................................................... 40 
8.1 
Screening ............................................................................................................... 44 
8.1.1 
Information to be collected on screening failures ................................. 44 
8.2 
Participant demographics/other baseline characteristics ....................................... 44 
8.3 
Efficacy .................................................................................................................. 45 
8.3.1 
Fluorescein angiography and indocyanine green angiography ............. 46 
8.3.2 
Optical coherence tomography ............................................................. 46 
8.3.3 
Optical coherence tomography angiography ........................................ 48 
8.3.4 
Color fundus photography .................................................................... 49 
8.3.5 
Best-Corrected Visual acuity ................................................................ 49 
8.3.6 
Disease activity assessments ................................................................. 49 
8.3.7 
Appropriateness of efficacy assessments .............................................. 50 
8.4 
Safety ..................................................................................................................... 50 
8.4.1 
Pregnancy .............................................................................................. 50 
8.4.2 
Ophthalmic examination ....................................................................... 51 
8.4.3 
IOP measurement .................................................................................. 52 
8.4.4 
Vital signs ............................................................................................. 52 
8.4.5 
Appropriateness of safety measurements .............................................. 52 
8.5 
Additional assessments .......................................................................................... 53 
8.5.1 
Clinical Outcome Assessments (COAs) ............................................... 53 
8.5.2 
Assessments in the fellow eye............................................................... 53 
9 
Study discontinuation and completion .............................................................................. 54 
9.1 
Discontinuation and completion ............................................................................ 54 
9.1.1 
Study treatment discontinuation and study discontinuation ................. 54 
9.1.1.1 
Replacement policy ............................................................................... 55 
9.1.2 
Withdrawal of informed consent ........................................................... 55 


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9.1.3 
Lost to follow-up ................................................................................... 56 
9.1.4 
Early study termination by the sponsor ................................................. 56 
9.2 
Study completion and post-study treatment .......................................................... 56 
10 Safety monitoring and reporting ........................................................................................ 57 
10.1 
Definition of adverse events and reporting requirements ...................................... 57 
10.1.1 
Adverse events ...................................................................................... 57 
10.1.2 
Serious adverse events .......................................................................... 58 
10.1.3 
SAE reporting ....................................................................................... 59 
10.1.4 
Pregnancy reporting .............................................................................. 60 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 60 
10.2 
Additional Safety Monitoring ................................................................................ 60 
11 Data Collection and Database management ...................................................................... 61 
11.1 
Data collection ....................................................................................................... 61 
11.2 
Database management and quality control ............................................................ 61 
11.3 
Site monitoring ...................................................................................................... 61 
12 Data analysis and statistical methods ................................................................................ 62 
12.1 
Analysis sets .......................................................................................................... 62 
12.2 
Participant demographics and other baseline characteristics ................................. 63 
12.3 
Treatment ............................................................................................................... 63 
12.4 
Analysis of the primary estimands ........................................................................ 63 
12.4.1 
Definition of primary endpoint(s)/estimand(s) ..................................... 63 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 64 
12.4.3 
Handling of remaining intercurrent events of primary estimand .......... 65 
12.4.4 
Handling of missing values not related to intercurrent event ............... 65 
12.4.5 
Sensitivity analyses for primary endpoint/estimand ............................. 65 
12.4.6 
Supplementary analysis ......................................................................... 65 
12.4.7 
Supportive analyses ............................................................................... 65 
12.5 
Analysis of secondary endpoints ........................................................................... 66 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................... 66 
12.5.2 
Safety endpoints .................................................................................... 67 
12.5.3 
Patient reported outcomes ..................................................................... 67 
12.6 
Interim analyses ..................................................................................................... 68 
12.7 
Sample size calculation.......................................................................................... 68 
12.7.1 
Primary endpoint(s) ............................................................................... 68 
13 Ethical considerations and administrative procedures ...................................................... 69 
13.1 
Regulatory and ethical compliance ........................................................................ 69 


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13.2 
Responsibilities of the Investigator and IRB/IEC ................................................. 69 
13.3 
Publication of study protocol and results .............................................................. 69 
13.4 
Quality Control and Quality Assurance ................................................................. 70 
14 Protocol adherence ............................................................................................................ 70 
14.1 
Protocol amendments............................................................................................. 70 
15 References ......................................................................................................................... 72 
16 Appendices ........................................................................................................................ 75 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs ......................... 75 
16.2 
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements .......................................................................................................... 76 
16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up...... 77 
List of tables 
Change rational 
12 
Table 2-1 
Objectives and related endpoints .......................................................... 22 
Table 6-1 
Investigational drug ............................................................................... 33 
Table 6-2 
Prohibited medication and procedures .................................................. 34 
Table 6-3 
Disease activity assessment and treatment occurrence according to 
visit type ................................................................................................ 38 
Table 8-1 
Assessment schedule ............................................................................. 42 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 60 
Table 12-1  
Primary estimand .................................................................................. 64 
List of figures 
Figure 3-1 
Study design .......................................................................................... 25 
Figure 6-1 
Treatment regimen ................................................................................ 38 
Figure 12-1 
Precision of the estimate scenario ......................................................... 69 


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List of abbreviations 
AE 
Adverse Event 
AIC 
Akaike Information Criterion 
AMD 
Age-related Macular Degeneration 
BCVA  
Best-corrected visual acuity 
CDS 
Core Data Sheet 
CFP 
Color Fundus Photography 
CFR 
Code of Federal Regulation 
CMO&PS  
Chief Medical Office and Patient Safety 
CNV 
Choroidal Neovascularization 
COVID-19 
Coronavirus Disease 2019 
CRC 
Central Reading Center 
CRO 
Contract Research Organization 
CRT 
Central Retinal Thickness 
CSR 
Clinical study report 
CSFT 
Central Subfield Thickness 
DA 
Disease Activity 
DAA 
Disease Activity Assessment 
eCRF 
Electronic Case Report Form  
EDC 
Electronic Data Capture 
ELM 
External Limiting Membrane 
EOS 
End-of-Study 
EOT 
End-of-Treatment 
EQ-5D-5L 
EuroQoL five dimensions and five levels 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
Fluorescein Angiography 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICGA 
Indocyanine Green Angiography 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IOI 
Intraocular Inflammation 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IRF 
Intraretinal Fluid 
IVT 
Intravitreal injection 
LOCF 
Last Observation Carried Forward 


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MedDRA 
Medical dictionary for regulatory activities  
mg 
milligram(s) 
NIH 
National Institutes of Health 
OCT 
Optical Coherence Tomography 
OCTA 
Optical Coherence Tomography 
PCV 
Polypoidal Choroidal Vasculopathy 
PED 
Pigment Epithelium Detachment 
PFS 
Prefilled Syringe 
PRN 
Pro re nata 
PRO 
Patient Reported Outcomes 
q8w 
every 8 weeks 
q12w 
every 12 weeks 
QMS  
Quality Management System 
RPE 
Retinal Pigment Epithelium 
RAO 
Retinal Artery Occlusion 
RAP 
Retinal Angiomatous Proliferation   
RECPAM 
Recursive Partitioning and Amalgamation 
RV 
Retinal Vasculitis 
RVO 
Retinal Vascular occlusion 
SAE 
Serious Adverse Event 
SAF 
Safety Set 
SAP 
Statistical Analysis Plan 
ScFv 
single-chain antibody fragment 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SHRM 
Subretinal Hyperreflective Material 
SLn 
Simultaneous Significance Levels 
SmPC 
Summary of Product Characteristics 
SRF 
Subretinal Fluid 
SUN 
Standardization uveitis nomenclature 
sub-RPE 
sub-Retinal Pigment Epithelium 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T&E 
Treat-and-Extend 
VAS 
Visual Analogue Scale 
VEGF 
Vascular endothelial growth factor 
wAMD 
wet Age-related Macular Degeneration 
WHO 
World Health Organization  
YAG 
Yttrium Aluminum Garnet 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Dosage 
Dose of the study treatment given to the participant 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 
participant or at a later point in time as defined by the protocol  
Enrollment 
Point/time of participant entry into the study at which informed consent 
must be obtained  
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 
Medication number 
A unique identifier on the label of medication kits 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study 
(i.e. concomitant or rescue therapy) 
Participant 
A trial participant (can be a healthy volunteer or a patient) 
Participant number 
A unique number assigned to each participant upon signing the 
informed consent. This number is the definitive, unique identifier for the 
participant and should be used to identify the participant throughout the 
study for all data collected, sample labels, etc. 
Patient-Reported 
Outcome (PRO) 
A measurement based on a report that comes directly from the patient 
about the status of a participant's health condition without amendment 
or interpretation of the patient's report by a clinician or anyone else 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-
up) which are described in the Protocol. Periods define the study 
phases and will be used in clinical trial database setup and eventually 
in analysis 
Personal data 
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data 
includes participant identifier information, study information and 
biological samples. 
Premature participant 
withdrawal 
Point/time when the participant 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 


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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. 
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 participant 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 participant  
Study treatment 
Any drug or combination of drugs   or intervention administered to the 
study participants as part of the required study procedures; includes 
investigational drug(s), control(s) or background therapy 
Study treatment 
discontinuation 
When the participant permanently stops taking any of the study drug(s) 
prior to the defined study treatment completion date (if any) for any 
reason; may or may not also be the point/time of study discontinuation  
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. 
Opposition to use data/biological samples occurs in the countries 
where collection and processing of personal data is justified by a 
different legal reason than consent.  


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Amendment 1 11-Nov-2021 
Amendment rationale  
The main purpose of this amendment is to implement the Urgent Safety Measures (USM) described the 
10-Aug-2021 Dear Investigator Letter (DIL) into the study protocol.  The USM were implemented for 
ongoing studies not achieving Last Patient Last Visit (LPLV) by 11-Aug-2021 and in response to the 
identification of a causal immune-mediated mechanism of the previously identified risk of retinal 
vasculitis (RV), and/or retinal vascular occlusion (RO), typically in the presence of intraocular 
inflammation (IOI) indicating a requirement to discontinue treatment with brolucizumab (RTH258) in 
patients who develop events of RV and/or RO. 
This amendment also includes information on gender imbalance on IOI following brolucizumab 
treatment and recommendations on the time window for a study subject to receive the COVID-19 
vaccine or vitrectomy.  Some other administrative changes have also been incorporated. 
Changes to the protocol 
Protocol sections changed in relation to this emerging safety measure are: 
• 
Section 1.1 Background: Information added to describe Urgent Safety Measures. 
• 
Section 4.5 Risk and benefits: Information added to describe Urgent Safety Measures and additional 
information on gender imbalance on IOI following brolucizumab treatment. 
• 
Section 6.7.2 Instruction for prescribing and taking study treatment: Requirement of treatment 
discontinuation for brolucizumab was added if subject developed RV and/or RO. 
• 
Section 8.4.2 Ophthalmic examination: Requirement of treatment discontinuation for brolucizumab 
was added if subject developed RV and/or RO. 
• 
Section 9.1.2 Clarified the definition of Withdrawal of Consent (WoC). 
Other changes incorporated in this amendment 
• 
The list of abbreviations and the glossary of terms has been updated to the latest template 
wording. 
• 
Section 6.2.1.1 Permitted concomitant therapy requiring caution and/or action: added 
recommendations on the time window for a study subject to receive the COVID-19 vaccine or 
vitrectomy. 
• 
Section 8.4.1 Pregnancy: Clarified when serum pregnancy test is positive brolucizumab treatment 
must be discontinued. 
• 
Section 9.1.1 Discontinuation of study treatment: Changes were made as follows: 
• 
Subject developing retinal a vasculitis and/or a retinal vascular occlusion event with 
brolucizumab.  
• 
Unsatisfactory therapeutic effect. 
• 
Other minor clarifications and corrections were made where applicable. 
Changes to specific sections of the protocol are shown in the track changes version of the protocol using 
strikethrough red font for deletions and red underlined for insertions. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent Ethics 
Committee (IECs) and Health Authorities. 


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The changes described in this amended protocol require IRB/IEC and Health Authority approval 
according to local regulations prior to implementation.  
The changes herein affect the Informed Consent.  Sites are required to update and submit for approval 
a revised Informed Consent that takes into account the changes described in this protocol amendment.  
 


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Change1 to the original protocol (v00 11-May-2020) 
Change rational 
The main purpose of this amendment is to provide clarification and guidance on safety assessments in 
accordance to the urgent safety measure regarding the post-marketing reports with brolucizumab 
(Beovu) in the treatment of nAMD, which were identified as retinal vasculitis and/or retinal vascular 
occlusion, typically in the presence of intraocular inflammation, that may result in severe vision loss. In 
addition, the amendment includes the modifications due to COVID-19 pandemic. 
Protocol sections changed in relation to the emerging safety issue are: 
• 
Section 1.1 Background. Information was added to describe new safety signal from post-
marketing case reports. 
• 
Section 6.2.2 Prohibited medications. Restrictions in use of corticosteroids have been removed 
to provide flexibility using systemic steroids for the treatment of AEs at the investigator’s 
discretion. 
• 
Section 6.7.2 Instruction for prescribing and taking study treatment. Additional guidance was 
added to this section emphasizing that if any sign of intraocular inflammation is present, an IVT 
injection must not be performed and patients should be treated for IOI according to clinical 
practice. 
• 
Additional examination and assessments included to fully characterize cases of intraocular 
inflammation were made in the following sections: 
• 
Section 8-1 Assessment schedule. 
• 
Section 8.3.1 Fluorescein angiography and indocyanine green angiography 
• 
Section 8.3.2 Optical coherence tomography 
• 
Section 8.3.3 Optical coherence tomography angiography 
• 
Section 8.3.4 Color fundus photography 
• 
Section 8.4.2 Ophthalmic Examination 
• 
Section 8.4.5 Appropriateness of safety measurements  
Changes were incorporated to address the COVID-19 pandemic in the following sections: 
• 
Section 5.2 Exclusion Criteria 
• 
Section 6.2.2 Prohibited medication 
• 
Section 8 Visit Schedule and Assessments 
• 
Section 8.4 Safety 
• 
Section 12 Data Analysis and statistical methods 
Other changes incorporated in this version: 
• 
Section 2 Objective and endpoint and related: added CFP for basal lesion type definition 
• 
Section 4.5 Risks and benefits and related: added IB for further information 
• 
Section 5.1 Added specification of other imaging modalities 
• 
Section 8.4.2 Ophthalmic Examination: clarification on timing for post-injection IOP 
measurement 
• 
Section 9 Added clarification about discontinuation 


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• 
Section 12 Database management and quality control: specification on the anonymization of 
the images sent to the CRC 
• 
Section 15 References 
• 
List of abbreviations 
 
Minor editorial changes (e.g. typographical mistakes, grammatical changes, rewording) to improve flow 
and consistency have been made throughout the protocol. Changes to specific sections of the protocol 
are shown in the track changes version of the protocol. 
 


