Clinical trial NCT04264819
Conditions: Neovascular Age-Related Macular Degeneration
Keywords: Macular degeneration age-related macular degeneration (ARMD) vision loss macula damage retina damage dry macular degeneration wet macular degeneration AMD diabetic macular edema DME neovascular age-related macular degeneration nAMD retinal vein occlusion RVO wetAMD neovascular choroidal neovascularization disease control
Sponsor: Novartis Pharmaceuticals
Start date: 2020-12-14; Completion date: 2023-05-10
Enrollment: 295 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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

Detailed description:
This is a prospective, single-arm, open-label, multicenter study to evaluate the efficacy and safety of brolucizumab 6 mg in pretreated suboptimal anatomically controlled patients with neovascular age-related macular degeneration (nAMD).

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 treat-to-control phase with adjustable treatment frequency based on disease activity from every 8 to up to 16 weeks; last treatment at week 44/46 based on the treatment regimen.
Interventions: intervention 1: RTH258/Brolucizumab
Intervention descriptions: intervention 1: Brolucizumab is a new generation of anti-VEGF (vascular endothelial growth factor). All patients will be treated with brolucizumab 6mg: 3 loading injections (at Screening/Baseline, Week 4 and Week 8), followed by Treat-to-Control regimen up to Week 44/46.

Protocol documents:
Prot_000.pdf: 


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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 (27-Jan-2020) ............................................................................................. 10 
Amendment 2 (21-Oct-2020) ............................................................................................ 11 
Amendment 3 (01-Sept-2021) ........................................................................................... 13 
Amendment 4 (25-Nov-2021) ........................................................................................... 16 
Amendment 5 (5-Apr-2022) .............................................................................................. 18 
Protocol summary .............................................................................................................. 19 
 
Introduction ....................................................................................................................... 22 
1.1 
Background ............................................................................................................ 22 
1.2 
Purpose .................................................................................................................. 24 
 
Objectives and endpoints ................................................................................................... 24 
 
Study design ...................................................................................................................... 25 
 
Rationale ............................................................................................................................ 28 
4.1 
Rationale for study design ..................................................................................... 28 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 28 
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...................................................................................... 35 
6.1.4 
Treatment duration ................................................................................ 35 
6.2 
Other treatments..................................................................................................... 35 
6.2.1 
Concomitant therapy ............................................................................. 35 
6.2.2 
Prohibited medication ........................................................................... 36 




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9.2 
Study completion and post-study treatment .......................................................... 55 
 Safety monitoring and reporting ........................................................................................ 55 
10.1 
Definition of adverse events and reporting requirements ...................................... 55 
10.1.1 
Adverse events ...................................................................................... 55 
10.1.2 
Serious adverse events .......................................................................... 57 
10.1.3 
Protocol exemption from reporting ....................................................... 58 
10.1.4 
SAE reporting........................................................................................ 58 
10.1.5 
Pregnancy reporting .............................................................................. 59 
10.1.6 
Reporting of study treatment errors including misuse/abuse ................ 59 
 Data collection and database management ........................................................................ 60 
11.1 
Data collection ....................................................................................................... 60 
11.2 
Database management and quality control ............................................................ 60 
11.3 
Site monitoring ...................................................................................................... 60 
 Data analysis and statistical methods ................................................................................ 61 
12.1 
Analysis sets .......................................................................................................... 61 
12.2 
Patient demographics and other baseline characteristics ....................................... 62 
12.3 
Treatments ............................................................................................................. 62 
12.4 
Analysis of the primary endpoint .......................................................................... 63 
12.4.1 
Definition of the primary endpoint ....................................................... 63 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 63 
12.4.3 
Handling of missing values/censoring/discontinuations ....................... 63 
12.4.4 
Sensitivity and supportive analyses ...................................................... 63 
12.5 
Analysis of secondary endpoints ........................................................................... 63 
12.5.1 
Effects of brolucizumab 6 mg on disease activity ................................ 63 
12.5.2 
Effect of brolucizumab 6 mg on anatomical parameters ...................... 64 
12.5.3 
Durability of brolucizumab 6 mg .......................................................... 64 
12.5.4 
Functional outcomes ............................................................................. 64 
12.5.5 
Safety endpoints .................................................................................... 64 
 
 65 
 
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 65 
12.7 
Interim analyses ..................................................................................................... 66 
12.8 
Sample size calculation.......................................................................................... 66 


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 Ethical considerations and administrative procedures ...................................................... 67 
13.1 
Regulatory and ethical compliance ........................................................................ 67 
13.2 
Responsibilities of the Investigator and IEC ......................................................... 67 
13.3 
Publication of study protocol and results............................................................... 67 
13.4 
Quality control and quality assurance.................................................................... 67 
 Protocol adherence ............................................................................................................ 68 
14.1 
Protocol amendments............................................................................................. 68 
 References ......................................................................................................................... 69 
 Appendices ........................................................................................................................ 70 
 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 24 
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 ................................................................................................ 41 
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 proportions (2 sided) ..................................... 66 
List of figures 
Figure 3-1 
Study design .......................................................................................... 26 
Figure 6-1 
Treatment regimen ................................................................................ 39 
 


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List of abbreviations  
AE 
Adverse Event 
AESI 
Adverse event of special interest 
BCVA 
Best-Corrected Visual Acuity 
BCNVA 
Best-Corrected Near Visual Acuity 
 
 
CFR 
Code of Federal Regulation 
CMO & PS 
Chief Medical Office & Patient Safety 
CNV 
Choroidal Neovascularization 
CRC 
Central Reading Center 
CRF 
Case Report/Record Form (paper or electronic) 
COVID-19 
Coronavirus disease 2019 
CRO 
Contract Research Organization 
CSFT 
Central Sub-Field Retinal 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 
 
 
 
 
FAS 
Full Analysis Set  
FIR 
First Interpretable Results 
GCP 
Good Clinical Practice 
IB 
Investigator's Brochure 
ICF 
Informed Consent Form 
 
 
ICH 
International Council for Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IOI 
Intraocular Inflammation 
 
 
IRB 
Institutional Review Board 
IRF 
Intraretinal Fluid 
IVT 
Intravitreal 
MedDRA 
Medical Dictionary for Regulatory Activities 
nAMD 
Neovascular Age-Related Macular Degeneration 
NIH 
National Institutes of Health 
OCT 
Optical Coherence Tomography 
PDT 
Photodynamic Therapy 
PED 
Pigment Epithelial Detachment 


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PFS 
Pre-Filled Syringe 
 
 
Q4 
Every 4 Weeks 
Q8 
Every 8 Weeks  
Q12 
Every 12 Weeks 
RO 
Retinal Vascular Occlusion 
RPE 
Retinal Pigmented Epithelium 
RV 
Retinal Vasculitis 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan  
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 
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 Code of Federal Regulation (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 will be 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 
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. 
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. 


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Study treatment 
Any drug administered to the study participants as part of the required study 
procedures; includes investigational drug (s), control(s) or non-investigational 
medicinal product(s) 
Study treatment 
discontinuation 
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date 
Unmasked/treating 
Investigator 
For the entire study duration and all study patients, the treating Investigator 
only performs the treatment (injection active/sham) and assesses patient 
safety following the active/sham injections. 
Variable 
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study 
Withdrawal of 
consent 
Withdrawal of consent from the study is defined as when a patient does not 
want to participate in the study any longer, and does not want any further 
visits or assessments, and does not want any further study related contact, 
and does not allow analysis of already obtained biologic material 
 
 
 


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Amendment 1 (27-Jan-2020) 
 
Rationale 
The purpose of this amendment is to incorporate changes which resulted from interactions with 
Regulatory Authorities, who required to clarify the washout period between the last dose of the 
anti-VEGF treatment received by the subject prior to be included in the study and the first dose 
of brolucizumab administrated in the study. 
In addition, changes have been made to clarify number of mandatory visits in the study and data 
to collect for the fellow eye. 
 
Changes to the protocol 
List the modifications implemented in the different sections, 
 Clarification of the washout period: Protocol summary, Study design, Inclusion criteria, 
Treatment duration, Concomitant therapy, Visit schedule and assessments (pages 32 and 
35) 
 Clarification on the number of mandatory visits: Study design 
 Clarification on the data to collect for the fellow eye: 8 Visit schedule and assessments 
 
IECs 
These changes are considered not-substantial. 
The amendment is to be sent to the IECs for information. 
These changes have no impact on the ICF. 
 
 
 




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• 
Section 6.7.2 Instruction for Prescribing and Taking Study Treatment: Language regarding 
the injection procedure was added replacing reference to an applicable manual. 
• 
Section 6.7.2.2 Treat-to-Control Phase: instruction in case of a patient misses a disease 
activity assessment visits. 
• 
Section 8.4.3 Ophthalmic examination: Added instructions for the patients in case of 
symptoms of inflammation. 
• 
Section 8 Visit Schedule and Assessments: clarification of treatment during unscheduled 
visit. 
• 
Section 10.1.4 SAE Reporting: Clarification of the SAE reporting period. 
• 
Section 12.1 Analysis Sets: Modified to include importance of Estimands per ICH E9(R1) 
guidance. 
• 
Section 12.8 (Primary endpoint): change of the patient recruitment period (from April 2020 
to December 2020 to January 2021 to September 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 IECs and HA for approval. 
These changes have impact on the ICF. 
 
 


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Amendment 3 (01-Sept-2021) 
 
Amendment Rationale 
The main reasons for the protocol amendment are: 
(1) To provide clarification and guidance on the early discontinuation of study treatment that is 
required for those subjects who are currently on q4w dosing beyond the first 3 monthly loading 
doses (“loading phase”) or would need q4w dosing beyond the “loading phase” based on the 
investigator’s assessment. This is as per the urgent safety measure dated 27-May-2021 based 
on CTH258AUS04 (MERLIN) Year 1 first interpretable results (FIR) indicating a higher 
frequency of IOI including Retinal Vasculitis (RV), and Retinal Vascular Occlusion (RO) in 
brolucizumab 6 mg q4w when compared to aflibercept 2 mg q4w (IOI: 9.3% vs 4.5% of which 
RV: 0.8% vs 0.0%; RO: 2.0% vs 0.0%, respectively). 
(2) Additionally, as per the Urgent Safety Measure dated 10-August-2021, the results of the 
mechanistic study BASICHR0049 identified a causal link with an immune-mediated 
mechanism of the previously identified risk of Retinal vasculitis (RV), and/or Retinal vascular 
occlusion (RO), typically in the presence of IOI. The protocol is hence amended to require 
discontinuation of study treatment in subjects who develop these events.  
(3) 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. 
(4) 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 that the interval between two 
brolucizumab doses should not be shorter than 8 weeks beyond loading, and that the impact 
on the risk/benefit balance is considered to be low when patients are dosed ≥q8w after the 
loading phase. Clarified that treatment intervals after the initiation phase will range from 8 
weeks to 16 weeks. In addition, the results of the mechanistic study BASICHR0049 of blood 
samples from nAMD patients exposed to brolucizumab and having subsequently developed 
RV and/or RO were added. 
 Section 3 Study design: Remove of the number of investigator sites. Clarified that if disease 
activity is observed at Week 14/Week 16, then the study treatment will be administered at 


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this visit and the further injections will be discontinued. Clarified the difference between 
study completion as per protocol versus early treatment discontinuation. Clarified that only 
during the loading phase injections should be at least 21 days apart. 
 Section 3 Study design; Section 4.2 Rationale for dose/regimen and duration of treatment; 
Section 6.7.2 Instruction for prescribing and taking study treatment: Modified to clarify the 
shortest treatment interval in the TtC phase. 
 Section 4.2 Rationale for dose/regimen and duration of treatment: Language added to 
provide background of the USM and impact on design. 
 Section 4.5 Risks and Benefits: Added the three urgent safety measures related to adverse 
events observed in patients treated with brolucizumab from the MERLIN 
(CRTH258AUS04) study, the post marketing reports and the causal link (results of the 
mechanistic study BASICHR0049). 
 Section 6.1.4 Treatment duration: Guidance added for subjects requiring injections every 4 
weeks. Added a paragraph to clarify that subjects who prematurely discontinue from study 
treatment should continue in the study and should return 4 weeks after last treatment to 
perform assessments for early treatment discontinuation. 
 Section 6.7.2 Instruction for prescribing and taking study treatment: Text added to show the 
treatment intervals allowed in the maintenance phase, following Week 8. In addition, 
changes made to clarify that subjects who require treatment every 4 weeks beyond the 
loading phase, should be discontinued from study treatment. Paragraph describing 
inspection visits at Week 14 for an interval extension from 4 weeks to 8 weeks was clarified. 
Changes also made to update that if RV and/or RO is confirmed, subjects should be 
discontinued from study treatment. If only IOI (without RV and/or RO) is confirmed, the 
subject should be closely monitored and the investigator should evaluate the appropriateness 
of continuing further with study treatment. This has also been updated Table 6-3. 
 Figure 6-1 Treatment regimen: Updated the range for treatment intervals. 
 Table 6-3 Disease activity assessment and treatment occurrence according to visit type: 
Remove of Week 12 visit. Added newly implemented visit type “ETD”. 
 Section 8 Visit schedule and assessments: Removed a sentence that two consecutive 
injections should be at least 21 days apart as this is no longer applicable since in the 
maintenance phase, any subject who requires treatment every 4 weeks has to be 
discontinued from study treatment. 
 Table 8-1 Assessment schedule: Remove of column for Week 12, no more possible. 
Columns added for early treatment discontinuation visits and for assessment visits after start 
of standard of care, including respective footnotes. In addition, footnotes #2 was updated to 
reflect the requirement to discontinue subjects from further treatment in case of disease 
activity at the inspection visit at Week 14; and a clarification was added in footnote #12 
with respect to ophthalmic examinations and images. Updated the name of the ophthalmic 
examination where “and imaging” was added. Footnotes #14, #15, and #16 added with 
respect to ETD and EOS assessments. 
 Section 8.3.1 Optical coherence tomography: clarification of CRC OCT review for all study 
visits. 
 Section 9.1.1 Discontinuation of study treatment: Instructions were added for subjects who 
discontinue from study treatment early.  


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 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.  
 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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 Section 11.2 “Database management and quality control”: 
 
 
 
 
 Section 13.2 “Responsibilities of the investigator and IRB/IEC”: 
 
 
 Section 15 “References”: 
 
Protocol sections changed in relation to the Beovu EU SmPC update on ‘Warnings and 
precautions for use’ section are: 
 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 8.4.3 
‘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. 
Protocol sections changed in relation to information on gender imbalance on IOI following 
brolucizumab treatment are: 
 Section 4.5 Risks and Benefits: Information added to describe information on gender 
imbalance on IOI following brolucizumab treatment.  
 
