Conditions: Neovascular Age-related Macular Degeneration
Keywords: neovascular age-related macular degeneration wet age-related macular degeneration wet AMD choroidal neovascularization individualized treatment anti-VEGF Macular degeneration age-related macular degeneration (ARMD) vision loss macula damage retina damage dry macular degeneration wet macular degeneration Subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 248
Healthy volunteers: no

Brief summary:
The purpose of this extension study was to evaluate the efficacy and safety of brolucizumab used in a Treat-to-Control-regimen for treatment of patients with neovascular age-related macular degeneration who have completed the CRTH258A2303 (TALON) study. The main objective was to assess brolucizumab's potential for long durability up to 20 weeks.

All eligible participants were treated with brolucizumab regardless of their treatment in the TALON study.

The study period was 56 weeks including post-treatment follow-up.

Detailed description:
This was a 56-week, open-label, one-arm extension study in subjects who had completed the CRTH258A2303 (TALON) (NCT04005352) study, referred to as the core study in this document. Subjects who provided written informed consent and met all the inclusion and none of the exclusion criteria were enrolled into this extension study to receive brolucizumab 6 mg in a treat-to-control (TtC) regimen, irrespective of the treatment received in the core study.

The maximum study duration for a subject was 56 weeks, including post-treatment follow-up.

There were two periods in this study:

* Treat-to-Control treatment period: from Baseline (Day 1) to Week 52
* Post-treatment follow-up period: from Week 52 to Week 56.

All participants were treated with brolucizumab regardless of their treatment in the TALON study (brolucizumab or aflibercept).

Treatment intervals were then extended by 4 weeks at a time based on the investigator's judgment of visual and/or anatomic outcomes. The treatment intervals were to have been 4 weeks at a time if disease activity recurs.

Arms:
arm 1: Participants received brolucizumab 6 mg/0.05 mL solution by intravitreal injection in a Treat-to-Control regimen with injection intervals from 4 up to 20 weeks. Intervals could have changed in steps of 4 weeks at a time per investigators' decisions determined by the disease activity.

Interventions: intervention 1: brolucizumab
Intervention descriptions: intervention 1: brolucizumab 6 mg/0.05 mL solution for intravitreal injection

Protocol document:
Prot_000.pdf: 
Novartis Research and Development 
RTH258/brolucizumab 
Clinical Trial Protocol CRTH258A2303E1/ NCT04597632
A 56-week phase IIIb/IV, open-label, one-arm extension 
study to assess the efficacy and safety of brolucizumab 6 
mg in a Treat-to-Control regimen with maximum treatment 
intervals up to 20 weeks for the treatment of patients with 
neovascular age-related macular degeneration who have 
completed the CRTH258A2303 (TALON) study 
Document type: 
Amended Protocol 
EUDRACT number: 
2020-002349-40  
Version number: 
02 (Clean) 
Clinical Trial Phase: 
IIIb/IV 
Release date: 
20-Oct-2021
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 4 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 8 
Amendment 2 (20-Oct-2021) ............................................................................................ 10 
Summary of previous amendments ................................................................................... 12 
Amendment 1 (13-Aug-2021) ........................................................................................... 12 
Protocol summary .............................................................................................................. 15 
1 
Introduction ....................................................................................................................... 17 
1.1 
Background ............................................................................................................ 17 
1.2 
Purpose .................................................................................................................. 19 
2 
Objectives and endpoints ................................................................................................... 19 
2.1 
Primary estimands ................................................................................................. 20 
2.2 
Secondary estimands ............................................................................................. 21 
3 
Study design ...................................................................................................................... 21 
4 
Rationale ............................................................................................................................ 23 
4.1 
Rationale for study design ..................................................................................... 23 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 24 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 25 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 25 
4.5 
Risks and benefits .................................................................................................. 25 
5 
Study population ................................................................................................................ 26 
5.1 
Inclusion criteria .................................................................................................... 26 
5.2 
Exclusion criteria ................................................................................................... 26 
6 
Treatment ........................................................................................................................... 27 
6.1 
Study treatment ...................................................................................................... 27 
6.1.1 
Investigational and control drugs .......................................................... 27 
6.1.2 
Additional study treatments .................................................................. 28 
6.1.3 
Treatment arms/group ........................................................................... 28 
6.1.4 
Treatment duration ................................................................................ 28 
6.2 
Other treatment(s) .................................................................................................. 28 
6.2.1 
Concomitant therapy ............................................................................. 28 
6.2.2 
Prohibited medication ........................................................................... 29 


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6.2.3 
Rescue medication ................................................................................ 30 
6.3 
Participant numbering, treatment assignment, randomization .............................. 30 
6.3.1 
Participant numbering ........................................................................... 30 
6.3.2 
Treatment assignment, randomization .................................................. 30 
6.4 
Treatment blinding ................................................................................................ 30 
6.5 
Dose escalation and dose modification.................................................................. 31 
6.6 
Additional treatment guidance ............................................................................... 31 
6.6.1 
Treatment compliance ........................................................................... 31 
6.7 
Preparation and dispensation ................................................................................. 31 
6.7.1 
Handling of study treatment and additional treatment .......................... 31 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 32 
7 
Informed consent procedures ............................................................................................ 35 
8 
Visit schedule and assessments ......................................................................................... 36 
8.1 
Screening ............................................................................................................... 39 
8.1.1 
Information to be collected on screening failures ................................. 39 
8.2 
Participant demographics/other baseline characteristics ....................................... 39 
8.3 
Efficacy .................................................................................................................. 39 
8.3.1 
Visual acuity.......................................................................................... 40 
8.3.2 
Optical coherence tomography ............................................................. 40 
8.3.3 
Color fundus photography and fluorescein angiography ...................... 41 
8.3.4 
Appropriateness of efficacy assessments .............................................. 41 
8.4 
Safety ..................................................................................................................... 42 
8.4.1 
Pregnancy and assessments of fertility ................................................. 44 
8.4.2 
Appropriateness of safety measurements .............................................. 45 
8.5 
Additional assessments .......................................................................................... 45 
9 
Study discontinuation and completion .............................................................................. 45 
9.1 
Discontinuation and completion ............................................................................ 45 
9.1.1 
Study treatment discontinuation and study discontinuation.................. 45 
9.1.2 
Withdrawal of informed consent ........................................................... 46 
9.1.3 
Lost to follow-up ................................................................................... 47 
9.1.4 
Early study termination by the sponsor ................................................. 47 
9.2 
Study completion and post-study treatment .......................................................... 48 
10 Safety monitoring and reporting ........................................................................................ 48 
10.1 
Definition of adverse events and reporting requirements ...................................... 48 
10.1.1 
Adverse events ...................................................................................... 48 
10.1.2 
Serious adverse events .......................................................................... 50 


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10.1.3 
SAE reporting........................................................................................ 51 
10.1.4 
Pregnancy reporting .............................................................................. 52 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 52 
10.2 
Additional Safety Monitoring ................................................................................ 52 
11 Data Collection and Database management ...................................................................... 52 
11.1 
Data collection ....................................................................................................... 52 
11.2 
Database management and quality control ............................................................ 53 
11.3 
Site monitoring ...................................................................................................... 53 
12 Data analysis and statistical methods ................................................................................ 54 
12.1 
Analysis sets .......................................................................................................... 54 
12.2 
Participant demographics and other baseline characteristics ................................. 55 
12.3 
Treatments ............................................................................................................. 55 
12.4 
Analysis of the primary endpoint(s)/estimand(s) .................................................. 55 
12.4.1 
Definition of primary endpoint(s)/estimand(s) ..................................... 55 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 63 
12.4.3 
Handling of remaining intercurrent events of primary estimand .......... 63 
12.4.4 
Handling of missing values not related to intercurrent event ............... 64 
12.4.5 
Sensitivity analyses for primary endpoint/estimand ............................. 64 
12.5 
Analysis of secondary endpoints/estimands .......................................................... 64 
12.5.1 
Efficacy and/or pharmacodynamic endpoint(s) .................................... 64 
12.5.2 
Safety endpoints .................................................................................... 65 
 
 66 
12.7 
Interim analyses ..................................................................................................... 66 
12.8 
Sample size calculation.......................................................................................... 66 
13 Ethical considerations and administrative procedures ...................................................... 68 
13.1 
Regulatory and ethical compliance ........................................................................ 68 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 68 
13.3 
Publication of study protocol and results............................................................... 69 
13.4 
Quality Control and Quality Assurance ................................................................. 69 
14 Protocol adherence ............................................................................................................ 69 
14.1 
Protocol amendments............................................................................................. 70 
15 References ......................................................................................................................... 71 
16 Appendices ........................................................................................................................ 73 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 19 


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Table 6-1 
Investigational drug ............................................................................... 27 
Table 6-2 
Prohibited medications and procedures ................................................ 29 
Table 6-3 
Disease Activity assessment and treatment occurrence according to 
visit type ................................................................................................ 34 
Table 8-1 
Assessment Schedule ............................................................................ 37 
Table 8-2 
Safety assessments ................................................................................ 42 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 52 
Table 12-1 
Primary and sensitivity estimands ......................................................... 56 
Table 12-2 
Duration of intervals as estimated based on simulation studies ............ 67 
Table 12-3 
Duration of intervals as estimated based on simulation studies and 
width of 95% Confidence Interval ........................................................ 67 
Table 12-4 
95% Confidence Interval for BCVA change assuming SD of the 
change is 13. .......................................................................................... 68 
List of figures 
Figure 3-1 
Study design .......................................................................................... 22 
Figure 6-1 
Treatment regimen ................................................................................ 32 
 


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List of abbreviations 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
AMD 
Age-related macular degeneration 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of Variance 
BCVA 
Best Corrected Visual Acuity 
CDP 
Clinical Development Plan 
CFP 
Color Fundus Photography 
CFR 
Code of Federal Regulation 
CI 
Confidence Interval 
CMO&PS  Chief Medical Office and Patient Safety 
CNV 
Choroidal Neovascularization 
CRC 
Central Reading Center 
CRF 
Case Report/Record Form  
CRO 
Contract Research Organization 
CSFT 
Central Subfield Thickness 
DA 
Disease Activity 
eCRF 
electronic Case Report/Record Form 
EDC 
Electronic Data Capture 
EOS 
End of Study 
EOT 
End of Treatment 
ETD 
Early Treatment Discontinuation 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
Fluorescein Angiography 
FAS 
Full Analyses Set 
FIR 
First Interpretable Results 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for Pharmaceuticals 
for Human Use 
IEC 
Independent Ethics Committee 
IOI 
Intraocular Inflammation 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IRF 
Intraretinal Fluid 
IRT 
Interactive Response Technology 
IVT 
Intravitreal injection 
LOCF 
Last observation carried forward 
MedDRA 
Medical dictionary for regulatory activities  


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MMRM 
Mixed Model for Repeated Measures 
mg 
milligram(s) 
mL 
milliliter(s) 
nAMD 
neovascular Age-related Macular Degeneration 
OCT 
Optical Coherence Tomography 
PDT 
Photodynamic Therapy 
PPS 
Per Protocol Set 
PRN 
Pro Re Nata (as needed) 
q12w 
Every 12 weeks 
q16w 
Every 16 weeks 
q20w 
Every 20 weeks 
q4w 
Every 4 weeks 
q8w 
Every 8 weeks 
QMS  
Quality Management System 
RO 
Retinal Vascular Occlusion 
RPE 
Retinal Pigment Epithelium 
RV 
Retinal Vasculitis 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
scFV 
single-chain antibody fragment 
SD 
Standard Deviation 
SD-OCT 
Spectral Domain Ocular Coherence Tomography 
SOC 
Standard of Care 
SOP 
Standard Operation Procedures 
SRF 
Subretinal Fluid 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T&E 
Treat-and-Extend 
TtC 
Treat-to-Control 
USM 
Urgent Safety Measures 
VEGF 
Vascular Endothelial Growth Factor 
 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study. 
Cohort 
A specific group of participants fulfilling certain criteria and generally treated at 
the same time. 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used to 
capture data transcribed from paper source forms used at the point of care. 
End of the clinical 
trial 
The end of the clinical trial is defined as the last visit of the last participant or 
at a later point in time as defined by the protocol. 
Enrollment 
Point/time of participant entry into the study at which informed consent must 
be obtained.  
Estimand  
A precise description of the treatment effect reflecting the clinical question 
posed by the trial objective. It summarizes at a population-level what the 
outcomes would be in the same patients under different treatment conditions 
being compared. Attributes of an estimand include the population, variable (or 
endpoint) and treatment of interest, as well as the specification of how the 
remaining intercurrent events are addressed and a population-level summary 
for the variable. 
Intercurrent events 
Events occurring after treatment initiation that affect either the interpretation or 
the existence of the measurements associated with the clinical question of 
interest. 
Investigational 
drug/ treatment 
The drug whose properties are being tested in the study. 
Medication number 
A unique identifier on the label of medication kits 
Mis-randomized 
participants 
Mis-randomized participants are those who were not qualified for 
randomization and who did not take study treatment, but have been 
inadvertently randomized into the study.  
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy). 
Participant 
A trial participant (can be a healthy volunteer or a patient). 
Participant number 
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc. 
Personal data 
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data includes 
participant identifier information, study information and biological samples. 
Premature 
participant 
withdrawal 
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned. 
Randomization 
number 
A unique identifier assigned to each randomized participant. 
Screen Failure 
A participant who did not meet one or more criteria that were required for 
participation in the study. 


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Source 
Data/Document 
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource. 
Start of the clinical 
trial 
The start of the clinical trial is defined as the signature of the informed consent 
by the first participant. 
Study treatment 
Any drug or combination of drugs or intervention administered to the study 
participants as part of the required study procedures; includes investigational 
drug(s), control(s) or background therapy. 
Study treatment 
discontinuation 
When the participant permanently stops taking any of the study drug(s) prior 
to the defined study treatment completion date (if any) for any reason; may or 
may not also be the point/time of study discontinuation.  
Treatment 
arm/group  
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts. 
Variable (or 
endpoint) 
The variable (or endpoint) to be obtained for each participant that is required 
to address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event. 
Withdrawal of 
study consent 
(WoC) 
Withdrawal of consent from the study occurs only when a participant does not 
want to participate in the study any longer and does not allow any further 
collection of personal data.  


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Amendment 2 (20-Oct-2021) 
Amendment rationale 
The main purpose of this amendment is to reduce the sample size for this study.  
The initial sample size calculation for this open-label, one arm extension study was mainly 
based on the assumption that all eligible subjects completing the core study could be enrolled. 
Following the USM dated 27-May-2021, subjects requiring study treatment every 4 weeks will 
be discontinued, therefore, the originally planned number of subjects transitioning from the core 
study into the extension study will be reduced. Consequently, the sample size was re-assessed 
with the focus on the estimation of subjects who will be on a q20w interval. This estimation can 
be achieved with acceptable precision with a sample size of 250. The study objectives will still 
be assessed with the revised sample size. 
In addition, information was included on the gender imbalance in the reported rates of 
intraocular inflammation-related adverse events following brolucizumab treatment. 
Changes to the protocol 
• Protocol summary: Aligned with amendment 2. 
• Section 3 Study design: Changed the number of participants to be enrolled from 
approximately 622 to 250. In addition, removed stipulation for minimum time interval 
between two injections of 21 days as a 4-week interval is no longer an option. 
• Section 4.5 Risk and benefits: Information added regarding the gender imbalance in the 
reported rates of intraocular inflammation-related adverse events following brolucizumab 
treatment. 
• Section 5 Study population: Changed the number of participants to be enrolled from 
approximately 622 at 190 sites to 250 at 60 sites.  
• Section 6.7.2 Instruction for prescribing and taking study treatment, and Section 10 Safety 
monitoring and reporting: For consistency, in the sentence “If retinal vasculitis and/or 
retinal vascular occlusion is confirmed, subjects should be discontinued from study 
treatment.”, replaced “should” with “must”. 
• Section 9.1.2 Withdrawal of informed consent: Section was replaced with updated 
language based on latest protocol template. 
• Section 10 Safety monitoring and reporting: For consistency, incorporated the mandatory 
safety phone call required two weeks after the first injection (defined in Table 8-2) in the 
consolidated list for safety monitoring. 
• Section 10.1.3 SAE reporting: Clarified the timing for SAE reporting to Novartis as per 
latest protocol template. 
• Section 12.8 Sample size calculation: Section updated to implement the sample size 
reduction from 622 down to approximately 250 participants expected to be enrolled into 
the extension study. 
• Minor editorial changes (e.g. typographical mistakes, grammatical changes, rewording) to 
improve flow and consistency have been made throughout the protocol. 


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IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
 


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Summary of previous amendments 
Amendment 1 (13-Aug-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) Finally, 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. 
Changes to 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. In sub-section “CRTH258A2303 study (TALON)”, clarified that, 
in the core study, the treatment intervals after the initiation phase with 3 monthly 
injections at Baseline, Week 4, and Week 8 will range from 8 weeks to 16 weeks, and that 
subjects requiring injections every 4 weeks after the loading phase will be discontinued 
from further study treatment. 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 2.1 Primary estimands, and Table 2-1 Objectives and related endpoints: Text 
added to clarify analysis of 4-week treatment intervals. 


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• Section 3 Study design: Changes were made to clarify the minimal treatment interval and 
the requirement to discontinue from study treatment if subjects require treatment every 4 
weeks beyond the loading phase. Reference to Section 9.1.1 added regarding early 
treatment discontinuation. 
• Figure 3-1 Study design: Updated the range for treatment intervals. 
• Section 4.1 Rationale for study design: Modified to clarify the shortest treatment interval 
• Section 4.2 Rationale for dose/regimen and duration of treatment: Language added to 
provide background of the USM. 
• 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 5.2 Exclusion criteria: Added criteria to exclude subjects who require anti-VEGF 
IVT injections every 4 weeks. 
• 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 6.2.1.1 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 6.7.2 Instruction for prescribing and taking study treatment: Changes were made 
to clarify the requirement to discontinue from study treatment if subjects require treatment 
every 4 weeks. Changes also made to update that if RV and/or RO is confirmed, subjects 
must 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.  
• Figure 6-1 Treatment regimen: Updated to update the range for treatment intervals. 
• Table 8-1 Assessment schedule: Columns added for assessment visits after start of 
standard of care and for early treatment discontinuation visits, including respective 
footnotes. 
• Section 9.1.1 Study treatment discontinuation and study discontinuation: Clarification and 
instructions were added for subjects who discontinue from study treatment early.  
• 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 must 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.  
• Table 12-1 Primary and sensitivity estimands: Clarification added regarding BCVA scores 
collected after start of standard of care. The estimands are re-ordered to match the order in 
the Table 2-1. In addition, sensitivity estimands are added regarding the proportion of 
q12w. 


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• Section 12.4.5 Sensitivity analyses for primary endpoint/estimand: Sensitivity analysis 
added regarding USM. Added MMRM abbreviation. 
Other changes incorporated in this amendment: 
• List of abbreviations: New abbreviations added in line with amendment 1. 
• Protocol summary: Aligned with amendment 1. 
• Section 2 Objectives and endpoints: Revised to make it clear that the baseline being 
referred to is that of the extension study and not the core study baseline. The prefix 
extension is added before the word “baseline”. There are no changes in the end-points or 
the primary analysis. The same prefix ”extension” will be added for the CSFT and OCT 
end-points with no changes made to the analyses.  
• Section 6.3.1 Participant numbering: Updated section on participant numbering, because 
participant IDs in EDC may be different in IRT. 
• Section 6.7.2 Instruction for prescribing and taking study treatment. Changes made to 
update that if 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 investigator should 
evaluate the appropriateness of continuing further with study treatment. This has been 
updated in several sections. 
• Section 7 Informed consent procedures: Removed text to align with Investigator Brochure 
and ICF. Section 8 Visit schedule and assessments: Clarification added for visit windows. 
• Table 8-1 Assessment schedule and Table 8-2 Safety assessments: Updated the visit 
window for mandatory safety phone call timing. The timing is changed from one week to 
two weeks and the window from +7 days to +14 days. Reason being that the median time 
of onset of AESI’s is about 21 days (as per Novartis Pharmacovigilance data) and 
therefore expanding the time frame may be more appropriate for picking up AE’s. 
• Section 8.4 Safety: Added a reference for monitoring, assessment and management of 
adverse events of inflammation, retinal vasculitis and/or retinal vascular occlusion. Also 
added imaging as key safety assessment. This change has been made in multiple sections 
of the protocol. 
• 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 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 10.1.4 Pregnancy reporting: Clarification added regarding follow-up during 
pregnancy and after childbirth. 
• Section 12.5.1 Correction of typographical error, and Section 12.5.2 Safety endpoints: 
Removed “by treatment” because only one treatment arm in the study, and clarified that 
clinically relevant abnormalities in vital signs will be listed. 
• Section 12.8 Sample size calculation: Clarification regarding sample size analyses. 