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Protocol summary 
Protocol 
number 
CRTH258AIT04 
Full Title 
One year, single arm, open label, multicenter, phase IV study using multimodal 
Imaging to Guide disease activity assessment through Innovative Early predictive 
anatomical biomarkers of fluid resolution in wAMD patients treated with 
brolucizumab– IMAGINE study 
Brief title 
Study of innovative multimodal imaging biomarkers to predict anatomical outcome 
in naive patients with wAMD treated with brolucizumab 
Sponsor and 
Clinical Phase 
Novartis Farma S.p.A 
Phase IV 
Investigation 
type 
Drug 
Study type 
Interventional  
Purpose and 
rationale 
To identify innovative early imaging parameters that could predict the long-term 
clinical response to brolucizumab in terms of fluid resolution, in patients with 
neovascular age-related macular degeneration also called wet AMD (wAMD), with 
the purpose to evaluate their potential in supporting the treatment regimen choice 
(q12w i.e. every 12 weeks or q8w i.e. every 8 weeks). 
Primary 
Objective(s)  
The primary objective of this study is to assess the predictive value of early 
anatomical parameters measured by multimodal imaging from Baseline to Week 
16, in brolucizumab-treated participants with wAMD who present fluid resolution 
at Week 48 and have maintained the q12w treatment regimen up to Week 48 after 
the loading phase (defined also as fluid-free response). 
The primary clinical question of interest is: what are the early anatomical 
parameters detectable by multimodal imaging techniques used for the diagnosis 
and monitoring of patients with wAMD that could predict the long-term clinical 
response to brolucizumab in terms of fluid resolution with a stable q12w treatment 
regimen? 
Secondary 
Objectives 
The secondary objectives of this study are: 
• 
To evaluate the effect of brolucizumab on the evolution of qualitative and 
quantitative anatomical and functional parameters in wAMD patients from 
Baseline to Week 48 
• 
To evaluate the reasons underlying the Investigators’ choice of 
brolucizumab treatment regimen (q8w or q12w) at Week 16 
• 
To evaluate the effect of brolucizumab treatment on Patient-Reported 
Outcomes (quality of life and anxiety/depression)  
• 
To assess the safety and tolerability of brolucizumab 
Study design 
The study is a one-year, open-label, single arm, multicenter, phase IV study in 
patients with wAMD. 
Study 
population 
The study will enroll approximately 263 (male and female) participants aged 50 
years or older with untreated active subfoveal choroidal neovascularization (CNV) 
secondary to wAMD in the study eye at approximately 30 centers located in Italy. 
Key Inclusion 
criteria 
• 
Signed written informed consent must be obtained prior to participation in 
the study 


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• 
Male or female patients ≥ 50 years of age at Screening 
• 
Active CNV secondary to AMD that affects the central subfield, including 
retinal angiomatous proliferation (RAP) with a CNV component, confirmed 
by presence of active leakage from CNV seen by fluorescein angiography 
(or other imaging modalities) and sequelae of CNV, e.g. pigment epithelial 
detachment (PED), subretinal or sub-retinal pigment epithelium (sub-
RPE) hemorrhage, blocked fluorescence, macular edema in the study 
eye at Screening. 
• 
Presence of intraretinal fluid (IRF) or subretinal fluid (SRF) affecting the 
central subfield (study eye), as seen by SD-OCT in the study eye at 
Screening. 
• 
Best-corrected visual acuity (BCVA) score greater than or equal to 23 
letters measured at 4-meters starting distance using Early Treatment 
Diabetic Retinopathy Study (EDTRS) visual acuity charts at both 
Screening and Baseline visits in the study eye. 
Key Exclusion 
criteria 
• 
Any active intraocular or periocular infection or active intraocular 
inflammation 
(e.g. 
infectious 
conjunctivitis, 
keratitis, 
scleritis, 
endophthalmitis, infectious blepharitis) in study eye at Screening or 
Baseline 
• 
Not interpretable OCTA and SD-OCT images according to Investigator’s 
clinical judgment at Screening in the study eye  
• 
Concomitant conditions or ocular disorders in the study eye, at 
Screening or Baseline which, in the opinion of the Investigator, could 
prevent response to study treatment or may confound interpretation of 
study results, compromise visual acuity or require planned medical or 
surgical intervention during the course of the study. 
• 
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. 
• 
Previous treatment with any anti-vascular endothelial growth factor (anti-
VEGF) drugs or investigational drugs (other than vitamin supplements) in 
the study eye at any time prior to Screening 
• 
Systemic anti-VEGF therapy at any time 
• 
Stroke or myocardial infarction in the 6-month period prior to Baseline. 
Study 
treatment 
Brolucizumab 6 mg, 120 mg/mL (RTH258 6mg/ 0.05 mL) solution for injection in 
pre-filled syringe 
Efficacy 
assessments 
• 
Spectral-domain OCT (SD-OCT) 
• 
OCT Angiography (OCTA) 
• 
Color Fundus Photography (CFP) 
• 
Fluorescein Angiography (FA) 
• 
Indocyanine Green Angiography (ICGA) 
• 
BCVA using ETDRS-like charts 
• 
Hospital Anxiety and Depression Scale (HADS) 


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• 
EuroQol-5D-5L (EQ-5D-5L) 
Key safety 
assessments 
• 
Monitoring of Adverse Events (AE) 
• 
Ophthalmology examination 
• 
IOP 
• 
Vital signs 
• 
Pregnancy testing 
Data analysis 
The primary analysis will be conducted when all enrolled participants have 
completed their Week 48 visit or discontinued prior to Week 48. 
In order to test whether any early anatomical parameter is a predictor of response 
in terms of fluid resolution, i.e. q12w fluid-free participants (participants without 
IRF and SRF at Week 48 who have maintained a stable q12w treatment regimen 
up to Week 48), the following imaging variables will be taken into account: 
• 
Basal CNV lesion type, as assessed by SD-OCT, FA, ICGA and CFP at 
Screening 
• 
OCTA parameters, of which the main quantitative parameters are CNV 
flow size and vessel density and the main qualitative ones are branching 
vessels, peripheral anastomotic arcades, vascular loops and dark halo.  
• 
SD-OCT parameters, of which the main are sub-RPE fluid, central retinal 
thickness (CRT), status of the External Limiting Membrane (ELM), 
subretinal hyperreflective material (SHRM), outer retinal tubulation and 
PED volume. 
A Recursive Partitioning and Amalgamation (RECPAM) classification-tree 
analysis will be used to evaluate interactions between imaging parameters 
assessed by OCT, OCTA, FA, ICGA and CFP to identify distinct and 
homogeneous subgroups of patients in terms of q12w fluid-free patients at Week 
48. 
A multivariable logistic regression will be applied to investigate the association 
between q12w fluid-free patients at Week 48 with different imaging parameters 
using the variables and cut-off selected by the RECPAM analysis. FA, ICGA and 
CFP variables included in the model are measured at Screening, while OCTA and 
SD-OCT variables included in the model are assessed at Screening, Baseline, 4, 
8, 12 and 16 Week. The variable selection will be based on an automated stepwise 
selection.  
An interim analysis is planned to obtain a preliminary evaluation of the reasons 
among BCVA and/or 3-field CFP and/or IRF, SRF, sub-RPE fluid, hemorrhage 
and/or CRT and/or other OCTA parameters which underlie the Investigators’ 
choice of brolucizumab treatment regimen at Week 16 (secondary objective). The 
interim database lock for the interim analysis will be conducted when 50% of 
participants who are planned to be enrolled have completed their Week 16 visit. 
Participants will remain in the study and will continue to receive treatment 
throughout the planned study duration of 48 weeks, to allow for further evaluation 
of efficacy and safety. 
For continuous variables, summary statistics will generally include: n, mean, 
standard deviation, median, minimum and maximum. For categorical variables, 
these will include: absolute and relative frequencies. 


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Key words 
Neovascular age-related macular degeneration, anti-VEGF, brolucizumab, 
choroidal neovascularization, multimodal imaging biomarkers, fluid resolution 


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1 
Introduction 
1.1 
Background 
Age-related macular degeneration (AMD) is a chronic, progressive disease that affects the 
macular region of the retina. AMD is a leading cause of visual impairment and severe vision 
loss in people, affecting 11.6% to 18.5% of individuals between 60 and 69 years old and 31.6% 
to 45.3% of individuals between 80 and 84 years old in North America, Europe, and Oceania 
(Wong et al., 2014). Globally, people who had moderate or severe vision impairment from 
AMD in 2015 were estimated to be 8.41 million, with AMD being the cause of 5.64% of cases 
of legal blindness (1.96 million people) (Flaxman et al., 2017). 
AMD is a multifactorial disorder influenced by several genetic and environmental factors. Age 
is the strongest risk factor, with the majority of AMD cases occurring in people older than 60 
years, while smoking is the strongest modifiable risk factor for AMD (Mitchell et al., 2018).  
Early-stage AMD is often asymptomatic and is characterized by the accumulation of 
extracellular deposits such as drusen, as well as abnormalities of the retinal pigment epithelium 
(RPE). Late-stage AMD affects central vision and can progress into two different clinical 
subtypes: the neovascular (exudative or wet) form (in weeks or months), and the non-
neovascular (atrophic) or dry form (in years or decades) (Mitchell et al., 2018). Although only 
20% of patients with AMD are diagnosed with wet AMD (wAMD) – also called as neovascular 
AMD - it causes 90% of vision loss cases (Nguyen et al., 2020).  
The loss of central vision that accompanies late-stage AMD pathology has a high personal cost, 
including a loss of independence and social interaction, decreased quality of life, increased 
levels of depression and greater risk for anxiety disorders (Cimarolli et al., 2016; Taylor et al., 
2016).  
AMD is generally diagnosed by stereoscopic biomicroscopy and additional examination of the 
macula by multimodal imaging, including fluorescein angiography (FA), indocyanine green 
angiography (ICGA) and optical coherence tomography (OCT). The patient’s visual status can 
be monitored with best-corrected visual acuity (BCVA) testing using Early Treatment Diabetic 
Retinopathy Study (ETDRS)-like charts (Schmidt-Erfurth et al., 2014).  
Neovascular AMD is characterized by the presence of choroidal neovascularization (CNV), a 
pathologic form of angiogenesis whereby new abnormal blood vessels originating from the 
choriocapillaris spread beneath the retina into the subretinal or below the sub-RPE space. The 
CNV complex in wAMD incorporates several typical lesions: presence of fluid or retinal 
hemorrhage (which can be intraretinal, subretinal, or below the RPE), retinal pigment epithelial 
detachments (PEDs), hard exudate, or subretinal fibrous scar (Mitchell et al., 2018). These 
clinical abnormalities lead to gradual loss of retinal photoreceptors, resulting in decreased 
vision and even blindness if disease progression is not prevented (Bhutto and Lutty, 2012). 
Multimodal imaging in wAMD 
The use of diagnostic imaging in the context of wAMD has allowed the definition of several 
pathology indicators that can be evaluated in a more objective and reproducible way compared 
with visual acuity (Sulzbacher et al., 2011). Multimodal imaging shows wAMD manifestations 


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clearly and provides information on the size, location, and extent of drusen, as well as the 
presence and activity of CNV (Mitchell et al., 2018).  
The anatomic location of CNV determined by multimodal imaging is used to subclassify the 
vascular component of the disease process. Type 1 neovascularization arises when CNV 
proliferation occurs below the RPE, and corresponds to an occult CNV with a poorly defined 
pattern of leakage on FA. Type 2 neovascularization refers to CNV proliferation above the RPE 
in the subretinal space, and corresponds to classic CNV with intense fluorescein leakage. Type 
3 neovascularization (or retinal angiomatous proliferation, i.e. RAP) occurs when the retinal 
circulation is involved, with an anastomosis between the choroidal and retinal circulations 
(Mitchell et al., 2018; Spaide et al., 2019).  
FA remains the gold standard for the diagnosis and classification of CNV, as it allows the 
visualization of retinal vasculature and neovascular retinal/choroidal proliferations as well as 
its dynamic features, such as perfusion and exudation (Schmidt-Erfurth et al., 2014). ICGA can 
be used to identify the entire extension of the CNV lesion due to its capability to visualize the 
sub-RPE components of the CNV (Sulzbacher et al., 2011). Besides, ICGA allows a better 
identification of the neovascular network of type 1 CNV lesions and is also useful in the 
diagnosis of RAP and polypoidal choroidal vasculopathy (PCV), which is a subtype of type 1 
CNV characterized by a large aneurysmal component. Both FA and ICGA are invasive and 
require dye injection (Gess et al., 2011). 
OCT is a noninvasive imaging technique able to visualize structural changes of the 
neurosensory retina and the RPE through high-resolution cross-sectional (tomographic) images 
(B-scans). OCT has changed the diagnostic approach to wAMD. Current commercial OCT 
systems based on the spectral domain technology, i.e. spectral-domain OCT (SD-OCT), allow 
dense scanning of the macula with an improved axial resolution. SD-OCT is widely used to 
support the initial diagnosis of CNV obtained from FA and ICGA, as it allows to define the 
morphological features of the CNV complex, such as retinal thickening, and to detect early 
signs of CNV activity, such as intraretinal (IRF), subretinal (SRF) and under RPE (sub-RPE) 
fluid, intraretinal cystoid spaces and PED, as well as edema. Thus, through SD-OCT it is 
possible to qualitatively and quantitatively define these wAMD anatomical changes, as well as 
to measure the thickness of the retina. Moreover, SD-OCT scans performed at different time 
points with the same instrument can be compared over time to follow the progression/ 
regression of the lesions (Keane et al., 2012).  
Recently, OCT Angiography (OCTA) has been introduced in clinical practice. OCTA is a non-
invasive imaging modality that provides cross-sectional, three-dimensional and high-resolution 
imaging of the retinal and choroidal vasculature with micrometer-scale depth resolution. As 
SD-OCT, OCTA does not require any dye injection, thus is devoid of risk of side effects proper 
of classical FA and ICGA. OCTA allows an improved visualization of the choroid, resulting in 
a detailed visualization of the CNV, especially of the sub-RPE component. In addition, 
available OCTA software automatically analyze retinal layer scans at different depths, 
providing more detailed images compared with other imaging technique, including also SD-
OCT (Coscas et al., 2019; Nikolopoulou et al., 2018). 
Comparative studies have demonstrated that OCTA can detect CNV blood flow with the same 
sensitivity as FA, while is able to show the area of type 1 CNV lesions more precisely than 


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ICGA (Coscas et al., 2018). In routine practice, OCTA is still coupled with FA for the diagnosis 
and follow-up of wAMD. Besides, to date, no clinical trial has been designed with OCTA-based 
endpoints, therefore caution is necessarily required in taking treatment decisions based on 
OCTA alone (Nikolopoulou et al., 2018). 
Based on the increased life expectancy and a growing negative impact of AMD environmental 
risk factors, AMD incidence is expected to continue rising (Wong et al., 2014). Therefore, early 
diagnosis and proper treatment are to be a major public health concern. 
wAMD treatment 
Improving or maintaining visual acuity is the main goal for wAMD treatment. Achieving this 
goal requires drying the affected retina through inhibiting new blood vessel growth and 
reducing the fluid leakage (Wykoff et al., 2018). 
Vascular endothelial growth factor (VEGF) by increasing retinal vascular permeability and 
promoting neovascularization is a major contributor to CNV (Mitchell et al., 2018). The use of 
intravitreal (IVT) pharmacotherapy targeting VEGF has greatly improved visual outcomes and 
the prognosis for patients with wAMD, and has become established as the standard of care in 
wAMD treatment (Nguyen et al., 2020; Wykoff et al., 2018). Anti-VEGF treatments, such as 
ranibizumab 0.5 mg (Lucentis®) and aflibercept 2 mg (Eylea®), block all VEGF isoforms and 
have been shown to halt the growth of neovascular lesions and resolve retinal edema. Phase III 
clinical trials on ranibizumab and aflibercept demonstrated their comparable efficacy in 
maintaining or improving vision in patients with wAMD over up to 2 years. Moreover, as 
reported in the key clinical trials, the incidence of serious ocular adverse events, as well as 
treatment-related serious systemic events after injections of anti-VEGF agents was low 
(Schmidt-Erfurth et al., 2014; Wykoff et al., 2018). 
The need for frequent injections can place a substantial burden on patients, as well as their 
caregivers, physician and the healthcare system, making patient adherence and monitoring 
difficult, which in turn has consequences for visual and anatomical outcomes. Indeed, long-
term observational studies and clinical experiences have revealed that a substantial proportion 
of wAMD patients who begin treatment with anti-VEGF agents experience significant vision 
loss over periods of 3 to 8 years (Schmidt-Erfurth et al., 2014; Wykoff et al., 2018).  
In an effort to lessen the treatment burden , increase treatment adherence and persistence and 
also to reduce costs associated with anti-VEGF treatment of wAMD, alternative dosing 
regimens, including pro re nata (PRN) or “as needed” and treat-and-extend (T&E), have been 
investigated. T&E treatment regimen, which allows to extend the treatment intervals usually by 
2 weeks at a time if no disease activity is detected, has been approved in the labels of 
ranibizumab and aflibercept in Europe and many other countries (Wykoff et al., 2018).  
Nevertheless, real-world studies indicate that relative under treatment of wAMD is very 
frequent and is associated with suboptimal outcomes. Further efforts are needed with regard to 
both diagnosis and treatment of wAMD in order to improve this unmet medical need. (Holz et 
al., 2014, 2015; Monés et al., 2020; Wykoff et al., 2018). 
 