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 5 (5-Apr-2022) 
 
Amendment Rationale 
The 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 295. 
The study objectives will still be assessed with the revised sample size 
 
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 5. 
 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 
 
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 
CRTH258AFR03 
Full title 
A one-year, single-arm, open-label, multicenter study assessing the effect of 
brolucizumab on disease control in adult patients with suboptimal 
anatomically controlled neovascular age-related macular degeneration 
(SWIFT) 
Brief title 
Study of brolucizumab in adult patients with suboptimal anatomically 
controlled neovascular age-related macular degeneration 
Sponsor and 
Clinical Phase 
Novartis/Phase 3b 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
Based on clinical data, it is expected that switching suboptimal anatomically 
controlled patients treated with current licensed anti-VEGF to a presumably 
more effective and longer lasting anti-VEGF agent like brolucizumab may 
lead to optimized disease control.  
The purpose of this study is to assess both early (at Week 16 just after the 
loading phase) and long-term (48 weeks) effects of brolucizumab on disease 
control in suboptimal anatomically controlled neovascular age-related 
macular degeneration (nAMD) patients.   
Primary objective 
To evaluate the effect of brolucizumab 6 mg on disease control 
Secondary 
objectives 
 To evaluate the long term effects of brolucizumab 6 mg on disease control  
 To evaluate the effect of brolucizumab 6 mg on anatomical parameters  
 To evaluate the durability of brolucizumab 6 mg  
 To evaluate functional outcomes  
 To assess the safety and tolerability of brolucizumab 6 mg  
Study design 
This is a prospective, single-arm, open-label, multicenter study to evaluate 
the efficacy and safety of brolucizumab 6 mg in pretreated suboptimal 
anatomically controlled patients with nAMD.  
Approximately 295 adult patients will be screened and included (10% dropout 
rate expected) in France. The maximum study duration for 1 patient is 48 to 
50 weeks, according to the patient schedule.  
Treatment intervals after the initiation phase will be either 8 weeks, 12 weeks, 
or 16 weeks. More frequent injections, i.e., treatment intervals of <8 weeks 
are not allowed. 
Population 
The study population will be male and female patients ≥ 50 years old 
diagnosed with active CNV secondary to nAMD and able to comply with 
study or follow-up procedures.  
Key inclusion 
criteria 
 
Patients must provide 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 nAMD diagnosed < 18 months prior to 
Screening/Baseline 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 
(FA) and sequelae of CNV, e.g. pigment epithelial detachment (PED), 
subretinal hemorrhage or sub-retinal pigmented epithelium (sub-RPE) 
hemorrhage, blocked fluorescence, or macular edema. 
 
Previous treatment with only one licensed anti-VEGF drug (i.e. Lucentis®, 
Eylea®) with a ≥ Q4 and ≤ Q8 treatment (treatment interval of 26 to 62 
days inclusive) with licensed anti-VEGF (a minimal washout period of 4 
weeks / 26 days is required). Patients must have received at least 3 


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injections of this anti-VEGF drug in the 6 months prior to 
Screening/Baseline 
 
Presence of residual fluid (intraretinal fluid (IRF) or subretinal fluid (SRF) 
that affects the central subfield under, as seen by OCT). 
 
Best-corrected visual acuity (BCVA) score must be ≤ 83 and ≥ 38 letters 
at an initial testing distance of 4 meters starting distance using Early 
Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity charts 
at Screening/Baseline.  
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. 
 
Presence of amblyopia, amaurosis, or ocular disorders in the fellow eye 
with BCVA < 35 ETDRS letters at Screening/Baseline (except when due 
to conditions whose surgery may improve visual acuity, e.g. cataract).  
 
Medical history of intraocular inflammation and/or retinal vascular 
occlusion within 12 months prior to Screening/Baseline 
Study eye 
 
Poor quality of OCT images at Screening/Baseline.  
 
Atrophy or fibrosis involving the center of the fovea in the study eye, as 
assessed by CFP and fundus autofluorescence (FAF). 
 
The total area of fibrosis or subretinal blood affecting the foveal center 
point comprising ≥ 50% of the lesion area in the study eye. 
 
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. 
 
Uncontrolled glaucoma in the study eye defined as intraocular pressure 
(IOP) > 25 mmHg on medication or according to Investigator’s judgment.  
 
Previous laser treatment for nAMD including photodynamic therapy 
(PDT) laser at any time prior to Screening/Baseline.  
Systemic conditions or treatments 
 
Stroke or myocardial infarction in the 6-month period prior to 
Screening/Baseline. 
 
Systemic anti-VEGF therapy at any time. 
Other 
 
Women of childbearing potential, defined as all women less than 1 year 
postmenopausal or less than 6 weeks since sterilization.  
Study treatment 
Brolucizumab 6 mg (RTH258 6 mg/ 0.05 mL) solution for injection in pre-filled 
syringe 
Efficacy 
assessments 
 OCT 
 
 
 
  
 
 
 
  
 
 
 Visual acuity using BCVA (EDTRS) 
 
 
Key safety 
assessments 
 
Vital signs  
 
Ophthalmic examination (
 biomicroscopy, indirect ophthalmoscopy) 
and imaging 




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Introduction 
1.1 
Background 
Neovascular age-related macular degeneration is characterized by the presence of choroidal 
neovascularization (CNV), which consists of abnormal blood vessels originating from the 
choroid that 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 studies.  
Brolucizumab is a new generation of anti-VEGF. Brolucizumab is the first humanized 
single-chain antibody fragment (scFv), which inhibits 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]) (Dugel et al 2019) comparing brolucizumab every 12 weeks (Q12) or every 
8 weeks (Q8) to aflibercept Q8 according to its approved label. In these studies, patients in both 
treatment arms received 3 loading doses every 4 weeks, followed by a Q12/Q8 maintenance 
regimen according to patient’s disease activity for the brolucizumab 6-mg arm and a Q8 
maintenance regimen for the aflibercept 2-mg arm. For the Q12/Q8 treatment regimen, Q12/Q8 
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 
Q12/Q8 regimen, the initial treatment schedule after the loading phase was Q12. If disease 
activity was identified by the Investigator in brolucizumab-treated patients at any of the disease 
activity assessments, dosing was adjusted to Q8 (i.e. “Q12/Q8 regimen”). Once patients were 
adjusted to a Q8 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 at Week 48 for the following mean change from Baseline in 
central subfield retinal thickness (CSFT); percentage of patients with intraretinal fluid and/or 
subretinal fluid (IRF and/or SRF); percentage of patients with subretinal pigment epithelium 
(sub-RPE) fluid; and at Week 16 for the percentage of patients with no disease activity (Dugel 
et al 2019). Safety was comparable between the treatment arms over 2 years. 
Since the first global marketing authorization approval in the US, in Oct-2019, for the treatment 
of nAMD, adverse events 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 
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 


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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. 
In addition, based on the USM (CRTH258AUS04 first interpretable results [FIR]), the interval 
between two brolucizumab doses should not be shorter than 8 weeks beyond the loading phase. 
These impacts on the risk/benefit balance of the product are considered to be low and the overall 
risk/benefit assessment remains positive, when patients are dosed at q8w or longer after the 
loading phase and when patients who develop RV and/or RO are discontinued from further 
treatment with brolucizumab. 
Despite the interesting results of brolucizumab treatment with a Q12/Q8 regimen in naïve 
nAMD patients, the most popular and used anti-VEGF treatment, both internationally 
(Wykoff et al 2018) and in France (Bourrhis 2019), is the Treat-and-Extend regimen (T&E). 
Accordingly, a new Phase 3b study (TALON, CRTH258A2303) is being conducted to evaluate 
the efficacy and safety of brolucizumab in a Treat-to-Control (TtC) regimen for the treatment 
of naïve patients with nAMD. In this TtC regimen, patients receive 3 consecutive injections 
every 4 weeks and then the injection interval is extended by 4 weeks up to a maximum of a 
16-week interval. The decision to extend or reduce the injection interval is taken by the 
Investigator at each visit based on his/her judgment of disease activity, according to the patient 
visual and/or anatomic outcomes. If there is no disease activity, the injection interval can be 
extended by 4 weeks; if disease activity occurs or recurs, the injection interval should be 
shortened accordingly by 4 weeks at a time or to a minimal interval of 8 weeks. The injection 
interval can also be maintained if the Investigator deems that the patient do not benefit from 
injection interval extension. 
Since all these studies were conducted in a naïve nAMD patient population, no data are 
available on the efficacy and safety of brolucizumab in pretreated nAMD patients who still 
present active exudation.  
Indeed, in interventional studies (EXCITE, Schmidt-Erfurth et al 2011; TREND, Silva et al 
2018; ALTAIR, Masahito 2017; FLUID, Guymer et al 2019; RIVAL, Gillies et al 2019) and 
real-life studies (LUEUR, Souied et al 2015; RAINBOW, Weber et al 2019), a number of 
patients treated with ranibizumab or aflibercept still presented persistent fluid when extended 
to Q6 or longer treatment intervals.  
Switching to another anti-VEGF treatment has become the second-line strategy for suboptimal 
anatomically controlled patients (Empeslidis et al 2019). Several studies have assessed the 
efficacy of switching nAMD patients to another anti-VEGF following unsatisfactory response 
to prior therapy. Despite very limited benefit from switching to another anti-VEGF in terms of 
visual outcome, the majority of the studies have shown substantial gains in terms of interval 
between injections and anatomical outcomes, with a total fluid resolution on OCT in 60% to 
72% of patients 1 year after the switch (Pinheiro-Costa et al 2015, Arcinue et al 2015, Sarao et 
al 2016).  
In conclusion, based on all these data, we could expect that switching suboptimal anatomically 
controlled patients treated with current licensed anti-VEGF to a presumably more effective and 


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longer lasting anti-VEGF agent like brolucizumab may lead to optimized fluid and disease 
control.  
The SWIFT study intends to complement the current clinical dataset on brolucizumab by 
generating new evidence in suboptimal anatomically controlled nAMD patients despite the 
anti-VEGF treatment. The study will evaluate the efficacy and safety of brolucizumab 
administered in a 4-week-adjustment TtC regimen with treatment intervals from 8 to 16 weeks 
after the initial three consecutive monthly injections and one treatment interval extension by 4 
weeks from Week 8 to Week 16 (“initiation phase”). Subjects requiring injections every 4 
weeks after the initiation phase will be discontinued from further study treatment. The study 
will assess if treatment with brolucizumab results in better disease control at Week 16 and over 
the 48 weeks in these suboptimal anatomically controlled patients. 
1.2 
Purpose 
The purpose of this study is to assess both early (at Week 16 just after the loading phase) and 
long-term (48 weeks) effects of brolucizumab on disease control in suboptimal anatomically 
controlled nAMD patients.   
 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints  
Objectives 
Endpoints 
Primary objective 
Endpoint for primary objective 
 
To evaluate the effect of brolucizumab 6 mg 
on disease control  
 
 Proportion of patients with no disease 
activity at Week 16  
Secondary objectives 
Endpoints for secondary objectives 
 
To evaluate the long term effects of 
brolucizumab 6 mg on disease control 
 
Proportion of patients with no disease 
activity at Week 48  
 
To evaluate the effect of brolucizumab 6 mg 
on anatomical parameters  
 
Change from Baseline in CFST as 
assessed by OCT over time up to Week 48  
 
Absence of IRF, SRF, and sub-RPE fluid 
as assessed by OCT over time up to Week 
48  
 
Proportion of patients with a dry retina 
(neither IRF nor SRF) up to Week 48  
 
To evaluate the durability of brolucizumab 
6 mg  
 
Distribution of the last interval with no 
disease activity up to Week 48  
 
Distribution of the maximal intervals with 
no disease activity up to Week 48  




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Patients will require attending 5 mandatory study visits: Screening/Baseline (Day 1), Weeks 4, 
8, 16, and 48/50. The other visit time points will depend on the injection regimen of the patient.  
Figure 3-1 
Study design 
 
a End of treatment: Week 38/40/42/44/46 according to treatment schedule.  
b End of study: at least 4 weeks after the end of treatment. For patients receiving the last IVT at Week 46, 
the EOS Visit will be at Week 50, 4 weeks following their last treatment 
 
The fellow eye will be treated at the discretion of the Investigator.  
 
Open-label Treatment Period: from Day 1 to Week 44/46 
The Screening Visit and the Baseline Visit (see Table 8-1) are the same visit.  
One time re-assessment of patients will be 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. 
Patients must have confirmed nAMD at Screening/Baseline and have received his/her last 
licensed anti-VEGF injection from 4 weeks to 8 weeks (from 26 to 62 days inclusive). 
After confirmation of eligibility, patients will be included and treated with brolucizumab 6 mg 
in a TtC regimen. A study visit schedule will be established at the time of inclusion for all 
patients. All efforts should be made to adhere to this 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 visit window. Treatment (including at Screening/Baseline) is 
intended to be administered on the day of study visit, or if this is not possible, within 3 days 


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after the study visit when the per-protocol assessments would have taken place, in which case 
study treatment administration should occur within the next 24 hours. 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-44 visit or at the Week-46 visit if the patients had 
received the study treatment at an odd number of inspection visits (see below). The Initiation 
Phase starts on Day 1 and ends on Week 8. The TtC regimen spans from Week 8 until end of 
treatment (Week 44/46).  
Patients will receive 3 consecutive injections every 4 weeks at Screening/Baseline, Week 4, and 
Week 8 (loading phase), which should be at least 21 days apart.  
At Week 8, based on Investigator’s judgment of visual and/or anatomic outcomes, the injection 
interval will be extended by 4 weeks at a time if there is no disease activity, as provided in the 
guidance to the Investigators, e.g. no change in visual acuity and in other signs of the disease 
(e.g. IRF, SRF, hemorrhage, leakage, etc.).  From Week 16, the injection interval can be 
maintained on Q8 (or Q12 from Week 28) if the Investigator deems that the patient will not 
benefit from treatment interval extension, with a minimal interval of 8 weeks. If disease activity 
recurs, the injection interval should be shortened accordingly by 4 weeks at a time or to a 
minimal interval of 8 weeks. The injection interval can also be maintained if the Investigator 
deems that the patient will not benefit from injection interval extension (see Section 6.7.2 for 
further details). Patients who require study treatment every 4 weeks after the initiation phase 
will be discontinued from further study treatment at the next visit. 
At the Investigator’s discretion, in case of interval extension, inspection visits can be performed 
at the midterm of the interval extension, e.g. 6 weeks after the last injection when the injection 
interval is extended from 4 weeks to 8 weeks.  If there is no disease activity in the study eye at 
the inspection visit, as assessed by the Investigator, no treatment will be administered at this 
inspection visit; the next visit and injection will take place 2 weeks later, i.e. 8 weeks after the 
previous study treatment. If disease activity is observed by the Investigator in the study eye at 
the inspection visit at Week 14, the study treatment will be administered by the Investigator and 
the patient will be discontinued from further study treatment at the next visit. Inspection visits 
10 weeks and 14 weeks after the last injection can be performed when the injection interval is 
extended from 8 weeks to 12 weeks and from 12 weeks to 16 weeks, respectively (see 
Section 6.7.2).  
 
Follow-up Period: from Week 44/46 to Week 48/50 
For all patients completing the study as per protocol, the End-of-Study (EOS) assessment will 
be performed at Week 48 (or Week 50 for patients receiving their last treatment at Week 46), 
at least 4 weeks (± 7 days) following the last possible study treatment administration. For 
patients who receive their last IVT at Week 46, the EOS assessment will be performed at Week 
50 (± 7 days), at least four weeks (± 7 days) following their last possible study treatment 
administration. For clarity reason, the EOS visit will be named Week 48 in the rest of this 
protocol. 