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Protocol summary 
Protocol 
number 
CRTH258A2303E1 
Full Title 
A 56-week, phase IIIb/IV, open-label, one-arm extension study to assess the 
efficacy and safety of brolucizumab 6 mg in a Treat-to-Control regimen with 
maximum treatment intervals up to 20 weeks for the treatment of patients with 
neovascular age-related macular degeneration who have completed the 
CRTH258A2303 (TALON) study 
Brief title 
An extension study assessing the efficacy and safety of brolucizumab in a Treat-
to-Control regimen in patients with neovascular age-related macular 
degeneration who have completed the CRTH258A2303 (TALON) study 
Sponsor and 
Clinical Phase 
Novartis 
Phase IIIb/IV 
Investigation 
type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
To evaluate the efficacy and safety of brolucizumab used in a Treat-to-Control 
regimen for treatment of patients with neovascular age-related macular 
degeneration with the objective to assess the potential for long durability up to 
20 weeks 
Primary 
Objective(s)  
To evaluate the extended durability of brolucizumab in a Treat-to-Control 
regimen assessed as duration of the last interval with no disease activity up to 
Week 56. To evaluate the functional outcomes of brolucizumab in a Treat-to-
Control regimen assessed as average change of best corrected visual acuity 
from the extension baseline at week 52 and week 56 
Secondary 
Objectives 
To evaluate the anatomical outcomes of brolucizumab in all patients and per 
randomized arm in the core study - assessed by central subfield thickness and 
number of visits with presence of intra-retinal fluid and/or sub-retinal fluid, and 
sub-retinal pigment epithelium fluid in the central subfield, as seen by spectral 
domain ocular coherence tomography at Week 52 and Week 56 
To assess the durability of brolucizumab in all patients and/or per randomized arm 
in the core study - measured as duration of last interval and maximum interval 
with no disease activity up to week 56, as well as change of the duration of last 
interval with no disease activity between extension baseline and Week 56  
To assess the functional outcomes of brolucizumab per randomized arm in the 
core study by measuring change of best corrected visual acuity from extension 
baseline to week 52 and week 56 
To assess the safety of brolucizumab – measured as occurrence of ocular and 
non-ocular adverse events up to week 56 
Study design 
This is a 56-week, one-arm, open-label, multi-center extension study where all 
patients are to be treated with brolucizumab up to week 52 in a Treat-to-Control 
regimen with treatment intervals from 8 weeks up to maximum 20 weeks  
Study 
population 
Approximately 250 of the subjects who have completed the CRTH258A2303 
(TALON) study are expected to be enrolled in approximately 60 sites worldwide 


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Key Inclusion 
criteria 
• 
Signed informed consent must be obtained prior to participation in the study 
• 
The participant has successfully completed the TALON core study at the 
week 64 visit (End of Study) 
Key Exclusion 
criteria 
• 
Participant has a medical condition or personal circumstance which 
precludes study participation or compliance with study procedures, as 
assessed by the Investigator 
• 
Participant has discontinued study treatment in the core study 
• 
Anti-VEGF treatment is futile in the study eye, in the investigator's opinion 
• 
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 
Study 
treatment 
Brolucizumab 6 mg/0.05 mL 
Efficacy 
assessments 
• 
Best corrected visual acuity using ETDRS-like charts 
• 
Spectral Domain Optical Coherence Tomography 
• 
Color Fundus Photography 
Key safety 
assessments 
• 
Monitoring of adverse events 
• 
Ophthalmic examinations and imaging 
• 
Vital signs (pulse and blood pressure) 
• 
Pregnancy testing 
Other 
assessments  
Ocular Coherence Tomography Angiography 
Data analysis 
The primary analyses will be conducted in the full analyses set with missing data 
imputed based on the last observation carried forward method. 
Duration of the last interval with no disease activity up to Week 56 will be 
estimated using proportions with two-sided 95% Binomial Confidence Intervals 
and simultaneous Confidence Intervals obtained based on Goodman method 
(1965). The change in best corrected visual acuity from extension baseline at 
Week 52 and Week 56 will be estimated based on an analysis of covariance 
model with baseline best corrected visual acuity and age. The estimates of the 
change in best corrected visual acuity will be accompanied by two-sided 95% 
Confidence Intervals.  
Additional analysis is planned to evaluate the impact of the COVID-19 pandemic 
and the q4w urgent safety measures on the primary and selected secondary 
endpoints. 
Key words 
Neovascular age-related macular degeneration, anti-VEGF, choroidal 
neovascularization, individualized treatment 


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1 
Introduction 
1.1 
Background 
Age-related macular degeneration (AMD) is a leading cause of severe vision loss in people, 
affecting 11.6% to 18.5% of individuals between 60 and 69 years old and 31.6% to 45.3% of 
individuals between 80 and 84 years old in North America, Europe, and Oceania 
(Wong et al 2014). Genetic, environmental and health factors play an important role in the 
pathogenesis of the disease. 
AMD is classified into 2 clinical subtypes: the non-neovascular (atrophic) or dry form, and the 
neovascular (exudative) or wet form (Ferris et al 1984, Lim et al 2012, Miller 2013). 
Neovascular AMD (nAMD) is characterized by the growth of abnormal new blood vessels 
(neovascularization) under the retinal pigment epithelium (RPE) or sub-retinal space from the 
subjacent choroid, termed choroidal neovascularization (CNV) (Ferris et al 1984). These newly 
formed vessels have an increased likelihood to leak blood and serum, damaging the retina by 
stimulating inflammation and scar tissue formation. This damage to the retina results in 
progressive, 
severe, 
and 
irreversible 
vision 
loss 
(Shah and Del Priore 2007, 
Shah and Del Priore 2009). Without treatment, most affected eyes will have poor central vision 
(20/200) within 12 months (Blinder et al 2003). Although the neovascular form of the disease 
is only present in about 10 % of all AMD cases, it accounted for approximately 90 % of the 
severe vision loss from AMD prior to the introduction of antivascular endothelial growth factor 
(anti-VEGF) treatments (Ferris 1983). 
Anti-VEGF in nAMD 
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). 
The use of intravitreal injection (IVT) pharmacotherapy targeting VEGF has significantly 
improved visual outcomes in patients with nAMD (Bloch et al 2012, Campbell et al 2012). 
Intravitreal administration of anti-VEGF treatments is the current standard of care in nAMD. 
Treat-and-Extend treatment regimen 
Typically, a Treat-and-Extend (T&E) treatment regimen includes a loading phase of monthly 
injections, followed by a maintenance phase during which the injection interval is progressively 
prolonged if there is no disease activity (DA), primarily determined by optical coherence 
tomography (OCT) and visual acuity assessment, or shortened if disease recurs. The T&E 
treatment regimen aims at identifying optimal individual injection intervals to minimize the 
number of injections and reduce visit burden while maintaining the vision gains obtained at the 
end of the loading phase during the maintenance phase. T&E treatment regimen has been 
approved in the labels of anti-VEGF treatments, such as ranibizumab (Lucentis®) and 
aflibercept (Eylea®) in Europe and many other countries. The treatment paradigm has come in 
a variety of regimens. 
Whereas most T&E regimens entail extending or shortening the injection interval based on 
absence or presence of DA, the Treat-to-Control (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 


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extension to be temporarily or lastingly maintained on a treatment interval. While T&E 
regimens have been associated with a reduction in treatment and visit burdens in AMD, the 
number of visits remain relatively high for most patients as the average number of injections in 
Lucentis® and Eylea® studies range from 8 to 10.1 in the first 12 months and from 10.4 to 18.6 
in 
the 
first 
2 
years 
(Wykoff et al 2015, 
DeCroos et al 2017, 
Wykoff et al 2017, 
Guymer et al 2018, Silva et al 2018, Gillies et al 2019, Kertes et al 2019, Ohji et al 2020). 
There still is a need for highly effective treatments that prolong intervals between injections and 
further reduce treatment burden, while maintaining vision gains. 
Brolucizumab 
Brolucizumab (RTH258, ESBA1008, AL-86810), is a humanized single-chain antibody 
fragment (scFv) with a molecular weight of ~26 kilodalton (kDa) which inhibits VEGF-A 
binding to its receptors VEGFR1 and VEGFR2. Brolucizumab is administered by intravitreal 
injection and has been approved by the US Food and Drug Administration on 7 Oct 2019 and 
many other countries (e.g. EU countries, Australia, Japan and Canada) subsequently, for the 
treatment of nAMD. 
The efficacy and safety of brolucizumab in subjects with nAMD has been demonstrated in two 
Phase III pivotal studies (RTH258-C001 [HAWK] and RTH258-C002 [HARRIER]). nAMD 
patients received brolucizumab every 12 weeks (q12w), with the option of adjusting to a q8w 
dosing interval based on DA, or aflibercept q8w, after three monthly loading doses. 
Brolucizumab was non-inferior to aflibercept with regards to change from Baseline in BCVA 
at week 48, with over half of the participants in the brolucizumab 6 mg arm maintained 
exclusively on the q12w dosing interval (56% in HAWK and 51% in HARRIER). Significantly 
fewer patients in the brolucizumab 6 mg arm had DA at Week 16 in a head-to-head comparison 
based on a matching dosing intervals, with a relative decrease of 30% (P = 0.0022) versus 
aflibercept. Significantly fewer patients on brolucizumab had intraretinal fluid (IRF) and/or 
subretinal fluid (SRF), with a 35% and 33% reduction relative to aflibercept at Week 16 (P < 
0.001 for both) in HAWK and HARRIER, respectively, and a 31% and 41% reduction relative 
to aflibercept at Week 48 in HAWK and HARRIER, respectively (P < 0.0001 for both). These 
advantages for brolucizumab were maintained in the second year. Safety was comparable 
between the treatment arms over 2 years.  
Since the first marketing authorization approval in October 2019 for the treatment of nAMD, 
adverse events of retinal vasculitis and/or retinal vascular occlusion, that may result in severe 
vision loss and typically in the presence of intraocular inflammation, have been reported from 
post-marketing experience with brolucizumab (Beovu®).  
Results of the mechanistic study BASICHR0049 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 “retinal vasculitis and/or retinal vascular occlusion, typically in the presence of IOI”. 
This finding supports the requirement to discontinue treatment with brolucizumab in patients 
who develop events of RV and/or RO. 


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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. 
For further details, please refer to the investigator brochure (IB) or package insert whichever is 
applicable. 
CRTH258A2303 study (TALON) 
There is an ongoing study CRTH258A2303 (TALON) which intends to complement the current 
clinical dataset on brolucizumab by generating new evidence based on the T&E concept 
prevalent in the current management of patients with nAMD. It will be comparing the efficacy 
and safety of brolucizumab and aflibercept administered in three monthly injections at Baseline, 
Week 4, and Week 8 (loading phase), followed by an identical 4-week-adjustment Treat-to-
Control regimen with treatment intervals from 8 to 16 weeks. Subjects requiring injections 
every 4 weeks after the loading phase will be discontinued from further study treatment. 
This study, CRTH258A2303E1, is an extension study of the CRTH258A2303 (TALON) study, 
aiming at gathering additional long-term efficacy and safety evidence about brolucizumab in a 
TtC treatment regimen with treatment intervals further extended up to 20 weeks in nAMD. It 
intends to contribute to the growing clinical dataset of brolucizumab by generating 
supplementary evidence on treatment safety, efficacy, and durability in nAMD. 
1.2 
Purpose 
The purpose of this study is to evaluate the efficacy and safety of brolucizumab used in a Treat-
to-Control (TtC) regimen with maximum treatment intervals up to 20 weeks for the treatment 
of patients with neovascular age-related macular degeneration (nAMD) who have completed 
the CRTH258A2303 study (TALON). 
In addition, switch data from aflibercept to brolucizumab is collected. 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To evaluate the extended durability of 
brolucizumab in a TtC regimen with respect 
to the duration of treatment intervals at 
Week 56 
• 
Duration of the last interval with no DA up to 
Week 56 
• 
To evaluate the functional outcomes of 
brolucizumab in a TtC regimen with respect 
• 
Change in BCVA from extension baseline at 
Week 52 and Week 56 


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Objective(s) 
Endpoint(s) 
to average change in BCVA at Week 52 and 
Week 56 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To evaluate the anatomical outcomes of 
brolucizumab in all patients and per 
randomized arm in the core study 
• 
Change in CSFT from extension baseline to 
Week 52 and Week 56 
Number of visits with presence of IRF and/or 
SRF, and sub-RPE fluid in the central 
subfield, as assessed by SD-OCT at Week 
52 and Week 56  
• 
To assess the durability of brolucizumab in 
all patients and/or per randomized arm in 
the core study 
• 
Duration of the last interval with no DA up to 
Week 56 
Duration of the maximal intervals with no DA 
up to Week 56 
Change of the duration of last interval with 
no DA between extension baseline and 
Week 56  
• 
To assess the functional outcomes of 
brolucizumab per randomized arm in the 
core study  
• 
Change in BCVA from extension baseline to 
Week 52 and Week 56  
• 
To assess the safety of brolucizumab 
• 
Occurrence of Ocular and Non-ocular AEs 
up to Week 56 
2.1 
Primary estimands 
There are two primary clinical questions of interest: 1. what is the effect of brolucizumab 6 mg 
on treatment interval extension? and 2. what is the effect of brolucizumab 6 mg on visual acuity 
change in a TtC regimen with maximum treatment intervals up to 20 weeks after treatment in 
patients with nAMD who have completed the CRTH258A2303 study? 
These two effects were targeted to estimate the effect of brolucizumab in a TtC regimen with 
maximum treatment intervals up to 20 weeks without breaking masking of the CRTH258A2303 
study (TALON). 
The primary estimand is described by the following attributes: 
1. Population: participants who have completed the CRTH258A2303 study (TALON) 
irrespective of the study treatment received in the core study. Further details about the 
population are provided in Section 5. 


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2. The co-primary variable 1 is change in BCVA from extension baseline at Week 52 and Week 
56, i.e. the average change in BCVA from extension Baseline to Week 52 and Week 56. The 
co-primary variable 2 is the duration of the last interval with no DA up to Week 56, i.e. the 
proportion of participants in q4w, q8w, q12w, q16w and q20w intervals (interval distribution) 
at last interval with no DA up to Week 56 (subjects who will be assigned to a 4-week interval 
will be analyzed as such, but discontinued from further study treatment). 
3. Treatment of interest: brolucizumab 6 mg will be taken for the entire study duration. Further 
details about the investigational drug are provided in Section 6. 
Handling of remaining intercurrent events: 
• Study treatment discontinuation: For the co-primary endpoint of change in BCVA, a 
hypothetical treatment strategy will be applied to estimate the treatment effect under the 
hypothetical assumption that the patient would not start an alternative anti-VEGF 
treatment (i.e. standard of care therapy) on the study eye. For the co-primary endpoint of 
duration of treatment interval, a ‘while on treatment strategy’ will be applied as disease 
stability assessment will not be performed after the patient discontinued treatment. 
• Study treatment interruption: For both the co-primary endpoints, a treatment policy 
strategy will be applied. 
The summary measure for the co-primary variable 1 is the interval distribution, and for the co-
primary variable 2 is the least square means. 
2.2 
Secondary estimands 
Not applicable 
3 
Study design 
This study is a 56-week, open-label, one-arm extension study in participants who have 
completed the CRTH258A2303 study (TALON). 
Participants who consent and meet all the inclusion and none of the exclusion criteria will be 
enrolled into this extension study and receive brolucizumab 6 mg in a TtC regimen, irrespective 
of the treatment received in the core study. 
Approximately 250 participants from the core study will enter the extension study. The 
maximum study duration for a participant is 56 weeks, including post-treatment follow-up. 
There will be two periods in this study, see Figure 3-1: 
• Treat-to-Control treatment period: from Baseline (Day 1) to Week 52 
• Post-treatment follow-up period: from Week 52 to Week 56.  


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Figure 3-1 
Study design 
 
Depending on visit schedules: 
* 62 weeks (core) / 54 weeks (extension) ** Week 62 (core) / Week 54 (extension) 
Baseline visit: Day 1 
Participants should sign informed consent no later than the Week 64 (EOS) visit of the core 
study. Baseline visit for the extension study (extension baseline) should occur on the same day 
as the Week 64 (EOS) visit of the core study. Participants will be assessed on inclusion and 
exclusion criteria of the extension study at the baseline visit. 
The study eye will be the same eye that received brolucizumab or aflibercept treatment in the 
core study. 
Treat-to-Control treatment period: Day 1 to Week 52 
All efforts should be made to adhere to the study visit schedule within a ±14day window 
(baseline visit should occur on the same day as the Week 64 (EOS) visit of the core study). For 
a given study visit, assessments can be performed on 2 consecutive days provided both days 
occur within the visit window. Study treatment is intended to be administered on the day of the 
study visit, or, if this is not possible, within 3 days after the assessments have taken place.  
The first injection visit in the extension study will be based on the planned treatment interval as 
decided by the investigator at the last injection visit of the core study. The treatment interval 
can then be extended by 4 weeks at a time based on the investigator’s judgment of visual and/or 
anatomic outcomes, as per guidance provided, for example, no change in visual acuity and in 
other signs of the disease (e.g. IRF, SRF, hemorrhage, leakage, etc.). Patients who have the last 
injection interval with no DA of q16w in the core study should be injected at another q16w 
 


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interval before start to extend intervals in the extension study. The maximal treatment interval 
is 20 weeks. 
The injection interval can also be maintained if the investigator deems that the patient will not 
benefit from injection interval extension.  
The interval should be shortened by 4 weeks at a time if DA recurs (to a minimal interval of 8 
weeks). 
The investigators have options to plan for an inspection visit when the treatment intervals are 
extended. Further details are provided in Section 6.7.2. 
For all participants, the last potential study treatment will be at the Week 52 visit. Participants 
who will receive a study treatment at an inspection visit may have a study visit at Week 54. For 
those participants, the Week 54 visit will take place in lieu of the visit at Week 52. 
Post-treatment follow-up period: Week 52 to Week 56 
For all participants completing the study, the EOS (Week 56 ±21 days) assessments will be 
performed 4 weeks after the last treatment administration (Week 52/54). 
Participants withdrawn from the study prior to study completion within less than 4 weeks after 
the last study treatment will be asked to return for an EOS visit, 4 weeks (±14 days) following 
their last study treatment administration (EOT). For early treatment discontinuations (ETD) 
refer to Section 9.1.1. 
4 
Rationale 
4.1 
Rationale for study design 
The primary research interest is to assess the durability and functional outcome of brolucizumab 
treatment effect with treatment intervals up to 20 weeks, in all the eligible participants who will 
have completed the CRTH258A2303 (TALON) study, which compared the efficacy and safety 
of brolucizumab and aflibercept administered in the same TtC regimen with the treatment 
intervals from 8 to 16 weeks. Hence, this study is designed as an open-label, one-arm study. 
And the treatment interval adjustment will continue from the last treatment interval in the 
CRTH258A2303 (TALON) study, i.e. q8w, q12w and q16w, with an additional treatment 
interval of 20 weeks added in the extension study. 
Co-primary efficacy endpoints based on treatment interval and BCVA were chosen to evaluate 
the benefits of treatment in terms of treatment durability and functional outcome, respectively:  
Treatment intervals may be extended, reduced, or maintained, based on the evaluation of DA 
by investigators. The distribution of the last interval with no DA up to Week 56 will be analyzed. 
If there is DA during the last interval up to Week 56, the last interval will be shortened by 4 
weeks down to a minimum of 8 weeks. 
The co-primary efficacy endpoint based on BCVA (ETDRS letters) will also be assessed. 
Historically, the change from baseline in BCVA at a selected time point is considered 
appropriate as the primary efficacy endpoint in confirmatory nAMD studies, based on the 


