Clinical trial NCT04239027
Conditions: Neovascular Age Related Macular Degeneration
Keywords: age-related macular degeneration, wetAMD, nAMD, neovascular, choroidal neovascularization, CNV, OCT-angiography
Sponsor: Novartis Pharmaceuticals
Start date: 2021-01-26; Completion date: 2023-02-02
Enrollment: 210 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Neovascular age-related macular degeneration (nAMD) is characterized by the presence of choroidal neovascularization (CNV). Choroidal neovascularization consists of abnormal blood vessels originating from the choroid and can lead to hemorrhage, fluid exudation, and fibrosis, resulting in photoreceptor damage and vision loss.

The safety and efficacy of brolucizumab has been demonstrated in 2 randomized, multicenter, double-masked, active controlled Phase 3 studies in nAMD patients (RTH258-C001 and RTH258-C002). Anatomical changes were evaluated in these studies using spectral domain optical coherence tomography (SD-OCT), which relied on indirect parameters for the diagnosis of active CNV. The OCT-angiography (OCT A) that directly visualize retinal circulation and image CNV and vascular diseases of the retina was not included in previous brolucizumab studies.

This single-arm, open-label, multicenter study was performed to evaluate the efficacy and safety of brolucizumab 6 mg in patients with nAMD.

OCT-A was used in this study to assess the morphological response of patients to brolucizumab in terms of percentage change in CNV lesion area in the short term (i.e. at Week 12) and in the long term (i.e. at Week 48), as well as changes in other OCT-A features up to Week 48.

Detailed description:
This was a prospective, single-arm, open-label, multicenter study to evaluate the efficacy and safety of brolucizumab 6 mg in patients with neovascular age-related macular degeneration (nAMD). Patients were required to attend 6 mandatory study visits: Screening/Baseline Visit (Day 1), Week 4, Week 8, Week 12, Week 16 and Week 48 visits. The timing of the interim visits between Week 16 and Week 48 depended on the patient's injection regimen, i.e. every 12 weeks (q12w) or every 8 weeks (q8w). Patients who consented and met all the inclusion and none of the exclusion criteria were screened to evaluate eligibility. After confirmation of eligibility, patients were included and treated with brolucizumab 6 mg. The maximum study duration for 1 patient was 48 weeks, including Screening. There were 2 periods in this study:

* Open-label treatment period: from Screening/Baseline (Day 1) to Week 40/Week 44 (depending on assigned regimen)
* Follow-up period: Week 40/Week 44 to Week 48

A Safety Review Committee (SRC) was established for this study to provide an independent, systematic, standardized and unbiased assessment of the review of intraocular inflammation (IOI), retinal vasculitis (RV) and/or retinal vascular occlusion (RO).

Arms: arm 1: This is a single-arm study in which all patients will be treated with brolucizumab 6mg: 3 loading injections (at Screening/Baseline, Week 4 and Week 8), followed by maintenance treatment from Week 16/Week 20 up to Week 40/Week 44.
Interventions: intervention 1: RTH258/Brolucizumab
Intervention descriptions: intervention 1: Brolucizumab is a new generation of anti-VEGF (vascular endothelial growth factor). All patients were treated with brolucizumab 6mg: 3 loading injections (at Screening/Baseline, Week 4 and Week 8), followed by maintenance treatment every 8 weeks (Q8W) or every 12 weeks (Q12W) depending on disease activity from Week 16/Week20 to Week 40/Week 44.

Brolucizumab was administered by an intravitreal (IVT) injection to the study. eye.

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development 
RTH258/Brolucizumab 
Clinical Trial Protocol CRTH258AFR01 / NCT04239027
A one-year, single-arm, open-label, multicenter study 
assessing the anatomic outcomes of brolucizumab 
assessed by OCT-A in adult patients with neovascular 
age-related macular degeneration (OCTOPUS) 
Document type: 
Amended Clinical Trial Protocol 
EUDRACT number: 
2019-003338-17 
Version number: 
04 (clean) 
Clinical trial phase: 
Phase 3b 
Release date: 
16 Nov 2021 
Property of Novartis Pharma A.G. Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 2.0 (01-Aug-2018) 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 8 
Amendment 1 (12-Dec-2019) ............................................................................................ 10 
Amendment 2 (21-Oct-2020) ............................................................................................ 11 
Amendment 3 (14-Sept-2021) ........................................................................................... 13 
Amendment 4 (16-Nov-2021) ........................................................................................... 16 
Protocol summary .............................................................................................................. 18 
 
Introduction ....................................................................................................................... 22 
1.1 
Background ............................................................................................................ 22 
1.2 
Purpose .................................................................................................................. 24 
 
Objectives and endpoints ................................................................................................... 25 
 
Study design ...................................................................................................................... 26 
 
Rationale ............................................................................................................................ 28 
4.1 
Rationale for study design ..................................................................................... 28 
4.1.1 
Rationale for choice of background therapy ......................................... 28 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 29 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 29 
4.4 
Purpose and timing of interim analyses ................................................................. 29 
4.5 
Risks and benefits .................................................................................................. 29 
 
Population .......................................................................................................................... 31 
5.1 
Inclusion criteria .................................................................................................... 31 
5.2 
Exclusion criteria ................................................................................................... 32 
 
Treatment ........................................................................................................................... 34 
6.1 
Study treatment ...................................................................................................... 34 
6.1.1 
Investigational treatment ....................................................................... 34 
6.1.2 
Additional study treatments .................................................................. 34 
6.1.3 
Treatment arms ...................................................................................... 34 
6.1.4 
Treatment duration ................................................................................ 34 
6.2 
Other treatments ..................................................................................................... 35 
6.2.1 
Concomitant therapy ............................................................................. 35 
6.2.2 
Prohibited medication ........................................................................... 36 


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6.2.3 
Rescue medication ................................................................................ 36 
6.3 
Patient numbering, treatment assignment, randomization ..................................... 36 
6.3.1 
Patient numbering ................................................................................. 36 
6.3.2 
Treatment assignment, randomization .................................................. 37 
6.4 
Treatment masking ................................................................................................ 37 
6.5 
Dose escalation and dose modification .................................................................. 37 
6.5.1 
Follow-up for toxicities ......................................................................... 37 
6.6 
Additional treatment guidance ............................................................................... 37 
6.6.1 
Treatment compliance ........................................................................... 37 
6.6.2 
Emergency breaking of assigned treatment code .................................. 37 
6.7 
Preparation and dispensing of study treatment ...................................................... 38 
6.7.1 
Handling of study treatment .................................................................. 38 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 38 
 
Informed consent procedures ............................................................................................ 41 
 
Visit schedule and assessments ......................................................................................... 42 
8.1 
Screening ............................................................................................................... 46 
8.1.1 
Information to be collected on screening failures ................................. 46 
8.2 
Patient demographics/other baseline characteristics ............................................. 46 
8.3 
Efficacy .................................................................................................................. 47 
8.3.1 
Optical coherence tomography ............................................................. 47 
8.3.2 
Color fundus, fundus autofluorescence and fluorescein and 
indocyanine angiography ...................................................................... 48 
8.3.3 
Visual acuity .......................................................................................... 49 
8.3.4 
Appropriateness of efficacy assessments .............................................. 49 
8.4 
Safety ..................................................................................................................... 49 
8.4.1 
Vital sign assessments ........................................................................... 50 
8.4.2 
Pregnancy and assessments of fertility ................................................. 50 
8.4.3 
Ophthalmic examination and imaging .................................................. 50 
8.4.4 
Appropriateness of safety measurements .............................................. 51 
8.5 
Additional assessments .......................................................................................... 52 
 
Study discontinuation and completion .............................................................................. 52 
9.1 
Discontinuation ...................................................................................................... 52 
9.1.1 
Discontinuation of study treatment ....................................................... 52 
9.1.2 
Withdrawal of informed consent ........................................................... 53 
9.1.3 
Lost to follow-up ................................................................................... 54 
9.1.4 
Early study termination by the sponsor ................................................. 54 
9.2 
Study completion and post-study treatment .......................................................... 54 


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 Safety monitoring and reporting ........................................................................................ 54 
10.1 
Definition of adverse events and reporting requirements ...................................... 55 
10.1.1 
Adverse events ...................................................................................... 55 
10.1.2 
Serious adverse events .......................................................................... 56 
10.1.3 
SAE reporting........................................................................................ 58 
10.1.4 
Pregnancy reporting .............................................................................. 58 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 59 
10.1.6 
Adjudication committee ........................................................................ 59 
 Data collection and database management ........................................................................ 59 
11.1 
Data collection ....................................................................................................... 59 
11.2 
Database management and quality control ............................................................ 59 
11.3 
Site monitoring ...................................................................................................... 60 
 Data analysis and statistical methods ................................................................................ 61 
12.1 
Analysis sets .......................................................................................................... 61 
12.2 
Patient demographics and other baseline characteristics ....................................... 61 
12.3 
Treatments ............................................................................................................. 62 
12.4 
Analysis of the primary endpoint .......................................................................... 62 
12.4.1 
Definition of primary endpoint ............................................................. 62 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 62 
12.4.3 
Handling of missing values/censoring/discontinuations ....................... 62 
12.4.4 
Estimand and Sensitivity analyses ........................................................ 63 
12.5 
Analysis of secondary endpoints ........................................................................... 63 
12.5.1 
Efficacy endpoints ................................................................................. 63 
12.5.2 
Safety endpoints .................................................................................... 64 
12.5.3 
Patient reported outcomes ..................................................................... 65 
12.6 
Analysis of exploratory endpoints ......................................................................... 65 
12.7 
Interim analyses ..................................................................................................... 65 
12.8 
Sample size calculation .......................................................................................... 65 
12.8.1 
Primary endpoint ................................................................................... 65 
 Ethical considerations and administrative procedures ...................................................... 66 
13.1 
Regulatory and ethical compliance ........................................................................ 66 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 66 
13.3 
Publication of study protocol and results............................................................... 66 
13.4 
Quality control and quality assurance .................................................................... 67 
 Protocol adherence ............................................................................................................ 67 
14.1 
Protocol amendments ............................................................................................. 67 


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 References ......................................................................................................................... 68 
 Appendices ........................................................................................................................ 69 
 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 25 
Table 6-1 
Investigational drug ............................................................................... 34 
Table 6-2 
Prohibited medication and procedures .................................................. 36 
Table 6-3 
Disease activity assessment and treatment occurrence according to 
visit type ................................................................................................ 40 
Table 8-1 
Assessment schedule for the study eye ................................................. 44 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 59 
Table 12-1 
Confidence intervals for one mean numeric: results for 2-sided 
confidence intervals with unknown standard deviation ........................ 65 
List of figures 
Figure 3-1 
Study design .......................................................................................... 26 
Figure 6-1 
Treatment regimen ................................................................................ 38 
 


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List of abbreviations 
 
AE 
Adverse Event 
AESI 
Adverse event of special interest 
AMD 
Age-related Macular Degeneration 
ATC 
Anatomic Therapeutic Chemical 
BCVA 
Best-Corrected Visual Acuity 
BCNVA 
Best Corrected Near Visual Acuity 
CI 
Confidence Interval(s) 
CFP 
Color Fundus Photography 
CFR 
Code of Federal Regulation 
CMO & PS 
Chief Medical Office & Patient Safety 
CNV 
Choroidal Neovascularization 
COVID-19 
Coronavirus disease 2019 
CRC 
Central Reading Center 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CRT 
Central Retinal Thickness 
CSFT 
Central Sub-Field Thickness 
CSR 
Clinical Study Report 
DA 
Disease Activity 
EDC 
Electronic Data Capture 
EOS 
End of Study 
ETD 
Early Treatment Discontinuation 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
Fluorescein Angiography 
FAF 
Fundus AutoFluorescence 
FAS 
Full Analysis Set  
FIR 
First Interpretable Results 
GCP 
Good Clinical Practice 
IB 
Investigator's Brochure 
ICF 
Informed Consent Form 
ICG 
Indocyanine Green Chorioangiography 
ICH 
International Council for Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IOI 
Intraocular Inflammation 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IRF 
Intraretinal Fluid 
IVT 
Intravitreal 
MedDRA 
Medical Dictionary for Regulatory Activities 


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MMRM 
Mixed Model Repeated Measures 
nAMD 
Neovascular Age-Related Macular Degeneration 
NIH 
National Institutes of Health 
OCT 
Optical Coherence Tomography 
PD 
Protocol Deviation 
PDT 
Photodynamic Therapy 
PED 
Pigment Epithelial Detachment 
PPS 
Per-Protocol Set  
q8w 
Every 8 Weeks  
q12w 
Every 12 Weeks 
QMS 
Quality Management System 
RAP 
Retinal Angiomatous Proliferation 
RO 
Retinal Vascular Occlusion 
RPE 
Retinal Pigmented Epithelium 
RV 
Retinal Vasculitis 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan  
scFV 
Single-Chain Antibody Fragment 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SMQ 
Standardized MedDRA Query 
SOC 
Standard Of Care 
SRF 
Subretinal Fluid 
Sub-RPE 
Sub Retinal Pigmented Epithelium 
SUN 
Standardization Uveitis Nomenclature 
USM 
Urgent Safety Measure 
VEGF 
Vascular Endothelial Growth Factor 
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 patient in a time unit. 
Electronic data 
capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used 
to capture data transcribed from paper source forms used at the point of 
care. 
Enrollment 
Point/time of patient entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the 
protocol) 
Investigational drug 
The study drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug” or “test substance” 
Investigational 
treatment 
All investigational drug(s) whose properties are being tested in the study as 
well as their associated treatment controls. This includes any placebos, any 
active controls, as well as approved drugs used outside of their 
indication/approved dosage or tested in a fixed combination. Investigational 
treatment generally does not include other treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used within approved indication/dosage. 
Masked/evaluating 
investigator 
For the entire study duration and all study patients, the masked/evaluating 
investigator is responsible for all aspects of the study (the 
conduct/supervision of all assessments and treatment decisions except the 
injection procedures and the safety assessment following the study drug 
injections). 
Medication number 
A unique identifier on the label of each study drug package. 
Medication pack 
number 
A unique identifier on the label of each drug package.  
Patient 
An individual with the condition of interest 
Period 
A subdivision of the study timeline; divides phases into smaller functional 
segments such as screening, baseline, etc. 
Premature patient 
withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all study drug administration and assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned. 
Screen failure 
A patient who is screened but is not treated  
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. 
Study completion 
Point/time at which the patient came in for a final evaluation visit or when 
study drug was discontinued whichever is later. 
Study drug 
discontinuation 
Point/time when patient permanently stops taking study drug for any reason; 
may or may not also be the point/time of premature patient withdrawal. 
Study treatment 
Any drug administered to the study participants as part of the required study 
procedures; includes investigational drug (s), control(s) or non-investigational 
medicinal product(s) 


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Study treatment 
discontinuation 
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date 
Patient 
A trial participant (can be a healthy volunteer or a patient) 
Patient number 
A unique number assigned to each patient upon signing the informed 
consent. This number is the definitive, unique identifier for the patient and 
should be used to identify the patient throughout the study for all data 
collected, sample labels, etc. 
Variable 
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study 
Withdrawal of 
consent 
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 (12-Dec-2019) 
 
Rationale 
The purpose of this amendment is to incorporate change which resulted from interactions with 
Ethic Committee, who required to exclude patients mentioned in Articles L.1121-5 to L.1121-
8 and L.1122-1-2 of the Code de Santé Publique (e.g. minors, protected adults, etc.) 
 
Changes to the protocol 
List the modifications implemented in the different sections, 
• Exclusion criteria (page 24) 
 
IECs 
These changes are considered not-substantial. 
The amendment is to be sent to the IECs for final approval. 
These changes have no impact on the ICF. 
 


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Amendment 2 (21-Oct-2020) 
 
Amendment Rationale 
The main purpose of this amendment is to provide clarification and guidance on safety 
assessments in accordance to the urgent safety measure regarding the post-marketing reports 
with brolucizumab (Beovu®) in the treatment of nAMD, which were identified as retinal 
vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular 
inflammation (IOI) that may result in severe vision loss. In addition, the amendment includes 
modifications due to the COVID-19 pandemic. 
Changes to the protocol 
Changes incorporated based on this emerging safety issue are as follows:  
• Section 1.1 (Background): Information was added to describe a new safety signal from 
post-marketing case reports and its impact on the benefit-risk balance. 
• Section 4.5 (Background): Information was added to describe a new safety signal from post-
marketing case reports and its impact on the benefit-risk balance. 
• Section 6.2.1.1 (Permitted concomitant therapy requiring caution and/or action): 
Restrictions in use of corticosteroids have been removed to provide flexibility using 
systemic steroids for the treatment of AEs at the investigator’s discretion. 
• Section 6.7.2 (Instructions for prescribing and taking study treatment): Additional guidance 
was added to this section emphasizing that if any sign of IOI is present, an IVT injection 
must not be performed and patients should be treated for IOI according to clinical practice. 
• Additional examination and assessments were included to fully characterize cases of IOI in 
the following sections: 
o Section 8, Table 8-1 (Assessment schedule for the study eye) 
o Section 8.3.2 (Color fundus , fundus autofluorescence and fluorescein and indocyanine 
angiography) 
o Section 8.4.3 (Ophthalmic examination) 
o Section 8.4.4 (Appropriateness of safety measurements) 
Changes incorporated to address the COVID-19 pandemic are as follows: 
• Section 5.2 (Exclusion criteria): Exclusion criterion no. 16 was updated to add exception in 
case of temporary use for COVID-19 treatment.  
• Section 6.2.2, Table 6-2 (Prohibited medication and procedures): Updated to add exception 
in case of temporary use of COVID-19 treatment.  
• Section 8 (Visit schedule and assessments) and Section 8.4 (Safety): Added instructions to 
follow in case COVID-19 pandemic impacts on study visits.  
• Section 12 (Data analysis) 
Other changes incorporated in this amendment were as follows: 


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• Section 5.1 (Inclusion criteria), Protocol summary (Inclusion criteria), and Section 8.3 
(Efficacy): Inclusion criterion no. 5, and other wording, was updated to clarify ETDRS 
testing occurs at an initial distance of 4 meters. 
• Section 6.7.2 (Instructions for prescribing and taking study treatment): Language regarding 
the injection procedure was added replacing reference to an applicable manual. 
• Section 8 (Visit schedule and assessments): Amended footnote no. 4 to clarify requirements 
for FA images.  And clarification of treatment during unscheduled visit 
• Section 8.4.3 (Ophthalmic examination): Added instructions for the patients in case of 
symptoms of inflammation. 
• Section 10.1.3 (SAE reporting): Clarification of the SAE reporting period. 
• Section 10.1.5, Table 10-1 (Guidance for capturing the study treatment errors including 
misuse/abuse): Amended to clarify that error should not be documented in the AE eCRF.  
• Section 12.1 (Analysis sets): Modified to include importance of estimands per ICH E9(R1) 
guidance. 
• Section 12.8.1 (Primary endpoint) : change of the patient recruitment period (from  Jan 2020 
to Sept 2020 to Jan 2021 to Sept 2021), due to study start delay ; the patient recruitment 
period remain of 9 months 
• Section 15 (References): Added two references. 
Minor editorial changes (e.g. typographical mistakes, grammatical changes, rewording) to 
improve flow and consistency have been made throughout the protocol. 
 
IECs 
These changes are considered substantial. 
The amendment will be sent to the HA/IECs for approval. 
These changes herein impact the ICF. Sites are required to update and submit for approval a 
revised ICF that takes into account the changes described in this protocol amendment. 
 
 


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Amendment 3 (14-Sept-2021) 
 
Amendment Rationale 
The main reason for the protocol amendment is to implement the Urgent Safety Measures 
(USM) described in the 10-Aug-21 Dear Investigator Letter (DIL) into the study protocol.  The 
USM were implemented 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. The protocol is hence amended to require discontinuation of study 
treatment in subjects who develop these events and provide clarification and guidance on the 
early discontinuation of study treatment. 
This amendment also includes information on gender imbalance on IOI following brolucizumab 
treatment. 
The safety sections were updated throughout the protocol including updating the Risks and 
Benefits section and creating a new section under Safety Monitoring to consolidate all the 
information regarding the risk mitigation into one section in the protocol. Additionally, as 
subjects treated with brolucizumab who experience intraocular inflammation may be at risk of 
developing retinal vasculitis and/or retinal vascular occlusion they should be closely monitored 
and the investigator needs to evaluate the appropriateness of continuing further with study 
treatment when IOI only (without RV and/or RO) is present. 
Finally, clarification is provided on record of prior Intraocular or periocular use of 
corticosteroids in the study eye and remove of the study timelines and number of sites 
 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
Editorial changes and spelling corrections are done throughout the protocol. 
Protocol sections changed in relation to urgent safety measures (USM) are: 
• Section 1.1 Background: Language was added to indicate the results of the mechanistic 
study BASICHR0049 of blood samples from nAMD patients exposed to brolucizumab and 
having subsequently developed RV and/or RO were added and that the impact on the 
risk/benefit balance is considered to be low when patients who develop RV and/or RO are 
discontinued from further treatment with brolucizumab.  
• Section 3 Study design: Remove of the number of investigator sites. Clarified the difference 
between study completion as per protocol versus early treatment discontinuation. 
• Section 4.5 Risks and Benefits: Information added to describe Urgent Safety Measures and 
additional information on gender imbalance on IOI following brolucizumab treatment. 
Added the urgent safety measures related to adverse events observed in patients treated with 


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brolucizumab from the MERLIN (CRTH258AUS04) study, the post marketing reports and 
the causal link (results of the mechanistic study BASICHR0049). 
• Section 6.1.4 Treatment duration: Guidance added to clarify that subjects who prematurely 
discontinue from study treatment should continue in the study, and should return 4 weeks 
after last treatment to perform assessments for early treatment discontinuation. 
• Section 6.7.2 Instruction for prescribing and taking study treatment: Text added to clarify 
that patients who require treatment every 4 weeks beyond the loading phase, should be 
discontinued from study treatment. Changes also made to update that if RV and/or RO is 
confirmed, subjects should be discontinued from study treatment. If only IOI (without RV 
and/or RO) is confirmed, the subject should be closely monitored and the investigator 
should evaluate the appropriateness of continuing further with study treatment. This has 
also been updated Table 6-3. 
• Section 8: Visit schedule and assessments: Removed a sentence that two consecutive 
injections should be at least 21 days apart as this is not applicable in the maintenance phase, 
any subject who requires treatment every 4 weeks has to be discontinued from study 
treatment. 
• Table 8-1 Assessment schedule: Columns added for early treatment discontinuation visits 
and for assessment visits after start of standard of care, including respective footnotes. A 
clarification was added in footnote #8 with respect to ophthalmic examinations and images. 
Updated the name of the ophthalmic examination where “and imaging” was added. 
Footnotes #10, #11, and #12 added with respect to ETD and EOS assessments. 
• Section 8.4.5 Ophthalmic examination: Requirement of treatment discontinuation for 
brolucizumab was added if subject developed RV and/or RO. 
• Section 9.1.1 Discontinuation of study treatment: Instructions were added for subjects who 
discontinue from study treatment early.  
• Section 12 Data analysis and statistical methods: Language added to include analysis of 
impact of USM. 
• Section 12.4.4 Sensitivity and supportive analyses: Sensitivity analysis added regarding 
impact of USM. 
Other changes incorporated in this amendment: 
• List of abbreviations: New abbreviations added in line with amendment 3. 
• Protocol summary: Aligned with amendment 3. 
• Section 6.2.1 Concomitant therapy: added instruction to record intraocular or periocular use 
of corticosteroids in the study eye taken up 6 months prior to Screening/Baseline  
• Section 6.2.1.1 Permitted concomitant therapy requiring caution and/or action: Added 
guidance regarding SARS-CoV-2 vaccinations which should occur at least 7 days before or 
after the administration of study treatment. 
• Section 8: Visit schedule and assessments: Clarification that 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. 
• Section 8.4 Safety: Added a reference for monitoring, assessment and management of 
adverse events of inflammation, retinal vasculitis and/or retinal vascular occlusion.  


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• Section 8.4.4 Ophthalmic examination: Added “and imaging” to the header and to the 
related paragraph. 
• Section 10 Safety monitoring and reporting: Consolidated the requirements for monitoring 
of adverse events of special interest that were already included in the previous version. 
Added the new requirement that if RV and/or RO is confirmed, subjects should be 
discontinued from study treatment. If only IOI (without RV and/or RO) is confirmed, the 
subject should be closely monitored and the investigator should evaluate the appropriateness 
of continuing further with study treatment.  
• Section 10.1.3 SAE reporting: Clarified the timing for SAE reporting to Novartis as per 
latest protocol template. 
• Section 12.8.1 Primary endpoints: Clarification regarding sample size analyses. Remove of 
the patient recruitment period duration and of the number of investigator sites 
 
 
IECs 
These changes are considered substantial. 
The amendment will be sent to the IECs and HA for approval. 
These changes have impact on the ICF. 
 
 
 


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Amendment 4 (16-Nov-2021) 
 
Amendment Rationale 
The main reason for the protocol amendment is to revise the sample size calculation. The initial 
sample size calculation for this study was done prior to COVID-19 pandemic and prior to the 
implementation of Urgent Safety Measures (USM). Due to COVID-19 and USMs, the 
originally planned number of patients can not be achieved. Thus, the sample size was re-
assessed. This estimation can be achieved with acceptable precision with a sample size of 210. 
The study objectives will still be assessed with the revised sample size 
 
 
 
 
 
This amendment also includes the Beovu brolucizumab EU SmPC update on ‘Warnings and 
precautions for use’ section, Patients treated with Beovu with a medical history of intraocular 
inflammation and/or retinal vascular occlusion (within 12 months prior to the first 
brolucizumab injection) should be closely monitored, since they are at increased risk of 
developing retinal vasculitis and/or retinal vascular occlusion. Besides, for patients developing 
intraocular inflammation events, even if not associated with retinal vasculitis and/or retinal 
vascular occlusion, treatment with Beovu should be discontinued and the events should be 
promptly managed. 
 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
Editorial changes and spelling corrections are done throughout the protocol. 
Protocol sections changed in relation to the sample size revision are: 
• Protocol summary: Aligned with amendment 4. 
• Section 3 “study design” and Section 5 “Population” : change of number of patients to 
include 
• Section 12.8.1 “Sample size calculation – Primary endpoint” : consideration of new 
estimation with acceptable precision 
 
 
 
 
 
 
 
 


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• 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol sections changed in relation to the Beovu EU SmPC update on ‘Warnings and 
precautions for use’ section are: 
• Protocol summary: Aligned with amendment 4. 
• Section 1.1 ‘Background’ and Section 4.5 ‘Risk and benefits’: add of the new EU SmPC 
wording on intraocular inflammation, including retinal vasculitis and/or retinal vascular 
occlusion 
• Section 5.2 ‘Exclusion criteria”: add of the exclusion criteria “Medical history of intraocular 
inflammation 
and/or 
retinal 
vascular 
occlusion 
within 
12 
months 
prior to 
Screening/Baseline” 
• Section 6.1.4 ‘Treatment duration’: precision that treatment must be discontinued in case of 
any intraocular inflammation event 
• Section 6.7.2 ‘Instruction for prescribing and taking study treatment’ and Section 
‘Ophthalmic examination and imaging’ and Section 9.1.1 ‘Discontinuation of study 
treatment” and Section 10 “Safety monitoring and reporting”: clarification that treatment 
must be discontinued in case of any intraocular inflammation event, even if IOI only. 
 
 
IECs 
These changes are considered substantial. 
The amendment will be sent to the IECs and HA for approval. 
These changes have impact on the ICF. 
 
 
 


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Protocol summary 
 
Protocol number 
CRTH258AFR01 
Full Title 
A one-year, single-arm, open-label, multicenter study assessing the anatomic 
outcomes of brolucizumab assessed by OCT-A in adult patients with 
neovascular age-related macular degeneration 
Brief title 
Study of brolucizumab in adult patients with neovascular age-related macular 
degeneration 
Sponsor and 
Clinical Phase 
Novartis/ Phase 3b 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
This multicenter study of patients with treatment-naïve neovascular age-
related macular degeneration (nAMD) is being performed to assess both short 
and long-term effects of brolucizumab, a new generation of anti-vascular 
endothelial growth factor (anti-VEGF), on choroidal neovascularization (CNV) 
structure and activity. 
The safety and efficacy of brolucizumab has been demonstrated in 
2 randomized, multicenter, double-masked, active controlled Phase 3 studies 
in nAMD patients (RTH258-C001 and RTH258-C002). Anatomical changes 
were evaluated in these studies using spectral domain optical coherence 
tomography (SD-OCT), which relied on indirect parameters for the diagnosis 
of active CNV. Since then, a new angiography tool, OCT-angiography (OCT-A) 
has been developed that allows direct visualization of retinal circulation. OCT-A 
has become an essential, widely used tool for imaging CNV and vascular 
diseases of the retina. The literature suggests OCT-A is a good marker for 
assessing anti-VEGF therapeutic response, especially lesion size that has 
been demonstrated to decrease under anti-VEGF therapy.  
OCT-A will be used in this study to assess the morphological response of 
patients to brolucizumab in terms of percentage change in CNV lesion area in 
the short term (i.e. at Week 12 just after loading doses) and in the long term 
(i.e. at Week 48), as well as changes in other OCT-A features up to Week 48.  
Primary objective 
• 
To evaluate the short-term effect of brolucizumab on CNV lesion area as 
measured by OCT-A in nAMD patients. 
Secondary 
objectives 
• 
To evaluate the long-term effects of brolucizumab on CNV morphology as 
measured by OCT-A in nAMD patients.  
• 
To evaluate the effect of brolucizumab on anatomical parameters as 
assessed by SD-OCT and fluorescein angiography (FA) up to Week 48. 
• 
To evaluate the efficacy of brolucizumab up to Week 48 by assessing 
changes in best-corrected visual acuity (BCVA). 
• 
To estimate the proportion of patients treated at every 12 weeks (q12w) 
frequency with brolucizumab. 
• 
To estimate the predictive value of the first q12w cycle for maintenance of 
q12w treatment with brolucizumab. 
• 
To evaluate the time from last intravitreal (IVT) injection in the initiation 
phase to first visit with no disease activity. 
• 
To evaluate the safety of brolucizumab. 


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Study design 
This is a prospective, single-arm, open-label, multicenter study to evaluate the 
efficacy and safety of brolucizumab 6 mg in patients with nAMD. 
Patients will be required to attend 6 mandatory study visits: Screening/Baseline 
Visit (Day 1), Week 4, Week 8, Week 12, Week 16 and Week 48 visits. The 
timing of the interim visits between Week 16 and Week 48 will depend on the 
patient’s injection regimen, i.e. q12w or every 8 weeks (q8w).  
Patients will receive 3 initial doses every 4 weeks (Day 1, Week 4 and Week 8), 
followed by treatment q12w with the possibility of adjusting to treatment q8w 
based on disease activity. Disease activity will be assessed by visual acuity 
and anatomical parameters at 2 visits (Week 16 and Week 20) during the first 
q12w interval and at each subsequent scheduled q12w visit (at Week 32 and 
Week 44). Patients who show disease activity at any of these visits will be 
adjusted to an q8w treatment regimen and will remain on this regimen until the 
end of the study at Week 48. 
Population 
The study population will be male and female patients ≥ 50 years old diagnosed 
with treatment-naïve active CNV secondary to nAMD and able to comply with 
study or follow-up procedures. 
Key inclusion 
criteria 
• 
Patients must give written informed consent before any study related 
procedures are performed. 
• 
Patients must be 50 years of age or older at Screening/Baseline. 
Study eye: 
• 
Active CNV lesions secondary to AMD that affect the central subfield, 
including retinal angiomatous proliferation (RAP) with a CNV component, 
confirmed by presence of active leakage from CNV seen by fluorescein 
angiography and sequellae of CNV, e.g. pigment epithelial detachment 
(PED), subretinal hemorrhage or sub-retinal pigment epithelium (sub-RPE) 
hemorrhage, blocked fluorescence, macular edema. 
• 
Intra and/or subretinal fluid affecting the central subfield of the study eye 
at Screening/Baseline.  
• 
BCVA between 83 and 23 letters, inclusive, in the study eye at 
Screening/Baseline using early treatment diabetic retinopathy study 
(ETDRS) at an initial testing distance of 4 meters. 
Key exclusion 
criteria 
• 
Any active intraocular or periocular infection or active intraocular 
inflammation 
(e.g. 
infectious 
conjunctivitis, 
keratitis, 
scleritis, 
endophthalmitis, 
infectious 
blepharitis) 
in 
either 
eye 
at 
Screening/Baseline. 
• 
Medical history of intraocular inflammation and/or retinal vascular 
occlusion within 12 months prior to Screening/Baseline 
Study eye: 
• 
Poor quality of OCT-A and SD-OCT images at Screening/Baseline.  
• 
Patient has received any approved or investigational treatment for nAMD 
(other than vitamin supplements) in the study eye at any time. 
• 
Concomitant conditions or ocular disorders in the study eye, including 
retinal diseases other than nAMD, that, in the judgment of the investigator, 
could require medical or surgical intervention during the course of the study 
to prevent or treat visual loss that might result from that condition, or that 
limits the potential to gain visual acuity upon treatment with the 
investigational product. 