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Brolucizumab 
Brolucizumab 6 mg (Beovu®), is a newly marketed humanized single-chain antibody fragment 
(scFv) inhibitor of VEGF-A for the treatment of wAMD. Brolucizumab lower molecular weight 
(~26 kDa) allows for the administration of 6 mg of the compound in a single 50 µL IVT 
injection, which may prolong its therapeutic effect and enable better tissue penetration in the 
retina. 
In two randomized, multicenter, double-masked, active-controlled, phase III studies (HAWK 
and HARRIER), wAMD patients on treatment with brolucizumab received three monthly 
injections followed by injections every 12 weeks (q12w), with the option of adjusting to every 
8 weeks (q8w) dosing based on disease activity. The patients in the aflibercept arm were treated 
according to the approved schedule at that time. Brolucizumab was non-inferior to aflibercept 
in BCVA change from baseline to Week 48, with more than a half of brolucizumab-treated 
patient maintained exclusively on q12w dosing regimen. Moreover, brolucizumab was a more 
potent drying agent, with a significantly greater proportion of patients demonstrating an absence 
of IRF/SRF fluid and disease activity at both Week 16 (matched comparison) and Week 48 
compared with aflibercept, as well as a significant reduction of central subfield thickness 
(CSFT) (Dugel et al., 2020). Both these advantages in anatomical parameters for brolucizumab 
and visual acuity gains observed in the first year were maintained in the second year. Safety 
was comparable between the treatment arms over 2 years (Nguyen et al., 2020). 
Brolucizumab (Beovu®) has been recently approved in US and EU for the treatment of wAMD 
at the recommended dose of 6 mg, administered by IVT monthly injection for the first three 
doses, followed by IVT injections every 8 or 12 weeks, depending on the activity of the disease. 
Since the first marketing authorization approval in October 2019 for the treatment of wAMD, 
adverse events of retinal vasculitis (RV) and/or retinal vascular occlusion (RVO), 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 (RV) and/or retinal vascular 
occlusion (RVO), taken together with accumulated data from HAWK, HARRIER and 
MERLIN, regarding the association of treatment-emergent immunogenicity and IOI, indicate a 
causal link between the treatment-emergent immune reaction against brolucizumab and the 
brolucizumab-related retinal vasculitis and/or retinal vascular occlusion, typically in the 
presence of IOI. Considering the incidence of these events is uncommon, the overall risk/benefit 
assessment remains positive. 
HAWK and HARRIER studies have proved that a careful early disease activity assessment 
based on OCT in the first months is crucial to determine patients’ follow-up. Indeed, patients 
deemed suitable for a q12w treatment in the first q12w interval after the loading phase had a 
probability of remaining on q12w treatment up to Week 48 greater than 80% (Dugel et al., 
2020). This further strengthens the relevance of assessing anatomical parameters in the 
evaluation of the therapeutic outcome and in helping the physician decide the appropriate 
therapeutic regimen for each patient.  
Besides, lessening the treatment burden in wAMD for patients and healthcare providers remain 
a major challenge and an important unmet need (Monés et al., 2020). Innovative biomarkers 


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predictive of disease progression and treatment response might further help to achieve 
treatments which are better tailored to the desired therapeutic outcome for each patient and 
eventually to reduce the substantial monitoring burden during follow-up, thus possibly 
improving patient adherence and persistence to anti-VEGF therapy.  
To the best of our knowledge, no clinical trial has prospectively investigated innovative early 
imaging parameters (OCTA and SD-OCT) at baseline and after the loading phase, which could 
predict the long-term clinical response to brolucizumab in wAMD patients, as measured by 
anatomical outcomes (fluid resolution). 
Evidence from this phase IV study, along with pivotal trial data proving the superior efficacy 
of brolucizumab with regard to anatomical outcomes, could help the physicians in deciding 
which treatment regimen (q12w or q8w) would be more suitable for each patient treated with 
brolucizumab in order to achieve the therapeutic goal, i.e. fluid resolution.  
1.2 
Purpose 
The purpose of this phase IV study is to identify innovative early imaging parameters as 
predictors of the long-term clinical response to brolucizumab in terms of fluid resolution in 
patients with wAMD with the purpose to evaluate their potential in supporting the treatment 
regimen choice (q12w or q8w). 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints  
Objective(s) 
Endpoint(s) 
Primary Objective 
The primary objective is to assess the predictive 
value of early anatomical parameters measured 
by multimodal imaging from Baseline to Week 
16, in brolucizumab-treated participants with 
wAMD who present fluid resolution (i.e. absence 
of IRF and SRF) at Week 48 and have 
maintained the q12w treatment regimen up to 
Week 48 after the loading phase, defined also 
as fluid-free response (q12w fluid-free 
participants), compared with participants under a 
more frequent regimen and/or not fluid-free at 
Week 48. 
Endpoint(s) for primary objective  
Early predictive factors of fluid-free response, 
which is defined as the absence of IRF and SRF 
(assessed by SD-OCT) at Week 48 in patients 
with a stable q12w treatment regimen up to Week 
48 after the loading phase. 
The variables considered as potential predictive 
factors in the statistical model will be selected 
among the following qualitative and quantitative 
anatomical parameters: 
1. Basal CNV lesion type, as assessed by SD-
OCT at Baseline and FA, ICGA and CFP at 
Screening 
2. Parameters assessed by OCTA at each visit 
from Baseline to Week 16, of which the main 
are presence/absence of branching vessels, 
peripheral anastomotic arcades, vascular 
loops and dark halo, and quantification of 
CNV flow size and vessel density 
3. Parameters assessed by SD-OCT at each 
visit from Baseline to Week 16, of which the 
main are presence/absence of sub-RPE fluid, 


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Objective(s) 
Endpoint(s) 
subretinal hyperreflective material (SHRM), 
outer retinal tubulation, status of the External 
Limiting Membrane (ELM) and measurement 
of central retinal thickness (CRT) and PED 
volume. 
Secondary Objective(s) 
1. To evaluate the effect of brolucizumab on the 
evolution of qualitative and quantitative 
OCTA parameters of wAMD from Baseline to 
Week 48 
 
 
2. To evaluate the effect of brolucizumab on the 
evolution of qualitative and quantitative SD-
OCT parameters of wAMD from Baseline to 
Week 48 
Endpoint(s) for secondary objective(s) 
1. Change in OCTA features assessed by 
qualitative (branching vessels, peripheral 
anastomotic arcades, vascular loops and 
dark halo) and quantitative criteria (CNV flow 
size, and vessel density) from Baseline up to 
Week 48  
2. Change in SD-OCT features assessed by 
qualitative (IRF, SRF, sub-RPE fluid, status 
of ELM, SHRM and outer retinal tubulation) 
and quantitative criteria (CRT and PED 
volume) from Baseline up to Week 48  
3. To evaluate the effect of brolucizumab on the 
evolution of functional parameters of wAMD 
from Baseline to Week 48 
3. Change in BCVA from Baseline up to Week 
48 
4. To evaluate the effect of brolucizumab on 
sustained dryness from Baseline to Week 48  
4. Time to reach sustained dryness of the study 
eye, as defined by the absence of IRF and 
SRF for at least 2 consecutive visits and for 
at least 3 consecutive visits  
4. Cumulative incidence of sustained dryness of 
the study eye, i.e. the absence of IRF and 
SRF for at least 2 consecutive visits and for 
at least 3 consecutive visits  
5. To evaluate the reasons underlying the 
Investigators’ 
choice 
of 
brolucizumab 
treatment regimen (q21w or q8w) at Week 16  
 
5. Determinants in the Investigator’s choice of 
brolucizumab dosing regimen (q12w or q8w) 
at Week 16 (i.e. BCVA, IRF, SRF, sub-RPE 
fluid, presence of hemorrhages, CRT, OCTA 
anatomical parameters and/or 3-field CFP)  
6. To evaluate anxiety/depression in patients 
with wAMD treated with brolucizumab   
6. Change in Hospital Anxiety and Depression 
Scale (HADS) scores from Baseline to Week 
48 
7. To evaluate quality of life in patients with 
wAMD treated with brolucizumab 
7. Change 
in 
EuroQol-5D-5L 
(EQ-5D-5L) 
scores from Baseline to Week 48 
8. To assess the safety and tolerability of 
brolucizumab 
8. Incidence of Ocular and Non-ocular AEs 
throughout the study 
 
2.1 
Primary estimands 
The primary clinical question of interest is: what are the early anatomical parameters detectable 
by multimodal imaging techniques used for the diagnosis and monitoring of patients with 


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wAMD that could predict the long-term clinical response to brolucizumab in terms of fluid 
resolution with a stable q12w treatment regimen? 
The justification for targeting this clinical question is that we will capture the early anatomical 
parameters that could predict long-term fluid resolution in patients with wAMD treated with 
brolucizumab every 12 weeks, after the initial loading phase. Further details can be found in 
Section 12. 
The primary estimand is described by the following attributes: 
1. Target population: male and female participants aged 50 years or older with untreated active 
subfoveal CNV secondary to wAMD in the study eye and with BCVA score greater than or 
equal to 23 letters at both Screening and Baseline. Further details about the population are 
provided in Section 5. 
2. Primary variables: predictive factors of fluid-free response, which is defined as the absence 
of IRF and SRF at Week 48 in patients with a stable q12w treatment regimen up to Week 
48. Qualitative and quantitative anatomical parameters measured by FA, ICGA and CFP at 
Screening, and SD-OCT and OCTA at each visit from Baseline to Week 16 will be included 
as potential predictive factors in the statistical model. 
3. Treatment of interest: The investigational treatment brolucizumab 6 mg taken for the entire 
study duration with the q8w or q12w regimen. The protocol defines the use of allowed 
concomitant medications for the target population, as well as medications which are 
prohibited. Further details about the investigational treatment are provided in Section 6. 
4. The summary measure is the odds ratio and/or beta estimates (fluid-free vs not fluid-free)  
 
Detailed description of the primary estimand is provided in Section 12.4. 
2.2 
Secondary estimands 
Not applicable.  
3 
Study design 
This is a one-year, open-label, single arm, multicenter, phase IV study that will be conducted 
at approximately 30 centers in Italy. Patients with untreated active subfoveal CNV secondary 
to wAMD who provide signed informed consent and meet all eligibility criteria will be included 
in the study. Approximately 300 patients will be screened (12% screening failure rate expected) 
to enroll 263 evaluable participants. The duration of the study treatment for enrolled patient will 
be of maximum 48 weeks. 
The study consists of a screening period of up to 2 weeks and a treatment period with 
brolucizumab from Baseline (Day 1) up to Week 48 (see Figure 3-1).  


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Figure 3-1 
Study design  
 
Screening period: Day-14 to Day-1 
A screening period of up to 2 weeks will be used to assess eligibility. 
Patients who provide signed informed consent will undergo screening procedures to verify 
fulfilment of the study’s inclusion/exclusion criteria. A BCVA assessment and a complete 
ophthalmic examination, which may include slit lamp exam, intraocular pressure (IOP) 
measurement and fundus exam will be performed on both eyes. SD-OCT, OCTA, FA, ICGA 
and 3-field color fundus photography (CFP) are to be performed on both eyes. The Investigator 
will also collect vital signs (blood pressure and pulse). Medical history, demographic features 
and prior/concomitant medications are also to be collected. A serum pregnancy test is to be 
performed in women of childbearing potential. 
One-time re-screening 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 re-screening 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 wAMD is not withheld in order for a patient to participate in the study. 
Patients must have confirmed wAMD at Screening. 
Treatment period: Day 1 to Week 48 
At the Baseline visit (Day 1), after confirmation of eligibility, patients will be included and 
treated with intravitreal (IVT) brolucizumab at the dose of 6 mg. Only one eye could be treated 
in the study. Participants will receive three monthly loading doses of brolucizumab 6 mg at 
Baseline, Week 4 and Week 8, followed by a maintenance regimen every 12 weeks (q12w), 
which may be adjusted to a treatment regimen every 8 weeks (q8w) if disease activity (DA) in 
the study eye is detected according to Investigator’s decision based on the disease activity 
assessments (DAAs) of visual and/or anatomical outcomes performed by the Investigator 
him/herself (“q12w/q8w regimen”). DA will be first assessed at Week 16 and then at each 
subsequent scheduled q12w/q8w treatment visit. In participants on q12w treatment regimen 
with DA occurrence at any of these visits, a q8w treatment regimen should be considered. If a 


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participant is adjusted to a q8w treatment regiment, he/she will subsequently be assessed at q8w 
treatment visits. In participants on q8w regimen without DA for two consecutive treatment 
visits, based on the Investigator’s judgment, the re-allocation to a q12w treatment regimen 
should be considered. DAAs are to be performed by the Investigator based on visual acuity 
(BCVA) and/or 3-field CFP and/or one or more anatomical parameters assessed by SD-OCT 
and/or by OCTA, as per clinical practice. Of note, only those anatomical parameters that are 
instrumental to define DA in the Investigator’s opinion will be recorded in the eCRF. All 
anatomical parameters collected by SD-OCT and OCTA throughout the study and by FA, ICGA 
(only for suspected PCV) and CFP at Screening and Week 48 (FA only) will be evaluated by 
an independent, treatment regimen-masked Central Reading Center (CRC) for the primary and 
secondary analyses at the end of the study. Of note, the Investigator will not be aware of the 
results of the CRC assessments during the study. For all participants, the last potential study 
treatment will be at the Week 44 visit or at the Week 48 visit, according to the different 
treatment regimen implemented. 
A study visit schedule will be established at Baseline for all participants. The mandatory visits 
of the study during the treatment period for all participants are Baseline, Week 4, Week 8, Week 
12 (no injection visit), Week 16 and Week 48. The timepoint of the other treatment visits will 
depend on the treatment regimen of each participant (q12w/q8w). BCVA assessment, SD-OCT, 
OCTA and 3-field CFP imaging are to be performed on the study eye at each assessment visit, 
as well as a urine pregnancy test in women of childbearing potential. FA and ICGA are to be 
performed at Week 48. Concomitant medications and any adverse events are to be recorded 
throughout the study. A complete ophthalmic examination, which may include slit lamp exam, 
fundus exam and IOP measurement and the collection of vital signs are to be performed at 
Baseline and at each subsequent visit by the Investigator. At each visit the Investigator have to 
exclude the presence of any active intraocular inflammation in the study eye. A complete 
ophthalmic examination is also to be performed at Week 48. Besides, IOP measurement is to 
be performed before and after each IVT injection. Patient’s anxiety/depression and quality of 
life will be evaluated at Baseline and Week 48 through the Hospital Anxiety and Depression 
Scale (HADS) and the EuroQol-5D-5L (EQ-5D-5L), respectively. BCVA, SD-OCT, CFP, 
OCTA, FA, ICGA, ophthalmic examination and IOP measurement are also to be performed on 
the fellow eye at Week 48. No monitoring visits are planned between the injection visits. All 
efforts should be made to adhere to this study visit schedule within a ± 7-day window (except 
Baseline). For a given protocol visit (except Baseline), assessments can be performed on two 
consecutive days, provided both days are within the ± 7-day window. Treatment is intended to 
be administered on the day of study visit, or if this is not possible, within 3 days after the study 
visit at which the per-protocol assessments have taken place (except Baseline, in which case 
study treatment administration should occur within the next 24 hours). Two consecutive study 
treatments should be at least 21 days apart. 
4 
Rationale 
4.1 
Rationale for study design 
This is a single-arm, non-randomized, open-label phase IV clinical trial aimed to identify 
innovative early imaging parameters that could predict the long-term clinical response to 


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brolucizumab, in terms of fluid resolution, in patients affected by wAMD with the purpose to 
evaluate their potential in supporting the treatment regimen choice (q12w or q8w) after the 
loading phase. 
 
The safety and efficacy of brolucizumab has been recently demonstrated in two randomized, 
multicenter, double-masked, active controlled Phase III studies in wAMD patients (RTH258-
C001 [HAWK] and RTH258-C002 [HARRIER]) up to 96 weeks, as described in Section 1.1. 
In these studies, anatomical changes were evaluated using SD-OCT, which relies on indirect 
parameters for the diagnosis and monitoring of active CNV.  
 
Concurrently, research has led to a substantial development and/or improvement of cutting-
edge imaging techniques in order to ensure the proper management of macular pathologies. The 
use of diagnostic imaging in the context of wAMD has allowed to define pathology indicators 
which can be evaluated in a more objective and reproducible manner, compared with visual 
acuity (VA). 
 
In particular, OCTA has been widely introduced in ophthalmology clinical practice. OCTA is 
a diagnostic tool that allows the retinal and choroid vessels to be viewed dynamically. In OCTA, 
the contrast medium is the blood itself within capillaries, thus preventing the use of contrast 
medium to be injected intravenously and the risk of side effects proper of classical FA. In 
addition, available OCTA software automatically analyze retinal layer scans at different depths, 
providing more detailed images compared with less recent imaging techniques. 
Several independent studies have been instrumental to understand and acknowledge the clinical 
relevance of OCTA for the qualitative and quantitative assessment of CNV lesions as an 
additional tool to evaluate the response to treatment in wAMD patients. This also provides 
promising evidence to suggest OCTA as relevant in treatment regimen decision, which 
generally relies only on the presence or absence of fluid on OCT B-scans. 
 