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evidence available from existing anti-VEGF treatments in nAMD (e.g. ranibizumab, 
aflibercept). 
The co-primary endpoint will be assessed as average change from the extension baseline in 
BCVA at Week 52 and Week 56. In the TtC phase, patients will receive injections at different 
intervals. Patients with longer treatment intervals may receive their last injection far earlier 
before the fixed assessment time point than those with shorter treatment intervals. A difference 
in the time since the last injection may affect BCVA gain and could introduce a bias on BCVA 
gain if measured at a single fixed assessment time point. Averaging change in BCVA from 
baseline at two time points 4 weeks apart will mitigate this potential bias. 
Approximately 52 weeks of treatment in a TtC regimen, allows up to two consecutive q20w 
intervals and the evaluation of the long-term safety and efficacy of brolucizumab. 
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 three times every four 
weeks during the loading phase, based on the previous clinical Phase III program in which 
1088 participants with nAMD received brolucizumab (RTH258-C001 - HAWK and 
RTH258-C002 - HARRIER). The nAMD study results regarding q12w/q8w maintenance 
dosing interval support stretching the interval between injections during the TtC phase to 
reduce the treatment burden (see Section 1.1). 
• In a recent Treat and Extend study, treatment intervals were extended to the maximum 
interval of 16 weeks as early as Week 40 for some Japanese patients with nAMD treated 
with aflibercept 2 mg in a Treat-and-Extend regimen where treatment intervals could be 
every 4-week adjusted based on DA, following 3 consecutive 4-week injections and a 8-
week injection (Ohji et al 2020). One could expect that patients could also be effectively 
and safely injected with brolucizumab 6 mg at 16-week intervals, as brolucizumab 6 mg 
dosed q12w/q8w was superior to aflibercept 2 mg dosed q8w in terms of fluid control and 
suppression of DA as seen in RTH258-C001 - HAWK and RTH258-C002 - HARRIER. 
Hence, the treatment interval range in the ongoing CRTH258A2303 (TALON) study is 
from 4 to 16 weeks for brolucizumab and aflibercept. 
• Evidence from ranibizumab study in nAMD (CRFB002A2413 – SUSTAIN) showed that 
20.5% of patients did not receive any additional dose during a PRN phase (re-treatment 
criteria were guided by VA and OCT variables) for periods lasting up to eight months. It 
indicates that some patients may not need frequent injections. These patients may benefit 
from brolucizumab 6 mg administered at 20-week intervals as in the current study. 
• 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 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 protocol was amended to discontinue subjects from study 
treatment who require treatment every 4 weeks during the extension study. 
• The route of administration is an intravitreal injection as for all anti-VEGF treatments 
currently approved for the treatment of nAMD. 
• Study duration of 56 weeks allows two consecutive 20-week intervals to assess long-term 
efficacy and safety of brolucizumab in a TtC regimen. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Not applicable 
4.4 
Purpose and timing of interim analyses/design adaptations 
Not applicable 
4.5 
Risks and benefits 
The risk to participants in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring described in Section 6.7.2, 
Section 8.4 and Section 10. 
Adverse events (AEs) of 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 and typically in the presence of intraocular 
inflammation. 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). 
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 “retinal vasculitis and/or retinal vascular occlusion, typically in the presence of IOI”. 
This finding supports the requirement to discontinue treatment with brolucizumab in patients 
who develop events of RV and/or RO. 
In addition, based on USM (CRTH258AUS04 FIR), the brolucizumab dosing interval should 
not be less than 8 weeks beyond the loading period. 
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study, and agree that in order 
to participate in the study they must adhere to the contraception requirements outlined in the 
exclusion criteria. If there is any question that the participant will not reliably comply, they 
should not be entered or continue in the study. 
In both Phase III studies (HAWK, HARRIER) in nAMD, brolucizumab demonstrated non-
inferiority to aflibercept in mean change in BCVA from baseline to Week 48. These results 


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were achieved while a majority of participants on brolucizumab 6 mg – 56% in HAWK and 
51% in HARRIER – were maintained on a q12w dosing interval following the loading phase 
through Week 48, i.e., with a reduced treatment frequency compared to aflibercept. 
Brolucizumab safety was comparable to aflibercept, with the overall incidence of adverse 
events balanced across all treatment groups in both studies. 
5 
Study population 
The study population will be adult male and female patients who have completed the 
CRTH258A2303 study (TALON) with the EOS visit at Week 64 and able to comply with study 
procedures. 
Approximately 250 participants are expected to be enrolled in approximately 60 sites 
worldwide. 
The study eye will be the same eye that received brolucizumab or aflibercept study treatment 
in the core study. 
5.1 
Inclusion criteria 
The investigator will assess the eligibility of the participant and the study eye at the baseline 
visit and confirm eligibility for the extension study. Participants eligible for inclusion in this 
study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study.  
2. The participant has successfully completed the TALON core study, as defined by providing 
assessments at the Week 64 visit (EOS) of the core study. 
5.2 
Exclusion criteria 
Patients fulfilling any of the following criteria at study entry are not eligible for inclusion in 
this study. No additional exclusions may be applied by the investigator, in order to ensure that 
the study population will be representative of all eligible patients. 
1. Participant has a medical condition or personal circumstance which precludes study 
participation or compliance with study procedures, as assessed by the Investigator. 
2. Participant has discontinued study treatment in the core study. 
3. Anti-VEGF treatment is futile in the study eye, in the investigator's opinion. 
4. 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. 
5. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during the 
study drug administration and for 3 months after stopping the investigational medication. 
Highly effective contraception methods include: 


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• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study 
treatment. In case of oophorectomy alone, only when the reproductive status of the woman 
has been confirmed by follow up hormone level assessment. 
• Male sterilization (at least 6 months prior to baseline). For female participants on the 
study, the vasectomized male partner should be the sole partner for that participant. 
• Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), 
or other forms of hormonal contraception that have comparable efficacy (failure rate < 
1%), for example hormone vaginal ring or transdermal hormone contraception. 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. Women are considered post-menopausal 
and not of child-bearing potential if they have had 12 months of natural (spontaneous) 
amenorrhea with an appropriate clinical profile (e.g. age, appropriate history of vasomotor 
symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total 
hysterectomy, or tubal ligation at least six weeks before taking study treatment. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment is she considered not of child-bearing potential. If local 
regulations deviate from the contraception methods listed above to prevent pregnancy, local 
regulations apply and will be described in the informed consent form. 
6. Subject requires study treatment every 4 weeks. 
6 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational and control drugs 
Table 6-1 
Investigational drug 
Investigational 
Drug  
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor (global 
or local) 
Brolucizumab 
6 mg (RTH258 
6 mg/0.05 mL) 
Solution for 
injection 
Intravitreal use 
Prefilled syringes 
/ Glass vials 
Global 
 
Brolucizumab will be provided in a single use, sterile glass vial, or may be provided in prefilled 
syringe (in selected countries), containing sufficient brolucizumab to deliver a 6 mg dose when 
administering a volume of 0.05 mL. 


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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 investigational drug is included in this trial. 
6.1.3 
Treatment arms/group 
All eligible participants will receive brolucizumab 6 mg TtC treatment from baseline to Week 
52. 
6.1.4 
Treatment duration 
The planned duration of treatment is 52 weeks (54 weeks for the participants who may have 
received study treatment at an odd number of inspection visits). Discontinuation of study 
treatment for a participant occurs when study drug is stopped earlier than the protocol planned 
duration and can be initiated by either the participant or the investigator.  
Study treatment will also be discontinued for patients who require injections every 4 weeks.  
If retinal vasculitis, and/or retinal vascular occlusion is confirmed, subjects must be 
discontinued from study treatment.  
Subjects who prematurely discontinue study treatment for any reason, except for withdrawal of 
consent, should continue in the study. Subjects should return 4 weeks after last study treatment 
to perform the assessments for early treatment discontinuation (ETD).  
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
The investigator must instruct the participant to notify the study site about any new medications 
the participant takes after enrollment in the study. All medications, procedures, and significant 
non-drug therapies (including physical therapy and blood transfusions) administered after the 
participant was enrolled into the study must be recorded on the appropriate eCRF. 
Concomitant medications which are ongoing at the time of the Week 64 (EOS) visit in the core 
study must be recorded, and entries in the extension study database should match those in the 
core study database as appropriate. 
Each concomitant drug must be individually assessed against the prohibited medication 
Table 6-2. If in doubt, the investigator should contact the Novartis medical monitor before 
enrolling a participant or allowing a new medication to be started. If the participant is already 
enrolled, contact Novartis to determine if the participant should continue participation in the 
study. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
Fellow eyes 


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During the study, standard of care or other treatments according to the investigator's practice 
for nAMD and other diseases in the fellow eye are permitted at any time and must be recorded 
in the appropriate eCRF page. Treatment of the fellow eye must be scheduled in a way not to 
disturb the schedule for visits and treatments in the study eye. The fellow eye must be monitored 
according to routine practice and adverse events (AEs) captured in the eCRF.  
Study eyes 
Administration of topical ocular corticosteroids in the study eye is allowed during the study. 
Corticosteroids administered via intra-nasal, inhaled, intra-articular or non-extensive dermal 
route (< 20% total body surface area) are also permitted during the study. For other routes of 
corticosteroid administration, refer to Section 6.2.2. 
If cataract surgery is necessary, attempt to schedule cataract surgery ≥ 7 days after the most 
recent study treatment. Study treatment may be resumed ≥ 14 days after cataract surgery, 
assuming an absence of surgically-related complications. 
If yttrium aluminum garnet (YAG) laser is necessary, it should be performed ≥ 7 days prior to 
the scheduled study visit. 
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 the below table are not allowed from the Week 64 (EOS) 
visit of the core study. 
Table 6-2 
Prohibited medications and procedures 
Medication 
Prohibition period 
Action taken 
Study Eye 
  
  
Any periocular injection 
or intraocular administration 
of corticosteroids  
(except if needed as a short-
term treatment of AE) 
 Anytime 
Discontinue study 
treatment (except if for 
treatment of AE) 
Anti-VEGF therapy other 
than assigned study medication 
 Anytime 
Discontinue study treatment 
Panretinal laser, PDT laser, 
or focal laser 
photocoagulation with 
involvement of the 
macular area 
Anytime 
Discontinue study treatment 
Any investigational 
drug, biologic or device 
Anytime 
Discontinue study treatment 
Systemic 
  
  
Anti-VEGF treatment 
Anytime 
Discontinue study treatment 


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Medication 
Prohibition period 
Action taken 
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/hydroxychloroquin
e, deferoxamine, 
phenothiazines and tamoxifen 
(except temporary use for 
COVID-19 treatment) 
Anytime 
Discontinue study treatment 
Fellow eye 
  
  
investigational drug, biological, 
device 
Anytime 
None 
 
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 
participant 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 9.1. 
6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each subject is identified in the study by a Subject Number (Subject No.) that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (4 digit number for Center No. as assigned by Novartis to the investigative site) with a 
sequential subject number suffixed to it (3 digit number for Subject No.), so that each subject 
is numbered uniquely across the entire database. Upon signing the informed consent form, the 
subject is assigned to the next sequential Subject No. available in the electronic data capture 
(EDC) system. 
6.3.2 
Treatment assignment, randomization 
All participants will be treated with brolucizumab, no randomization will be performed in this 
study.  
IRT will be used to assign kit numbers for each treatment occasion, in order to manage study 
drug supply at site level. 
6.4 
Treatment blinding 
Treatment will be open to participants, investigators/site personnel, sponsor clinical trial team 
(CTT) and monitors while randomization data from the core study will be kept strictly 


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confidential for participants, investigators/site personnel, sponsor CTT and monitors until 
database lock. 
Should there be a reasonable need to unmask the core study treatment before the database lock 
of this extension study, investigator shall contact Novartis.  
6.5 
Dose escalation and dose modification 
Investigational treatment dose adjustment is not permitted. Interruption of study treatment is 
allowed if warranted by an AE. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
IRT needs to be accessed by study personnel at every visit. Registration of all visits in the IRT 
system is necessary and when treatment is warranted, IRT will provide a medication (kit) 
number to administer the investigational product to the participant. 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 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 
syringes counts and information provided by the pharmacist or by the study personnel. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under investigational 
drugs Section 6.1. A unique medication number is printed on the study medication label. 
Investigator staff will identify the study medication kits to dispense to the participant by 
contacting the IRT and obtaining the medication number(s). The study medication has a 2-part 
label (base plus tear-off label), immediately before dispensing the medication kit to the 
participant, site personnel will detach the outer part of the label from the packaging and affix it 
to the source document. 
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be registered in the IRT 
system and stored according to the instructions specified on the labels and in the Investigator’s 
Brochure. 
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. 


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Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The investigator/site personnel must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Monitoring of drug accountability will be 
performed by monitors during site visits or remotely and at the completion of the trial.  
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator/site personnel will return all unused study treatment, packaging, drug labels, and a 
copy of the completed drug accountability log to the Novartis monitor or to the Novartis address 
provided in the investigator folder at each site. 
6.7.2 
Instruction for prescribing and taking study treatment 
There will be only one treatment phase in the extension study which is similar to the TtC phase 
of the core study and is defined as follows: 
Figure 6-1 
Treatment regimen 
 
 
#The treatment interval can also be maintained if the investigator deems that the patient will 
not benefit from treatment interval extension 
*week 54, depending on visit schedule 
Treat-to-Control treatment phase (Baseline/Day 1 to Week 52):  
Treatment intervals will be either 8 weeks, 12 weeks, 16 weeks, or 20 weeks. A subject must 
be discontinued from further study treatment if treatment is required every 4 weeks. 


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The participant will receive the first injection based on the next planned injection interval 
decided by the investigator at the last injection visit of the core study. For example, if a 
participant has the last injection visit at Week 60 of the core study, and the next planned 
injection interval is a q12w interval, the first injection visit for this participant will be planned 
at Week 8 of the extension study (12 weeks from Week 60 of the core study).  
At each injection visit, DA should be assessed using anatomic and functional outcomes (e.g. 
SD-OCT, BCVA, etc.). Based on investigator’s judgment of visual and/or anatomic outcomes, 
the treatment interval can be further extended by 4 weeks at a time, if there is no DA, i.e. no 
change in visual acuity and in other signs of the disease (e.g. IRF, SRF, hemorrhage, leakage, 
etc.). 
Participants whose last injection interval in the core study is q16w and are without DA should 
be injected at another q16w interval in the extension study before extending to q20w in the 
extension study.  
The treatment interval can also be maintained if the investigator deems the participant will not 
benefit from treatment interval extension. 
If DA recurs, the interval should be shortened accordingly by 4 weeks at a time, to a minimal 
interval of 8 weeks. 
When the investigator decides to extend the treatment interval from 16 to 20 weeks, the 
investigator has the option to plan for an inspection visit 4 weeks before the next treatment visit 
(i.e. 16 weeks after the last treatment visit) to assess DA. If the study eye has no DA at the 
inspection visit, the participant will not receive study treatment at the inspection visit 
but 4 weeks later. If the investigator observes DA in the study eye at the inspection visit, the 
participant will receive study treatment at this visit. The treatment interval will then be reduced 
by 4 weeks and the next study treatment visit will be planned 12 weeks after the inspection 
visit.  
When the investigator decides to extend the treatment interval from 8 to 12 weeks, the 
investigator has the option to plan for an inspection visit 2 weeks before the next treatment visit 
(i.e. 10 weeks after the last treatment visit) to assess DA. If the study eye has no DA at the 
inspection visit, the participant will not receive study treatment at the inspection visit 
but 2 weeks later. If the investigator observes DA in the study eye at the inspection visit, the 
participant will receive study treatment at the inspection visit. The next treatment interval will 
be reduced to 8 weeks. The same optional inspection visit 2 weeks earlier than the next 
treatment visit will be offered, when the investigator decides to extend the treatment interval 
from 12 to 16 weeks. If the study eye has no DA at the inspection visit, the participant will not 
receive study treatment at the inspection visit but 2 weeks later. If DA is observed in the study 
eye at the inspection visit, the participant will receive study treatment at the inspection visit. 
The next treatment interval will be reduced to 12 weeks. If the patient requires a reduction of 
the treatment interval down to 4 weeks, the patient will receive an injection at the visit, but will 
be discontinued from further study treatment at the next visit. 
Regardless of treatment administration, Week 52 and Week 56 visits are mandatory. 
Participants who will receive study treatment at an inspection visit may also have a study visit 


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at Week 54; for these participants, the Week 54 visit will take place in lieu of the visit at Week 
52 (unless this visit is inspection visit), respectively. 
The last potential study treatment may be administered at the Week 52 visit (or at the Week 54 
visit for the participants who will have received study treatment at an odd number of inspection 
visits). 
DA assessments will be recorded in the IRT system by the investigator or his/her delegate.  
A DA assessment will also be performed at the Week 56/EOS visit; however, no study treatment 
will be administered. 
The different types of study visits are summarized in Table 6-3 with a description of when DA 
assessments and treatments take place. 
Table 6-3 
Disease Activity assessment and treatment occurrence according to 
visit type 
Type 
Study Period 
DA Assessment 
Treatment 
Baseline visit 
TtC-Phase 
Yes 
Only if treatment was 
planned according to 
the individual TtC 
regimen of the core 
study 
Treatment visits 
TtC-Phase 
Yes 
Yes 
Inspection visits 
(optional) 
TtC-Phase 
Yes 
Based on DA, as per 
investigator`s 
judgement 
Week 52/54* 
TtC-Phase 
Yes 
Only if treatment was 
planned according to 
the individual TtC 
regimen 
ETD visit and EOS 
visit (Week 56) 
Follow-Up 
Yes 
No 
Brolucizumab should be administered in the study eye on the day of the study visit, or, if this is 
not possible, within 3 days after the occurrence of the study visit (except for Baseline / Day 1, 
in which case study treatment administration should occur within the next 24 hours) or no later 
than within the visit window (±14 days) as described in Section 3 and Section 8. When 
assessments and treatments take place on the same day, treatment must occur after completion 
of the efficacy assessments described in Section 8.3 and pre-injection safety measures 
(tonometry, slit lamp and fundus examinations) described in Section 8.4. If study visit 
assessments and the corresponding treatment occur on separate days, a repeat safety checkup 
should be performed prior to treatment of the eye and results should be 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 
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IVT injection is contraindicated in participants with active intraocular or periocular infections 
and in participants with active intraocular inflammation; therefore, the investigators must verify 
that these conditions are not present in the study eye prior to every injection. Any adverse events 
must be recorded in the eCRF. 
If any sign of intraocular inflammation (IOI) is present, then an IVT injection must not be 
performed. Additional ophthalmic examination and imaging should be performed to evaluate 
IOI, see Section 8.4 . 
If retinal vasculitis, and/or retinal vascular occlusion is confirmed, subjects must be 
discontinued from study treatment. In addition, subjects who experience IOI only (without RV 
and/or RO) may be at risk of developing retinal vasculitis and /or retinal vascular occlusion and 
should be closely monitored and the investigator should evaluate the appropriateness of 
continuing further with study treatment. 
The IVT injection procedure, including aseptic and antimicrobial requirements, will be 
performed according to local clinical practice. 
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the participants' representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her understanding. If the participant is capable of doing so, he/she must 
indicate agreement by personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH E6 GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB) and/or Core Data Sheet (CDS) for countries where 
brolucizumab is in the market. This information will be included in the participant informed 
consent and should be discussed with the participant during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification or 
an aggregate safety finding. 
The following informed consents are included in this study: 
• Main study consent, which also included:  
• A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during this 
study. 


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• As applicable, Pregnancy Outcomes Reporting Consent for female participants or the 
female partners of any male participants who took study treatment. 
Women of childbearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study, they must adhere to the contraception requirements. 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
Participants might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience.  
As new information becomes available, informed consent to be updated and then must be 
discussed with the participant.  
During the COVID-19 pandemic that may challenge the ability to obtain a standard written 
informed consent due to limits that prevent an on-site visit, the Investigator may conduct the 
informed consent discussion remotely (e.g. telephone, videoconference). Guidance issued by 
local regulatory bodies on this aspect prevail and must be implemented and documented (e.g. 
the presence of an impartial witness, sign/dating separate ICFs by trial participant and person 
obtaining informed consent, etc.). Remote informed consent should be appropriately 
documented and confirmed by way of standard informed consent procedures at the earliest 
opportunity when the participant will be back at the trial sites. 
8 
Visit schedule and assessments 
The Assessment Schedule Table 8-1 lists all of the assessments and indicates with an “X” or 
“S” the visits when they are performed. All data obtained from these assessments must be 
supported in the participant’s source documentation. 
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
Table 8-1 or as close to the designated day/time as possible. Missed or rescheduled visits should 
not lead to automatic discontinuation. Participants who prematurely discontinue the study for 
any reason should be scheduled for a visit as soon as possible, at which time all of the 
assessments listed for the final visit will be performed. At this final visit, the adverse event and 
concomitant medications should be recorded on the CRF. 
If the COVID-19 pandemic limits or prevents on-site study visits, study treatment could not be 
administered and other study assessments may not be performed. Alternative methods of safety 
monitoring may be implemented. Depending on local regulations, site capabilities and patient’s 
visit status in the study, phone calls or virtual contacts (e.g. teleconsult) can be performed for 
safety follow-up for the duration of the pandemic, until it is safe for the participant to visit the 
site again.  