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• 
Uncontrolled glaucoma in the study eye defined as intraocular pressure 
(IOP) > 25 mmHg on medication or according to investigator’s judgment at 
Screening/Baseline. 
• 
Stroke or myocardial infarction in the 6-month period prior to 
Screening/Baseline. 
• 
Systemic anti-VEGF therapy at any time. 
• 
Women of childbearing potential, defined as all women less than 1 year 
postmenopausal 
or 
less 
than 
6 
weeks 
since 
sterilization 
at 
Screening/Baseline 
Study treatment 
Brolucizumab 6 mg 120 mg/mL (RTH258 6 mg/ 0.05 mL) solution for injection 
in pre-filled syringe 
Efficacy 
assessments 
• 
OCT-A 
• 
SD-OCT 
• 
Color Fundus Photography (CFP)  
• 
Fundus AutoFluorescence (FAF) 
• 
Fluorescein Angiography (FA) and Indocyanine Green Chorioangiography 
(ICG) (optional) 
• 
BCVA (EDTRS) 
Key safety 
assessments 
• 
Ophthalmology examination and imaging 
• 
Adverse events (AEs) 
• 
Vital signs 
Data analysis 
Primary analysis data set 
The primary data set for efficacy evaluation is the full analysis set (FAS). The 
FAS includes all patients to whom study treatment has been assigned and who 
received at least one IVT injection of study treatment. Supportive and 
sensitivity analyses will be performed which may include using the Per Protocol 
Set (PPS) and alternative methods of handling missing values including a 
mixed model repeated measures (MMRM). 
Primary endpoint 
The primary endpoint is the percentage change from baseline in CNV lesion 
area measured by OCT-A at Week 12. 
Primary statistical method 
Descriptive statistics for the primary endpoint (actual value, change from 
baseline, percentage change from baseline) will be presented based on 
observed data using the FAS. Furthermore a 2-sided 95% confidence interval 
(CI) using Student’s t-distribution will also be provided. 
The interim database lock for the primary analyses will be conducted when the 
last patient included completed Week 12 visit. Subjects will remain in the study 
and will continue to receive treatment through the planned study duration of 48 
weeks, to allow for further evaluation of efficacy and safety. 
 
 
 
Sample size justification 
A sample size of  180 to 400 patients produces a 2-sided 95% CI with a 
distance from the mean difference in percentage change in CNV lesion area 


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measured by OCT-A from baseline to Week 12 to the limits ranging from 5.1 
to 3.4 when the estimated standard deviation is 35. Therefore, to have a 
precision of 5.0%, a sample size of 189 patients will be needed. To take into 
account a dropout rate and uninterpretable images of 10%, a total of 210 
patients will be included.  
Ethical and 
regulatory 
obligations 
The study will be performed in accordance with 
• 
The European Directive 2001/20/EC. 
• 
The European General Data Protection Regulation. 
• 
The ICH Harmonized Tripartite Guidelines for GCP. 
• 
The ethical principles laid down in the Declaration of Helsinki.  
Key words 
Neovascular age-related macular degeneration, anti-VEGF, choroidal 
neovascularization, OCT-A 


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Introduction 
1.1 
Background 
Neovascular age-related macular degeneration (nAMD) is characterized by the presence of 
choroidal neovascularization (CNV). Choroidal neovascularization consists of abnormal blood 
vessels originating from the choroid and can lead to hemorrhage, fluid exudation, and fibrosis, 
resulting in photoreceptor damage and vision loss.   
Vascular endothelial growth factor (VEGF) has been shown to be elevated in patients with 
nAMD and is thought to play a key role in the neovascularization process (Spilsbury et al 2000). 
Anti-vascular endothelial growth factor (anti-VEGF) treatments, such as ranibizumab 
(Lucentis®) and aflibercept (Eylea®) have been demonstrated to improve visual acuity in 
patients with nAMD in multiple clinical trials.  
Brolucizumab is a new generation of anti-VEGF. Brolucizumab is the first humanized 
single-chain antibody fragment (scFv), which inhibits vascular endothelial growth factor A 
(VEGF-A). The safety and efficacy of brolucizumab were assessed in 2 randomized, 
multicenter, double-masked, active treatment-controlled Phase 3 studies in nAMD patients (the 
HAWK study (RTH258-C001 [NCT02307682]) and the HARRIER study (RTH258-C002 
[NCT02434328]) comparing brolucizumab every 12 weeks (q12w) or every 8 weeks (q8w) to 
aflibercept q8w according to its approved label.  
In these studies, patients in both treatment arms received 3 loading doses every 4 weeks (Day 0, 
Week 4 and Week 8), followed by an q12w/q8w maintenance regimen for brolucizumab 6 mg 
arm and an q8w maintenance regimen for the aflibercept 2 mg arm. For the q12w/q8w treatment 
regimen, q12w/q8w treatment frequencies were allocated according to patient’s individual 
treatment need based on disease activity assessments performed by the investigator at 
pre-specified visits. Within the q12w/q8w regimen, the initial treatment schedule after the 
loading phase was q12w. If disease activity was identified by the investigator in 
brolucizumab-treated patients at any of the disease activity assessments, dosing was adjusted to 
q8w (i.e. “q12w/q8w regimen”). Once patients were adjusted to a q8w interval, they stayed on 
that interval until the end of the study (Week 96/Exit). 
Brolucizumab met the primary endpoint of non-inferiority in change in best-corrected visual 
acuity (BCVA) from Baseline to Week 48 vs. aflibercept and achieved pre-specified superior 
anatomic outcomes vs. aflibercept for the following: mean change from Baseline in central sub-
field retinal thickness (CSFT); percentage of patients with intraretinal fluid and/or subretinal 
fluid; percentage of patients with subretinal pigment epithelium (sub-RPE) fluid; and 
percentage of patients with no disease activity. The anatomical changes were evaluated with 
spectral domain-optical coherence tomography (SD-OCT) systems. As SD-OCT is not able to 
define the vascular network of CNV, the diagnosis of active CNV via SD-OCT relies on indirect 
parameters including assessment of the presence of subretinal or intraretinal fluid that is not 
specific to CNV.  
Since the first global marketing authorization approval in the US, in Oct-2019, for the treatment 
of nAMD, adverse events (AEs) of intraocular inflammation (IOI), including retinal vasculitis 
and/or retinal vascular occlusion, that may result in severe vision loss, have been reported from 
post-marketing experience with brolucizumab (Beovu®).  Results of the mechanistic study 


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BASICHR0049 of blood samples from nAMD patients exposed to brolucizumab and having 
subsequently developed Retinal Vasculitis (RV) and/or Retinal Vascular Occlusion (RO), taken 
together with accumulated data of the association of treatment-emergent immunogenicity and 
intraocular inflammation (IOI) indicate a causal link between the treatment-emergent immune 
reaction against brolucizumab and the brolucizumab-related “Intraocular inflammation, 
including retinal vasculitis and/or retinal vascular occlusion”. This finding supports the 
requirement to discontinue treatment with brolucizumab in patients who develop events of 
intraocular inflammation, including RV and/or RO. 
These impacts on the risk/benefit balance of the product are considered to be low and the overall 
risk/benefit assessment remains positive, when patients who develop RV and/or RO are 
discontinued from further treatment with brolucizumab. 
 
A new angiography tool, namely optical coherence tomography-angiography (OCT-A), was 
developed around 2010 to directly visualize retinal circulation (Jia et al 2012). OCT-A is a 
dye-less angiographic procedure based on split-spectrum-decorrelation-amplitude angiography. 
It enables the capture of scattered intra-vessel particles (mainly erythrocyte cells) at all levels 
of the retinal and inner-choroidal vasculature, thus providing 3-D imaging of the retinal 
circulation. OCT-A was not used for the HAWK and HARRIER studies.  
OCT-A has since become an essential and widely used tool, particularly for imaging CNV and 
vascular diseases of the retina (Mastropasqua et al 2015). Follow-up of nAMD by means of 
OCT-A has been widely studied in recent years in the literature, describing OCT-A 
characteristics using both qualitative and quantitative criteria. A recent study (Malamos et al 
2017) showed concordance between the changes demonstrated by B-scan OCT and the 
alterations of CNV flow morphology depicted by OCT-A in nAMD patients treated by anti-
VEGF. Furthermore, several manuscripts have described OCT-A changes after anti-VEGF 
treatment.  
The literature suggests that OCT-A is a good marker for assessing anti-VEGF therapeutic 
response, especially lesion size, which has been demonstrated to decrease under anti-VEGF 
therapy (de Carlo et al 2015, Miere et al 2017). A 75% decrease in mean lesion area (SD: 21%) 
1 month (29.6 days) after anti-VEGF injection in 17 naïve eyes with type 3 nAMD was reported 
in one study (Phasukkijwatana et al 2017). This remarkable response was associated with 
resolution of intraretinal and subretinal fluid on structural OCT in all cases. Similarly, another 
study (Muakkassa et al 2015) in CNV treatment-naïve patients (including patients with nAMD) 
reported a 23.6% mean decrease in greatest linear CNV dimension and 29.8% mean decrease 
in CNV area 4.8 weeks after initiation of a single anti-VEGF treatment.  
Another study (Coscas et al 2015) reported on the response of patients with a mixed type I–II 
CNV to aflibercept therapy, with a reduction of the lesion area by 24% in the type II CNV 
component and by 11.3% in the type I CNV component at Week 12, 4 weeks after the last 
injection of a series of 3-monthly aflibercept injections. The anti-VEGF loading treatment effect 
in nAMD type I, type II and mixed CNV has been demonstrated in another study (Miere et al 
2018) with a significant 65% decrease in CNV lesion area at Month 3, 4 weeks after the last 
loading phase injection in 13 naïve patients treated with anti-VEGF (from 0.66 ± 0.84 mm2 at 


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Baseline to 0.23 ± 0.3 mm2 at Month 3, Wilcoxon signed-rank test). This suggests that CNV 
lesion size might be a marker for assessing therapeutic response.  
The long-term evolution of OCT-A features have been described in another study 
(Miere et al 2017) that reported a 21.6% decrease in CNV lesion area after a mean treatment 
duration of 11.7 months and 7.1 anti-VEGF treatments.  
1.2 
Purpose 
Considering the efficacy and safety findings demonstrated in the pivotal trials of brolucizumab, 
and the literature findings summarized above, this multicenter study of treatment-naïve nAMD 
patients is being performed to assess both early (at Week 12 just after loading phase) and long 
term (48 weeks [12 months]) effects of brolucizumab on CNV structure and activity.   


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Objectives and endpoints 
Table 2-1 
Objectives and related endpoints  
Objectives 
Endpoints 
Primary objectives 
Endpoints for primary objectives 
• 
To evaluate the short-term effect of 
brolucizumab on CNV lesion area as 
measured by OCT-A in nAMD patients. 
• 
Percentage change in CNV lesion area 
measured by OCT-A from Baseline to 
Week 12. 
Secondary objectives 
Endpoints for secondary objectives 
• 
To evaluate the long-term effects of 
brolucizumab on CNV morphology as 
measured by OCT-A in nAMD patients.  
• 
Percentage change in CNV lesion area 
measured by OCT-A from Baseline to 
Week 48. 
• 
Change in OCT-A features assessed by 
qualitative and quantitative criteria from 
Baseline by visit at Week 12 up to Week 
48. 
• 
To evaluate the effect of brolucizumab on 
anatomical parameters as assessed by SD-
OCT and FA from Week 12 up to Week 48. 
• 
Change in SD-OCT and FA features 
assessed by qualitative and quantitative 
criteria (e.g. (CSFT, sub- and/or intraretinal 
fluid, sub-RPE fluid) from Baseline by visit 
up to Week 48.  
• 
To evaluate the efficacy of brolucizumab up to 
Week 48 by assessing changes in BCVA. 
• 
Change in BCVA from Baseline up to 
Week 48. 
• 
To estimate the proportion of patients treated 
at q12w frequency with brolucizumab. 
• 
Proportion of patients who are maintained 
on an exclusive q12w interval following the 
loading phase through to Week 48. 
• 
To estimate the predictive value of the first 
q12w cycle for maintenance of q12w 
treatment with brolucizumab. 
• 
The probability of the first q12w interval for 
determining successful q12w maintenance 
at Week 48. 
• 
To evaluate the time from last IVT injection in 
the initiation phase to first visit with no 
disease activity. 
• 
Time from last IVT injection in the initiation 
phase to first visit with no disease activity.  
• 
To evaluate the safety of brolucizumab. 
• 
Incidence of AEs (serious and non-serious) 
reported in patients treated with 
brolucizumab. 
AEs=adverse events, BCVA=best corrected visual acuity, CNV=choroidal neovascularization, 
CSFT=central sub-field retinal thickness, FA=fluorescein angiography, IVT=intravitreal 
nAMD=neovascular age-related macular degeneration,  
OCT-A=optical coherence tomography-angiography,  
SD-OCT=spectral domain optical coherence tomography,  
sub-RPE=subretinal pigmented epithelium 


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Study design 
This is a prospective, single-arm, open-label, multicenter study to evaluate the efficacy and 
safety of brolucizumab 6 mg in patients with nAMD. 
Patients will be required to attend 6 mandatory study visits: Screening/Baseline Visit (Day 1), 
Week 4, Week 8, Week 12, Week 16 and Week 48 visits. The timing of the interim visits 
between Week 16 and Week 48 will depend on the patient’s injection regimen, i.e. q12w or 
q8w.  
Patients who consent and meet all the inclusion and none of the exclusion criteria will be 
screened to evaluate eligibility. After confirmation of eligibility, patients will be included and 
treated with brolucizumab 6 mg. 
Approximately 210 adult patients will be screened and included (10% drop-out rate and 
uninterpretable images at Baseline and Week 12 are expected) in France. The maximum study 
duration for 1 patient is 48 weeks, including Screening. 
There will be 2 periods in this study (see Figure 3-1): 
• Open-label treatment period: from Screening/Baseline (Day 1) to Week 40/Week 44 
(depending on assigned regimen) 
• Follow-up period: Week 40/Week 44 to Week 48  
Figure 3-1 
Study design 
 
* Week 40 or Week 44 according to treatment schedule 
** End of study visit: 4 or 8 weeks after the last IVT, depending on the last IVT date  
 


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Treatment period: Day 1 to Week 40/Week 44 
The Screening Visit and Baseline Visit (see Table 8-1) are the same visit.    
One time re-assessment of patients is allowed, except for the purpose of capturing new BCVA 
or imaging assessments that previously failed to qualify the patient (except if image quality is 
poor and needs to be redone). As long as testing can be repeated within 14 days of the first 
screening, the other screening assessments do not need to be repeated. If rescreening is to occur 
beyond 14 days from the original Screening Visit date, then all screening procedures must be 
repeated. Medical judgment should be exercised to ensure that treatment of nAMD is not 
withheld in order for a patient to participate in the study. 
After confirmation of eligibility, patients will be included in the study. A study visit schedule 
will be established at the time of Screening/Baseline Visit for all patients. All efforts should be 
made to adhere to the study visit schedule within a ± 7‑day window. For a given protocol visit, 
assessments can be performed on 2 consecutive days, provided both days are within the ± 7‑day 
window. Treatment (including at Screening/Baseline) is intended to be administered on the day 
of the study visit, or if this is not possible, within 3 days after the study visit when the per-
protocol assessments will have taken place. 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.  
The Screening/Baseline Visit is defined as Screening/Baseline/Day 1. For all patients, the last 
potential study treatment will be at the Week 40 visit or at the Week 44 visit depending on 
whether patients receive the study treatment under the q8w or under the q12w schedule. The 
initiation phase starts on Day 1 and ends on Week 8. The q12w/q8w treatment regimen starts 
on Week 16 and ends on either Week 40 or Week 44 (see Section 6.7.2). 
Patients will receive 3 initial doses every 4 weeks (Day 1, Week 4 and Week 8) (loading phase), 
which should be at least 21 days apart, followed by treatment q12w with the possibility of 
adjusting to treatment q8w based on disease activity. Disease activity will be assessed based on 
investigator’s judgment of visual acuity and anatomical parameters as provided in the guidance 
to the investigators, e.g. decrease of visual acuity and/or other signs of the disease (e.g. 
intraretinal fluid (IRF), subretinal fluid (SRF), sub-retinal pigmented epithelium (sub-RPE) 
fluid, retinal hemorrhage, central retinal thickness (CRT) increase, etc.). Disease activity will 
be assessed during the first q12w interval at Week 16. If no disease activity is observed by the 
investigator in the study eye, disease activity will be assessed every 12 weeks (at Week 20, 
Week 32 and Week 44). If disease activity is observed by the investigator in the study eye at 
any of these visits, the study treatment will be adjusted by the investigator to a q8w treatment 
regimen and will remain on this regimen until Week 40/Week 44 (see Section 6.7.2). Patients 
who require study treatment every 4 weeks after the initiation phase will be discontinued from 
further study treatment at the next visit. 
The mandatory study visits during the treatment phase are Day 1, Week 4 and Week 8 
(assessment of CNV lesion evolution during initiation phase), Week 12 (primary endpoint), 
Week 16 (first time to reach disease activity criteria and first possible treatment) and Week 48 
(last efficacy assessment) visits. The timing of the interim visits between Week 16 and Week 48 
will depend on the patient’s injection regimen, i.e. q12w or q8w. No visits are planned between 
the injection visits (see Section 6.7.2). 


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Post-treatment follow-up period: from Week 40/44 to Week 48 
For all patients completing the study as per protocol, the End of Study (EOS) assessment will 
be performed at Week 48, 4 weeks (for patients treated at Week 44) or 8 weeks (for patients 
treated at Week 40) (± 7 days) following their last possible study treatment administration. 
Patients withdrawn from the study prior to study completion will be asked to return for an 
EOS/Early Discontinuation Visit, 4 weeks (± 7 days) following their last study treatment 
administration. For early treatment discontinuations (ETD) refer to Section 9.1.1. 
 
Rationale 
4.1 
Rationale for study design 
This multicenter study of treatment-naïve nAMD patients is being performed to assess both 
early (at Week 12 just after loading phase) and long term (48 weeks) effects of brolucizumab, 
a new generation anti-VEGF treatment, on CNV structure and activity.  
The safety and efficacy of brolucizumab has been demonstrated in 2 randomized, multicenter, 
double-masked, active controlled Phase 3 studies in nAMD patients (RTH258-C001 and 
RTH258-C002) up to 96 weeks as described in Section 1.1. Anatomical changes were evaluated 
in these studies using SD-OCT, which relied on indirect parameters for the diagnosis of active 
CNV. Since then, a new angiography tool, OCT-A has been developed that allows direct 
visualization of retinal circulation. 
OCT-A is a dye-less angiographic procedure based on split-spectrum-decorrelation-amplitude 
angiography that has become an essential and widely used tool, particularly for imaging CNV 
and vascular diseases of the retina. The literature suggests that OCT-A is a good marker for 
assessing anti-VEGF therapeutic response, especially the lesion size that has been demonstrated 
to decrease under anti-VEGF therapy.  
OCT-A will be used in this study to assess the morphological response of patients to 
brolucizumab in terms of percentage change in CNV lesion area in the short term (i.e. at 
Week 12 just after loading doses) and in the long term (i.e. at Week 48 [12 months]), as well as 
changes in other OCT-A features up to Week 48.  
The primary endpoint is the percentage change in CNV lesion area measured by OCT-A from 
Baseline to Week 12. The Week 12 time point has been selected as peak efficacy has been 
demonstrated in the pivotal trials of brolucizumab for this time point.  
The CNV lesion area percentage reduction measured by OCT-A from Baseline to Week 48, and 
change in OCT-A features from Baseline by visit at Week 12 up to Week 48, will be assessed 
as secondary endpoints. This will allow the long-term effects of brolucizumab on CNV 
morphology to be assessed.  
4.1.1 
Rationale for choice of background therapy 
Not applicable.  


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4.2 
Rationale for dose/regimen and duration of treatment 
The dose and regimen for brolucizumab is based on the following considerations: 
x Brolucizumab is well tolerated at a dose of 6 mg administered 3 times every 4 weeks during 
the loading phase, based on the previous pivotal registration clinical phase 3 program in 
which 1088 patients with nAMD received brolucizumab (
). The q12w/q8w treatment regimen used in the present study is the same as the 
 and 
 studies (see Section 1.1). 
x 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 assessment of disease activity. 
x The route of administration is an intravitreal (IVT) injection as for all anti-VEGF treatments 
currently approved for the treatment of nAMD. 
x Prefilled syringes (PFS) have been selected for administration of study treatment in this 
study, as this form will be the one commercialized in France.  
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Not applicable.  
4.4 
Purpose and timing of interim analyses 
The primary analysis will be conducted when all ongoing patients have completed their 
Week 12 visit. An interim analysis will be performed when the last included patient completed 
Week 12 visit.  
Patients will remain in the study and will continue to receive treatment for the maximum 
planned duration of treatment of 40 to 44 weeks in accordance with the designated treatment 
regimen to allow for further evaluation of efficacy and safety. 
4.5 
Risks and benefits 
In a comprehensive Phase 3 program (see Section 1.1), consisting of 2 large, randomized, 
double-masked, multicenter, studies (RTH258-C001 and RTH258-C002) treatment with 
brolucizumab resulted in robust visual gains and superior anatomical outcomes compared to 
aflibercept, with the majority of patients maintained on an q12w dosing interval at 48 weeks, 
and the remainder maintained on an q8w dosing interval. Anatomical benefits and vision gains 
were maintained for 2 years. 
The RTH258-C001 and RTH258-C002 studies successfully evaluated a novel treatment 
regimen, combining the prolonged duration of effect of brolucizumab with treatment frequency 
guided by disease activity. Reflecting clinical practice, investigators assessed disease activity 
using both visual function and anatomical disease parameters (e.g. retinal thickness and retinal 
fluid). Robust clinically meaningful results were observed for both functional and anatomical 
outcomes in a representative nAMD population over 48 weeks and sustained up to 96 weeks.  
PPD
PPD
PPD


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These benefits were consistent across subgroups (e.g. age, gender, race, Baseline visual acuity, 
Baseline retinal thickness, lesion type, lesion size, fluid status), replicated in 2 independent 
Phase 3 studies. Less than half of patients were identified with disease activity after the loading 
phase and most disease activity with adjustment of dosing interval was identified during the 
initial q12w interval; the vast majority of patients without disease activity during the initial 
q12w interval continued to be maintained on an q12w treatment interval for the remainder of 
the treatment period indicating the benefit of early treatment monitoring in maintaining long-
term efficacy. These results thus addressed the unmet medical need of delivering efficacy 
comparable to standard of care, while reducing the treatment and monitoring burden. 
Sustained visual acuity is a key validation for the q12w/q8w regimen, as it relates to the unmet 
medical need of maintaining patients’ long-term vision. 
The overall safety and tolerability profile of brolucizumab was consistent with aflibercept, an 
established therapy in patients with nAMD. While there was a higher incidence of intraocular 
inflammation (IOI) AEs for brolucizumab compared to aflibercept, no preferred term (PT) was 
reported for more than 1.5% of patients. Over 90% of IOI AEs were mild to moderate in severity 
and 79% resolved with no sequelae. The impact of IOI on the benefit-risk balance of 
brolucizumab is considered to be low. 
Adverse events (AEs) of Intraocular inflammation, including retinal vasculitis and/or retinal 
vascular occlusion have occurred since the Oct-2019 marketing authorization approval for 
brolucizumab (Beovu®) in the treatment of nAMD. These AEs may result in severe vision loss. 
Results of the mechanistic study BASICHR0049 of blood samples from nAMD patients 
exposed to brolucizumab and having subsequently developed Retinal Vasculitis (RV) and/or 
Retinal Vascular Occlusion (RO) taken together with accumulated data of the association of 
treatment-emergent immunogenicity and intraocular inflammation (IOI) indicate a causal link 
between the treatment-emergent immune reaction against brolucizumab and the brolucizumab-
related “Intraocular inflammation, including retinal vasculitis and/or retinal vascular occlusion”. 
This finding supports the requirement to discontinue treatment with brolucizumab in patients 
who develop events of Intraocular inflammation, including RV and/or RO. 
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). 
In addition, based on USM (CRTH258AUS04 FIR), the brolucizumab dosing interval should 
not be less than 8 weeks beyond the loading period, that is not allowed in the present study 
protocol. 
Intravitreal injections, including those with brolucizumab, have been associated with 
endophthalmitis and retinal detachment. The injection procedure must be carried out under 
aseptic conditions. Patients should be instructed to report any symptoms suggestive of the 
above-mentioned events without delay. 
Transient and sustained increases in intraocular pressure (IOP) have been seen with 
brolucizumab, similar to those observed with IVT administration of other VEGF inhibitors. 
Both IOP and perfusion of the optic nerve head must be monitored and managed appropriately. 


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Brolucizumab must not be administered in case of hypersensitivity to the active substance or to 
any of the excipients, active or suspected ocular or periocular infection, or active intraocular 
inflammation (IOI). 
Appropriate eligibility criteria are included in this protocol. The risk to patients in this trial may 
be minimized by compliance with the eligibility criteria and study procedures, as well as close 
clinical monitoring described in Section 6.7.2, Section 8.4.4 and Section 10. 
Women of child bearing potential will be excluded. 
Sexually active males 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. If there is any 
question that the patient will not reliably comply, they should not be entered or continue in the 
study. 
In conclusion, the benefit-risk balance of brolucizumab 6 mg, when treatment interval is not 
less than every 8 weeks after the first 3 monthly initial doses (loading phase) is positive, and 
comparable to aflibercept (an established therapy in nAMD) in the treatment of patients with 
nAMD. 
 
Population 
The study population will be male and female patients ≥ 50 years old diagnosed with treatment-
naïve active CNV secondary to nAMD and able to comply with study or follow-up procedures. 
Approximately 210 adult patients will be screened and included (10% dropout rate and 
uninterpretable images at Baseline and Week 12 expected) in France.  
If both eyes are eligible as per the inclusion and exclusion criteria described below, the eye with 
the worse BCVA at Screening should be selected as the study eye, unless the investigator deems 
it more appropriate to select the eye with better BCVA, based on medical reasons or local ethical 
requirements. If both eyes have the same BCVA, then it is recommended to select the right eye 
as the study eye. 
5.1 
Inclusion criteria 
Patients eligible for inclusion in this study must meet all of the following criteria: 
1. Patients must provide written informed consent before any study related procedures are 
performed. 
2. Patients must be 50 years of age or older at Screening/Baseline. 
Study eye: 
3. Active CNV lesions secondary to AMD that affect the central subfield, including retinal 
angiomatous proliferation (RAP) with a CNV component, confirmed by presence of active 
leakage from CNV seen by fluorescein angiography and sequellae of CNV, e.g. pigment 
epithelial detachment (PED), subretinal hemorrhage or sub-retinal pigment epithelium (sub-
RPE) hemorrhage, blocked fluorescence, macular edema. 


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4. Intra- and/or subretinal fluid affecting the central subfield of the study eye at 
Screening/Baseline.  
5. BCVA between 83 and 23 letters, inclusive, in the study eye at Screening/Baseline using 
early treatment diabetic retinopathy study (ETDRS) at an initial testing distance of 4 meters. 
5.2 
Exclusion criteria 
Patients meeting any of the following criteria are not eligible for inclusion in this study. 
Ocular conditions 
1. Any active intraocular or periocular infection or active intraocular inflammation (e.g. 
infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis) in 
either eye at Screening/Baseline. 
2. Presence of amblyopia, amaurosis or ocular disorders in the fellow eye with BCVA 
< 35 ETDRS letters at Screening (except when due to conditions whose surgery may 
improve visual acuity, e.g. cataract). 
3. Medical history of intraocular inflammation and/or retinal vascular occlusion within 12 
months prior to Screening/Baseline 
Study eye 
4. Poor quality of OCT-A and SD-OCT images at Screening/Baseline.  
5. Atrophy or fibrosis involving the center of the fovea in the study eye, as assessed by color 
fundus photography and fundus autofluorescence (FAF) at Screening/Baseline. 
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/Baseline. 
7. Concomitant conditions or ocular disorders in the study eye, including retinal diseases other 
than nAMD, that, in the judgment of the investigator, could require medical or surgical 
intervention during the course of the study to prevent or treat visual loss that might result 
from that condition, or that limits the potential to gain visual acuity upon treatment with the 
investigational product. 
8. 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. 
9. Current vitreous hemorrhage or history of vitreous hemorrhage in the study eye within 
4 weeks prior to Screening/Baseline. 
10. Uncontrolled glaucoma in the study eye defined as IOP > 25 mmHg on medication or 
according to the investigator’s judgment at Screening/Baseline. 
11. Aphakia and/or absence of the posterior capsule in the study eye at Screening/Baseline. 
Ocular treatments (study eye) 
12. Patient has received any approved or investigational treatment for nAMD (other than 
vitamin supplements) in the study eye at any time. 
13. Intraocular or periocular use of corticosteroids in the study eye during the 6-month period 
prior to Screening/Baseline. 


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14. Previous penetrating keratoplasty or vitrectomy at any time prior to Screening/Baseline. 
15. History or evidence of the following in the study eye within the 90-day period prior to 
Screening/Baseline: 
• Intraocular or refractive surgery. 
• Previous panretinal photocoagulation. 
• Previous submacular surgery, other surgical intervention or laser treatment for nAMD 
including photodynamic therapy (PDT). 
Systemic conditions or treatments 
16. End stage renal disease requiring dialysis or renal transplant. 
17. 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 Screening/Baseline except temporary use for COVID-19 
treatment. 
18. Participation in an investigational drug, biologic, or device study within 30 days or the 
duration of 5 half-lives of the investigational product (whichever is longer) prior to 
Screening/Baseline. Note: observational clinical studies solely involving over-the-counter 
vitamins, supplements, or diets are not exclusionary. 
19. Systemic anti-VEGF therapy at any time. 
20. Stroke or myocardial infarction in the 6-month period prior to Screening/Baseline. 
21. Uncontrolled blood pressure defined as a systolic value ≥ 160 mmHg or diastolic value 
≥ 100 mmHg at Screening/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). 
22. History of a medical condition (disease, metabolic dysfunction with exception of type 1 or 
2 diabetes mellitus, physical examination finding, or clinical laboratory finding) that, in the 
judgment of the investigator, would preclude scheduled study visits, completion of the study, 
or a safe administration of investigational product. 
23. 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. 
24. History of hypersensitivity to any component of the test article, control article, or clinically 
relevant sensitivity to fluorescein dye, as assessed by the investigator. 
Other 
25. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive human 
chorionic gonadotropin (hCG) pregnancy test. 
26. Women of childbearing potential, defined as all women less than 1 year postmenopausal or 
less than 6 weeks since sterilization at Screening/Baseline 
Women are considered post-menopausal and not of childbearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before 


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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 childbearing potential. 
27. Patients mentioned in Articles L.1121-5 to L.1121-8 and L.1122-1-2 of the Code de Santé 
Publique (e.g. minors, protected adults, etc.) 
 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational treatment 
Study treatment characteristics are presented in Table 6-1.  
Table 6-1 
Investigational drug 
Investigational 
Drug 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Supplier  
Brolucizumab 
6 mg (RTH258 
6 mg/ 0.05 mL ) 
Solution for 
injection 
Intravitreal use 
Pre-filled syringe 
Novartis 
Brolucizumab will be provided in a single use, sterile PFS containing sufficient brolucizumab 
to deliver a 6 mg dose when administering a volume of 0.05 mL 
The content of the study drug PFS must not be split. 
Novartis will ensure sufficient supplies of brolucizumab for treatment use to allow for 
completion of the study. 
6.1.2 
Additional study treatments 
No other treatment beyond the investigational drug is included in this trial. 
6.1.3 
Treatment arms 
This is a single-arm study in which all patients will be treated with:  
• Brolucizumab 6 mg: 3 loading injections (at Screening/Baseline, Week 4 and Week 8), 
followed by maintenance treatment from Week 16/Week 20 up to Week 40/Week 44. 
6.1.4 
Treatment duration 
The maximum planned duration of treatment for each patient is 40 to 44 weeks in accordance 
with the designated treatment regimen. Discontinuation of study treatment for a patient occurs 
when study treatment is stopped earlier than the protocol planned duration and can be initiated 
by either the patient or the investigator. 
After the initiation phase (Week 8), study treatment will be discontinued for patients who 
require injections every 4 weeks.  
If intraocular inflammation, including retinal vasculitis, and/or retinal vascular occlusion, is 
confirmed, patients must be discontinued from study treatment.  