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Patients withdrawn from the study prior to study completion will be asked to return for an early 
discontinuation (EOS) 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 pretreated suboptimal anatomically controlled nAMD patients will be 
performed to assess both early (at Week 16) and long-term (48 weeks) effects of brolucizumab, 
a new-generation anti-VEGF treatment, on disease activity in a TtC regimen.  
The TtC regimen emphasizes sustained disease control to determine the optimal treatment 
interval for each patient rather than solely adjusting treatment intervals. For instance, it allows 
patients that may not benefit from treatment interval adjustment to be temporarily or lastingly 
maintained on a treatment interval. This treatment adjustment is particularly needed in these 
difficult-to-treat patients that are not controlled with a previous anti-VEGF treatment. 
The safety and efficacy of brolucizumab has been demonstrated in naive nAMD patients in 2 
randomized, multicenter, double-masked, active-controlled Phase 3 studies (HAWK 
RTH258-C001 and HARRIER RTH258-C002) up to 96 weeks (see Section 1.1), an additional 
Phase 3b study (TALON CRTH2582303) will evaluate the efficacy and safety of brolucizumab 
in a TtC regimen. Disease control was evaluated in these studies using visual and/or anatomic 
outcomes, and HAWK and HARRIER studies have demonstrated that brolucizumab increase 
disease control in more patients compared to aflibercept, with relative additional 30% more 
patients without disease activity at Week 16 with brolucizumab compared to aflibercept 
(respectively p = 0.0013 and p = 0.0021). 
 
4.2 
Rationale for dose/regimen and duration of treatment 
The dose and regimen for brolucizumab is based on the following considerations: 
 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 (RTH258-C001, RTH258-C002). 
The nAMD study results regarding Q12/Q8 maintenance dosing interval support stretching 
the interval between injections during the Treat-to-Control Phase to reduce the treatment 
burden (see Section 1.1). 
 CRTH258AUS04 (MERLIN) is a two-year, multicenter, randomized, double masked, 
Phase IIIa study evaluating brolucizumab 6 mg q4w versus aflibercept 2 mg q4w in patients 
with nAMD with persistent fluid. Review of the 52-week FIR led to an urgent safety 
communication based on an increased incidence of intraocular inflammation (IOI) and 
related adverse events including retinal vasculitis (RV), and retinal vascular occlusion (RO) 
in patients with q4w dosing with brolucizumab beyond the “loading phase”. IOI including 
RV, and RO were reported at a higher frequency in brolucizumab 6 mg q4w when compared 
to aflibercept 2 mg q4w (IOI: 9.3% vs 4.5% of which RV: 0.8% vs 0.0%; RO: 2.0% vs 0.0%, 


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respectively). Accordingly, the CRTH258AFR03 protocol is being amended to discontinue 
subjects from study treatment who require treatment every 4 weeks. 
 In line with current clinical practice, ophthalmology association recommendations, and 
labels of approved anti-VEGF drugs in most countries worldwide, the treatment frequency 
can be adjusted based on the Investigator’s assessment of disease activity.  
 Current evidence from large ranibizumab studies in nAMD (CRF002A2411 - TREND, 
CRF002ACA06 - CAN-TREAT, CRF002AAU15 - FLUID, CRF002AAU17 - RIVAL) 
indicates that the Treat-and-Extend regimen is efficient and clinically comparable to 
monthly injections in improving visual acuity while reducing the number of visits and 
treatments (see Section 1.1). 
 In this SWIFT study, patients will be suboptimal anatomically controlled (active CNV with 
residual IRF and/or SRF) despite a Q4 to Q8 anti-VEGF treatment. For these non/partially 
responder patients, the treatment should be as frequent as needed. That is why a Q8 
treatment will be allowed since Week 8 and the interval extension will be optional after the 
loading phase. 
 The route of administration is intravitreal (IVT) as for all anti-VEGF treatments currently 
approved for nAMD. 
 Prefilled syringes (PFS) have been selected for administration of study treatment because 
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-16 visit. An interim analysis will be performed when the last patient included completed 
Week-16 visit. 
Patients will remain in the study and continue to receive treatment for the maximum planned 
duration of treatment of 44/46 weeks. The final analysis will be performed at the end of study 
when all patients have completed their last study visit.  
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 Q12 dosing interval at 48 weeks, and 
the remainder maintained on an Q8 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 


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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.  
These benefits were consistent across subgroups (e.g. age, gender, race, baseline visual acuity, 
baseline retinal thickness, lesion type, lesion size, and 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 Q12 interval; the vast majority of patients without disease activity during the initial Q12 
interval continued to be maintained on an Q12 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.  
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. 
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 immediately. 
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 study 
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 childbearing 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 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 active 
CNV secondary to nAMD and able to comply with study or follow-up procedures. 
Approximately 295 adult patients will be screened and included in France. 
If both eyes are eligible as per the inclusion and exclusion criteria described below, the eye with 
the worse BCVA at Screening/Baseline 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 
Eligible patients 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 nAMD diagnosed < 18 months prior to 
Screening/Baseline that affect the central subfield, including retinal angiomatous 
proliferation (RAP) with a CNV component, confirmed by presence of active leakage from 
CNV seen by FA and sequelae of CNV, e.g. pigment epithelial detachment (PED), 
subretinal hemorrhage or sub-RPE hemorrhage, blocked fluorescence, or macular edema.  
4. Previous treatment with only one licensed anti-VEGF drug (i.e. Lucentis®, Eylea®) with a 
≥ Q4 and ≤ Q8 treatment (treatment interval of 26 to 62 days inclusive) with licensed anti-
VEGF (a minimal washout period of at least 4 weeks / 26 days is required). Patients must 


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have received at least 3 injections of this anti-VEGF in the 6 months prior to 
Screening/Baseline. 
5. Presence of residual fluid (IRF or SRF that affects the central subfield under, as seen by 
OCT) 
6. BCVA score must be ≤ 83 and ≥ 38 letters at an initial distance of 4 meters starting distance 
using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity charts at 
Screening/Baseline.  
5.2 
Exclusion criteria  
Patients meeting any of the following criteria will not be eligible for inclusion in the 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/Baseline (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 image at Screening/Baseline.  
5. Atrophy or fibrosis involving the center of the fovea in the study eye, as assessed by CFP 
and fundus autofluorescence (FAF). 
6. The total area of fibrosis or subretinal blood affecting the foveal center point comprising 
≥ 50% of the lesion area in the study eye. 
7. 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, RPE rip/tear scar, laser burn, at the time of 
Screening/Baseline 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. 


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Ocular treatments (study eye) 
12. Patient has received any investigational treatment for nAMD (other than vitamin 
supplements) in the study eye at any time. 
13. Previous use of intraocular or periocular of corticosteroids in the study eye within the 
6-month period prior to Screening/Baseline. 
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 and peripheral laser photocoagulation. 
 Previous macular surgery or other intraocular surgical intervention 
16. Previous laser treatment for nAMD including photodynamic therapy (PDT) laser at any time 
prior to Screening/Baseline.  
17. Previous treatment with investigational drugs. 
Systemic conditions or treatments 
18. End-stage renal disease requiring dialysis or renal transplant. 
19. Systemic medications known to be toxic to the lens, retina or optic nerve (e.g. deferoxamine, 
chloroquine/hydroxychloroquine, tamoxifen, phenothiazines and ethambutol) used during 
the 6-month period prior to Baseline except temporary use for COVID-19 treatment. 
20. 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 Baseline. 
Note: observational clinical studies solely involving over-the-counter vitamins, supplements, 
or diets are not exclusionary. 
21. Systemic anti-VEGF therapy at any time. 
22. Stroke or myocardial infarction in the 6-month period prior to Screening/Baseline. 
23. Uncontrolled blood pressure defined as a systolic value ≥ 160 mmHg or diastolic value 
≥ 100 mmHg. (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). 
24. 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. 
25. 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. 
26. History of hypersensitivity to the study drug or its excipients or to drugs of similar classes, 
or clinically relevant sensitivity to fluorescein dye, as assessed by the Investigator. 


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Other 
27. 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. 
28. Women of childbearing potential, defined as all women less than 1 year postmenopausal or 
less than 6 weeks since sterilization.  
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 
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. 
29. 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 Pre-Filled Syringe (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 study. 


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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 Baseline, Week 4, and Week 8), followed by a TtC regimen phase based 
on disease activity from Week 8 up to Week 44/46 (according to the treatment regimen). 
6.1.4 
Treatment duration 
The study treatment will be start after a minimum washout period of at least 4 weeks / 26 days 
and maximum 8 weeks/62 days after the last licensed antiVEGF injection. 
The maximum planned duration of treatment for each patient is 44 or 46 weeks in accordance 
with the 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 14/Week 16), study treatment will also 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.  
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). The last licensed antiVEGF 
injection must be received at least 4 weeks / 26 days and at maximum 8 weeks / 62 days before 
patient inclusion in the study. 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 is 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 


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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 AEs captured in the eCRF. 
Administration of topical ocular corticosteroids in the study eye is allowed during the study. 
Corticosteroids administered intranasal, inhaled, intra-articular, or via non-extensive dermal 
route (< 20% of total body surface area) are also permitted during the study. Refer to Section 
6.2.2 for other routes of corticosteroid administration. 
If cataract surgery were 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 surgery-related complications. 
If yttrium aluminum garnet laser (YAG) were 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. 
6.2.2 
Prohibited medication 
Use of the treatments displayed in Table 6-2 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 AEs) 
Anytime  
Discontinue study treatment 
(except if for treatment of AEs) 
Anti-VEGF therapy other than assigned 
study medication 
Anytime 
Discontinue study treatment  
Panretinal laser, photodynamic 
therapy 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 


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In the fellow eye, treatment with investigational products (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 study. The Patient No. consists of the study site 
number (4-digit number assigned by Novartis) with a sequential patient number suffixed to it 
(3-digit number), so that each patient is numbered uniquely across the entire database. Upon 
signing the informed consent form (ICF), the patient is assigned to the next sequential Patient 
No. available in the electronic data capture (EDC) system. 
Patients who have failed screening, 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 (at Screening/Baseline, Week 4, and Week 8). After the 
Week 8 treatment visit, the Investigator can decide, based on disease activity, to extend the 
injection interval by 4 weeks to an 8-week interval to Week 16.  
From Week 8, based on Investigator’s judgment of visual and/or anatomic outcomes, the 
injection interval can be extended by 4 weeks at a time, if there is no disease activity, as 
provided in the guidance to the Investigators, e.g. no change in visual acuity and in other signs 
of the disease (e.g. IRF, SRF, hemorrhage, leakage, etc.). From Week 16, the injection interval 
can be maintained on Q8 (or Q12 from Week 28) if there is no disease activity. If disease activity 
recurs, the injection interval should be shortened accordingly by 4 weeks at a time or to a 


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minimal interval of 8 weeks. The injection interval can also be maintained if the Investigator 
deems that the patient will not benefit from injection interval adjustment (see Figure 6-1). 
Neither study treatment dose modification nor deviations from the allowed dose intervals (in 
accordance with disease activity assessments) will be permitted. 
Interruption of study treatment will be 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. 
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, study 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 
study 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 legal requirements. They will 
include storage conditions for the study treatment, but not information about the patient except 
for the medication number. 


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The Investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a Drug Accountability Log. Drug accountability will be performed by monitors 
during study site visits or remotely, and at the completion of the study.  
At the conclusion of the study, and as appropriate during its course, 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 study 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  
 
 
a From Week 16, the treatment interval can also be maintained if the Investigator deems that the 
patient will not benefit from treatment interval extension, with a minimal interval of 8 weeks.  
6.7.2.1 
Initiation Phase 
In the Initiation Phase, brolucizumab 6 mg will be injected 3 times at 4-week intervals, at 
Screening/Baseline (Day 1), Week 4, and Week 8.  
6.7.2.2 
Treat-to-Control Phase 
After the Initiation Phase, the Treat-to-Control Phase will start from Week 8, where the 
injection interval will be extended by 4 weeks to Week 16 (according to disease activity).   


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The Treat-to-Control Phase rules are defined as follows: 
 Following Week 8, treatment intervals will be either 8 weeks, 12 weeks, or 16 weeks. A 
patient must be discontinued from further study treatment if treatment is required more 
frequently, i.e., every 4 weeks. 
 The assessment of disease activity will be performed at each visit by the Investigator. 
 At Week 8, based on Investigator’s judgment of visual and/or anatomic outcomes, treatment 
intervals will be extended by 4 weeks at a time, if there is no disease activity, i.e. no change 
in visual acuity and in other signs of the disease (e.g. IRF, SRF, hemorrhage, leakage, etc.). 
From Week 16, the injection interval can be maintained on Q8 (or Q12 from Week 28) if 
the Investigator deems that the patient will not benefit from treatment interval extension, 
with a minimal interval of 8 weeks. 
 If disease activity recurs, treatment intervals should be shortened accordingly by 4 weeks at 
a time or to a minimal interval of 8 weeks. 
 At the Investigator’s discretion, an inspection visits at Week 14, i.e. 6 weeks after the 3rd 
injection, can be performed. If there is no disease activity in the study eye at Week 14, as 
assessed by the Investigator, the study treatment will not be administered; the next visit and 
injection will take place at Week 16. If disease activity is observed by the Investigator in 
the study eye at Week 14, the study treatment will be administered by the Investigator, and 
the subject will be discontinued from further study treatment.  
 Inspection visits 10 weeks after the last injection can be performed at the Investigator's 
discretion when the injection interval is extended from 8 weeks to 12 weeks. If there is no 
disease activity in the study eye at the inspection visit as assessed by the Investigator, the 
study treatment will not be administered; the next visit and injection will take place 2 weeks 
later, i.e. 12 weeks after the previous study treatment. If disease activity is observed by the 
Investigator in the study eye at the inspection visit, the study treatment will be administered 
by the Investigator; the injection interval will be reduced to 8 weeks and the next injection 
visit will be 8 weeks after the inspection visit. 
 Similarly, inspection visits 14 weeks after the last injection can be performed at the 
Investigator's discretion when the injection interval is extended from 12 weeks to 16 weeks, 
respectively. If there is no disease activity in the study eye at the inspection visit as assessed 
by the Investigator, the study treatment will not be administered; the next visit and injection 
will take place 2 weeks later, i.e. 16 weeks after the previous study treatment. If disease 
activity is observed by the Investigator in the study eye at the inspection visit, the study 
treatment will be administered by the Investigator; the injection interval will be reduced to 
12 weeks and the next injection visit will be 12 weeks after the inspection visit. 
 The last potential study treatment may be administered at Week 44/46 according to the 
treatment schedule. 
 A disease activity assessment will also be performed at the Week 48/EOS visit; however, 
no study treatment will be administered.  
 
If a patient misses a disease activity assessment visits (Week 8 and the following), the patient 
should come to the visit as soon as possible. The investigator is recommended to consider the 


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patient to have met the disease activity criterion at the missed visit and the patient next treatment 
interval should be modified accordingly (e.g. shortened by 4 weeks). 
If a patient misses Week 16, then the last visit values (Week 8 or Week 14) will be applied as 
the reference for disease activity assessments for the primary endpoint. 
 