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Table 8-1 
Assessment Schedule 
Period 
Treat-to-Control phase 
Follow-up 
Visit Name 
Baseline Visit 1 
n2 
W52/EOT3 
ETD10 
W56/EOS11 
m12 
Visit Numbers1 
1 
110 
120 
130 
130 
 
Weeks 
1 
2 to 50 
52 
 
56 
 
Informed consent 
X 
  
 
 
  
 
Inclusion / Exclusion criteria 
X 
  
  
 
  
 
Demography 
X4 
  
  
 
  
 
Medical history/current medical 
conditions 
X 
  
  
 
  
 
Prior/concomitant medication 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
S4 
S 
S 
S 
S 
 
Vital signs (sitting pulse and 
blood pressure) 
X4 
X 
X 
X 
X 
 
BCVA score (ETDRS) 
X4 
X 
X 
X 
X 
X 
Intraocular Pressure (IOP) 
X4 
X 
X 
X 
X 
 
Ophthalmic examination 5,6 
X 
X 
X 
X 
X 
 
CFP6 
X4 
X 
X 
X 
X 
 
Fluorescein Angiography6 
X4 
  
  
  
  
 
SD-OCT6 
X4 
X 
X 
X 
X 
 
OCT Angiography 6,7 
X4 
X 
X 
X 
X 
 
Disease activity assessment 
X4 
X 
X 
X 
X 
 
Contact IRT 
X 
X 
X 
X 
X 
 
Study drug administration8 
X 
X 
X 
  
  
 
Telephone follow-up post 
injection9 
X after 1st injection 
  
 
  
 
Adverse Events 
X 
X 
X 
X 
X 
X 


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Period 
Treat-to-Control phase 
Follow-up 
Visit Name 
Baseline Visit 1 
n2 
W52/EOT3 
ETD10 
W56/EOS11 
m12 
Visit Numbers1 
1 
110 
120 
130 
130 
 
Weeks 
1 
2 to 50 
52 
 
56 
 
 
1 Visit structure given for internal programming purpose only 
2 The number of weeks between visits will vary depending on the disease stability and length of intervals between injections as determined by disease activity 
assessment. Study treatment at the optional inspection visits (10 weeks after the last injection when the interval is extended from 8 weeks to 12 weeks, 14 weeks from 
the last injection when the interval is extended from 12 weeks to 16 weeks, and 16 weeks when the interval is extended from 16 to 20 weeks) is at the discretion of the 
investigator based on disease activity assessment. 
3 Week 52 is the last visit when study treatment may be administered. End-of-Treatment visit will take place on Week 54 in lieu of Week 52 for the participants who have 
a planned injection visit on Week 54, unless the Week 52 visit is an inspection visit with injection administered.  
4 Assessments at the Week 64 (EOS) visit of the core study will be used as the baseline.  
5 May include visual acuity check, optic nerve perfusion, and tonometry, for safety assessment before and after IVT, as well as slit lamp examination, fundus examination 
before IVT. In case of an ocular AE, the assessments shall be recorded in the eCRF.  
6 Additional ophthalmic examinations and images will be performed in case of any signs of intraocular inflammation, retinal vasculitis and/or retinal vascular occlusion. 
7 OCT Angiography will only be performed at a subset of sites. 
8 Study treatments are dependent on disease activity assessments and latest treatment interval.  
9 A telephone follow-up on safety should be performed two weeks after the first injection (a window for the phone call is +14 days). From the second injection onwards, 
similar phone calls should be made at investigator’s discretion per local practice. 
10 ETD: Early treatment discontinuation applies to subjects who discontinue early from study treatment and continue in the study. This can occur at any time point. The 
assessments should be performed 4 weeks after the last injection of study drug. For visits conducted after ETD and up to Week 56 (end of study), while subject is on 
standard of care, only BCVA, new/any concomitant medications, and/or adverse events/ serious adverse events have to be recorded. Additional safety assessments and 
imaging can also be performed if required, as per investigators discretion. In addition, after ETD, subjects are not required to attend the mandatory visit at Week 52. 
11 The EOS assessments only apply to subjects who completed the study per protocol. The assessments are not required for subjects who have undergone ETD 
assessments and continued in the study without study treatment. 
12 For subjects who continue in the study after ETD and up to Week 56 (end of study) while subject is on standard of care. This can occur at any time point. Additional 
safety assessments and imaging can also be performed if required, as per investigators discretion. In addition, after ETD, subjects are not required to attend the 
mandatory visits at Week 52. The last visit should be at week 56. 


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8.1 
Screening 
8.1.1 
Information to be collected on screening failures 
Participants who sign an informed consent form and subsequently found to be ineligible will be 
considered a screen failure. The reason for screen failure should be entered on the applicable 
Case Report Form. The demographic information, informed consent, and Inclusion/Exclusion 
pages must also be completed for screen failure participants. No other data will be entered into 
the clinical database for participants who are screen failures, unless the participant experienced 
a serious adverse event during the evaluation of eligibility (see SAE Section 10.1.3 for reporting 
details). 
Participants who sign an informed consent and are considered eligible but fail to be started on 
treatment for any reason will be considered an early terminator. The reason for early termination 
should be captured on the appropriate disposition Case Report Form. 
8.2 
Participant demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with eCRF. 
Assessments performed at the Week 64 (EOS) visit of the core study will serve as the baseline 
for this extension study.  
The following information will be documented at baseline visit for each enrolled participant: 
• Age 
• Sex 
• Race/Ethnicity 
• Vital signs 
• Study eye 
• Visual acuity 
• Intraocular pressure 
• Ophthalmic examinations 
• Retinal imaging 
• Prior/Concomitant medications 
• 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 visual 
function, retinal structure and vascular leakage: 
• Best-corrected visual acuity with ETDRS-like charts 


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• Anatomical retinal evaluation of SD-OCT images 
• Color Fundus Photography 
All efficacy assessments should be performed prior to any administration of study treatment. 
8.3.1 
Visual acuity 
Visual acuity will be assessed in the study eye at every study visit and in the fellow eye at the 
baseline and Week 56/EOS visits using best correction determined from protocol refraction 
(BCVA). BCVA measurements will be taken in a sitting position using ETDRS–like visual 
acuity testing charts at an initial testing distance of 4 meters. The details of the refraction 
technique and VA testing, as well as training material, are provided in the applicable manual. 
Certification of the assessment procedures and assessors will occur prior to any evaluation of 
study participants. 
Participants at sites in some Asian countries will undergo BCVA testing using numerical charts 
rather than letter charts. Therefore, all references in the protocol to changes in letters read will 
be changes in numbers in these countries. 
8.3.2 
Optical coherence tomography 
Spectral Domain Optical Coherence Tomography (SD-OCT) images will be obtained and 
assessed in the study eye at every study visit and in the fellow eye at baseline and Week 56/EOS 
visits. Only SD-OCT machines can be used (i.e. no time-domain nor swept-source OCT). 
These assessments will be performed by a trained technician or investigator at the sites and 
should be performed after BCVA assessment and prior to any study drug administration. 
Investigators will evaluate the SD-OCT images to assess the status of disease stability. The SD-
OCT machine used for an individual participant should not change for the duration of the study. 
Central sub-field thickness (CSFT) will be measured by SD-OCT. The CSFT evaluated in this 
study represents the average retinal thickness of the circular area within 1 mm diameter around 
the foveal center. 
In addition to the standard SD-OCT assessment, at sites that have the applicable equipment, 
OCT angiography should be performed at each visit in the study eye. If OCT angiography was 
not assessed at baseline of the study, then it should not be introduced at later visits. OCT 
angiography will be used to identify or confirm the presence of CNV and its evolution. 
The investigator will evaluate the images according to their standard of clinical practice and 
may use any of the SD-OCT and OCT angiography if available - imaging findings to inform 
his/her decision for treatment. However, their assessed findings of both quantitative and 
qualitative parameters will not be captured in the eCRF but must be included in the source 
documentation at the study site. 
A CRC will be used in this study. The CRC will provide sites with a Study Manual and training 
materials for the specified study ocular images. Before any study images are obtained, site 
personnel, test images, systems and software will be certified and validated by the CRC as 
specified in the Study Manual. All SD-OCT and OCT angiography images will be obtained by 
trained and study-certified site personnel at the study sites. All SD-OCT and OCT angiography 


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images will be forwarded to the CRC for independent standardized analysis, and be forwarded 
to Novartis or Contract Research Organization (CRO) for storage. 
The CRC will create a database with the agreed variables as indicated in the CRC grading 
charter (a separate document) and will transfer the data from this database to Novartis for 
analysis. The CRC data will be used for the evaluation of the objectives having SD-OCT and 
OCT angiography parameters to ensure a standardized evaluation. For further procedural 
details, the investigator should refer to the applicable manual provided by the CRC. 
8.3.3 
Color fundus photography and fluorescein angiography 
Color fundus photography (CFP) will be performed in the study eye at each scheduled 
injection visit, and in the fellow eye at baseline and Week 56/EOS visits.  
Fluorescein angiography (FA) will be performed in both eyes at baseline (captured at EOS of 
the core study) visit. FA may be performed at other visits at the investigator's discretion. 
Additional images will be taken in case of any signs of intraocular inflammation. OCT, CFP 
and FA (preferably wide-field or with peripheral sweeps) should be performed for safety 
evaluation, see Table 8-2.  
The investigator will evaluate the images according to their standard of clinical practice and 
may use any of the CFP imaging findings to inform his/her decision for treatment. However, 
their assessed findings of both quantitative and qualitative parameters will not be captured in 
the eCRF but must be included in the source documentation at the study site. 
All images, from scheduled and unscheduled visits, must be sent to the Central Reading Center 
(CRC). The CRC will provide sites with a Study Manual and training materials for the specified 
study ocular images. Before any study images are obtained, site personnel, test images, systems 
and software will be certified and validated by the CRC as specified in the Study Manual. All 
CFP and FA images will be obtained by trained and study-certified site personnel at the study 
sites and forwarded to the CRC for independent standardized analysis and to Novartis or a 
CRO for storage. 
The CRC will create a database with the agreed variables as indicated in the CRC grading 
charter (a separate document) and will transfer the data from this database to Novartis for 
analysis. The CRC data will be used for the evaluation of the objectives having CFP 
parameters and their change over time as endpoints to ensure a standardized evaluation. For 
further procedural details, the investigator should refer to the applicable manual provided by 
the CRC. 
8.3.4 
Appropriateness of efficacy assessments 
The use of BCVA as a measure of retinal function as well as SD-OCT images to analyze 
anatomical changes are standard assessments in this indication and are required for a 
comparative evaluation of this trial with the existing evidence from previous trials. 
Color fundus photography (CFP) is used to inspect retinal pathology. 


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8.4 
Safety 
Safety assessments will include vital signs, ophthalmic examinations, imaging and local 
laboratory evaluation (as per investigators' discretion) as well as monitoring and recording type, 
frequency, and severity for all AEs. 
If the COVID-19 pandemic limits or prevents on-site study visits, phone calls or virtual contacts 
should be conducted for safety monitoring and discussion of the participant´s health status, until 
the participant can again visit the site. 
For details on monitoring, assessment and management of adverse events of inflammation, 
retinal vasculitis and/or retinal vascular occlusion, refer to Section 10. For details on AE 
collection and reporting, refer to AE Section 10.1. 
Safety assessments are specified below: 
Table 8-2 
Safety assessments 
Assessment 
Specification 
Vital signs 
Vital signs include assessment of sitting blood 
pressure (systolic and diastolic pressure in 
mmHg) and pulse rate (beats per minute) and 
will be collected at all visits. 
On days when study drug is administered, vital 
signs will be measured before administration of 
study medication. The results will be recorded in 
the eCRF. 
Ophthalmic exam 
and 
additional safety measures 
The ophthalmic exam will consist of the 
following: 
Intraocular pressure (IOP) will be assessed in 
the study eye, pre-dose and post-dose at every 
scheduled visit. The same method of tonometry 
has to be used through the whole study. In the 
fellow eye, IOP will be assessed at baseline and 
Week 56/EOS visit. The values recorded in 
mmHg for either eye will be entered into the 
eCRF. Treatment and close monitoring of IOP 
should be performed by the investigator for any 
non-transient elevation in intraocular pressure 
(≥ 25 mmHg). Intravitreal injection is not 
recommended unless normalization of the IOP 
has been achieved. Post-dose IOP should be 
assessed within 60 minutes after injection and if 
≥ 25 mmHg, assessment should be repeated 
until back to normal. Monitoring of optic nerve 
head perfusion after injection may be 
appropriate, at the discretion of the investigator 
and/or according to local requirements/practices. 
Results of these procedures will be recorded as 
appropriate in the source documents, and if the 
findings constitute an AE, it should be recorded 
in the eCRF. 


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Assessment 
Specification 
Anterior biomicroscopy (slit lamp 
examination) will be completed pre-dose at 
every scheduled and unscheduled visit to 
examine the anterior segment structures of the 
study eye (e.g., eyelids/lashes, conjunctiva, 
cornea, anterior chamber, iris, lens and anterior 
part of the vitreous). The fellow eye will be 
examined at baseline for eligibility, and at other 
visits at the discretion of the investigator. The 
results of the examination of either eye will be 
recorded in the source documents. 
Slit lamp examination must be carefully 
performed before each study treatment. If there 
are any signs of IOI, severity of anterior 
chamber cells and flare should be assessed 
according to the standardization of uveitis 
nomenclature (SUN) working group grading 
system (Jabs et al 2005). The test results will be 
recorded in the source documents (e.g., 
ophthalmic examination tool) and captured in the 
appropriate eCRF as applicable. 
Posterior segment (indirect fundus) 
examination will be conducted by the 
investigator at the baseline visit for both eyes. 
An examination of the peripheral retina must 
also be conducted to ensure that the intravitreal 
injection can safely be performed. 
Posterior segment examination must be 
performed carefully before each study treatment. 
The results of the examination including any 
abnormalities (e.g. vitreous cells/haze, retinal 
tear/detachment, hemorrhage and vascular 
occlusion, vasculitis, etc.) should be recorded in 
the source documents. 
If there are any signs of IOI, vitreous cells and 
haze should be assessed using National 
Institutes of Health (NIH) grading system 
(Nussenblatt et al 1985). The outcome of the 
examination will be documented in the source 
document (e.g., ophthalmic examination tool) 
and appropriate eCRF page as applicable. 
Clinically significant abnormal findings from slit 
lamp or ophthalmoscopy observations should be 
recorded as an AE in the eCRF. 


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Assessment 
Specification 
A phone call two weeks after the first injection (a 
window for the phone call is +14 days) must be 
made to check whether there are any changes 
in vision or any symptoms of intraocular 
inflammation. It should be documented in the 
source document and eCRF. From the second 
injection onwards, similar phone calls should be 
made at investigator’s discretion per local 
practice. 
In addition, instruct the patient to contact the 
site for any changes in vision or any 
symptoms of inflammation between 
scheduled visits. Every effort should be 
made to bring the participant for immediate 
examination.  
Imaging: When IOI, retinal vasculitis, and/or 
retinal vascular occlusion is present or 
suspected during a visit, investigators must 
perform thorough ophthalmic examination, and 
conduct OCT, fluorescein angiography and color 
fundus photography (preferably wide-field or 
with peripheral sweeps). These additional 
assessments will be documented in the source 
and appropriate eCRF pages as applicable. The 
images are requested to be uploaded onto the 
CRC portal. 
Site visits for safety assessments (unscheduled 
visits) also can be made at any time during 
follow-up as needed. 
No central laboratory will support the study. However, investigators may at their discretion request 
laboratory tests, which should be performed by a local laboratory. 
8.4.1 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have urine pregnancy testing. 
Urine pregnancy testing will be performed at the site before anti-VEGF injections at every visit. 
If a urine test is positive after inclusion in the study, a serum pregnancy test must be performed 
for confirmation; if the serum test is positive, the participant should discontinue study 
medication. Additional pregnancy testing might be performed if requested by local 
requirements. 
Assessments of fertility 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child-
bearing potential must also be available as source documentation in the following cases: 
1. Surgical bilateral oophorectomy without a hysterectomy 
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile. 


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In the absence of the above medical documentation, FSH testing is required of any female 
participant regardless of reported reproductive/menopausal status at screening/baseline. 
8.4.2 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/participant population. 
If there are any signs of IOI, additional assessment will be performed as described in Table 8-2 
and Section 10. 
8.5 
Additional assessments 
No additional tests will be performed on participants entered into this study. 
9 
Study discontinuation and completion 
9.1 
Discontinuation and completion 
The investigator should discontinue study treatment for a given participant and/or withdraw the 
participant from the study if, on balance, he/she believes that continuation would be detrimental 
to the participant’s well-being. 
A participant will be considered to have completed the study when the participant has completed 
the last visit planned in the protocol. 
The investigator and/or referring physician will recommend the appropriate follow-up medical 
care, if needed, for all participants who are prematurely withdrawn from the study. 
9.1.1 
Study treatment discontinuation and study discontinuation 
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration and can be initiated by either the participant or the 
investigator. 
The investigator must discontinue study treatment for a given participant if he/she believes that 
continuation would negatively impact the participant's well-being. 
Study treatment must be discontinued under the following circumstances: 
• Subject requires treatment on a q4w interval  
• Subject develops retinal vasculitis and/or retinal vascular occlusion 
• Participant/guardian decision 
• Pregnancy 
• Use of prohibited treatment as per recommendations in the prohibited treatment section 
• Any situation in which study participation might result in a safety risk to the participant 
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information. 


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Participants who discontinue study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see 'Withdrawal of Informed Consent' Section 9.1.2). If they fail to return for 
these assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be 
made to contact the participant/pre-designated contact as specified in the Lost to follow-up 
Section 9.1.3. This contact should preferably be done according to the study visit schedule. 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the 
participant. This telephone contact should preferably be done according to the study visit 
schedule. 
After premature study treatment discontinuation, at a minimum, in abbreviated visits, the 
following data should be collected at clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 
• BCVA 
Additional safety assessments and imaging can be performed if required, as per investigator’s 
discretion. 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
Subjects must return 4 weeks after last study treatment to perform the Early Treatment 
Discontinuation (ETD). ETD assessments should be performed before start of standard of care 
treatment. 
• 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 subjects 
with active intraocular or periocular infections and in subjects with active intraocular 
inflammation; therefore, the investigators must verify that these conditions are not present 
in the study eye prior to every injection.  
• Dosing of SOC and follow-up visits as per investigators discretion. Subjects are not 
required to attend the mandatory visit at Week 52. The last visit should be at Week 56. 
9.1.2 
Withdrawal of informed consent 
Withdrawal of consent/opposition to use data/biological samples occurs when a participant: 
• Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples) 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts) 
This request should be in writing (depending on local regulations) and recorded in the source 
documentation. 


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In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their 
consent/opposition to use data/biological samples and record this information. 
Where consent to the use of Personal and Coded Data is not required in a certain country's legal 
framework, the participant therefore cannot withdraw consent. However, they still retain the 
right to object to the further collection or use of their Personal Data. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/opposition to use data/biological samples should be made as detailed in the assessment 
table (refer to Section 8). 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation, including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition. 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g. dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed or until the end of the study. 
9.1.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination: 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of study drug development 
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a prematurely withdrawn participant. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the participant’s interests. The investigator or sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.  


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9.2 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes their EOS visit and any repeat 
assessments associated with this visit have been documented and followed-up appropriately by 
the Investigator or, in the event of an early study termination decision, the date of that decision. 
After study completion the participant may receive standard of care or other treatments, at the 
discretion of the investigator and/or referring physician, if needed. 
10 
Safety monitoring and reporting 
Subjects should be closely monitored for adverse events.  
For adverse events of special interest, intraocular inflammation, including retinal vasculitis 
and/or retinal vascular occlusion please ensure compliance with the following: 
• A phone call two weeks after the first injection (window: +14 days) must be made to 
check whether there are any changes in vision or any symptoms of intraocular 
inflammation. From the second injection onwards, similar phone calls should be made at 
investigator’s discretion per local practice (Table 8-2). 
• Instruct the patient to contact the site for any changes in vision or any symptoms of 
inflammation between scheduled visits (refer to the optional patient brochure). Every 
effort should be made to bring the subject for immediate examination.  
• Close patient monitoring and thorough examination of the eye should be done to detect 
potential signs of inflammation (Table 8-2). 
• When IOI, retinal vasculitis, and/or retinal vascular occlusion is present or suspected 
during a visit, investigators must perform thorough ophthalmic examination, and will 
conduct OCT, fluorescein angiography and color fundus photography (preferably wide-
field or with peripheral sweeps). The images are requested to be uploaded onto the CRC 
portal. 
• If any sign of intraocular inflammation is present, an IVT injection must not be performed. 
Therefore investigators must verify that these conditions are not present in the study eye 
prior to every injection.  
• Subjects who experience intraocular inflammation only (without RV and/or RO) may be 
at risk of developing retinal vasculitis and/or retinal vascular occlusion and should be 
closely monitored. The investigator should carefully evaluate the appropriateness of 
continuing further with study treatment. 
• If retinal vasculitis and/or retinal vascular occlusion is confirmed, subjects must be 
discontinued from study treatment.  
• Participants should be treated for these events promptly according to clinical practice. 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 


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investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The severity grade:  
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant 
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported 
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken regarding with study treatment. 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/withdrawn 
6. Its outcome  
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 


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Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease.  
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 


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• is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines)). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days after the last study visit must be reported to 
Novartis safety immediately, without undue delay, under no circumstances later than within 24 
hours of obtaining knowledge of the events (Note: If more stringent, local regulations regarding 
reporting timelines prevail). Detailed instructions regarding the submission process and 
requirements are to be found in the investigator folder provided to each site. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
Any SAEs experienced after the 30 day period after the last study visit should only be reported 
to Novartis Safety if the investigator suspects a causal relationship to study treatment. 