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Patients who prematurely discontinue study treatment for any reason, except for withdrawal of 
consent, should continue in the study. Patients should return 4 weeks after last study treatment 
to perform the assessments for early treatment discontinuation (ETD). Please refer to Table 8-
1. 
6.2 
Other treatments 
6.2.1 
Concomitant therapy 
Prior medication, i.e. any medication taken up to 90 days prior to Screening/Baseline, must be 
recorded on the appropriate electronic case report forms (eCRFs). Intraocular or periocular use 
of corticosteroids in the study eye taken up 6 months prior to Screening/Baseline must be 
recorded. 
The investigator must instruct the patient to notify the study site about any new medications the 
patient takes after enrollment in the study. All medications, procedures and significant non-drug 
therapies (including physical therapy and blood transfusions) administered after the patient was 
enrolled into the study must be recorded on the appropriate eCRFs. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medications. If in doubt the investigator should contact the Novartis medical monitor before 
enrolling a patient or allowing a new medication to be started. If the patient is already enrolled, 
Novartis should be contacted to determine if the patient 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 nAMD and other diseases in the fellow eye are permitted at any time and must be recorded 
in the appropriate eCRF page. Treatment of the fellow eye must be scheduled in a way so as 
not to disturb the schedule for visits and treatments in the study eye. The fellow eye must be 
monitored according to routine practice and adverse events (AEs) captured in the eCRF. 
Administration of topical ocular corticosteroids in the study eye is allowed during the study. 
Corticosteroids administered via intra-nasal, inhaled, intra-articular or non-extensive dermal 
route (< 20% total body surface area) are also permitted during the study.  For other routes of 
corticosteroid administration, refer to Section 6.2.2. 
If cataract surgery is necessary, it should be scheduled ≥ 7 days after the most recent study 
treatment, if possible. Study treatment may be resumed ≥ 14 days after cataract surgery, 
assuming an absence of surgically-related complications. 
If yttrium aluminum garnet (YAG) laser is necessary, it should be performed ≥ 7 days prior to 
the scheduled study visit. 
Ideally, while adhering to the visit schedule specified in the protocol, study drug should be 
administered at least 7 days before or after SARS-CoV-2 vaccinations. This will allow to 
separate potential drug-drug interactions and side effects caused by vaccination. This 7-day 
time window would also be recommended for the first study treatment at the Baseline visit. 


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6.2.2 
Prohibited medication 
Use of the treatments displayed in the below table are not allowed after Screening/Baseline. 
Table 6-2 
Prohibited medication and procedures 
Medication/Procedure 
Prohibition period 
Action taken 
Study eye 
  
  
Any periocular injection or intraocular 
administration of corticosteroids (except if 
needed as short term treatment of AE) 
Anytime  
Discontinue study treatment 
(except if for treatment of AE) 
Anti-VEGF therapy other than assigned 
study medication 
Anytime 
Discontinue study treatment  
Panretinal laser, PDT laser, or focal laser 
photocoagulation with involvement of the 
macular area  
Anytime 
Discontinue study treatment 
Any investigational drug, biologic or device 
Anytime 
Discontinue study treatment 
Systemic 
  
  
Anti-VEGF treatment 
Anytime 
Discontinue study treatment 
Any investigational drug, biologic or device 
Anytime 
Discontinue study treatment 
Medications known to be toxic to the lens, 
retina or optic nerve, including ethambutol, 
chloroquine, hydroxychloroquine, 
deferoxamine, phenothiazines and 
tamoxifen (except temporary use for 
COVID-19 treatment) 
Anytime 
Discontinue study treatment 
PDT: photodynamic therapy 
In the fellow eye, treatment with investigational product (drug, biologic or device) is prohibited. 
Any marketed medication used to treat the fellow eye should be recorded in the appropriate 
eCRF page. 
6.2.3 
Rescue medication 
There will be no rescue medication for nAMD in the study eye. 
In case of lack of efficacy with the investigational drug for nAMD and if the investigator deems 
it is in the best interest of the patient to receive prohibited treatment (Section 6.2.2) in the study 
eye, the investigator should follow the instructions for study treatment discontinuation or study 
discontinuation provided in Section 9.   
6.3 
Patient numbering, treatment assignment, randomization 
6.3.1 
Patient numbering 
Each patient is identified in the study by a Patient Number (Patient No.) that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Patient No. consists of the Center 
Number (4 digit number for Center No. as assigned by Novartis to the investigative site) with a 
sequential patient number suffixed to it (3 digit number for Patient No.), so that each patient is 
numbered uniquely across the entire database. Upon signing the informed consent form (ICF), 


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the patient is assigned to the next sequential Patient No. available in the electronic data capture 
(EDC) system. 
Patients who have been screen failures but are rescreened (see Section 8.1) will be assigned a 
new Patient No.  
6.3.2 
Treatment assignment, randomization 
No randomization will be performed in this study. The assignment of patients to treatment will 
be coordinated by Novartis.  
6.4 
Treatment masking 
Treatment will be open to patients, investigator staff, persons performing the assessments, the 
Clinical Trial Team, and the Central Reading Center (CRC).  
6.5 
Dose escalation and dose modification 
In this study, brolucizumab 6 mg (0.05 mL) will be administered by IVT injection every 
4 weeks (monthly) for the first 3 doses. Thereafter, brolucizumab is administered every 
12 weeks (3 months). The investigator can individualize treatment intervals based on disease 
activity as assessed by visual acuity and/or anatomical parameters so that the treatment interval 
can be as frequent as every 8 weeks (2 months). Patients needing the q8w treatment regimen 
will remain on this regimen until the end of the treatment at Week 40/Week 44. 
No study treatment dose modification is allowed and no deviation to the allowed dose intervals 
(in accordance with disease activity assessments) is allowed. 
Interruption of study treatment is allowed if warranted by an AE or cataract surgery 
(Section 6.2.1.1). 
6.5.1 
Follow-up for toxicities 
Not applicable. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
The date and time of all study treatment injections administered during the study and any 
deviations from the protocol treatment schedule will be captured by the study personnel or by 
the field monitor on the appropriate study treatment dispensing form. 
Exposure to the study treatment will be based on the number of injections administered. 
Compliance with the study treatment will be assessed by the field monitor at each visit using 
PFS counts and information provided by the pharmacist or study personnel. 
6.6.2 
Emergency breaking of assigned treatment code 
Not applicable as this is a single-arm, open-label study. 


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6.7 
Preparation and dispensing of study treatment 
Each study site will be supplied with study drug in packaging as described under the 
investigational drugs section (Section 6.1.1). 
A unique medication number is printed on the study medication label. The study medication 
has a 2-part label (base plus tear-off label); immediately before dispensing the package to the 
patient, site personnel will detach the outer part of the label from the package and affix it to the 
patient’s source document. The number must be written into the eCRF. 
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 secure location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the Investigator’s Brochure (IB). Clinical supplies are 
to be dispensed only in accordance with the protocol. Technical complaints are to be reported 
to the respective Novartis CO Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements. They 
will include storage conditions for the study treatment but no information about the patient 
except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be 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 
There will be 2 treatment phases (see Figure 6-1). 
Figure 6-1 
Treatment regimen 
 


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* The end of treatment will occur at either Week 40 or Week 44 according to the treatment schedule.  
DA=disease activity, IVT=intravitreal, Q8=every 8 weeks, Q12=every 12 weeks, W=week, OCT= optical 
coherence tomography  
Initiation phase 
In the initiation phase, treatment with brolucizumab 6 mg will initially be injected 3 times at 
4-week intervals, at Screening/Baseline/Day 1, Week 4 and Week 8. Following the loading 
doses, each patient will be injected q12w or q8w up to Week 40 or Week 44 (according the 
treatment regimen). 
During the initiation phase, disease activity will be assessed at Day 1, Week 4 and Week 8. 
q12w/q8w treatment phase 
The mandatory visit at Week 12 will be performed to evaluate the primary endpoint of the study. 
No treatment will be administered at Week 12; the next visit will take place at Week 16. Disease 
activity will be assessed at Week 12 for endpoint assessment purposes. 
The q12w/q8w treatment phase starts at Week 16 and is defined as follows: 
• Following Week 8, treatment intervals will be either 8 weeks or 12 weeks. A patient must 
be discontinued from further study treatment if treatment is required more frequently, i.e., 
every 4 weeks. 
• The first assessment of disease activity during this phase will be performed at the Week 16 
visit by the investigator. 
• Based on investigator’s judgment of visual and/or anatomic outcomes, the treatment can be 
adjusted by the investigator to a q8w treatment regimen if there is disease activity as 


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provided in the guidance to the investigators, e.g. decrease of visual acuity and/or other 
signs of the disease (e.g. IRF, SRF, sub-RPE fluid, retinal hemorrhage, CRT increase, etc.). 
• The disease activity assessment is performed at each subsequent visit by the investigator. 
• If disease activity is identified, the patient will be reassigned to receive injections q8w 
thereafter up to Week 40/Week 44. 
• Regardless of treatment administration, Week 16 and Week 48 visits are mandatory.  
• The timing of the interim visits between Week 16 and Week 48 will depend on the patient’s 
injection regimen, i.e. q12w or q8w.  
• No visits are planned between the injection visits. 
• The last potential study treatment may be administered at the Week 40 visit or at the 
Week 44 visit according to the patient’s treatment regimen.  
• A disease activity assessment will also be performed at the Week 48/EOS visit; however, 
no study treatment will be administered. 
The different types of visits occurring through the study are summarized in Table 6-3 with a 
description of when disease activity assessment and treatment take place. 
Table 6-3 
Disease activity assessment and treatment occurrence according to 
visit type 
Type 
Study Period or Phase 
Disease Activity 
Assessment 
Treatment 
Screening / Baseline (Day 1) visit 
Initiation phase 
Yes 
Yes 
Week 4 visit 
Initiation phase 
Yes 
Yes 
Week 8 visit 
Initiation phase 
Yes 
Yes 
Week 12 visit 
Primary endpoint 
Yes 
No 
Week 16 visit 
Q12w / q8w phase 
Yes 
Yes, according 
to disease 
activity 
assessment 
Treatment visits (interim visits 
between Week 20 and Week 48 
where treatment is administered) 
Q12w / q8w phase 
Yes 
Yes 
ETD visit and EOS visit (Week 48) 
Follow-up 
Yes 
No 
 
Brolucizumab should be administered in the study eye on the day of the study visit or, if this is 
not possible, within 3 days after the occurrence of the study visit or no later than within the visit 
window (± 7 days) as described in Section 3 and Section 8. When assessments and treatments 
take place on the same day, treatment must occur after completion of the efficacy assessments 
described in Section 8.3 and pre-injection safety measures (tonometry, slit lamp and fundus 
examinations) described in Section 8.4.3. If study visit assessments and the corresponding 
treatment occur on separate days, a repeat safety 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. Injections are 
contraindicated in patients with active intraocular or periocular infections and in patients with 


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active IOI; therefore, the investigators must verify that these conditions are not present in the 
study eye prior to every injection. Any AEs must be recorded in the eCRF.  
If any signs of IOI are present, then an IVT injection must not be performed. Additional 
ophthalmic examination and imaging should be performed to evaluate IOI (see Section 8.4.3). 
If intraocular inflammation, including retinal vasculitis, and/or retinal vascular occlusion, is 
confirmed, subjects should be discontinued from study treatment.  
The injection procedure for brolucizumab including aseptic and antimicrobial requirements, 
will be performed according to local clinical practice. Injections will be administered by the 
investigator.  
Every effort should be made to ensure that the patient adheres to the visit/treatment schedule. 
Disease activity criteria 
Disease activity criteria will be assessed by the investigator based on whether nAMD is still 
active or has been re-activated. Guidance for the investigator are as follows (disease is active if 
at least one of the following criteria is observed by the investigator):  
• BCVA decrease ≥ 5 letters from the best value since Baseline due to disease activity.  
• Any significant increase in CRT (based on investigator assessment). 
• Retinal hemorrhage. 
• Intraretinal fluid or SRF due to disease activity (degenerative cysts allowed). 
• Increase of sub-RPE fluid. 
These criteria are for guidance only, the investigator may define disease activity based on 
his/her own assessment.  
Anatomic parameters measured by OCT-A and by SD-OCT will be analyzed by a CRC. The 
main aim of the CRC analysis is to confirm anatomic features from OCT-A and SD-OCT 
images for the primary endpoint. The CRC will have no involvement in assessment of disease 
activity, which is solely the investigator’s responsibility.  
A patient who misses Week 16 will undergo the disease activity assessment at Week 20 as 
he/she would have done if the visit had not been missed. If, however, a patient misses any of 
the following disease activity assessment visits (Week 20, Week 32) then the patient will be 
assumed to have met the disease activity criterion at the missed visit and will be reassigned to 
an q8w regimen up to study exit.  
If a patient misses Week 12, then the Week 8 values will be applied as the reference for disease 
activity assessments up to and including Week 44.  
 
Informed consent procedures 
Eligible patients may only be included in the study after providing (witnessed, where required 
by law or regulation), Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-
approved informed consent. 
If applicable, in cases where the patient’s representative(s) gives consent (if allowed according 
to local requirements), the patient must be informed about the study to the extent possible given 


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his/her understanding. If the patient 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 
documented in the patient source documents. 
Novartis will provide to investigators in a separate document a proposed ICF that complies with 
the International Council on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) 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 by Novartis before submission to the 
IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the patient informed consent and should 
be discussed with the patient during the study as needed. Any new information regarding the 
safety profile of the investigational drug that is identified between IB updates will be 
communicated as appropriate, for example, via an investigator notification or an aggregate 
safety finding. As new information becomes available, informed consent to be updated and then 
must be discussed with the subject. 
Male patients must be informed that if a female partner becomes pregnant while he is enrolled 
in the study, contact with the female partner will be attempted to request her consent to collect 
pregnancy outcome information. 
A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval. 
 
Visit schedule and assessments 
The Assessment Schedule for the study eye (Table 8-1) lists all of the assessments when they 
are performed. All data obtained from these assessments must be supported in the patient’s 
source documentation. All data requested by eCRF must be entered in a timely manner (see 
Section 11.1). 
A planned study visit schedule will be established at Screening/Baseline/Day 1 for all patients. 
All post-Baseline and/or subsequent scheduled visits will be calculated based on the 
Screening/Baseline/Day 1 visit date. During the q12w/q8w phase, from Week 16 to Week 44, 
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 should the patient be unable to return per the 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 medication (brolucizumab).  
Assessments can be performed on 2 consecutive days in which both days must occur within the 
± 7 days visit window. 


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Treatment is intended to be administered on the day of the study visit, or if this is not possible, 
within 3 days after the study visit at which the per-protocol assessments took place. 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. For all visits, efficacy assessments (Section 8.3) and safety assessments 
(Section 8.4) should be performed prior to any administration of study treatment. 
Missed or rescheduled visits should not lead to automatic discontinuation.  
If the COVID-19 pandemic limits or prevents on-site study visits, study treatment should 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 
patients’ 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. 
Patients who prematurely discontinue study treatment for any reason should return for the EOS 
visit assessments as scheduled in Table 8-1, except for patients who withdraw their consent 
from the study and do not wish to do so (refer to Section 9.1.2). 


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Table 8-1 
Assessment schedule for the study eye 
Period 
Treatment Period 
Follow-up 
 
Initiation Phase 
q12w/q8w Phase 
 
 
Visit 
Screening/Baseline1  
 
 
 
 
Interim 
Visits2 
EOT‡ 
EOS 10 
ETD 11 
M 12 
 
Day 1 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Every 8 or 
12 weeks 
according 
to 
treatment 
regimen 
Week 
40/ 
Week 
44 
Week 48 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
  
  
  
  
 
 
  
  
Demography 
X 
 
 
 
 
 
 
 
 
Medical 
history/current 
medical conditions 
X 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior/concomitant 
medications 
(including surgery 
and procedures) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BCVA score 
(ETDRS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IOP 
X 
 
 
 
 
 
 
X 
 
Ophthalmic 
examination and 
imaging 3,8 
X 
X 
X 
X 
X 
X 
X 
X 
 
SD-OCT8 
X 
X 
X 
X 
X 
X 
X 
X 
 
OCT-A8 
X 
X 
X 
X 
X 
X 
X 
X 
 
CFP8 
 X 
  
  
X 
  
 
 
X 
 
FAF 
X 
 
 
X 
 
 
 
X 
 
FA8 
X 4 
  
  
X 
  
 
 
 
 
ICG 5,8 
X 
 
 
X 
 
 
 
 
 
Disease activity 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug IVT 
injection 7 
X 
X 
X 
 
X6 
X6 
X6 
 
 
Telephone follow-up 
post injection 9 
X after 1st injection 
 
 
 
 
 
 
 
 
Note: Mandatory study visits are highlighted in grey.  
Abbreviations: BCVA=best-corrected visual acuity, CFP=color fundus photography, EOS=end of study, 
ETDRS=early treatment diabetic retinopathy study, FA=fluorescein angiography, FAF=fundus 
autofluorescence, ICG=indocyanine green chorioangiography, IVT=intravitreal, OCT=optical coherence 
tomography 


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‡ The end of treatment will occur at either Week 40 or Week 44 according to the treatment schedule.  
1 The Screening/Baseline visit are performed on the same Visit.     
2 The number of weeks between visits will vary depending on the disease stability and length of intervals 
between injections as determined by disease activity assessment.  
3 Include slit lamp examination and fundus examination 
4 If FA has been made as required by the protocol during the 15 days prior to screening, FA does not 
need to be repeated on Screening/Baseline visit. In this case, FA image needs to be collected and 
reviewed by the CRC. 
5 ICG is optional at the discretion of the investigator. ICG should be performed at week 12 if it has been 
performed at Screening/Baseline. 
6 Treatment according to investigator decision based on disease activity assessment.  
7 Intraocular pressure (IOP) will be assessed in the study eye, pre-dose and post-dose at every injection. 
The same method of tonometry has to be used through the whole study. Close monitoring of IOP should 
be performed by the investigator for any non-transient elevation in IOP (≥ 25 mmHg). Intravitreal injection 
is not recommended unless normalization of the IOP has been achieved. Post-dose IOP should be 
assessed within 60 minutes after injection and if ≥ 25 mmHg, assessment should be repeated until back 
to normal. Monitoring of the optic nerve head perfusion after injection may be appropriate, at the 
discretion of the investigator. Results of these procedures will be recorded as appropriate in the source 
documents and if the findings constitute an AE, it should be recorded in the eCRF. 
8 Additional ophthalmic examinations and images will be performed in case of any signs of intraocular 
inflammation (IOI), retinal vasculitis, and/or retinal vascular occlusion. 
9 A telephone follow-up on safety should be performed one week after the first injection (a window for 
the phone call is +7 days). From the second injection onwards, similar phone calls should be made at 
investigator’s discretion per local practice. 
10 The week 48 EOS assessments only apply to patients who completed the study per protocol. The 
assessments are not required for patients who have undergone ETD assessments and continued in the 
study without study treatment. 
11 ETD: Early treatment discontinuation applies to patients who discontinue early from study treatment 
and continue in the study. The assessments should be performed 4 weeks after the last injection of 
study drug. This can occur at any time point. 
12 For patients who continue in the study after ETD and up to Week 48 (end of study) while patient is on 
standard of care. Additional safety assessments and imaging can also be performed if required, as per 
investigators discretion. In addition, after ETD, subjects are not required to attend the mandatory visits 
at Week 12 and Week 48 The last visit should be at week 48. This can occur at any time point. 
 
Assessments in the fellow eye 
The following assessments will be performed for the fellow eye: 
• At Screening : BCVA, ophthalmic examination, IOP, SD-OCT, CFP, FAF and FA (and 
optional ICG). 
• At Week 48: BCVA, ophthalmic examination, IOP, SD-OCT, CFP and FAF. 
The fellow eye will be examined only at Screening/Baseline and Week 48/EOS 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. 
All data obtained from these assessments must be supported in the patient’s source 
documentation.  
Only best corrected near visual acuity (BCNVA) for the study eye will be analyzed. It is not 
requested for the purpose of this study to do any self-assessment measure of the fellow eye. 


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Unscheduled visits 
If a patient returns to the site prior to his/her next scheduled study visit, the investigator will 
capture the unscheduled visit in the eCRF only in the case of a clinically significant abnormal 
finding. 
If this finding leads to an AE and/or the decision to treat the patient prior to his/her next 
scheduled treatment, all the procedures listed for the Interim Visit need to be conducted and 
captured in the eCRF. 
In the case of a treatment decision for nAMD treatment is made during the unscheduled visit 
(at the exception of AE treatment), the assigned study medication can not be administrated. In 
case of administration of an anti-VEGF medication during an unscheduled visit, it will be 
considered as the use of a prohibited treatment and should be managed as described in Section 
9.1.1. 
8.1 
Screening 
The Screening Visit and Baseline Visit (see Table 8-1) are the same Visit.     
For the purpose of Screening/Baseline, FA images from a previous routine evaluation may be 
used as long as the FA was performed within 15 days of the Screening/Baseline Visit. 
One time re-assessment of patients is allowed, except for the purpose of capturing new BCVA 
assessments that previously failed to qualify the patient (except if the image quality is poor and 
needs to be redone). As long as testing can be repeated within 14 days of the first screening, the 
other screening assessments do not need to be repeated (see Table 8-1). If rescreening is to 
occur beyond 14 days from the original screening visit date, then the patient must be re-
consented and all Screening/Baseline procedures must be repeated. Medical judgment should 
be exercised to ensure that treatment of nAMD is not withheld in order for a patient to 
participate in the study. 
Patients must have confirmed nAMD at Screening/Baseline.  
8.1.1 
Information to be collected on screening failures 
Patients who sign an ICF and who are 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, inclusion/exclusion and disposition eCRF 
pages must also be completed for screen failure patients. No other data will be entered into the 
clinical database for patients who are screen failures, unless the patient experienced a SAE 
during the Screening Phase (see Section 10.1.2 for reporting details). Adverse events that are 
not SAEs will be followed by the investigator and collected only in the source data.  
Patients who sign an ICF and are considered eligible but fail to be started on treatment for any 
reason will be considered an early terminator. The reason for early termination should be 
captured on the appropriate disposition eCRF.  
8.2 
Patient demographics/other baseline characteristics 
The following information will be collected/documented at the Screening/Baseline Visit for 
each enrolled patient: 


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• Age 
• Sex 
• Vital signs 
• Study eye 
• BCVA 
• CNV characteristics (assessed via SD-OCT, OCT-A, CFP and FA, and optional ICG) 
• Intraocular pressure 
• Ophthalmic examinations (fundus examination and slit lamp examination) 
• Retinal imaging (assessed via SD-OCT, OCT-A, CFP, FAF, and FA) 
• Concomitant medications (including surgery and procedures) 
• Medical history and current medical conditions 
Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF whenever, in their judgment, the test abnormality occurred prior to the informed consent 
signature. 
8.3 
Efficacy 
The following assessments will be performed to evaluate the effect of brolucizumab on retinal 
structure, vascular leakage, and visual function: 
• Anatomical retinal evaluation of OCT-A and SD-OCT images 
• CFP 
• FAF 
• Vascular evaluation by FA (and optionally by ICG)  
• BCVA with ETDRS-like charts at an initial testing distance of 4 meters  
All efficacy assessments should be performed prior to any administration of study treatment 
and/or rescue medication. 
8.3.1 
Optical coherence tomography 
Optical coherence tomography angiography (OCT-A) images will be obtained and assessed 
in the study eye at the visits indicated in the visit assessment schedule (Table 8-1). OCT-A will 
be used to identify or confirm the presence of CNV and its evolution. 
OCT-A will be performed using a 3 x 3 and a 6 x 6 scanning area.  
Spectral domain optical coherence tomography (SD-OCT) images will be obtained and 
assessed in the study eye at the visits indicated in the visit assessment schedule (Table 8-1). 
Only SD-OCT machines can be used (i.e. no time-domain nor swept-source OCT). 
Central sub-field thickness (CSFT) will be measured by SD-OCT. The CSFT evaluated in this 
study represents the average retinal thickness of the circular area within 1 mm diameter around 
the foveal center. 
For disease activity assessment, both OCT-A and SD-OCT assessments will be performed 
after BCVA assessment and prior to any study drug administration. The investigator will 


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evaluate the OCT-A and SD-OCT images to assess the status of disease stability. The OCT-A 
and SD-OCT machines used for an individual patient should not change for the duration of the 
study. 
The investigator will evaluate the images according to their standard of clinical practice and 
may use any of the OCT-A and SD-OCT imaging findings to inform his/her decision for 
treatment.  
A CRC will be used in this study only for the study endpoint assessment. The CRC will not be 
in charge of eligibility assessments or disease activity assessments, which will be evaluated 
only by the investigator. 
The CRC will read OCT-A and SD-OCT at all Visits: Screening / Baseline, Week 4, Week 8, 
Week 12, Week 16, at all Interim Visits and Week 48.  
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 validated by the CRC as specified in the Study Manual. All OCT-A and 
SD-OCT images will be obtained by trained site personnel at the study sites. All OCT-A and 
SD-OCT images will be forwarded to the CRC for independent standardized analysis. All 
OCT-A and SD-OCT images will also be forwarded to Novartis or designated Contract 
Research Organization (CRO) for storage. 
For eligibility assessments, the Screening/Baseline Visit will be used at the investigator’s 
discretion. For the primary and secondary endpoints of anatomical change analysis, images read 
by the CRC for Screening/Baseline and the identified follow-up time points will be referenced.  
The CRC will create a database with the agreed variables as indicated in the CRC grading 
charter (a separate document) and will transfer the data from this database to Novartis for 
analysis. The CRC data will be used for the evaluation of the objectives having OCT-A and 
SD-OCT parameters to ensure a standardized evaluation. For further procedural details, the 
investigator should refer to the applicable manual provided by the CRC. 
8.3.2 
Color fundus, fundus autofluorescence and fluorescein and 
indocyanine angiography 
Color fundus photography (CFP), fundus autofluorescence (FAF) and fluorescein 
angiography (FA) will be performed in the study eye at the visits indicated in the visit 
assessment schedule (Table 8-1). CFP, FAF and FA may be performed at other visits at the 
investigator’s discretion but they are not mandatory for the study.  
For the purpose of Screening/Baseline, FA images from a previous routine evaluation may be 
used as long as FA was performed within 15 days of the Screening/Baseline Visit. 
An ICG could be performed at Screening/Baseline at the investigator discretion. ICG should be 
performed at week 12 if it has been performed at Screening/Baseline. 
In case of premature discontinuation from the study, there is no need to repeat the CFP and FAF 
if there was a CFP and FAF performed within the previous 12 weeks, except if there is 
significant disease worsening, in the opinion of the investigator. 


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CFP and FAF assessments will not be reviewed by the CRC, the investigator will evaluate the 
images according to their standard of clinical practice.  
FA and ICG assessments at Screening / Baseline and Week 12 will be reviewed by the CRC. 
The CRC will provide sites with a Study Manual and training materials for the specified study 
ocular images. All FA and ICG images will be forwarded to the CRC for independent 
standardized analysis and will also be forwarded to Novartis or designated CRO for storage. 
Additional images will be taken in case of any signs of IOI. OCT, color fundus photography, 
FA and indocyanine green chorioangiography (preferably wide-field or with peripheral sweeps) 
should be performed for safety evaluation as described in Section 8.4.3. 
8.3.3 
Visual acuity 
Visual acuity will be assessed in the study eye at the visits indicated in the visit assessment 
schedule as described in Table 8-1 using best correction determined from protocol refraction 
(via BCVA). BCVA of the fellow eye will be assessed at Screening/Baseline and at 
Week 48/EOS Visit. BCVA measurements will be taken in a sitting position using ETDRS-like 
visual acuity testing charts at an initial testing distance of 4 meters.  
8.3.4 
Appropriateness of efficacy assessments 
The use of SD-OCT images to analyze anatomical changes are standard assessments in this 
indication, and were used in the pivotal trials of brolucizumab in patients with nAMD. 
Since the pivotal trials were performed, a new angiography tool, OCT-A, has become an 
essential and widely used tool for imaging CNV and vascular diseases of the retina. It will 
therefore be used in this study to analyze anatomical changes in patients with nAMD as 
described in Section 4.1. The literature suggests that OCT-A is a good marker for assessing 
anti-VEGF therapeutic response, especially lesion size that has been shown to decrease under 
anti-VEGF therapy.  
CFP and FAF are used to inspect retinal pathology. 
FA is also an established procedure that helps to classify the type of lesion and is used to assess 
vascular leakage. ICG will be an optional procedure at the discretion of the investigator. 
BCVA is used as a standard measure of retinal function in this indication. 
8.4 
Safety 
Safety assessments will include vital signs, and ophthalmic examinations 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 monitoring, assessment and management of adverse events of inflammation, 
retinal vasculitis and/or retinal vascular occlusion, refer to Section 10. For details on AE 
collection and reporting, refer to Section 10.1.  
If the COVID-19 pandemic limits or prevents on-site study visits, study treatment should not 
be administered and other study assessments may not be performed. Alternative methods of 


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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 
Vital sign assessments 
Vital signs include assessment of sitting blood pressure (systolic and diastolic pressure in 
mmHg) and pulse rate (beats per minute) and will be collected at the visits indicated in the visit 
assessment schedule (Table 8-1). In case there is an elevated blood pressure measurement as 
specified in the exclusion criteria, at the Screening/Baseline visits, the blood pressure 
measurement should be repeated after 20 minutes. If the repeat measurement is elevated as 
specified in the exclusion criteria, then the patient is not eligible to be enrolled into the study. 
On days when study treatment is administered, vital signs will be measured before 
administration of study medication. The results will be recorded in the eCRF. 
8.4.2 
Pregnancy and assessments of fertility 
All women of childbearing potential, defined as all women less than 1 year postmenopausal or 
less than 6 weeks since sterilization at Screening/Baseline, are excluded from this study. No 
pregnancy test is needed. Subsequent medical documentation must be retained as source 
documents to confirm that the woman is not of childbearing potential. 
Male patients must be informed that if a female partner becomes pregnant while he is enrolled 
in the study, contact with the female partner will be attempted to request her consent to collect 
pregnancy outcome information. 
8.4.3 
Ophthalmic examination and imaging 
The ophthalmic exam will consist of the following: 
• Intraocular pressure (IOP) will be assessed in the study eye, pre-dose and post-dose at 
listed scheduled visit. The same method of tonometry has to be used through the whole 
study. IOP will be captured on eCRF only at Screening/Baseline and Week48/EOS, or in 
case of AE. In the fellow eye, IOP will be assessed at Screening/Baseline and Week 48 / 
EOS. The pre-dose values recorded in mmHg for either eye will be entered into the eCRF. 
Treatment and close monitoring of IOP should be performed by the investigator for any 
non-transient elevation in IOP (≥ 25 mmHg). Intravitreal injection is not recommended 
unless normalization of the IOP has been achieved. Post-dose IOP should be assessed within 
60 minutes after injection and if ≥ 25 mmHg, assessment should be repeated until back to 
normal. Monitoring of the optic nerve head perfusion after injection may be done. Results 
of these procedures will be recorded as appropriate in the source documents and if the 
findings constitute an AE, it should be recorded in the eCRF. 
• Anterior biomicroscopy (slit lamp examination) will be completed at every (scheduled 
and unscheduled) visit to examine the anterior segment structures (e.g. eyelids/lashes, 
conjunctiva, cornea, anterior chamber, iris, lens and anterior part of the vitreous) of the 
study eye. The fellow eye will be examined at screening/baseline and at the discretion of 
the investigator. The results of the examination of either eye must be recorded in the source 
documents. Slit lamp examination must be carefully performed before each study treatment. 


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If there are any signs of IOI, severity of anterior chamber cells and flare should be assessed 
according to the standardization uveitis nomenclature (SUN) working group grading system 
(Jabs et al 2005). The test results will be recorded in the source documents (e.g. ophthalmic 
examination tool) and captured in the appropriate eCRF as applicable. 
• Posterior segment (indirect fundus) examination will be conducted by the investigator at 
the Screening/Baseline Visit for both eyes. An examination of the peripheral retina must 
also be conducted to ensure that the IVT injection can safely be performed. Posterior 
segment examination must be performed carefully before each study treatment. The results 
of the examination including any abnormalities (e.g. vitreous cells/haze, retinal 
tear/detachment, hemorrhage and vascular occlusion, vasculitis, etc.) should be recorded in 
the source documents. If there are any signs of IOI, vitreous cells and haze should be 
assessed using National Institutes of Health (NIH) grading system (Nussenblatt et al 1985). 
The outcome of the examination will be documented in the source document (e.g. 
ophthalmic examination tool) and appropriate eCRF page as applicable. 
• The fundus examination and FAF will be performed at the ophthalmic exam visits indicated 
in the visit assessment schedule (Table 8-1) for the study eye only. Except for 
Screening/Baseline visit and Week 48/EOS Visit, the fellow eye will be examined at the 
discretion of the investigator. The results of the examination of either eye must be recorded 
in the source documents. 
Pupil dilation for slit lamp examination and indirect ophthalmoscopy is optional according to 
investigator practice.  
Clinically significant abnormal findings (as judged by the investigator) from the slit lamp or 
ophthalmoscopy observations should be recorded as an AE in the eCRF. 
A phone call one week after the first injection (a window for the phone call is +7 days) must be 
made to check whether there are any changes in vision or any symptoms of intraocular 
inflammation. It should be documented in the source document. From the second injection 
onwards, similar phone calls should be made at investigator’s discretion per local practice. 
Instruct the patient to contact the site for any changes in vision or any symptoms of 
inflammation between scheduled visits. Every effort should be made to bring the subject for 
immediate examination.  
Imaging : When IOI, retinal vasculitis, and/or retinal Vascular occlusion (RO) is present or 
suspected during a visit, investigators must perform thorough ophthalmic examination, and will 
conduct OCT, fluorescein angiography, indocyanine green chorioangiography and color fundus 
photography (preferably wide-field or with peripheral sweeps). These additional assessments 
will be documented in the source and appropriate eCRF pages as applicable. The images are 
requested to be uploaded onto the CRC portal. 
If subject develops intraocular inflammation, including retinal vasculitis and/or retinal vascular 
occlusion, based on the investigator’s evaluation, the study treatment of brolucizumab must be 
discontinued.  
8.4.4 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population. If there are 
any signs of IOI, additional assessments will be performed as described in Section 8.4.3. 


