Clinical trial NCT04047472
Conditions: Neovascular Age-Related Macular Degeneration
Keywords: Macular degeneration age-related macular degeneration (AMD) vision loss macula damage retina damage wet macular degeneration AMD
Sponsor: Novartis Pharmaceuticals
Start date: 2019-11-29; Completion date: 2024-02-28
Enrollment: 397 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To compare brolucizumab to aflibercept in Chinese patients with untreated active choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD)

Detailed description:
This was a randomized, double-masked, multicenter, parallel-group, active-controlled study. The study included 14 scheduled visits over 48 weeks. After confirmation of eligibility at baseline, participants were randomized in a 1:1 ratio to one of the 2 treatment arms:

* Brolucizumab 6 mg: 3 monthly intravitreal injections of brolucizumab 6 mg in the loading treatment period (q4w regimen) up to Week 8 followed by injections every 12 weeks (q12w regimen) or 8 weeks (q8w) up to Week 40 or Week 44, depending on disease activity status.
* Aflibercept 2 mg: 3 monthly intravitreal injections of aflibercept 2 mg in the loading treatment period (q4w regimen) up to Week 8 followed by injections every 8 weeks (q8w) up to Week 40. Disease activity assessments (DAAs) were conducted by the masked investigator for both treatment arms at Weeks 16, 20, 32 and 44 to determine the regimen of brolucizumab arm (i.e., q12w or q8w).

Arms: arm 1: 3 monthly intravitreal injections of brolucizumab 6 mg in the loading treatment period (q4w regimen) up to Week 8 followed by injections every 12 weeks (q12w regimen) or 8 weeks (q8w) up to Week 40 or Week 44, depending on disease activity status. arm 2: 3 monthly intravitreal injections of aflibercept 2 mg in the loading treatment period (q4w regimen) up to Week 8 followed by injections every 8 weeks (q8w) up to Week 40.
Interventions: intervention 1: Brolucizumab 6mg intervention 2: Aflibercept 2 mg
Intervention descriptions: intervention 1: Intravitreal injection intervention 2: Intravitreal injection

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development
RTH258
Clinical Trial Protocol CRTH258A2307 / NCT04047472
A Twelve-Month, Randomized, Double-Masked, Multicenter, 
Phase III, Two-Arm Study Comparing the Efficacy and 
Safety of Brolucizumab 6 mg versus Aflibercept in Chinese 
Patients with Neovascular Age-Related Macular 
Degeneration (HOBBY)
Document type:
Amended Protocol Version
EUDRACT number:
N/A
Version number:
04 (Clean)
Clinical Trial Phase:
III
Release date:
14-Jun-2022
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template version 1.0 dated 01-Dec-2017


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Amendment 4 (14-Jun-2022) ............................................................................................12
Amendment 3 (14-Jan-2022).............................................................................................14
Amendment 2 (14-Oct-2021)............................................................................................15
Amendment 1 (08-Jun-2020) ............................................................................................17
Protocol summary..............................................................................................................19
1
Introduction .......................................................................................................................22
1.1
Background............................................................................................................22
1.2
Purpose ..................................................................................................................24
2
Objectives and endpoints...................................................................................................24
3
Study design ......................................................................................................................25
4
Rationale............................................................................................................................26
4.1
Rationale for study design .....................................................................................26
4.2
Rationale for dose/regimen and duration of treatment ..........................................27
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................27
4.4
Purpose and timing of interim analyses/design adaptations..................................28
4.5
Risks and benefits..................................................................................................28
5
Population..........................................................................................................................29
5.1
Inclusion criteria ....................................................................................................29
5.2
Exclusion criteria...................................................................................................29
6
Treatment...........................................................................................................................31
6.1
Study treatment......................................................................................................31
6.1.1
Investigational and control drugs..........................................................31
6.1.2
Additional study treatments ..................................................................32
6.1.3
Treatment arms/group ...........................................................................32
6.1.4
Treatment duration................................................................................32
6.2
Other treatment(s)..................................................................................................32
6.2.1
Concomitant therapy.............................................................................33
6.2.2
Prohibited medication ...........................................................................33
6.2.3
Rescue medication ................................................................................33
6.3
Subject numbering, treatment assignment, randomization....................................34