A detailed multimodal imaging will be performed in this study to assess the predictive value of 
early anatomical parameters up to Week 16 for the long-term clinical response to brolucizumab 
in terms of fluid resolution and treatment regimen. 
 
The basal type of CNV lesions assessed by Baseline SD-OCT and FA, ICGA and CFP at 
Screening and several SD-OCT and OCTA anatomical parameters evaluated from Baseline to 
Week 16 are to be considered as variables for the predictive model applied for the primary 
analysis. Moreover, brolucizumab response for the primary analysis is defined as the absence 
of IRF and SRF at Week 48, as hallmarks of wAMD pathology and signs of disease activity, in 
participants who have maintained the q12w regimen up to Week 48. 
After the loading phase, participants are to be treated with a q12w regimen, with the possibility 
of adjusting to q8w based on disease activity. Disease activity will be assessed by the 
Investigator based on visual acuity and/or anatomical parameters and the first assessment is to 
be performed at Week 16, as recommended in the approved label. The possibility to switch back 
to q12w is foreseen when participants on the q8w regimen do not present disease activity for 
two consecutive visits, based on the Investigator’s judgment. 


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Besides, brolucizumab efficacy and safety have been consistently demonstrated in previous 
trials at the same dose and regimen (q12w/q8w) in comparison with aflibercept, as mainstay of 
treatment for wAMD, leading to the recent approval of brolucizumab for the treatment of 
wAMD in EU and US.  
To reduce any bias due to unblinding the assessment of the anatomical parameters measured by 
FA, ICGA, CFP, SD-OCT and OCTA for the primary and secondary analysis of the study will 
be performed by an independent, treatment regimen-masked CRC. Moreover, the Investigator 
will not be aware of the results of the CRC assessments when he/she assesses disease activity, 
as per clinical practice. 
4.2 
Rationale for dose/regimen and duration of treatment 
The dose and regimen for brolucizumab are based on the following considerations: 
• The dose, regimen and route of administration of brolucizumab are as per European 
approved label (Beovu® SmPC, 2020). 
• The study duration of 48 weeks allows to assess long-term efficacy and safety of this 
treatment regimen, as demonstrated in pivotal trials for registration of anti-VEGF 
treatments. 
• In line with current clinical practice, ophthalmology association recommendations and 
labels of approved anti-VEGF drugs in most countries worldwide, the treatment 
frequency can be adjusted based on the Investigator’s assessment of disease activity.  
• The route of administration is an intravitreal (IVT) injection as for all anti-VEGF drugs 
currently approved for the treatment of wAMD.  
• Prefilled syringes (PFS) have been selected for the administration of study treatment in 
this study as this dosage form will be the one marketed in Italy. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Not applicable.  
4.4 
Purpose and timing of interim analyses 
An interim analysis is planned after approximately 50% of participants planned to be enrolled 
have reached Week 16 in the study to obtain a preliminary evaluation of the clinical – functional 
and anatomical parameters (i.e. BCVA and/or IRF, SRF, sub-RPE fluid, hemorrhage and/or 
CRT and/or OCTA parameters and/or 3-field CFP) underlying the Investigators’ choice of 
brolucizumab treatment regimen at Week 16, as secondary efficacy objective of the study.  
4.5 
Risks and benefits 
The risk to participants in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring. 
Based on the results of phase III studies HAWK and HARRIER (Dugel et al., 2020), 
brolucizumab (Beovu®) has been recently approved in US and EU for the treatment of wAMD 


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at the recommended dose of 6 mg, administered by IVT monthly injection for the first three 
doses, followed by IVT injections every 8 or 12 weeks, depending on disease activity. 
A total of 1088 patients, treated with brolucizumab, constituted the safety population in HAWK 
and HARRIER, with a cumulative 96-week exposure to brolucizumab and 730 patients treated 
with the recommended dose of 6 mg. Brolucizumab safety was comparable to aflibercept, with 
an overall incidence of adverse events balanced across all treatment groups in both HAWK and 
HARRIER.  
For further details on safety information available for brolucizumab (Beovu®) treatment in 
wAMD, please refer to the Summary of Product Characteristics (Beovu® SmPC, 2020) and to 
the Investigator’s Brochure (IB). 
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study, and agree that in order 
to participate in the study they must adhere to the contraception requirements outlined in the 
exclusion criteria (Section 5.2). If there is any question that the participant will not reliably 
comply, they should not be entered or continue in the study. 
Retinal vasculitis (RV) and/or vascular occlusion (RVO), typically in the presence of IOI have 
been reported following brolucizumab injection. These immune mediated adverse events may 
occur following the first intravitreal injection. Discontinuation of study treatment for 
brolucizumab is required in subjects who develop these events. In addition, subjects who 
experience IOI may be at risk of developing retinal vasculitis (RV) and/or retinal vascular 
occlusion (RVO) and should be closely monitored. 
Based on clinical studies, IOI related adverse events, including retinal vasculitis and retinal 
vascular occlusion, were reported more frequently in female patients treated with brolucizumab 
than male patients (e.g. 5.3% females vs. 3.2% males in HAWK and HARRIER, Novartis data 
on file).  
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 assessment for brolucizumab remains positive.  
As regards efficacy, in addition to the non-inferior BCVA improvement, the lower probability 
of disease activity after the head-to-head comparison at Week 16, the greater reduction in CSFT 
and the lower proportion of patients with SRF and/or IRF through Week 48 for brolucizumab 
versus aflibercept in HAWK and HARRIER are anticipated to confer a longer duration of effect 
that will translate into a greater durability and longer injection intervals for brolucizumab 6 mg, 
with non-inferior efficacy (see Section 1.1 for more details). Of note, a reduced treatment and 
monitoring visit frequency will provide benefit to both subjects and caregivers/physicians. 
Thus, it seems safe to assume that the benefits of brolucizumab 6 mg treatment in wAMD 
outweigh the risks. 
5 
Study Population 
The study population includes male and female participants aged 50 years or older diagnosed 
with active subfoveal CNV secondary to wAMD in the study eye, not treated previously with 


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any anti-VEGF drugs or investigational drugs (other than vitamin supplements)  for this disease 
and able to comply with study procedures.  
Assuming a 12% screening failure rate, approximately 300 patients will be screened and 
approximately 263 participants will be enrolled at approximately 30 sites in Italy. From 
Baseline, the expected duration of participation in the study is 48 weeks for each participant. 
If both eyes are eligible as per the inclusion and exclusion criteria described below only one 
eye should be treated during the study, the eye with the worse visual acuity (BCVA) at Baseline 
will be selected as the study eye. If both eyes have the same BCVA, it is recommended to select 
the right eye as the study eye. 
5.1 
Inclusion criteria 
The Investigator will assess the eligibility of the patient and the study eye at the Screening visit 
and confirm eligibility at Baseline. Participants 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. 
3. Active CNV secondary to AMD that affects the central subfield, including retinal 
angiomatous proliferation (RAP) with a CNV component, confirmed by presence of active 
leakage from CNV seen by fluorescein angiography (FA) (or other imaging modalities) and 
sequelae of CNV, e.g. pigment epithelial detachment (PED), subretinal hemorrhage or sub-
retinal pigment epithelium (sub-RPE) hemorrhage, blocked fluorescence, macular edema in 
the study eye at Screening.  
4. Presence of intraretinal (IRF) and/or subretinal fluid (SRF) affecting the central subfield 
of the study eye as seen by SD-OCT in the study eye at Screening.  
5. Best-corrected visual acuity (BCVA) score greater than or equal to 23 letters measured at 
4-meters starting distance using Early Treatment Diabetic Retinopathy Study (EDTRS) 
visual acuity charts at both Screening and Baseline in the study eye.  
5.2 
Exclusion criteria 
Participants 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, 
in the opinion of the Investigator, could prevent response to study treatment or may 
confound interpretation of study results, compromise visual acuity or require planned 
medical or surgical intervention during the course of the study. 
2. Any active intraocular or periocular infection or active intraocular inflammation (e.g. 
infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis) in study 
eye at Screening or Baseline. 
3. Uncontrolled glaucoma in the study eye defined as intraocular pressure (IOP) > 25 mmHg 
on medication or according to Investigator’s judgment at Screening or Baseline. 


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4. Presence of amblyopia, amaurosis or ocular disorders in the fellow eye with BCVA < 
20/200 at Screening (except when due to conditions whose surgery may improve VA, e.g. 
cataract). 
5. Atrophy or fibrosis involving the center of the fovea in the study eye, as assessed by color 
fundus photography at Screening.  
6. The total area of fibrosis or subretinal blood affecting the foveal center point comprising ≥ 
50% of the lesion area in the study eye at Screening. 
7. Structural damage within 0.5 disc diameter of the center of the macula in the study eye, e.g. 
vitreomacular traction, epiretinal membrane, retinal pigment epithelium (RPE) rip/tear scar, 
laser burn, at the time of Screening that in the Investigator’s opinion could preclude visual 
function improvement with treatment. 
8. Current vitreous hemorrhage or history of vitreous hemorrhage in the study eye within 4 
weeks prior to Screening.  
Ocular treatment (study eye) 
9. Previous treatment with any anti-VEGF drugs or investigational drugs (other than vitamin 
supplements) in the study eye at any time prior to Screening. 
10. Previous use of intraocular or periocular steroids in the study eye within the 6-month period 
prior to Screening. 
11. Macular laser photocoagulation (focal/grid) or photodynamic therapy (PDT) in the study 
eye at any time prior to Baseline and peripheral laser photocoagulation in the study eye 
within 3 months prior to Baseline. 
12. Intraocular surgery in the study eye within 3 months prior to Baseline. 
13. Vitreoretinal surgery in the study eye at any time prior to Baseline. 
14. Aphakia with the absence of posterior capsule in the study eye. 
Systemic conditions and treatments 
15. Stroke or myocardial infarction in the 6-month period prior to Baseline. 
16. End stage renal disease requiring dialysis or renal transplant. 
17. 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). 
18. Systemic anti-VEGF therapy at any time. 
19. 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 COVID-19 treatment. 
20. 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. 
21. 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. 
22. History of a medical condition (e.g. metabolic dysfunction disease with exception of type 1 
or 2 diabetes mellitus, physical examination finding, or clinical laboratory finding) that, in 


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the judgment of the Investigator, would preclude scheduled study visits, completion of the 
study, or a safe administration of investigational product. 
23. Use of systemic investigational drugs within 5 half-lives of baseline or within 30 days/until 
the expected pharmacodynamic effect has returned to baseline, whichever is longer; or 
longer if required by local regulations (observational clinical studies solely involving over-
the-counter vitamins, supplements, or diets are not exclusionary). 
Other 
24. Not interpretable OCTA and SD-OCT images according to Investigator’s clinical judgment 
at Screening in the study eye 
25. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
pregnancy test. 
26. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant unless they are using highly effective methods of contraception during 
dosing of study drug administration and for 3 months after stopping the investigational 
medication.  
Effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant). Be aware that periodic abstinence (e.g. calendar, ovulation, 
symptothermal, postovulation methods) and withdrawal are not acceptable methods 
of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least 6 weeks before Baseline. In case of 
oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment. 
• Male sterilization (at least 6 months prior to Baseline). For female participants in 
the study, the vasectomized male partner should be the sole partner for that 
participant. 
• Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate < 1%), for 
example hormone vaginal ring or transdermal hormone contraception. In case of use 
of oral contraception women should have been stable on the same pill for a minimum 
of 3 months before taking study treatment. 
• Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
Women are considered post-menopausal and not of child-bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks 
before taking study treatment. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child-bearing potential. 


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6 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational drug 
Table 6-1 
Investigational drug 
Investigational 
Drug  
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor (global 
or local) 
Brolucizumab 6 
mg (Beovu® 120 
mg/ml) 
Solution for 
injection  
Intravitreal use 
Open label bulk 
supply; pre-filled 
syringes 
Local 
Brolucizumab will be provided in single use, sterile, pre-filled syringes. Each pre-filled syringe 
contains 19.8 mg brolucizumab in 0.165 ml solution. This provides a usable amount to deliver 
a single dose of 0.05 ml solution containing 6 mg of brolucizumab. 
Since the volume contained in the pre-filled syringe (0.165 ml) is greater than the recommended 
dose (0.05 ml), a portion of the volume contained in the pre-filled syringe must be discarded 
prior to administration. To expel the air bubble along with excess medicinal product, the plunger 
should be slowly depressed until the edge below the dome of the rubber stopper is aligned with 
the 0.05 ml dose mark (equivalent to 50 μl, i.e. 6 mg brolucizumab). 
Novartis will ensure sufficient supplies of brolucizumab for treatment use to allow for 
completion of the study. 
6.1.2 
Additional study treatments 
No control drug or other treatments beyond investigational drug are included in this trial. 
6.1.3 
Treatment arms/group 
Eligible participants will be assigned at Baseline to the treatment with IVT brolucizumab 6 mg. 
Each participant will receive three monthly injections (at Baseline, Week 4 and Week 8), 
followed by a q12w or q8w treatment regimen, according to Investigator’s decision upon the 
evaluation of disease activity based on visual and/or anatomical parameters at Week 16.   
If DA is identified, at any scheduled visit following Week 16, the assignment of the participant 
on q12w regimen to a q8w regimen thereafter should be considered. If the participant on q8w 
regimen is DA-free for two consecutive treatment visits based on the Investigator’s judgment, 
the re-allocation to a q12w regimen should be considered.  
For all participants, the last potential study treatment will be at the Week 44 visit or at the Week 
48 visit, according to the different treatment regimen implemented. 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
The Investigator has to instruct the participant to notify the study site about any new 
medications the participant takes after enrollment in the study. All medications, procedures, and 


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significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the participant was enrolled into the study must be recorded on the appropriate page in the 
electronic Case Report Form (eCRF). 
Each concomitant medication must be individually assessed against all exclusion 
criteria/prohibited medication. If in doubt, the Investigator should contact the Novartis medical 
monitor before enrolling a participant or allowing a new medication to be started. If the 
participant is already enrolled, contact Novartis to determine if the participant should continue 
participation in the study. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
During the study, standard of care or other treatments according to the Investigator's practice 
for wAMD 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. 
Corticosteroids administered via intra-nasal, inhaled, intra-articular or non-extensive dermal 
route (< 20% total body surface area) are permitted during the study. For other routes of 
corticosteroid administration, refer to Section 6.2.2. 
If cataract surgery is necessary, attempt to schedule cataract surgery ≥ 7 days after the most 
recent study treatment. Study treatment may be resumed ≥ 14 days after cataract surgery, 
assuming an absence of surgically related complications. 
If yttrium aluminum garnet (YAG) laser is necessary, it should be performed ≥ 7 days prior to 
the scheduled study visit. 
If vitrectomy is necessary in the study eye, it should be attempted to schedule the surgery ≥ 14 
days after the most recent study treatment. Study treatment may be given during vitrectomy 
surgery if deemed necessary according to investigator’s discretion.  
If the subject is planning to receive a COVID-19 vaccine that is authorized by local regulation, 
it is recommended to receive the vaccine at least 7 days before or after the study treatment visit 
including Baseline (Day 1) visit. 
 