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 will take place. 
Table 6-3 
Disease activity assessment and treatment occurrence according to 
visit type  
Type 
Study phase 
Disease activity 
assessment 
Treatment 
Screening/Baseline 
(Day 1) Visit 
Initiation Phase 
Yes 
Yes 
Weeks 4 and 8 visits 
Initiation Phase 
Yes 
Yes 
Week 16 visit 
Treat-to-Control Phase 
Yes 
Yes a 
Treatment visits  
Treat-to-Control Phase 
Yes 
Yes a 
Inspection visits 
(optional) 
Treat-to-Control Phase 
Yes 
Based on DA, as per 
Investigator's judgment 
ETD visit and EOS 
visit (Week 48/50b) 
Follow up 
Yes 
No 
a Treatment according to Investigator’s decision based on assessment of disease activity.   
b The EOS Visit will take place at least 4 weeks after the last injection, e.g. at Week 48 or at Week 50 
for patients receiving his/her last injection at Week 46.  
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 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 the results documented 
in the source documents. If any safety concern related to the study eye arises that, in the opinion 
of the Investigator, may be further impacted by the study treatment or injection procedure, the 
treatment needs to be cancelled.  
Injections are contraindicated in patients with active intraocular or periocular infections and in 
those with active intraocular inflammation (IOI); therefore, the Investigator must verify that 
these conditions are not present in the study eye prior to every injection. Any AE must be 
recorded in the eCRF.  
If any signs of intraocular inflammation (IOI) are present, then an IVT injection must not be 
performed. 


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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. 
 
Informed consent procedures 
Eligible patients may only be included in the study after providing (witnessed, where required 
by law or regulation) 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 
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 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 after 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 


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documentation. All data requested by eCRF must be entered in a timely manner (see 
Section 11.1). 
The study treatment will be administrated after a minimum washout period of at least 4 weeks 
/ 26 days and maximum 8 weeks / 62 days after the last licensed antiVEGF injection (see 
Inclusion Criteria section). 
A planned study visit schedule will be established at Screening/Baseline/Day 1 for all patients. 
All post-Screening/Baseline and/or subsequent scheduled visits will be calculated based on the 
Day 1 visit date. During the Treat-to-Control Phase, from Week 8 to Week 44/46, 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 will be 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 
visit window. 
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 could not be 
administered and other study assessments may not be performed. Alternative methods of safety 
monitoring may be implemented. Depending on local regulations, site capabilities and patient’s 
visit status in the study, phone calls or virtual contacts (e.g. teleconsult) can be performed for 
safety follow-up for the duration of the pandemic, until it is safe for the participant to visit the 
site again. 
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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Period (see Section 10.1.2 for reporting details). Non-serious AEs 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 early terminators. 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: 
 Age 
 Sex 
 Vital signs 
 Study eye 
 Study eye status at nAMD diagnosis (date of diagnosis, BCVA at diagnosis, CSFT at 
diagnosis...) 
 History of treatment with the previous antiVEGF of the study eye (nature of the previous 
antiVEGF, date of the first IVT, date of the last IVT, total number of previous IVTs, total 
number of monitoring consultations...) 
 BCVA 
 CNV characteristics (assessed via OCT, 
) 
 
 
 Ophthalmic examinations (
 slit-lamp examination) 
 Retinal imaging (assessed via OCT, 
) 
 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 images 
  
 
   
 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. 












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 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 
 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 
study site staff should maintain regular telephone contact with the patient, or with a person 


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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 Table 8-1).  
Novartis will continue to keep and use collected study information according to applicable law. 
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 




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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 study-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 study 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. 
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. 


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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 Screening/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 
 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 


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 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).  
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. 
10.1.3 
Protocol exemption from reporting 
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.     
10.1.4 
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 study 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. 


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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. 
10.1.5 
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.  
10.1.6 
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 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). 
 
 


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Data collection and database management 
11.1 
Data collection 
Designated Investigator staff will enter the data required by the protocol into the eCRFs, which 
have been built using fully validated secure web-enabled software that conforms to 21 CFR 
Part 11 requirements. Study 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 study site. 
All data must be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
11.2 
Database management and quality control 
Novartis (or designated CRO) personnel will review the data entered by investigative staff for 
completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
study site via the EDC system. Designated Study 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 protocol deviations will be determined at Week 16 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 study 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 study sites’ data. The field monitor will visit the study site to check the completeness of 




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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 Screening/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, n, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented. 
Relevant medical histories and current medical conditions at Screening/Baseline will be listed. 
The last available assessment taken prior to the first IVT injection of study treatment is taken 
as the “baseline” assessment. 
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 number of IVT injections received from 
Screening/Baseline to the end of the treatment period will be descriptively summarized. 
Furthermore, the number of patients in each injection category (1 injection, 2 injections up to 
the maximum number of injections) from Screening/Baseline to the end of the treatment period 
will be presented.  
The dosing regimen received at W48 will be presented descriptively. 
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-
Screening/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.  


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12.4 
Analysis of the primary endpoint  
12.4.1 
Definition of the primary endpoint 
The primary objective of this study is to evaluate the effect of brolucizumab 6 mg on disease 
control. The primary efficacy endpoint is the proportion of patients with no disease activity at 
Week 16. This analysis will be performed in the FAS and will focus on the study eye only. 
12.4.2 
Statistical model, hypothesis, and method of analysis  
The number (%) and proportion of patients with no disease activity at Week 16 will be provided 
with the associated 95% confidence interval using Clopper-Pearson method.  
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. 
12.4.4 
Sensitivity and supportive analyses 
In order to assess the robustness of the primary endpoint, sensitivity and supportive analyses 
are planned. These may include, but are not limited to: 
 Imputation of missing data : 
 Considering missing data as disease activity 
 LOCF imputation 
 Repetition of the primary analysis using the PPS. 
Sensitivity estimand in exposed and non-exposed to the urgent safety measures: As a 
sensitivity analysis for the disease activity at Week 16, the proportion of subjects with no 
disease activity at Week 16 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 fluids type (IRF, SRF), number of previous antiVEGF injections, and time since 
nAMD diagnosis subgroup analyses will also be performed on the primary endpoint.   
12.5 
Analysis of secondary endpoints 
All secondary efficacy analyses will be based on the FAS. The analyses performed at eye level 
will focus on the study eye only. 
12.5.1 
Effects of brolucizumab 6 mg on disease activity 
The number (%) and proportion of subjects with no disease activity up to Week 48 will be 
provided. 


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12.5.2 
Effect of brolucizumab 6 mg on anatomical parameters  
Summary statistics of the change from Baseline in CSFT up to Week 48 will be provided. 
The number (%) and proportion of subjects with absence of IRF, SRF, and sub-RPE fluid as 
assessed by OCT over time up to Week 48 will be presented.  
The number (%) and proportion of subjects with dry retina (no IRF nor SRF) up to Week 48 
will be presented. 
12.5.3 
Durability of brolucizumab 6 mg 
Summary statistics of the time (in days) of the last interval with no disease activity before or at 
Week 48 will be provided. If there is disease activity, the last interval will be shortened by 
4 weeks down to a minimum of 4 weeks. The distribution of the last interval is the proportion 
of subjects with no disease activity (Q4, Q8, and Q12) up to Week 48.  
Summary statistics of time (in days) of the longest interval of treatment with no disease activity 
before or at  Week 48 will be provided. The distribution of the maximal interval is the 
proportion of patients with no disease activity ( Q8, Q12 and Q16) up to Week 48.  
12.5.4 
Functional outcomes  
Summary statistics of the average change from Baseline in BCVA at Week 48 will be provided. 
12.5.5 
Safety endpoints 
The Safety Set will be used for all safety analyses. 
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. 
12.5.5.1 Adverse events 
Summary tables for AEs will summarize only on-treatment events with start date during the 
on-treatment period. Separate summary tables will be provided for AEs of the study eye, the 
fellow eye, and for non-ocular AEs. 
The on-treatment period lasts from the date of first administration of study treatment to 30 days 
after the last administration of study treatment or EOS whichever is the latest. 
All information obtained on AEs will be displayed by patient. All collected AEs will be listed.  






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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 IEC 
Before initiating a study, the Investigator/institution must obtain approval/favorable opinion 
from the IEC for the study 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, IECs, and regulatory authorities as required.  
If an inspection of the study 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 study will be submitted for publication 
and posted in a publicly accessible database of clinical study results, such as the Novartis 
clinical study 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 study Investigator 
meetings. 
13.4 
Quality control and quality assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of study sites, vendors, and Novartis systems are performed by auditors, independent 
from those involved in conducting, monitoring or performing quality control of the clinical 
study. 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. 


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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 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 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 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 IEC at the study site should be informed according to local 
regulations. 


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References 
References are available upon request. 
Arcinue CA, Ma F, Barteselli G, et al (2015) One-year outcomes of aflibercept in recurrent or 
persistent neovascular age-related macular degeneration. Am J Ophthalmol; 159(3):426-36.e2.  
Bourhis, Maculart congress 2019, June 23rd, Poster 007 
Dugel PU, Koh A, Ogura Y, et al (2019) HAWK and HARRIER: Phase 3, multicenter, 
randomized, double-masked trials of brolucizumab for neovascular age-related macular 
degeneration. Ophthalmology; S0161-6420(18)33018-5.  
Empeslidis T, Storey M, Giannopoulos T, et al (2019) How successful is switching from 
bevacizumab or ranibizumab to aflibercept in age-related macular degeneration? A systematic 
overview. Adv Ther; 36(7):1532-48.  
Gillies MC, Hunyor AP, Arnold JJ, et al (2019) Effect of ranibizumab and aflibercept on 
best-corrected visual acuity in treat-and-extend for neovascular age-related macular 
degeneration: A randomized clinical trial. JAMA Ophthalmol; 137(4):372-379.  
Guymer RH, Markey CM, McAllister IL, et al (2019) Tolerating subretinal fluid in neovascular 
age-related macular degeneration treated with ranibizumab using a treat-and-extend regimen: 
FLUID study 24-month results. Ophthalmology; 126(5):723-34.  
Jabs DA, Nussenblatt RB, Rosenbaum JT, Standardization of uveitis nomenclature (SUN) 
Working Group (2005) Standardization of uveitis nomenclature for reporting clinical data. 
Results of the first international workshop. Am J Ophthalmol;140(3): 509-16. 
Masahito O – EURETINA 2017 – Oral presentation, September 8th 
Nussenblatt RB, Palestine AG, Chan CC, Roberge F. (1985) Standardization of vitreal 
inflammatory activity in intermediate and posterior uveitis. Ophthalmology;92(4): 467-71 
Pinheiro-Costa J, Costa JM, Beato JNet al (2015) Switch to aflibercept in the treatment of 
neovascular AMD: One-year results in clinical practice. Ophthalmologica; 233(3-4):155-61.  
Sarao V, Parravano M, Veritti D, et al (2016) Intravitreal aflibercept for choroidal 
neovascularization due to age-related macular degeneration unresponsive to ranibizumab 
therapy. Retina; 36(4):770-7.  
Schmidt-Erfurth U, Eldem B, Guymer R, et al (2011) Efficacy and safety of monthly versus 
quarterly ranibizumab treatment in neovascular age-related macular degeneration: The EXCITE 
study. Ophthalmology; 118(5):831-9.  
Silva R, Berta A, Larsen M, et al (2018) Treat-and-extend versus monthly regimen in 
neovascular age-related macular degeneration: Results with ranibizumab from the TREND 
study. Ophthalmology; 125(1):57-65.  
Souied EH, Cohen SY, de Pouvourville G, et al (2015) Treatment of wet age-related macular 
degeneration by ranibizumab in "real life" in France: treatment behaviours and associated visual 
outcome. Acta Ophthalmol; 93(2):e179-80. 
Spilsbury K1, Garrett KL, Shen WY, et al (2000) Overexpression of vascular endothelial 
growth factor (VEGF) in the retinal pigment epithelium leads to the development of choroidal 
neovascularization. Am J Pathol; 157(1):135-44. 


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Protocol (Version No. 05) 
 
Protocol No. CRTH258AFR03 
 
Weber M, Velasque L, Coscas Fet al (2019) Effectiveness and safety of intravitreal aflibercept 
in patients with wet age-related macular degeneration treated in routine clinical practices across 
France: 12-month outcomes of the RAINBOW study. BMJ Open Ophthalmol; 4(1): e000109.  
Wykoff CC, Clark WL, Nielsen JS, et al (2018) Optimizing anti-VEGF treatment outcomes for 
patients with neovascular age-related macular degeneration J Manag Care Spec Pharm; 24(2a 
Suppl): S3-S15.  
 
Appendices 
Not applicable.  

SAP_001.pdf: 
Clinical Development
RTH258A/Brolucizumab
CRTH258AFR03 / NCT04264819
A one-year, single-arm, open-label, multicenter study 
assessing the effect of brolucizumab on disease control in 
adult patients with suboptimal anatomically controlled 
neovascular age-related macular degeneration (SWIFT) 
Statistical Analysis Plan (SAP)  
Author:
Statistician, 
Document type:
SAP Documentation
Document status:
Amendment1.0
Release date:
27-APR-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)
27-01-2021
Creation of 
initial version
N/A - First version
NA
27-04-2023
Creation of 
amendment 
1.0
Description of PRO removed from list of 
abbreviation of PRO removed from list of 
abbreviation
USM description added in list of 
abbreviation 
List of abbreviations
Updated protocol version and protocol 
release date 
Section 1 Introduction
Updated sample size in study design
Section 1.1 Study 
design
Drop the PRO objective from objectives 
and related endpoints
Section 1.2 Study 
objectives and 
endpoints
Updated population for patient disposition 
and protocol deviation
Section 2.4.1 Patient 
disposition and 
Section 2.4.2 Protocol 
deviation
Updated Baseline characteristics 
Section 2.4.4 Baseline 
characteristics
Added section for prior and post aVEGF 
and concomitant procedures 
Section 2.5.2 Prior and 
concomitant and post 
therapies
Updated the subgroup modalities
Section 2.6.2 
Supportive analysis
Updated the population for primary and 
secondary endpoint 
Added USM estimand in primary analysis
Section 2.6.1 Primary 
endpoint, Section 2.7.1 
secondary endpoint
Drop the percentage change from baseline 
for BCVA  
Section 2.7.1.4 
Function outcomes 
(BCVA)
Updated the sequence of variable for time 
to event analysis
Section 2.7.1.2.4 Time 
to dryness, Section 
2.7.1.2.5 Maximum 
duration of dryness and 
Section 2.8.1.3
Time to no disease 
activity
Changed increase to gain for BCVA 
outcome
Section 2.8.1.4 
Functional outcome 
(BCVA)
Added p-value in COVID-19 analysis
Section 2.8.1.5 COVID-
19 pandemic


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Date
Reason for 
update
Outcome for update
Section and title 
impacted (Current)
Dropped MedDRA query and PT table, 
updated ocular categories and other 
updates in modalities for type of adverse 
event & action taken.
Included urgent safety measure analysis
Section 2.9.1 Adverse 
event
Updated the AESI section to provide more 
details
Section 2.9-1.1 AESI
 
Updated the sample size 
Section 3 Sample size 
calculation
Added procedure and medical history 
(nAMD) in date imputation section 
Section 5.1.3
Concomitant 
medication 
(CM)/procedure (PR) 
and and medical history 
(nAMD) date imputation
Updated MedDRA version
Section 5.2 AEs 
coding/grading
Dropped correlation and Bland Altman plot 
SAS code
Section 5.4 Statistical 
method
Updated severity code for protocol 
deviation
Section 5.5 Rule of 
exclusion criteria of 
analysis set