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6.3.1
Subject numbering ................................................................................34
6.3.2
Treatment assignment, randomization ..................................................34
6.4
Treatment masking ................................................................................................34
6.5
Dose escalation and dose modification..................................................................36
6.5.1
Dose modifications................................................................................36
6.6
Additional treatment guidance...............................................................................36
6.6.1
Treatment compliance...........................................................................36
6.6.2
Emergency breaking of assigned treatment code..................................37
6.7
Preparation and dispensation.................................................................................37
6.7.1
Handling of study treatment and additional treatment..........................38
6.7.2
Instruction for prescribing and taking study treatment .........................38
7
Informed consent procedures ............................................................................................41
8
Visit schedule and assessments .........................................................................................42
8.1
Screening ...............................................................................................................46
8.1.1
Information to be collected on screening failures.................................46
8.2
Subject demographics/other baseline characteristics.............................................46
8.3
Efficacy..................................................................................................................47
8.3.1
Visual acuity..........................................................................................47
8.3.2
Optical coherence tomography .............................................................47
8.3.3
Color fundus photography and fluorescein angiography......................47
48
8.3.5
Appropriateness of efficacy assessments..............................................48
8.4
Safety.....................................................................................................................48
8.4.1
Laboratory evaluations..........................................................................49
8.4.2
Pregnancy and assessments of fertility .................................................49
8.4.3
Ophthalmic examination.......................................................................50
8.4.4
Other safety evaluations........................................................................51
8.4.5
Appropriateness of safety measurements..............................................51
8.5
Additional assessments..........................................................................................51
8.5.1
Clinical Outcome Assessments (COAs) ...............................................51
8.5.2
Pharmacokinetics ..................................................................................52
8.5.3
Other Assessments ................................................................................52
9
Study discontinuation and completion ..............................................................................52
9.1
Discontinuation......................................................................................................52
9.1.1
Discontinuation of study treatment .......................................................52
9.1.2
Withdrawal of informed consent /Opposition to use data/biological 
samples..................................................................................................53


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9.1.3
Lost to follow-up...................................................................................54
9.1.4
Early study termination by the sponsor.................................................54
9.2
Study completion and post-study treatment ..........................................................55
10 Safety monitoring and reporting........................................................................................55
10.1
Definition of adverse events and reporting requirements......................................55
10.1.1
Adverse events ......................................................................................55
10.1.2
Serious adverse events ..........................................................................56
10.1.3
SAE reporting........................................................................................57
10.1.4
Pregnancy reporting ..............................................................................58
10.1.5
Reporting of study treatment errors including misuse/abuse................58
10.2
Additional Safety Monitoring................................................................................59
10.2.1
Data Monitoring Committee .................................................................59
11 Data Collection and Database management......................................................................59
11.1
Data collection.......................................................................................................59
11.2
Database management and quality control............................................................60
11.3
Site monitoring ......................................................................................................60
12 Data analysis and statistical methods ................................................................................61
12.1
Analysis sets ..........................................................................................................61
12.2
Subject demographics and other baseline characteristics......................................62
12.3
Treatments .............................................................................................................62
12.4
Analysis of the primary endpoint(s) ......................................................................63
12.4.1
Definition of primary endpoint(s).........................................................63
12.4.2
Statistical model, hypothesis, and method of analysis..........................63
12.4.3
Handling of missing values/censoring/discontinuations.......................64
12.4.4
Sensitivity and Supportive analyses......................................................65
12.5
Analysis of secondary endpoints ...........................................................................65
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................65
12.5.2
Safety endpoints....................................................................................66
12.5.3
Pharmacokinetics ..................................................................................67
12.5.4
DNA......................................................................................................68
12.5.5
Biomarkers............................................................................................68
12.5.6
PK/PD relationships..............................................................................68
12.5.7
Patient reported outcomes.....................................................................68
12.5.8
Anti-drug antibody................................................................................68
68
12.7
Interim analyses.....................................................................................................69
12.8
Sample size calculation..........................................................................................69