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8.5 
Additional assessments 
Not applicable 
 
Study discontinuation and completion 
9.1 
Discontinuation 
9.1.1 
Discontinuation of study treatment 
Discontinuation of study treatment for a patient occurs when study treatment is stopped earlier 
than the protocol planned duration, and can be initiated by either the patient or the investigator. 
The investigator must discontinue study treatment for a given patient if he/she believes that 
continuation would negatively impact the patient’s well-being. 
The investigator and/or referring physician will recommend the appropriate follow-up medical 
care, if needed, for all patients who are prematurely withdrawn from the study. 
Study treatment must be discontinued under the following circumstances:  
• Patient requires treatment on a q4w interval after the initiation phase, i.e., after the three 
monthly injections at Baseline, Week 4, and Week 8, followed by the first interval extension 
• Patient develops intraocular inflammation, including retinal vasculitis and/or retinal 
vascular occlusion  
• Patient/guardian decision 
• Pregnancy 
• Use of prohibited treatment  
• Any situation in which study participation might result in a safety risk to the patient 
If premature discontinuation of study treatment occurs, the following should be done as 
appropriate: 
• The investigator should make a reasonable effort to understand and document the primary 
reason for the patient’s premature discontinuation of study treatment using the appropriate 
eCRF page. 
• Patients who prematurely discontinue study treatment for any reason should return 4 weeks 
after last study treatment to perform the assessments for early treatment discontinuation 
(ETD). Please refer to Table 8-1, except for patients who withdraw their consent from the 
study and do not wish to do so (refer to Section 9.1.2). 
• After these assessments are performed, patient can be switched to standard of care (SOC) 
anti-VEGF IVT as per investigators discretion. IVT injection is contraindicated in patients 
with active intraocular or periocular infections and in patients with active intraocular 
inflammation; therefore, the investigators must verify that these conditions are not present 
in the study eye prior to every injection.  
• After premature study treatment discontinuation, at a minimum till week 48, in abbreviated 
visits, the following data should be collected at clinic visits or via telephone/email contact:  
• New/concomitant treatments 


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• Adverse events/Serious Adverse Events  
• BCVA  
Additional safety assessments and imaging can be performed if required, as per 
investigator’s discretion. 
Dosing of SOC and follow-up visits as per investigators discretion. Patients are not required 
to attend the mandatory visits at Week 16 and Week 48. 
• Patients 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, patients should return for the EOS visit assessments to be performed 
as scheduled in Table 8-1. EOS visit assessments on Table 8-1 do not need to be repeated 
at week 48 for patients on standard of care as they would have been performed as ETD 
assessment prior to standard of care switch.  
• If a patient fails to return for study visits without stating an intention to discontinue or 
withdraw, the investigator must show “due diligence” by documenting in the source 
documents steps taken to contact the patient, e.g. dates of telephone calls, registered letters, 
etc. A patient should not be considered as lost to follow-up until due diligence has been 
completed (see Section 9.1.3). If the patient cannot or is unwilling to attend any visit(s), the 
site staff should maintain regular telephone contact with the patient, or with a person pre-
designated by the patient. This telephone contact should preferably be done according to 
the study visit schedule. 
9.1.1.1 
Replacement policy 
Patients who started treatment but prematurely discontinued treatment and/or study will not be 
replaced. 
9.1.2 
Withdrawal of informed consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient: 
• Does not want to participate in the study anymore, and 
• Does not allow further collection of personal data. 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the patient’s decision to withdraw his/her consent and 
record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
assessment table (Table 8-1).  
Novartis will continue to keep and use collected study information. according to applicable law. 


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9.1.3 
Lost to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show “due diligence” by 
documenting in the source documents steps taken to contact the patient, e.g. dates of telephone 
calls, registered letters, etc.  
A patient should not be considered as lost to follow-up until due diligence has been completed.  
9.1.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. Reasons for early termination may include:  
• Unexpected, significant, or unacceptable safety risk to patients enrolled in the study 
• Discontinuation of study drug development 
• Practical reasons, including slow enrollment 
• Regulatory or medical reasons 
In taking the decision to terminate, Novartis will always consider patient welfare and safety. 
Should early termination be necessary, patients must be seen as soon as possible and treated as 
a prematurely withdrawn patient. The investigator may be informed of additional procedures to 
be followed in order to ensure that adequate consideration is given to the protection of the 
patient’s interests. The investigator 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 patient finishes their EOS/Early Withdrawal Visit, 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the investigator, or in the event of an early study termination decision, the date 
of that decision. 
After study completion, the patient may receive standard of care or other treatments, at the 
discretion of the investigator and/or referring physician, if needed. 
 
Safety monitoring and reporting 
Patients should be closely monitored for adverse events.  
For adverse events of special interest, intraocular inflammation, including retinal vasculitis 
and/or retinal vascular occlusion please ensure compliance with the following: 
• Instruct the patient to contact the site for any changes in vision or any symptoms of 
Intraocular inflammation, including retinal vasculitis and/or retinal vascular occlusion, 
between scheduled visits (refer to the optional patient brochure). Every effort should be 
made to bring the subject for immediate examination.  
• Close patient monitoring and thorough examination of the eye should be done to detect 
potential signs of inflammation (Section 8.4.4). 
• When IOI, retinal vasculitis, and/or retinal vascular occlusion is present or suspected during 
a visit, investigators must perform thorough ophthalmic examination, and will conduct OCT, 


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fluorescein angiography and color fundus photography (preferably wide-field or with 
peripheral sweeps). The images are requested to be uploaded onto the CRC portal. 
• If any signs of intraocular inflammation is present, an IVT injection must not be performed. 
Therefore investigators must verify that these conditions are not present in the study eye 
prior to every injection.  
• If Intraocular inflammation, including retinal vasculitis and/or retinal vascular occlusion, is 
confirmed, patients should be discontinued from study treatment.  
• Patients should be treated for these events promptly according to clinical practice. 
For additional information related to safety assessments refer to Section 6.7.2 and Section 8.4.4 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An AE is any untoward medical occurrence (e.g. any unfavorable and unintended sign, 
symptom or disease) in a patient 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 patient and 
identifying AEs. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of AEs must be sought by non-directive questioning of the patient at each visit 
during the study. AEs may also be detected when they are volunteered by the patient during or 
between visits or through physical examination findings, or other assessments. 
AEs must be recorded in the Adverse Events eCRF under the signs, symptoms or diagnosis 
associated with them, accompanied by the following information (as far as possible) (if the 
event is serious refer to Section 10.1.2): 
1. The severity grade (mild, moderate or severe as defined below)  
• 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 and 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 to study treatment will usually be ‘Not suspected’. 
The rationale for this guidance is that the symptoms of a lack of efficacy or progression of 
underlying illness are not caused by the trial drug, they happen in spite of its administration 
and/or both lack of efficacy and progression of underlying disease can only be evaluated 
meaningfully by an analysis of treatment arms, not on a single patient. 
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not recovered/not 
resolved must be reported. 


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4. Whether it constitutes a SAE (see for definition of SAE) and which seriousness criteria have 
been met. 
5. Action taken with the study treatment. All AEs must be treated appropriately. Treatment 
may include one or more of the following: 
• No action taken (e.g. Further observation only) 
• Investigational treatment interrupted/withdrawn 
• Concomitant medication or non-drug therapy given 
• Patient hospitalized/patient's hospitalization prolonged (see Section 10.1.2 for 
definition of SAE) 
6. Its outcome: 
• Not recovered/not resolved 
• Recovered/resolved 
• Recovered/resolved with sequelae 
• Fatal or unknown. 
7. Its location (ocular event / non ocular event) 
Conditions that were already present at the time of informed consent should be recorded in the 
medical history of the patient. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued until 30 days (safety follow-up) after the last 
administration of study treatment (see “Post-treatment follow-up period” in Section 3). 
Once an AE 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 IB. 
Abnormal test results constitute AEs only if they fulfill at least one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal 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 patients with the underlying disease. 
Investigators have the responsibility for managing the safety of individual patients and 
identifying AEs.  
10.1.2 
Serious adverse events 
An SAE is defined as any AE (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 


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• Life-threatening 
• Life-threatening in the context of a SAE refers to a reaction in which the patient was at 
risk of death at the time of the reaction; it does not refer to a reaction that hypothetically 
might have caused death if it were more severe (please refer to the ICH-E2D 
Guidelines). 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• Routine treatment or monitoring of the study 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 patient’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 patient 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 patient 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). 
In this study, nAMD recurrences and their clinical manifestations are exempt from reporting. 
Patient treatment is based on disease activity, which is assessed and recorded throughout the 
study in the eCRF. Moreover, nAMD is a progressive disease while its treatment is a non-
continuous drug administration so disease activity might mean that a patient needs more 
frequent dosing rather than lack of efficacy.     
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event (SAE) irrespective if a clinical event has occurred. 


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10.1.3 
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until the last study visit or 30 days after the last administration 
of study treatment whichever is later must be reported to Novartis safety immediately, without 
undue delay, under no circumstances later than within 24 hours of learning of its occurrence. 
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the study treatment, a Chief Medical Office & Patient Safety (CMO & 
PS) Department associate may urgently require further information from the investigator for 
health authority reporting. Novartis may need to issue an investigator notification (IN) to inform 
all investigators involved in any study with the same study treatment that this SAE has been 
reported. 
Suspected unexpected serious adverse reactions (SUSARs) will be collected and submitted to 
the Competent Authorities and relevant Ethics Committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements. 
Any SAE occurring after the patient has provided informed consent and until the last study visit 
or 30 days after the last administration of study treatment whichever is later will be reported.  
Any SAEs experienced after the above mentioned period should only be reported to Novartis 
Safety if the investigator suspects a causal relationship to study treatment. 
10.1.4 
Pregnancy reporting 
Women of childbearing potential are excluded from this study. 
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence (female participants only). 
The pregnancy (for female participants) should be followed up to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded and reported by the investigator to the Novartis CMO & PS 
Department. Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to brolucizumab (investigational) with any pregnancy 
outcome. 
Any SAE experienced during pregnancy must be reported.  


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10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (European Medicines Agency definition). 
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the dose administration record in the eCRF and in the Dispensing Log at the study site, 
irrespective of whether or not associated with an AE/SAE and reported to Safety only if 
associated with an SAE. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dose 
Administration (DAR) 
eCRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes (only date and 
time of injection) 
No 
Only if associated with 
an SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections (Section 10.1.1, Section 10.1.2 and Section 10.1.3). 
10.1.6 
Adjudication committee 
Not applicable. 
 
Data collection and database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the eCRFs. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
Code of Federal Regulations (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 patient data for archiving at 
the investigative site. 
All data must be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
11.2 
Database management and quality control 
Novartis (or designated CRO) personnel will review the data entered by investigative staff for 
completeness and accuracy. Electronic data queries stating the nature of the problem and 


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requesting clarification will be created for discrepancies and missing values and sent to the 
investigative 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 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Ocular images will be handled as described in Section 8.3.1 and Section 8.3.2. The Data 
management staff will review data received from the CRC. Data Review will be done for data 
structure and data completeness / accuracy as defined in Vendor Data Transfer Specifications. 
The occurrence of relevant PDs will be determined at Week 12 before the interim database lock 
for the primary analysis and at the conclusion of the study. Once all the necessary actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked. 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/ 
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 
employs several methods of ensuring protocol and GCP compliance and the quality/integrity of 
the sites’ data. The field monitor will visit the site to check the completeness of patient records, 
the accuracy of data capture / data entry, the adherence to the protocol and to GCP, the progress 
of enrollment, and to ensure that study treatment is being stored, dispensed, and accounted for 
according to specifications. Key study personnel must be available to assist the field monitor 
during these visits. Continuous remote monitoring of each site’s data may be performed by a 
centralized Novartis/ designated CRO. Additionally, a central analytics organization may 
analyze data & identify risks & trends for site operational parameters, and provide reports to 
Novartis clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, retinal images (CFP, FAF, FA, ICG, OCT-A, SD-OCT), and the results of any 
other tests or assessments. All information on eCRFs must be traceable to these source 
documents in the patient’s file. The investigator must also keep the original ICF signed by the 
patient (a signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be 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 
patients will be disclosed. 


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Data analysis and statistical methods 
The primary efficacy and safety analysis will be based on the Week 12 data, i.e. data up to and 
including Week 12. This analysis will be performed once all patients have completed their 
Week 12 visit or prematurely discontinued the study before/on their Week 12 visit, while 
patients will continue to receive study treatment until their Week 40/Week 44 visit, dependent 
on their treatment regimen. The analysis of the data after the EOS/Week 48 visit will be 
performed once all patients have completed or prematurely discontinued the study. 
The data will be analyzed by Novartis and/or a designated CRO. Any data analysis carried out 
independently by the investigator should be submitted to Novartis before publication or 
presentation. 
It is planned that the data from all centers that participate in this protocol will be pooled, so that 
an adequate number of patients will be available for analysis.  
In addition to the statistical methods outlined below, further details will be described in the 
Statistical Analysis Plan (SAP). 
 
 
12.1 
Analysis sets 
The Enrolled Set (ENS) includes all patients who signed an ICF and are assigned patient 
numbers. 
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
and who received at least one IVT injection of study treatment.  
The Safety Set includes all patients who received at least one IVT injection of study treatment.  
The Per-Protocol Set (PPS) is a subset of patients of the FAS without PDs with impact. The list 
of PD criteria will be provided in a separate document.  
However, when assessing the robustness of the overall efficacy conclusions, considerations will 
be given to the analysis based on the estimand using FAS and PPS. Expectation of comparing 
of both estimands is to have similar conclusions. Inconsistencies in the results will be examined 
and discussed in the Clinical Study Report (CSR). 
12.2 
Patient demographics and other baseline characteristics 
Demographic and other Baseline data including disease characteristics will be listed and 
summarized descriptively for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented. 
The last available assessment taken prior to the first IVT injection of study treatment is taken 
as the “Baseline” assessment. 
Relevant medical histories and current medical conditions at Baseline will be listed. 


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12.3 
Treatments 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. 
The extent of exposure to study treatment as the number of IVT injections received from 
Baseline to the end of the treatment period will be descriptively summarized. In addition, the 
number of patients at each injection category (1 injection, 2 injections up to the maximum 
number of injections) from Baseline to the end of the treatment period will be presented.  
Prior medications are defined as treatments taken and stopped prior to first IVT injection. Any 
medication given at least once between the day of first IVT injection and the date of the last 
study visit will be a concomitant medication, including those which were started pre-Baseline 
and continued into the period where study treatment is administered.  
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed according to the Anatomical Therapeutic Chemical (ATC) 
classification system.  
Anti-VEGF medications (other than the study treatment) will be summarized separately.  
12.4 
Analysis of the primary endpoint 
12.4.1 
Definition of primary endpoint 
The primary endpoint is the percentage change in CNV lesion area measured by OCT-A from 
Baseline to Week 12. This analysis will focus on the study eye only. 
The analysis of the primary variable will be based on the following estimand:  
• Analysis set: FAS  
• Variable of interest: Percentage change from Baseline in CNV lesion area measured by 
OCT-A to Week 12 
• Intervention effects: Effect at Week 12, while on study treatment 
• Intercurrent events: Discontinuing study treatment; treatment interruption 
• Measure of intervention effect: Difference from Baseline in variable means  
12.4.2 
Statistical model, hypothesis, and method of analysis 
Descriptive statistics for the primary endpoint (actual value, change from Baseline, percentage 
change from Baseline) will be presented based on observed data using the FAS. Furthermore a 
two-sided 95% CI using Student’s t-distribution will also be provided. 
12.4.3 
Handling of missing values/censoring/discontinuations 
For patients who: 
• Discontinue study treatment but continue in the study, the efficacy data will be censored at 
the time the patient stopped study treatment in the study eye. 
• Interrupt treatment, the efficacy data will be censored at the time the study treatment was 
first interrupted. 


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12.4.4 
Estimand and Sensitivity analyses 
In case of significant outliers or deviations from normality assumptions, a non-parametric 
analysis may be performed. 
In order to assess the robustness of the primary endpoint, estimand and sensitivity  analyses are 
planned. These may include, but are not limited to: 
• Consistent results from analyses based on the FAS and the PPS increases confidence in the 
trial results. Difference between FAS and PPS in incidence of intercurrent of event like 
COVID-19 regardless of whether patients discontinue assigned treatment. Performing 
comparison on the observed data between FAS vs PPS with the same handling rules for 
censoring as outlined in Section 12.4.3. for the efficacy endpoints. 
• Repeating the primary analysis using the PPS. 
Sensitivity estimand in exposed and non-exposed to the urgent safety measures: As a 
sensitivity analysis for the change in CNV lesion area measured by OCT-A at Week 12, the 
change in CNV lesion area measured by OCT-A at Week 12 will be compared before and after 
the urgent safety measures were introduced. The analyses will be performed in FAS and PPS. 
Further details about the analyses will be given in the SAP. Any major discrepancies in the 
results across analyses will be investigated as needed. 
Age, Baseline lesion type, and time since nAMD diagnosis subgroup analyses will also be 
performed on the primary endpoint.  
12.5 
Analysis of secondary endpoints 
12.5.1 
Efficacy endpoints 
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 endpoints are as follows: 
• Functional outcomes of brolucizumab  
• Change in BCVA from Baseline up to Week 48. 
• Anatomical outcomes of brolucizumab 
• Percentage change in CNV lesion area measured by OCT-A from Baseline to Week 48. 
• Change in OCT-A features assessed by qualitative and quantitative criteria from 
Baseline by visit at Week 12 up to Week 48. 
• Change in SD-OCT features assessed by qualitative and quantitative criteria (e.g. CSFT, 
sub- and/or intraretinal fluid, sub-RPE fluid) from Baseline by visit at Week 12 up to 
Week 48.  
The continuous functional and anatomical outcomes will be analyzed using the same primary 
method of analysis as the primary efficacy analysis. The factors in the respective model will be 
defined by the study Steering Committee. These details will be provided in the SAP. The 
qualitative dichotomous anatomical outcomes with 2 categories will be assessed using 
Cochran’s Q Test and those with more than 2 categories by the Generalized McNemar’s Test. 
In addition, the functional and anatomical outcomes will be described descriptively. 


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• Dosing regimen of brolucizumab 
• Proportion of patients who are maintained on an exclusive q12w interval following the 
loading phase through Week 48. 
• The probability of the first q12w interval for determining successful q12w maintenance 
at Week 48. 
• Time from last IVT injection in the initiation phase to first visit with no disease activity 
The binomial proportion and 95% confidence interval (CI) using the Clopper-Pearson method 
will be provided for disease status (i.e. q12w treatment status) at each disease activity 
assessment visit. The estimate of the probability for a patient to be maintained on the q12w 
regimen up to end of treatment will be summarized based on a Kaplan-Meier analysis of time 
to first q8w need. The time from last IVT injection in the initiation phase to first visit with no 
disease activity will also be summarized using a Kaplan-Meier analysis. In addition, descriptive 
statistics will also be provided. 
12.5.2 
Safety endpoints 
For all safety analyses, the Safety Set will be used.  
The secondary safety endpoint of this study is as follows: 
• Incidence of AEs (serious and non serious) reported in patients treated with brolucizumab. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of Baseline data, which will also be summarized where appropriate (e.g. change from 
Baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events of special 
interest (AESIs) 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 IVT injection of study 
treatment to 30 days after the date of the last actual administration of IVT injection of study 
treatment. 
Adverse events 
All information obtained on AEs will be displayed by patient. 
The number (and percentage) of patients with treatment emergent AEs (events started after the 
first IVT injection of study medication or events present prior to start of IVT injection but 
increased in severity based on preferred term) will be summarized in the following ways: 
• Primary system organ class and preferred term. 
• Primary system organ class, preferred term and maximum severity. 
Separate summaries will be provided for study medication related AEs, death, serious AESIs, 
other AEs leading to discontinuation. 
The number (and proportion) of patients with AEs of special interest will be summarized by 
Standardized MedDRA Query (SMQ) and preferred term. 


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A patient with multiple AEs within a primary system organ class is only counted once towards 
the total of the primary system organ class. 
Vital signs 
All vital signs data will be listed by patient and visit/time and if ranges are available, 
abnormalities will be flagged. Summary statistics will be provided by visit. 
Other safety evaluations  
All ophthalmic examinations data will be listed by patient and visit and if normal ranges are 
available, abnormalities will be flagged. In addition, summary statistics for clinically relevant 
abnormalities will be provided by visit/time. 
12.5.3 
Patient reported outcomes 
Not applicable 
12.6 
Analysis of exploratory endpoints 
Not applicable.  
12.7 
Interim analyses 
The analysis based on the Week 12 data, i.e. data up to and including Week 12 will be the 
primary (first) analysis for this study.  
A second planned analysis of the data after the EOS/Week 48 visit will be performed once all 
patients completed or prematurely discontinued the study. 
12.8 
Sample size calculation 
12.8.1 
Primary endpoint 
The primary objective of the study is to evaluate the effect of brolucizumab on CNV lesion area 
as measured by OCT-A in nAMD patients starting treatment with brolucizumab. This will be 
evaluated by the percentage change in CNV lesion area measured by OCT-A from Baseline to 
Week 12. The sample size calculation is based on the hypothesis of a standard deviation of 35% 
for this reduction proportion (Miere et al 2018).  
A sample size of 180 to 400 patients produces a 2-sided 95% CI with a distance from the mean 
to the limits ranges from 5.1 to 3.4 when the estimated standard deviation is 35.0 (nQuery 
Advisor version 8.0). Therefore, to have a precision of 5.0%, a sample size of 189 patients will 
be needed (Table 12-1).  
To take into account a dropout rate and uninterpretable images of 10%, a total of 210 patients 
will be included.  
Table 12-1 
Confidence intervals for one mean numeric: results for 2-sided 
confidence intervals with unknown standard deviation  
Confidence Level 
Sample Size  
(N) 
 
Distance from 
Mean to Limits 
Standard 
Deviation (S) 


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0.950 
180 
 
5.1 
35.0 
0.950 
189 
 
5.0 
35.0 
0.950 
233 
 
4.5 
35.0 
0.950 
250 
 
4.4 
35.0 
0.950 
300 
 
4.0 
35.0 
0.950 
350 
 
3.7 
35.0 
0.950 
385 
 
3.5 
35.0 
0.950 
400 
 
3.4 
35.0 
 
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 GCP, 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 IRB/IEC for the trial protocol, written ICF, consent form updates, patient recruitment 
procedures (e.g., advertisements) and any other written information to be provided to patients. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required.  
If an inspection of the clinical site is requested by a regulatory authority, the investigator must 
inform Novartis immediately that this request has been made. 
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 (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 


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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. 
 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction 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 patient 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 patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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References 
References are available upon request. 
Coscas G, Lupidi M, Coscas F, et al (2015) Optical coherence tomography angiography during 
follow-up: qualitative and quantitative analysis of mixed type I and II choroidal 
neovascularization after vascular endothelial growth factor trap therapy. Ophthalmic 
Res.;542:57-63.  
de Carlo TE, Bonini Filho MA, Chin AT, et al (2015) Spectral-domain optical coherence 
tomography angiography of choroidal neovascularization. Ophthalmology;122:1228-38.  
Jabs DA, Nussenblatt RB, Rosenbaum JT, et al (2005) Standardization of uveitis nomenclature 
(SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. 
Results of the first international workshop. Am J Ophthalmol;140(3): 509-16. 
Jia Y, Tan O, Tokayer J, et al (2012) Split-spectrum amplitude-decorrelation angiography with 
optical coherence tomography. Opt Express; 20:4710-25.  
Malamos P, Tsolkas G, Kanakis M, et al (2017) OCT-Angiography for monitoring and 
managing neovascular age-related macular degeneration. Curr Eye Res; 42(12):1689-1697.   
Mastropasqua R, Di Antonio L, Di Staso S, et al (2015) Optical coherence tomography 
angiography in retinal vascular diseases and choroidal neovascularization. J Ophthalmol; 
2015:1–8.  
Miere A, Butori P, Cohen SY, et al (2017) Vascular remodeling of choroidal neovascularization 
after anti-vascular endothelial growth factor therapy visualized on optical coherence 
tomography angiography. Retina;39(3):548-557. 
Miere A, Oubraham H, Amoroso F, et al (2018) Optical Coherence Tomography Angiography 
to Distinguish Changes of Choroidal Neovascularization after Anti-VEGF Therapy: Monthly 
Loading Dose versus Pro Re Nata Regimen. J Ophthalmol. Epublished at [doi: 
10.1155/2018/3751702].  
Muakkassa NW, Chin AT, de Carlo T, et al (2015) Characterizing the effect of anti-vascular 
endothelial growth factor therapy on treatment-naive choroidal neovascularization using optical 
coherence tomography angiography. Retina;35(11):2252-9.  
Nussenblatt RB, Palestine AG, Chan CC, et al (1985) Standardization of vitreal inflammatory 
activity in intermediate and posterior uveitis. Ophthalmology;92(4): 467-71 
Phasukkijwatana N, Tan ACS, Chen X, et al (2017) Optical coherence tomography angiography 
of type 3 neovascularisation in age-related macular degeneration after antiangiogenic therapy. 
Br J Ophthalmol; 101(5):597-602.  
Spilsbury K1, Garrett KL, Shen WY, Constable IJ, Rakoczy PE. Overexpression of vascular 
endothelial growth factor (VEGF) in the retinal pigment epithelium leads to the development 
of choroidal neovascularization. Am J Pathol. 2000 Jul;157(1):135-44. 
[HAWK] 
ClinicalTrials.gov. 
Identifier 
NCT02307682. 
Available 
at 
https://clinicaltrials.gov/ct2/show/NCT02307682 (link is external). Accessed November 2017. 
[HARRIER] 
ClinicalTrials.gov. 
Identifier 
NCT02434328. 
Available 
at 
https://clinicaltrials.gov/ct2/show/NCT02434328 (link is external). Accessed November 2017. 


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Appendices 
None.  

SAP_001.pdf: 
Clinical Development 
RTH258/Brolucizumab 
CRTH258AFR01 / NCT04239027
A one-year, single-arm, open-label, multicenter study 
assessing the anatomic outcomes of brolucizumab 
assessed by OCT-A in adult patients with neovascular 
age-related macular degeneration (OCTOPUS) 
Statistical Analysis Plan (SAP)  
Author: 
Statistician, 
 
Document type: 
SAP Documentation 
Document status: 
Amendment version 2.0 
Release date: 
25-Jan-2023
Number of pages: 
38 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template Version 3.0, Effective from 01-Jul-2020 


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Document History – Changes compared to previous final version of SAP 
Date 
Reason for update 
Outcome for update 
Section and title 
impacted 
(Current) 
02-03-2020 
Creation of initial 
version 
N/A - First version 
NA 
20-11-2020 
Amendment v1.0 
 
 
 
Visit window 
modified 
Visit window updated as per 
protocol 
Section 2.1.2 
 
Baseline 
characteristics 
include more 
variables  
Additional Baseline 
characteristics  from  central 
reading center in Vienna are 
included 
Section 2.3.4 
 
Prior and 
concomitant Surgery 
and Procedures was 
not included 
Added Prior and concomitant 
Surgery and Procedures as 
a new section 
Section 2.4.3 
 
Study treatment 
exposure removed, 
the not required 
compliance section 
Updated study treatment 
exposure  
Section 2.4.1 
 
Dry retina details 
Section added for dry retina 
Section 2.5.1 
 
Presence of fluid 
add more details 
Updated presence of fluid 
Section 2.6.1 
 
Fluorescein 
Angiography (FA) 
add more details 
Updated Fluorescein 
Angiography (FA) 
Section 2.6.1 
 
Estimand not 
included 
Added section for estimand 
as new section 
Section 2.7 
 
Dry retina  
Section added for dry retina 
Section 2.6.1 
 
 
 
 
 
25-01-2023 
Update in protocol 
Updated protocol version 
number and release date 
Section 1 
 
Update number of 
patients and drop 
the number of site 
Sample size re – estimated 
and number of planned site 
dropped, change disease 
activity assesment 
Section 1.1 
 
 
 
 
 
  
 
 
Update in on-
treatment period 
defination 
On treatment period updated 
to 28 days from last 
treatment day 
Section 2.1.1 
 
Update in visit 
window interval 
Lower and upper value for 
visit window updated 
Section 2.1.2 


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Date 
Reason for update 
Outcome for update 
Section and title 
impacted 
(Current) 
 
Update in population  
for disposition and 
protocol deviation  
Population set for disposition 
table and listing updated 
Section 2.3.1 and 
2.3.2 
 
Update in baseline 
characteristics 
nAMD category added 
 
 
Section 2.3.4 
 
Update in ocular 
category 
Ocular category was 
updated  
Section 2.3.5, 
2.4.2, 2.4.3 and 
2.9.1 
 
Update in treatment 
exposure 
New category added 
Section 2.4.1 
 
Update in unit  
CNV lesion area unit 
updated 
Section 2.5.1 
 
Update in BCVA 
group 
Loss of BCVA category 
updated 
Section 2.6.1.4 
 
Update in date 
Start date and end date 
consideration updated 
Section 2.6.1.5.1  
 
 
Start date consideration 
updated 
Section 2.6.1.6.1 
 
Update in CPF and 
fundus examination 
question  
Vasculitis added in CFP and 
fundus examination 
Section 2.8.1 and 
2.8.5 
 
Update in FAF 
question  
Foveal atrophy added in FAF 
question 
Section 2.8.2 
 
Update in AEs 
section 
Added procedure related, 
remove EudraCT 
requirement 
Section 2.9.1 
 
Update in AESI 
analysis  
Details for AESI analysis is 
added 
Section 2.9.1.1 
 
 
 
 
 
  
 
 
Update in sample 
size calculation  
Sample size re-estimation  
Section 3 
 
Added protocol 
change analysis 
Added protocol change 
analysis for estimand 
Section 4 
 
Update in statistical 
methodology 
SAS code for correlation and 
Bland-Altman plot is deleted. 
Added code AESI derivation 
Section 5.4 
 
Update in protocol 
deviation list and 
severity code 
New protocol deviation 
category added, severity 
updated and patient 
classification updated 
Section 5.5 


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SAP Amendment Version 2.0 
 
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Hyperlinks were not updated for the aendment v1.0 for the versions dated 20-11-2020 due change in 
section numbers. 