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Table of contents
Table of contents .................................................................................................................4
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
Figure 1-1 Study design...........................................................................................8
1.2
Study objectives and endpoints ...............................................................................9
Table 2-1 Objectives and related endpoints.............................................................9
2
Statistical methods.............................................................................................................10
2.1
Data analysis general information .........................................................................10
2.1.1
General definitions................................................................................10
2.2
Visit windows for data analysis.............................................................................13
2.3
Analysis sets ..........................................................................................................14
2.4
Patient disposition, demographics and other baseline characteristics ...................15
2.4.1
Patient disposition.................................................................................15
2.4.2
Protocol deviation .................................................................................15
2.4.3
Demographic characteristics.................................................................16
2.4.4
Baseline characteristics.........................................................................16
2.4.5
Relevant medical history/ current medical condition............................17
2.5
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................18
2.5.1
Study treatment exposure......................................................................18
2.5.2
Prior, concomitant and post therapies...................................................18
2.5.3
Prior and concomitant Surgery and Procedures....................................19
2.5.4
History of anti – VEGF Therapy...........................................................19
2.6
Analysis of the primary objective..........................................................................20
2.6.1
Primary endpoint...................................................................................20
2.6.2
Supportive analyses...............................................................................20
2.7
Analysis of secondary efficacy objective(s)..........................................................21
2.7.1
Secondary endpoints .............................................................................21
23
2.9
Safety analyses.......................................................................................................27
2.9.1
Adverse events ......................................................................................27
2.9.2
Deaths....................................................................................................28
2.9.3
Laboratory data .....................................................................................29
2.9.4
Other safety data ...................................................................................29
2.10
Pharmacokinetic endpoints....................................................................................29


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2.11
PD and PK/PD analyses.........................................................................................29
29
2.13
Biomarkers.............................................................................................................30
2.14
Other Exploratory analyses....................................................................................30
2.15
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 (CM)/procedure (PR) and and medical 
history (nAMD) date imputation...........................................................33
5.2
AEs coding/grading ...............................................................................................35
5.3
Laboratory parameters derivations ........................................................................35
5.4
Statistical models...................................................................................................35
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 
CNV
Choroidal Neovascularization 
 
CI
Confidence Interval
CRO
Contract Research Organization
CSFT
Central Sub-Field Retinal Thickness 
CRT
Central Retinal Thickness
CSR
Clinical Study report
ENR
Enrolled set
 
 
FAS
Full Analysis Set
ECS
Edit checks specification
eCRF
Electronic Case Report Form
ICF
Informed Consent Form 
 
 
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
q12w
Every 12 Weeks 
SAP
Statistical Analysis Plan
SAF
Safety analysis set
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SOC
System Organ Class
TFL
Tables, Figures, Listings
TtC 
Treat-to-Control
USM
Urgent Safety Measure
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 (Protocol-Section 12) in the 
clinical protocol (CRTH258AFR03, version no: 05, release date 05Apr2022). This document 
will be used to prepare 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, which 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 pretreated suboptimal anatomically controlled patients with 
nAMD. 
Approximately 295 adult patients will be screened and included (10% dropout rate expected) 
in France. 
Before inclusion in the study, a patient must have a washout period of 4 weeks to 8 weeks (from 
26 to 62 days inclusive) versus his/her last administration of a licensed anti-VEGF drug (i.e. 
Lucentis®, Eylea®).
The maximum study duration for 1 patient is 48 to 50 weeks, according to the patient schedule. 
The study will consist of 2 periods (Figure 1-1):

Open-label Treatment Period (from Screening/Baseline (Day 1) to Week 44 or Week 46 
according to patient schedule) 

Follow-up Period (from Week 44 to Week 48 or from Week 46 to Week 50 according 
to patient schedule) 
According to the patient treatment schedule, the last treatment can be at Week 44 or Week 46. 
If the last treatment visit is at Week 46, the End-of-study visit will be at Week 50 (at least 4 
weeks after the last injection) instead of at Week 48.  
Patients will require attending 5 mandatory study visits: Screening/Baseline (Day 1), Weeks 4, 
8, 16, and 48/50. The other visit time points will depend on the injection regimen of the patient.  


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Figure 1-1 Study design 
a End of treatment: Week 38/40/42/44/46 according to treatment schedule. 
b End of study: at least 4 weeks after the end of treatment. For patients receiving the last IVT at Week 46, the EOS Visit will 
be at Week 50, 4 weeks following their last treatment. 
The fellow eye will be treated at the discretion of the Investigator.
The Screening Visit and the Baseline Visit are the same visit in this study. Patients will receive 
3 initial doses every 4 weeks (Day 1, Week 4 and Week 8). From Week 8, based on 
Investigator’s judgment of visual and/or anatomic outcomes, the injection interval can be 
maintained on Q4 regimen or extended by 4 weeks at a time if there is no disease activity, as 
per Investigators decision, e.g. no change in visual acuity and in other signs of the disease (e.g. 
IRF, SRF, hemorrhage, leakage, etc.). If disease activity recurs, the injection interval should be 
shortened accordingly by 4 weeks at a time or to a minimal interval of 4 weeks.
Patients who show disease activity at any of visits after week 8 will be adjusted to treatment 
interval and will remain on this interval until the end of the study at Week 48/50.
At the Investigator’s discretion, in case of interval extension, inspection visits can be performed 
at the midterm of the interval extension, e.g. 6 weeks after the last injection when the injection 
interval is extended from 4 weeks to 8 weeks. If there is no disease activity in the study eye at 
the inspection visit, as assessed by the Investigator, no treatment will be administered at this 
inspection visit; the next visit and injection will take place 2 weeks later, i.e. 8 weeks after the 
previous study treatment. If disease activity is observed by the Investigator in the study eye at 
the inspection visit, the study treatment will be administered by the Investigator; the injection 
interval will be reduced to 4 weeks and the next visit will be 4 weeks after the inspection visit. 
Similarly, inspection visits 10 weeks and 14 weeks after the last injection can be performed 
when the injection interval is extended from 8 weeks to 12 weeks and from 12 weeks to 16
weeks, respectively.


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1.2
Study objectives and endpoints
Table 2-1 Objectives and related endpoints
Objectives
Endpoints
Primary objective
Endpoint for primary objective
•
To evaluate the effect of brolucizumab 6 mg on 
disease control 
•  Proportion of patients with no disease activity at 
Week 16  
Secondary objectives
Endpoints for secondary objectives
• To evaluate the long term effects of brolucizumab 6 
mg on disease control 
• Proportion of patients with no disease activity at 
Week 48  
•
To evaluate the effect of brolucizumab 6 mg on 
anatomical parameters  
•
Change from Baseline in CFST as assessed by 
OCT over time up to Week 48  
•
Absence of IRF, SRF, and sub-RPE fluid as 
assessed by OCT over time up to Week 48  
•
Proportion of patients with a dry retina 
(neither IRF nor SRF) up to Week 48  
•
To evaluate the durability of brolucizumab 6 
mg  
•
Distribution of the last interval with no disease 
activity up to Week 48  
•
Distribution of the maximal intervals with no 
disease activity up to Week 48  
• To evaluate functional outcomes  
•
Average change in BCVA from Baseline up to 
Week 48  
•
To assess the safety and tolerability of 
brolucizumab 6 mg 
•
Incidence of AEs (serious and non-serious) up to 
Week 48 
AEs=adverse events, BCVA=best corrected visual acuity,
CSFT=central sub-field retinal 
thickness,
 IRF=intraretinal fluid, OCT= optical coherence tomography,
SRF= subretinal fluid.


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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 and maximum, 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, SE and 95% CI 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 a Treat-to-Control (TtC) regimen phase based on disease activity from Week 8 up to Week 
44/46 (according to the treatment regimen). 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 
eCRF 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).
  
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 


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). 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 
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.
Proportion: A proportion refers to the fraction of the total that possesses a certain attribute. In 
this study attribute is disease free activity.
Disease control: When patients have no disease activity after taking study treatment then 
patient will be consider as disease control.
On-treatment period: The on-treatment period lasts from the date of first administration of 
study treatment to 30 days after the date of the last actual administration of any study treatment.
Treatment duration: The maximum planned duration of treatment for each patient is 44 to 46 
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.
Last interval: The last treatment interval (defined by the investigator) before Week 48.
Maximum interval: The longest interval of treatment reached by the patient over the study 
period.
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 no disease 
activity. If patients with active disease status or early discontinue then patients will be 
considered as censored for disease activity.
Dry retina: Absence of fluid (IRF/SRF/ sub-RPE) will be considered as dry retina.
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 if both eyes are eligible as per the inclusion and exclusion criteria, unless 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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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. 


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2.2
Visit windows for data analysis
Visit windows will be used for the data analysis, as per the planned visits in the protocol. During 
the q4w/q8w/q12w 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 78 – 90
Week 14
14
98
Day 92 – 104
Week 16
16
112
Day 106 – 118
Week 18
18
126
Day 120 – 132
Week 20
20
140
Day 134 – 146
Week 22
22
154
Day 148 – 160
Week 24
24
168
Day 162 – 174
Week 26
26
182
Day 176 – 188
Week 28
28
196
Day 190 – 202
Week 30
30
210
Day 204 – 216
Week 32
32
224
Day 218 – 230
Week 34
34
238
Day 232 – 244
Week 36
36
252
Day 246 – 258
Week 38
38
266
Day 260 – 272
Week 40
40
280
Day 274 – 286
Week 42
42
294
Day 288 – 300
Week 44
44
308
Day 302 – 314
Week 46
46
322
Day 316 – 328
Week 48
48
336
Day 330 – 342
Week 50
50
350
Day 344 – 356
* Baseline measurement before the first treatment administration.
The number of weeks between visits will vary depending on the disease activity and length of 
intervals between injections as determined by disease activity assessment. Study treatment at 
the optional inspection visits (6 weeks after the last injection when the interval is extended from 
4 weeks to 8 weeks, 10 weeks after the last injection when the interval is extended from 8 weeks 


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to 12 weeks, and 14 weeks from the last injection when the interval is extended from 12 weeks 
to 16 weeks) is at the discretion of the Investigator based.
According to the patient treatment schedule, the last treatment can be at Week 44 or to Week 46. 
If the last treatment visit is Week 46, the end of study visit will be at Week 50 (at least 4 weeks 
after the last injection) instead of Week 48.
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 (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.
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.
2.3
Analysis sets
The Enrolled Set (ENR) includes all patients who signed an ICF and are assigned patient 
numbers. 
The Safety Set (SAF) includes all patients who received at least one IVT injection of study 
treatment. 
The Full Analysis Set (FAS) will be the same as the Safety Set in this study and will be used 
as primary population to analyze the efficacy endpoints. 
Urgent Safety Measure Set (USM): If any subject needs Q4 treatment interval at any time 
point after initial loading phase then that subject qualify for USM.
The Per-Protocol Set (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 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 due to COVID-19.
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 of both estimands is to have similar conclusions. Inconsistencies in the results will 
be examined and discussed in the CSR.


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2.4
Patient disposition, demographics and other baseline 
characteristics
2.4.1
Patient disposition
The ENR will be used to prepare a summary and listing of patient disposition.
The number and percentage of patients who completed and discontinued from the study and 
treatment will be summarized with reasons for premature discontinuation for the FAS. 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 ENR.
Study treatment will be discontinued under the following circumstances:

Adverse event which could lead to study treatment discontinuation

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
2.4.2
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 screened 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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2.4.3
Demographic characteristics
Demographic and Baseline characteristics will be listed and summarized descriptively overall 
patients on the FAS and the SAF.
The following demographic and vital signs variables collected in the eCRF at Baseline will be 
summarized:
1. Sex (Male, Female)
2. Age (in years)
3. Age category (< 50, 50 - 65, 65 - 75, 75 - 85, ≥ 85)
4. Study eye (Left [OS], Right [OD])
5. Vital signs (sitting systolic/diastolic blood pressure [mmHg], sitting pulse rate [bpm])
2.4.4
Baseline characteristics
The following Baseline characteristics collected in the eCRF at Baseline will be summarized 
for study eye and fellow eye (wherever applicable):

Study eye status at nAMD diagnosis (date of diagnosis, BCVA at diagnosis, CSFT at 
diagnosis)

Time since nAMD diagnosis

Time since nAMD diagnosis (< 2.5 - 5, 5- 8, 8-11, 11-18).

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
 

SD-OCT (analyzed by Duke [CRC]) 
1. Lesion type (only at Baseline) (type 1, type 2, type 3)
2. CSFT (µm)
3. 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
 
1. CNV lesion area (at the biggest surface) (mm²)
 

Ophthalmic abnormalities (Yes, No)
 

Disease activity assessment (Present)

History of primary diagnosis: 
1. Disease (Neovascular Age-Related Macular Degeneration)
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 and peripheral laser photocoagulation
3. Previous macular surgery or other intraocular surgical intervention

Concomitant medication at Baseline

Medical history

Co morbidities 

Current medical condition
2.4.5
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 


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be summarized for the FAS by primary system organ class (SOC), preferred term (PT) by eye 
(study eye, fellow eye and any 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 
comorbidities will be summarized and listed separately for eye (study eye, fellow eye and any
eye).
2.5
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.5.1
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. Summary statistics of number of injection (n, q1, median, q3, min and max) will be 
provided.
2. Number of injections (n, q1, median, q3, min and max) before or at Week 8 and greater
than Week 8.
3. Number of patients with injection category (1 injection, 2 injections up to the maximum 
number of injections) from Baseline to the end of the treatment period (Week 44/46)
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. The number of time the injection interval shorting and the number of time the injections 
interval increasing.
6. Summary statistics (n, mean, std, q1, median, q3, min and max) for overall duration will 
be provided.
The number and percentage of patients with changes in brolucizumab 6 mg treatment patterns 
over time (i.e. treatment interval adjustments, 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 on the SAF and the FAS. The exposure data will be listed 
on the FAS.
2.5.2
Prior, concomitant and post therapies
Each medication has the start and end dates recorded on the eCRF. Prior 
medications/procedures 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/procedures


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
Concomitant medications/procedures which started prior to first dose of study treatment

Concomitant medications/procedures 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 study eye and the fellow eye. A 
listing of all prior and concomitant medications and concomitant procedures will be provided.
For AESIs, a separate summary of prior and post aVEGF therapies 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.
2.5.3
Prior and concomitant Surgery and Procedures
All prior and concomitant surgery and procedures indications will be summarized and listed by 
category (general, ocular) and eye (study, fellow, any). 
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.
2.5.4
History of anti – VEGF Therapy
The anti-VEGF therapy will be collected in CRF at Baseline. All recent anti-VEGF therapy will 
be listed and summarized. Table will present nature of the previous anti-VEGF, summary 
statistics for total number of previous IVTs, number of patients and percentages of previous 
anti-VEGF (3,4,5,6...), summary statistics for time since first anti-VGEF, time since last anti-
VEGF along with below interval summary statistics.
1.
Inclusion vs last anti-VEGF
2.
Last anti-VEGF and second anti-VEGF
3.
Second last anti-VEGF and third last anti-VEGF
The listing will include nature of the previous anti-VEGF, date of the last anti-VEGF treatment, 
interval of the last anti-VEGF treatment, date of the second last anti-VEGF treatment , interval 
of the second last anti-VEGF treatment, date of the third last anti-VEGF treatment, interval of 
the third last anti-VEGF treatment, date of the first anti-VEGF treatment, interval of the first 
anti-VEGF treatment and total number of anti-VEGF treatments (including the last one).
The below characteristics prior to first anti-VEGF will be summarized.
1. The summary statistics of BCVA and CSFT.
2. Number and percentage of IRF, SRF and Sub-RPE. 
3. Summary statistics of height for IRF, SRF, Sub-RPE (if available). 