6.2.2 
Prohibited medication 
Use of the treatments displayed in the table below are not allowed after the start of the study 
i.e., Screening. In addition, there are certain washout periods to be respected, as also outlined 
in the exclusion criteria (Section 5.2).  
Table 6-2 
Prohibited medication and procedures 
Medication 
Prohibition period 
Action taken 
Study Eye 
 
 
Any anti-VEGF drugs or 
investigational drugs, 
biologics or devices 
Any time 
Discontinue study treatment 


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Medication 
Prohibition period 
Action taken 
Study Eye 
 
 
(other than vitamin 
supplements)  
Any periocular injection 
or intraocular 
administration of 
corticosteroids (except if 
needed as short term 
treatment of AE) 
Any time 
Discontinue study treatment  
(except if for treatment of AE) 
Laser treatment for 
wAMD (except if needed 
as short-term treatment 
of AE) 
Any time 
Discontinue study treatment 
Fellow eye 
 
 
Any investigational drug, 
biologic or device (other 
than vitamin 
supplements) 
Any time 
Discontinue study treatment 
Systemic 
 
 
Anti-VEGF treatment 
Any time 
Discontinue study treatment 
Any investigational drug, 
biologic or device (other 
than vitamin 
supplements) 
Any time 
Discontinue study treatment 
Medications known to 
be toxic to the lens, 
retina or optic nerve, 
including ethambutol, 
chloroquine/ 
hydroxychloroquine, 
deferoxamine, 
phenothiazines and 
tamoxifen (except 
temporary use for 
COVID-19 treatment) 
Any time 
Discontinue study treatment 
6.2.3 
Rescue medication 
There will be no rescue medication for wAMD in the study eye. 
In case of lack of efficacy with investigational drug for wAMD 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 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. The Participant No. consists of the Center Number 


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(Center No.) (as assigned by Novartis to the investigative site) with a sequential participant 
number suffixed to it, so that each participant’s participation is numbered uniquely across the 
entire database. Upon signing the informed consent form, the participant is assigned to the next 
sequential Participant No. available in the electronic data capture (EDC) system. 
Participants who have been screen failures but are rescreened (see Section 8.1) will be assigned 
a new Participant No. if rescreening occurs beyond 14 days from the original screening date. 
6.3.2 
Treatment assignment, randomization 
This is a single arm study; hence no randomization will be performed. All eligible participants 
are to be assigned to brolucizumab treatment at Baseline. 
The Investigator will confirm that the participant has fulfilled all the inclusion/exclusion criteria 
in the source documents and the appropriate page on the eCRF. The Investigator will then assign 
the participant to treatment. 
6.4 
Treatment blinding 
This is a single arm, open-label, phase IV study; thus, study participants, Investigators, study 
staff, sponsor clinical study team, field monitors and statisticians will all be unblinded to 
treatment (i.e. brolucizumab 6 mg) and treatment regimen (q12w or q8w). 
An independent, treatment regimen-masked reading of SD-OCT, OCTA, FA, ICGA and CFP 
images collected at pre-defined timepoints (see Table 8-1, Section 8.3.2 and Section 8.3.3) for 
participants enrolled in the study will be performed at a Central Reading Centre (CRC). 
Of note, the Investigator will not be aware of the results of the CRC assessments when he/she 
assesses disease activity throughout the study, as per clinical practice. 
6.5 
Dose escalation and dose modification 
No study treatment dose adjustment is permitted. 
Deviations to dose intervals during the initiation phase and/or dose adjustments during the 
whole study are not allowed. 
Interruption of study treatment is allowed if warranted by an AE. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
Registration of all visits in the eCRF is necessary. The date and time of all study treatment 
injections administered during the study and any deviations from the protocol treatment 
schedule will be captured 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 Investigator at each visit. 


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6.7 
Preparation and dispensation 
Each study site will be supplied with study drug as described under investigational drug section 
(Section 6.1.1).  
The study medication has a 2-part label (base plus tear-off label). A unique medication number 
is printed on each part of this label. Immediately before dispensing the package to the 
participant, the Investigator or his/her delegates will detach the outer part of the label from the 
package and affix it to the participant’s source document. 
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 
site personnel have access. Upon receipt, the study treatment must be stored in a refrigerator 
(2°C - 8°C), keeping the pre-filled syringe in its sealed blister and in the outer carton in order 
to protect from light, according to the instructions specified on the labels and in the Summary 
of Product Characteristics (SmPC). Prior to use, the unopened blister may be kept at room 
temperature (below 25°C) for up to 24 hours (Beovu® SmPC, 2020). 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Country Organization Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of the 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The Investigator or his/her delegates 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 monitors during site visits or remotely and at the completion of the trial. 
At the conclusion of the study, and as appropriate during the course of the study, the Investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the Investigator 
folder at each site. 
6.7.2 
Instruction for prescribing and taking study treatment 
The study consists of a treatment period with brolucizumab from Baseline (Day 1) up to Week 
48, as shown in Figure 6-1. 


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Figure 6-1 
Treatment regimen 
 
As per Beovu® SmPC, the recommended dose of 6 mg brolucizumab (0.05 ml solution) is to be 
administered by intravitreal injection every 4 weeks (monthly) for the first 3 doses. Thereafter, 
the Investigator may individualize treatment intervals based on DA in the study eye as assessed 
by visual acuity and/or anatomical parameters (BCVA and/or IRF, SRF, sub-RPE fluid, 
hemorrhage, CRT and/or OCTA parameters and/or 3-field CFP). A first DA assessment is to 
be performed at Week 16, as recommended in Beovu® SmPC. In participants without DA, 
treatment every 12 weeks (q12w) should be considered. In patients with DA, treatment every 8 
weeks (q8w) should be considered. DA will be first assessed at Week 16 and then at each 
subsequent scheduled q12w/q8w treatment visit. In participants on q12w regimen with DA at 
any of these visits, a q8w treatment regimen should be considered. In participants on q8w 
regimen without DA for two consecutive treatment visits in the opinion of the Investigator, the 
re-allocation to a q12w regimen should be considered.  
Regardless of treatment administration, Baseline, Week 4, Week 8, Week 12, Week 16 and 
Week 48 visits are mandatory for all participants. The timepoints of the other treatment visits 
will depend on the treatment regimen of each participant (q12w/q8w). No monitoring visits are 
planned between the injection visits. 
For all participants, the last potential study treatment will be at the Week 44 visit or at the Week 
48 visit, according to the different treatment regimen implemented. 
The different types of visits occurring through the study are summarized in Table 6-3 with a 
description of when disease activity assessment and treatment take place. 
Table 6-3 
Disease activity assessment and treatment occurrence according to 
visit type  
Type 
Disease Activity Assessment 
Treatment 
Screening visit 
No 
No 
Baseline (Day 1) visit 
No 
Yes 
Week 4 and 8 visits 
No 
Yes 
Week 12 visit 
No 
No 


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Type 
Disease Activity Assessment 
Treatment 
Week 16 visit 
Yes 
Yes  
(if DA is present) 
Treatment visits (every 8 or 12 
weeks according to 
Investigator’s decision) 
Yes 
Yes (every 8 or 12 weeks 
according to Investigator’s 
decision) 
Week 48 visit  
Yes 
Only if a treatment was 
planned at the visit, based on 
treatment regimen 
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 (except for Baseline/Day 1, in 
which case study treatment administration should occur within the next 24 hours) or no later 
than within the visit window (± 7 days) as described in Section 3 and Section 8. When 
assessments and treatment 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 examination) described in Section 8.4.4. If study visit 
assessments and the corresponding treatment occur on separate days, a repeat safety check-up 
should be performed prior to treatment of the eye and results documented in the source 
documents. If any safety concern arises related to the study eye that, in the opinion of the 
Investigator, may be further impacted by the study treatment or injection procedure, treatment 
needs to be cancelled. IVT injection is contraindicated in subjects with active intraocular 
inflammation (IOI); therefore, the Investigators must verify that these conditions are not present 
in the study eye prior to every injection.  
If any sign of IOI is present, then an IVT injection must not be performed. Additional 
ophthalmic examination and imaging should be performed to evaluate IOI (see Section 8.4.2). 
If IOI confirmed, subjects should be treated for IOI according to clinical practice and closely 
monitored since they may be at risk of developing retinal vasculitis and/or retinal vascular 
occlusion. If subject develops retinal vasculitis (RV) and/or retinal vascular occlusion (RO) 
based on the investigator’s evaluation, the study treatment of brolucizumab must be 
discontinued. 
Any adverse events must be recorded in the eCRF.  
Every effort should be made to ensure that the subject adheres to the visit/treatment schedule.  
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the participants’ representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her understanding. If the participant is capable of doing so, he/she must 
indicate agreement by personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
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Novartis will provide to Investigators in a separate document a proposed informed consent form 
to ensure that complies with the International Council for Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) E6 Good Clinical Practice (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 to by 
Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the SmPC and the Core Data Sheet (CDS) for a marketed drug. This information will 
be included in the participant informed consent and should be discussed with the participant 
during the study as needed. Any new information regarding the safety profile of the 
investigational drug will be communicated as appropriate, for example, via an Investigator 
notification or an aggregate safety finding. As new information becomes available, informed 
consent will be updated and then must be discussed with the participant. 
Women of childbearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study, they must adhere to the contraception requirements. 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
8 
Visit schedule and assessments 
The Assessment Schedule (Table 8-1) lists all of the assessments and indicates with an “X” the 
visits when they are performed. All data obtained from these assessments must be supported in 
the participant’s source documentation. All data must be entered in the eCRF in a timely manner 
(see Section 11.1).  
A planned study visit schedule will be established at Baseline/Day 1 (first day of treatment) for 
all participants. All subsequent scheduled visits will be calculated based on the Day 1 visit date. 
The mandatory post-Baseline visits of the study are Week 4, Week 8, Week 12, Week 16 and 
Week 48. After Week 16, the treatment visit intervals will be determined 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/Day 1, should the participant be unable 
to return per scheduled visit. All efforts should be made to revert back to the planned visit 
schedule taking into consideration the restrictions on the minimum treatment interval for the 
study treatment, i.e. two consecutive injections should be at least 21 days apart. 
For a given protocol visit (except for Baseline), assessments can be performed on two 
consecutive days, provided both days are 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 have taken place 
(except Baseline, in which case study treatment administration should occur within the next 24 
hours). For all visits, efficacy assessments (Section 8.3) and safety assessments (Section 8.4) 
should be performed prior to any administration of study treatment. 


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Missed or rescheduled visits should not lead to automatic discontinuation. Participants who 
prematurely discontinue the study for any reason should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for the final visit will be performed.  
If the COVID-19 pandemic limits or prevents on-site study visits, study treatment could not be 
administered and other study assessments may not be performed. Alternative methods of safety 
monitoring may be implemented. Depending on local regulations, site capabilities and patient’s 
visit status in the study, phone calls or virtual contacts (e.g. teleconsult) can be performed for 
safety follow-up for the duration of the pandemic, until it is safe for the participant to visit the 
site again. 
 


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Table 8-1 
Assessment schedule  
 
Period 
Screening 
Treatment 
End of 
Study 
Visit Name 
Screening* 
Baseline 
Day 1 
W4 
W8 
W12 
W16 
Treatment visits 
W48* 
Visit number 
1 
2 
3 
4 
5 
6 
7-13 
14 
Weeks 
Up to 2 
weeks 
1 
4 
8 
12 
16 
20 to 441  
48 
Obtain informed 
consent 
 X 
  
  
  
  
  
  
  
Demography 
 X 
  
  
  
  
  
  
  
Inclusion/ 
exclusion 
criteria 
 X 
 X 
  
  
  
  
  
  
Relevant 
medical 
history/current 
medical history 
 X 
  
  
  
  
  
  
  
Vital Signs2, 3 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
Prior/ 
Concomitant 
systemic 
medications 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
Prior/ 
Concomitant 
ocular 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
Serum β-hCG 
Pregnancy Test4 
 X 
 
 
 
 
 
 
 
Urine 
Pregnancy Test4 
  
 X 
 X 
 X 
 X 
 X 
 X 
 X 
BCVA score 
(ETDRS) 
X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
IOP 
measurement5 
X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
Complete 
ophthalmic 
examination2, 6  
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
SD-OCT9  
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
OCTA 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
FA9 
 X 
 
 
 
 
 
 
 X 
ICGA 
 X 
 
 
 
 
 
 
 X 
Color Fundus 
Photography 
(CFP)    
 X 
 X 
 X 
 X 
 X 
X 
 X 
 X 
EQ-5D-5L 
  
 X 
  
  
  
  
  
 X 
HADS 
 
 X 
 
 
 
 
 
 X 




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8.1 
Screening 
Screening 
A screening period of up to 2 weeks will be used to assess patient eligibility. The screening 
period starts with the signing of the informed consent. 
A BCVA assessment, as well as a complete ophthalmic examination, which may include slit-
lamp exam, IOP measurement and fundus exam will be performed on both eyes. SD-OCT, 
OCTA, FA, ICGA and 3-field CFP are to be performed on both eyes and the diagnosis of active 
subfoveal CNV secondary to wAMD is to be confirmed in the study eye. The study Investigator 
will also collect vital signs (blood pressure and pulse). Medical history, demographic features 
and prior/concomitant medications are also to be collected. A serum pregnancy test is to be 
performed in women of childbearing potential. 
One-time re-screening 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 re-screening 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 wAMD is not withheld in order for a patient to participate in the study. 
8.1.1 
Information to be collected on screening failures 
Participants who sign an informed consent form and subsequently found to be ineligible 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 eCRF 
pages must also be completed for screen failure participants. No other data will be entered into 
the clinical database for participants who are screen failures, unless the participant experienced 
a serious adverse event (SAE) during the screening phase (see Section 10.1.3 for reporting 
details).  
8.2 
Participant demographics/other baseline characteristics 
The following information will be collected/documented at Screening/Baseline visit for each 
participant: 
• Age (Screening) 
• Sex (Screening) 
• Race/Ethnicity (Screening) 
• Vital signs, i.e. sitting blood pressure (systolic and diastolic pressure in mmHg) and 
pulse rate (beats per minute) (Screening and Baseline). Of note, in case there is an 
elevated blood pressure measurement as specified in the exclusion criteria, at Screening, 
the blood pressure measurement should be repeated after 20 minutes. If the repeat 
measurement is elevated as specified in the exclusion criteria, then the patient is not 
eligible to be enrolled into the study.  


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• Pregnancy test results for all women of childbearing potential (Screening and Baseline) 
• Visual acuity (BCVA) (Screening and Baseline)  
• Complete ophthalmic examination (Screening and Baseline) 
• Retinal imaging (SD-OCT, OCTA and 3-field CFP at Screening and Baseline; FA and 
ICGA at Screening) 
• EQ-5D-5L questionnaire (Baseline) 
• HADS questionnaire (Baseline) 
• Prior/concomitant medications (all prescription medications, over-the-counter drugs 
and significant non-drug therapies must be documented. See Section 6.2.1 for further 
details) (Screening and Baseline) 
• Medical history and current medical conditions (Screening) 
Investigators will have the option to record abnormal test findings on the medical history eCRF 
page whenever, in their judgment, the test abnormality occurred prior to the informed consent 
signature. 
8.3 
Efficacy 
The following assessments will be performed to assess the predictive value of early anatomical 
parameters measured by multimodal imaging at each visit from Baseline to Week 16 in q12w 
fluid-free participants (i.e. participants without IRF and SRF at Week 48 who have maintained 
a stable q12w treatment regimen up to Week 48 after the loading phase), as well as to evaluate 
the effect of brolucizumab on visual function, retinal structure, vascular leakage, quality of life 
and anxiety and depressive status: 
• CNV lesion type assessed by FA, CFP and ICGA at Screening and SD-OCT at Baseline  
• OCTA parameters, of which the main quantitative parameters are CNV flow size and 
vessel density and the main qualitative ones are branching vessels, peripheral 
anastomotic arcades, vascular loops and dark halo (from Baseline to Week 48) 
• SD-OCT parameters, of which the main quantitative parameters are CRT and PED 
volume, and the main qualitative ones are IRF, SRF, sub-RPE fluid, status of the ELM, 
SHRM and outer retinal tubulation (from Baseline to Week 48) 
• FA and ICGA (at Screening and Week 48) 
• 3-field CFP (from Baseline to Week 48) 
• BCVA with ETDRS-like charts at 4 meters (from Baseline to Week 48) 
• EQ-5D-5L questionnaire (at Baseline and Week 48) 
• HADS questionnaire (at Baseline and Week 48) 
All efficacy assessments should be performed prior to any administration of study treatment. 


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8.3.1 
Fluorescein angiography and indocyanine green angiography 
Fluorescein angiography (FA) and indocyanine green angiography (ICGA) will be performed 
in both eyes at Screening and Week 48. All FA and ICGA images will be obtained by trained 
and study-certified site personnel at the study sites and evaluated by the Investigator according 
to his/her standard of clinical practice to confirm the diagnosis of wAMD at Screening. 
Certification of the equipment and examiners at each investigative site will occur prior to 
evaluation of study participants. 
For the purpose of screening, FA and ICGA images from previous routine evaluations may be 
used as long as FA was performed within 3 days of the Screening visit using CRC-certified 
equipment and technician/Investigator. 
A treatment regimen-masked Central Reading Centre (CRC) will be used in this study. The 
CRC will provide sites with a Study Manual and training materials for the specified study ocular 
images. Before any study images are obtained, site personnel, test images, systems and software 
will be certified and validated by the CRC as specified in the Study Manual. FA and ICGA 
screening images and FA images at week 48 will be forwarded to the CRC for independent 
standardized analysis. The CRC data will be used for the evaluation of the objectives 
comprising the assessment of FA and ICGA parameters (i.e. to classify the type of CNV lesions) 
to ensure a standardized evaluation. Further details about all parameters to be evaluated by the 
CRC are reported in the CRC grading charter (a separate document). The CRC will create a 
database with the agreed variables as indicated in the CRC charter and will transfer the data 
from this database to Novartis/CRO for analysis. 
Additional images will be taken in case of any signs of intraocular inflammation. Fluorescein 
angiography should be performed for safety evaluation as described in Section 8.4.2. and 
uploaded onto the CRC portal. 
 