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SAP Amendment Version 2.0 
 
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Table of contents 
Table of contents ................................................................................................................. 5 
List of abbreviations ............................................................................................................ 7 
1 
Introduction ......................................................................................................................... 9 
1.1 
Study design............................................................................................................. 9 
1.2 
Study objectives and endpoints ............................................................................. 11 
2 
Statistical methods ............................................................................................................. 12 
2.1 
Data analysis general information ......................................................................... 12 
2.1.1 
General definitions ................................................................................ 12 
2.1.2 
Visit windows for data analysis ............................................................ 15 
2.2 
Analysis sets .......................................................................................................... 16 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 16 
2.3.1 
Patient disposition ................................................................................. 16 
2.3.2 
Protocol deviation ................................................................................. 17 
2.3.3 
Demographic characteristics ................................................................. 17 
2.3.4 
Baseline characteristics ......................................................................... 17 
2.3.5 
Relavent medical history / current medical condition ........................... 19 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies .............. 19 
2.4.1 
Study treatment exposure ...................................................................... 19 
2.4.2 
Prior, concomitant and post therapies ................................................... 20 
2.4.3 
Prior and concomitant surgery and procedures ..................................... 20 
2.5 
Analysis of the primary objective .......................................................................... 21 
2.5.1 
Primary endpoint ................................................................................... 21 
2.5.2 
Supportive analyses ............................................................................... 21 
2.6 
Analysis of secondary efficacy objectives ............................................................. 21 
2.6.1 
Secondary endpoints ............................................................................. 21 
 
 25 
 
 25 
2.8 
Analysis of other efficacy variables ...................................................................... 26 
2.8.1 
Color fundus photography..................................................................... 26 
2.8.2 
Fundus autofluorescence (FAF) ............................................................ 26 
2.8.3 
Indocyanine green angiography (ICG).................................................. 26 
2.8.4 
Intraocular pressure ............................................................................... 26 
2.8.5 
Fundus examination .............................................................................. 27 
2.9 
Safety analyses ....................................................................................................... 27 
2.9.1 
Adverse events (AEs) ............................................................................ 27 


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2.9.2 
Deaths .................................................................................................... 28 
2.9.3 
Laboratory data ..................................................................................... 29 
2.9.4 
Other safety data ................................................................................... 29 
2.10 
Pharmacokinetic endpoints .................................................................................... 29 
2.11 
PD and PK/PD analyses......................................................................................... 29 
2.12 
Biomarkers ............................................................................................................. 29 
2.13 
Other exploratory analyses .................................................................................... 29 
2.14 
Interim analysis ...................................................................................................... 29 
3 
Sample size calculation ..................................................................................................... 30 
4 
Change to protocol specified analyses .............................................................................. 30 
5 
Appendix ........................................................................................................................... 30 
5.1 
Imputation rules ..................................................................................................... 30 
5.1.1 
Study treatment ..................................................................................... 30 
5.1.2 
AE date imputation ............................................................................... 31 
5.1.3 
Concomitant medication date imputation ............................................. 32 
5.2 
AEs coding/grading ............................................................................................... 34 
5.3 
Vital signs parameters derivations ......................................................................... 34 
5.4 
Statistical methodology ......................................................................................... 34 
5.5 Rule of exclusion criteria of analysis sets ................................................................... 36 
6 
Reference ........................................................................................................................... 38 


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List of abbreviations 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Classification 
BCVA 
Best-Corrected Visual Acuity  
BCNVA 
Best Corrected Near Visual Acuity 
CNV 
Choroidal Neovascularization  
CFP 
Color Fundus Photography  
COVID-19 
Coronavirus disease 2019 
CI 
Confidence Interval 
CRC 
Central Reading Center  
CRO 
Contract Research Organization 
CSFT 
Central Sub-Field Retinal Thickness  
CRT 
Central Retinal Thickness 
CSR 
Clinical Study Report 
eCRF 
Electronic Case Report Form 
ENR 
Enrolled set 
FA 
Fluorescein Angiography  
FAF 
Fundus AutoFluorescence  
FAS 
Full Analysis Set 
ICF 
Informed Consent Form  
IGC 
Indocyanine Green Chorioangiography  
IOP 
Intraocular Pressure  
IVT 
Intravitreal  
KM 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
nAMD 
Neovascular Age-Related Macular Degeneration  
OCT 
Optical Coherence Tomography  
PK 
Pharmacokinetics 
PD 
Protocol deviation 
PDS 
Programming Datasets Specifications 
PPS 
Per-Protocol Set 
PT 
Preferred Term 
q8w 
Every 8 Weeks  
q12w 
Every 12 Weeks  
SAP 
Statistical Analysis Plan 
SAF 
Safety analysis set 
SD-OCT  
Spectral Domain Optical Coherence Tomography  


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SOC 
System Organ Class 
SRC 
Safety review commitee 
TFL 
Tables, Figures, Listings 
WHO 
World Health Organization 
 
 


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1 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to describe the implementation of the 
statistical methods for all safety and efficacy analyses planned (Section 12) in the clinical 
protocol (CRTH258AFR01, version no: 04, release date 16Nov2021). This document will be 
used to prepared the statistical results and the corresponding Clinical Study Report (CSR).  
The details of CSR deliverables (shells for tables, figures and listings) and further programming 
specifications will be described in the Tables, Figures & Listings (TFL) shells and 
Programming Datasets Specifications (PDS) respectively will be included in this document.  
Data will be analyzed by Novartis and/or the designated Contract Research Organization (CRO). 
Statistical software SAS version 9.4 or higher will be used for generating TFLs.  
1.1 
Study design 
This is a prospective, single-arm, open-label, multicenter study to evaluate the efficacy and 
safety of brolucizumab 6 mg in patients with nAMD. 
Patients will be required to attend 6 mandatory study visits: Screening/Baseline Visit (Day 1), 
Week 4, Week 8, Week 12, Week 16 and Week 48 visits. The timing of the interim visits 
between Week 16 and Week 48 will depend on the patient’s injection regimen, i.e. q12w or 
q8w.  
Planned number of patients 
Approximately 210 adult patients will be screened and included (10% dropout rate and 
uninterpretable images at Baseline and Week 12 are expected) in France. The maximum study 
duration for 1 patient is 48 weeks, including Screening. 
There will be 2 periods in this study (see Figure 1-1): 
• Open-label treatment period: from Screening/Baseline (Day 1) to Week 40/Week 44 
(depending on assigned regimen) 
• Follow-up period: Week 40/Week 44 to Week 48  


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Figure 1-1 
Study design 
 
* Week 40 or Week 44 according to treatment schedule  
** End of study visit: 4 or 8 weeks after the last IVT, depending on the last IVT date 
Patients will receive 3 initial doses every 4 weeks (Day 1, Week 4 and Week 8) loading phase), 
which should be at least 21 days apart, followed by treatment q12w with the possibility of 
adjusting to treatment q8w based on disease activity.  
Disease activity will be assessed based on investigator’s judgment of visual acuity and 
anatomical parameters as provided in the guidance to the investigators, e.g. decrease of visual 
acuity and/or other signs of the disease (e.g. intraretinal fluid (IRF), subretinal fluid (SRF), 
sub-retinal pigmented epithelium (sub-RPE) fluid, retinal hemorrhage, central retinal thickness 
(CRT) increase, etc.). Disease activity will be assessed during the first q12w interval at Week 
16. If no disease activity is observed by the investigator in the study eye, disease activity will 
be assessed every 12 weeks (at Week 20, Week 32 and Week 44). If disease activity is observed 
by the investigator in the study eye at any of these visits, the study treatment will be adjusted 
by the investigator to a q8w treatment regimen and will remain on this regimen until 
Week 40/Week 44. Patients who require study treatment every 4 weeks after the initiation phase 
will be discontinued from further study treatment at the next visit. 


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1.2 
Study objectives and endpoints 
Table 1-1 
Objectives and related endpoints  
Objectives 
Endpoints 
Primary objectives 
Endpoints for primary objectives 
• 
To evaluate the short-term effect of 
brolucizumab on CNV lesion area as 
measured by OCT-A in nAMD patients. 
• 
Percentage change in CNV lesion area 
measured by OCT-A from Baseline to 
Week 12. 
Secondary objectives 
Endpoints for secondary objectives 
• 
To evaluate the long-term effects of 
brolucizumab on CNV morphology as 
measured by OCT-A in nAMD patients.  
• 
Percentage change in CNV lesion area 
measured by OCT-A from Baseline to 
Week 48. 
• 
Change in OCT-A features assessed by 
qualitative and quantitative criteria from 
Baseline by visit at Week 12 up to 
Week 48. 
• 
To evaluate the effect of brolucizumab on 
anatomical parameters as assessed by SD-
OCT and FA from Week 12 up to Week 48. 
• 
Change in SD-OCT and FA features 
assessed by qualitative and quantitative 
criteria (e.g. CSFT, sub- and/or intraretinal 
fluid, sub-RPE fluid) from Baseline by 
visit up to Week 48.  
• 
To evaluate the efficacy of brolucizumab up 
to Week 48 by assessing changes in BCVA. 
• 
Change in BCVA from Baseline up to 
Week 48. 
• 
To estimate the proportion of patients treated 
at q12w frequency with brolucizumab. 
• 
Proportion of patients who are maintained 
on an exclusive q12w interval following 
the loading phase through to Week 48. 
• 
To estimate the predictive value of the first 
q12w cycle for maintenance of q12w 
treatment with brolucizumab. 
• 
The probability of the first q12w interval 
for determining successful q12w 
maintenance at Week 48. 
• 
To evaluate the time from last IVT injection 
in the initiation phase to first visit with no 
disease activity. 
• 
Time from last IVT injection in the 
initiation phase to first visit with no disease 
activity.  
• 
To evaluate the safety of brolucizumab. 
• 
Incidence of AEs (serious and non-serious) 
reported in patients treated with 
brolucizumab. 
AEs= adverse events, BCVA= best corrected visual acuity, CNV= choroidal neovascularization, 
CSFT= central sub-field retinal thickness, FA= fluorescein angiography, IVT= intravitreal 
nAMD= neovascular age-related macular degeneration,  
OCT-A= optical coherence tomography-angiography,  
SD-OCT= spectral domain optical coherence tomography, sub-RPE= subretinal pigmented epithelium 
 


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2 
Statistical methods 
2.1 
Data analysis general information 
Patients who consent and meet all the inclusion and none of the exclusion criteria will be 
screened to evaluate eligibility. After confirmation of eligibility, patients will be included and 
treated with brolucizumab 6 mg and data will be analyzed. 
All categorical data will be presented in terms of frequencies and percentages. Summaries of 
continuous data will be presented in terms of n (the number of non-missing data points), mean, 
standard deviation (SD), median, lower and upper quartiles, minimum, maximum and the 
number of missing data points. 
For descriptive statistics, the following rules for number of decimal places will be applied: 
arithmetic mean, median, lower quartile and upper quartile to 1 more decimal places than the 
raw data; minimum and maximum to the same number of decimal places as the raw data and 
SD to 2 more decimal places than the raw data. Percentages will be presented to 1 decimal place.  
2.1.1 
General definitions  
Study treatment: This is a single-arm study and all patients will be treated with brolucizumab 
6 mg. Three loading injections (at Screening/Baseline/Day 1, Week 4 and Week 8), followed 
by maintenance treatment from Week 16/Week 20 up to Week 40/Week 44. The investigator 
can individualize treatment intervals depending on disease activity, to adjust patient’s injection 
regimen. 
Study treatment start and end date: Study treatment start date is defined as the first date study 
treatment is administered and recorded on the treatment administration record (DAR) electronic 
case report form (eCRF) page. Similarly, study treatment end date is defined as the last date of 
study treatment is administered and recorded on the study treatment completion CRF page. 
Generally, study day 1 is considered as the day of inclusion of the patient. However in this study, 
treatment is intended to be administered on the same day or if this is not possible, within 3 days 
after the day of inclusion of the patient.  
Study day will be calculated as (event date – study treatment start date + 1 day) for events that 
occurred on or after study treatment start date (e.g. visit, AEs). For events prior to study 
treatment start date (e.g. time since diagnosis), study day will be negative and calculated as 
(event date – study treatment start date).  
Baseline and post-baseline: Baseline value refers to the value of the last non-missing 
measurement collected prior to administration of the first dose of study treatment (Screening or 
Baseline visit). Intraocular pressure (IOP) will be assessed in the study eye, pre-dose and 
post-dose at every injection. The last available assessment taken prior to the first IVT injection 
of study treatment is taken as the “Baseline” assessment.   
A “post-baseline” value refers to a measurement taken after the first dose of study treatment. 
When assessments and treatments take place on the same day, treatment must occur after 
completion of the efficacy assessments and pre-injection safety measures (tonometry, slit lamp 
and fundus examinations). If study visit assessments and the corresponding treatment occur on 
separate days, a repeat safety check-up will be performed prior to treatment of the eye and 


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results documented in the source documents. More post-baseline safety measurements will be 
recorded in source document; visit window will be applied to OCT and IVT visits. 
Change from Baseline: The difference of measure between post-baseline and Baseline is called 
change from Baseline. 
Percent change from Baseline: The percent change from Baseline will be calculated as below: 
((post-baseline value – Baseline value) /Baseline value)*100. 
On-treatment period: The on-treatment period lasts from the date of first administration of 
study treatment to 28 days after the date of the last actual administration of any study treatment. 
Treatment duration: The maximum planned duration of treatment for each patient is 40 to 44 
weeks in accordance with the designated treatment regimen. Discontinuation of study treatment 
for a patient occurs when study treatment is stopped earlier than the protocol planned duration 
and can be initiated by either the patient or the investigator. 
Treatment discontinuation: When patients discontinue study treatment but continue in the 
study, the efficacy data will be used at the time the patient stopped study treatment. 
Dry retina: Absence of fluid (IRF/SRF/sub-RPE) will be considered as dry retina. 
Event for maintenance q12w interval: In case the investigator selects q12w interval for a 
patient and the patient maintains the q12w interval until the first q8w interval has started then 
this will be considered as an event. In case the investigator maintains q12w interval (does not 
select q8w interval at any time in study) until EOS or patients got early discontinuation from 
study then patients will be considered as censored. 
Event for no disease activity: When patients will be with no disease status as per investigator 
decision after last dose in initiation phase then the patients will consider as event for disease 
activity. If patients with active disease status or early discontinue then patients will be 
considered as censored for disease activity. 
Event for dry retina: When patients have absence of fluid then it will be considered as an event 
of dry retina. If patients have a presence of fluid before/at EOS or early discontinuation then 
will be censored. 
Study eye and fellow eye: The investigator selects the eye with the worse BCVA at Screening 
as the study eye. Otherwise, the investigator deems as a study eye more appropriate to select 
the eye with better BCVA, based on medical reasons or local ethical requirements. If both eyes 
are eligible as per the inclusion and exclusion criteria, then it is recommended to select the right 
eye as the study eye. 
The fellow eye will be examined only at Screening/Baseline and Week 48/EOS visits. Only 
best corrected near visual acuity (BCNVA) for the fellow eye will be analyzed. It is not 
requested for the purpose of this study to do any self-assessment measure of the fellow eye. 
CNV lesion area 
A new angiography tool, namely optical coherence tomography-angiography (OCT-A) is a 
dye-less angiographic procedure based on split-spectrum-decorrelation-amplitude angiography 
that has become an essential and widely used tool, particularly for imaging CNV and vascular 


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diseases of the retina. The literature suggests that OCT-A is a good marker for assessing 
anti-VEGF therapeutic response, especially the lesion size that has been demonstrated to 
decrease under anti-VEGF therapy.  
OCT-A will be used in this study to assess the morphological response of patients to 
brolucizumab in terms of percentage change in CNV lesion area in the short term (i.e. at 
Week 12 just after loading doses) and in the long term (i.e. at Week 48 [12 months]), as well as 
changes in other OCT-A features up to Week 48.  
The primary endpoint is the percentage change in CNV lesion area measured by OCT-A from 
Baseline to Week 12. The Week 12 time point has been selected as peak efficacy has been 
demonstrated in the pivotal trials of brolucizumab for this time point. 
Anatomic parameters measured by OCT-A and SD-OCT 
Anatomic parameters measured by OCT-A and by SD-OCT will be analyzed by a CRC. The 
main aim of the CRC analysis is to confirm anatomic features from OCT-A and SD-OCT 
images for the primary endpoint. The investigator will evaluate the OCT-A and SD-OCT 
images to assess the status of disease stability. 
Disease activity criteria 
Disease activity criteria will be assessed by the investigator based on whether nAMD is still 
active or has been re-activated. Guidance for the investigator is as follows (disease is active if 
at least one of the following criteria is observed by the investigator):  
• BCVA decrease ≥ 5 letters from the best value since Baseline due to disease activity.  
• Any significant increase in CRT (based on investigator assessment). 
• Retinal hemorrhage. 
• Intraretinal fluid or SRF due to disease activity (degenerative cysts allowed). 
• Increase of sub-RPE fluid. 
These criteria are for guidance only, the investigator may define disease activity based on 
his/her own assessment.  
A patient who misses Week 16 will undergo the disease activity assessment at Week 20 as 
he/she would have done if the visit had not been missed. If, however, a patient misses any of 
the following disease activity assessment visits (Week 20, Week 32) then the patient will be 
assumed to have met the disease activity criterion at the missed visit and will be reassigned to 
a q8w regimen up to study exit.  
If a patient misses Week 12, then the Week 8 values will be applied as the reference for disease 
activity assessments up to and including Week 44.  
Fluorescein angiography: Fluorescein angiography (FA) is a diagnostic procedure that uses a 
special camera to record the blood flow in the RETINA – the light sensitive tissue at the back 
of the eye.  
Color fundus photography (CFP): CFP is a diagnostic procedure that involves the use of a 
device known as a fundus camera to record colored images of the interior surface of the eye. 
The goal of this procedure is to monitor the presence of disorders and their change with time.  


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Fundus autofluorescence (FAF): Fundus autofluorescence imaging is an in vivo imaging 
method for metabolic mapping of naturally or pathologically occurring fluorophores of the 
ocular fundus. 
Indocyanine green angiography (ICG): ICG is a diagnostic procedure that uses ICG dye to 
examine the blood flow in the choroid – the layer of blood vessels that lies underneath the retina. 
ICG is injected into a vein in the arm/hand. As the dye passes through the blood vessels of the 
eye, photographs are taken to record the blood flow. 
Intraocular pressure (IOP): IOP is the fluid pressure of the eye. IOP is measured in 
millimeters of mercury (mmHg). Normal eye pressure is usually considered to be between 10 
and 25 millimeters of mercury (mmHg). 
Fundus examination: Fundus examination used to assess diagnose vitro-retinal diseases (such 
as retinal haemorrhage, vitreal haemorrhage, retinal tear and detachment), optic nerve defects 
and hereditary diseases. 
 
2.1.2 
Visit windows for data analysis 
Visit windows will be used for the data analysis, as per the planned visits in the protocol. During 
the q12w/q8w phase, i.e., from Week 16 to Week 44, the treatment visit intervals will be 
determined by the investigator, based on the patient’s disease activity. 
Table 2-1 
Assessment windows for scheduled visits 
Analysis Visit 
Week 
Scheduled Day 
Visit Window 
Screening/Baseline 
BL 
1 
-14 days to Day 1* 
Week 4 
4 
28 
Day 22 - 34 
Week 8 
8 
56 
Day 50 – 62 
Week 12 
12 
84 
Day 71 – 97 
Week 16 
16 
112 
Day 99 – 119 
Week 20 
20 
140 
Day 127 – 153 
Week 24 
24 
168 
Day 155 – 182 
Week 28 
28 
196 
Day 183 – 209 
Week 32 
32 
224 
Day 211 – 237 
Week 36 
36 
252 
Day 239 – 265 
Week 40 
40 
280 
Day 267 – 293 
Week 44 
44 
308 
Day 395 – 321 
Week 48 
48 
336 
Day 323 – 349 
* Baseline measurement before the first treatment administration. 
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. Injections are contraindicated in patients with active intraocular 


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or periocular infections and in patients with active intraocular inflammation; therefore, the 
investigators should verify that these conditions are not present in the study eye prior to every 
injection. Any AEs must be recorded in the eCRF.  
The injection procedure for brolucizumab will be performed according to local clinical practice. 
Injections will be administered by the investigator.  
Data collected at unscheduled visits will not be used in ‘by-visit’ tabulations or graphs and will 
be presented in listings. 
2.2 
Analysis sets 
Enrolled Analysis Set (ENR): The ENR set includes all patients who signed an ICF and are 
assigned patient numbers. 
Full Analysis Set (FAS): The FAS comprises all patients to whom study treatment has been 
assigned and who received at least one IVT injection of study treatment.  
Safety Set (SAF): The SAF set includes all patients who received at least one IVT injection of 
study treatment.  
Per-Protocol Set (PPS): The PPS is a subset of patients in the FAS without PDs with impact. 
The list of PD criteria will be provided in edit checks specification (ECS) document.  
Full Analysis Set Estimand (FAS-EST): The FAS-EST comprises all patients who are in the 
FAS and did not discontinue treatment in the entire study due to COVID-19. 
Per-Protocol Set Estimand (PPS-EST): The PPS-EST is a subset of patients of the FAS-EST 
without PDs with impact. 
When assessing the robustness of the overall efficacy conclusions, considerations will be given 
to the analysis based on the estimand using FAS-EST and PPS-EST. The expectation for 
comparing both estimands is to have similar conclusions. Inconsistencies in the results will be 
examined and discussed in the CSR. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
The FAS will be used to prepare the summary and ENR will be used for listing of patient 
disposition. 
The number and percentage of patients who completed the study and discontinued from the 
study will be summarized with reasons for premature discontinuation for the ENR. In addition, 
the number of screen failures with reasons will be presented for all screened patients. The 
patient identification number and whether patients completed or discontinued from the study 
will be listed, with date of last dose and primary reason for premature discontinuation.  
A separate summary of disposition and listing for rescreened patients will be presented for the 
ENR. 
Study treatment will be discontinued under the following circumstances:  


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• Adverse event 
• Death 
• Lost to follow-up 
• Physician decision  
• Pregnancy  
• Progressive disease 
• Protocol deviation  
• Study terminated by sponsor 
• Technical problem 
• Patient decision 
• New therapy for study indication  
• Lack of efficacy 
• Use of prohibited treatment  
• Any situation in which study participation might result in a safety risk to the patient 
2.3.2 
Protocol deviation 
The number and percentage of patients with protocol deviations will be tabulated by category 
and deviation for the FAS. Patients with protocol deviations will be listed with date and study 
day of occurrence, deviation and severity codes for the ENR. 
The number of patients included in each analysis set will be tabulated for all enrolled patients. 
Reasons for exclusion from analysis sets will be tabulated for the ENR. Patient exclusion from 
analysis sets will be listed for all patients with reasons for exclusion (i.e., both protocol and 
non-protocol deviations). 
2.3.3 
Demographic characteristics 
Demographic and Baseline characteristics will be listed and summarized descriptively for 
overall patients on FAS and Safety Set. 
The following demographic and vital signs variables collected in the eCRF at Baseline will be 
summarized: 
• Sex (male, female) 
• Age (in years) 
• Age category (< 50, 50 - 65, 65 - 75, 75 - 85, ≥ 85) 
• Study eye (left [OS], right [OD])  
• Vital signs (sitting systolic/diastolic blood pressure [mmHg], sitting pulse rate [bpm]) only 
on the days study treatment is administered, it is measured prior study treatment  
2.3.4 
Baseline characteristics 
The following Baseline characteristics collected in the eCRF at Baseline will be summarized 
for study eye and fellow eye (wherever applicable): 
• Time since nAMD diagnosis 


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• Time since nAMD diagnosis (< 1 month, 1-3 months and > 3 months) 
• Unilateral versus bilateral nAMD 
• BCVA 
• BCVA (≤ 55, 56 - 70, ≥ 71) 
• BCVA categories (count fingers, hand motion, light perception, no light perception) in 
case BCVA score is 0 
• FA (analyzed by Vienna [CRC]) 
1. Lesion type (only at Baseline) (predominantly classic, minimally classic, occult) 
2. Lesion type (only at Baseline) (type 1 / type 2 / type 3 / type 1 with aneuvrism / 
polyps) 
3. CNV location (subfoceal, juxtafoveal, extrafoveal) 
4. Area of lesion associated with CNV (mm2) 
• ICG (analyzed by Vienna [CRC]) 
1. Lesion type (only at Baseline) (type 1 / type 2 / type 3 / type 1 with aneuvrism / 
polyps) 
2. Area of lesion associated with CNV (mm2) 
• SD-OCT (analyzed by Vienna [CRC])  
• Lesion type (only at Baseline) (type 1, type 2, type 3) 
• CSFT (µm) 
• Baseline CSFT (< 300, ≥ 300 - 450, ≥ 450 - < 650, ≥ 650 [μm]) 
• Presence of fluid (YES/NO) 
1. Intraretinal fluid 
2. Subretinal fluid 
3. Sub-RPE fluid 
• Volume (mm3) and height (µm) of each fluid (in case of presence) 
1. Intraretinal fluid 
2. Subretinal fluid 
3. Sub-RPE fluid 
• In case of sub-RPE /  PED : nature : serious PED / fibrovascular PED / mixed PED 
• OCT-A (analyzed by Vienna)  
1. CNV location (only at Baseline) 
2. CNV lesion area (at the biggest surface) (mm²/µm²) 
• Fundus observation  
1. Retinal hemorrhage (none, retinal macular and retinal non-macular) 
2. Presence of vitreal hemorrhage (Yes, No) 
3. Retinal tear/ detachment (none, tear, detachment, both) 
• Color fundus photography (CFP) 
1. Presence of retinal or subretinal hemorrhage (Yes, No) 
2. Presence of fibrosis (Yes, No) 
3. Presence of atrophy (Yes, No) 
4. Subretinal blood affecting foveal center point and/ or > 50% of total lesion (Yes, No) 
• Fundus autofluorescence (FAF) 
1. Presence of macular atrophy (Yes, No) 
2. Area of macular atrophy 


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• Intraocular pressure 
• Intraocular pressure (≤ 10, 10-25, 25-30 and ≥ 30 [mmHg]) 
• Disease activity assessment (Present) 
• History of primary diagnosis:  
1. Disease (neovascular age-related, macular degeneration [nAMD]) 
2. Age of diagnosis 
3. Eye (OD, OS) 
4. Ongoing (Yes, No) 
• History or evidence of the following in the study eye within the 90-day period prior to 
Screening/Baseline: 
1. Intraocular or refractive surgery 
2. Previous panretinal photocoagulation 
3. Previous submacular surgery, other surgical intervention or laser treatment for nAMD 
including photodynamic therapy (PDT) 
• Concomitant medication at Baseline  
• Medical history 
• Co morbidities  
2.3.5 
Relavent medical history / current medical condition 
Medical history / current medical conditions (general and ocular) will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) terminology. History/conditions will 
be summarized for the FAS by primary system organ class (SOC), preferred term (PT) by eye 
(any eye, study eye and fellow eye). Verbatim recorded history/conditions will be listed together 
with the coded terms, date of diagnosis/surgery and whether the problem was ongoing at start 
of the study. The ongoing medical history will be considered as co morbidities. The co 
morbidities will be summarized and listed separately for eye (any eye, study eye and fellow eye 
and both eye). 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies 
2.4.1 
Study treatment exposure 
Extent of exposure to study treatment is calculated as the number of IVT injections received. 
The following summaries will be presented: 
1. Overall number of injections (n, q1, median, q3, min and max) will presented. 
2. Number of injection (n, q1, median, q3, min and max) before or at Week 8 and greater 
than Week 8. 
3. Number of injections (n, q1, median, q3, min and max) before or at Week 12 and greater 
than Week 12. 
4. Number of patients with injection (1 injection, 2 injections up to the maximum number of 
injections) from Baseline to the end of the treatment period will be presented. 
5. Treatment exposure by visit: The number and percentage of patients who received 
injections, missed a treatment and missed visits will be presented by visit. 


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6. Summary statistics (n, mean, std, median, min and max) for overall duration will be 
provided. 
The number and percentage of patients for changes in brolucizumab 6 mg treatment patterns 
over time (i.e. interruptions or permanent discontinuations) along with reasons, will be 
summarized. Discontinuations and primary reasons for treatment and/or study discontinuation 
will also be described. 
Exposure data will be summarized for the Safety Set and FAS. The exposure data will be listed 
for the FAS. 
2.4.2 
Prior, concomitant and post therapies 
Each medication has the start and end dates recorded on the eCRF. Prior medications are defined 
as those medications which were taken and stopped prior to first dose of study treatment. 
Concomitant medications are defined as any medication given at least once between the day of 
first dose of study treatment and the last day of study visit, including those which were started 
pre-baseline and continued into the treatment period. The below summary tables will be 
reported: 
• Prior medication 
• Concomitant medications which started prior to first dose of study treatment 
• Concomitant medications which started on/after first of study treatment 
All prior and concomitant medications will be coded using the most recent version of the WHO 
drug dictionary. All concomitant medications (general and ocular) will be listed and 
summarized in alphabetic order according to anatomical therapeutic chemical (ATC) 
classification system and PT. Tables will also show the overall number and percentage of 
patients receiving at least one treatment of a particular ATC. 
For prior and concomitant ocular medications, as well as ocular procedures performed during 
the study, separate tabular summaries will be prepared for the any eye, study eye and the fellow 
eye. A listing of all prior and concomitant medications and concomitant procedures will be 
provided. 
For handling of missing or incomplete start and end dates, see Appendix 5.1.3 of this document. 
All summaries will be performed on the Safety Set. 
2.4.3 
Prior and concomitant surgery and procedures 
All prior and concomitant surgery and procedures will be summarized and listed by category 
(general, ocular) and eye (any eye, study eye and fellow eye).  
For handling of missing or incomplete start and end dates, see Appendix 5.1.3 of this document. 
All summaries will be performed on the Safety Set. 


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2.5 
Analysis of the primary objective 
2.5.1 
Primary endpoint 
OCT-A will be used in this study to assess the morphological response of patients to 
brolucizumab. In terms of percentage change in CNV lesion area (at the biggest surface) (mm²). 
The primary endpoint is the percentage change in CNV lesion area measured by OCT-A from 
Baseline to Week 12 in the study eye. The percentage change from Baseline at Week 12 in the 
lesion area will be derived as follows: 
([Lesion area at Week 12 – Lesion area at Baseline]*100)/ Lesion area at Baseline 
Descriptive statistics (n, mean, std, median, min and max) for the primary endpoint (actual value, 
change from Baseline, percentage change from Baseline) will be presented based on observed 
data using the FAS. Furthermore, a 2-sided 95% CI using Student’s t-distribution will also be 
provided. In case of significant outliers or deviations from normality assumptions then IQR will 
be presented. 
The last observation carried forward (LOCF) method will be used as sensitivity analysis to 
impute missing record for CNV lesion area at post baseline. If there is significant amount of 
missing record then another table with LOCF records should be created.  
The above analysis will be done only on the study eye. The analysis will be performed on FAS. 
The analysis will be performed on the PPS, if there is more than a 10% difference in patients, 
between the FAS and PPS.  
2.5.2 
Supportive analyses 
Subgroups analyses according to patient characteristics, like sex (male, female), age class 
(≤ 64, > 65 - 75, 75 - 85, ≥ 85), Baseline lesion type (type 1, type 2, type 3) and time since 
nAMD diagnosis (< 1 month, 1-3 months, and > 3 months). 
2.6 
Analysis of secondary efficacy objectives 
2.6.1 
Secondary endpoints 
2.6.1.1 
Oct-A long-term effects 
The first secondary endpoint is the percentage change in CNV lesion area (mm²) measured by 
OCT-A for nAMD patients from Baseline to Week 48. Descriptive statistics (n, mean, std, 
median, min and max) for the change in CNV lesion (actual value, change from Baseline, 
percentage change from Baseline) will be presented based on observed data by visit. 
Furthermore, a 2-sided 95% CI using Student’s t-distribution will be provided.  
The number and percentage of lesion type (predominantly classic, minimally classic and occult) 
will be presented by visit. 
The above analysis will be done only on the study eye. The analysis will be performed on the 
FAS. 


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2.6.1.2 
Spectral domain optical coherence tomography (SD-OCT) 
The following secondary efficacy parameters based on SD-OCT will be analyzed as given 
below. 
2.6.1.2.1 Central sub-field retinal thickness (CSFT) 
Summary statistics of central sub-field retinal thickness (CSFT) measured by SD-OCT for 
nAMD patients will be presented by visit along with change and percentage change from 
Baseline in CSFT. 
The number and percentage of patient with CSFT category (< 300, ≥ 300 - 450, ≥ 450 - < 650, 
≥ 650 (μm)) will be presented by visit. 
The above analysis will be done only on the study eye. The analysis will be performed on FAS.   
2.6.1.2.2 Presence of fluid (YES/NO) 
The number and percentage of patients with below fluid will presented by visit. 
1. Intraretinal fluid 
2. Subretinal fluid  
3. Sub-RPE fluid  
4. Without IRF or SRF  
5. Without any fluid (IRF/SRF/sub-RPE) 
6. In case of sub-RPE /  PED : nature : (serious PED / fibrovascular PED / mixed PED) 
Volume (mm3) and height (µm) of intraretinal fluid, subretinal fluid and/or sub-RPE fluid will 
be presented the summary statistics (n, mean, std, median, min and max) by visit, if available.  
The above analysis will be done only on the study eye. The analysis will be performed on the 
FAS.   
2.6.1.2.3 Dry retina 
The proportion of patients without both fluids (IRF and SRF), without IRF, without SRF, 
without sub-RPE will be presented by visit, separately, up to Week 48/Week 50. 
The proportion of patients without fluid (IRF and SRF) and having fluid (IRF and/or SRF) in 
entire study will be presented. 
The 95% confidence interval (CI) for proportion using the Clopper-Pearson method will be 
provided by visit and overall. 
The above analysis will be done only on the study eye. The analysis will be performed on the  
FAS. 
2.6.1.2.4 Time to dryness 
The median time to dryness will be obtained from Kaplan-Meier (KM) analysis along with 
2-sided 95% CI will be presented. KM plot will be provided. Detailed KM results will be 
presented including time (week), number of patients with dry retina at visit, number of patients 
under risk at visit (without dry retina), probability of dry retina (survival probability) at visit 
and 95% CI at visit.  


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Variable 
Definition 
Start date 
Start date of IVT injection  
Event  
Dry retina (absence of IRF and/or SRF)  
End date of event 
Start date of first dry retina 
Censoring (end date)  
Earliest of: 
• Absence of dry retina until EOS 
• Early discontinuation without dry retina  
Duration of time 
(End date – start date) +1 
The above analysis will be done only on the study eye. The analysis will be performed on the 
FAS.   
2.6.1.2.5 Maximum duration of dryness 
The median of maximum duration of dryness until Week 48/50 will be presented. The median 
will be obtained from the KM analysis along with 2-sided 95% CI. KM plot will be provided. 
Detailed KM results will be presented including time (week), total number of patients having 
fluids, number of patients under risk, probability of with dry retina (survival probability) and 
95% CI.  
Variable 
Definition 
Start date 
Start date of dryness  
Event  
Dryness  
End date of event 
End date of dryness  
Censoring (end date)  
Earliest of: 
• Presence of dryness until EOS 
• Early discontinuation with presence of dryness 
Duration of time 
(End date – start date) +1 (Maximum  duration will be used) 
The above analysis will be done only on the study eye. The analysis will be performed on FAS.   
2.6.1.3 
Fluorescein angiography (FA) 
The number and percentage of CNV location (subfocal, juxtafoveal, extrafoveal) at Week 12 
will be presented for both study eye and fellow eye. 
The summary statistics (n, mean, std, median, min and max) of area of lesion associated with 
CNV (mm**2) will be presented at Week 12 for study eye and fellow eye, along with change 
from Baseline and percentage change from Baseline. 
The above analysis will be done only on the study eye. The analysis will be performed on the 
FAS.   
2.6.1.4 
Best corrected visual acuity (BCVA) 
The summary statistics (n, mean, std, median, min and max) of BCVA for nAMD patients will 
be presented along with change and percentage change from Baseline in BCVA by visit. Along 
with below BCVA category. 