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12.8.1
Primary endpoint(s)...............................................................................69
13 Ethical considerations and administrative procedures ......................................................69
13.1
Regulatory and ethical compliance........................................................................69
13.2
Responsibilities of the investigator and IRB/IEC..................................................69
13.3
Publication of study protocol and results...............................................................70
13.4
Quality Control and Quality Assurance.................................................................70
14 Protocol adherence ............................................................................................................70
14.1
Protocol Amendments ...........................................................................................71
15 References .........................................................................................................................72
16 Appendices ........................................................................................................................75


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List of tables
Table 2-1
Objectives and related endpoints ..........................................................24
Table 6-1
Investigational and control drug............................................................31
Table 6-2
Prohibited medication ...........................................................................33
Table 6-3
Masking levels ......................................................................................36
Table 8-1
Assessment Schedule ............................................................................43
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................59
Table 12-1
Primary and supplementary estimands..................................................64
Table 12-2
Non-compartmental pharamcokinetic parameters ................................68
List of figures
Figure 3-1
Study design..........................................................................................26
Figure 6-1
Dosing schedule ....................................................................................39


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List of abbreviations
A/G
albumin/globulin
ADA
anti-drug antibodies
AE
adverse event
ALT
alanine transferase
AMD
age-related macular degeneration
ANOVA
analysis of variance
AR
analysis restriction
AST
aspartate transferase
AUC
area under the curve
BCVA
best-corrected visual acuity
BUN
blood urea nitrogen
CFR
Code of Federal Regulation
CI
confidence interval
Cmax
maximum concentration
CMO&PS
Chief Medical Office and Patient Safety
CNV
choroidal neovascularization
CO
country organization
COA
clinical outcomes assessment
COVID-19
Coronavirus disease 2019
CRC
Central Reading Center
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSFT
Central Subfield Thickness
CSFTns
Central Subfield Thickness-neurosensory retina
CSFTtot
Central Subfield Thickness Total
CSR
Clinical Study Report
CV
coefficient of variation
DAA
disease activity assessment
DAR
dose administration record
DMC
Data Monitoring Committee
EC
Ethics committee
EDC
Electronic Data Capture
EMA
European Medicines Agency
EOS
End of Study
EOT
End of Treatment
eSAE
Electronic Serious Adverse Event
ESI
Event of Special Interest
ETDRS
Early Treatment Diabetic Retinopathy Study 
EU
European Union
FA
fluorescein angiography
FAS
Full Analysis Set
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GGT
gamma glutamyl transaminase
HRQL
health related quality of life


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IB
Investigator’s Brochure
ICH
International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human 
Use
ICF
Informed consent form
IEC
Independent Ethics Committee
IOI
Intraocular inflammation
IN
Investigator Notification
IOP
intraocular pressure 
IP
investigational product
IRB
Institutional Review Board
IRC
intraretinal cysts
IRF
intraretinal fluid
IRT
Interactive Response Technology
IUD
intrauterine device 
IUS
intrauterine system
IVT
intravitreal
LDH
lactate dehydrogenase
LFT
Liver function test
LLOQ
lower limit of quantification
LOCF
last observation carried forward
LPLV
Last Patient Last Visit
MedDRA
Medical dictionary for regulatory activities
MMRM
mixed model repeated measures
nAMD
neovascular age-related macular degeneration
NEI
national eye institute
NIH
National Institutes of Health
OCT
Optical Coherence Tomography
PD
protocol deviation
PK
pharmacokinetic(s)
PPS
per-protocol set
PRO
patient reported outcome
PT
preferred term
q12w
every 12 weeks
QMS
Quality Management System
QoL
quality of life
RAP
retinal angiomatous proliferation
RAS 
randomized analysis set
RAO
Retinal artery occlusion
RBC
red blood cell(s)
RO
Retinal vascular occlusion
RoW
rest of world
RPE
retinal pigment epithelium
RV
Retinal vasculitis
SAE
serious adverse event
SAP
Statistical Analysis Plan
scFv
single-chain variable fragment