8.3.2 
Optical coherence tomography 
Spectral Domain Optical Coherence Tomography (SD-OCT) images will be obtained and 
assessed in the study eye at every study visit and in the fellow eye at Screening and at Week 
48. Only SD-OCT machines can be used (i.e. no time-domain nor swept-source OCT).  
These assessments will be performed by a trained technician or Investigator at the sites and 
should be performed after BCVA assessment and prior to any study drug administration. The 
SD-OCT machine used for an individual participant should not change for the duration of the 
study. Certification of the equipment and examiners at each investigative site will occur prior 
to evaluation of study participants. 
The following main parameters will be qualitatively evaluated by SD-OCT: 
• Intraretinal fluid (IRF), i.e. the fluid that accumulates within the neurosensory retina due 
to the disruption of the external limiting membrane (ELM)-photoreceptor complex in 
the outer retina by the active CNV membrane. On SD-OCT, diffuse retinal thickening 
and/or the formation of intraretinal cystoid spaces are indicative of the presence of IRF 
(Keane et al., 2012). 


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• Subretinal fluid (SRF), i.e. the fluid that commonly accumulates between the 
neurosensory retina and the RPE due to the profuse leakage from blood vessels of the 
CNV complex. On SD-OCT, SRF could be seen as hyporeflective or sparsely 
hyperreflective spaces between the retina and the RPE when the exudate is serous or 
contains fibrin or red blood cells, respectively (Keane et al., 2012).  
• sub-retinal pigment epithelium (sub-RPE) fluid, i.e. the fluid that accumulates under the 
RPE, thus often leading to PEDs (Keane et al., 2012). 
• Subretinal Hyperreflective Material (SHRM), i.e. a poorly defined, medium-to-
hyperreflective mass between the neurosensory layers and the RPE on SD-OCT, which 
is indicative of the neurovascular membrane, particularly in type II CNV lesions, and of 
disciform scar formation (Keane et al., 2012). 
• Outer retinal tubulation, i.e. branching tubular structures located in the outer nuclear 
layer of the retina, which seems to be indicative of a rearrangement of degenerating 
photoreceptors in a variety of retinal diseases, including wAMD. On SD-OCT, outer 
retinal tubulation appears as well-defined round or ovoid hyporeflective spaces with 
hyperreflective borders (Goldberg et al., 2013). 
• The status of the ELM, as an indicator of retinal integrity (Oishi et al., 2010). 
The following main parameters will be quantitatively evaluated by SD-OCT: 
• Volume of Pigment-Epithelium Detachment (PEDs), i.e. irregularly elevated lesions 
produced by the growth of the choroidal neovascular membrane and the accumulation 
of fluid or material in the sub-RPE space. On SD-OCT, PEDs appear as broad elevations 
of the RPE band relative to Bruch’s membrane (Keane et al., 2012).  
• Central retinal thickness (CRT) measurement, as main quantitative morphological 
parameter of wAMD. The CRT evaluated in this study represents the average retinal 
thickness of the circular area within 1 mm diameter around the foveal center. 
The Investigator will evaluate the SD-OCT images according to his/her standard of 
clinical practice to assess disease activity. The Investigator’s assessed findings of both 
quantitative and qualitative parameters (i.e. IRF; SRF, sub-RPE fluid, hemorrhage and/or CRT) 
will not be captured in the eCRF but must be included in the source documents at the study site. 
Only parameters used by the Investigator to assess DA will be recorded in the eCRF. 
The treatment regimen-masked CRC will provide sites with a Study Manual and training 
materials for the specified study ocular images. Before any study images are obtained, site 
personnel, test images, systems and software will be certified and validated by the CRC as 
specified in the Study Manual. All SD-OCT images will be forwarded to the CRC for 
independent standardized analysis. The CRC data will be used for the evaluation of the 
objectives comprising the assessment of SD-OCT parameters to ensure a standardized 
evaluation. Further details about all qualitative and quantitative parameters to be evaluated by 
the CRC are reported in the CRC grading charter (a separate document). The CRC will create 
a database with the agreed variables as indicated in the CRC charter and will transfer the data 
from this database to Novartis/CRO for analysis.   


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Additional images will be taken in case of any signs of intraocular inflammation. OCT should 
be performed for safety evaluation as described in Section 8.4.2 and uploaded onto the CRC 
portal. 
8.3.3 
Optical coherence tomography angiography 
Optical Coherence Tomography Angiography (OCTA) images will be obtained and assessed in 
the study eye at every study visit and in the fellow eye at Screening and Week 48.  
These assessments will be performed by a trained technician or Investigator at the sites and 
should be performed after BCVA assessment and prior to any study drug administration. The 
OCTA machine used for an individual participant should not change for the duration of the 
study. Certification of the equipment and examiners at each investigative site will occur prior 
to evaluation of study participants. 
The morphology of the CNV complex will be evaluated qualitatively by assessing by OCTA 
the following main parameters: presence/absence of branching vessels, peripheral anastomotic 
arcades, vascular loops and dark halo. The presence of tiny vessels branching from bigger 
vessels, peripheral anastomotic arcades at the vessel termini, vascular loops or dark halo 
(hypointense area considered as a region of choriocapillaris alteration, corresponding to local 
flow impairment) are indicative of an active CNV lesion (Al-Sheikh et al., 2018; Coscas et al., 
2018; Darwish, 2017). 
The following main parameters will be quantitatively evaluated by OCTA: 
• CNV flow size, visualized by calculating the decorrelation of signal amplitude from 
consecutive B-scans, thus creating a contrast between static and non-static tissue, 
through an appropriate algorithm. To quantify the blood flow within the CNV, the CNV 
area and flow index were calculated from the 2D maximum projection outer retina CNV 
angiogram (Jia et al., 2014). 
• vessel density of the lesion, calculated as a ratio of the area occupied by vessels to the 
total area of the lesion (Jia et al., 2014). 
The Investigator will evaluate the OCTA images according to his/her standard of clinical 
practice to assess disease activity. The Investigator’s assessed findings of both quantitative 
and qualitative parameters will not be captured in the eCRF but must be included in the source 
documents at the study site. Only parameters used by the Investigator to assess DA will be 
recorded in the eCRF. 
The treatment regimen-masked CRC will provide sites with a Study Manual and training 
materials for the specified study ocular images. Before any study images are obtained, site 
personnel, test images, systems and software will be certified and validated by the CRC as 
specified in the Study Manual. All OCTA images will be forwarded to the treatment regimen-
masked CRC for independent standardized analysis. The CRC data will be used for the 
evaluation of the objectives comprising the assessment of OCTA parameters to ensure a 
standardized evaluation. Further details about all qualitative and quantitative parameters to be 
evaluated by the CRC are reported in the CRC grading charter (a separate document). The CRC 
will create a database with the agreed variables as indicated in the CRC charter and will transfer 
the data from this database to Novartis/CRO for analysis. 


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8.3.4 
Color fundus photography 
3-field color fundus photography (CFP) will be performed in the study eye at every study visit 
and in the fellow eye at Screening and Week 48. All 3-field color fundus photographic images 
will be obtained by trained and study-certified site personnel at the study sites and evaluated by 
the Investigator according to his/her standard of clinical practice to assess disease activity. 
Certification of the equipment and examiners at each investigative site will occur prior to 
evaluation of study participants. 
A treatment regimen-masked Central Reading Centre (CRC) will be used in this study. The 
CRC will provide sites with a Study Manual and training materials for the specified study ocular 
images. Before any study images are obtained, site personnel, test images, systems and software 
will be certified and validated by the CRC as specified in the Study Manual. CFP images at 
screening will be forwarded to the CRC for independent standardized analysis. The CRC data 
will be used for the evaluation of the objectives comprising the assessment of CFP parameters 
(i.e. to classify the type of CNV lesions) to ensure a standardized evaluation. Further details 
about all parameters to be evaluated by the CRC are reported in the CRC grading charter (a 
separate document). The CRC will create a database with the agreed variables as indicated in 
the CRC charter and will transfer the data from this database to Novartis/CRO for analysis. 
 CFP 
(preferably wide-field or with peripheral sweeps) should be performed for safety evaluation as 
described in Section 8.4.2 and uploaded onto the CRC portal. 
8.3.5 
Best-Corrected Visual acuity 
Visual acuity will be assessed in the study eye at every study visit and in the fellow eye at 
Screening and Week 48, using best correction determined from protocol refraction (BCVA). 
Visual acuity testing should precede any examination requiring administration of eye drops to 
dilate the eye or any examination requiring contact with the eye. 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 ETDRS chart has been established as the gold standard for objective 
VA measurement in clinical trials and consists of 14 rows of 5 letters each, for a total of 70 
letters (Wykoff et al., 2018).  
8.3.6 
Disease activity assessments 
The Investigator will perform a disease activity assessment (DAAs) on the study eye at Week 
16 and at each subsequent scheduled q8w/q12w treatment visit. In participants on q12w 
treatment regimen with DA at any of these visits, a q8w treatment regimen should be 
considered. If a participant is adjusted to a q8w treatment regiment, he/she will subsequently 
be assessed at q8w treatment visits. In participants on q8w dosing regimen without signs of DA 
for two consecutive visits, based on the Investigator’s judgment, the re-allocation to a q12w 
regimen should be considered. Of note, the Investigator will not be aware of the results of the 
CRC assessments at the time of performing each planned DAA. 
DAAs are to be performed by the Investigator based on BCVA and/or one or more anatomical 
parameters detected by SD-OCT among IRF, SRF, sub-RPE fluid, hemorrhage, CRT and/or 
other OCTA parameters and/or 3-field CFP, as per clinical practice. The Investigator’s assessed 
findings of both quantitative and qualitative SD-OCT and/or OCTA parameters will not be 


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captured in the eCRF but must be included in the source documents at the study site. Exclusively 
which of these parameters the Investigator considered instrumental to assess DA will be 
recorded in the eCRF. 
8.3.7 
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. 
FA is still considered the gold standard for the diagnosis and classification of CNV lesions, 
whereas ICGA is a well-established procedure that helps to classify the type of lesion by 
identifying its entire extension. CFP is commonly used to inspect retinal pathology. 
OCTA is an emerging valid non-dye imaging tool that has been widely introduced in 
ophthalmology clinical practice to detect the neovascular complex in wAMD. In routine 
practice, OCTA is still coupled with FA and other imaging techniques for the diagnosis and 
follow-up of wAMD. 
The EQ-5D-5L questionnaire is one of the most widely used instruments for measuring health-
related quality of life analysis, while the HADS questionnaire is one of the National Institute 
for Health and Care Excellence recommended tools for diagnosis of depression and anxiety. 
8.4 
Safety 
Safety assessments will include complete ophthalmic examination, including IOP measurement 
prior and after each IVT injection, and vital signs, as well as monitoring and recording type, 
frequency, and severity for all AEs. 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 
For details on AE collection and reporting, refer to Section 10.1. 
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. 
8.4.1 
Pregnancy 
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements. 
Highly effective contraception, as summarized in the protocol’s exclusion criteria (Section 5.2), 
is required for women of childbearing potential during dosing of study treatment and for 3 
months after the final study injection. 
A serum pregnancy test will be conducted for all women of childbearing potential to assess 
pregnancy before inclusion into the study at Screening visit and recorded on the eCRF. During 
the study, urine pregnancy testing will be performed at all visits. Of note, a positive urine test 


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should be confirmed by a serum pregnancy test. If the serum test is positive, the subject must 
discontinue study treatment of brolucizumab. Results of all pregnancy testing must be available 
as source documents. 
8.4.2 
Ophthalmic examination 
A complete ophthalmic examination will be performed on the study eye at Screening, Baseline 
and Week 48 and may be performed at each in-between scheduled visit by the Investigator. At 
each visit the Investigator have to exclude the presence of any active intraocular inflammation 
in the study eye. This exam is also to be performed on the fellow eye at Screening and Week 
48. 
The ophthalmic exam may consist of the following: 
• biomicroscopy (slit lamp examination) which includes the evaluation of the lids/lashes, 
conjunctiva, cornea, anterior chamber aqueous reaction (cell and flare), iris, lens and 
anterior part of the vitreous body will be completed at every (scheduled and 
unscheduled) visit. The results of the examination of either eye will be recorded in the 
source documents. 
Slit lamp examination must be carefully performed before each study treatment. If there 
are any signs of IOI, severity of anterior chamber cells and flare should be assessed 
according to the standardization uveitis nomenclature (SUN) working group grading 
system (Jabs et al., 2005). The test results will be recorded in the source documents (e.g. 
ophthalmic examination tool) and captured in the appropriate eCRF as applicable. 
• fundus (posterior segment) exam, which includes the evaluation of the vitreous, retina, 
macula, choroid, and optic nerve will be conducted at every scheduled and unscheduled 
visit by Investigator according to the clinical practice (fellow eye will be examined at 
the discretion of the investigator). Pupil dilation is to be performed at the discretion of 
the Investigator. An examination of the peripheral retina must also be performed, to 
ensure that the intravitreal injection can safely be performed as needed. Posterior 
segment examination must be performed carefully before each study treatment. The 
results of the examination including any abnormalities (e.g. vitreous cells/haze, retinal 
tear/detachment, hemorrhage and vascular occlusion, vasculitis, etc.) should be recorded 
in the source documents if appropriate. If there are any signs of IOI, vitreous cells and 
haze should be assessed using National Institutes of Health (NIH) grading system 
(Nussenblatt et al., 1985). The outcome of the examination will be documented in the 
source document (e.g., ophthalmic examination tool) and appropriate eCRF page as 
applicable. Any clinically significant abnormalities of either eye identified prior to 
signing the informed consent will be recorded on the medical history eCRF page, and 
on the adverse event page of the eCRF for any findings identified after signing the 
informed consent. 
• intraocular pressure (IOP) measurement. Further details are reported in Section 8.4.3. 
Results of these procedures will be recorded as appropriate in the source documents. Clinically 
significant abnormalities (as judged by the Investigator) should be recorded as an AE in the 
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8.5 
Additional assessments 
8.5.1 
Clinical Outcome Assessments (COAs) 
Patient reported outcomes (PRO) 
The impact of brolucizumab treatment on patient quality of life and status of anxiety/depression 
will be assessed at Baseline and Week 48 by the EuroQoL five dimensions and five levels 
questionnaire (EQ-5D-5L) and the Hospital Anxiety and Depression Scale (HADS), 
respectively.  
The participant must be given the questionnaires to be completed at the scheduled visit before 
any clinical assessments are conducted. Participant’s refusal to complete all or any part of a 
PRO measures should be documented in the study data capture system and should not be 
captured as a protocol deviation. Handling of protocol deviations can be modified if needed per 
study protocol. 
Completed questionnaires will be reviewed and examined by the Investigator for responses that 
may indicate potential AE or SAE, which should be confirmed and recorded into eCRF based 
on the Investigator’s judgement (see Section 10.1.1 and Section 10.1.2 of the protocol). 
EQ-5D-5L questionnaire 
The EQ-5D-5L is a standardized widely used instrument for measuring generic health status. It 
comprises the following five dimensions: mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression. Each dimension has 5 levels. i.e. no problems, slight problems, 
moderate problems, severe problems and extreme problems, corresponding to digit numbers 
ranging from 1 to 5. The EQ-5D-5L total score is determined through a Visual Analogue Scale 
(VAS) and ranges from 0 to 100 with higher scores indicative of a better health status. 
Hospital Anxiety and Depression Scale 
The Hospital Anxiety and Depression Scale (HADS) is a fourteen-item scale that generates 
ordinal data. Seven items relate to anxiety and seven relate to depression. This patient-reported 
outcome measure was specifically developed to avoid reliance on anxiety/depression aspects 
which are also common somatic symptoms of illness, such as fatigue and insomnia or 
hypersomnia.  
Calculations of scores: each item is rated on a 4-point scale (‘Yes, definitely’, ‘Yes, sometimes’, 
‘No, not much’ and ‘No, not at all’). All items except items 7 and 10 are scored as ‘Yes, 
definitely’ = 3 to ‘No, not at all’ = 0. Items 7 and 10 are scored as ‘Yes, definitely’ = 0 to ‘No, 
not at all’ = 3. The HADS consists of two sub-scores: the HAD-A for anxiety and HAD-D for 
depression. Each sub-score ranges from 0 to 21 points: scores ≥11 indicate the presence of an 
anxious or depressive disorder, scores between 8-10 points are borderline abnormal, and scores 
≤7 indicate that an anxious or depressive disorder is not present. 
8.5.2 
Assessments in the fellow eye  
The following assessments will be performed for the fellow eye:  
• At Screening: BCVA, ophthalmic examination, IOP, SD-OCT, OCTA, CFP, FA and 
ICGA. Images will be sent and stored by the CRC. 