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1. BCVA (≤ 55, 56 - 70 and ≥ 71). 
2. Increase of ≥ 5, ≥ 10 and ≥ 15 letters in BCVA from Baseline up to Week 48. 
3. Loss of ≥ 5, ≥ 10, ≥ 15 and ≥ 30 letters in BCVA from Baseline up to Week 48. 
4. BCVA ≥ 84.  
The above analysis will be done only on the study eye. The analysis will be performed on FAS. 
2.6.1.5 
Dosing regimen of brolucizumab 
The binomial proportion and 95% CI using the Clopper-Pearson method will be provided for 
patients who are maintained on an exclusive q12w interval following the loading phase through 
Week 48.  
The number and percentage of q8w dose frequency patients will be presented along with 
95% CI using the Clopper-Pearson method.  
Duration of dose is defined as (date of last dose – start date of dose).  
The summary statistics (n, mean, std, first quartile, median, third quartile, min and max) for 
duration of dose will be provided for patients who are maintained on an exclusive q12w interval 
following the loading phase through Week 48. In the study design the 3 × 4-week dosing 
frequency, in initiation phase. 
The above analysis will be done only on the study eye. The analysis will be performed on the 
FAS. 
2.6.1.5.1 Predictive value of the first q12w cycle for maintenance of q12w 
treatment with brolucizumab 
The probability of the first q12w interval will be derived from KM time to event analyses. KM 
plot will be provided. Detailed KM results will be presented including time (week), number of 
patients with first q8w or discontinue at visit, number of patients under risk at visit, probability 
of maintaining on q12w (survival probability) and 95% CI for maintaining on q12w.  
Variable 
Definition 
Start date 
First date when patients on q12w interval  
Event  
Maintain q12w interval 
End date 
Last date of initital q12w interval (before or on first start of q8w interval) 
End of study (week 48) 
Censoring (end date)  
Earliest of: 
• 
In case investigator does not select first q8w interval until EOS. 
• 
Early discontinue from study. 
Duration of time 
(End date – start date) +1 
The above analysis will be done only on the study eye. The analysis will be performed on FAS. 


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2.6.1.6 
Disease activity assessments 
The number and percentage will be presented by visit for disease activity assessment. 
The above analysis will be done only on the study eye. The analysis will be performed on FAS. 
2.6.1.6.1 Duration of time from start of dose to till no disease activity 
The median of duration of time is obtained from KM analysis along with 2-sided 95% CI will 
be presented. KM plots will be provided. 
Detailed KM results will be presented including time (week), number of patients with no disease 
activity at visit, number of patients under risk at visit (with disease activity), probability of 
disease activity (survival probability) at visit and 95% CI at visit.  
 
Variable 
Definition 
Start date 
Start date of start of IVT injection/ last IVT injection in the initiation phase 
Event  
No disease activity 
End date of event 
Date of first visit with no disease activity  
Censoring (end date)  
Earliest of: 
• 
With disease activity until EOS 
• 
Early discontinuation  
Duration of time 
(End date – start date) +1 
The above analysis will be done only on the study eye. The analysis will be performed on FAS. 


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2.8 
Analysis of other efficacy variables 
2.8.1 
Color fundus photography 
The number and percentage will be provided at Screening/Baseline, week 12 and end of study 
(Week 48) for below questions: 
• Was color fundus photography performed? If not, then reason for not performed CFP. 
• Presence of retinal hemorrhage in central subfield. 
• Presence of subretinal hemorrhage in central subfield. 
• Presence of fibrosis in the central subfield the diameter of 3000 µm. 
• Presence of atrophy in the central subfield the diameter of 3000 µm. 
• Is there subretinal blood affecting the foveal center point and/or >50% of total lesion. 
• Presence of Vasculitis. 
The above analysis will be done on both eyes. The analysis will be performed on the FAS.   
2.8.2 
Fundus autofluorescence (FAF) 
The number and percentage will be provided at Baseline, week 4 and end of study (week 48) 
for below question. 
• Fundus auto-fluorescennce performed at visit. If not then reason for not performed FAF.  
• Presence of macular atrophy in the central subfield (center 1 mm circle). 
• Presence of foveal atrophy. 
The summary statistics (n, mean, std, median, min and max) of area of macular atrophy (mm2) 
will be presented at Baseline, Week 4 and Week 48 along with change from Baseline and 
percentage change from Baseline in FAF. 
The above analysis will be done on the both eye. The analysis will be performed on FAS.   
2.8.3 
Indocyanine green angiography (ICG) 
The number and percentage of lesion type (only at Baseline) (type 1 / type 2 / type 3 / type 1 
with aneuvrism / polyps) at Baseline will be provided. 
The summary statistics (n, mean, std, median, min and max) for area of lesion associated with 
CNV (mm2) at Baseline and Week 12 will be provided along with summary statistics for change 
from Baseline and percentage change from Baseline at week 12 for area of lesion. 
The above analysis will be done on both eyes. The analysis will be performed on the FAS.   
2.8.4 
Intraocular pressure 
Intraocular pressure will be collected in the CRF at Baseline and Week 48. The summary 
statistics of IOP for nAMD patients will be presented at Week 48 along with change from 
Baseline and percentage change from Baseline in IOP. In addition, the number and percentage 
of patients with IOP (≤ 10, 10-25, 25-30 and ≥ 30 [mmHg]) will be presented at Week 48. 
The above analysis will be done on both eyes. The analysis will be performed on the FAS.   


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2.8.5 
Fundus examination  
The below variables of number and percentage will presented for study eye and fellow eye by 
visit. 
• Retinal hemorrhage (none, retinal macular and retinal non-macular) 
• Presence of vitreal hemorrhage (no, yes) 
• Retinal tear/detachment (0- none, 1- retinal tear, 2- retinal detachment, 3- retinal tear and 
detachment) 
• Presence of intraocular inflammation (no, yes) 
• Presence of vasculitis. 
Listing of fundus examination parameter will be provided by patient and visit. 
The above analysis will be done on the both eye. The analysis will be performed on the FAS.   
2.9 
Safety analyses 
Safety measurements include duration of exposure, vital signs and adverse events. All safety 
endpoints will be summarized using the Safety Set. Patients will be analyzed according to 
treatment received. No imputation will be carried out for missing data.   
2.9.1 
Adverse events (AEs) 
All information obtained on AEs will be displayed by patient. Summary tables for AEs will 
summarize only on-treatment events, with a start date during the on-treatment period (see 
Section 2.1.1) for definition of on-treatment period).  
The count of treatment-emergent AEs, number (and percentage) of patients with treatment-
emergent AEs (defined as events started after the first dose of study treatment or events present 
prior to start of study treatment but increased in severity based on PT) will be summarized in 
the following ways:  
• By primary SOC and PT.  
• By primary SOC, PT and maximum severity.  
Separate summaries will be provided for study treatment related AEs, procedure related, death, 
SAEs andother significant AEs action taken leading to study study treatment interruption & 
treatment withdrawn .  
Adverse events will be summarized by presenting, the number and percentage of patients having 
any AE, having an AE in each primary SOC and having each individual AE (PT). Summaries 
will also be presented for AEs by severity. Summaries for AE will be presented for study 
treatment and procedure related to AEs. If a patient reported more than one AE with the same 
PT, the AE with the greatest severity will be presented. System organ classes will be presented 
in alphabetical order, PTs will be sorted within SOC in descending frequency of AEs. If a 
patients reported more than one AE within the same primary SOC, the patient will be counted 
only once with the greatest severity at the SOC level, where applicable. The AE will be 
presented in separate sections of ocular and non-ocular. For ocular then it will be presented by 
any eye, study eye and fellow eye. 


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For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AEs in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
 In addition, all treatment emergent AEs will also be listed. 
The by-patients listing will include: SOC/PT/Verbatim term, start date, end date, severity, 
relationship to study treatment and procedures, whether or not it is a SAE, action taken with 
study treatment and outcome. Duration will be calculated as (end date – start date + 1) and for 
ongoing AE (last visit date – start date + 1) by ocular and non-ocular. For ocular then it will be 
presented by any eye, study eye and fellow eye. 
A summary of action taken with number and percentage of patients will presented with dose 
increased, no dose change, dose reduced, treatment interrupted, drug withdrawn, not applicable 
and unknown. 
2.9.1.1 
Adverse events of special interest / grouping of AEs 
 
The number (%) of patients with AESIs will be summarized by standardized MedDRA query 
and PT. Listing will also be provided. 
Case Retrieval Sheet (CRS) with the exact composition of the AE groupings is to be used to 
map reported AEs to the AESI groupings. This file may be updated (i.e.live document) based 
on review of accumulating trial data, and therefore the groupings are also subject to potential 
change. The most up-to-date version of the CRS will be used at the time of the analysis. 
The number and percentage of patients having any AESI, AESI by SOC(confirmed by SRC) 
and PT will be presented.  
The number and percentage of patients for AESI type along with incidence rate per patient and 
per 1000 injection will be provided. Incidence rate per patient is defined as number of patients 
in AESI type/total number of patients in safety analysis set and incidence rate per 1000 injection 
is define as (number of occurrence of AESI type/total number of injections)*1000. 
The number and type of AESI will be plotted according to the time after last brolucizumab 
injection and time since first brolucizumab injection. 
Summary statistics for change from baseline in BCVA after end date of AESI will be provided 
for each AESI type and change from baseline in BCVA will be plotted overall and for each type 
of AESI. 
Patients demographics, baseline characteristics and medical history will be provided for AESI 
patient with safety set. 
2.9.2 
Deaths 
A separate summary of deaths including on-treatment and post-treatment deaths will be 
provided. 


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All deaths in the clinical database will be listed with the investigator-reported principal cause. 
Deaths occurring after the first dose of study treatment until 30 days after the date of last 
treatment will be summarized. In addition, deaths occurring after the first dose of study 
treatment until the date of last treatment will also be summarized. 
2.9.3 
Laboratory data 
Not applicable 
2.9.4 
Other safety data 
Not applicable 
2.9.4.1 
ECG and cardiac imaging data 
Not applicable 
2.9.4.2 
Vital signs 
Vital signs will include blood pressure and pulse rate measurements. 
All vital signs data will be listed by patient, and visit, and if ranges are available, abnormalities 
will be flagged. Abnormal values are marked in Section 5.3. All data, including data from 
unscheduled visits, will be considered when identifying abnormal values. Analysis of vital sign 
measurements using summary statistics for the change from Baseline for each post-Baseline 
visit will be performed. These descriptive summaries will be presented for each vital sign. 
Change from Baseline will only be summarized for patients with both Baseline and post-
Baseline values. 
2.10 
Pharmacokinetic endpoints   
Not applicable 
2.11 
PD and PK/PD analyses 
Not applicable 
2.12 
Biomarkers 
Not applicable. 
2.13 
Other exploratory analyses 
Not applicable. 
2.14 
Interim analysis 
The analysis based on the Week 12 data, i.e. data up to and including Week 12 will be the 
primary (first) analysis for this study.  
A second planned analysis of the data after the EOS/Week 48 visit will be performed once all 
patients have completed or prematurely discontinued the study. 


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3 
Sample size calculation 
The primary objective of the study is to evaluate the effect of brolucizumab on CNV lesion area 
as measured by OCT-A in nAMD patients starting treatment with brolucizumab. This will be 
evaluated by the percentage change in CNV lesion area measured by OCT-A from Baseline to 
Week 12. The sample size calculation is based on the hypothesis of a standard deviation of 35% 
for this reduction proportion (Miere et al 2018).  
A sample size of 180 to 400 patients produces a 2-sided 95% CI with a distance from the mean 
to the limits ranges from 5.1 to 3.4 when the estimated standard deviation is 35.0 (nQuery 
Advisor version 7.0). Therefore, to have a precision of 5%, a sample size of 189 patients will 
be needed (Table 3-1).  
To take into account a dropout rate and uninterpretable images of 10%, a total of 210 patients 
will be included.  
Table 3-1 
Confidence intervals for one mean numeric results for 2-sided 
confidence intervals with unknown standard deviation 
 
Confidence Level 
Sample Size  
(N) 
Distance from Mean 
to Limits 
Standard Deviation 
(S) 
0.950 
180 
5.1 
35.0 
0.950 
189 
5.0 
35.0 
0.950 
233 
4.5 
35.0 
0.950 
250 
4.4 
35.0 
0.950 
300 
4.0 
35.0 
0.950 
350 
3.7 
35.0 
0.950 
385 
3.5 
35.0 
0.950 
400 
3.4 
35.0 
 
 
 
 
 
4 
Change to protocol specified analyses 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study treatment 
The following rules should be used for the imputation of the dose end date for a given study 
treatment component:  
Scenario 1  


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If the date of last IVT is completely missing and there is no end of treatment (EOT) page and 
no death date, the patient is considered as on-going.  
The patient should be treated as on-going and the cut-off date should be used as the last dosing 
date.  
Scenario 2  
If the dose end date is completely or partially missing and the EOT page is available:  
• Case 1: The dose end date is completely missing and the EOT completion date is 
complete, then this latter date should be used.  
• Case 2: Only year (YYYY) of the dose end date is available and YYYY < the year of 
EOT date, then use 31DECYYYY. 
• Case 3: Only year (YYYY) of the dose end date is available and YYYY = the year of 
EOT date, then use EOT date. 
• Case 4: Both year (YYYY) and month (MMM) are available for dose end date and YYYY 
= the year of EOT date and MMM < the month of EOT date, then use last day of the 
Month (MMM)  
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study.  
After imputation, compare the imputed date with start date of treatment.  
If the imputed date is < start date of treatment, then use the treatment start date. 
Otherwise, use the imputed date  
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should 
not be imputed.  
5.1.2 
AE date imputation 
AE date imputation is based only on a comparison of the partial AE start date to the treatment 
start date as mentioned in the below. 
• If the AE start date year value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the AE year value is missing, the imputed AE start date is set to 
NULL. 
• If the AE start date year value is less than the treatment start date year value, the AE 
started before treatment. Therefore: 
1. If the AE year is less than the treatment year and the AE month is missing, the 
imputed AE start date is set to the mid-year point (01JulYYYY). 
2. Else if the AE year is less than the treatment year and the AE month is not missing, 
the imputed AE start date is set to the mid-month point (15MONYYYY). 
• If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment. Therefore: 
1. If the AE year is greater than the treatment year and the AE month is missing, the 
imputed AE start date is set to the year start point (01JanYYYY). 


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2. Else if the AE year is greater than the treatment year and the AE month is not 
missing, the imputed AE start date is set to the month start point (01MONYYYY). 
• If the AE start date year value is equal to the treatment start date year value: 
1. And the AE month is missing or the AE month is equal to the treatment start month, 
the imputed AE start date is set to one day after treatment start. 
2. Else if the AE month is less than the treatment start month, the imputed AE start date 
is set to the mid-month point (15MONYYYY). 
3. Else if the AE month is greater than the treatment start month, the imputed AE start 
date is set to the start month point (01MONYYYY). 
 
 
MON 
MON < CFM 
MON = CFM 
MON > CFM 
 
MISSING 
YYYY 
MISSING NULL 
NULL 
NULL 
NULL 
 
Uncertain 
Uncertain 
Uncertain 
Uncertain 
YYYY < 
CFY 
(D) = 01JULYYYY 
(C)= 15MONYYYY 
(C)= 15MONYYYY 
(C)= 15MONYYYY 
 
Before Treatment Start Before Treatment Start Before Treatment Start Before Treatment Start 
YYYY = 
CFY 
(B)= TRTSTD+1 
(C)= 15MONYYYY 
(A)= TRTSTD+1 
(A)= 01MONYYYY 
 
Uncertain 
Before Treatment Start Uncertain 
After Treatment Start 
YYYY > 
CFY 
(E)= 01JANYYYY 
(A)= 01MONYYYY 
(A)= 01MONYYYY 
(A)= 01MONYYYY 
 
After Treatment Start  After Treatment Start  After Treatment Start  After Treatment Start  
Before Treatment Start  
Partial indicates date prior to Treatment Start Date 
After Treatment Start  
Partial indicates date after Treatment Start Date 
Uncertain 
Partial insufficient to determine relationship to Treatment Start Date 
LEGEND: 
(A) 
 MAX(01MONYYYY,TRTSTD+1) 
 
(B) 
TRTSTD+1 
 
 
(C) 
15MONYYYY 
 
 
(D) 
01JULYYYY 
 
 
(E) 
01JANYYYY 
 
 
 
5.1.3 
Concomitant medication date imputation 
This algorithm is used when event is the partial start date of the concomitant medication. 
The following table explains the notation used in the logic matrix. Please note that missing start 
dates will not be imputed. 
Day 
Month 
Year 
Partial CM Start Date 
Not used 
MON 
YYYY 


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Treat
 
m
 
ent 
StartTRTSDT ) Not used 
TRTM 
TRTY 
The following matrix explains the logic behind the imputation. 
MON MISSING 
MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY MISSING 
(C2) 
Uncertain 
(C1) 
Uncertain 
(C1) 
Uncertain 
(C1) 
Uncertain 
YYYY < TRTY 
(D) 
Before Treatment 
Start 
(A) 
Before Treatment 
Start 
(A) 
Before Treatment 
Start 
(A) 
Before Treatment 
Start 
YYYY = TRTY 
(C2) 
Uncertain 
(A) 
Before Treatment 
Start 
(C1) 
Uncertain 
(B) 
After Treatment Start 
YYYY > TRTY 
(E) 
After Treatment Start 
(B) 
After Treatment Start 
(B) 
After Treatment Start 
(B) 
After Treatment Start 
The following table is the legend to the logic matrix. 
Relationship 
Before Treatment Start Partial date indicates CMD start date prior to Treatment Start Date 
After Treatment Start 
Partial date indicates CMD start date after Treatment Start Date 
Uncertain 
Partial date insufficient to determine relationship of CMD start date relative to 
Treatment 
Start Date 
Imputation Calculation 
(A) 
15MONYYYY 
(B) 
01MONYYYY 
(C1 or C2) 
IF relative reference start 
= 
before treatment 
start 
THEN TRTSDT -1 
ELSE IF relative reference start =
‘ ’ THEN 
 TRTSDT +1 
(D) 
01JULYYYY 


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(E) 
01JANYYYY 
 
Concomitant Medication End Date Imputation 
If not ongoing then - 
Imputed date = date part of CMENDTC, if complete date 
Imputed date = min(completion/discontinuation visit date,  DEC 31) , if month is missing, (C2, 
D, E) 
Imputed date = min(completion/discontinuation visit date, last day of the Month) , if day is 
missing. (A, B, C1) 
Concomitant Medication Date Flag 
If not a complete date then 
Y - If year of the imputed date is not equal to YYYY  else M – If month of the imputed date is 
not equal to MON else D. 
5.2 
AEs coding/grading 
The verbatim term recorded on CRF will be identified as adverse event and will be coded by 
primary SOC and PT using Medical Dictionary for Regulatory Activities (MedDRA) version 
22.1 and above. 
5.3 
Vital signs parameters derivations 
The criteria for clinically notable abnormalities are defined as follows: 
Clinically notable elevated values  
• Systolic blood pressure of ≥ 140 mmHg (hypertension) 
• Diastolic blood pressure of ≥ 90 mmHg (hypertension) 
• Pulse rate ≥ 100 bpm (tachycardia). 
Clinically notable below normal values 
• Systolic blood pressure of < 90 mmHg (hypotension) 
• Diastolic blood pressure of < 60 mmHg (hypotension) 
• Pulse rate < 60 bpm (bradycardia)  
5.4 
Statistical methodology  
The below SAS code will used for statistical value. 
Frequency and proportion: 
proc freq data = <........>; 
tables response_variable/ chisq; 
run; 


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Summary Statistics: 
Univariate procedure will be used for continuous response. 
proc univariate data=<........>; 
 
var response_variable; 
output out=<........> n=_n mean=_mean std=_sd  min=_min median=_med           
max=_max; 
run; 
95% CI 
proc means data=adxe N NMISS CLM  ; 
 
var aval; 
run; 
Time to event analysis 
proc lifetest data=comb1 alpha=0.05 conftype=loglog method=KM alphaqt=0.05 
outsurv=survest; 
 
time AVALW*cnsr(0); 
run; 
Paired t-test 
proc ttest data = cnv_w12; 
paired FAS_EST*PPS_EST; 
run; 
Wilcoxon rank-sum test 
proc npar1way wilcoxon data = rnksm (label=’CNV lesion area at week 12’); 
class estimand;  
var area; 
run; 
 
AESI reported by investigator 
 
if AEDECOD in ("Anterior chamber cell", "Anterior chamber inflammation", 
"Vitritis", "Iritis", "Cyclitis", "Choroiditis", "Chorioretinitis", "Anterior 
chamber fibrin", "Uveitis","Noninfective chorioretinitis", "Ophthalmia 
neonatorum", "Aqueous fibrin", "Uveitis-glaucoma-hyphaema syndrome", "Retinitis", 
"Tubulointerstitial nephritis and uveitis syndrome", "Toxic anterior segment 
syndrome","Infective uveitis", "Vitreous haze", "Keratic precipitates", "Vitreous 
abscess", "Anterior chamber flare", "Cogan''s syndrome", "Noninfective retinitis", 
"Oculomucocutaneous syndrome","Eye infection intraocular", "Iridocyclitis", "Viral 
uveitis", "Viral keratouveitis", "Hypopyon", "Cyclitic membrane", "Eye 
inflammation", "Optic neuritis","Ocular pemphigoid", "Oculorespiratory syndrome", 
"Idiopathic orbital inflammation", "Papillitis") then 
 do; 
 
 
AEBODSYS1="Intraocular inflammation"; 
 
 
AESI="Y"; 
 
    end; 
else if  AEDECOD in ("Choroidal infarction", "Eyeinfarction", "Macular ischaemia", 
"Ocular ischaemic syndrome", "Retinal artery embolism", "Retinal artery 
occlusion","Retinal artery stenosis", "Retinal artery thrombosis", "Retinal 
infarction", "Retinal ischaemia", "Retinal vascular occlusion", "Retinal vascular 
thrombosis", "Retinal vein occlusion","Retinal vein thrombosis", "Necrotising 
retinitis", "Ocular vasculitis", "Retinal vasculitis","Retinal occlusive 
vasculitis") then  
do; 


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AEBODSYS1="Retinal Vasculitis and / or retinal vascular occlusion"; 
 
 
AESI="Y"; 
 
end; 
5.5 Rule of exclusion criteria of analysis sets  
Table 5-1 
Protocol deviations that cause patients to be excluded 
 
Deviation ID 
Description of Deviation 
Exclusion in Analyses 
Severity 
code 
INCL01 
Signed informed consent not obtained 
Excluded from FAS and 
PPS analysis 
1 
INCL02 
Age less than 50 year 
Included in everything  
0 
INCL03 
No active CNV lesions 
Excluded from FAS and 
PPS  
1 
INCL04 
No Intra- and/or subretinal fluid 
Excluded from FAS and 
PPS  
1 
INCL05 
Study eye BCVA out of range  
Excluded from PPS  
2 
EXCL01 
Active infection in either eye 
Excluded from PPS  
2 
EXCL02 
Fellow eye ocular disease 
Included in everything 
0 
EXCL03 
Poor quality images 
Included in everything 
0 
EXCL03a 
History of IOI 
Included in everything 
0 
EXCL05 
Study eye lesion area ≥50% 
Included in everything 
0 
EXCL05a 
Study eye atropathy or fibrosis 
Included in everything 
0 
EXCL07 
Study eye concomitant condition 
Included in everything 
0 
EXCL08 
Study eye macula damage 
Included in everything 
0 
EXCL09 
Study eye vitreous hemorrhage 
Included in everything 
0 
EXCL10 
Study eye uncontrolled glaucoma 
Included in everything 
0 
EXCL11 
Study eye aphakaia 
Included in everything 
0 
EXCL12 
Other treatment in study eye 
Excluded from PPS 
2 
EXCL13 
Steroids in study eye 
Included in everything 
0 
EXCL14 
Prior keratoplasty/vitrectomy 
Included in everything 
0 
EXCL15 
Study eye previous ocular treatment 
Included in everything 
0 
EXCL16 
End stage renal disease requiring 
dialysis or renal transplant 
Included in everything 
0 
EXCL17 
Systematic drug toxic to eye  
Included in everything 
0 
EXCL18 
Participation in another study  
Excluded from PPS  
2 
EXCL19 
Systematic anti-VEGF therapy  
Included in everything 
0 
EXCL20a 
Stroke or myocardial infraction  
Included in everything 
0 
EXCL21 
Uncontrolled blood pressure  
Included in everything 
0 
EXCL22 
Malignancy 
Included in everything 
0 
EXCL22a 
Medical condition impact 
Included in everything 
0 


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Deviation ID 
Description of Deviation 
Exclusion in Analyses 
Severity 
code 
EXCL24 
Hypersensitivity 
Included in everything 
0 
EXCL25 
Pregnant or nursing woman 
Included in everything 
0 
EXCL26 
Women of childbearing potential 
Included in everything 
0 
EXCL27 
Minor or protected adult  
Excluded from PPS  
2 
COMD01 
Prohibited medication/procedures  
Included in everything 
0 
COMD02 
Steroids use 5 days prior to IP 
Included in everything 
0 
TRT01 
Wrong IP administered 
Excluded from PPS  
2 
TRT02 
Incorrect dose administered 
Excluded from PPS  
2 
TRT03 
Pregnancy but not discontinued 
Included in everything 
0 
TRT04 
Short 
treatment 
window 
between 
treatment 
Included in everything 
0 
TRT05 
Treatment > 3 days after injection visit 
Included in everything 
0 
TRT06 
Injection given at Week 12 
Excluded from PPS 
2 
TRT07 
Q8W IVT out of window 
Included in everything 
0 
TRT08 
Q12W IVT out of window 
Included in everything 
0 
TRT09 
COVID-19 Drug supply change 
Included in everything 
0 
TRT10 
COVID-19 Treatment not given 
Included in everything 
0 
TRT11 
Missed Injection loading phase 
Excluded from PPS 
1 
TRT12 
Missed Injection 
Included in everything 
0 
TRT13 
No Disease activity but injection is given 
Included in everything 
0 
TRT14 
Treatment 
admin 
prior 
effic/safty 
evaluation 
Included in everything 
0 
TRT15 
Treatment given at EOS 
Included in everything 
0 
WITH01 
Withdrew consent not discontinued 
Excluded from FAS and 
PPS  
1 
OTHER01 
Patient rescreened > once 
Included in everything 
0 
OTHER02 
Severe ICH-GCP non-compliance 
Excluded from FAS and 
PPS  
1 
OTHER03 
New ICF is missing-rescreened 
Excluded from FAS and 
PPS  
1 
OTHER04 
Mishandling IP 
Included in everything 
0 
OTHER05 
Temperature excursion IP administered 
Included in everything 
0 
OTHER06 
Treatment regimen wrongly adjusted 
Included in everything 
0 
OTHER07 
Missed mandatory visit 
Excluded from PPS  
2 
OTHER08 
Missed injection visit 
Included in everything 
0 


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Deviation ID 
Description of Deviation 
Exclusion in Analyses 
Severity 
code 
OTHER09 
FA out of window 
Included in everything 
0 
OTHER10 
Rescreen due to BCVA results 
Included in everything 
0 
OTHER11 
Rescreen 
>14days 
w/o 
screening 
procedure 
Included in everything 
0 
OTHER13 
COVID-19 Missed visit 
Included in everything 
0 
OTHER14 
COVID-19 Visit not at site 
Included in everything 
0 
OTHER15 
COVID-19 Assessment changed 
Included in everything 
0 
OTHER16 
COVID-19 Discontinuation 
Included in everything 
0 
OTHER17 
Efficacy assessment not done 
Excluded from PPS  
2 
OTHER18 
Safety assessment not done 
Included in everything 
0 
OTHER19 
BCVA not done correctly 
Included in everything 
0 
OTHER20 
Visit window > 7 days 
Included in everything 
0 
OTHER21 
Vital signs/safety call not done 
Included in everything 
0 
OTHER22 
Imaging analyzed after WoC 
Included in everything 
0 
 
Table 5-2 
Patient Classification 
Analysis Set 
Severity codes that cause a subject to be excluded  
ENR 
NA 
FAS 
1 
FAS-EST 
1 
PPS 
1,2 (All specified PD in Table 5.1 due to COVID) 
PPS-EST 
1, 2 (All specified PD in Table 5.1 due to COVID-19) 
SAF 
NA 
 
 
6 
Reference 
Miere A, Oubraham H, Amoroso F, et al (2018) Optical Coherence Tomography 
Angiography to Distinguish Changes of Choroidal Neovascularization after Anti-VEGF 
Therapy: Monthly Loading Dose versus Pro Re Nata Regimen. J Ophthalmol. Epublished at 
[doi: 10.1155/2018/3751702]. 
 


Clinical Development 
RTH258/Brolucizumab 
CRTH258AFR01 / NCT04239027
A one-year, single-arm, open-label, multicenter study 
assessing the anatomic outcomes of brolucizumab 
assessed by OCT-A in adult patients with neovascular 
age-related macular degeneration (OCTOPUS) 
Statistical Analysis Plan (SAP)  
Author: 
Statistician, 
 
Document type: 
SAP Documentation 
Document status: 
Addendum version 1.0 
Release date: 
21-Jun-2023
Number of pages: 
39 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template Version 3.0, Effective from 01-Jul-2020 


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CRTH258AFR01 
 
Document History – Changes compared to previous final version of SAP 
Date 
Reason for update 
Outcome for update 
Section and title 
impacted 
(Current) 
02-03-2020 
Creation of initial 
version 
N/A - First version 
NA 
20-11-2020 
Amendment v1.0 
 
 
 
Visit window 
modified 
Visit window updated as per 
protocol 
Section 2.1.2 
 
Baseline 
characteristics 
include more 
variables  
Additional Baseline 
characteristics from  central 
reading center in Vienna are 
included 
Section 2.3.4 
 
Prior and 
concomitant Surgery 
and Procedures was 
not included 
Added Prior and concomitant 
Surgery and Procedures as 
a new section 
Section 2.4.3 
 
Study treatment 
exposure removed, 
the not required 
compliance section 
Updated study treatment 
exposure  
Section 2.4.1 
 
Dry retina details 
Section added for dry retina 
Section 2.5.1 
 
Presence of fluid 
add more details 
Updated presence of fluid 
Section 2.6.1 
 
Fluorescein 
Angiography (FA) 
add more details 
Updated Fluorescein 
Angiography (FA) 
Section 2.6.1 
 
Estimand not 
included 
Added section for estimand 
as new section 
Section 2.7 
 
Dry retina  
Section added for dry retina 
Section 2.6.1 
 
 
 
 
 
25-01-2023 
Amendment v2.0 
 
 
 
Update in protocol 
Updated protocol version 
number and release date 
Section 1 
 
Update number of 
patients and drop 
the number of site 
Sample size re – estimated 
and number of planned site 
dropped, change disease 
activity assessment 
Section 1.1 
 
 
 
 
 
 
 
 
 
Update in on-
treatment period 
definition 
On treatment period updated 
to 28 days from last 
treatment day 
Section 2.1.1 
 
Update in visit 
window interval 
Lower and upper value for 
visit window updated 
Section 2.1.2 


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CRTH258AFR01 
 
Date 
Reason for update 
Outcome for update 
Section and title 
impacted 
(Current) 
 
Update in population 
for disposition and 
protocol deviation  
Population set for disposition 
table and listing updated 
Section 2.3.1 and 
2.3.2 
 
Update in baseline 
characteristics 
nAMD category added
 
Section 2.3.4 
 
Update in ocular 
category 
Ocular category was 
updated  
Section 2.3.5, 
2.4.2, 2.4.3 and 
2.9.1 
 
Update in treatment 
exposure 
New category added 
Section 2.4.1 
 
Update in unit  
CNV lesion area unit 
updated 
Section 2.5.1 
 
Update in BCVA 
group 
Loss of BCVA category 
updated 
Section 2.6.1.4 
 
Update in date 
Start date and end date 
consideration updated 
Section 2.6.1.5.1  
 
 
Start date consideration 
updated 
Section 2.6.1.6.1 
 
Update in CPF and 
fundus examination 
question  
Vasculitis added in CFP and 
fundus examination 
Section 2.8.1 and 
2.8.5 
 
Update in FAF 
question  
Foveal atrophy added in FAF 
question 
Section 2.8.2 
 
Update in AEs 
section 
Added procedure related, 
remove EudraCT 
requirement 
Section 2.9.1 
 
Update in AESI 
analysis  
Details for AESI analysis is 
added 
Section 2.9.1.1 
 
 
 
 
 
 
 
 
 
Update in sample 
size calculation  
Sample size re-estimation  
Section 3 
 
Added protocol 
change analysis 
Added protocol change 
analysis for estimand 
Section 4 
 
Update in statistical 
methodology 
SAS code for correlation and 
Bland-Altman plot is deleted. 
Added code AESI derivation 
Section 5.4 
 
Update in protocol 
deviation list and 
severity code 
New protocol deviation 
category added, severity 
updated and patient 
classification updated 
Section 5.5 
05-04-2023 
Amendment V3.0 
 
 


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CRTH258AFR01 
 
Date 
Reason for update 
Outcome for update 
Section and title 
impacted 
(Current) 
 
Update in visit 
window 
Lower limit for Week 44 
updated 
Section 2.1.2 
 
Dropped category 
for ≤ Week 12 and > 
Week 12 
Under drug exposure ≤ 
Week 12 and > Week 12 
dropped 
Section 2.4.1 
 
Update in sequence 
of variable 
Sequence of expected 
variable changed 
Section 2.6.1.2.4, 
2.6.1.2.5, 
2.6.1.5.1 
 
 
 
 
 
Update in Date 
imputation rule 
The same method for date 
imputation used for medical 
history (nAMD) 
Section 5.1.3 
 
Updated in SAS 
code for t-test 
SAS code for t-test updated 
Section 5.4 
15-06-2023 
Addendum V1.0 
 
 
 
Added definition for 
maximum duration 
of dry retina 
Added definition for 
maximum duration of dry 
retina 
Section 2.1.1 
General 
definitions 
 
Updated date and 
censor  
Logic for start date, end date 
and censor was updated 
Section 2.6.1.2.5 
Maximum 
duration of 
dryness 
 
Event and censor 
logic updated 
Updated event and censor 
description for need of first 
q12w 
Section 2.6.1.5.1 
Predictive value of 
first q12w cycle 
maintenance 
 
nAMD date impution 
rule 
Rule for partial nAMD history 
dates should similar to prior 
concomitant medication 
Section 5.1.3 
Concomitant 
medication and 
medical history 
(nAMD) date 
imputation 
Hyperlinks were not updated for the amendment v1.0 for the versions dated 20-11-2020 due change in 
section numbers. 