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10.1.4 
Pregnancy reporting 
Pregnancies 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign pregnancy consent form to allow the Study 
Doctor ask about her pregnancy. To ensure participant safety, each pregnancy occurring after 
signing the informed consent must be reported to Novartis within 24 hours of learning of its 
occurrence. The pregnancy should be followed up until birth and one year after childbirth 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 Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment 
with any pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition). 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
No 
No 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional Safety Monitoring 
Not applicable. 
11 
Data Collection and Database management 
11.1 
Data collection 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 


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Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff. 
The investigator/designee is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. The 
Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 
11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Dates of visits and data about study treatments dispensed to the participant, will be tracked 
using an Interactive Response Technology (IRT). The system will be supplied by a vendor, who 
will also manage the database. The data will be sent electronically to Novartis (or a designated 
CRO) at specific timelines. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for data analysis. Any changes to 
the database after that time can only be made after written agreement by Novartis development 
management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a 
Novartis/delegated CRO representative will review the protocol and data capture requirements 
(i.e. eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of participant records, the 
accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical 
Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the field monitor during these visits. Continuous remote monitoring of each site’s data 


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may be performed by a centralized Novartis/delegated CRO/CRA organization. Additionally, 
a central analytics organization may analyze data & identify risks & trends for site operational 
parameters, and provide reports to Novartis clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
participant's file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
12 
Data analysis and statistical methods 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
Continuous variables will be summarized for the measured values at each visit and change from 
the baseline values using the number of observations, mean, standard deviation, quartiles, 
minimum and maximum. Categorical variables will be summarized with counts and percent in 
each category. Endpoints characterizing TtC regimen will be presented together with two-sided 
95% Confidence Intervals (CI). When appropriate, two-sided p-values will be presented as a 
descriptive statistics.  
All the endpoints, including the primary endpoint, are defined with respect to the study eye. 
Additional analysis may be also conducted to evaluate the impact of the COVID-19 pandemic 
and the urgent safety measure. 
In addition to the statistical methods outlined below, further details will be described in the 
statistical analyses plan (SAP). 
12.1 
Analysis sets 
The following analyses sets are defined: 
The Enrolled Analysis Set (EAS) includes all participants who signed ICF and are assigned 
participant numbers. This analyses set will be used to summarize disposition of participants and 
pre-treatment adverse events. 
The Full Analysis Set (FAS) comprises all participants who received at least one dose of study 
treatment in the extension study. This set will serve as the primary analyses set for all efficacy 
and safety analyses. 


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The Per-Protocol Set (PPS) is a subset of participants of the FAS with no protocol deviation 
with impact in the core study or the extension. The list of protocol deviations criteria will be 
provided in a separate document. 
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively in all participants for all analyses sets. 
Medical history (ocular and non-ocular) will be tabulated by system organ class. 
Relevant medications and procedures will be summarized using number and percentage by 
ATC class and preferred term according to the WHO Drug Reference list dictionary in all sets, 
and also listed by ocular and non-ocular events. Other relevant baseline information will be 
listed and summarized with descriptive statistics as appropriate. 
12.3 
Treatments 
The FAS will be used for the analyses described below. 
 
 
The duration to the treatment exposure will be summarized descriptively by counts and 
percentage of participants in 4-week, 8-week, 12-week, 16-week and 20-week intervals at each 
visit. Frequency of selected treatment patterns will be shown. 
Percentages of participants who completed the study as per protocol without treatment 
discontinuation and interruptions will be summarized in all participants up to Week 56, and 
within the treatment intervals. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the ATC classification system in all 
participants up to Week 56. 
12.4 
Analysis of the primary endpoint(s)/estimand(s) 
The primary objectives of the study are: 
• To evaluate the extended durability of brolucizumab in a TtC regimen with respect to the 
duration of treatment intervals up to Week 56 
• To evaluate the functional outcomes of brolucizumab in a TtC regimen with respect to 
average change in BCVA at Week 52 and Week 56, i.e. change from the extension 
baseline to the average of Week 52 and Week 56 
12.4.1 
Definition of primary endpoint(s)/estimand(s) 
The primary endpoints of the study are: 
• Duration of the last interval with no DA up to Week 56  
• Change in BCVA from extension baseline at Week 52 and Week 56 
Primary estimands along with the sensitivity estimands are in Table 12-1. 


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Table 12-1 
Primary and sensitivity estimands 
Endpoint 
Estimand 
Estimand 
definition 
Analysis set 
Data 
included in 
analysis 
Statistical 
methods 
(including 
missing data 
strategy) 
Duration 
of last 
interval 
with no DA 
Primary 
estimand 1 
Duration of 
the last 
interval with 
no DA, i.e. 
distribution of 
the last 
interval with 
no DA up to 
Week 56, i.e. 
proportion of 
participants in 
last interval 
with no DA 
that is 
4/8/12/16/20-
week intervals 
FAS 
*Last interval 
with no DA up 
to Week 56 
Two-sided 
95% Confiden
ce Interval of 
proportions. If 
there was DA, 
the last 
interval will be 
shortened by 
4 weeks, 
down to a 
minimum of 4 
weeks 


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Endpoint 
Estimand 
Estimand 
definition 
Analysis set 
Data 
included in 
analysis 
Statistical 
methods 
(including 
missing data 
strategy) 
Change 
in 
BCVA 
Primary 
estimand 2 
Change in 
BCVA from 
extension 
Baseline at 
Week 52 and 
Week 56, i.e. 
the average 
difference in 
BCVA from 
extension 
Baseline over 
the period 
Week 52 
through Week 
56  
FAS 
All data 
collected until 
the participant 
discontinued 
study 
treatment and 
started SOC 
treatment(s)  
will be 
included.  
Two-sided 
95% 
Confidence 
Interval 
obtained from 
ANCOVA with 
age at the 
baseline 
categories 
and BCVA at 
the baseline 
categories 
with (LOCF) 
imputation / 
replacement 
for missing 
data (e.g data 
unavailable 
due to lost to 
follow-up) / 
censored data 
(e.g. data 
unavailable 
due to use of 
alternative 
anti-VEGF) 


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Endpoint 
Estimand 
Estimand 
definition 
Analysis set 
Data 
included in 
analysis 
Statistical 
methods 
(including 
missing data 
strategy) 
Duration of 
last interval 
with no DA 
excluding 
participants 
with protocol 
deviations 
with impact 
Sensitivity 
estimand 1.1 
Duration of 
the last 
interval with 
no DA up to 
Week 56, i.e. 
distribution of 
the last 
interval with 
no DA up to 
Week 56, i.e. 
proportion of 
participants in 
last interval 
with no DA 
that is 
4/8/12/16/20-
week 
intervals, 
excluding 
participants 
with protocol 
deviations 
with impact as 
per PPS 
**PPS 
*Last interval 
with no DA up 
to Week 56 
Two-sided 
95% Confiden
ce Interval of 
proportions. If 
there was DA, 
the last 
interval will be 
shortened by 
4 weeks, 
down to a 
minimum of 4 
weeks 


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Endpoint 
Estimand 
Estimand 
definition 
Analysis set 
Data 
included in 
analysis 
Statistical 
methods 
(including 
missing data 
strategy) 
Change 
in BCVA 
excluding 
participants 
with protocol 
deviations 
with impact 
Sensitivity 
estimand 2.1 
Change in 
BCVA from 
extension 
Baseline at 
Week 52 and 
Week 56, i.e. 
the average 
difference in 
BCVA from 
extension 
Baseline over 
the period 
Week 52 
through Week 
56; excluding 
participants 
with protocol 
deviations 
with impact as 
per definition 
of PPS 
**PPS 
All data 
collected until 
the participant 
discontinued 
study 
treatment and 
started 
alternative 
treatment(s), 
will be 
included.  
Two-sided 
95% 
Confidence 
Interval 
obtained from 
ANCOVA with 
age at the 
baseline 
categories 
and BCVA at 
the baseline 
categories 
and with 
(LOCF) 
imputation / 
replacement 
for missing 
data (e.g data 
unavailable 
due to lost to 
follow-up) / 
censored data 
(e.g. data 
unavailable 
due to use of 
alternative 
anti-VEGF). 


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Endpoint 
Estimand 
Estimand 
definition 
Analysis set 
Data 
included in 
analysis 
Statistical 
methods 
(including 
missing data 
strategy) 
Duration of 
last interval 
with no DA 
excluding 
participants 
with protocol 
deviations 
with impact 
either in the 
core study or 
in the 
extension 
study 
Sensitivity 
estimand 1.2 
Duration of 
the last 
interval with 
no DA up to 
Week 56, i.e. 
distribution of 
the last 
interval with 
no DA up to 
Week 56, i.e. 
proportion of 
participants in 
last interval 
with no DA 
that is 
4/8/12/16/20-
week 
intervals, 
excluding 
participants 
with protocol 
deviations 
with impact 
either in the 
core or in the 
extension as 
per PPS 
**PPS 
*Last interval 
with no DA up 
to Week 56 
Two-sided 
95% Confiden
ce Interval of 
proportions. If 
there was DA, 
the last 
interval will be 
shortened by 
4 weeks, 
down to a 
minimum of 4 
weeks 


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Endpoint 
Estimand 
Estimand 
definition 
Analysis set 
Data 
included in 
analysis 
Statistical 
methods 
(including 
missing data 
strategy) 
Change 
in BCVA 
excluding 
participants 
with protocol 
deviations 
with impact 
either in the 
core study, or 
in the 
extension 
study 
Sensitivity 
estimand 2.2 
Change in 
BCVA from 
extension 
Baseline at 
Week 52 and 
Week 56, i.e. 
the average 
difference in 
BCVA from 
extension 
Baseline over 
the period 
Week 52 
through Week 
56; excluding 
participants 
with protocol 
deviations 
with impact 
either in the 
core study or 
in the 
extension 
study as per 
definition of 
PPS 
**PPS 
All data 
collected until 
the participant 
discontinued 
study 
treatment and 
started 
standard of 
care (SOC) 
treatment(s), 
will be 
included.  
Two-sided 
95% 
Confidence 
Interval 
obtained from 
ANCOVA with 
age at the 
baseline 
categories 
and BCVA at 
the baseline 
categories 
variables with 
(LOCF) 
imputation / 
replacement 
for missing 
data (e.g data 
unavailable 
due to lost to 
follow-up) / 
censored data 
(e.g. data 
unavailable 
due to use of 
alternative 
anti-VEGF). 
Proportion of 
participants 
with at least 
16-weeks 
duration 
of last 
interval 
with no 
disease 
activity 
Sensitivity 
estimand 1.3 
Proportion of 
participants in 
last interval 
with no 
disease 
activity that is 
at least16-
weeks 
intervals up to 
Week 56 
FAS 
*Last interval 
with no 
disease 
activity up to 
Week 56 
Two-sided 
95% Confiden
ce Interval of 
proportions. If 
there was 
disease 
activity, the 
last interval 
will be 
shortened by 
4 weeks, 
down to a 
minimum of 4 
weeks 


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Endpoint 
Estimand 
Estimand 
definition 
Analysis set 
Data 
included in 
analysis 
Statistical 
methods 
(including 
missing data 
strategy) 
Change 
in BCVA 
Sensitivity 
estimand 2.3 
Change in 
BCVA from 
extension 
Baseline at 
Week 52 and 
Week 56, i.e. 
the average 
difference in 
BCVA from 
extension 
Baseline over 
the period 
Week 52 
through Week 
56 
FAS 
All data 
collected until 
the participant 
discontinued 
study 
treatment and 
started SOC 
treatment(s)  
will be 
included. 
Two-sided 
95% Confiden
ce Interval 
obtained 
based on 
mixed effects 
models with 
age at the 
baseline 
categories 
and BCVA at 
the baseline 
categories 
Proportion of 
participants 
with at least 
16-weeks 
duration of 
last interval 
with no 
disease 
activity 
excluding 
participants 
with important 
protocol 
deviations 
Sensitivity 
estimand 1.4 
Proportion of 
participants in 
last interval 
with no 
disease 
activity that is 
at least 16-
weeks 
intervals at 
Week 56, 
excluding 
participants 
with important 
protocol 
deviations as 
per PPS 
PPS** 
*Last interval 
with no 
disease 
activity up to 
Week 56 
Two-sided 
95% Confiden
ce Interval of 
proportions. If 
there was 
disease 
activity, the 
last interval 
will be 
shortened by 
4 weeks, 
down to a 
minimum of 4 
weeks 


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Endpoint 
Estimand 
Estimand 
definition 
Analysis set 
Data 
included in 
analysis 
Statistical 
methods 
(including 
missing data 
strategy) 
Proportion of 
participants 
with at least 
16-weeks 
duration of the 
last interval 
with no 
disease 
activity 
excluding 
participants 
with important 
protocol 
deviations 
either in the 
core study or 
in the 
extension 
study 
Sensitivity 
estimand 1.5 
Proportion of 
participants in 
last interval 
with no 
disease 
activity that is 
at least 16-
weeks 
intervals, 
excluding 
participants 
with important 
protocol 
deviations 
either in the 
core or in the 
extension as 
per PPS 
PPS** 
*Last interval 
with no 
disease 
activity up to 
Week 56 
Two-sided 
95% Confiden
ce Interval of 
proportions. If 
there was 
disease 
activity, the 
last interval 
will be 
shortened by 
4 weeks, 
down to a 
minimum of 4 
weeks 
*: If the duration of the last interval falls within the following ranges of [q4w, q8w) or [q8w, q12w), 
[q12w, q16w), [q16w, q20w) or ≥ q20w then the floor value of these ranges i.e. q4w, q8w, q12w, q16w, 
q20w, respectively, will be used for imputation. 
  
**: Patients who take prohibited concomitant medication are already excluded from PPS as taking 
prohibited medication is considered a deviation with impact. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The average change in BCVA from extension baseline at Week 52 and Week 56 will be 
estimated in Analyses of Covariance (ANCOVA) with baseline age categories and baseline 
BCVA categories. The estimate of BCVA change will be accompanied by 95% CI. 
The distribution of the last interval with no DA up to Week 56 will be described based on counts 
and proportions of participants at 4-week, 8-week, 12-week, 16-week, and 20-week intervals. 
The proportions will be accompanied by 95% Confidence Intervals (CI). 
12.4.3 
Handling of remaining intercurrent events of primary estimand 
In case of an intercurrent event, i.e. treatment interruption or discontinuation, the treatment 
interval will be defined as the last interval with no DA. If there was DA at the last interval, the 
last interval will be shortened by 4 weeks down to a minimum of 4 weeks. 
Missing BCVA data due to intercurrent events, i.e. treatment interruption or discontinuation, 
will be imputed using last observation carried forward (LOCF) method. Observed values from 
both scheduled and unscheduled visits will be used for the LOCF imputation. 


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For participants who discontinue treatment but continue in the study, the BCVA data will be 
censored at the time the participant started Standard of Care treatment in the study eye. 
12.4.4 
Handling of missing values not related to intercurrent event 
In case of a missing visit for reasons other than specified in Section 12.4.3, the treatment 
interval will be defined as the last interval with no DA. If there was DA at the last interval, the 
last interval will be shortened by 4 weeks down to a minimum of 4 weeks. 
Missing BCVA values for reasons other than specified in Section 12.4.3 will also be imputed 
using LOCF method. 
12.4.5 
Sensitivity analyses for primary endpoint/estimand 
Sensitivity analyses to examine robustness with respect to protocol deviations will be performed 
based on the PPS. 
Sensitivity analyses will be performed in a subset excluding participants with protocol 
deviations with impact either in the core study, or in the extension study. 
To evaluate robustness of the analyses based on the LOCF method, sensitivity analyses will be 
performed on the observed data in the FAS and mixed models for repeated measures (MMRM). 
Sensitivity estimands in exposed and non-exposed to the urgent safety measures: As a 
sensitivity analyses, the proportion of participants with at least 16-weeks as the last interval 
with no disease activity at Week 56 will be estimated in pre- and post- the urgent safety 
measures were introduced. The estimates of proportions will be accompanied by 95% CI 
obtained using Goodman (1965). The analyses will be performed FAS and PPS (excluding 
participants with important protocol deviations in the extension study and either in the core 
study or in the extension study). 
12.5 
Analysis of secondary endpoints/estimands 
12.5.1 
Efficacy and/or pharmacodynamic endpoint(s) 
FAS will be used to analyze durability, functional and anatomical outcomes. 
To evaluate the anatomical outcomes of brolucizumab in all patients and per randomized arm 
in the core study 
• Change in CSFT from extension baseline to Week 52 and Week 56 
• Number of visits with presence of IRF and/or SRF, and sub-RPE fluid in the central 
subfield as assessed by SD-OCT at Week 52 and Week 56 
To assess the durability of brolucizumab in all patients and/or per randomized arm in the core 
study 
• Duration of the last interval with no DA up to Week 56 
• Duration of the maximal intervals with no DA up to Week 56 
• Change of the duration of last interval with no DA between extension baseline and Week 
56  


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To assess the functional outcomes of brolucizumab per randomized arm in the core study  
• Change in BCVA from extension baseline to Week 52 and Week 56  
Counts and proportions for the endpoints describing durability, tolerability and anatomical 
outcomes (i.e. number of visits with presence of IRF and/or SRF) will be accompanied by two-
sided 95% CI inferred based on binomial distribution for each endpoint and two-sided 95% 
simultaneous CIs inferred using the Goodman method (Goodman 1965).The Goodman method 
is used for obtaining simultaneous confidence intervals (might be better than single binomial 
confidence intervals) for the parameters of a multinominal distribution, for example for a 
multinomial endpoint (4-week interval, 8-week interval, 12-week interval, 16-week interval, 
and 20-week interval). These analyses will be performed for all participants. 
For the analyses of functional and anatomical outcome (i.e. change in CSFT) the 95% CI will 
be inferred based on ANOVA analyses. 
12.5.2 
Safety endpoints 
The following endpoints assess the safety of brolucizumab 
• Occurrence of Ocular and Non-ocular AEs up to Week 56 
For all safety analyses, the FAS will be used. All listings and tables will be presented in all 
participants. 
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 will be provided. In particular, 
summary tables for adverse events (AEs) will summarize only on-treatment events, with a start 
date during the on-treatment period. A separate summary table will be provided for AEs of 
study eye, fellow eye and non-ocular AEs. 
The on-treatment period lasts from the date of first administration of study treatment to 30 days 
after the last administration of study treatment (EOT) or EOS whichever is the latest. 
Adverse events 
Treatment emergent AEs are defined as AEs which start on or after the time of the first injection 
of study treatment in this extension study and until the patient exits the study. AEs which start 
prior to the date/time of the first injection of study treatment in this extension study will be 
listed only. Treatment emergent AEs occurring during the last 6 months of the core study, for 
the same set of participants included in the extension study safety set will be presented. All 
treatment emergent SAEs/AEs as documented in the core study will be listed as medical history. 
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of the extension 
study but increased in severity based on preferred term) will be summarized in the following 
ways: 
• by primary system organ class and preferred term. 
• by primary system organ class, preferred term and maximum severity. 
• by Standardized MedDRA Query (SMQ) and preferred term. 


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Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation.  
The number (and proportion) of participants with adverse events of special interest will be 
summarized. 
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. 
Adverse events which will be counted for a specific treatment period (i.e. baseline to Week 52) 
are those which are treatment-emergent. These events are those with an onset after the start of 
the treatment period, or which were present prior to the start of the treatment period but 
increased in severity, changed from being not suspected to being suspected of study drug 
relationship, or developed into SAEs after the start of the treatment period. 
Vital signs 
Clinically relevant abnormalities in vital signs data will be listed by participant and visit/time 
and if ranges are available, abnormalities will be flagged. Summary statistics will be provided 
by visit/time. 
12.7 
Interim analyses 
There is no interim analysis planned for the study. 
12.8 
Sample size calculation 
It is planned to enroll approximately 250 participants in the extension study. 
The below described simulation studies were conducted before the USM were introduced. 
With a standard deviation of the change in BCVA of 13, the 95% Confidence Interval (CI) of 
the change is estimated to be (-2.1, 0.13) assuming the observed change is -1. 