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SD-OCT
Spectral Domain Optical Coherence Tomography
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SOC
system organ class
SOP
Standard Operating Procedure
SRF
subretinal fluid
SUN
Standardization uveitis nomenclature
SUSAR
Suspected Unexpected Serious Adverse Reactions
ULQ
upper limit of quantification
US
United States
USM
Urgent Safety Measures
VEGF
vascular endothelial growth factor 
VFQ-25
Visual Function Questionnaire-25
WBC
white blood cell(s)
WHO
World Health Organization


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Control drug
Any drug (an active drug or an inactive drug, such as a placebo) which is used as a 
comparator to the investigational drug being tested in the trial
Dosage
Dose of the study treatment given to the subject in a time unit
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study data using 
data collection systems, such as Web-based applications, interactive voice response 
systems and clinical laboratory interfaces. EDC includes the use of Electronic Case 
Report Forms (eCRFs) which are used to capture data transcribed from paper source 
forms used at the point of care.
Enrollment
Point/time of subject entry into the study at which informed consent must be obtained (i.e. 
prior to starting any of the procedures described in the protocol)
Estimand
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.
Healthy volunteer
A person with no known significant health problems who volunteers to be a study 
participant 
Investigational 
drug
The study drug whose properties are being tested in the study; this definition is consistent 
with US CFR 21 Section 312.3 and is synonymous with “investigational new drug” or 
“investigational medicinal product”.
Investigational 
treatment
All investigational drug(s) whose properties are being tested in the study as well as their 
associated treatment controls. This includes any placebos, any active controls, as well as 
approved drugs used outside of their indication/approved dosage or tested in a fixed 
combination. Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed by the protocol 
when used within approved indication/dosage.
Medication 
number
A unique identifier on the label of each study drug package in studies that dispense study 
drug using an IRT system.
Patient
An individual with the condition of interest
Period
A minor subdivision of the study timeline; divides phases into smaller functional segments 
such as screening, baseline, titration, washout, etc.
Personal data
Subject information collected by the Investigator that is transferred to Novartis for the 
purpose of the clinical trial. This data includes the subject identifier information, study 
information and biological samples.
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned completion of all 
study drug administration and assessments; at this time all study drug administration is 
discontinued and no further assessments are planned.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding to a specific 
treatment arm assignment
Screen Failure
A subject who is screened but is not treated or randomized
Study completion
Point/time at which the subject came in for a final evaluation visit or when study drug was 
discontinued whichever is later.
Study drug 
discontinuation
Point/time when subject permanently stops taking study drug for any reason; may or may 
not also be the point/time of premature subject withdrawal.
Study treatment
Any drug administered to the study participants as part of the required study procedures; 
includes investigational drug (s), control(s) or non-investigational medicinal product(s)
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the defined study 
treatment completion date
Subject
An individual who has consented to participate in this study. The term Subject may be 
used to describe either a healthy volunteer or a patient.


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Subject number
A number assigned to each subject who enrolls in the study. When combined with the 
center number, a unique identifier is created for each subject in the study.
Variable
A measured value or assessed response that is determined in specific assessments and 
used in data analysis to evaluate the drug being tested in the study
Withdrawal of 
study consent 
(WoC)
Withdrawal of consent from the study occurs when the participant explicitly requests to 
stop use of their data and biological samples (opposition to use data and biological 
samples) AND no longer wishes to receive study treatment, AND does not agree to 
further protocol required assessments. This request should be in writing (depending on 
local regulations) and recorded in the source documentation.
Opposition to use data/biological samples occurs in the countries where collection and 
processing of personal data is justified by a different legal reason than consent.