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SAP Addendum Version 1.0 
 
CRTH258AFR01 
 
Table of contents 
Table of contents ................................................................................................................. 5 
List of abbreviations ............................................................................................................ 7 
1 
Introduction ......................................................................................................................... 9 
1.1 
Study design ............................................................................................................ 9 
1.2 
Study objectives and endpoints ............................................................................. 11 
2 
Statistical methods ............................................................................................................. 12 
2.1 
Data analysis general information ......................................................................... 12 
2.1.1 
General definitions ................................................................................ 12 
2.1.2 
Visit windows for data analysis ............................................................ 15 
2.2 
Analysis sets .......................................................................................................... 16 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 17 
2.3.1 
Patient disposition ................................................................................. 17 
2.3.2 
Protocol deviation ................................................................................. 17 
2.3.3 
Demographic characteristics ................................................................. 18 
2.3.4 
Baseline characteristics ......................................................................... 18 
2.3.5 
Relevant medical history / current medical condition ........................... 19 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies) ............. 20 
2.4.1 
Study treatment exposure ...................................................................... 20 
2.4.2 
Prior, concomitant and post therapies ................................................... 20 
2.4.3 
Prior and concomitant surgery and procedures ..................................... 21 
2.5 
Analysis of the primary objective .......................................................................... 21 
2.5.1 
Primary endpoint ................................................................................... 21 
2.5.2 
Supportive analyses ............................................................................... 21 
2.6 
Analysis of secondary efficacy objectives ............................................................. 22 
2.6.1 
Secondary endpoints ............................................................................. 22 
 
 26 
 
 26 
2.8 
Analysis of other efficacy variables ...................................................................... 26 
2.8.1 
Color fundus photography..................................................................... 26 
2.8.2 
Fundus autofluorescence (FAF) ............................................................ 26 
2.8.3 
Indocyanine green angiography (ICG) .................................................. 27 
2.8.4 
Intraocular pressure ............................................................................... 27 
2.8.5 
Fundus examination .............................................................................. 27 
2.9 
Safety analyses....................................................................................................... 27 
2.9.1 
Adverse events (AEs) ............................................................................ 28 


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CRTH258AFR01 
 
2.9.2 
Deaths .................................................................................................... 29 
2.9.3 
Laboratory data ..................................................................................... 29 
2.9.4 
Other safety data ................................................................................... 29 
2.10 
Pharmacokinetic endpoints .................................................................................... 30 
2.11 
PD and PK/PD analyses ........................................................................................ 30 
2.12 
Biomarkers ............................................................................................................. 30 
2.13 
Other exploratory analyses .................................................................................... 30 
2.14 
Interim analysis ...................................................................................................... 30 
3 
Sample size calculation ..................................................................................................... 30 
4 
Change to protocol specified analyses .............................................................................. 31 
5 
Appendix ........................................................................................................................... 31 
5.1 
Imputation rules ..................................................................................................... 31 
5.1.1 
Study treatment ..................................................................................... 31 
5.1.2 
AE date imputation ............................................................................... 32 
5.1.3 
Concomitant medication and medical history (nAMD) date 
imputation ............................................................................................. 33 
5.2 
AEs coding/grading ............................................................................................... 34 
5.3 
Vital signs parameters derivations ......................................................................... 35 
5.4 
Statistical methodology ......................................................................................... 35 
5.5 Rule of exclusion criteria of analysis sets ................................................................... 36 
6 
Reference ........................................................................................................................... 39 


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SAP Addendum Version 1.0 
 
CRTH258AFR01 
 
List of abbreviations 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Classification 
BCVA 
Best Corrected Visual Acuity  
BCNVA 
Best Corrected Near Visual Acuity 
CNV 
Choroidal Neovascularization  
CFP 
Color Fundus Photography  
COVID-19 
Coronavirus disease 2019 
CI 
Confidence Interval 
CRC 
Central Reading Center  
CRO 
Contract Research Organization 
CSFT 
Central Sub-Field Retinal Thickness  
CRT 
Central Retinal Thickness 
CSR 
Clinical Study Report 
eCRF 
Electronic Case Report Form 
ENR 
Enrolled set 
FA 
Fluorescein Angiography  
FAF 
Fundus AutoFluorescence  
FAS 
Full Analysis Set 
ICF 
Informed Consent Form  
IGC 
Indocyanine Green Chorioangiography  
IOP 
Intraocular Pressure  
IVT 
Intravitreal  
KM 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
nAMD 
Neovascular Age-Related Macular Degeneration  
OCT 
Optical Coherence Tomography  
PK 
Pharmacokinetics 
PD 
Protocol deviation 
PDS 
Programming Datasets Specifications 
PPS 
Per-Protocol Set 
PT 
Preferred Term 
q8w 
Every 8 Weeks  
q12w 
Every 12 Weeks  
SAP 
Statistical Analysis Plan 
SAF 
Safety analysis set 
SD-OCT  
Spectral Domain Optical Coherence Tomography  


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CRTH258AFR01 
 
SOC 
System Organ Class 
SRC 
Safety review commitee 
TFL 
Tables, Figures, Listings 
WHO 
World Health Organization 
 
 


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1 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to describe the implementation of the 
statistical methods for all safety and efficacy analyses planned (Section 12) in the clinical 
protocol (CRTH258AFR01, version no: 04, release date 16Nov2021). This document will be 
used to prepared the statistical results and the corresponding Clinical Study Report (CSR).  
The details of CSR deliverables (shells for tables, figures and listings) and further programming 
specifications will be described in the Tables, Figures & Listings (TFL) shells and 
Programming Datasets Specifications (PDS) respectively will be included in this document.  
Data will be analyzed by Novartis and/or the designated Contract Research Organization (CRO). 
Statistical software SAS version 9.4 or higher will be used for generating TFLs.  
1.1 
Study design 
This is a prospective, single-arm, open-label, multicenter study to evaluate the efficacy and 
safety of brolucizumab 6 mg in patients with nAMD. 
Patients will be required to attend 6 mandatory study visits: Screening/Baseline Visit (Day 1), 
Week 4, Week 8, Week 12, Week 16 and Week 48 visits. The timing of the interim visits 
between Week 16 and Week 48 will depend on the patient’s injection regimen, i.e. q12w or 
q8w.  
Planned number of patients 
Approximately 210 adult patients will be screened and included (10% dropout rate and 
uninterpretable images at Baseline and Week 12 are expected) in France. The maximum study 
duration for 1 patient is 48 weeks, including Screening. 
There will be 2 periods in this study (see Figure 1-1): 
• Open-label treatment period: from Screening/Baseline (Day 1) to Week 40/Week 44 
(depending on assigned regimen) 
• Follow-up period: Week 40/Week 44 to Week 48  


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Figure 1-1 
Study design 
 
* Week 40 or Week 44 according to treatment schedule  
** End of study visit: 4 or 8 weeks after the last IVT, depending on the last IVT date 
Patients will receive 3 initial doses every 4 weeks ((Day 1, Week 4 and Week 8) loading phase), 
which should be at least 21 days apart, followed by treatment q12w with the possibility of 
adjusting to treatment q8w based on disease activity.  
Disease activity will be assessed based on investigator’s judgment of visual acuity and 
anatomical parameters as provided in the guidance to the investigators, e.g. decrease of visual 
acuity and/or other signs of the disease (e.g. intraretinal fluid (IRF), subretinal fluid (SRF), 
sub-retinal pigmented epithelium (sub-RPE) fluid, retinal hemorrhage, central retinal thickness 
(CRT) increase, etc.). Disease activity will be assessed during the first q12w interval at Week 
16. If no disease activity is observed by the investigator in the study eye, disease activity will 
be assessed every 12 weeks (at Week 20, Week 32 and Week 44). If disease activity is observed 
by the investigator in the study eye at any of these visits, the study treatment will be adjusted 
by the investigator to a q8w treatment regimen and will remain on this regimen until 
Week 40/Week 44. Patients who require study treatment every 4 weeks after the initiation phase 
will be discontinued from further study treatment at the next visit. 


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1.2 
Study objectives and endpoints 
Table 1-1 
Objectives and related endpoints  
Objectives 
Endpoints 
Primary objectives 
Endpoints for primary objectives 
• 
To evaluate the short-term effect of 
brolucizumab on CNV lesion area as 
measured by OCT-A in nAMD patients. 
• 
Percentage change in CNV lesion area 
measured by OCT-A from Baseline to 
Week 12. 
Secondary objectives 
Endpoints for secondary objectives 
• 
To evaluate the long-term effects of 
brolucizumab on CNV morphology as 
measured by OCT-A in nAMD patients.  
• 
Percentage change in CNV lesion area 
measured by OCT-A from Baseline to 
Week 48. 
• 
Change in OCT-A features assessed by 
qualitative and quantitative criteria from 
Baseline by visit at Week 12 up to 
Week 48. 
• 
To evaluate the effect of brolucizumab on 
anatomical parameters as assessed by SD-
OCT and FA from Week 12 up to Week 48. 
• 
Change in SD-OCT and FA features 
assessed by qualitative and quantitative 
criteria (e.g. CSFT, sub- and/or intraretinal 
fluid, sub-RPE fluid) from Baseline by 
visit up to Week 48.  
• 
To evaluate the efficacy of brolucizumab up 
to Week 48 by assessing changes in BCVA. 
• 
Change in BCVA from Baseline up to 
Week 48. 
• 
To estimate the proportion of patients treated 
at q12w frequency with brolucizumab. 
• 
Proportion of patients who are maintained 
on an exclusive q12w interval following 
the loading phase through to Week 48. 
• 
To estimate the predictive value of the first 
q12w cycle for maintenance of q12w 
treatment with brolucizumab. 
• 
The probability of the first q12w interval 
for determining successful q12w 
maintenance at Week 48. 
• 
To evaluate the time from last IVT injection 
in the initiation phase to first visit with no 
disease activity. 
• 
Time from last IVT injection in the 
initiation phase to first visit with no disease 
activity.  
• 
To evaluate the safety of brolucizumab. 
• 
Incidence of AEs (serious and non-serious) 
reported in patients treated with 
brolucizumab. 
AEs= adverse events, BCVA= best corrected visual acuity, CNV= choroidal neovascularization, 
CSFT= central sub-field retinal thickness, FA= fluorescein angiography, IVT= intravitreal 
nAMD= neovascular age-related macular degeneration, OCT-A= optical coherence tomography-
angiography, SD-OCT= spectral domain optical coherence tomography, sub-RPE= subretinal 
pigmented epithelium 
 


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2 
Statistical methods 
2.1 
Data analysis general information 
Patients who consent and meet all the inclusion and none of the exclusion criteria will be 
screened to evaluate eligibility. After confirmation of eligibility, patients will be included and 
treated with brolucizumab 6 mg and data will be analyzed. 
All categorical data will be presented in terms of frequencies and percentages. Summaries of 
continuous data will be presented in terms of n (the number of non-missing data points), mean, 
standard deviation (SD), median, lower and upper quartiles, minimum, maximum and the 
number of missing data points. 
For descriptive statistics, the following rules for number of decimal places will be applied: 
arithmetic mean, median, lower quartile and upper quartile to 1 more decimal places than the 
raw data; minimum and maximum to the same number of decimal places as the raw data and 
SD to 2 more decimal places than the raw data. Percentages will be presented to 1 decimal place.  
2.1.1 
General definitions  
Study treatment: This is a single-arm study and all patients will be treated with brolucizumab 
6 mg. Three loading injections (at Screening/Baseline/Day 1, Week 4 and Week 8), followed 
by maintenance treatment from Week 16/Week 20 up to Week 40/Week 44. The investigator 
can individualize treatment intervals depending on disease activity, to adjust patient’s injection 
regimen. 
Study treatment start and end date: Study treatment start date is defined as the first date study 
treatment is administered and recorded on the treatment administration record (DAR) electronic 
case report form (eCRF) page. Similarly, study treatment end date is defined as the last date of 
study treatment is administered and recorded on the study treatment completion CRF page. 
Generally, study day 1 is considered as the day of inclusion of the patient. However in this study, 
treatment is intended to be administered on the same day or if this is not possible, within 3 days 
after the day of inclusion of the patient.  
Study day will be calculated as (event date – study treatment start date + 1 day) for events that 
occurred on or after study treatment start date (e.g. visit, AEs). For events prior to study 
treatment start date (e.g. time since diagnosis), study day will be negative and calculated as 
(event date – study treatment start date).  
Baseline and post-baseline: Baseline value refers to the value of the last non-missing 
measurement collected prior to administration of the first dose of study treatment (Screening or 
Baseline visit). Intraocular pressure (IOP) will be assessed in the study eye, pre-dose and 
post-dose at every injection. The last available assessment taken prior to the first IVT injection 
of study treatment is taken as the “Baseline” assessment.   
A “post-baseline” value refers to a measurement taken after the first dose of study treatment. 
When assessments and treatments take place on the same day, treatment must occur after 
completion of the efficacy assessments and pre-injection safety measures (tonometry, slit lamp 
and fundus examinations). If study visit assessments and the corresponding treatment occur on 
separate days, a repeat safety check-up will be performed prior to treatment of the eye and 


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results documented in the source documents. More post-baseline safety measurements will be 
recorded in source document; visit window will be applied to OCT and IVT visits. 
Change from Baseline: The difference of measure between post-baseline and Baseline is called 
change from Baseline. 
Percent change from Baseline: The percent change from Baseline will be calculated as below: 
((post-baseline value – Baseline value) /Baseline value)*100. 
On-treatment period: The on-treatment period lasts from the date of first administration of 
study treatment to 28 days after the date of the last actual administration of any study treatment. 
Treatment duration: The maximum planned duration of treatment for each patient is 40 to 44 
weeks in accordance with the designated treatment regimen. Discontinuation of study treatment 
for a patient occurs when study treatment is stopped earlier than the protocol planned duration 
and can be initiated by either the patient or the investigator. 
Treatment discontinuation: When patients discontinue study treatment but continue in the 
study, the efficacy data will be used at the time the patient stopped study treatment. 
Dry retina: Absence of fluid (IRF/SRF/sub-RPE) will be considered as dry retina. 
Event for maintenance q12w interval: In case the investigator selects q12w interval for a 
patient and the patient maintains the q12w interval until the first q8w interval has started then 
this will be considered as an event. In case the investigator maintains q12w interval (does not 
select q8w interval at any time in study) until EOS or patients got early discontinuation from 
study then patients will be considered as censored. 
Event for no disease activity: When patients will be with no disease status as per investigator 
decision after last dose in initiation phase then the patients will consider as event for disease 
activity. If patients with active disease status or early discontinue then patients will be 
considered as censored for disease activity. 
Event for dry retina: When patients have absence of fluid then it will be considered as an event 
of dry retina. If patients have a presence of fluid before/at EOS or early discontinuation then 
will be censored. 
Maximum duration of dry retina: The longest consecutive interval of dryness will be 
considered as maximum duration of dryness. This duration will be obtained from end date of 
dryness and start date of dryness for longest interval. If subjects obtain dryness at end of study 
then duration will be obtained from end of treatment. 
Study eye and fellow eye: The investigator selects the eye with the worse BCVA at Screening 
as the study eye. Otherwise, the investigator deems as a study eye more appropriate to select 
the eye with better BCVA, based on medical reasons or local ethical requirements. If both eyes 
are eligible as per the inclusion and exclusion criteria, then it is recommended to select the right 
eye as the study eye. 
The fellow eye will be examined only at Screening/Baseline and Week 48/EOS visits. Only 
best corrected near visual acuity (BCNVA) for the fellow eye will be analyzed. It is not 
requested for the purpose of this study to do any self-assessment measure of the fellow eye. 


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CNV lesion area 
A new angiography tool, namely optical coherence tomography-angiography (OCT-A) is a 
dye-less angiographic procedure based on split-spectrum-decorrelation-amplitude angiography 
that has become an essential and widely used tool, particularly for imaging CNV and vascular 
diseases of the retina. The literature suggests that OCT-A is a good marker for assessing 
anti-VEGF therapeutic response, especially the lesion size that has been demonstrated to 
decrease under anti-VEGF therapy.  
OCT-A will be used in this study to assess the morphological response of patients to 
brolucizumab in terms of percentage change in CNV lesion area in the short term (i.e. at 
Week 12 just after loading doses) and in the long term (i.e. at Week 48 [12 months]), as well as 
changes in other OCT-A features up to Week 48.  
The primary endpoint is the percentage change in CNV lesion area measured by OCT-A from 
Baseline to Week 12. The Week 12 time point has been selected as peak efficacy has been 
demonstrated in the pivotal trials of brolucizumab for this time point. 
Anatomic parameters measured by OCT-A and SD-OCT 
Anatomic parameters measured by OCT-A and by SD-OCT will be analyzed by a CRC. The 
main aim of the CRC analysis is to confirm anatomic features from OCT-A and SD-OCT 
images for the primary endpoint. The investigator will evaluate the OCT-A and SD-OCT 
images to assess the status of disease stability. 
Disease activity criteria 
Disease activity criteria will be assessed by the investigator based on whether nAMD is still 
active or has been re-activated. Guidance for the investigator is as follows (disease is active if 
at least one of the following criteria is observed by the investigator):  
• BCVA decrease ≥ 5 letters from the best value since Baseline due to disease activity.  
• Any significant increase in CRT (based on investigator assessment). 
• Retinal hemorrhage. 
• Intraretinal fluid or SRF due to disease activity (degenerative cysts allowed). 
• Increase of sub-RPE fluid. 
These criteria are for guidance only, the investigator may define disease activity based on 
his/her own assessment.  
A patient who misses Week 16 will undergo the disease activity assessment at Week 20 as 
he/she would have done if the visit had not been missed. If, however, a patient misses any of 
the following disease activity assessment visits (Week 20, Week 32) then the patient will be 
assumed to have met the disease activity criterion at the missed visit and will be reassigned to 
a q8w regimen up to study exit.  
If a patient misses Week 12, then the Week 8 values will be applied as the reference for disease 
activity assessments up to and including Week 44.  


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Fluorescein angiography: Fluorescein angiography (FA) is a diagnostic procedure that uses a 
special camera to record the blood flow in the RETINA – the light sensitive tissue at the back 
of the eye.  
Color fundus photography (CFP): CFP is a diagnostic procedure that involves the use of a 
device known as a fundus camera to record colored images of the interior surface of the eye. 
The goal of this procedure is to monitor the presence of disorders and their change with time.  
Fundus autofluorescence (FAF): Fundus autofluorescence imaging is an in vivo imaging 
method for metabolic mapping of naturally or pathologically occurring fluorophores of the 
ocular fundus. 
Indocyanine green angiography (ICG): ICG is a diagnostic procedure that uses ICG dye to 
examine the blood flow in the choroid – the layer of blood vessels that lies underneath the retina. 
ICG is injected into a vein in the arm/hand. As the dye passes through the blood vessels of the 
eye, photographs are taken to record the blood flow. 
Intraocular pressure (IOP): IOP is the fluid pressure of the eye. IOP is measured in 
millimeters of mercury (mmHg). Normal eye pressure is usually considered to be between 10 
and 25 millimeters of mercury (mmHg). 
Fundus examination: Fundus examination used to assess diagnose vitro-retinal diseases (such 
as retinal haemorrhage, vitreal haemorrhage, retinal tear and detachment), optic nerve defects 
and hereditary diseases. 
 
2.1.2 
Visit windows for data analysis 
Visit windows will be used for the data analysis, as per the planned visits in the protocol. During 
the q12w/q8w phase, i.e., from Week 16 to Week 44, the treatment visit intervals will be 
determined by the investigator, based on the patient’s disease activity. 
Table 2-1 
Assessment windows for scheduled visits 
Analysis Visit 
Week 
Scheduled Day 
Visit Window 
Screening/Baseline 
BL 
1 
-14 days to Day 1* 
Week 4 
4 
28 
Day 22 - 34 
Week 8 
8 
56 
Day 50 – 62 
Week 12 
12 
84 
Day 71 – 97 
Week 16 
16 
112 
Day 99 – 119 
Week 20 
20 
140 
Day 127 – 153 
Week 24 
24 
168 
Day 155 – 182 
Week 28 
28 
196 
Day 183 – 209 
Week 32 
32 
224 
Day 211 – 237 
Week 36 
36 
252 
Day 239 – 265 
Week 40 
40 
280 
Day 267 – 293 
Week 44 
44 
308 
Day 295 – 321 
Week 48 
48 
336 
Day 323 – 349 


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* Baseline measurement before the first treatment administration. 
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. Injections are contraindicated in patients with active intraocular 
or periocular infections and in patients with active intraocular inflammation; therefore, the 
investigators should verify that these conditions are not present in the study eye prior to every 
injection. Any AEs must be recorded in the eCRF.  
The injection procedure for brolucizumab will be performed according to local clinical practice. 
Injections will be administered by the investigator.  
Data collected at unscheduled visits will not be used in ‘by-visit’ tabulations or graphs and will 
be presented in listings. 
2.2 
Analysis sets 
Enrolled Analysis Set (ENR): The ENR set includes all patients who signed an ICF and are 
assigned patient numbers. 
Full Analysis Set (FAS): The FAS comprises all patients to whom study treatment has been 
assigned and who received at least one IVT injection of study treatment.  
Safety Set (SAF): The SAF set includes all patients who received at least one IVT injection of 
study treatment.  
Per-Protocol Set (PPS): The PPS is a subset of patients in the FAS without PDs with impact. 
The list of PD criteria will be provided in edit checks specification (ECS) document.  
Full Analysis Set Estimand (FAS-EST): The FAS-EST comprises all patients who are in the 
FAS and did not discontinue treatment in the entire study due to COVID-19. 
Per-Protocol Set Estimand (PPS-EST): The PPS-EST is a subset of patients of the FAS-EST 
without PDs with impact. 
When assessing the robustness of the overall efficacy conclusions, considerations will be given 
to the analysis based on the estimand using FAS-EST and PPS-EST. The expectation for 
comparing both estimands is to have similar conclusions. Inconsistencies in the results will be 
examined and discussed in the CSR. 


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2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
The FAS will be used to prepare the summary and ENR will be used for listing of patient 
disposition. 
The number and percentage of patients who completed the study and discontinued from the 
study will be summarized with reasons for premature discontinuation for the ENR. In addition, 
the number of screen failures with reasons will be presented for all screened patients. The 
patient identification number and whether patients completed or discontinued from the study 
will be listed, with date of last dose and primary reason for premature discontinuation.  
A separate summary of disposition and listing for rescreened patients will be presented for the 
ENR. 
Study treatment will be discontinued under the following circumstances:  
• Adverse event 
• Death 
• Lost to follow-up 
• Physician decision  
• Pregnancy  
• Progressive disease 
• Protocol deviation  
• Study terminated by sponsor 
• Technical problem 
• Patient decision 
• New therapy for study indication  
• Lack of efficacy 
• Use of prohibited treatment  
• Any situation in which study participation might result in a safety risk to the patient 
2.3.2 
Protocol deviation 
The number and percentage of patients with protocol deviations will be tabulated by category 
and deviation for the FAS. Patients with protocol deviations will be listed with date and study 
day of occurrence, deviation and severity codes for the ENR. 
The number of patients included in each analysis set will be tabulated for all enrolled patients. 
Reasons for exclusion from analysis sets will be tabulated for the ENR. Patient exclusion from 
analysis sets will be listed for all patients with reasons for exclusion (i.e., both protocol and 
non-protocol deviations). 


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2.3.3 
Demographic characteristics 
Demographic and Baseline characteristics will be listed and summarized descriptively for 
overall patients on FAS and Safety Set. 
The following demographic and vital signs variables collected in the eCRF at Baseline will be 
summarized: 
• Sex (male, female) 
• Age (in years) 
• Age category (< 50, 50 - 65, 65 - 75, 75 - 85, ≥ 85) 
• Study eye (left [OS], right [OD])  
• Vital signs (sitting systolic/diastolic blood pressure [mmHg], sitting pulse rate [bpm]) only 
on the days study treatment is administered, it is measured prior study treatment  
2.3.4 
Baseline characteristics 
The following Baseline characteristics collected in the eCRF at Baseline will be summarized 
for study eye and fellow eye (wherever applicable): 
• Time since nAMD diagnosis 
• Time since nAMD diagnosis (< 1 month, 1-3 months and > 3 months) 
• Unilateral versus bilateral nAMD 
• BCVA 
• BCVA (≤ 55, 56 - 70, ≥ 71) 
• BCVA categories (count fingers, hand motion, light perception, no light perception) in 
case BCVA score is 0 
• FA (analyzed by Vienna [CRC]) 
1. Lesion type (only at Baseline) (predominantly classic, minimally classic, occult) 
2. Lesion type (only at Baseline) (type 1 / type 2 / type 3 / type 1 with aneuvrism / 
polyps) 
3. CNV location (subfoceal, juxtafoveal, extrafoveal) 
4. Area of lesion associated with CNV (mm2) 
• ICG (analyzed by Vienna [CRC]) 
1. Lesion type (only at Baseline) (type 1 / type 2 / type 3 / type 1 with aneuvrism / 
polyps) 
2. Area of lesion associated with CNV (mm2) 
• SD-OCT (analyzed by Vienna [CRC])  
• Lesion type (only at Baseline) (type 1, type 2, type 3) 
• CSFT (µm) 
• Baseline CSFT (< 300, ≥ 300 - 450, ≥ 450 - < 650, ≥ 650 [μm]) 
• Presence of fluid (YES/NO) 
1. Intraretinal fluid 
2. Subretinal fluid 
3. Sub-RPE fluid 
• Volume (mm3) and height (µm) of each fluid (in case of presence) 
1. Intraretinal fluid 


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2. Subretinal fluid 
3. Sub-RPE fluid 
• In case of sub-RPE /  PED : nature : serious PED / fibrovascular PED / mixed PED 
• OCT-A (analyzed by Vienna)  
1. CNV location (only at Baseline) 
2. CNV lesion area (at the biggest surface) (mm²/µm²) 
• Fundus observation  
1. Retinal hemorrhage (none, retinal macular and retinal non-macular) 
2. Presence of vitreal hemorrhage (Yes, No) 
3. Retinal tear/ detachment (none, tear, detachment, both) 
• Color fundus photography (CFP) 
1. Presence of retinal or subretinal hemorrhage (Yes, No) 
2. Presence of fibrosis (Yes, No) 
3. Presence of atrophy (Yes, No) 
4. Subretinal blood affecting foveal center point and/ or > 50% of total lesion (Yes, No) 
• Fundus autofluorescence (FAF) 
1. Presence of macular atrophy (Yes, No) 
2. Area of macular atrophy 
• Intraocular pressure 
• Intraocular pressure (≤ 10, 10-25, 25-30 and ≥ 30 [mmHg]) 
• Disease activity assessment (Present) 
• History of primary diagnosis:  
1. Disease (neovascular age-related, macular degeneration [nAMD]) 
2. Age of diagnosis 
3. Eye (OD, OS) 
4. Ongoing (Yes, No) 
• History or evidence of the following in the study eye within the 90-day period prior to 
Screening/Baseline: 
1. Intraocular or refractive surgery 
2. Previous panretinal photocoagulation 
3. Previous submacular surgery, other surgical intervention or laser treatment for nAMD 
including photodynamic therapy (PDT) 
• Concomitant medication at Baseline  
• Medical history 
• Co morbidities  
2.3.5 
Relevant medical history / current medical condition 
Medical history / current medical conditions (general and ocular) will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) terminology. History/conditions will 
be summarized for the FAS by primary system organ class (SOC), preferred term (PT) by eye 
(any eye, study eye and fellow eye). Verbatim recorded history/conditions will be listed together 
with the coded terms, date of diagnosis/surgery and whether the problem was ongoing at start 
of the study. The ongoing medical history will be considered as co morbidities. The co 
morbidities will be summarized and listed separately for eye (any eye, study eye and fellow eye 
and both eye). 


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2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies) 
2.4.1 
Study treatment exposure 
Extent of exposure to study treatment is calculated as the number of IVT injections received. 
The following summaries will be presented: 
1. Overall number of injections (n, q1, median, q3, min and max) will presented. 
2. Number of injection (n, q1, median, q3, min and max) before or at Week 8 and greater 
than Week 8. 
3. Number of patients with injection (1 injection, 2 injections up to the maximum number of 
injections) from Baseline to the end of the treatment period will be presented. 
4. Treatment exposure by visit: The number and percentage of patients who received 
injections, missed a treatment and missed visits will be presented by visit. 
5. Summary statistics (n, mean, std, median, min and max) for overall duration will be 
provided. 
The number and percentage of patients for changes in brolucizumab 6 mg treatment patterns 
over time (i.e. interruptions or permanent discontinuations) along with reasons, will be 
summarized. Discontinuations and primary reasons for treatment and/or study discontinuation 
will also be described. 
Exposure data will be summarized for the Safety Set and FAS. The exposure data will be listed 
for the FAS. 
2.4.2 
Prior, concomitant and post therapies 
Each medication has the start and end dates recorded on the eCRF. Prior medications are defined 
as those medications which were taken and stopped prior to first dose of study treatment. 
Concomitant medications are defined as any medication given at least once between the day of 
first dose of study treatment and the last day of study visit, including those which were started 
pre-baseline and continued into the treatment period. The below summary tables will be 
reported: 
• Prior medication 
• Concomitant medications which started prior to first dose of study treatment 
• Concomitant medications which started on/after first of study treatment 
All prior and concomitant medications will be coded using the most recent version of the WHO 
drug dictionary. All concomitant medications (general and ocular) will be listed and 
summarized in alphabetic order according to anatomical therapeutic chemical (ATC) 
classification system and PT. Tables will also show the overall number and percentage of 
patients receiving at least one treatment of a particular ATC. 
For prior and concomitant ocular medications, as well as ocular procedures performed during 
the study, separate tabular summaries will be prepared for the any eye, study eye and the fellow 
eye. A listing of all prior and concomitant medications and concomitant procedures will be 
provided. 


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For handling of missing or incomplete start and end dates, see Appendix 5.1.3 of this document. 
All summaries will be performed on the Safety Set. 
2.4.3 
Prior and concomitant surgery and procedures 
All prior and concomitant surgery and procedures will be summarized and listed by category 
(general, ocular) and eye (any eye, study eye and fellow eye).  
For handling of missing or incomplete start and end dates, see Appendix 5.1.3 of this document. 
All summaries will be performed on the Safety Set. 
2.5 
Analysis of the primary objective 
2.5.1 
Primary endpoint 
OCT-A will be used in this study to assess the morphological response of patients to 
brolucizumab. In terms of percentage change in CNV lesion area (at the biggest surface) (mm²). 
The primary endpoint is the percentage change in CNV lesion area measured by OCT-A from 
Baseline to Week 12 in the study eye. The percentage change from Baseline at Week 12 in the 
lesion area will be derived as follows: 
([Lesion area at Week 12 – Lesion area at Baseline]*100)/ Lesion area at Baseline 
Descriptive statistics (n, mean, std, median, min and max) for the primary endpoint (actual value, 
change from Baseline, percentage change from Baseline) will be presented based on observed 
data using the FAS. Furthermore, a 2-sided 95% CI using Student’s t-distribution will also be 
provided. In case of significant outliers or deviations from normality assumptions then IQR will 
be presented. 
The last observation carried forward (LOCF) method will be used as sensitivity analysis to 
impute missing record for CNV lesion area at post baseline. If there is significant amount of 
missing record then another table with LOCF records should be created.  
The above analysis will be done only on the study eye. The analysis will be performed on FAS. 
The analysis will be performed on the PPS, if there is more than a 10% difference in patients, 
between the FAS and PPS.  
2.5.2 
Supportive analyses 
Subgroups analyses according to patient characteristics, like sex (male, female), age class 
(≤ 64, > 65 - 75, 75 - 85, ≥ 85), Baseline lesion type (type 1, type 2, type 3) and time since 
nAMD diagnosis (< 1 month, 1-3 months, and > 3 months). 