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The listing of above last anti-VEGF characteristics will include patients identification number, 
therapies name and date of therapy, BCVA, CSFT, IRF, SRF, Sub-RPE and height for IRF,
SRF, Sub-RPE (if available). The above analysis will be performed on the Safety set.
2.6
Analysis of the primary objective
2.6.1
Primary endpoint
The primary objective of this study is to evaluate the effect of brolucizumab 6 mg on disease 
control. The primary efficacy endpoint is the proportion of patients with no disease activity at 
Week 16 in the study eye. 
Estimation for the proportion of disease control involves only calculating the ratio of successes. 
In this study
Event: 1= no disease activity (disease control)
           0= disease activity (failure)
Count: Frequency or number of patients with no disease activity (disease control) at Week 16.
Proportion: Number of patients with no disease activity (disease control) at Week 16/Total 
number of patients in the FAS.
The number of disease control patients at Week 16, total number of evaluable patients, 
percentage of disease control and 95% confidence interval (CI) using the Clopper-Pearson 
method will be provided.
Sensitivity analysis will be performed for primary endpoint using last observation carried 
forward (LOCF) method and considering disease activity for missing data at Week 16.
A sensitivity analysis in patients exposed and not-exposed to USM will be performed for below 
estimand.
a) Proportion of patients with no disease activity at Week 16.
b) Status of patients with disease activity before and after introduce of USM.
The above analysis will be done on the FAS and only on the study eye. 
The analysis will be performed on the PPS, if there is more than a 10% difference in patients, 
between FAS and the PPS. 
2.6.2
Supportive analyses
Subgroup analysis according to patient characteristics, like gender (male, female), age class (< 
50, 50 - 65, 65 - 75, 75 - 85, ≥ 85), Baseline fluids type (IRF, SRF, both), number of previous 
anti-VEGF injections ( 3, 4 – 6, 7 - 9 and ≥ 10), interval (in week) since previous anti-VEGF 
injection (4, 5, 6, 7, 8) and time since nAMD diagnosis (2.5 – 5 month, 5 - 8 months, 8 - 11
months, 11 - 18 months and > 18 months).


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2.7
Analysis of secondary efficacy objective(s)
2.7.1
Secondary endpoints
2.7.1.1
Long term disease activity criteria
The first secondary objective of this study is to evaluate the effect of brolucizumab 6 mg on 
disease control at Week 48. The first secondary efficacy endpoint is the proportion of patients 
with no disease activity (disease control) at end of study (EOS) Week 48.
The number of disease control patients at Week 48, total number of evaluable patients, 
percentage of disease control and 95% confidence interval (CI) using the Clopper-Pearson 
method will be provided.
The above analysis will be done on the FAS and only on the study eye.  
2.7.1.2
Optical coherence Tomography (OCT)
The following secondary efficacy parameters based on OCT will be analyzed as given below.
2.7.1.2.1 Central sub-field retinal thickness (CSFT)
The summary statistics of central sub-field retinal thickness (CSFT) measured by OCT for 
nAMD patients, change and percentage change from Baseline in CSFT will be presented by 
visit along with first anti-VEGF Treatment CSFT.
The number and percentage of patient with CSFT category (< 300, ≥300 - 450, ≥450 - < 650, 
≥650 [μm]) will be presented by visit along with first anti-VEGF Treatment CSFT.
The above analysis will be done on the FAS and only on the study eye. 
2.7.1.2.2 Presence of fluid (Yes/No)
The number and percentage of patients with fluid as shown below will be presented by visit
along with first anti-VEGF Treatment.
1. Intraretinal fluid
2. Subretinal fluid 
3. Sub-RPE fluid 
4. Without any fluid (IRF/SRF/sub-RPE)
5. 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 on the FAS and only on the study eye.   
2.7.1.2.3 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.


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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 on the FAS and only on the study eye. 
2.7.1.2.4 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. Details KM result will be presented 
including time (week), number of patients under at risk at week (without dry retina), number of 
patients with dry retina at week (event), probability of dry retina (survival probability) at week 
and 95% CI at week. 
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 on the FAS and only on the study eye. 
2.7.1.2.5 Maximum duration of dryness
The median maximum duration of dryness until Week 48/50 will be presented. The median,
obtained from KM analysis will be presented along with the 2-sided 95% CI. KM plot will be 
provided.
The detailed Kaplan-Meier result will be presented including (week), number of patients under 
at risk (with fluids), number of patients without fluids (event), probability of 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 on the FAS and only on the study eye. 


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2.7.1.3
Durability
2.7.1.3.1 Last interval
The last treatment interval (defined by the investigator) before or at Week 48.
The distribution of the last interval, e.g., the proportion of last interval (Q8, Q12, and Q16) will 
be provided.  
The above analysis will be done on the FAS and only on the study eye. 
2.7.1.3.2 Maximal interval
The maximal interval is defined as the longest interval of treatment before 48. The duration (in 
days) of the maximal interval will be defined as (start date of maximal interval – start date of 
study drug dose). Summary statistics (n, mean, std, first quartile, median, third quartile, min 
and max) for the duration (in weeks) of the maximal interval will be provided. 
The distribution of the maximal interval is the proportion of patients with no disease activity 
(Q8, Q12 and Q16). 
The above analysis will be done on the FAS and only on the study eye. 
2.7.1.4
Function outcomes (Best Corrected Visual Acuity (BCVA))
Summary statistics (n, mean, std, median, min and max) of BCVA for nAMD patients will be 
presented along with change from Baseline in BCVA by visit along with first anti-VEGF 
Treatment BCVA. 
The above analysis will be done on the FAS and only on the study eye. 


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2.9
Safety analyses
Safety measurements include duration of exposure, vital signs, and adverse events (AEs). All 
safety endpoints will be summarized using the Safety Set. Patients will be analyzed according 
to the treatment received. No imputation will be carried out for missing data. 
2.9.1
Adverse events
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, study procedure related 
AEs, need of USM, death, SAEs, other significant AEs action taken leading to study treatment 
withdrawn and AEs leading to dose interval adjustment (interval increase, interval reduce). 
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. SOC will be presented in alphabetical 
order, preferred terms 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 study eye, 
fellow eye, and any eye.
For the legal requirements of ClinicalTrials.gov and EudraCT, 2 required tables on treatment 
emergent AEs which are not SAEs with an incidence greater than 5% and on treatment emergent 
SAEs and SAEs suspected to be related to study treatment will be provided by system organ 
class and PT on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same system organ class and PT:

A single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE.

More than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE.


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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 AE's 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, procedure 
and SAEs irrespective of study treatment relationship will be provided by SOC and PT.
In addition, all treatment emergent AEs and SAE will also be listed.
The by-patients listing will include: SOC/PT/Verbatim term, start date, end date, severity, USM, 
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 study eye, fellow eye and any eye.
A summary of action taken with number and percentage of patients will presented with 
treatment interrupted, treatment withdrawn, not applicable and unknown. 
2.9.1.1
Adverse events of special interest / grouping of AEs
The number (%) of patients with adverse events of special interest (AESI) will be summarized 
by Standardized MedDRA Query and PT. A listing will also be provided.
A 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. it is a living 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 with any AESI, having an AESI in each SOC and having 
each individual AE (PT) will be presented by SOC and PT. 
The number and percentage of patients by AESI type along with incidence rate per patient and 
per 1000 injections 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 


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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 by 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 
 
 
 
 
 
 
 
 


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2.13
Biomarkers
Not applicable 
2.14
Other Exploratory analyses
Not applicable 
2.15
Interim analysis
An interim analysis was performed when the last patient included completed the Week-16 visit.  
Patients remained in the study and continued to receive treatment through the maximum 
planned duration of treatment of 44/46 weeks to allow for further evaluation of efficacy and 
safety. 
3
Sample size calculation
The sample size calculation is based on the hypothesis of 25% to 35% of patients with no 
disease activity at Week 16. The sample size analyses were performed before the USM were 
introduced.


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Table 3-1 
Confidence intervals for proportions (2 sided)  
Confidence level 
Sample size (N) 
Expected 
proportion 
Target distance from 
proportion to limit 
0.950 
250 
0.25 
0.054 
0.950 
300 
0.25 
0.049 
0.950 
325 
0.25 
0.047 
0.950 
400 
0.25 
0.042 
0.950 
250 
0.30 
0.057 
0.950 
300 
0.30 
0.052 
0.950
325
0.30
0.050
0.950 
400 
0.30 
0.045 
0.950 
250 
0.35 
0.059 
0.950 
300 
0.35 
0.054 
0.950 
325 
0.35 
0.052 
0.950 
400 
0.35 
0.047 
A sample size of 250 to 400 patients produces a 2-sided 95% confidence interval with a distance 
from the proportion to the limits ranges from 0.042 to 0.059 when the estimated proportion 
varies from 0.25 to 0.35 (nQuery Advisor version 7.0).  
In the HAWK and HARRIER studies, the proportion of naïve nAMD patients treated with 
brolucizumab who had disease activity at Week 16 was 30% less than for patients treated by 
aflibercept. 
To determine a similar 30% proportion of patients with no disease activity at Week 16 in this 
pretreated study with a precision of 5% and alpha 5% (2-sided 95% confidence interval of width 
11%), a total of 265 patients have to be observed in this study. 
Slow recruitment rate was observed in conduct phase of study due to COVID-19, therefore, the
sample size was adjusted. The adjusted sample size was significant enough to provide 95% 
confidence interval.
Considering a dropout rate of 10%, a total of 295 patients will be included.
4
Change to protocol specified analyses
Not applicable
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: 


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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.
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.
1. 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.
2. If the AE start date year value is less than the treatment start date year value, the AE 
started before treatment. Therefore:
a.
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).
b. 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).


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3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment. Therefore:
a.
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).
b. 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).
4. If the AE start date year value is equal to the treatment start date year value:
a.
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.
b. 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).
c.
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 (CM)/procedure (PR) and and medical history 
(nAMD) 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.


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Day
Month
Year
Partial CM Start Date
Not used
MON
YYYY
Treatment Start Date (TRTSDT)
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)
BeforeTreatment Start
(A)
BeforeTreatment Start
(A)
BeforeTreatment Start
(A)
BeforeTreatment Start
YYYY = TRTY
(C2)
Uncertain
(A)
BeforeTreatment 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
(E)
01JANYYYY
Concomitant Medication End Date Imputation
If not ongoing then -
Imputed date = date part of CMENDTC, if complete date


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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 the MedDRA version 25.1 and above.
5.3
Laboratory 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 models
The below SAS code will used for statistical value.
Frequency and proportion:
proc freq data = <........>;
tables response_variable/ chisq riskdiff;
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;


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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;
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 
1
INCL02
Age less than 50 year
Included in everything
0
INCL03
No CNV lesions or >18M
Excluded from FAS and PPS 
1
INCL04a
>1 previous anti-VEGF
Excluded from FAS and PPS 
1
INCL04b
<3 previous aVEGF injections
Excluded from FAS and PPS 
1
INCL04c
Prev aVEGF intvl out of range
Included in everything
0
INCL05
No residual fluid
Excluded from FAS and PPS 
1
INCL06
Study eye BCVA out of range
Excluded from PPS 
2
EXCL01
Active inflammation/infection
Excluded from PPS 
2
EXCL02
Fellow eye ocular disease
Included in everything
0
EXCL03
History of IOI
Included in everything
0
EXCL04
Poor quality images
Included in everything
0
EXCL05
Study eye atropathy or fibrosis
Included in everything
0
EXCL06
Study eye lesion area ≥50%
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 uncotrolled glaucoma
Included in everything
0
EXCL11
Study eye aphakaia
Included in everything
0
EXCL12
Other trt in study eye
Excluded from PPS 
2
EXCL13
Steroids in study eye
Included in everything
0
EXCL14
Prior keratoplasty/vitrectomy
Included in everything
0
EXCL15a
Study eye surgery
Included in everything
0
EXCL15b
Study eye laser photocoagul
Included in everything
0
EXCL15c
Study eye macular surgery
Included in everything
0
EXCL16
Previous laser treatment
Included in everything
0


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Deviation ID
Description of Deviation
Exclusion in Analyses
Severity 
code
EXCL17
previous brolucizuamb trt study eye
Excluded from FAS and PPS
1
EXCL18
ESRD
Included in everything
0
EXCL19
Systemic drugs toxic to eye
Included in everything
0
EXCL20
Participation in another study
Excluded from PPS 
2
EXCL21
Systemic anti-VEGF therapy
Included in everything
0
EXCL22
Stroke or myocardial infarction
Included in everything
0
EXCL23
Uncontrolled blood pressure
Included in everything
0
EXCL24
Medical condition impact
Included in everything
0
EXCL25
Malignancy
Included in everything
0
EXCL26
Hypersensitivity
Included in everything
0
EXCL27
Pregnant or nursing woman
Included in everything
0
EXCL28
WOCP
Included in everything
0
EXCL29
Minors/protected adults
Excluded from PPS 
2
COMD01
Prohibited medication/procedures 
Included in everything
0
COMD02
Non-permitted steroid use
Included in everything
0
TRT01
Trt > 3 days after inj visit
Included in everything
0
TRT02
Missed injection visit
Included in everything
0
TRT03
Wrong IP/volume administered
Included in everything
2
TRT04
IVT interval<than 21 days
Included in everything
0
TRT05
TRT admin prior effic/safty eval
Included in everything
0
TRT06
COVID-19 Drug supply change
Included in everything
0
TRT07
COVID-19 Treatment not given
Included in everything
0
TRT08
Missed Injection loading phase
Excluded from FAS and PPS
1
TRT09
Missed Injection
Included in everything
0
TRT10
No Disease acty bt INJ is given
Included in everything
0
TRT11
Treatment given at EOS
Included in everything
0
TRT12
anti-VEGF therapy during tria
Included in everything
0
WITH01
Withdrew consnt nt discontinued
Excluded from FAS and PPS 
1
OTHER01
Missed mandatory visit
Excluded from PPS 
2
OTHER02
Subject rescreened > once
Excluded from PPS analysis
0
OTHER03
New ICF is missing-rescreened
Excluded from FAS and PPS 
1
OTHER04
Rescrn >14days w/o scr proc
Included in everything
0
OTHER05
Odysight used w/o consent
Included in everything
0
OTHER06
Temp excursion IP administered
Included in everything
0
OTHER07
SAE not reported
Included in everything
0
OTHER08
Crit met to failure
Included in everything
0
OTHER09
The patient done rescreening
Included in everything
0
OTHER10
COVID-19 Missed visit
Included in everything
0
OTHER11
COVID-19 Visit not at site
Included in everything
0
OTHER12
COVID-19 Assessment changed
Included in everything
0


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Deviation ID
Description of Deviation
Exclusion in Analyses
Severity 
code
OTHER13
COVID-19 Discontinuation
Included in everything
0
OTHER14
Visit window > 7 days
Included in everything
0
OTHER15
Efficacy assessment not done
Excluded from PPS
2
OTHER16
Safety assessment not done
Included in everything
0
OTHER17
BCVA not done correctly
Included in everything
0
OTHER18
Trt regimen wrongly adjusted
Included in everything
0
OTHER19
Vital signs/safety call not done
Included in everything
0
OTHER20
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
PPS
1, 2
SAF
NA
6
Reference
[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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Document History – Changes compared to previous final version of SAP 
 