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Amendment 4 (14-Jun-2022) 
Amendment rationale 
In the spirit of the bridging concept under ICH E5, and also based on the cumulative evidence 
on brolucizumab as of today (i.e., from the two successful global pivotal Phase III studies 
RTH258-C001 (HAWK) and RTH258-C002 (HARRIER)), the main purpose of this 
amendment is to adjust the alpha level from 0.05 to 0.1 to result in a sample size reduction 
from approximately 494 to 390 subjects.
In particular, data from the two global pivotal studies, RTH258-C001 (HAWK) and RTH258-
C002 (HARRIER), have demonstrated an overall favorable benefit-risk profile of 
brolucizumab in the treatment of subjects with nAMD. A total of 687 subjects were treated 
with brolucizumab 6 mg and completed Week 48 for the two pivotal studies. Both studies 
confirmed the hypotheses of non-inferiority of brolucizumab 6 mg to aflibercept 2 mg for the 
primary endpoint, BCVA change from Baseline to Week 48, with a non-inferiority margin of 
4 letters (1-sided significance level of 0.025). The least squares mean difference between the 
brolucizumab and aflibercept arms for RTH258-C001 (HAWK) and RTH258-C002 
(HARRIER) studies was respectively −0.2 letters and –0.7 letters, with a lower limit of the 
95% CI being −2.1 letters (p < 0.0001), and −2.4 letters (p= 0.0001). Intraocular inflammation 
(IOI), an AE of special interest, was observed from 5.3% and 2.7% of the subjects in the 
brolucizumab 6 mg arm in their study eyes up to Week 48, respectively in the RTH258-C001 
(HAWK) and RTH258-C002 (HARRIER) studies.
To demonstrate consistency in efficacy among Chinese subjects with what was observed in 
the two global pivotal studies, a statistical design with an alpha level of 0.1 is considered 
sufficient, which resulted in a sample size of approximately 390 subjects. Moreover, the 
proposed sample size will also provide sufficient evidence for the safety evaluation.  
Assuming similar IOI rates as observed from RTH258-C001 (HAWK) and RTH258-C002 
(HARRIER) studies, with approximately 195 subjects in the brolucizumab arm, there is a 
99.6% and 85.4% probability respectively to observe at least 3 subjects that would experience 
IOI.   
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strikethrough (red font for deletions and red underlined for insertions).
Protocol sections changed in relation to this population reduction are:

Protocol Summary: Population sample size and significance level alpha for data analysis 
are updated.

Section 5 Population: Population sample size updated.

Section 12.4.2 Statistical model, hypothesis, and method of analysis: Significance level 
alpha is updated for statistical hypotheses testing.

Section 12.5.1 Efficacy and/or Pharmacodynamic endpoint(s): Confidence interval level 
updated for secondary efficacy endpoints.


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
Section 12.8.1 Primary endpoint(s): Sample size calculation is updated with significance 
level alpha = 0.1.
Other minor clarifications and corrections were made where applicable.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation. 
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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Amendment 3 (14-Jan-2022) 
Amendment rationale 
Amendment version 2 did not carry through some of the changes that had already been 
implemented in Amendment version 1 in Section 12 Data analysis and statistical methods of 
the protocol.  The purpose of this amendment is to reinstate these changes from Amendment 
version 1.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strikethrough (red font for deletions and red underlined for insertions).
Protocol sections changed include Section 12.4.2, Table 12-1, and Section 12.4.4, in order to 
reflect the changes amended in protocol version 1.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval, according to local regulations, prior to implementation. 


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Amendment 2 (14-Oct-2021) 
Amendment rationale 
The main purpose of this amendment is to implement the Urgent Safety Measures (USM) 
described in the 10-Aug-2021 Dear Investigator Letter (DIL) into the study protocol.  The 
USM were implemented for ongoing studies not achieving Last Patient Last Visit (LPLV) by 
11-Aug-2021 and in response to the identification of a causal immune-mediated mechanism 
of the previously identified risk of retinal vasculitis (RV), and/or retinal vascular occlusion 
(RO), typically in the presence of intraocular inflammation (IOI) indicating a requirement to 
discontinue treatment with brolucizumab (RTH258) in patients who develop events of RV 
and/or RO.
This amendment also includes information on gender imbalance on IOI following 
brolucizumab treatment and recommendations on the time window for a study subject to 
receive the COVID-19 vaccine. Some other administrative changes have also been 
incorporated.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strikethrough (red font for deletions and red underlined for insertions).
Protocol sections changed in relation to this emerging safety measure are:

Section 1.1 Background: Information added to describe Urgent Safety Measures

Section 4.5 Risk and benefits: Information added to describe Urgent Safety Measures and 
additional information on gender imbalance on IOI following brolucizumab treatment

Section 8.4.3 Ophthalmic examination: Requirement of treatment discontinuation was 
added if subject developed RV and/or RO.
Other changes incorporated in this amendment

Table 2-1 Objectives and related endpoints: 
 

Section 6.2.1.1 Permitted concomitant therapy requiring caution and/or action: added 
recommendations on the time window for a study subject to receive the COVID-19 
vaccine.