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• At Week 48: BCVA, ophthalmic examination, IOP, SD-OCT, OCTA, CFP, FA and 
ICGA. Images will be sent and stored by the CRC. 
 
The fellow eye will be examined only at Screening and Week 48 visits. Other assessments of 
the fellow eye may be performed at the Investigator’s discretion in accordance with routine 
practice at other time points; however, these will not be collected or analyzed in this study.  
9 
Study discontinuation and completion 
9.1 
Discontinuation and completion 
9.1.1 
Study treatment discontinuation and study discontinuation 
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration and can be initiated by either the participant or the 
Investigator. 
The Investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant’s well-being. 
Study treatment must be discontinued under the following circumstances: 
• Participant decision 
• Pregnancy (see Section 8.4.1 and Section 10.1.4) 
• Use of prohibited treatment as per recommendations in Section 6.2.2 
• Any situation in which study participation might result in a safety risk to the participant 
• Subject develops a retinal vasculitis and/or a retinal vascular occlusion event in the 
brolucizumab arm 
• Unsatisfactory therapeutic effect 
If discontinuation of study treatment occurs, the Investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information. 
Participants 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 activity assessment, administration of study treatment, post-
injection assessment and adherence to prohibited medication list) until Week 48, at the 
discretion of the Investigator or the participant. If a participant discontinues study treatment 
before Week 16 (visit 6), he/she will complete monthly visits until Week 16 (visit 6) and after 
Week 16 he/she will continue with bimonthly visits until Week 48. 
Participants 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, participants should return for the Week 48 (end of study) assessments to be 
performed as indicated in the Assessment Schedule (Table 8-1). If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be made 
to contact the participant/pre-designated contact as specified in the lost to follow-up section. 


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This contact should preferably be done according to the study visit schedule. If the participant 
cannot or is unwilling to attend any visit(s), the site staff should maintain regular telephone 
contact with the participant. This telephone contact should preferably be done according to the 
study visit schedule. 
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 
The Investigator must also register in the appropriate eCRF page the participant’s 
discontinuation from study treatment. 
9.1.1.1 
Replacement policy 
Participants who started treatment, but prematurely discontinued treatment and/or study will 
not be replaced.  
9.1.2 
Withdrawal of informed consent 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only 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 his/her consent 
/opposition to use data and record this information. 
Where consent to the use of personal and coded data is not required in a certain country's legal 
framework, participant therefore cannot withdraw consent. They still retain the right to object 
to the further use of 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. 


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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). 
All efforts should be made to complete the assessments prior to study discontinuation. A final 
evaluation at the time of the participant’s study discontinuation should be made as detailed in 
the assessment table. 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation. No new Personal Data (including biological samples) will be 
collected following withdrawal of consent/opposition. 
9.1.3 
Lost to follow-up 
For participants 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 participant, e.g. dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed or until the end of the study. 
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, but are not limited to: 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of study drug development 
• Practical reasons, including slow enrollment 
• Regulatory or medical reasons 
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a prematurely withdrawn participant. 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 participant’s interests. The Investigator or sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.  
9.2 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes their End of Study visit (Week 
48) 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 participant may receive standard of care or other treatments, at the 
discretion of the Investigator and/or referring physician, if needed. 


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10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign, symptom or disease) in a clinical investigation participant 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 participant 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 participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings or other assessments. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The severity grade: 
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
2. Its relationship to the study treatment or the 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 cohorts, not on a single participant 
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not recovered/not 
resolved must be reported 
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken regarding with study treatment. 
All adverse events must be treated appropriately. Treatment may include one or more of 
the following: 
• no action taken (e.g. further observation only)  
• investigational treatment interrupted/withdrawn 
• concomitant medication or non-drug therapy given 


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• participant hospitalized/participant’s hospitalization prolonged (see Section 10.1.2 for 
definition of SAE) 
6. Its outcome: 
• not recovered/not resolved 
• recovered/resolved 
• recovered/resolved with sequelae 
• fatal or unknown 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events should be described using a diagnosis whenever possible, rather than individual 
underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days following the last 
administration of study treatment. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the SmPC 
and in the IB. 
Abnormal 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 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 participant with the underlying disease. 
10.1.2 
Serious adverse events 
Any 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 participant 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 


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• 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 participant’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 participant 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 participant 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 new 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 participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 4 weeks after the last study visit must be reported to 
Novartis Patient Safety within 24 hours of learning of its occurrence. Detailed instructions 
regarding the submission process and requirements are to be found in the Investigator folder 
provided to each site.  
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the Investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
If the SAE is not previously documented in the SmPC and is thought to be related to the study 
treatment, a Chief Medical Office and Patient Safety (CMO & PS) Department associate may 
urgently require further information from the Investigator for health authority reporting. 


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Novartis may need to issue an Investigator Notification (IN) to inform all Investigators involved 
in any study with the same study treatment that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
Any SAEs experienced after the 4-week period after the last study visit (study discontinuation) 
should only be reported to Novartis Safety if the Investigator suspects a causal relationship to 
study treatment. 
10.1.4 
Pregnancy reporting 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign pregnancy consent form to allow the Study 
Doctor ask about her pregnancy. To ensure participant safety, each pregnancy occurring after 
signing the informed consent must be reported to Novartis within 24 hours of learning of its 
occurrence. The pregnancy (for female participants) should be followed up to determine 
outcome, including spontaneous or voluntary termination, details of the birth, and the presence 
or absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. 
Pregnancy should be recorded and reported by the Investigator to the Novartis CMO&PS. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to brolucizumab 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, participant or 
consumer (European Medicines Agency definition). 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate eCRF page and in the Dispensing Log at the study site, irrespective of whether 
or not associated with an AE/SAE and reported to Safety only if associated with an SAE.  
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
eCRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes (only data 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. 


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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 (eCRFs). 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 participant 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 (or designated CRO) personnel will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated Investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
SD-OCT, OCTA, FA, ICGA and CFP images, appropriately anonymized from the 
Investigators, will be processed centrally by the Central Reading Center and the results will be 
sent electronically to the CRO working on behalf of Novartis. The Data management staff will 
review data received from the CRC for data structure and data completeness / accuracy as 
defined in the Data Transfer Specifications document. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for data analysis. Any changes to 
the database after that time can only be made after written agreement by Novartis development 
management. 
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. 
eSource DDE or eCRFs) with the Investigators and their staff. During the study, Novartis 


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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 participant 
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 participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments, including retinal images. All information on eCRFs must be traceable to these 
source documents in the participant’s file. The Investigator must also keep the original informed 
consent form signed by the participant (a signed copy is given to the participant). 
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
12 
Data analysis and statistical methods 
Any data analysis carried out independently by the Investigator should be submitted to Novartis 
before publication or presentation. 
All data will be listed and summarized as appropriate: continuous data will be summarized by 
mean, standard deviation (SD), median, minimum and maximum, Q1 and Q3; categorical data 
will be presented as absolute and relative frequencies. 95% confidence intervals will be 
provided as relevant. 
In addition to the statistical methods outlined below, further details will be described in the 
Statistical Analysis Plan (SAP). 
Additional analysis may be also conducted to evaluate the impact of COVID-19 pandemic. 
12.1 
Analysis sets 
The Screened patient population consists of all screened patients. 
The Full Analysis Set (FAS) comprises all enrolled participants, i.e. participants who 
completed the Baseline visit. 
The Safety Set (SAF) includes all FAS participants who received at least one dose of the study 
drug. 


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All statistical analyses are to be conducted on the Safety Set, if not differently specified.  
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics evaluated at 
Screening/Baseline will be listed and summarized descriptively for the FAS and Safety set. 
Eye disease history will be summarized descriptively as appropriate (e.g. time from wAMD 
diagnosis, bilateral disease etc.). 
Relevant medical histories and current medical conditions at Screening will be summarized by 
system organ class, preferred term and ongoing status. 
12.3 
Treatment 
The Safety set will be used for the analyses below.  
The duration of exposure to brolucizumab as number of IVT injections received from Baseline 
to Week 48 will be summarized by means of descriptive statistics. Furthermore, the number of 
participants at each injection category (e.g. 1 injection, 2 injections, etc.) from Baseline to Week 
48 will be provided. All collected injection data will be listed. 
The treatment regimen (q12w or 18w) will also be provided. 
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. 
12.4 
Analysis of the primary estimands 
The primary aim of the study is to assess the predictive value of early anatomical parameters 
measured by multimodal imaging at each visit from Baseline to Week 16, in brolucizumab-
treated participants with wAMD who present fluid resolution at Week 48 and have maintained 
the q12w treatment regimen up to Week 48 (i.e. q12w fluid-free participants), compared with 
participants on a q8w regimen and/or not fluid-free at Week 48. 
12.4.1 
Definition of primary endpoint(s)/estimand(s) 
The primary estimand of the study is to identify the q12w fluid-free predictive factors. 
A patient will be considered q12w fluid-free if does not present IRF and SRF at Week 48 and 
remains on the q12w regimen up to Week 48. 
The following qualitative and quantitative anatomical parameters measured by FA, ICGA, CFP, 
SD-OCT and OCTA will be considered as potential predictive factors in the statistical model: 
• Basal CNV lesion type, as assessed by SD-OCT, FA, ICGA and CFP at Screening 
• Parameters assessed by OCTA from Baseline to Week 16, of which the main are 
presence/absence of branching vessels, peripheral anastomotic arcades, vascular 
loops and dark halo, and quantification of CNV flow size and vessel density  
• Parameters assessed by SD-OCT from Baseline to Week 16, of which the main are 
presence/absence of sub-RPE fluid, SHRM, outer retinal tubulation and status of 
ELM, measurement of CRT and PED volume 


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The primary estimand of interest is described in Table 12-1 below, together with its key 
attributes. The estimand outlined below will be discussed in further details in the SAP. 
Table 12-1  
Primary estimand 
Estimand definition 
Analysis set 
Use of data after 
intercurrent event (missing 
data imputation techniques) 
Statistical methods 
Proportion of q12 fluid-
free participants 
SAF 
 
Participants who prematurely 
discontinued the study should 
be considered a not q12 fluid-
free  
Multivariable logistic 
regression model 
12.4.2 
Statistical model, hypothesis, and method of analysis 
To test whether the above-mentioned anatomical parameters are predictors of response to 
brolucizumab in terms of fluid resolution and stable q12w regimen, participants within the 
Safety Set are to be divided in: 
• q12w fluid-free participants, defined as participants who have maintained a stable q12w 
regimen up to Week 48 and are devoid of IRF and SRF at Week 48 
• not q12w fluid-free participants, defined as participants who present IRF or SRF at 
Week 48 or have been on a q8w regimen at any time during the study or have dropped 
out at any time after Baseline 
A Recursive Partitioning and Amalgamation (RECPAM) classification-tree analysis will be 
used to evaluate interactions between imaging measurements assessed by OCT, OCTA, FA, 
ICGA and CFP and to identify distinct and homogeneous subgroups of participants in terms of 
q12w fluid-free participants at Week 48.  
This tree-based method integrates the advantages of main effects logistic regression and tree-
growing techniques. At each partitioning step, the method chooses the covariate and its best 
binary split to maximize the difference in the outcome of interest. The algorithm stops when 
user-defined conditions (stopping rules) are met. To obtain more robust and stable splits, a 
permutation approach will be adopted to choose the best splitting variable. Global and local 
adjustment for possible confounders will be accounted for. Global variables will adjust the tree 
structure iteratively and add global coefficients to the model. Local variables will add different 
adjustment terms for any terminal node in a tree. 
The RECPAM construction proceeds in the following three steps: 
Step 1: Construction of a large tree.  
Starting from the Safety Set (i.e. root node), the maximum dissimilarity between q12w fluid-
free patients vs non q12w fluid-free patients for the Split Defining Statement (SDS) family (i.e. 
predictors variable) will be searched. This will identify the first branch of the tree and the 
corresponding tree. The same search will be performed recursively on the descendants of the 
root node, until a minimum node size specified by the user is reached. This defines the leaves 
of the larger tree. 
Step 2: Pruning of the large tree and selection of the honest tree.  
The best tree will be select considering jointly the two criteria: the Akaike Information Criterion 
(AIC) and the simultaneous significance levels (SLn). According to the minimum AIC principle 


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(Akaike, 1974), the honest tree should be the tree of the pruning sequence having the smallest 
AIC. This criterion is justified by the asymptotic equivalence of the minimum AIC model 
choice and leave-one-out cross validation. According to the SL approach, on the other hand, we 
should choose the smallest tree such that SLn is larger than a pre-fixed value, e.g. 0.05 or 0.01. 
Since the AIC sequence decreases, reaches a minimum and then increases with a characteristic 
jump in the increment, while SL sequence can only decrease but up to a point at which the SL 
drops rather abruptly, we will choose the point in which both curves show a characteristic elbow 
(Ciampi et al., 1995).   
Step 3: Construction of the amalgamation tree and selection of the RECPAM classification.  
For a given statistical significance ɑ level, the leaves of the honest tree will be amalgamated 
successively until any couple of leaves is dissimilar at the nominal ɑ level. This results in a 
sequence of nested partitions of the set of leaves of the honest tree, forming the amalgamation 
tree. The partition corresponding to the minimum AIC, is selected: it defines the RECPAM 
classification (Ciampi et al., 1991).  
A multivariable logistic regression will then be applied to study the association between q12w 
fluid-free patients at Week 48 with different imaging parameters using the above-mentioned 
variables and the cut-off selected by the RECPAM analysis. FA, ICGA and CFP variables 
included in the model are measured at Screening, while OCTA and SD-OCT variables included 
in the model are assessed at Screening (only SD-OCT), Baseline and Weeks 4, 8, 12 and 16. 
The variables selection will be based on an automated stepwise selection. 
12.4.3 
Handling of remaining intercurrent events of primary estimand 
As described in Table 12-1, participants who prematurely discontinued the study should be 
considered a not q12w fluid-free at Week 48. 
12.4.4 
Handling of missing values not related to intercurrent event 
Imputation of missing values will be done following the Last Observation Carried Forward 
(LOCF) method mainly for the secondary endpoints. An observed approach will be also 
considered. 
12.4.5 
Sensitivity analyses for primary endpoint/estimand 
A sensitivity analysis on the primary model will be performed using the LOCF approach in case 
of missing SD-OCT or OCTA evaluations between Week 4 and Week 16. 
12.4.6 
Supplementary analysis 
Not applicable.  
12.4.7 
Supportive analyses 
To investigate the robustness of the primary analysis with respect to a potential selection bias due 
to dropouts, the following approach will be used: a weighted multivariable logistic regression 
will be applied to provide a robust inferential procedure for the analysis of predictors of 
patients’ responses in presence of missingness. Since excluding participants because of missing 
values could introduce a selection bias, in order to restore the complete-case analysis to its 


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original sample representation, each complete participant will be weighted for the inverse of 
his/her missingness probability (evaluated by means of a logistic regression considering all 
baseline available covariates and the dropouts during the one-year period as response variables) 
(Höfler et al., 2005). 
Further details will be provided in the Statistical Analysis Plan (SAP). 
12.5 
Analysis of secondary endpoints 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
All secondary efficacy analyses will be based on the FAS. The analyses performed at eye level 
will focus on the study eye only.  
The secondary efficacy objective and endpoints of this study are as follows: 
To evaluate the effect of brolucizumab on the evolution of qualitative and quantitative 
OCTA parameters of wAMD from Baseline to Week 48 
Summary statistics of each parameter assessed by OCTA, of which the main quantitative 
parameters are CNV flow size and vessel density, and the main qualitative ones are branching 
vessels, peripheral anastomotic arcades, vascular loops and dark halo, from Baseline up to Week 
48 will be provided, including changes vs Baseline. Paired t-test or Wilcoxon signed rank test, 
based on data distribution, will be used to test the difference at each time point vs Baseline for 
continuous parameters. In case of a dichotomous parameter, a McNemar test will be used.  
To evaluate the effect of brolucizumab on the evolution of qualitative and quantitative 
SD-OCT parameters of wAMD from Baseline to Week 48 
Summary statistics of each parameter assessed by SD-OCT, of which the main quantitative 
parameters are CRT and PED volume, and the main qualitative ones are IRF, SRF, sub-RPE 
fluid, status of ELM, SHRM and outer retinal tubulation, from Baseline up to Week 48 will be 
provided, including changes vs Baseline. 
Paired t-test or Wilcoxon signed rank test, based on data distribution, will be used to test the 
difference at each time point vs Baseline for continuous parameters. In case of a dichotomous 
parameter, a McNemar test will be used. 
To evaluate the effect of brolucizumab on the evolution of functional parameters of 
wAMD from Baseline to Week 48 
Summary statistics of BCVA from Baseline at each visit up to Week 48 as well as changes vs 
Baseline will be provided. Paired t-test or signed rank test, based on data distribution, will be 
used to test the difference at each time point vs Baseline. 
Frequency of patients with an improvement of at least 5/10/15 letters or worsening will be also 
provided. 
To evaluate the effect of brolucizumab on sustained dryness from Baseline to Week 48 
• Time to reach sustained dryness of the study eye, as defined by the absence of IRF and 
SRF for at least 2/3 consecutive visits, will be descriptively summarized. Survival 
Kaplan-Meier curve will also be provided including summary estimates. 