Date 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
18-10-2022 Creation 
of 
initial version 
N/A - First version 
NA 
20-01-2023 Creation 
of 
addendum V.0 
 
 
 
Added 
imputation rule 
for 
medical 
history 
Added imputation rule for 
medical history  
 
Section 5.1.4 
 
Added 
section 
for 
confirmed 
SRC event 
Added the section for safety 
review committee 
Section 5.3 
 
Added 
derivation term 
for AESI 
Derivation term for AESI 
added 
Section 5.5 
 
 


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Table of contents 
 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 6 
1.1 
Study design............................................................................................................. 6 
Figure 1-1  Study design ....................................................................................... 7 
1.2 
Study objectives and endpoints for interim analysis ............................................... 8 
Table 2-1 Objectives and related endpoints ............................................................. 8 
2 
Statistical methods ............................................................................................................... 9 
2.1 
Data analysis general information ........................................................................... 9 
2.1.1 
General definitions .................................................................................. 9 
2.2 
Visit windows for data analysis ............................................................................. 12 
2.3 
Analysis sets .......................................................................................................... 14 
2.4 
Timepoints of interest ............................................................................................ 14 
2.5 
Patient disposition, demographics and other baseline characteristics ................... 14 
2.5.1 
Patient disposition ................................................................................. 14 
2.5.2 
Protocol deviation ................................................................................. 16 
2.5.3 
Demographic characteristics ................................................................. 16 
2.5.4 
Baseline characteristics ......................................................................... 16 
2.5.5 
Relevant medical history/current medical condition ............................. 18 
2.6 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 18 
2.6.1 
Study treatment exposure ...................................................................... 18 
2.6.2 
Prior, concomitant medication and procedures ..................................... 19 
2.6.3 
Prior and concomitant surgeries and procedures .................................. 19 
2.6.4 
History of anti–VEGF therapy .............................................................. 19 
2.7 
Analysis of the primary objective .......................................................................... 20 
2.7.1 
Primary endpoint ................................................................................... 20 
2.7.2 
Supportive analyses ............................................................................... 20 
2.8 
Analysis of secondary efficacy objectives ............................................................. 21 
2.8.1 
Secondary endpoints ............................................................................. 21 
 
 22 
2.10 
Safety analyses ....................................................................................................... 25 
2.10.1 
Adverse events ...................................................................................... 25 
2.10.2 
Deaths .................................................................................................... 26 
2.10.3 
Laboratory data ..................................................................................... 27 


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2.10.4 
Other safety data ................................................................................... 27 
2.11 
Pharmacokinetic endpoints .................................................................................... 27 
2.12 
PD and PK/PD analyses......................................................................................... 27 
 
 27 
2.14 
Biomarkers ............................................................................................................. 27 
 
 27 
3 
Sample size calculation ..................................................................................................... 27 
4 
Change to protocol specified analyses .............................................................................. 28 
5 
Appendix ........................................................................................................................... 28 
5.1 
Imputation rules ..................................................................................................... 28 
5.1.1 
Study treatment ..................................................................................... 28 
5.1.2 
AE date imputation ............................................................................... 29 
5.1.3 
Concomitant medication (CM) /procedure (PR) date imputation ......... 30 
5.1.4 
Medical history date of diagnosis imputation ....................................... 32 
5.2 
AEs coding/grading ............................................................................................... 32 
5.3 
Confirmed SRC event ............................................................................................ 32 
5.4 
Laboratory parameters derivations ........................................................................ 32 
5.5 
Statistical models ................................................................................................... 33 
5.5 Rule of exclusion criteria of analysis sets ................................................................... 34 
6 
Reference ........................................................................................................................... 36 


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List of abbreviations 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Classification 
BCVA 
Best-Corrected Visual Acuity  
CNV 
Choroidal Neovascularization  
 
  
CI 
Confidence Interval 
CRO 
Contract Research Organization 
CSFT 
Central Sub-Field Retinal Thickness  
CRT 
Central Retinal Thickness 
CSR 
Clinical Study report 
ENR 
Enrolled set 
 
  
 
  
FAS 
Full Analysis Set 
ECS 
Edit checks specification 
eCRF 
Electronic Case Report Form 
IA 
Interim Analysis  
IA-SAP 
Interim Analysis Statistical Analysis Plan 
ICF 
Informed Consent Form  
 
  
 
  
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 
q12w 
Every 12 Weeks  
SAP 
Statistical Analysis Plan 
SAF 
Safety analysis set 
SD-OCT  
Spectral Domain Optical Coherence Tomography  
SOC 
System Organ Class 
SRC 
Safety Review committee  
TFL 
Tables, Figures, Listings 
TtC  
Treat-to-Control 
WHO 
World Health Organization 
 


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1 
Introduction 
The purpose of this Interim Analysis Statistical Analysis Plan (IA-SAP) is to describe the 
implementation of the statistical methods for all safety and efficacy analyses planned (Protocol-
Section 12) in the clinical protocol (CRTH258AFR03, version no: 05, release date 05Apr2022). 
This document will be used to prepare the statistical results and the corresponding Interim 
Clinical Study Report (iCSR).  
The results of the interim analysis may either be submitted for publication in the form of a 
manuscript or poster format to a national or international conference. 
This interim analysis is planned for the study. As defined in the study protocol, an interim 
analysis is planned to be performed when all enrolled patients have completed Week 16 
evaluations to allow data collection prior to the end of the study period. 
This document will be stored in the CREDI folder: RTH258AFR03/Administrative Files (study 
level)/RAP or RAMP Meeting. 
The details of iCSR 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.  
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 pretreated suboptimal anatomically controlled patients with 
nAMD.  
Approximately 295 adult patients will be screened and included (10% dropout rate expected) 
in France. Data up to Week 16 will be analyzed in this Interim Analysis (IA).  
The cutoff date for the IA will be 20-Oct-2022. 
 
Before inclusion in the study, a patient must have a washout period of 4 weeks to 8 weeks (from 
26 to 62 days inclusive) from the last administration of a licensed anti-VEGF drug (i.e. 
Lucentis®, Eylea®). 
The maximum study duration for 1 patient is 48 to 50 weeks, according to the patient schedule.  
The study consists of 2 periods (Figure 1-1):  
• Open-label Treatment Period (from Screening/Baseline (Day 1) to Week 44 or Week 46 
according to patient schedule)  
• Follow-up Period (from Week 44 to Week 48 or from Week 46 to Week 50 according 
to patient schedule)  
According to the patient treatment schedule, the last treatment can be at Week 44 or Week 46. 
If the last treatment visit is at Week 46, the End-of-study visit will be at Week 50 (at least 4 
weeks after the last injection) instead of at Week 48.   


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Patients will require attending 5 mandatory study visits: Screening/Baseline (Day 1), Weeks 4, 
8, 16, and 48/50. The other visit time points will depend on the injection regimen of the patient.   
 
Figure 1-1  
Study design  
 
a End of treatment: Week 38/40/42/44/46 according to treatment schedule.  
b End of study: at least 4 weeks after the end of treatment. For patients receiving the last IVT at Week 46, the EOS Visit will 
be at Week 50, 4 weeks following their last treatment.  
The fellow eye will be treated at the discretion of the Investigator. 
The Screening Visit and the Baseline Visit are the same visit in this study. Patients will receive 
3 initial doses every 4 weeks (Day 1, Week 4 and Week 8). From Week 8, based on 
Investigator’s judgment of visual and/or anatomic outcomes, the injection interval can be 
maintained on Q4 regimen or extended by 4 weeks at a time if there is no disease activity, as 
per Investigators decision, e.g. no change in visual acuity and in other signs of the disease (e.g. 
IRF, SRF, hemorrhage, leakage, etc.). If disease activity recurs, the injection interval should be 
shortened accordingly by 4 weeks at a time or to a minimal interval of 4 weeks. 
Patients who show disease activity at any of visits after week 8 will be adjusted to treatment 
interval and will remain on this interval until the end of the study at Week 48/50. 
At the Investigator’s discretion, in case of interval extension, inspection visits can be performed 
at the midterm of the interval extension, e.g. 6 weeks after the last injection when the injection 
interval is extended from 4 weeks to 8 weeks. If there is no disease activity in the study eye at 
the inspection visit, as assessed by the Investigator, no treatment will be administered at this 
inspection visit; the next visit and injection will take place 2 weeks later, i.e. 8 weeks after the 
previous study treatment. If disease activity is observed by the Investigator in the study eye at 
the inspection visit, the study treatment will be administered by the Investigator; the injection 
interval will be reduced to 4 weeks and the next visit will be 4 weeks after the inspection visit. 
Similarly, inspection visits 10 weeks and 14 weeks after the last injection can be performed 
when the injection interval is extended from 8 weeks to 12 weeks and from 12 weeks to 16 
weeks, respectively. 


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1.2 
Study objectives and endpoints for interim analysis 
The study objectives and endpoints as per protocol are presented in Table 2-1; those that are 
being assessed for the IA are marked (with ‡) with relevant flag denoting assessment at Week 
16 as applicable.    
This IA is planned to evaluate applicable efficacy and safety endpoints for patients who have 
completed Week 16 evaluations.                            
Table 2-1 Objectives and related endpoints 
Objectives  
Endpoints  
Primary objective  
Endpoint for primary objective  
•  
To evaluate the effect of brolucizumab 6 mg on 
disease control   
•  Proportion of patients with no disease activity at 
Week 16 ‡ 
Secondary objectives  
Endpoints for secondary objectives  
• To evaluate the long-term effects of brolucizumab 6 
mg on disease control  
• Proportion of patients with no disease activity at 
Week 48 § 
•  
To evaluate the effect of brolucizumab 6 mg on 
anatomical parameters   
• 
Change from Baseline in CFST as assessed by 
OCT over time up to Week 48 ‡   
• 
Absence of IRF, SRF, and sub-RPE fluid as 
assessed by OCT over time up to Week 48 ‡   
• 
Proportion of patients with a dry retina  
(neither IRF nor SRF) up to Week 48 ‡   
•  
To evaluate the durability of brolucizumab 6 
mg   
• 
Distribution of the last interval with no disease 
activity up to Week 48 §   
• 
Distribution of the maximal intervals with no 
disease activity up to Week 48 §   
•  
To evaluate functional outcomes   
•  
Average change in BCVA from Baseline up to 
Week 48 ‡     
•  
To assess the safety and tolerability of 
brolucizumab 6 mg  
•  
Incidence of AEs (serious and non-serious) up to 
Week 48 ‡    


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§ These endpoints will not be assessed for the IA. 
‡ These endpoints will be assessed for the Week 16 timepoint only for the IA.  
AEs=adverse events, BCVA=best corrected visual acuity, 
 CSFT=central sub-field retinal 
thickness, 
 IRF=intraretinal fluid, OCT= optical coherence tomography, 
 
 SRF= subretinal fluid. 
2 
Statistical methods 
2.1 
Data analysis general information 
Patients who consented and meet all the inclusion and none of the exclusion criteria was 
screened to evaluate eligibility. After confirmation of eligibility, patients were 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 and maximum, 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, SE and 95% CI 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 a Treat-to-Control (TtC) regimen phase based on disease activity from Week 8 up to Week 
44/46 (according to the treatment regimen). 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 
eCRF 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). 




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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. 
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.  






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treatment needs to be cancelled. Injections are contraindicated in patients with active intraocular 
or periocular infections and in patients with active intraocular inflammation (IOI); therefore, 
the investigators must verify that these conditions are not present in the study eye prior to every 
injection. Any 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. 
2.3 
Analysis sets 
The Enrolled Set (ENR) includes all patients who signed an ICF and are assigned patient 
numbers.  
The Safety Set (SAF) includes all patients who received at least one IVT injection of study 
treatment.  
The Full Analysis Set (FAS) will be the same as the Safety Set in this study without protocol 
deviation with impact and will be used as primary population to analyze the efficacy endpoints.  
The Per-Protocol Set (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.   
2.4 
Timepoints of interest 
Demographics and Baseline characteristics will be summarized at Visit 1. All other parameters 
will be summarized based on the following timepoints: Baseline, Week 16 and other visits 
wherever data is available until Week 16 (e.g. Week 4, Week 8 and Week 12).  
2.5 
Patient disposition, demographics and other baseline 
characteristics 
2.5.1 
Patient disposition 
The FAS will be used to prepare a 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 till Week 8 and till Week 16 will be summarized with reasons for premature 
discontinuation for the FAS. 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. 
Subjects who sign an informed consent form and who are subsequently found to be ineligible 
to enroll will be considered a screen failure. Number and percent of subjects who are screen 
failures (i.e. were not enrolled) will be presented. Number (%) of patients who were enrolled 
(based on ICF date). 
   
• 
Number (%) of patients who were enrolled. 


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• 
Number (%) of patients who enrolled and treated. 
• 
Number (%) of patients who enrolled but not treated. 
 
A subject is considered to have completed Week 8 if he/she did not discontinue study prior to 
the Week 8 visit. Discontinuation at Week 8 with exit visit assessment performed is considered 
as completed Week 8. 
• 
Number (%) of patients who completed Week 8 dosing. 
• 
Number (%) of patients who discontinued study medication before or on week 
8 dosing. 
• 
Primary reason for discontinued study medication before or on week 8 
dosing. 
 
A subject is considered to have completed the study Week 16 if he/she did not discontinue 
study prior to the Week 16 visit. Discontinuation at Week 16 with exit visit assessment 
performed is considered as completed for the Week 16 analysis. 
• 
Number (%) of patients who are on-treatment (completed) at week 16. 
• 
Number (%) of patients who discontinued before or on week 16. 
• 
Primary reason for discontinued before or on week 16. 
• 
Number (%) of patients who are on-treatment (ongoing) after week 16. 
A separate summary of disposition and listing for rescreened patients will be presented for ENR. 
Study treatment will be discontinued under the following circumstances: 
• Adverse event which could lead to study treatment discontinuation 
• 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 






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3. Previous macular surgery or other intraocular surgical intervention 
• Concomitant medication at Baseline 
• Medical history 
• Co morbidities  
• Current medical condition 
2.5.5 
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 
(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 (study eye and fellow eye). 
2.6 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.6.1 
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. Summary statistics of number of injection (n, q1, median, q3, min and max) will be 
provided. 
2. Number of injections (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 16 and greater 
than Week 16. 
4. Number of patients with injection category (1 injection, 2 injections up to the maximum 
number of injections) from Baseline to the end of the treatment period (Week 44/46) 
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. 
6. The number of time the injection interval shorting and the number of time the injections 
interval increasing. 
7. Summary statistics (n, mean, std, q1, median, q3, 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. treatment interval adjustments, interruptions or permanent discontinuations) 
along with reasons, will be summarized. Discontinuations and primary reasons for treatment 
and/or study discontinuation will also be described. 