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Table 12-2 shows the distribution of duration as estimated based on simulation studies along 
with precision as estimated based on the simulations. Table 12-3 shows width of 95% CI as 
estimated based on a sample size (number of participants completing the extension study) 
varying from 503 to 100. The numbers are chosen based on assuming that 90% / 80% / 70% / 
etc. of participants from the core study enter the extension and also assuming that 10% / 20 % 
/ 30 % / etc of participants drop out reaching EOS of the extension. Similarly, Table 12-4 shows 
95% CI for the estimate in the change in BCVA, assuming that the observed change is -1 and 
the standard deviation of the change is 13. 
For example, when the number of participants completing the extension study decreases from 
503 to 250, width of the 95% CI increases from 5.8% to 8.3% for the estimated proportion of 
12.7% participants being on the 16-weeks interval; and from 6.9% to 9.8% for the estimated 
proportion of 19.4% of participants being on 20-weeks intervals. With the same reduction in 
the sample size, the 95% CI for the estimated change in BCVA goes from (-2.1, 0.14) to (-2.6, 
0.62). 
Table 12-2 
Duration of intervals as estimated based on simulation studies  
Interval 
duration 
4-weeks 
8-weeks 
12-weeks 
16-weeks 
20-weeks 
Frequency (SD 
as assessed by 
simulations) 
8.6% (1.7%) 
30.2% (1.9%)  
29.2% (2.3%) 
12.7% (1.7%) 
19.4% (2.4%) 
Table 12-3 
Duration of intervals as estimated based on simulation studies and width 
of 95% Confidence Interval 
Duration of the treatment 
interval 
4-weeks 
8-weeks 
12-weeks 
16-weeks 
20-weeks 
Frequency  
(SD from simulations) 
8.6% 
(1.7%) 
30.2% 
(1.9%) 
29.2% 
(2.3%) 
12.7% 
(1.7%) 
19.4% 
(2.4%) 
N of participants 
completing the 
extension study 
Width of 95% Confidence Interval 
503 
4.9% 
8.0% 
7.9% 
5.8% 
6.9% 
447 
5.2% 
8.5% 
8.4% 
6.2% 
7.3% 
391 
5.6% 
9.1% 
9.0% 
6.6% 
7.8% 
447 
5.2% 
8.5% 
8.4% 
6.2% 
7.3% 
398 
5.5% 
9.0% 
8.9% 
6.5% 
7.8% 
348 
5.9% 
9.6% 
9.6% 
7.0% 
8.3% 
391 
5.6% 
6.6% 
9.0% 
6.6% 
7.8% 
348 
5.9% 
9.6% 
9.6% 
7.0% 
8.3% 
304 
6.3% 
10.3% 
10.2% 
7.5% 
8.9% 
250 
7% 
11.4% 
11.3% 
8.3% 
9.8% 


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200 
8.3% 
13.1% 
13.0% 
9.7% 
11.4% 
170 
9.0% 
14.3% 
14.2% 
10.6% 
12.4% 
150 
9.6% 
15.2% 
15.1% 
11.3% 
13.2% 
120 
10.9% 
17.1% 
16.9% 
12.7% 
14.9% 
100 
12.0% 
18.8% 
18.6% 
14.0% 
16.3% 
Table 12-4 
95% Confidence Interval for BCVA change assuming SD of the change 
is 13. 
N of participants completing the extension 
study 
95% Confidence Interval of BCVA change 
assuming the observed change is -1. 
503 
(-2.1, 0.14) 
447 
(-2.2, 0.21) 
391 
(-2.3, 0.29) 
447 
(-2.2, 0.21) 
398 
(-2.3, 0.28) 
348 
(-2.4, 0.37) 
391 
(-2.3, 0.29) 
348 
(-2.4, 0.37) 
304 
(-2.5, 0.47) 
250 
(-2.6, 0.62) 
200 
(-2.8, 0.81) 
170 
(-3.0, 0.97) 
150 
(-3.1, 1.1) 
120 
(-3.4, 1.4) 
100 
(-3.6, 1.6) 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 


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procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
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 (SOPs) as well as applicable global/local GCP regulations and ICH 
Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk-based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 


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Novartis and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
References 
References are available upon request. 
Blinder KJ, Bradley S, Bressler NM, et al (2003) Effect of lesion size, visual acuity, and 
lesion composition on visual acuity change with and without verteporfin therapy for choroidal 
neovascularization secondary to age-related macular degeneration: TAP and VIP report no. 1. 
Am. J Ophthalmol; 136(3):407-18 
Bloch SB, Larsen M, Munch IC (2012) Incidence of legal blindness from age-related macular 
degeneration in Denmark: year 2000 to 2010. Am. J Ophthalmol; 153:209–13. 
Campbell JP, Bressler SB, Bressler NM (2012) Impact of availability of anti-vascular 
endothelial growth factor therapy on visual impairment and blindness due to neovascular age-
related macular degeneration. Arch Ophthalmol; 130(6):794-5. 
DeCroos FC, Reed D, Adam MK, et al (2017) Treat-and-Extend Therapy Using Aflibercept 
for Neovascular Age-related Macular Degeneration: A Prospective Clinical Trial. Am J 
Ophthalmol; 180:142–50. 
Ferris FL (1983) Senile macular degeneration: review of epidemiologic features. Am. J 
Epidemiol; 118(2):132-51.  
Ferris FL, Fine SL, Hyman L (1984) Age-related macular degeneration and blindness due to 
neovascular maculopathy. Arch Ophthalmol; 102:1640 2. 
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):372-79.  
Goodman, LA (1965) On Simultaneous Confidence Intervals for Multinomial Proportions. 
Technometrics; 7(2):247-54.  
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; 126:723-34.  
Jabs DA, Nussenblatt RD, Rosenbaum DT (2005) 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; 140:509 16.  
Kertes PJ, Galic IJ, Greve M, et al (2019) Canadian Treat-and-Extend Analysis Trial with 
Ranibizumab in Patients with Neovascular Age-Related Macular Disease: One-Year Results 
of the Randomized Canadian Treat-and-Extend Analysis Trial with Ranibizumab Study. 
Ophthalmology; 126:841-48.  
Lim LS, Mitchell P, Seddon JM, et al (2012) Age-related macular degeneration. Lancet; 
379:1728–38.  
Miller JW (2013) Age-related macular degeneration revisited--piecing the puzzle: the LXIX 
Edward Jackson memorial lecture. Am J Ophthalmol; 155:1–35. 


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Nussenblatt RB, Palestine AG, Chan CC, et al (1985) Standardization of vitreal inflammatory 
activity in intermediate and posterior uveitis. Ophthalmology; 92(4):467-71. 
Ohji M, Takahashi K, Okada AA, et al (2020) Efficacy and Safety of Intravitreal Aflibercept 
Treat-and-Extend Regimens in Exudative Age-Related Macular Degeneration: 52- and 96-
Week Findings from ALTAIR: A Randomized Controlled Trial. Adv Ther; 37:1173–87.  
Shah AR, Del Priore LV (2007) Progressive visual loss in subfoveal exudation in age-related 
macular degeneration: a meta-analysis using Lineweaver-Burke plots. Am J Ophthalmol; 
143:83 89. 
Shah AR, Del Priore LV (2009) Natural history of predominantly classic, minimally classic, 
and occult subgroups in exudative age-related macular degeneration. Ophthalmology; 
116:1901-7. 
Silva R, Berta A, Larsen M, et al (2018) Treat-and-Extend versus Monthly Regimen in 
Neovascular Age-Related Macular Degeneration: Results with Ranibizumab from the 
TREND Study. Ophthalmology; 125:57-65.  
Spilsbury K, Garrett 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. 
Wong WL, Su X, Li X, et al (2014) Global prevalence of age-related macular degeneration 
and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. 
Lancet Glob Health; 2: e106 16. 
Wykoff CC, Croft DE, Brown DM, et al (2015) Prospective Trial of Treat-and-Extend versus 
Monthly Dosing for Neovascular Age-Related Macular Degeneration: TREX-AMD 1-Year 
Results. Ophthalmology; 122(12): 2514-22. 
Wykoff CC, Ou WC, Brown DM, et al (2017) Randomized Trial of Treat-and-Extend versus 
Monthly Dosing for Neovascular Age-Related Macular Degeneration: 2-Year Results of the 
TREX-AMD Study. Ophthalmol Retina; 1(4): 314-321. 


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16 
Appendices 
Not applicable 

SAP_001.pdf: 
Novartis Research and Development 
RTH258/Brolucizumab 
CRTH258A2303E1 / NCT04597632
A 56-week phase IIIb/IV, open-label, one-arm extension 
study to assess the efficacy and safety of brolucizumab 6 
mg in a Treat-to-Control regimen with maximum treatment 
intervals up to 20 weeks for the treatment of patients with 
neovascular age-related macular degeneration who have 
completed the CRTH258A2303 (TALON) study 
Statistical Analysis Plan (SAP) 
Document type: 
SAP Documentation (Amendment) 
Document status: 
Final 
Release date: 
May 05 2023 
Number of pages: 
31 
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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SAP 
 
CRTH258A2303E1 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time point 
Reason for update 
Outcome for update 
Section 
and 
title impacted 
(Current) 
12-Oct-2020 
17-May-2021 
 
 
 
 
 
 
8-Mar-2022 
Prior to DB lock 
Prior to DB lock 
 
 
 
 
 
 
Prior to DB lock 
Creation of first draft 
Addition of covid-19 
impact analyses 
Added are paragraphs 
describing the 
analyses of AEs 
starting in the Core, 
prior medical 
procedures, etc 
Addition of analyses 
addressing the urgent 
safety measures 
Clarification on AEs 
leading to treatment 
discontinuation 
Extended sample size 
analyses  
Clarified “extension 
baseline” when 
“baseline” is stated 
and meant the 
extension baseline, as 
in the protocol 
 
Removed duplicate 
sentences and re-
arranged paragraphs 
Medical history 
description moved 
from Sec 2.4.2 to 2.3  
Amended protocol 02 
as a reference 
BCVA categories to be 
the same as in the  
Core SAP 
Added detail about 
missing data handling 
Added IRF/SRF and 
CSFT summaries at 
the last treatment 
visits and 4 weeks 
after for discontinued 
participants 
Added detail on the 
laboratory data 
analyses 
N/A - First version 
Amendment 1 
 
 
 
 
 
Amendment 2 
 
N/A 
Section 2.2.1 
Section 2.3.1 
Section 2.4.2 
Section 2.5.4 
Section 2.7.1 
Section 2.8 
 
 
Section 2.2.1 
Section 2.5.4 
Section 2.6.1 
Section 2.7.1 
 
 
 
Section 2.7.1 
 
Section 3 
Section 1.1 
Section 1.2 
Section 2.2.1 
Section 2.3 
Section 2.4.1 
Section 2.4.2 
Section 2.5 
Section 2.6.1 
Section 2.7.1 
Section 2.7.4 
Section 2.12 
 
Section 2.7.1 
 
Section 2.3 
Section 2.4.2 
 
Section 1 
 
Section 2.2.1 
Section 2.5.3 
Section 2.6.3 
Section 2.6.1 


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SAP 
 
CRTH258A2303E1 
 
Date 
Time point 
Reason for update 
Outcome for update 
Section 
and 
title impacted 
(Current) 
The sentence revised 
to be the same as in 
the Core SAP 
 
Section 2.7.1 
Section 2 
28-Mar-2023 
Prior to DB lock 
Adjusted the wording 
and formatting of the 
SAP 
Specified the analysis 
responsibilities  
Revised the name of 
Enrollment Set and 
the definition of PPS  
Removed the 
subgroup analysis   
 
 
 
Removed the 
duplications  
Updated the statistical 
model for ANCOVA 
and MMRM   
 
Updated the primary, 
supportive and 
sensitivity estimands  
 
Updated the analysis 
part for secondary 
endpoints  
Added the defintion of 
TEAE and contend for 
CTSD  
Added the loss in 
BCVA  
Remove section for 
laboratory data 
Added the PD list and 
AR that cause 
participants to be 
excluded from PPS  
Amendment 3 
 
 
 
 
Section 2 
 
Section 2.2 
 
Section 2.2.1 
Section 2.3 
Section 2.5.4 
Section 2.7.1 
 
Section 2.4.1 
 
Section 2.5.2 
Section 2.5.4 
Section 2.6.2 
 
Section 2.5.3 
Section 2.5.4 
 
Section 2.6.1 
 
 
Section 2.7.1 
 
 
Section 2.7.3 
 
Section 2.7.4 
 
Section 5.5 
 


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SAP 
 
CRTH258A2303E1 
 
Table of contents 
Table of contents ................................................................................................................. 4 
List of tables ........................................................................................................................ 6 
List of abbreviations ............................................................................................................ 7 
1 
Introduction ......................................................................................................................... 9 
1.1 
Study design ............................................................................................ 9 
1.2 
Study objectives and endpoints ............................................................... 9 
2 
Statistical methods ............................................................................................................. 10 
2.1 
Data analysis general information ......................................................... 10 
2.1.1 
General definitions ................................................................................ 11 
2.2 
Analysis sets .......................................................................................... 11 
2.2.1 
Subgroup of interest .............................................................................. 12 
2.3 
Patient disposition, demographics and other baseline characteristics ... 12 
2.3.1 
Patient disposition ................................................................................. 13 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) ....................................................................................................... 13 
2.4.1 
Study treatment / compliance ................................................................ 13 
2.4.2 
Prior, concomitant and post therapies ................................................... 13 
2.5 
Analysis of the primary objective ......................................................... 14 
2.5.1 
Primary endpoint ................................................................................... 14 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 14 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 15 
2.5.4 
Sensitivity analyses ............................................................................... 18 
2.6 
Analysis of secondary objectives .......................................................... 18 
2.6.1 
Secondary endpoints ............................................................................. 18 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 19 
2.6.3 
Handling of missing values/censoring/discontinuations ....................... 20 
2.7 
Safety analyses ...................................................................................... 20 
2.7.1 
Adverse events (AEs) ............................................................................ 20 
2.7.2 
Deaths .................................................................................................... 22 
2.7.3 
Loss in best corrected visual acuity ...................................................... 22 
2.7.4 
Laboratory data ..................................................................................... 22 
2.7.5 
Other safety data ................................................................................... 22 
2.8 
Pharmacokinetic endpoints ................................................................... 23 
2.9 
PD and PK/PD analyses ........................................................................ 23 
2.10 
Patient-reported outcomes ..................................................................... 23 
2.11 
Biomarkers ............................................................................................ 23 


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SAP 
 
CRTH258A2303E1 
 
 
 23 
2.13 
Interim analysis ..................................................................................... 24 
3 
Sample size calculation ..................................................................................................... 24 
4 
Change to protocol specified analyses .............................................................................. 26 
5 
Appendix ........................................................................................................................... 26 
5.1 
Imputation rules .................................................................................... 26 
5.1.1 
Study drug ............................................................................................. 26 
5.1.2 
AE date imputation ............................................................................... 26 
5.1.3 
Concomitant medication date imputation ............................................. 28 
5.2 
AEs coding/grading ............................................................................... 30 
5.3 
Laboratory parameters derivations ........................................................ 30 
5.4 
Statistical models .................................................................................. 30 
5.5 
Rule of exclusion criteria of analysis sets ............................................. 30 
6 
Reference ........................................................................................................................... 31 
 


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SAP 
 
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List of tables 
Table 1-1 
Study objectives and endpoints ............................................................... 9 
Table 2-1 
Primary and sensitivity estimands ......................................................... 16 
Table 2-2 
Critical changes in vital signs ............................................................... 22 
Table 3-1 
Duration of intervals as estimated based on simulation studies ............ 24 
Table 3-2 
Duration of intervals as estimated based on simulation studies and 
width of 95% confidence Interval ......................................................... 25 
Table 3-3  
95% Confidence interval for BCVA change assuming SD of the 
change is 13 ........................................................................................... 25 
Table 5-1 
Patient classification .............................................................................. 30 
Table 5-2 
Non-protocol deviations (analysis restrictions) .................................... 31 
 


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SAP 
 
CRTH258A2303E1 
 
List of abbreviations 
 
Abbreviation Definition 
AE(s) 
Adverse Event(s) 
AESI 
Adverse Event of Special Interest 
ANOVA  
Analysis of Variance 
AR 
Analysis Restrictions 
ATC 
Anatomical Therapeutic Chemical 
BCVA  
CI(s) 
Best-Corrected Visual Acuity 
Confidence Interval(s) 
CFP  
Color Fundus Photography 
CM 
Concomitant Medication 
CNV  
Choroidal Neovascularization 
COVID-19 
Coronavirus disease 2019 
CRF  
Case Report/Record Form (paper or electronic) 
CSR 
Clinical Study Report 
CRS 
Case Retrieval Sheet 
CSFT  
Central Subfield Thickness 
DA 
Disease Activity 
CSR 
DAA 
Clinical Study Report 
Disease Activity Assessment 
eCRF 
Electronic CRF 
EOS  
End of Study 
EOT  
End of Treatment 
FA  
Fluorescein Angiography 
FAS  
Full Analysis Set 
ICF 
Inform Consent Form 
LLN 
Lower Limit of Normal 
IRF 
Intraretinal Fluid 
IOP 
Intraocular Pressure 
LOCF  
Last Observation Carried Forward 
LSM 
Least-Squares Mean 
MedDRA 
Medical dictionary for regulatory activities 
MMRM  
Mixed Model for Repeated Measures 
nAMD  
neovascular Age-related Macular Degeneration 
OCT  
Optical Coherence Tomography 
PD(s) 
Protocol Deviation(s) 
PDS 
Programming Datasets Specifications 
PPS  
Per-Protocol Set 
PT 
Preferred Term 
RPE  
Retinal Pigment Epithelium 
SAE  
Serious Adverse Event 


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SAP 
 
CRTH258A2303E1 
 
Abbreviation Definition 
SAP  
Statistical Analysis Plan 
SD-OCT  
Spectral Domain Optical Coherence Tomography 
SE 
Standard Error 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
SRF  
Subretinal Fluid 
TFL 
Tables, Figures and Listings 
TtC  
Treat-to-Control 
ULN 
Upper Limit of Normal 
VEGF  
Vascular Endothelial Growth Factor 
WHO 
World Health Organization 
 


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SAP 
 
CRTH258A2303E1 
 
1 
Introduction 
This document describes the detailed statistical methodology to be used for the Clinical Study 
Report (CSR) of the TALON-extension study CRTH258A2303E1; a 56-week, phase IIIb/IV, 
open-label, one-arm extension study to assess the efficacy and safety of brolucizumab 6 mg in 
a Treat-to-Control (TtC) regimen with maximum treatment intervals up to 20 weeks for the 
treatment of participants with neovascular age-related macular degeneration (nAMD) who have 
completed the CRTH258A2303 (TALON-core) study.  
The content of this Statistical Analysis Plan (SAP) is based on amended protocol version 02. 
All decisions regarding the final analysis, as defined in this SAP document, will be made prior 
to final database lock and unblinding of the study data. 
CSR deliverables (shells for tables, figures, listings [TFLs]) and further programming 
specifications will be described in the TFL shells and Programming Datasets Specifications 
(PDS), respectively. 
1.1 
Study design 
The study is a 56-week open-label, multi-center, one-arm extension study in participants with 
nAMD who have completed the TALON core study. 
Approximately 250 participants from the core study (CRTH258A2303, TALON) will enter this 
extension study. The primary analyses will be conducted when all ongoing participants have 
completed their Week 56 visit and after the database lock. 
1.2 
Study objectives and endpoints 
The study objectives and corresponding endpoints as specified in the protocol are provided in 
Table 1-1. 
Table 1-1 
Study objectives and endpoints 
Objectives 
Endpoints 
Analysis 
Primary objectives 
Endpoints for primary 
objectives 
Analysis 
• 
To evaluate the extended durability of 
brolucizumab in a TtC regimen with 
respect to the duration of treatment 
intervals at Week 56 
• 
Duration of the last interval 
with no DA up to Week 56 
Section 2.5 
• 
To evaluate the functional outcomes of 
brolucizumab in a TtC regimen with 
respect to average change in BCVA at 
Week 52 and Week 56 
• 
Change in BCVA from 
extension baseline at 
Week 52 and Week 56 
 
Secondary objectives 
Endpoints for secondary 
objectives 
Analysis 
• 
To evaluate the anatomical outcomes of 
brolucizumab in all patients and per 
randomized arm in the core study 
• 
Change in CSFT from 
extension baseline to 
Week 52 and Week 56 
Number of visits with 
presence of IRF and/or SRF, 
Section 2.6 


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Objectives 
Endpoints 
Analysis 
and sub-RPE fluid in the 
central subfield, as assessed 
by SD-OCT at Week 52 and 
Week 56  
• 
To assess the durability of brolucizumab in 
all patients and/or per randomized arm in 
the core study 
• 
Duration of the last interval 
with no DA up to Week 56 
Duration of the maximal 
intervals with no DA up to 
Week 56 
Change of the duration of last 
interval with no DA between 
extension baseline and 
Week 56  
 
• 
To assess the functional outcomes of 
brolucizumab per randomized arm in the 
core study  
• 
Change in BCVA from 
extension baseline to 
Week 52 and Week 56  
 
• 
To assess the safety of brolucizumab 
• 
Occurrence of Ocular and 
Non-ocular AEs up to 
Week 56 
Section 2.7 
 
2 
Statistical methods 
All analyses described in the SAP will be performed by Novartis. Any additional (or other) data 
analysis carried out independently by the investigators should be submitted to Novartis before 
publication or presentation. 
2.1 
Data analysis general information 
Categorical data will be presented as frequencies and percentages. For continuous data, n, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented (when applicable).  