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2.6 
Analysis of secondary efficacy objectives 
2.6.1 
Secondary endpoints 
2.6.1.1 
Oct-A long-term effects 
The first secondary endpoint is the percentage change in CNV lesion area (mm²) measured by 
OCT-A for nAMD patients from Baseline to Week 48. Descriptive statistics (n, mean, std, 
median, min and max) for the change in CNV lesion (actual value, change from Baseline, 
percentage change from Baseline) will be presented based on observed data by visit. 
Furthermore, a 2-sided 95% CI using Student’s t-distribution will be provided.  
The number and percentage of lesion type (predominantly classic, minimally classic and occult) 
will be presented by visit. 
The above analysis will be done only on the study eye. The analysis will be performed on the 
FAS. 
2.6.1.2 
Spectral domain optical coherence tomography (SD-OCT) 
The following secondary efficacy parameters based on SD-OCT will be analyzed as given 
below. 
2.6.1.2.1 Central sub-field retinal thickness (CSFT) 
Summary statistics of central sub-field retinal thickness (CSFT) measured by SD-OCT for 
nAMD patients will be presented by visit along with change and percentage change from 
Baseline in CSFT. 
The number and percentage of patient with CSFT category (< 300, ≥ 300 - 450, ≥ 450 - < 650, 
≥ 650 (μm)) will be presented by visit. 
The above analysis will be done only on the study eye. The analysis will be performed on FAS.   
2.6.1.2.2 Presence of fluid (YES/NO) 
The number and percentage of patients with below fluid will presented by visit. 
1. Intraretinal fluid 
2. Subretinal fluid  
3. Sub-RPE fluid  
4. Without IRF or SRF  
5. Without any fluid (IRF/SRF/sub-RPE) 
6. In case of sub-RPE /  PED : nature : (serious PED / fibrovascular PED / mixed PED) 
Volume (mm3) and height (µm) of intraretinal fluid, subretinal fluid and/or sub-RPE fluid will 
be presented the summary statistics (n, mean, std, median, min and max) by visit, if available.  
The above analysis will be done only on the study eye. The analysis will be performed on the 
FAS.   


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2.6.1.2.3 Dry retina 
The proportion of patients without both fluids (IRF and SRF), without IRF, without SRF, 
without sub-RPE will be presented by visit, separately, up to Week 48/Week 50. 
The proportion of patients without fluid (IRF and SRF) and having fluid (IRF and/or SRF) in 
entire study will be presented. 
The 95% confidence interval (CI) for proportion using the Clopper-Pearson method will be 
provided by visit and overall. 
The above analysis will be done only on the study eye. The analysis will be performed on the 
FAS. 
2.6.1.2.4 Time to dryness 
The median time to dryness will be obtained from Kaplan-Meier (KM) analysis along with 
2-sided 95% CI will be presented. KM plot will be provided. Detailed KM results will be 
presented including time (week), number of patients under risk at visit (without dry retina), 
number of patients with dry retina at visit (event), probability of dry retina (survival probability) 
at visit and 95% CI at visit.  
 
Variable 
Definition 
Start date 
Start date of IVT injection  
Event  
Dry retina (absence of IRF and/or SRF)  
End date of event 
Start date of first dry retina 
Censoring (end date)  
Earliest of: 
• Absence of dry retina until EOS 
• Early discontinuation without dry retina  
Duration of time 
(End date – start date) +1 
The above analysis will be done only on the study eye. The analysis will be performed on the 
FAS.   
2.6.1.2.5 Maximum duration of dryness 
The median of maximum duration of dryness until Week 48/50 will be presented. The median 
will be obtained from the KM analysis along with 2-sided 95% CI. KM plot will be provided. 
Detailed KM results will be presented including time (week), total number of patients having 
fluids (risk), number of patients under achieved maximum duration (event), probability of 
maximum duration of dryness (survival probability) and 95% CI.  
Variable 
Definition 
Start date 
Start date of treatment  
Event  
Dryness  
End date of event 
Start date of dryness  
Censoring (end date)  
Earliest of: 
• Absence of dryness until EOS 


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• Early discontinuation with absence of dryness 
Duration of time 
(End date – start date) +1 (Maximum duration will be used) 
The above analysis will be done only on the study eye. The analysis will be performed on FAS.   
2.6.1.3 
Fluorescein angiography (FA) 
The number and percentage of CNV location (subfocal, juxtafoveal, extrafoveal) at Week 12 
will be presented for both study eye and fellow eye. 
The summary statistics (n, mean, std, median, min and max) of area of lesion associated with 
CNV (mm**2) will be presented at Week 12 for study eye and fellow eye, along with change 
from Baseline and percentage change from Baseline. 
The above analysis will be done only on the study eye. The analysis will be performed on the 
FAS.   
2.6.1.4 
Best corrected visual acuity (BCVA) 
The summary statistics (n, mean, std, median, min and max) of BCVA for nAMD patients will 
be presented along with change and percentage change from Baseline in BCVA by visit. Along 
with below BCVA category. 
1. BCVA (≤ 55, 56 - 70 and ≥ 71). 
2. Increase of ≥ 5, ≥ 10 and ≥ 15 letters in BCVA from Baseline up to Week 48. 
3. Loss of ≥ 5, ≥ 10, ≥ 15 and ≥ 30 letters in BCVA from Baseline up to Week 48. 
4. BCVA ≥ 84.  
The above analysis will be done only on the study eye. The analysis will be performed on FAS. 
2.6.1.5 
Dosing regimen of brolucizumab 
The binomial proportion and 95% CI using the Clopper-Pearson method will be provided for 
patients who are maintained on an exclusive q12w interval following the loading phase through 
Week 48.  
The number and percentage of q8w dose frequency patients will be presented along with 
95% CI using the Clopper-Pearson method.  
Duration of dose is defined as (date of last dose – start date of dose).  
The summary statistics (n, mean, std, first quartile, median, third quartile, min and max) for 
duration of dose will be provided for patients who are maintained on an exclusive q12w interval 
following the loading phase through Week 48. In the study design the 3 × 4-week dosing 
frequency, in initiation phase. 
The above analysis will be done only on the study eye. The analysis will be performed on the 
FAS. 


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2.6.1.5.1 Predictive value of the first q12w cycle for maintenance of q12w 
treatment with brolucizumab 
The probability of the first q12w interval will be derived from KM time to event analyses. KM 
plot will be provided. Detailed KM results will be presented including time (week), number of 
patients under risk at visit, number of patients with first q12w or discontinue at visit, probability 
of maintaining on q12w (survival probability) and 95% CI for maintaining on q12w.  
Variable 
Definition 
Start date 
First date when patients on q12w interval  
Event  
Fail maintain to q12w interval  
End date 
Last date of initial q12w interval (before or on first start of q8w interval) 
Censoring (end date)  
Completed/Discontinue with q12w 
Duration of time 
(End date – start date) +1 
The above analysis will be done only on the study eye. The analysis will be performed on FAS. 
2.6.1.6 
Disease activity assessments 
The number and percentage will be presented by visit for disease activity assessment. 
The above analysis will be done only on the study eye. The analysis will be performed on FAS. 
2.6.1.6.1 Duration of time from start of dose to till no disease activity 
The median of duration of time is obtained from KM analysis along with 2-sided 95% CI will 
be presented. KM plots will be provided. 
Detailed KM results will be presented including time (week), number of patients with no disease 
activity at visit, number of patients under risk at visit (with disease activity), probability of 
disease activity (survival probability) at visit and 95% CI at visit.  
 
Variable 
Definition 
Start date 
Start date of start of IVT injection/ last IVT injection in the initiation phase 
Event  
No disease activity 
End date of event 
Date of first visit with no disease activity  
Censoring (end date)  
Earliest of: 
• 
With disease activity until EOS 
• 
Early discontinuation  
Duration of time 
(End date – start date) +1 
The above analysis will be done only on the study eye. The analysis will be performed on FAS. 


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2.8 
Analysis of other efficacy variables 
2.8.1 
Color fundus photography 
The number and percentage will be provided at Screening/Baseline, week 12 and end of study 
(Week 48) for below questions: 
• Was color fundus photography performed? If not, then reason for not performed CFP. 
• Presence of retinal hemorrhage in central subfield. 
• Presence of subretinal hemorrhage in central subfield. 
• Presence of fibrosis in the central subfield the diameter of 3000 µm. 
• Presence of atrophy in the central subfield the diameter of 3000 µm. 
• Is there subretinal blood affecting the foveal center point and/or >50% of total lesion. 
• Presence of Vasculitis. 
The above analysis will be done on both eyes. The analysis will be performed on the FAS.   
2.8.2 
Fundus autofluorescence (FAF) 
The number and percentage will be provided at Baseline, week 4 and end of study (week 48) 
for below question. 
• Fundus auto-fluorescennce performed at visit. If not then reason for not performed FAF.  
• Presence of macular atrophy in the central subfield (center 1 mm circle). 
• Presence of foveal atrophy. 


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The summary statistics (n, mean, std, median, min and max) of area of macular atrophy (mm2) 
will be presented at Baseline, Week 4 and Week 48 along with change from Baseline and 
percentage change from Baseline in FAF. 
The above analysis will be done on the both eye. The analysis will be performed on FAS.   
2.8.3 
Indocyanine green angiography (ICG) 
The number and percentage of lesion type (only at Baseline) (type 1 / type 2 / type 3 / type 1 
with aneuvrism / polyps) at Baseline will be provided. 
The summary statistics (n, mean, std, median, min and max) for area of lesion associated with 
CNV (mm2) at Baseline and Week 12 will be provided along with summary statistics for change 
from Baseline and percentage change from Baseline at week 12 for area of lesion. 
The above analysis will be done on both eyes. The analysis will be performed on the FAS.   
2.8.4 
Intraocular pressure 
Intraocular pressure will be collected in the CRF at Baseline and Week 48. The summary 
statistics of IOP for nAMD patients will be presented at Week 48 along with change from 
Baseline and percentage change from Baseline in IOP. In addition, the number and percentage 
of patients with IOP (≤ 10, 10-25, 25-30 and ≥ 30 [mmHg]) will be presented at Week 48. 
The above analysis will be done on both eyes. The analysis will be performed on the FAS.   
2.8.5 
Fundus examination  
The below variables of number and percentage will presented for study eye and fellow eye by 
visit. 
• Retinal hemorrhage (none, retinal macular and retinal non-macular) 
• Presence of vitreal hemorrhage (no, yes) 
• Retinal tear/detachment (0- none, 1- retinal tear, 2- retinal detachment, 3- retinal tear and 
detachment) 
• Presence of intraocular inflammation (no, yes) 
• Presence of vasculitis. 
Listing of fundus examination parameter will be provided by patient and visit. 
The above analysis will be done on the both eye. The analysis will be performed on the FAS.   
2.9 
Safety analyses 
Safety measurements include duration of exposure, vital signs and adverse events. All safety 
endpoints will be summarized using the Safety Set. Patients will be analyzed according to 
treatment received. No imputation will be carried out for missing data.   


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2.9.1 
Adverse events (AEs) 
All information obtained on AEs will be displayed by patient. Summary tables for AEs will 
summarize only on-treatment events, with a start date during the on-treatment period (see 
Section 2.1.1) for definition of on-treatment period).  
The count of treatment-emergent AEs, number (and percentage) of patients with treatment-
emergent AEs (defined as events started after the first dose of study treatment or events present 
prior to start of study treatment but increased in severity based on PT) will be summarized in 
the following ways:  
• By primary SOC and PT.  
• By primary SOC, PT and maximum severity.  
Separate summaries will be provided for study treatment related AEs, procedure related, death, 
SAEs and other significant AEs action taken leading to study treatment interruption & treatment 
withdrawn.  
Adverse events will be summarized by presenting, the number and percentage of patients having 
any AE, having an AE in each primary SOC and having each individual AE (PT). Summaries 
will also be presented for AEs by severity. Summaries for AE will be presented for study 
treatment and procedure related to AEs. If a patient reported more than one AE with the same 
PT, the AE with the greatest severity will be presented. System organ classes will be presented 
in alphabetical order, PTs will be sorted within SOC in descending frequency of AEs. If a 
patients reported more than one AE within the same primary SOC, the patient will be counted 
only once with the greatest severity at the SOC level, where applicable. The AE will be 
presented in separate sections of ocular and non-ocular. For ocular then it will be presented by 
any eye, study eye and fellow eye. 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AEs in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
 In addition, all treatment emergent AEs will also be listed. 
The by-patients listing will include: SOC/PT/Verbatim term, start date, end date, severity, 
relationship to study treatment and procedures, whether or not it is a SAE, action taken with 
study treatment and outcome. Duration will be calculated as (end date – start date + 1) and for 
ongoing AE (last visit date – start date + 1) by ocular and non-ocular. For ocular then it will be 
presented by any eye, study eye and fellow eye. 
A summary of action taken with number and percentage of patients will presented with dose 
increased, no dose change, dose reduced, treatment interrupted, drug withdrawn, not applicable 
and unknown. 
2.9.1.1 
Adverse events of special interest / grouping of AEs 
The number (%) of patients with AESIs will be summarized by standardized MedDRA query 
and PT. Listing will also be provided. 


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Case Retrieval Sheet (CRS) with the exact composition of the AE groupings is to be used to 
map reported AEs to the AESI groupings. This file may be updated (i.e.live document) based 
on review of accumulating trial data, and therefore the groupings are also subject to potential 
change. The most up-to-date version of the CRS will be used at the time of the analysis. 
The number and percentage of patients having any AESI, AESI by SOC (confirmed by SRC) 
and PT will be presented.  
The number and percentage of patients for AESI type along with incidence rate per patient and 
per 1000 injection will be provided. Incidence rate per patient is defined as number of patients 
in AESI type/total number of patients in safety analysis set and incidence rate per 1000 injection 
is define as (number of occurrence of AESI type/total number of injections)*1000. 
The number and type of AESI will be plotted according to the time after last brolucizumab 
injection and time since first brolucizumab injection. 
Summary statistics for change from baseline in BCVA after end date of AESI will be provided 
for each AESI type and change from baseline in BCVA will be plotted overall and for each type 
of AESI. 
Patients demographics, baseline characteristics and medical history will be provided for AESI 
patient with safety set. 
2.9.2 
Deaths 
A separate summary of deaths including on-treatment and post-treatment deaths will be 
provided. 
All deaths in the clinical database will be listed with the investigator-reported principal cause. 
Deaths occurring after the first dose of study treatment until 30 days after the date of last 
treatment will be summarized. In addition, deaths occurring after the first dose of study 
treatment until the date of last treatment will also be summarized. 
2.9.3 
Laboratory data 
Not applicable 
2.9.4 
Other safety data 
Not applicable 
2.9.4.1 
ECG and cardiac imaging data 
Not applicable 
2.9.4.2 
Vital signs 
Vital signs will include blood pressure and pulse rate measurements. 
All vital signs data will be listed by patient, and visit, and if ranges are available, abnormalities 
will be flagged. Abnormal values are marked in Section 5.3. All data, including data from 
unscheduled visits, will be considered when identifying abnormal values. Analysis of vital sign 
measurements using summary statistics for the change from Baseline for each post-Baseline 


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visit will be performed. These descriptive summaries will be presented for each vital sign. 
Change from Baseline will only be summarized for patients with both Baseline and post-
Baseline values. 
2.10 
Pharmacokinetic endpoints   
Not applicable 
2.11 
PD and PK/PD analyses 
Not applicable 
2.12 
Biomarkers 
Not applicable. 
2.13 
Other exploratory analyses 
Not applicable. 
2.14 
Interim analysis 
The analysis based on the Week 12 data, i.e. data up to and including Week 12 will be the 
primary (first) analysis for this study.  
A second planned analysis of the data after the EOS/Week 48 visit will be performed once all 
patients have completed or prematurely discontinued the study. 
3 
Sample size calculation 
The primary objective of the study is to evaluate the effect of brolucizumab on CNV lesion area 
as measured by OCT-A in nAMD patients starting treatment with brolucizumab. This will be 
evaluated by the percentage change in CNV lesion area measured by OCT-A from Baseline to 
Week 12. The sample size calculation is based on the hypothesis of a standard deviation of 35% 
for this reduction proportion (Miere et al 2018).  
A sample size of 180 to 400 patients produces a 2-sided 95% CI with a distance from the mean 
to the limits ranges from 5.1 to 3.4 when the estimated standard deviation is 35.0 (nQuery 
Advisor version 7.0). Therefore, to have a precision of 5%, a sample size of 189 patients will 
be needed (Table 3-1).  
To take into account a dropout rate and uninterpretable images of 10%, a total of 210 patients 
will be included.  
Table 3-1 
Confidence intervals for one mean numeric results for 2-sided 
confidence intervals with unknown standard deviation 
 
Confidence Level 
Sample Size  
(N) 
Distance from Mean 
to Limits 
Standard Deviation 
(S) 
0.950 
180 
5.1 
35.0 
0.950 
189 
5.0 
35.0 


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0.950 
233 
4.5 
35.0 
0.950 
250 
4.4 
35.0 
0.950 
300 
4.0 
35.0 
0.950 
350 
3.7 
35.0 
0.950 
385 
3.5 
35.0 
0.950 
400 
3.4 
35.0 
 
4 
Change to protocol specified analyses 
 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study treatment 
The following rules should be used for the imputation of the dose end date for a given study 
treatment component:  
Scenario 1  
If the date of last IVT is completely missing and there is no end of treatment (EOT) page and 
no death date, the patient is considered as on-going.  
The patient should be treated as on-going and the cut-off date should be used as the last dosing 
date.  
Scenario 2  
If the dose end date is completely or partially missing and the EOT page is available:  
• Case 1: The dose end date is completely missing and the EOT completion date is 
complete, then this latter date should be used.  
• Case 2: Only year (YYYY) of the dose end date is available and YYYY < the year of 
EOT date, then use 31DECYYYY. 
• Case 3: Only year (YYYY) of the dose end date is available and YYYY = the year of 
EOT date, then use EOT date. 
• Case 4: Both year (YYYY) and month (MMM) are available for dose end date and YYYY 
= the year of EOT date and MMM < the month of EOT date, then use last day of the 
Month (MMM)  
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study.  
After imputation, compare the imputed date with start date of treatment.  
If the imputed date is < start date of treatment, then use the treatment start date. 


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Otherwise, use the imputed date  
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should 
not be imputed.  
5.1.2 
AE date imputation 
AE date imputation is based only on a comparison of the partial AE start date to the treatment 
start date as mentioned in the below. 
• If the AE start date year value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the AE year value is missing, the imputed AE start date is set to 
NULL. 
• If the AE start date year value is less than the treatment start date year value, the AE 
started before treatment. Therefore: 
1. If the AE year is less than the treatment year and the AE month is missing, the 
imputed AE start date is set to the mid-year point (01JulYYYY). 
2. Else if the AE year is less than the treatment year and the AE month is not missing, 
the imputed AE start date is set to the mid-month point (15MONYYYY). 
• If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment. Therefore: 
1. If the AE year is greater than the treatment year and the AE month is missing, the 
imputed AE start date is set to the year start point (01JanYYYY). 
2. Else if the AE year is greater than the treatment year and the AE month is not 
missing, the imputed AE start date is set to the month start point (01MONYYYY). 
• If the AE start date year value is equal to the treatment start date year value: 
1. And the AE month is missing or the AE month is equal to the treatment start month, 
the imputed AE start date is set to one day after treatment start. 
2. Else if the AE month is less than the treatment start month, the imputed AE start date 
is set to the mid-month point (15MONYYYY). 
3. Else if the AE month is greater than the treatment start month, the imputed AE start 
date is set to the start month point (01MONYYYY). 
 
 
MON 
MON < CFM 
MON = CFM 
MON > CFM 
 
MISSING 
YYYY 
MISSING NULL 
NULL 
NULL 
NULL 
 
Uncertain 
Uncertain 
Uncertain 
Uncertain 
YYYY < 
CFY 
(D) = 01JULYYYY 
(C)= 15MONYYYY 
(C)= 15MONYYYY 
(C)= 15MONYYYY 
 
Before Treatment Start Before Treatment Start Before Treatment Start Before Treatment Start 
YYYY = 
CFY 
(B)= TRTSTD+1 
(C)= 15MONYYYY 
(A)= TRTSTD+1 
(A)= 01MONYYYY 
 
Uncertain 
Before Treatment Start Uncertain 
After Treatment Start 


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YYYY > 
CFY 
(E)= 01JANYYYY 
(A)= 01MONYYYY 
(A)= 01MONYYYY 
(A)= 01MONYYYY 
 
After Treatment Start  After Treatment Start  After Treatment Start  After Treatment Start  
Before Treatment Start  
Partial indicates date prior to Treatment Start Date 
After Treatment Start  
Partial indicates date after Treatment Start Date 
Uncertain 
Partial insufficient to determine relationship to Treatment Start Date 
LEGEND: 
(A) 
 MAX (01MONYYYY,TRTSTD+1) 
 
(B) 
TRTSTD+1 
 
 
(C) 
15MONYYYY 
 
 
(D) 
01JULYYYY 
 
 
(E) 
01JANYYYY 
 
 
 
5.1.3 
Concomitant medication and medical history (nAMD) date imputation 
This algorithm is used when event is the partial start date of the concomitant medication and 
medical history (nAMD). 
The following table explains the notation used in the logic matrix. Please note that missing start 
dates will not be imputed. 
Day 
Month 
Year 
Partial CM Start Date 
Not used 
MON 
YYYY 
Treatment 
StartTRTSDT ) Not used 
TRTM 
TRTY 
The following matrix explains the logic behind the imputation. 
 
MON MISSING 
MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY MISSING 
(C2) 
Uncertain 
(C1) 
Uncertain 
(C1) 
Uncertain 
(C1) 
Uncertain 
YYYY < TRTY 
(D) 
Before Treatment 
Start 
(A) 
Before Treatment 
Start 
(A) 
Before Treatment 
Start 
(A) 
Before Treatment 
Start 
YYYY = TRTY 
(C2) 
Uncertain 
(A) 
Before Treatment 
Start 
(C1) 
Uncertain 
(B) 
After Treatment Start 
YYYY > TRTY 
(E) 
After Treatment Start 
(B) 
After Treatment Start 
(B) 
After Treatment Start 
(B) 
After Treatment Start 
 
The following table is the legend to the logic matrix. 
 


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Relationship 
Before Treatment Start Partial date indicates CMD start date prior to Treatment Start Date 
After Treatment Start 
Partial date indicates CMD start date after Treatment Start Date 
Uncertain 
Partial date insufficient to determine relationship of CMD start date relative to 
Treatment 
Start Date 
Imputation Calculation 
(A) 
15MONYYYY 
(B) 
01MONYYYY 
(C1 or C2) 
IF relative reference start 
= 
before treatment 
start 
THENTRTSDT-1 
ELSE IF relative reference start = 
‘ ’ THEN 
TRTSDT +1 
(D) 
01JULYYYY 
(E) 
01JANYYYY 
 
Concomitant Medication End Date Imputation 
If not ongoing then - 
Imputed date = date part of CMENDTC, if complete date 
Imputed date = min(completion/discontinuation visit date,  DEC 31) , if month is missing, (C2, 
D, E) 
Imputed date = min(completion/discontinuation visit date, last day of the Month) , if day is 
missing. (A, B, C1) 
Concomitant Medication Date Flag 
If not a complete date then 
Y - If year of the imputed date is not equal to YYYY else M – If month of the imputed date is 
not equal to MON else D. 
5.2 
AEs coding/grading 
The verbatim term recorded on CRF will be identified as adverse event and will be coded by 
primary SOC and PT using Medical Dictionary for Regulatory Activities (MedDRA) version 
22.1 and above. 


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5.3 
Vital signs parameters derivations 
The criteria for clinically notable abnormalities are defined as follows: 
Clinically notable elevated values  
• Systolic blood pressure of ≥ 140 mmHg (hypertension) 
• Diastolic blood pressure of ≥ 90 mmHg (hypertension) 
• Pulse rate ≥ 100 bpm (tachycardia). 
Clinically notable below normal values 
• Systolic blood pressure of < 90 mmHg (hypotension) 
• Diastolic blood pressure of < 60 mmHg (hypotension) 
• Pulse rate < 60 bpm (bradycardia)  
5.4 
Statistical methodology  
The below SAS code will used for statistical value. 
Frequency and proportion: 
proc freq data = <........>; 
tables response_variable/ chisq; 
run; 
Summary Statistics: 
Univariate procedure will be used for continuous response. 
proc univariate data=<........>; 
 
var response_variable; 
output out=<........> n=_n mean=_mean std=_sd  min=_min median=_med           
max=_max; 
run; 
95% CI 
proc means data=adxe N NMISS CLM  ; 
 
var aval; 
run; 
Time to event analysis 
proc lifetest data=comb1 alpha=0.05 conftype=loglog method=KM alphaqt=0.05 
outsurv=survest; 
 
time AVALW*cnsr(0); 
run; 
 t-test 
proc ttest data = pccnv_w12; 
 
class population_group; 
var pchg 
run; 
Wilcoxon rank-sum test 
proc npar1way wilcoxon data= rnksm (label=’CNV lesion area at week 12’); 
class estimand;  
var area; 


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run; 
 
AESI reported by investigator 
 
if AEDECOD in ("Anterior chamber cell", "Anterior chamber inflammation", 
"Vitritis", "Iritis", "Cyclitis", "Choroiditis", "Chorioretinitis", "Anterior 
chamber fibrin", "Uveitis","Noninfective chorioretinitis", "Ophthalmia 
neonatorum", "Aqueous fibrin", "Uveitis-glaucoma-hyphaema syndrome", "Retinitis", 
"Tubulointerstitial nephritis and uveitis syndrome", "Toxic anterior segment 
syndrome","Infective uveitis", "Vitreous haze", "Keratic precipitates", "Vitreous 
abscess", "Anterior chamber flare", "Cogan''s syndrome", "Noninfective retinitis", 
"Oculomucocutaneous syndrome","Eye infection intraocular", "Iridocyclitis", "Viral 
uveitis", "Viral keratouveitis", "Hypopyon", "Cyclitic membrane", "Eye 
inflammation", "Optic neuritis","Ocular pemphigoid", "Oculorespiratory syndrome", 
"Idiopathic orbital inflammation", "Papillitis") then 
 do; 
 
 
AEBODSYS1="Intraocular inflammation"; 
 
 
AESI="Y"; 
 
    end; 
else if  AEDECOD in ("Choroidal infarction", "Eyeinfarction", "Macular ischaemia", 
"Ocular ischaemic syndrome", "Retinal artery embolism", "Retinal artery 
occlusion","Retinal artery stenosis", "Retinal artery thrombosis", "Retinal 
infarction", "Retinal ischaemia", "Retinal vascular occlusion", "Retinal vascular 
thrombosis", "Retinal vein occlusion","Retinal vein thrombosis", "Necrotising 
retinitis", "Ocular vasculitis", "Retinal vasculitis","Retinal occlusive 
vasculitis") then  
do; 
 
 
AEBODSYS1="Retinal Vasculitis and / or retinal vascular occlusion"; 
 
 
AESI="Y"; 
 
end; 
5.5 Rule of exclusion criteria of analysis sets  
Table 5-1 
Protocol deviations that cause patients to be excluded 
 
Deviation ID 
Description of Deviation 
Exclusion in Analyses 
Severity 
code 
INCL01 
Signed informed consent not obtained 
Excluded from FAS and 
PPS analysis 
1 
INCL02 
Age less than 50 year 
Included in everything  
0 
INCL03 
No active CNV lesions 
Excluded from FAS and 
PPS  
1 
INCL04 
No Intra- and/or subretinal fluid 
Excluded from FAS and 
PPS  
1 
INCL05 
Study eye BCVA out of range  
Excluded from PPS  
2 
EXCL01 
Active infection in either eye 
Excluded from PPS  
2 
EXCL02 
Fellow eye ocular disease 
Included in everything 
0 
EXCL03 
Poor quality images 
Included in everything 
0 
EXCL03a 
History of IOI 
Included in everything 
0 
EXCL05 
Study eye lesion area ≥50% 
Included in everything 
0 


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Deviation ID 
Description of Deviation 
Exclusion in Analyses 
Severity 
code 
EXCL05a 
Study eye atropathy or fibrosis 
Included in everything 
0 
EXCL07 
Study eye concomitant condition 
Included in everything 
0 
EXCL08 
Study eye macula damage 
Included in everything 
0 
EXCL09 
Study eye vitreous hemorrhage 
Included in everything 
0 
EXCL10 
Study eye uncontrolled glaucoma 
Included in everything 
0 
EXCL11 
Study eye aphakaia 
Included in everything 
0 
EXCL12 
Other treatment in study eye 
Excluded from PPS 
2 
EXCL13 
Steroids in study eye 
Included in everything 
0 
EXCL14 
Prior keratoplasty/vitrectomy 
Included in everything 
0 
EXCL15 
Study eye previous ocular treatment 
Included in everything 
0 
EXCL16 
End stage renal disease requiring 
dialysis or renal transplant 
Included in everything 
0 
EXCL17 
Systematic drug toxic to eye  
Included in everything 
0 
EXCL18 
Participation in another study  
Excluded from PPS  
2 
EXCL19 
Systematic anti-VEGF therapy  
Included in everything 
0 
EXCL20a 
Stroke or myocardial infraction  
Included in everything 
0 
EXCL21 
Uncontrolled blood pressure  
Included in everything 
0 
EXCL22 
Malignancy 
Included in everything 
0 
EXCL22a 
Medical condition impact 
Included in everything 
0 
EXCL24 
Hypersensitivity 
Included in everything 
0 
EXCL25 
Pregnant or nursing woman 
Included in everything 
0 
EXCL26 
Women of childbearing potential 
Included in everything 
0 
EXCL27 
Minor or protected adult  
Excluded from PPS  
2 
COMD01 
Prohibited medication/procedures  
Included in everything 
0 
COMD02 
Steroids use 5 days prior to IP 
Included in everything 
0 
TRT01 
Wrong IP administered 
Excluded from PPS  
2 
TRT02 
Incorrect dose administered 
Excluded from PPS  
2 
TRT03 
Pregnancy but not discontinued 
Included in everything 
0 
TRT04 
Short 
treatment 
window 
between 
treatment 
Included in everything 
0 
TRT05 
Treatment > 3 days after injection visit 
Included in everything 
0 
TRT06 
Injection given at Week 12 
Excluded from PPS 
2 
TRT07 
Q8W IVT out of window 
Included in everything 
0 
TRT08 
Q12W IVT out of window 
Included in everything 
0 
TRT09 
COVID-19 Drug supply change 
Included in everything 
0 


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Deviation ID 
Description of Deviation 
Exclusion in Analyses 
Severity 
code 
TRT10 
COVID-19 Treatment not given 
Included in everything 
0 
TRT11 
Missed Injection loading phase 
Excluded from PPS 
1 
TRT12 
Missed Injection 
Included in everything 
0 
TRT13 
No Disease activity but injection is given 
Included in everything 
0 
TRT14 
Treatment 
admin 
prior 
effic/safty 
evaluation 
Included in everything 
0 
TRT15 
Treatment given at EOS 
Included in everything 
0 
WITH01 
Withdrew consent not discontinued 
Excluded from FAS and 
PPS  
1 
OTHER01 
Patient rescreened > once 
Included in everything 
0 
OTHER02 
Severe ICH-GCP non-compliance 
Excluded from FAS and 
PPS  
1 
OTHER03 
New ICF is missing-rescreened 
Excluded from FAS and 
PPS  
1 
OTHER04 
Mishandling IP 
Included in everything 
0 
OTHER05 
Temperature excursion IP administered 
Included in everything 
0 
OTHER06 
Treatment regimen wrongly adjusted 
Included in everything 
0 
OTHER07 
Missed mandatory visit 
Excluded from PPS  
2 
OTHER08 
Missed injection visit 
Included in everything 
0 
OTHER09 
FA out of window 
Included in everything 
0 
OTHER10 
Rescreen due to BCVA results 
Included in everything 
0 
OTHER11 
Rescreen 
>14days 
w/o 
screening 
procedure 
Included in everything 
0 
OTHER13 
COVID-19 Missed visit 
Included in everything 
0 
OTHER14 
COVID-19 Visit not at site 
Included in everything 
0 
OTHER15 
COVID-19 Assessment changed 
Included in everything 
0 
OTHER16 
COVID-19 Discontinuation 
Included in everything 
0 
OTHER17 
Efficacy assessment not done 
Excluded from PPS  
2 
OTHER18 
Safety assessment not done 
Included in everything 
0 
OTHER19 
BCVA not done correctly 
Included in everything 
0 
OTHER20 
Visit window > 7 days 
Included in everything 
0 
OTHER21 
Vital signs/safety call not done 
Included in everything 
0 
OTHER22 
Imaging analyzed after WoC 
Included in everything 
0 
 


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Table 5-2 
Patient Classification 
Analysis Set 
Severity codes that cause a subject to be excluded  
ENR 
NA 
FAS 
1 
FAS-EST 
1 
PPS 
1,2 (All specified PD in Table 5.1 due to COVID) 
PPS-EST 
1, 2 (All specified PD in Table 5.1 due to COVID-19) 
SAF 
NA 
 
 
6 
Reference 
Miere A, Oubraham H, Amoroso F, et al (2018) Optical Coherence Tomography 
Angiography to Distinguish Changes of Choroidal Neovascularization after Anti-VEGF 
Therapy: Monthly Loading Dose versus Pro Re Nata Regimen. J Ophthalmol. Epublished at 
[doi: 10.1155/2018/3751702].