Section 6.7.2 Instruction for administering study treatment: Requirement of treatment 
discontinuation was added if subject developed RV and/or RO, in both arms.

Table 8-1 Assessment Schedule: footnote was added to clarify that PK parameters will be 
measured by using blood collection for ADA analysis at visit 6 since PK and ADA testing 
are both required at this visit in the study.

Section 8.5.2 Pharmacokinetics: to make consistent with the following wordings 
(approximately 12 subjects per treatment arm to maintain masking).


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
Section 8.5.3 Other Assessments: To clarify that PK parameters would be determined 
using the blood collected for ADA analysis at visit 6. 

Section 9.1.1 Discontinuation of study treatment: Changes were made as follows:
Subject develops a retinal vasculitis and/or a retinal vascular occlusion event

Section 9.1.2 Withdrawal of informed consent /Opposition to use data/biological samples: 
To further clarify the definition of withdrawal of informed consent.
 

Other minor clarifications and corrections were made where applicable.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation. 
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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Amendment 1 (08-Jun-2020)
Amendment rationale 
The main purpose of this amendment is to provide clarification and guidance on safety 
assessments in accordance to the urgent safety measure regarding the post-marketing reports 
with brolucizumab (Beovu®) in the treatment of nAMD, which were identified as retinal 
vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular 
inflammation, that may result in severe vision loss. In addition, the amendment includes the 
modifications due to COVID-19 pandemic. 
Changes to the protocol
Protocol sections changed in relation to this emerging safety issue are: 

Section 1.1 Background: Information was added to describe new safety signal from 
post-marketing case reports.

Section 6.7.2 Instructions for prescribing and taking study treatment: Additional guidance 
was added to this section emphasizing that if any sign of intraocular inflammation is 
present, an IVT injection must not be performed and patients should be treated for IOI 
according to clinical practice. 

Additional examination and assessments included to fully characterize cases of intraocular 
inflammation were made in the following sections: 

Table 8-1 Assessment schedule

Section 8.3.3 Color fundus photography and fluorescein angiography 

Section 8.4.3 Ophthalmic Examination

Section 8.4.5 Other safety evaluations 
Changes were incorporated to address the COVID-19 pandemic in the following sections:

Section 7 Informed Consent Procedures

Section 8 Visit Schedule and Assessments

Section 8.4 Safety 

Section 8.4.1 Laboratory evaluations 

Section 12 Data analysis and statistical methods
Other changes incorporated in this amendment: 

Section 1.1 Background: Updated HAWK/ HARRIER study status. 

Section 6.4 Treatment masking: Language was added to clarify unmasked investigator/site 
personnel must not be switched to a masked role at any time after randomization. 

Table 8-1 Assessment schedule: delete the row of visit number and related footnote 
since it is only for internal use. Update the superscript and number of footnote.

Section 8.2 Subject demographics/other baseline characteristics: Removed ethnicity since 
it was not collected in the study. 

Section 8.3.3 Color fundus photography and fluorescein angiography 
 
: Change the previous routine evaluation period of 
image before screening visit from 3 days to 14 days to be consistent with other studies in 
RTH program.


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
Section 8.4.3 Ophthalmic examination: Expanded IOP measurement to non-contact 
tonometer to follow the local clinical practice. Clarification on the timing for post-
injection IOP measurement.

Section 8.5.3 Other assessments

Section 10.1.3 SAE Reporting: Clarification of the SAE reporting period.

Section 12 Analysis sets and statistical methods: Language was adapted to clarify primary 
and supplementary estimands and analyses based on estimands

Section 12.2 Subject demographics and other baseline characteristics: Removed ethnicity 
analysis to align with change in section 8.2. 