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2.1.1 
General definitions  
All the definitions, e.g. baseline, on-treatment period, are referring to the current extension 
study unless otherwise stated, e.g. baseline of the core study. 
Study treatment is defined as brolucizumab 6 mg/0.05 mL. 
Date of first administration of study treatment is defined as the first date when a non-zero 
dose of study treatment is administered and recorded on the case report form (CRF) dose 
administration page. The date of first administration of study treatment will also be referred to 
as start of study treatment. 
Date of last administration of study treatment is defined as the last date when a non-zero 
dose of study treatment is administered and recorded on the CRF dose administration page. The 
last administration of study treatment will also be referred as end of treatment (EOT). 
Study day will be calculated as: 
• The date of the event (visit date, onset date of an event, assessment date etc.) – treatment 
start date + 1, if event is on or after the treatment start date; 
• The date of the event (visit date, onset date of an event, assessment date etc.) – treatment 
start date, if event precedes the treatment start date. 
Baseline/Day 1 is the end of study (EOS)/Week 64 of the core study.  
On-treatment period is defined from Day 1 of the study to 30 days after the last administration 
of study treatment (i.e. EOT) or end of study (EOS), whichever is the latest. 
Treatment interval is defined as the time period from one injection until the next injection. In 
this study, treatment intervals of q4w, q8w, q12w, q16w and q20w, meaning that there are 4, 8, 
12, 16 and 20 weeks between 2 injections, are of special interest. The last (treatment) interval 
at Week X is referred to the last complete interval where injections at both ends of the interval 
have occurred on or before Week X. The last interval with/without disease activity is referred 
to the last interval with/without disease activity as observed at the end of the interval. 
The first treatment is defined by the treatment interval of the core study. For example, a patient 
who started a 16-weeks interval at Week 56 of the core study will have the first treatment 8 
weeks after the start of the extension study (i.e. 8 weeks after Week 64).  
Participants will be assessed for eligibility based on inclusion and exclusion criteria for the 
extension study at the baseline visit. 
The study day will be displayed in data listings. All data from scheduled and unscheduled visits 
will be analyzed based on “Week XX” recorded in the CRF (except for baseline), unless 
otherwise stated. 
2.2 
Analysis sets 
The Enrollment Set includes all participants who signed the informed consent form (ICF) and 
are assigned participant numbers. This analysis set will be used to summarize the disposition of 
participants, pre-treatment adverse events (AEs) and counts of AEs during the on-treatment 
period. 


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The Full Analysis Set (FAS) comprises of all participants who received at least one dose of 
study treatment in the extension study. This analysis set will serve as the primary analysis set 
for all efficacy and safety analyses. 
The Per-Protocol Set (PPS) is a subset of participants in the FAS with major protocol deviation 
(with impact).  Patients with important PDs but without impact will be reported as PD and will be 
included in PPS. 
The list of protocol deviation criteria will be provided in the edit check specification document. 
Please refer to Table 5-1 for more details. 
2.2.1 
Subgroup of interest 
Primary endpoint analysis for BCVA will be conducted using the following baseline BCVA 
and age categories: 
• Baseline BCVA categories: < 55, 55-< 73, ≥ 73 letters read, 
• Age categories: < 75, ≥ 75 years old. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
Demographic and other extension study baseline data including disease characteristics will be 
summarized by appropriate descriptive statistics for all analyses sets. A listing will also be 
provided.  
A baseline (of the extension study) disease characteristic table will be provided by treatment 
groups of the core study and overall, including:  
• Primary diagnosis of nAMD, time since diagnosis of nAMD (days), whether nAMD is 
unilateral or bilateral and intraocular pressure (IOP). 
• BCVA (as a continuous variable and using categories (< 55, 55-< 73, ≥ 73 letters read)), 
• OCT angiography parameters – if collected. 
• SD-OCT parameters (IRF, SRF, sub-RPE, CSFT (as a continuous variable and using 
categories (< 400, ≥ 400 µm)) and lesion type). 
• CFP parameters (intra-retinal hemorrhage – central subfield, sub-retinal hemorrhage – 
central subfield, RPE atrophy – outer subfield, RPE atrophy – central subfield, fibrosis – 
inner subfield, fibrosis – central subfield). 
• FA parameters (type of CNV, area of CNV within the lesion, CNV location, leakage from 
CNV). 
Relevant medical histories and current medical conditions at baseline of the extension study 
will be summarized separately by system organ class and preferred term for the FAS.  
Medical history/current medical conditions will be coded using the latest version of Medical 
Dictionary for Regulatory Activities (MedDRA) terminology available at the time of the 
analyses. The MedDRA version used for reporting will be specified in the clinical study report 
(CSR) and as a footnote in the applicable tables/listings. 
Medical histories which started before the core study and are ongoing on Day 1 of the extension 
study will be recorded on the Medical History eCRF. Data collected for the Medical History 


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eCRF for the extension study will be presented by the treatment arm in the core study and 
overall. Columns will be included to identify if the event started before the core study, during 
the core study, or during the extension study; and if the event is ongoing or ended during the 
Extension study. 
2.3.1 
Patient disposition 
Patient disposition for all participants will be summarized based on the Enrollment Set. A listing 
will also be provided. 
The number (%) of participants in the FAS and PPS will be presented based on the Enrollment 
Set. Participants excluded from the FAS and PPS including the corresponding reasons will be 
presented in a listing. 
A listing of all important protocol deviations with their respective deviation/restriction 
categories will be provided. A summary table for PDs will also be provided (if appropriate). 
The number and percentage of participants with important PDs will be presented by 
deviation/restriction category. Due to the COVID-19 pandemic, a higher number of PDs are 
expected. To evaluate the PDs occurring due to the COVID-19 pandemic, the number and 
percentage of participants with PDs occurring due to the COVID-19 outbreak will also be 
provided by deviation category. A listing of PDs will be provided by participant, including the 
relationship to COVID-19, and the information if the PD led to exclusion of the participant from 
an analysis set. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The FAS will be used for the analyses below. 
 
 
 
 
2.4.2 
Prior, concomitant and post therapies 
Concomitant medications and significant non-drug therapies prior to and after start of study 
treatments will be summarized according to the Anatomical Therapeutic Chemical (ATC) 
classification system based on Enrollment Set.  
Medications taken at least once during the extension study and medications started on the end 
of study visit date for the core study/extension study baseline visit date will be recorded on the 
Concomitant Medications eCRF.   
Prior medications (ocular and non-ocular) will be summarized using number and percentage of 
patients by ATC class and PT according to the World Health Organization (WHO) drug 
reference list directory. Prior ocular medications will be summarized overall and separately for 


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the study and fellow eye; and by the treatment arm in the core study. Prior medications are those 
that have a start date prior to the date of the first administration of study treatment in this 
extension study. 
A concomitant medication is defined as any medication taken at least once after the first 
administration of study treatment in this extension study. Concomitant medications will be 
summarized. 
Procedures occurring during the extension study and procedures occurring on the end of study 
visit date for the core study/extension study baseline visit date will be recorded on the 
Procedures eCRF. 
Prior surgical and medical procedures are those that have a start date prior to the date of the first 
injection of study treatment in this extension study. 
2.5 
Analysis of the primary objective 
The primary objectives of the study are: 
• To evaluate the extended durability of brolucizumab in a TtC regimen with respect to the 
duration of treatment intervals up to Week 56. 
• To evaluate the functional outcomes of brolucizumab in a TtC regimen with respect to 
average change in BCVA at Week 52 and Week 56, i.e., change from the extension study 
baseline to the average of Week 52 and Week 56. 
2.5.1 
Primary endpoint 
The primary endpoints of the study are: 
• Duration of the last interval with no disease activity up to Week 56. 
• Average change in BCVA from baseline of the extension study at Week 52 and Week 56. 
Primary estimands along with the sensitivity estimands are shown in Table 2-1.   
2.5.2 
Statistical hypothesis, model, and method of analysis  
The average change in BCVA from baseline of the extension study at Week 52 and 
Week 56 will be estimated by an analysis of variance (ANOVA) with baseline age categories, 
baseline BCVA categories and treatment arm in the core study included as fixed effects. The 
estimate of BCVA change will be accompanied by the 95% CI. 
For the analysis of durability, the first step is to identify the last (treatment) interval with respect 
to Week 56 for each participant, i.e. the last interval for which injections have occurred at both 
ends of this interval before/at Week 56. If there is disease activity at the end of the last interval, 
then the last interval will be shortened by 4 weeks, down to a minimum of q4w. Subjects who 
do not receive any injection (or only one injection) of study drug in the extension study will be 
excluded from this analysis. In case of any treatment interruption or permanent study treatment 
discontinuation, the imputation techniques as per the estimand framework in Section 2.5.3 will 
be considered. Then, the proportion of participants with last interval of q4w, q8w, q12w, q16w, 
and q20w will be specified. These proportions will be referred as the distribution of the last 
interval. 


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The distribution of the last interval with no disease activity up to Week 56 will be described 
based on counts and proportions of participants at 4-week, 8-week, 12-week, 16-week, and 
20-week intervals. These proportions will be accompanied by 95% CIs. The counts and 
proportions will be accompanied by 2-sided 95% CIs inferred based on binomial distribution 
for each endpoint and 2-sided 95% simultaneous CIs inferred using the Goodman method 
(Goodman 1965). The Goodman method is used for obtaining simultaneous CIs for the 
parameters of a multinominal distribution, for example for a multinomial endpoint (4-week 
interval, 8-week interval, 12-week interval, 16-week interval, and 20-week interval).  
2.5.3 
Handling of missing values/censoring/discontinuations 
The imputation of missing data will be handled by defining the estimand framework. The 
primary estimands is described by the following attributes: 
1. Population: participants who have completed the CRTH258A2303 study (TALON) 
irrespective of the study treatment received in the core study.  
2. The co-primary variable 1 is change in BCVA from extension baseline at Week 52 and 
Week 56, i.e. the average change in BCVA from extension baseline to Week 52 and Week 
56. The co-primary variable 2 is the duration of the last interval with no disease activity up 
to Week 56, i.e. the proportion of participants in q4w, q8w, q12w, q16w and q20w intervals 
(interval distribution) at last interval with no disease activity up to Week 56 (subjects who 
will be assigned to a 4-week interval will be analyzed as such, but discontinued from further 
study treatment). 
3. Treatment of interest: brolucizumab 6 mg will be taken for the entire study duration.  
4. Handling of remaining intercurrent events: 
• Study treatment discontinuation: For the co-primary endpoint of change in BCVA, a 
hypothetical treatment strategy will be applied to estimate the treatment effect under 
the hypothetical assumption that the patient would not start an alternative anti-VEGF 
treatment (i.e. standard of care therapy) on the study eye. For the co-primary endpoint 
of duration of treatment interval, a ‘while on treatment strategy’ will be applied as 
disease stability assessment will not be performed after the patient discontinued 
treatment. 
• Study treatment interruption: For both the co-primary endpoints, a treatment policy 
strategy will be applied. 
The summary measure for the co-primary variable 1 is the interval distribution, and for the 
co-primary variable 2 is the least square means. 
The primary estimands and other supportive estimands of interest are described in Table 2-1 
below, together with their key attributes. 
For all participants, the last potential study treatment will be at the Week 52 visit. Participants 
who will receive a study treatment at an inspection visit may have a study visit at Week 54. For 
those participants, the Week 54 visit will take place in lieu of the visit at Week 52. Hence 
throughout this document, analyses based on Week 52 BCVA and other efficacy data are 
performed if Week 52 data are available. If Week 52 BCVA and other efficacy data are not 
available, Week 54 BCVA and other efficacy data will be used instead of Week 52. Otherwise, 
LOCF will be used to impute missing BCVA as per the estimand framework. 


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Table 2-1 
Primary and sensitivity estimands 
Estimand 
Estimand 
definition 
Analysis set, 
data included 
in the 
analyses 
Use of data after intercurrent 
event (missing data 
imputation techniques) 
Statistical 
methods 
Discontinuati
on of study 
treatments 
Treatment 
interruption 
Primary 
estimand 1  
(Duration 
of last 
interval 
with no 
disease 
activity) 
Duration of 
the last 
interval with 
no disease 
activity, i.e., 
distribution of 
the last 
interval with 
no disease 
activity up to 
Week 56, i.e., 
proportion of 
participants in 
last interval 
with no 
disease 
activity that is 
4/8/12/16/20-
weeks 
intervals 
FAS 
 
*Last interval 
with no 
disease 
activity up to 
Week 56. 
‘While on 
treatment 
strategy’ will 
be applied as 
disease 
stability 
assessment 
will not be 
performed 
after the 
patient 
discontinued 
treatment.  
Treatment 
policy strategy 
will be 
applied, i.e., 
include data 
collected after 
treatment 
interruption 
Two-sided 
95% CI of 
proportions. If 
there was 
disease 
activity, the 
last interval 
will be 
shortened by 
4 weeks, 
down to a 
minimum of 
4 weeks 
Primary 
estimand 2 
(change in 
BCVA) 
Change in 
BCVA from 
baseline of 
the extension 
study at 
Week 52 and 
Week 56, i.e., 
the average 
difference in 
BCVA 
between 
baseline of 
the extension 
study and the 
average of  
Week 52 and 
Week 56 
FAS 
 
All data 
collected until 
the participant 
discontinued 
the study 
treatment and 
started 
alternative 
treatment(s) 
will be 
included.  
The 
hypothetical 
treatment 
strategy will 
be applied , 
i.e, exclude 
data collected 
after study 
treatment 
discontinuatio
n, treat them 
as missing 
and impute 
with LOCF 
 
Treatment 
policy strategy 
will be 
applied, i.e., 
include data 
collected after 
treatment 
interruption 
Two-sided 
95% CI 
obtained from 
ANOVA with 
baseline age 
categories, 
baseline 
BCVA 
categories 
and treatment 
arm in the 
core study 
included as 
fixed effects 


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Estimand 
Estimand 
definition 
Analysis set, 
data included 
in the 
analyses 
Use of data after intercurrent 
event (missing data 
imputation techniques) 
Statistical 
methods 
Discontinuati
on of study 
treatments 
Treatment 
interruption 
Sensitivity 
estimand 1.2  
(Duration 
of last 
interval 
with no 
disease 
activity, and 
excluding 
participants 
with important 
protocol 
deviations as 
per PPS)  
Duration of 
the last 
interval with 
no disease 
activity, i.e., 
distribution of 
the last 
interval with 
no disease 
activity up to 
Week 56, i.e., 
proportion of 
participants in 
last interval 
with no 
disease 
activity that is 
4/8/12/16/20-
weeks 
intervals. 
PPS** 
 
*Last interval 
with no 
disease 
activity up to 
Week 56. 
 
 
‘While on 
treatment 
strategy’ will 
be applied as 
disease 
stability 
assessment 
will not be 
performed 
after the 
patient 
discontinued 
treatment.  
Treatment 
policy strategy 
will be 
applied, i.e., 
include data 
collected after 
treatment 
interruption 
Two-sided 
95% CI of 
proportions. If 
there was 
disease 
activity, the 
last interval 
will be 
shortened by 
4 weeks, 
down to a 
minimum of 
4 weeks 
Sensitivity 
estimand 2.2 
(change in 
BCVA, and 
excluding 
participants 
with important 
protocol 
deviations as 
per PPS)  
Change in 
BCVA from 
Baseline of 
the extension 
study at Week 
52 and Week 
56, i.e., the 
average 
difference in 
BCVA 
between 
Baseline of 
the extension 
study and the 
average of 
Week 52 and 
Week 56 
PPS 
 
All data 
collected until 
the participant 
discontinued 
the study 
treatment and 
started 
alternative 
treatment(s) 
will be 
included. 
The 
hypothetical 
treatment 
strategy will 
be applied, 
i.e, exclude 
data collected 
after study 
treatment 
discontinuatio
n, treat them 
as missing 
and impute 
with LOCF 
 
Treatment 
policy strategy 
will be 
applied, i.e., 
include data 
collected after 
treatment 
interruption 
Two-sided 
95% CI 
obtained from 
ACOVA with 
baseline age 
categories, 
baseline 
BCVA 
categories 
and treatment 
arm in the 
core study 
included as 
fixed effects 


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Estimand 
Estimand 
definition 
Analysis set, 
data included 
in the 
analyses 
Use of data after intercurrent 
event (missing data 
imputation techniques) 
Statistical 
methods 
Discontinuati
on of study 
treatments 
Treatment 
interruption 
Sensitivity 
estimand 2.3 
(change in 
BCVA)  
Change in 
BCVA from 
Baseline of 
the extension 
study at 
Week 52 and 
Week 56, i.e., 
the average 
difference in 
BCVA 
between 
Baseline of 
the extension 
study and the 
average of 
Week 52 and 
Week 56 
FAS 
 
All data 
collected until 
the participant 
discontinued 
the study 
treatment and 
started 
alternative 
treatment(s) 
will be 
included. 
Analyze on 
observed data 
only 
Analyze on 
observed data 
only 
Two-sided 
95% CI 
obtained from 
MMRM with 
age 
categories at 
the baseline, 
BCVA 
categories at 
the baseline, 
treatment arm 
in the core 
study, and 
assessment 
visit as the 
fixed effect 
and 
participant as 
a random 
effect 
* If the duration of the last interval falls within the following ranges of [q4w, q8w) or [q8w, q12w), [q12w, 
q16w), [q16w, q20w)  or ≥ q20w then the floor value of these ranges i.e., q4w, q8w, q12w, q16w, q20w, 
respectively, will be used for imputation. 
** Participants who take prohibited concomitant medication are already excluded from PPS as taking 
prohibited medication is considered a deviation with impact.  
2.5.4 
Sensitivity analyses 
Sensitivity analyses for the two co-primary endpoints will be performed to examine robustness 
with respect to PDs based on the PPS. 
To evaluate robustness of the analyses for the co-primary endpoint (change in BCVA from 
extension baseline at Week 52 and Week 56) that were based on the LOCF method, sensitivity 
analyses will be performed on the observed data in the FAS and MMRM. The MMRM model 
will include the change in BCVA as the dependent variable, age categories at baseline, BCVA 
categories at baseline, treatment arm in the core study, and assessment visit as the fixed effects 
and participant as a random effect.  
2.6 
Analysis of secondary objectives 
The FAS will be used to analyze durability, functional, tolerability and anatomical outcomes. 
2.6.1 
Secondary endpoints 
The following secondary endpoints evaluate the anatomical outcomes of brolucizumab in all 
participants and per randomized arm in the core study: 


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• Summary statistics of average change in CSFT from baseline of the extension study at Week 
52 and Week 56 will be provided. In addition, equivalent summaries will be provided for 
participants who discontinued the study treatment early at the date of the last treatment and 
4 weeks after.  
• Summary statistics of average change in CSFT from baseline of the core study to Week 52 
and Week 56 will be provided.  
• Number (%) of patients with presence of IRF and/or SRF and sub-RPE fluid in the central 
subfield, as assessed by SD-OCT at Week 52 and Week 56 and by the number of visits will 
be provided. In addition, equivalent summaries will be provided for participants who 
discontinued the study treatment early at the date of the last treatment and 4 weeks after. 
The following secondary endpoints evaluate the durability of brolucizumab in all participants 
and per randomized arm in the core study: 
• Distribution of the duration of the last interval with no disease activity up to Week 56 will 
be provided. 
• Distribution of the duration of the maximal intervals with no disease activity up to Week 56 
will be provided. 
• Distribution of the change of the duration of last interval with no disease activity between 
baseline of the extension study and Week 56 will be provided. 
The following secondary endpoints evaluate the functional outcomes of brolucizumab per 
randomized arm in the core study: 
• Summary statistics of the average change in BCVA from baseline of the extension study to 
Week 52 and Week 56 will be provided.  
The following secondary endpoints evaluate the functional outcomes of brolucizumab in all 
participants and per randomized arm in the core study: 
• Summary statistics of the change in BCVA from the baseline of the core study by visit will 
be provided. Boxplots with a trend line and the line plot of LSM (+/-SE) by visit will also 
be graphed. 
• Summary statistics for the average change in BCVA from the baseline of the core study to 
Week 52 and Week 56 will be provided.  
2.6.2 
Statistical hypothesis, model, and method of analysis 
Counts and proportions for the endpoints describing durability, tolerability, and anatomical 
outcomes (i.e., number of visits with presence of IRF and/or SRF) will be accompanied by 
2-sided 95% CI inferred based on binomial distribution for each endpoint and 2-sided 95% 
simultaneous CIs inferred using the Goodman method (Goodman 1965). The Goodman method 
is used for obtaining simultaneous CIs (better than single binomial CIs) for the parameters of a 
multinominal distribution, for example for a multinomial endpoint (4-week interval, 8-week 
interval, 12-week interval, 16-week interval, and 20-week interval). These analyses will be 
performed for all participants and within the two regimens. 
For the analyses of functional and anatomical outcome (i.e., change in CSFT) the 95% CI will 
be inferred based on ANOVA analyses. The same analysis model as used for change from 


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baseline in BCVA will be used with the baseline BCVA categories replaced by baseline CSFT 
categories.  
2.6.3 
Handling of missing values/censoring/discontinuations 
In case of treatment interruption, if the duration of the last interval falls within the following 
ranges of [q4w, q8w) or [q8w, q12w), [q12w, q16w), [q16w, q20w) or ≥ q20w then the floor 
value of these ranges i.e., q4w, q8w, q12w, q16w, q20w, respectively, will be used for 
imputation. 
The last potential study treatment may be administered at the Week 52 visit (or at the Week 54 
visit for the participants who will have received study treatment at an odd number of inspection 
visits). Hence throughout this document, analyses based on Week 52 BCVA and other efficacy 
data are performed if Week 52 data are available. If Week 52 BCVA and other efficacy data 
are not available, Week 54 BCVA and other efficacy data will be used instead of Week 52. 
Otherwise, LOCF will be used to impute missing BCVA as per the estimand framework. 
For participants who discontinue study treatment but continue in the study, data collected after 
the switch to alternative treatment in the study eye will be censored for the primary analysis. 
Censored data will be replaced using LOCF with the last observation collected prior to/on the 
start of an alternative treatment in the study eye. 
2.7 
Safety analyses 
The following endpoint will be used to assess the safety and tolerability of brolucizumab 
• Occurrence of Ocular and Non-ocular AEs up to Week 56.  
The primary population for safety analyses is the FAS. Additionally, the Enrollment Set will be 
used to summarize pre-treatment AEs and all AEs that occur during the extension study. All 
listings and tables will be presented for all participants. 
Safety summaries (tables, figures) will include only data from the baseline of the extension 
study, which is also EOS/Week 64 of the core study.   
2.7.1 
Adverse events (AEs) 
Note that AEs which start during the core study and end prior to the core EOS are not recorded 
on the Medical History eCRF, nor the Adverse Event eCRF. These AEs are considered as the 
Medical History in the extension study, hence the data from the core AE will be 
programmatically merged with the Medical History eCRF. Therefore, these events are not 
included in any AE summaries or listings but will be included in Medical History listings.  
Treatment-emergent Adverse Events: The primary summaries of AEs will be based on 
treatment-emergent adverse events (TEAE). A TEAE is defined as any AE that develops 
on/after the first injection of study treatment or any event already present that worsens following 
the first injection of study treatment.  
The number (and percentage) of participants with TEAEs will be summarized separately for 
ocular (study eye and fellow eye) and non-ocular in the following ways: 


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• Overall summary of subjects with death, any TEAE, any severe TEAE, any study 
treatment related TEAE, any TEAE leading to study treatment discontinuation, any 
treatment-emergent serious AE (TESAE), any study treatment related TESAE; 
• TEAE, TESAE by primary SOC and PT; 
• TEAE by primary SOC, PT, and maximum severity 
• TEAE by Standardized MedDRA Query (SMQ) and PT;  
• TEAEs related to study treatment by primary SOC and PT; 
• TEAEs leading to study treatment discontinuation by primary SOC. 
A subject with multiple AEs within a primary SOC is only counted once towards the total of 
the SOC. 
Ocular TEAE in the study eye with occurrence greater than or equal to 1% and non-ocular 
TEAE with occurrence greater than or equal to 2% will be summarized by PT.  
 