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Exposure data will be summarized on the SAF. The exposure data will be listed on the FAS. 
2.6.2 
Prior, concomitant medication and procedures 
Each medication/therapies has the start and end dates recorded on the eCRF. Prior medications/ 
procedures are defined as those medications/procedures which were taken/done and stopped 
prior to the first dose of study treatment. Concomitant medications/procedures are defined as 
any medication/procedures 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/procedures  
• Concomitant medications/procedures which started prior to first dose of study treatment 
• Concomitant medications/procedures 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/procedures (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 study eye and the fellow eye. A 
listing of all prior and concomitant medications and concomitant procedures will be provided. 
For AESIs, a separate summary of prior and post aVEGF 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. 
2.6.3 
Prior and concomitant surgeries and procedures 
All prior and concomitant surgeries and procedures indications will be summarized and listed 
by category (general, ocular) and eye (study and  fellow).  
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. 
2.6.4 
History of anti–VEGF therapy 
The anti – VEGF therapy will be collected in CRF at Baseline. All recent anti – VEGF therapy 
will be listed and summarized. Table will present nature of the previous antiVEGF, summary 
statistics for total number of previous IVTs, number of patients and percentages of previous 
antiVEGF (3,4,5,6...), summary statistics for time since first antiVGEF, time since last 
antiVEGF along with below interval summary statistics. 
1. 
Inclusion vs last antiVEGF 
2. 
Last antiVEGF and second antiVEGF 
3. 
Second last antiVEGF and third last antiVEGF 


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The listing will include nature of the previous antiVEGF, date of the last anti VEGF treatment, 
interval of the last anti VEGF treatment, date of the second last anti VEGF treatment , interval 
of the second last anti VEGF treatment, date of the third last anti VEGF treatment, interval of 
the third last anti VEGF treatment, date of the first anti VEGF treatment, interval of the first 
anti VEGF treatment and total number of anti VEGF treatments (including the last one). 
The below characteristics prior to first antiVEGF will be summarized. 
1. The summary statistics of BCVA and CSFT. 
2. Number and percentage of IRF, SRF and Sub-RPE.  
3. Summary statistics of height for IRF, SRF, Sub-RPE (if available).  
The listing of above last antiVEGF characteristics will include patients identification number, 
therapies name and date of therapy, BCVA, CSFT, IRF, SRF, Sub-RPE and height for IRF, 
SRF, Sub-RPE (if available). The above analysis will be performed on the Safety set. 
2.7 
Analysis of the primary objective 
2.7.1 
Primary endpoint 
The primary objective of this study is to evaluate the effect of brolucizumab 6 mg on disease 
control. The primary efficacy endpoint is the proportion of patients with no disease activity at 
Week 16 in the study eye.  
Estimation for the proportion of disease control involves only calculating the ratio of successes. 
In this study 
Event: 1= no disease activity (disease control) 
           0= disease activity (failure) 
Count: Frequency or number of patients with no disease activity (disease control) at Week 16. 
Proportion: Number of patients with no disease activity (disease control) at Week 16/Total 
number of patients in the FAS. 
The number of disease control patients at Week 16, total number of evaluable patients, 
percentage of disease control and 95% confidence interval (CI) using the Clopper-Pearson 
method will be provided. 
Sensitivity analysis will be performed for the primary endpoint using last observation carried 
forward (LOCF) method and considering disease activity for missing data at Week 16. 
The above analysis will be done on the FAS and only on the study eye.  
The analysis will be performed on the PPS, if there is more than a 10% difference in patients, 
between FAS and the PPS.  
2.7.2 
Supportive analyses 
Subgroup analysis according to patient characteristics, like gender (male, female), age class (< 
50, 50 - 65, 65 - 75, 75 - 85, ≥ 85), Baseline fluids type (IRF, SRF, both), number of previous 
antiVEGF injections (3, 4 – 6, 7 - 9 and ≥ 10), interval (in week) since previous antiVEGF 


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injection (4, 5, 6, 7, 8 and >8), and time since nAMD diagnosis (2.5 – 5 month, 5 - 8 months, 8 
- 11 months, 11 - 18 months and > 18 months). 
2.8 
Analysis of secondary efficacy objectives 
2.8.1 
Secondary endpoints 
2.8.1.1 
Long-term disease activity criteria 
Not applicable for IA. 
2.8.1.2 
Optical coherence tomography (OCT) 
The following secondary efficacy parameters based on OCT will be analyzed as given below. 
2.8.1.2.1 Central sub-field retinal thickness (CSFT) 
The summary statistics of central sub-field retinal thickness (CSFT) measured by OCT for 
nAMD patients, change and percentage change from Baseline in CSFT will be presented by 
visit along with first anti VEGF Treatment CSFT. 
The number and percentage of patient with CSFT category (< 300, ≥ 300 - 450, ≥ 450 - < 650, 
≥650 [μm]) will be presented by visit along with first anti VEGF Treatment CSFT. 
The above analysis will be done on the FAS and only on the study eye.  
2.8.1.2.2 Presence of fluid (Yes/No) 
The number and percentage of patients with fluid as shown below will be presented by visit 
along with first anti VEGF Treatment. 
1. Intraretinal fluid 
2. Subretinal fluid  
3. Sub-RPE fluid  
4. Without any fluid (IRF/SRF/sub-RPE) 
5. 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 on the FAS and only on the study eye.  
2.8.1.2.3 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 16 
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 FAS and on the study eye.  








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2.10 
Safety analyses 
Safety measurements include duration of exposure, vital signs, and adverse events (AEs). All 
safety endpoints will be summarized using the Safety Set. Patients will be analyzed according 
to the treatment received. No imputation will be carried out for missing data.  
2.10.1 
Adverse events 
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, study procedure related 
AEs, death, SAEs, other significant AEs action taken leading to study treatment withdrawn and 
AEs leading to dose interval adjustment (interval increase, interval reduce). Separate summaries 
will be provided for AESI. 
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. SOC will be presented in alphabetical 
order, preferred terms 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 study eye, 
fellow eye, and any eye. 
Separate summaries will be presented for ≤ 16 weeks and > 16 weeks. 
For the legal requirements of ClinicalTrials.gov and EudraCT, 2 required tables on treatment 
emergent AEs which are not SAEs with an incidence greater than 5% and on treatment emergent 
SAEs and SAEs suspected to be related to study treatment will be provided by system organ 
class and PT on the safety set population. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same system organ class and PT: 
• A single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE. 
• More than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE. 


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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 AE's 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, procedure 
and SAEs irrespective of study treatment relationship will be provided by SOC and PT. 
In addition, all treatment emergent AEs and SAE 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 study eye, fellow eye and any eye. 
A summary of action taken with number and percentage of patients will presented with 
treatment interrupted, treatment withdrawn, not applicable and unknown.  
2.10.1.1 Adverse events of special interest / grouping of AEs 
The number (%) of patients with adverse events of special interest (AESI) will be summarized 
by Standardized MedDRA Query and PT. A listing will also be provided. 
A 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. it is a living 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, having an AESI in each SOC and 
having each individual AE (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. 
2.10.2 
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 


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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. 
2.10.3 
Laboratory data 
Not applicable. 
2.10.4 
Other safety data 
Not applicable.  
2.10.4.1 ECG and cardiac imaging data 
Not applicable.  
2.10.4.2 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 by vital sign. Change 
from Baseline will only be summarized for patients with both Baseline and post-baseline values. 
2.11 
Pharmacokinetic endpoints   
Not applicable.  
2.12 
PD and PK/PD analyses 
Not applicable.  
2.13 
Patient questionnaire 
Not applicable for IA. 
2.14 
Biomarkers 
Not applicable  
2.15 
Other Exploratory analyses 
Not applicable  
3 
Sample size calculation 
The sample size calculation is based on the hypothesis of 25% to 35% of patients with no 
disease activity at Week 16. The sample size analyses were performed before the urgent safety 
measures were introduced. 


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Table 3-1  
Confidence intervals for proportions (2 sided)   
Confidence level  
Sample size (N)  
Expected 
proportion  
Target distance from 
proportion to limit  
0.950  
250  
0.25  
0.054  
0.950  
300  
0.25  
0.049  
0.950  
325  
0.25  
0.047  
0.950  
400  
0.25  
0.042  
0.950  
250  
0.30  
0.057  
0.950  
300  
0.30  
0.052  
0.950  
325  
0.30  
0.050  
0.950  
400  
0.30  
0.045  
0.950  
250  
0.35  
0.059  
0.950  
300  
0.35  
0.054  
0.950  
325  
0.35  
0.052  
0.950  
400  
0.35  
0.047  
A sample size of 250 to 400 patients produces a 2-sided 95% confidence interval with a distance 
from the proportion to the limits ranges from 0.042 to 0.059 when the estimated proportion 
varies from 0.25 to 0.35 (nQuery Advisor version 7.0).   
In the HAWK and HARRIER studies, the proportion of naïve nAMD patients treated with 
brolucizumab who had disease activity at Week 16 was 30% less than for patients treated by 
aflibercept.  
To determine a similar 30% proportion of patients with no disease activity at Week 16 in this 
pretreated study with a precision of 5% and alpha 5% (2-sided 95% confidence interval of width 
11%), a total of 265 patients have to be observed in this study.  
Considering a dropout rate of 10%, a total of 295 patients will be included. 
4 
Change to protocol specified analyses 
Not applicable 
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.  


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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. 
1. 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. 
2. If the AE start date year value is less than the treatment start date year value, the AE 
started before treatment. Therefore: 
a. 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). 
b. 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). 
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment. Therefore: 
a. 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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Concomitant Medication/Procedure 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. 
5.1.4 
Medical history date of diagnosis imputation 
Completely missing dates will not be imputed. Partial dates of diagnosis will be compared to 
the treatment start date. 
• If DIAG year < study treatment start date year and DIAG month is missing, the imputed 
DIAG date is set to the mid-year point (01JULYYYY).  
• Else if DIAG month is not missing, the imputed DIAG date is set to the mid-month point 
(15MONYYYY). 
• If DIAG year = study treatment start date year and (DIAG month is missing OR DIAG 
month is equal to study treatment start month), the imputed DIAG date is set to one day 
before study treatment start date. 
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 the MedDRA version 22.0 and above. 
5.3 
Confirmed SRC event  
List of confirmed SRC event will be provided by study team. Trial programmer will derive below 
variable to performed the related analysis. 
a) SRC start and SRC event date 
b) Number of IVT injection prior to start of AESI event confirmed by SRC 
c) Duration(day) since last IVT injection to start of AESI event confirmed by SRC 
5.4 
Laboratory 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)  


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5.5 
Statistical models  
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; 
 
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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IA-SAP Addendum Version1.0 
 
CRTH258AFR03 
 
 
 
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  
1 
INCL02 
Age less than 50 year 
Included in everything 
0 
INCL03 
No CNV lesions or >18M 
Excluded from FAS and PPS  
1 
INCL04a 
>1 previous antiVEGF 
Excluded from FAS and PPS  
1 
INCL04b 
<3 previous aVEGF injections 
Excluded from FAS and PPS  
1 
INCL04c 
Prev aVEGF intvl out of range 
Included in everything 
0 
INCL05 
No residual fluid 
Excluded from FAS and PPS  
1 
INCL06 
Study eye BCVA out of range 
Excluded from PPS  
2 
EXCL01 
Active inflammation/infection 
Excluded from PPS  
2 
EXCL02 
Fellow eye ocular disese 
Included in everything 
0 
EXCL03 
History of IOI 
Included in everything 
0 
EXCL04 
Poor quality images 
Included in everything 
0 
EXCL05 
Study eye atropathy or fibrosis 
Included in everything 
0 
EXCL06 
Study eye lesion area ≥50% 
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 uncotrolled glaucoma 
Included in everything 
0 
EXCL11 
Study eye aphakaia 
Included in everything 
0 
EXCL12 
Other trt in study eye 
Excluded from PPS  
2 
EXCL13 
Steroids in study eye 
Included in everything 
0 
EXCL14 
Prior keratoplasty/vitrectomy 
Included in everything 
0 
EXCL15a 
Study eye surgery 
Included in everything 
0 
EXCL15b 
Study eye laser photocoagul 
Included in everything 
0 
EXCL15c 
Study eye macular surgery 
Included in everything 
0 
EXCL16 
Previous laser treatment 
Included in everything 
0 
EXCL17 
previous brolucizuamb trt study eye 
Excluded from FAS and PPS 
1 
EXCL18 
ESRD 
Included in everything 
0 
EXCL19 
Systemic drugs toxic to eye 
Included in everything 
0 
EXCL20 
Participation in another study 
Excluded from PPS  
2 
EXCL21 
Systemic anti-VEGF therapy 
Included in everything 
0 
EXCL22 
Stroke or myocardial infarction 
Included in everything 
0 
EXCL23 
Uncontrolled blood pressure 
Included in everything 
0 


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IA-SAP Addendum Version1.0 
 
CRTH258AFR03 
 
Deviation ID Description of Deviation 
Exclusion in Analyses 
Severity 
code 
EXCL24 
Medical condition impact 
Included in everything 
0 
EXCL25 
Malignancy 
Included in everything 
0 
EXCL26 
Hypersensitivity 
Included in everything 
0 
EXCL27 
Pregnant or nursing woman 
Included in everything 
0 
EXCL28 
WOCP 
Included in everything 
0 
EXCL29 
Minors/protected adults 
Excluded from PPS  
2 
COMD01 
Prohibited medication/procedures  
Included in everything 
0 
COMD02 
Non-permitted steroid use 
Included in everything 
0 
TRT01 
Trt > 3 days after inj visit 
Included in everything 
0 
TRT02 
Missed injection visit 
Included in everything 
0 
TRT03 
Wrong IP/volume administered 
Excluded from PPS 
2 
TRT04 
IVT interval<than 21 days 
Included in everything 
0 
TRT05 
TRT admin prior effic/safty eval 
Included in everything 
0 
TRT06 
COVID-19 Drug supply change 
Included in everything 
0 
TRT07 
COVID-19 Treatment not given 
Included in everything 
0 
TRT08 
Missed Injection loading phase 
Excluded from FAS and PPS 
1 
TRT09 
Missed Injection 
Included in everything 
0 
TRT10 
No Disease acty bt INJ is given 
Included in everything 
0 
WITH01 
Withdrew consnt nt discontinued 
Excluded from FAS and PPS  
1 
OTHER01 
Missed mandatory visit 
Excluded from PPS  
2 
OTHER02 
Subject rescreened > once 
Excluded from PPS analysis 
0 
OTHER03 
New ICF is missing-rescreened 
Excluded from FAS and PPS  
1 
OTHER04 
Rescrn >14days w/o scr proc 
Included in everything 
0 
OTHER05 
Odysight used w/o consent 
Included in everything 
0 
OTHER06 
Temp excursion IP administered 
Included in everything 
0 
OTHER07 
SAE not reported 
Included in everything 
0 
OTHER08 
Crit met to failure 
Included in everything 
0 
OTHER09 
The patient done rescreening 
Included in everything 
0 
OTHER10 
COVID-19 Missed visit 
Included in everything 
0 
OTHER11 
COVID-19 Visit not at site 
Included in everything 
0 
OTHER12 
COVID-19 Assessment changed 
Included in everything 
0 
OTHER13 
COVID-19 Discontinuation 
Included in everything 
0 
OTHER14 
Visit window > 7 days 
Included in everything 
0 
OTHER15 
Efficacy assessment not done 
Excluded from PPS 
2 
OTHER16 
Safety assessment not done 
Included in everything 
0 
OTHER17 
BCVA not done correctly 
Included in everything 
0 
OTHER18 
Trt regimen wrongly adjusted 
Included in everything 
0 
OTHER19 
Vital signs/safety call not done 
Included in everything 
0 
 


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IA-SAP Addendum Version1.0 
 
CRTH258AFR03 
 
Table 5-2 
Patient Classification  
Analysis Set 
Severity codes that cause a subject to be excluded 
ENR 
NA 
FAS 
1 
PPS 
1, 2 
SAF 
NA 
 
6 
Reference 
[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.