Section 15 References: References were added regarding grading systems of anterior 
chamber cells and flare, and vitreous cells and haze. 
Updated the List of Abbreviations and Glossary of terms 
Other minor clarifications were made where applicable. Changes to specific sections of the 
protocol are shown in the track changes version of the protocol using strike through red font for 
deletions and red underlined for insertions.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
This amendment is required for patient safety (i.e. necessary to eliminate immediate hazards to 
the trial subjects ICH GCP 3.3.8). Therefore it will be implemented prior to IRB/IEC approval, 
but will be sent for approval as well.
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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Protocol summary
Protocol number
CRTH258A2307
Full Title
A Twelve-Month, Randomized, Double-Masked, Multicenter, Phase III, Two-Arm Study 
Comparing the Efficacy and Safety of Brolucizumab 6 mg versus Aflibercept in Chinese 
Patients with Neovascular Age-Related Macular Degeneration (HOBBY)
Brief title
Study of efficacy and safety of brolucizumab vs. aflibercept in Chinese patients with 
Neovascular Age-Related Macular Degeneration
Sponsor and 
Clinical Phase
Novartis Phase III
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
This study is designed to evaluate the efficacy and safety of brolucizumab in treatment 
of Chinese patients with Neovascular Age-Related Macular Degeneration (nAMD)
Primary 
Objective(s) 
To demonstrate that brolucizumab 6 mg is not inferior to aflibercept 2 mg with respect to 
the change in Best Corrected Visual Acuity (BCVA) after 48 weeks of treatment
Secondary 
Objectives
To assess the efficacy and the ocular and systemic safety of brolucizumab:

To estimate the proportion of q12w subjects (1 injection every 12 weeks) up to 
Week 48 in the brolucizumab 6 mg treatment arm

To estimate the predictive value of the first q12w cycle for maintenance of q12w 
treatment up to Week 48 in the brolucizumab 6 mg treatment arm

To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg over the 
time period up to Week 48 by assessing changes in BCVA

To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg over the 
time period up to Week 48 by assessing changes in anatomical parameters of 
disease activity

To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg at the 
end of the matched treatment phase

To assess the safety and tolerability of brolucizumab 6 mg relative to aflibercept 2 
mg

To assess visual function-related subject reported outcomes following treatment 
with brolucizumab 6 mg relative to aflibercept 2 mg

To assess immunogenicity of brolucizumab 6 mg

To assess systemic PK of brolucizumab at 6 mg following a single intravitreal (IVT) 
injection
Study design
In this twelve-month, randomized, double-masked, multicenter, active controlled study, 
consenting patients will participate in a screening period, lasting up to 14 days. Eligible 
patients will be randomized in a 1:1 ratio to one of the two treatment arms:

Brolucizumab 6 mg: 3 x q4w followed by q12w/q8w up to Week 40 or Week 44, 
depending on disease activity status.

Aflibercept 2 mg: 3 x q4w followed by q8w up to Week 40
Population
Approximately 390 randomized Chinese patients ≥ 50 years of age with untreated active 
choroidal neovascularization (CNV) secondary to Age-Related Macular Degeneration 
(AMD) in the study eye
Key Inclusion 
criteria
1.
Written informed consent must be obtained before any assessment is performed.
2.
Male or female Chinese patient ≥ 50 years of age at the time of screening.
Study Eye
1.
Active choroidal neovascularization (CNV) lesions secondary to AMD that affect the 
central subfield (including retinal angiomatous proliferation (RAP) lesions with a 
CNV component) in the study eye at screening


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2.
Total area of CNV (including both classic and occult components) must comprise > 
50% of the total lesion area in the study eye at screening and confirmed by the 
Central Reading Center (CRC).
3.
Intra and/or subretinal fluid affecting the central subfield of the study eye at 
screening and confirmed by the CRC.
4.
BCVA between 78 and 23 letters, inclusive, in the study eye at screening and 
Baseline using Early Treatment Diabetic Retinopathy Study (ETDRS) testing.
Key Exclusion 
criteria
1.
Any active intraocular or periocular infection or active intraocular inflammation (e.g. 
infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis, 
uveitis) in study eye at Baseline.
2.
Central subfield of the study eye affected by fibrosis or geographic atrophy 
assessed by color fundus photography at screening and confirmed by the CRC.
3.
Total area of fibrosis ≥ 50% of the total lesion at screening
4.
Subretinal blood affecting the foveal center point and/or ≥50% of the lesion at 
screening
5.
Previous treatment with any approved or investigational drugs for neovascular AMD 
in the study eye (other than vitamin supplements).
6.
Retinal pigment epithelium (RPE) rip/tear in the study eye at screening.
7.
Current vitreous hemorrhage or history of vitreous hemorrhage in the study eye 
within 4 weeks prior to Baseline.
Study treatment