Pre-treatment Adverse Events: In addition to TEAEs, AEs which start on/after day 1 of the 
extension study and prior to the date/time of the first injection of the study treatment in the 
extension study will be summarized using number and percentage of patients by ocular (study 
eye and fellow eye)/non-ocular, primary SOC and PT using the Enrollment Set.  
Study-emergent Adverse Events: All AEs that occur during the on-treatment period (defined 
in Section 2.1.1) will be summarized separately for ocular (study eye and fellow eye) and non-
ocular events using the Enrollment Set in the following ways: 
• AEs by primary SOC and PT; 
• SAEs by primary SOC and PT; 
• SAEs by primary SOC and PT, and maximum severity; 
• Study treatment related SAEs, by primary SOC and PT 
All deaths, SAEs or AEs leading to permanent study treatment discontinuation during the study 
will be summarized.  
Adverse events are coded using MedDRA terminology.  
For the legal requirements of ClinicalTrials.gov and EudraCT, two tables are mandatory: 
• <on-treatment/treatment emergent> adverse events which are not serious adverse events 
with an incidence greater than X%. Detailed threshold (X%) will be determined by 
safety disclosure 
• <on-treatment/treatment emergent> serious adverse events and SAE suspected to be 
related to study treatment will be provided by system organ class and preferred term 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 SOC 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 and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
2.7.1.1 
Adverse events of special interest / grouping of AEs. 
The number (%) of subjects with treatment-emergent AESIs will be summarized by category 
and PT.  
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.  
AESIs related to the study treatment and/or study treatment procedure will be summarized by 
category and PT term.  
2.7.2 
Deaths 
On-treatment deaths and all deaths including those that occurred outside the on-treatment period 
will be summarized by primary SOC and PT. A listing will also be provided. 
2.7.3 
Loss in best corrected visual acuity 
Number and % of subjects who lost ≥ 15/ ≥ 30 letters in BCVA from baseline up to Week 56 
will be presented for the study eye. Missing data will not be imputed.  Number of subjects with 
≥ 15/ ≥30 letter loss at the last visit will also be summarized. In addition, a listing for subjects 
who lost ≥ 15/ ≥ 30 letters in the study eye from the baseline at Week 56 will be provided. 
2.7.4 
Laboratory data 
Not applicable. 
2.7.5 
Other safety data 
2.7.5.1 
Vital signs 
Summary statistics of vital signs will be provided based on data from the on-treatment period 
excpet for baseline data which will be summarized where appropriate. 
Clinically relevant abnormalities in vital signs data i.e., sitting blood pressure (systolic and 
diastolic pressure in mmHg) and pulse rate (beats per minute) will be listed by subject, and 
visit/study day and abnormalities as per normal range and critical values as per Table 2-2 will 
be flagged.  
Number (%) of participants with critical abnormalities will also be provided. 
Table 2-2 
Critical changes in vital signs 
Variable 
Category 
Critical Values 


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Systolic blood pressure 
(mmHg) 
High 
Either > 180 with an increase from baseline of the extension
study > 30 or > 200 absolute 
Low 
Either < 90 with a decrease from baseline of the extension
study > 30 or < 75 absolute 
Diastolic blood pressure 
(mmHg) 
High 
Either > 105 with an increase from baseline of the extension
study > 20 or > 115 absolute 
Low 
Either < 50 with a decrease from baseline of the extension
study > 20 or < 40 absolute 
Pulse rate (bpm) 
High 
Either > 120 with an increase from baseline of the extension
study > 25 or > 130 absolute 
Low 
Either < 50 with a decrease from baseline of the extension
study > 30 or <40 absolute 
Summary statistics will also be provided by visits. 
Intraocular pressure (IOP) measurements will be recorded in mmHg. 
Summary statistics of pre-dose observed IOP values and change from baseline of the extension 
study for both study and fellow eyes will be presented by visit.  
Furthermore, summary statistics of pre-dose and post-dose observed IOP values and respective 
change from pre-dose for the study eye will be presented by visit. 
Listing of clinically significant elevations in pre- and post-dose IOP measurements for both 
study and fellow eyes will be provided by visit/study day and elevated IOPs (≥ 25 mmHg) will 
be flagged.  
2.8 
Pharmacokinetic endpoints   
Not applicable. 
2.9 
PD and PK/PD analyses 
Not applicable. 
2.10 
Patient-reported outcomes 
Not applicable.  
2.11 
Biomarkers 
Not applicable. 


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2.13 
Interim analysis 
Not applicable. 
3 
Sample size calculation 
All participants who completed Week 64/EOS in the core study and meet all inclusion and 
exclusion criteria will be eligible for enrollment into the extension study. The initial sample size 
analyses assumed that all participants completing the core study and eligible for enrollment in 
the extension study will be enrolled in the extension study. After the protocol amendment, it is 
planned that approximately 250 participants will be enrolled the extension study. Simulation 
studies conducted before the urgent safety measures were introduced are described below.  
Table 3-1 shows the distribution of duration as estimated based on simulation studies along with 
precision as estimated based on the simulations. Table 3-2 shows width of 95% CI as estimated 
based on a sample of size (number of participants completing the extension study) varying from 
503 to 100. The numbers are chosen based on assuming that 90%/80%/70%/etc of participants 
from the core study enter the extension and also assuming that 10%/20%/30%/etc of 
participants drop out reaching EOS of the extension. Similarly, Table 3-3 shows 95% CI for the 
estimate in the change of BCVA, assuming that the observed change is -1 and the standard 
deviation of the change is 13.  
For example, when the number of participants completing the extension study decreases from 
503 to 212, width of the 95% CI increases from 5.8% to 9% for the estimated proportion of 
12.7% participants being on the 16-weeks interval; and from 6.9% to 9.8% for the estimated 
proportion of 19.4% of participants being on 20-weeks interval. With the same reduction in the 
sample size, the 95% CI for the estimated change in BCVA goes from (-2.1, 0.14) to (-2.8, 0.8). 
The 95% CI are obtained using PASS 11. 
Table 3-1 
Duration of intervals as estimated based on simulation studies  
Interval 
duration 
4-weeks 
8-weeks 
12-weeks 
16-weeks 
20-weeks 
Frequency 
(SD as 
assesed by 
simulations) 
8.6% (1.7%) 
30.2% (1.9%) 
29.2% (2.3%) 
12.7% (1.7%) 
19.4% (2.4%) 


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Table 3-2 
Duration of intervals as estimated based on simulation studies and 
width of 95% confidence Interval 
Duration of the treatment interval 
4-weeks 
8-weeks 
12-weeks 
16-weeks 
20-weeks 
Frequency  
(SD from simulations) 
8.6% 
(1.7%) 
30.2% 
(1.9%) 
29.2% 
(2.3%) 
12.7% 
(1.7%) 
19.4% 
(2.4%) 
N of participants completing the 
extension study  
 
Width of 95% Confidence Interval 
503 
4.9% 
8.0% 
7.9% 
5.8% 
6.9% 
447  
5.2% 
8.5% 
8.4% 
6.2% 
7.3% 
391  
5.6% 
9.1% 
9.0% 
6.6% 
7.8% 
348  
5.9% 
9.6% 
9.6% 
7.0% 
8.3% 
304  
6.3% 
10.3% 
10.2% 
7.5% 
8.9% 
250  
7% 
11.4% 
11.3% 
8.3% 
9.8% 
212  
7.5% 
12.4% 
12.2% 
9% 
10.6% 
200 
8.3% 
13.1% 
13.0% 
9.7% 
11.4% 
170 
9.0% 
14.3% 
14.2% 
10.6% 
12.4% 
150 
9.6% 
15.2% 
15.1% 
11.3% 
13.2% 
120 
10.9% 
17.1% 
16.9% 
12.7% 
14.9% 
100 
12.0% 
18.8% 
18.6% 
14.0% 
16.3% 
Table 3-3  
95% Confidence interval for BCVA change assuming SD of the change 
is 13 
N of participants completing the extension study 
95% Confidence Interval of BCVA change 
assuming the observed change is -1. 
503 
(-2.1, 0.14) 
447 
(-2.2, 0.21) 
391 
(-2.3, 0.29) 
348 
(-2.4, 0.37) 
304 
(-2.5, 0.47) 
250 
(-2.6, 0.62) 
212 
(-2.8, 0.76) 
200 
(-2.8, 0.81) 
170 
(-3.0, 0.97) 
150 
(-3.1, 1.1) 
120 
(-3.4, 1.4) 
100 
(-3.6, 1.6) 


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4 
Change to protocol specified analyses 
Added in the SAP is the secondary endpoint characterizing the change from the baseline of the 
core study for all participants and per randomized arm in the core study. Specifically,  
• Change in CSFT from the baseline of the core study by visit. 
• Average change in CSFT from the baseline of the core study at Week 52 and Week 56.  
• Change in BCVA from the baseline of the core study by visit. 
• Average change in BCVA from the baseline of the core study at Week 52 and Week 56. 
Statistical analyses are described in Section 2.6.1. 
BCVA categories are the same as in the SAP for the core study. 
5 
Appendix 
5.1 
Imputation rules 
Not applicable. 
5.1.1 
Study drug 
Not applicable. 
5.1.2 
AE date imputation 
Adverse event end date imputation 
1. If the AE end date month is missing, the imputed end date should be set to the earliest of 
the ( 31DECYYYY, date of death). 
2. If the AE end date day is missing, the imputed end date should be set to the earliest of the 
(last day of the month, date of death). 
3. If AE year is missing or AE is ongoing, the end date will not be imputed. 
If the imputed AE end date is less than the existing AE start date then use AE start date as AE 
end date. 
Adverse event start date imputation 
The following table explains the notation used in the logic matrix. Please note that completely 
missing start dates will not be imputed. 
The following table explains the notation used in the logic matrix. 
Day 
Month 
Year 
Partial Adverse Event Start
Date 
Not used 
MON 
YYYY 
Treatment Start Date 
Not used 
TRTM 
TRTY 
 


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The following matrix explains the logic behind the imputation. 
 
MON 
MISSING 
MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY 
MISSING 
( 1 ) 
No convention 
( 1 ) 
No convention 
( 1 ) 
No convention 
( 1 ) 
No convention 
YYYY < TRTY 
( 2.a) 
Before Treatment 
Start 
( 2.b) 
Before Treatment 
Start 
( 2.b) 
Before Treatment 
Start 
(2.b) 
Before Treatment 
Start 
YYYY = TRTY 
(4.a ) 
Uncertain 
(4.b ) 
Before 
Treatment 
Start 
(4.c) 
Uncertain 
(4.c ) 
After 
Treatment 
Start 
YYYY > TRTY 
(3.a ) 
After 
Treatment 
Start 
(3.b ) 
After 
Treatment 
Start 
(3.b ) 
After 
Treatment 
Start 
(3.b ) 
After 
Treatment 
Start 
Before imputing AE start date, find the AE start reference date. 
1. If the (imputed) AE end date is complete and the (imputed) AE end date < treatment start 
date then AE start reference date = min (informed consent date, earliest visit date). 
2. Else AE start reference date = treatment start date  
Impute AE start date - 
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 AE month is missing, the imputed AE start date is set to the mid-year point 
(01JulYYYY). 
b. Else if 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 month is missing, the imputed AE start date is set to the year start point 
(01JanYYYY). 
b. Else if the AE month is not missing, the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day). 
4. If the AE start date year value is equal to the treatment start date year value: 
a. And the AE month is missing the imputed AE start date is set to the AE reference start 
date + 1 day. 
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). 


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c. Else if the AE month is equal to the treatment start date month or greater than the 
treatment start date month, the imputed AE start date is set to the later of (month start 
point (01MONYYYY), AE start reference date + 1 day). 
If complete (imputed) AE end date is available and the imputed AE start date is greater than the 
(imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end date. 
5.1.3 
Concomitant medication date imputation 
1. If the CM end date year value is missing, the date uncertainty is too high to impute a rational 
date. Therefore, if the CM end year value is missing or ongoing, the imputed CM end date 
is set to NULL. 
2. Else, if the CM end date month is missing, the imputed end date should be set to the earliest 
of the (treatment follow up period date, 31DECYYYY, and date of death). 
3. If the CM end date day is missing, the imputed end date should be set to the earliest of the 
(treatment follow up period date, last day of the month, date of death). 
If the imputed CM end date is less than the existing CM start date, use the CM start date as the 
imputed CM end date. 
Concomitant medication start date imputation 
To classify a medication as prior and prior/concomitant, it may be necessary to impute the start 
date. 
Completely missing start dates will be set to one day prior to treatment start date. As a 
conservative approach, such treatments will be classified as prior and concomitant (and 
summarized for each output). 
Concomitant treatments with partial start dates will have the date or dates imputed. The 
following table explains the notation used in the logic matrix 
 
Day 
Month 
Year 
Partial CMD Start Date 
Not used 
MON 
YYYY 
Treatment Start Date 
Not used 
TRTM 
TRTY 
The following matrix explains the logic behind the imputation. 
MON 
MISSING 
MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY 
MISSING 
( 1 ) 
Uncertain 
( 1 ) 
Uncertain 
( 1 ) 
Uncertain 
( 1 ) 
Uncertain 
YYYY < TRTY (2. a ) 
Before 
Treatment
Start 
(2. b ) 
Before 
Treatment
Start 
(2. b ) 
Before 
Treatment
Start 
( 2.b ) 
Before 
Treatment 
Start 


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YYYY = TRTY (4. a ) 
Uncertain 
(4. b ) 
Before 
Treatment
Start 
(4.a ) 
Uncertain 
(4. 
c 
) 
After  
Treatment Start 
YYYY > TRTY (3. a ) 
After Treatment Start 
(3.b ) 
After Treatment Start 
(3.b ) 
After Treatment Start 
(3.b ) 
After Treatment Start 
1. If the CM start date year value is missing, the imputed CM start date is set to one day prior 
to treatment start date. 
2. If the CM start date year value is less than the treatment start date year value, the CM started 
before treatment. Therefore: 
a. If the CM month is missing, the imputed CM start date is set to the mid-year point 
(01JulYYYY). 
b. Else if the CM month is not missing, the imputed CM start date is set to the mid- month 
point (15MONYYYY). 
3. If the CM start date year value is greater than the treatment start date year value, the CM 
started after treatment. Therefore: 
a. If the CM month is missing, the imputed CM start date is set to the year start point 
(01JanYYYY). 
b. Else if the CM month is not missing, the imputed CM start date is set to the month start 
point (01MONYYYY). 
4. If the CM start date year value is equal to the treatment start date year value: 
a. And the CM month is missing or the CM month is equal to the treatment start date 
month, then the imputed CM start date is set to one day prior to treatment start date. 
b. Else if the CM month is less than the treatment start date month, the imputed CM 
start date is set to the mid-month point (15MONYYYY). 
c. Else if the CM month is greater than the treatment start date month, the imputed 
CM start date is set to the month start point (01MONYYYY). 
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM  
end date. 
5.1.3.1 
Prior therapies date imputation 
Not applicable. 
5.1.3.2 
Post therapies date imputation 
Not applicable. 
5.1.3.3 
Other imputations 
Not applicable. 


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5.2 
AEs coding/grading 
Adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.  
The below severity grade will be used in this study: 
• Mild: usually transient in nature and generally not interfering with normal activities 
• Moderate: sufficiently discomforting to interfere with normal activities 
• Severe: prevents normal activities 
5.3 
Laboratory parameters derivations 
Not applicable. 
5.4 
Statistical models  
Not applicable. 
5.5 
Rule of exclusion criteria of analysis sets  
The classification in Table 5-1 will be used for the analysis sets. Participants with PDs as per 
the PD specification document will be excluded from the PPS. 
Table 5-1 
Patient classification 
Analysis Set 
PD ID that 
    
cause 
participants 
to 
be 
excluded 
Non-PD criteria that cause  
participants to be excluded 
FAS 
P_INCL01_ICF 
not 
obtained 
before start 
 
Not in Randomized Analysis Set; 
 
PPS 
P_INCL01_ICF 
not 
obtained 
before start 
M_INCL03_No 
Active 
CNV 
secondary to AMD 
M_INCL04_Absence of IRF/SRF 
study eye 
M_EXCL01_Confounding 
condition study eye 
M_EXCL03_Confound 
med/procedure study eye 
M_EXCL04_Confound 
syst 
condition or Trt 
M_EXCL07_Systemic 
investigational drugs 
M_OTH02_Trt interval wrongly 
adjusted 
M_COMD01_Prohibited meds or 
procedure 
M_TRT04_Under Treatment 
M_TRT05_Over Treatment 
Not in FAS 
AR_EST_01 
AR_ETD_01 
AR_MD_01 
 


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Analysis Set 
PD ID that 
    
cause 
participants 
to 
be 
excluded 
Non-PD criteria that cause  
participants to be excluded 
M_OTH08_Any other PD with 
impact 
 
Table 5-2 lists the non-protocol deviations (analysis restrictions, AR) that may lead to exclusion 
from per-protocol analysis. AR address limitations in the evaluability which result from missing 
or confounding data with underlying background not qualifying as a PD (e.g. early study 
terminations, early treatment discontinuations, missing DAA or BCVA assessments) 
Rules of determination of ARs by programming will be specified in the Programming Data 
Specifications (PDS) documentation. 
Table 5-1 
Non-protocol deviations (analysis restrictions) 
AR ID 
Description of AR 
Inclusion/Exclusion 
in Analysis 
AR_EST_01 
Early study termination due to reasons 
other than lack of efficacy/safety 
Exclude from PPS  
AR_ETD_01 
Early study treatment termination due to 
reasons other than lack of efficacy/safety 
Exclude from PPS 
analyses  
AR_MD_01 
No valid BCVA assessment between 
Week 52 and Week 56 
Exclude from PPS 
analysis 
 
6 
Reference 
Goodman, LA (1964) Simultaneous Confidence Intervals for Contrasts Among Multinomial 
Populations. Ann. Math. Statist; 35 (2):716--725. doi:10.1214/aoms/1177703569.