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• Summary statistics of cumulative incidence of sustained dryness of the study eye will 
be provided by means of absolute and relative frequencies of participants with sustained 
dryness as defined above at each timepoint from Week 8 to Week 48. The binomial 
proportion and 95% confidence interval (CI) using the Clopper-Pearson method will also 
be provided. 
To evaluate the reasons underlying the Investigators’ choice of brolucizumab treatment 
regimen (q21w or q8w) at Week 16 
The reasons underlying the Investigator’s choice of brolucizumab dosing regimen (q12w or 
q8w) at Week 16 among BCVA and/or IRF, SRF, sub-RPE fluid, hemorrhage and/or CRT 
and/or OCTA parameters and/or 3-field CFP will be descriptively summarized. A multivariate 
logistic regression model will also be implemented in order to evaluate which of these factors 
are determinants for the selection of the dosing regimen at Week 16. 
Further details will be provided in the Statistical Analysis Plan (SAP). 
12.5.2 
Safety endpoints 
The safety set will be used for all safety analyses.  
Safety summaries include only data from the on-treatment period. 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). 
The on-treatment period lasts from the date of first administration of study treatment to 30 days 
after the date of the last actual administration of the study treatment or the end of study, 
whichever is the latest. 
Adverse events 
All information obtained on adverse events will be summarized overall and listed by participant. 
The number (and percentage) of participants with treatment-emergent adverse events (events 
started after the first dose of study medication) will be summarized in the following ways: 
• by primary system organ class and preferred term. 
• by primary system organ class, preferred term and maximum severity. 
Separate summaries will be provided for study medication related treatment-emergent adverse 
events, death, serious treatment-emergent adverse events and other significant treatment-
emergent adverse events leading to permanent treatment discontinuation.  
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. 
12.5.3 
Patient reported outcomes 
Quality of Life – EQ-5D-5L 
Summary statistics of EuroQol-5D-5L (EQ-5D-5L) VAS scores at each time point as well as 
changes from Baseline will be provided. Paired t-test or signed rank test, based on data 
distribution, will be used to test the difference in VAS scores at Week 48 vs Baseline. 


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Hospital Anxiety and Depression Scale  
Descriptive statistics of HAD-A and HAD-D score at each time point with changes vs Baseline 
will be provided. Paired t-test or signed rank test, based on data distribution, will be used to test 
the difference in HAD-A and HAD-D scores at Week 48 vs Baseline. 
The sub-scores, HAD-A and HAD-D, will also be displayed per class (i.e. scores ≥11 indicate 
the presence of anxious or depressive disorders; scores between 8-10 points are borderline 
abnormal, and scores of ≤7 indicate that the disorder is not present) at each time point by means 
of a shift table.  
In addition, the prevalence of anxiety and depression will be presented on the basis of the 
following three criteria: as per the score on the corresponding sub-scores of the HAD 
questionnaire, in terms of the treatment they are receiving for anxiety/depression, and according 
to both criteria. 
12.6 
Interim analyses 
An interim analysis will be conducted when 50% of the participants planned to be enrolled have 
completed their Week 16 visit to evaluate the reasons underlying the Investigators’ choice of 
brolucizumab treatment regimen at Week 16. The reasons underlying the Investigator’s choice 
of brolucizumab dosing regimen (q12w or q8w) at Week 16 among BCVA and/or IRF, SRF, 
sub-RPE fluid, hemorrhage and/or CRT and/or OCTA parameters and/or 3-field CFP will be 
descriptively summarized. A multivariate logistic regression model will also be implemented 
in order to evaluate which of these factors are determinants for the selection of the dosing 
regimen.  
12.7 
Sample size calculation 
12.7.1 
Primary endpoint(s) 
The sample size calculation is based on the assumption of an expected percentage of participants 
who have maintained the q12w regimen up to Week 48 equal to 56%, as derived from the 
HAWK study, and the hypothesis of a maximum percentage of not-fluid free participants out 
of these q12w-regimen participants at Week 48 equal to 18%. Therefore, the percentage of 
responders, defined as fluid-free participants who have maintained a q12w stable regimen up 
to Week 48, could range between 56% to 46%.  
Considering a percentage of responders of 56% and a maximum width of the 95% confidence 
interval of 12%, 263 patients should be enrolled. Applying the rules of thumb, with 263 patients 
and a percentage of responders of 56%, a maximum number of 12 covariates can be included 
in the multivariate regression model (Harrell, 2015). As shown in Figure 12-1, the precision of 
the estimate remains stable around 12%, considering a percentage of responders ranging 
between 56% to 46%. Similar considerations can be made with a number of covariates that 
remains equal to 12. 
Finally, to account for a screening failure rate of 12%, a total of approximately 300 participants 
will be screened in order to enroll 263 evaluable participants. 
The sample size calculations were performed with Nquery 7.0. 


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Figure 12-1 
Precision of the estimate scenario  
 
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, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the Investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the Investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion and finalization of the study report 
the results of this trial will be submitted for publication and posted in a publicly accessible 
database of clinical trial results, such as the Novartis clinical trial results website and all required 


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Health Authority websites (e.g. Clinicaltrials.gov, EudraCT etc.). Results from the interim 
analyses may be published prior to study completion. 
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 participants 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 participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any participant included in this 


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study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
References 
References are available upon request. 
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in Age-related Macular Degeneration Using Optical Coherence Tomography 
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Bhutto I and Lutty G (2012) Understanding age-related macular degeneration (AMD): 
relationships between the photoreceptor/retinal pigment epithelium/Bruch’s 
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Ciampi A, Du Berger R, Taylor H, et al. (1991) RECPAM: A computer program for recursive 
partition and amalgamation for survival data and other situations frequently occurring in 
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Cimarolli VR, Casten RJ, Rovner BW, et al. (2016) Anxiety and depression in patients with 
advanced macular degeneration: Current perspectives. Clin Ophthalmol 10: 55–63. 
Coscas F, Cabral D, Pereira T, et al. (2018) Quantitative optical coherence tomography 
angiography biomarkers for neovascular age-related macular degeneration in remission. 
PloS one 13(10): e0205513. 
Coscas F, Lupidi M, Boulet JF, et al. (2019) Optical coherence tomography angiography in 
exudative age-related macular degeneration: A predictive model for treatment decisions. 
Br J Ophthalmol 103(9): 1342–1356. 
Darwish A (2017) OCT angiography for the evaluation of wet age related macular 
degeneration. EC Ophthalmol 6(1): 06-18. 
Dugel PU, Koh A, Ogura Y, et al. (2020) HAWK and HARRIER: Phase 3, Multicenter, 
Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related 
Macular Degeneration. Ophthalmology 127(1): 72–84. 
Flaxman SR, Bourne RRA, Resnikoff S, et al. (2017) Global causes of blindness and distance 
vision impairment 1990–2020: a systematic review and meta-analysis. Lancet Glob 
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Gess AJ, Fung AE and Rodriguez JG (2011) Imaging in neovascular age-related macular 
degeneration. Semin Ophthalmol 26(3): 225–233. 
Goldberg NR, Greenberg JP, Laud K, et al. (2013) Outer retinal tubulation in degenerative 
retinal disorders. Retina (Philadelphia, Pa.) 33(9): 1871–6. 
Harrell FE (2015) Regression Modeling Strategies: With Applications to Linear Models, 
Logistic and Ordinal Regression, and Survival Analysis. 2nd ed. Springer International 


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Publishing AG. 
Höfler M, Pfister H, Lieb R, et al. (2005) The use of weights to account for non-response and 
drop-out. Soc Psychiatry Psychiatr Epidemiol 40(4): 291–299. 
Holz FG, Schmitz-Valckenberg S and Fleckenstein M (2014) Recent developments in the 
treatment of age-related macular degeneration. J Clin Invest 124(4): 1430–1438. 
Holz FG, Tadayoni R, Beatty S, et al. (2015) Multi-country real-life experience of anti-
vascular endothelial growth factor therapy for wet age-related macular degeneration. Br J 
Ophthalmol 99(2): 220–226. 
Jabs DA, Nussenblatt RB, Rosenbaum JT, et al. (2005) Standardization of uveitis 
nomenclature for reporting clinical data. Results of the First International Workshop. 
American journal of ophthalmology 140(3): 509–16. 
Jia Y, Bailey ST, Wilson DJ, et al. (2014) Quantitative optical coherence tomography 
angiography of choroidal neovascularization in age-related macular degeneration. 
Ophthalmology 121(7): 1435–44. 
Keane PA, Patel PJ, Liakopoulos S, et al. (2012) Evaluation of Age-related Macular 
Degeneration With Optical Coherence Tomography. Surv Ophthalmol 57(5): 389–414. 
Mitchell P, Liew G, Gopinath B, et al. (2018) Age-related macular degeneration. Lancet 392: 
1147–1159. 
Monés J, Singh RP, Bandello F, et al. (2020) Undertreatment of Neovascular Age-Related 
Macular Degeneration after 10 Years of Anti-Vascular Endothelial Growth Factor 
Therapy in the Real World: The Need for A Change of Mindset. Ophthalmologica 
243(1): 1–8. 
Nguyen QD, Das A, Do D V., et al. (2020) Brolucizumab: Evolution Through Preclinical and 
Clinical Studies, and the Implications for the Management of nAMD. Ophthalmology: 
Epub ahed of print. 
Nikolopoulou E, Lorusso M, Micelli Ferrari L, et al. (2018) Optical Coherence Tomography 
Angiography versus Dye Angiography in Age-Related Macular Degeneration: 
Sensitivity and Specificity Analysis. BioMed Res Int: 6724818. 
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activity in intermediate and posterior uveitis. Ophthalmology 92(4): 467–71. 
Oishi A, Hata M, Shimozono M, et al. (2010) The Significance of External Limiting 
Membrane Status for Visual Acuity in Age-Related Macular Degeneration. Am J 
Ophthalmol 150(1): 27–32.e1. 
Schmidt-Erfurth U, Chong V, Loewenstein A, et al. (2014) Guidelines for the management of 
neovascular age-related macular degeneration by the European Society of Retina 
Specialists (EURETINA). Br J Ophthalmol 98(9): 1144–1167. 
Spaide RF, Jaffe GJ, Sarraf D, et al. (2019) Consensus Nomenclature for Reporting 
Neovascular Age-Related Macular Degeneration Data: Consensus on Neovascular Age-
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of print. 
Sulzbacher F, Kiss C, Munk M, et al. (2011) Diagnostic evaluation of type 2 (classic) 
choroidal neovascularization: Optical coherence tomography, indocyanine green 
angiography, and fluorescein angiography. Am J Ophthalmol 152(5): 799–806.e1. 
Taylor DJ, Hobby AE, Binns AM, et al. (2016) How does age-related macular degeneration 
affect real-world visual ability and quality of life? A systematic review. BMJ Open 
6(12): 1–13. 
Wong WL, Su X, Li X, et al. (2014) Global prevalence of age-related macular degeneration 
and disease burden projection for 2020 and 2040: A systematic review and meta-
analysis. Lancet Glob Health 2(2): e106–e116. 
Wykoff CC, Clark WL, Nielsen JS, et al. (2018) Optimizing Anti-VEGF Treatment Outcomes 
for Patients with Neovascular Age-Related Macular Degeneration. J Manag Care Spec 
Pharm 24(2–a Suppl): S3–S15. 
 


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16 
Appendices 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs 
Not applicable. 


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16.2 
Appendix 2: Liver event and laboratory trigger definitions & 
follow-up requirements 
Not applicable. 


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16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event 
Follow-up 
Not applicable. 
 

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All notices and disclosures will be sent to you electronically 


 
Unless you tell us otherwise in accordance with the procedures described herein, we will provide 
electronically to you through the DocuSign system all required notices, disclosures, 
authorizations, acknowledgements, and other documents that are required to be provided or made 
available to you during the course of our relationship with you. To reduce the chance of you 
inadvertently not receiving any notice or disclosure, we prefer to provide all of the required 
notices and disclosures to you by the same method and to the same address that you have given 
us. Thus, you can receive all the disclosures and notices electronically or in paper format through 
the paper mail delivery system. If you do not agree with this process, please let us know as 
described below. Please also see the paragraph immediately above that describes the 
consequences of your electing not to receive delivery of the notices and disclosures 
electronically from us. 
 
 
How to contact 
 
You may contact us to let us know of your changes as to how we may contact you electronically, 
to request paper copies of certain information from us, and to withdraw your prior consent to 
receive notices and disclosures electronically as follows: 
To contact us by email send messages to: 
 
 
 
To advise 
 of your new email address 
To let us know of a change in your email address where we should send notices and disclosures 
electronically to you, you must send an email message to us at 
 and in the 
body of such request you must state: your previous email address, your new email address. We 
do not require any other information from you to change your email address. 
 
If you created a DocuSign account, you may update it with your new email address through your 
account preferences. 
 
 
To request paper copies from 
 
To request delivery from us of paper copies of the notices and disclosures previously provided 
by us to you electronically, you must send us an email to 
 and in the body 
of such request you must state your email address, full name, mailing address, and telephone 
number. We will bill you for any fees at that time, if any. 
 
 
To withdraw your consent with 
 
 
To inform us that you no longer wish to receive future notices and disclosures in electronic 
format you may: 


 
i. decline to sign a document from within your signing session, and on the subsequent page, 
select the check-box indicating you wish to withdraw your consent, or you may; 
 
ii. send us an email to 
 and in the body of such request you must state 
your email, full name, mailing address, and telephone number. We do not need any other 
information from you to withdraw consent.. The consequences of your withdrawing consent for 
online documents will be that transactions may take a longer time to process.. 
 
 
Required hardware and software 
The minimum system requirements for using the DocuSign system may change over time. The 
current system requirements are found here: 
 
 
 
 
Acknowledging your access and consent to receive and sign documents electronically 
To confirm to us that you can access this information electronically, which will be similar to 
other electronic notices and disclosures that we will provide to you, please confirm that you have 
read this ERSD, and (i) that you are able to print on paper or electronically save this ERSD for 
your future reference and access; or (ii) that you are able to email this ERSD to an email address 
where you will be able to print on paper or save it for your future reference and access. Further, 
if you consent to receiving notices and disclosures exclusively in electronic format as described 
herein, then select the check-box next to ‘I agree to use electronic records and signatures’ before 
clicking ‘CONTINUE’ within the DocuSign system. 
 
By selecting the check-box next to ‘I agree to use electronic records and signatures’, you confirm 
that: 
 
• 
You can access and read this Electronic Record and Signature Disclosure; and 
• 
You can print on paper this Electronic Record and Signature Disclosure, or save or send 
this Electronic Record and Disclosure to a location where you can print it, for future 
reference and access; and 
• 
Until or unless you notify 
 as described above, you consent to receive 
exclusively through electronic means all notices, disclosures, authorizations, 
acknowledgements, and other documents that are required to be provided or made 
available to you by 
 during the course of your relationship with