Brolucizumab 6 mg

Aflibercept 2 mg
Efficacy 
assessments

Visual Acuity

Optical Coherence Tomography (OCT)

Color fundus photography and fluorescein angiography (FA)
Pharmacokinetic 
assessments 

Systemic brolucizumab exposure
Key safety 
assessments

Adverse Events, including Adverse Events of special interest

Vital Signs

Blood chemistry/hematology/urinalysis

Standard ophthalmic examinations
Other 
assessments 

Visual Function Questionnaire-25 (VFQ-25)

Anti-drug antibody (ADA) status of brolucizumab
Data analysis
Primary analysis data set: The primary data set for all efficacy analyses is the full 
analysis set (FAS) with missing values imputed by last observation carried forward 
(LOCF). The FAS comprises all subjects to whom study treatment has been assigned 
by randomization and who receive at least one IVT injection of the study treatment. 
Primary and key secondary endpoints:
The primary efficacy endpoint is the change from Baseline in BCVA at Week 48.
The first key secondary endpoint is average change in BCVA from Baseline over the 
period Week 36 through Week 48.
Statistical Hypotheses and testing strategy:
The statistical hypothesis for the primary endpoint and first key secondary endpoint is 
non-inferiority of brolucizumab 6 mg to aflibercept 2 mg within a margin of 4 letters. The 
following 2 hypotheses will be tested in the pre-specified hierarchical sequence according 
to their numbering (HAn, n = 1, 2). Consequently, confirmatory testing of the second 
hypothesis requires rejection of the first null hypothesis. In this setting, each hypothesis 
will be assessed at a one-sided significance level of 0.05, while keeping the global type I 
error rate at 0.05. 
The following noninferiority hypotheses are related to a noninferiority margin of 4 letters.


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48 = Week 48, 36-48 = Week 36 through 48, R= brolucizumab 6 mg, A= aflibercept 2 mg
H01: μ48R - μ48A ≤ -4 letters vs HA1: μ48R - μ48A > -4 letters
μ48R and μ48A being the corresponding unknown true mean BCVA changes from Baseline 
to Week 48.
H02: μ36-48R - μ36-48A ≤ -4 letters vs HA2: μ36-48R - μ36-48A > -4 letters
μ36-48R and μ36-48A being the corresponding unknown true mean values for the average 
change in BCVA from Baseline over the period Week 36 through 48.
Primary statistical method: For the test of non-inferiority, a two-sided 90% CI for the 
treatment difference will be derived from an analysis of variance (ANOVA) model with 
treatment, Baseline BCVA categories (≤ 55, 56-70, ≥ 71 letters) and age categories (< 
75, ≥ 75 years) as factors. In order to demonstrate non-inferiority, the lower limit of the 
two-sided 90% CI for the treatment difference (brolucizumab 6 mg – aflibercept 2 mg) 
must be greater than -4 letters. 
Sample size justification: In the spirit of bridging concept under ICH E5, A sample size 
of 175 subjects per treatment arm is sufficient to demonstrate noninferiority (margin = 4 
letters) of brolucizumab 6 mg versus aflibercept 2 mg with respect to the BCVA change 
from Baseline to Week 48 at a one-sided alpha level of 0.05 with a power of approximately 
80% assuming equal efficacy and a common standard deviation of 15 letters. A power of 
at least 80% can be expected for the first key secondary endpoint assuming that 
averaging BCVA change from Baseline over the 4 time points will not lead to an increase 
in the standard deviation. To account for a drop-out rate of 10%, a total of 195 subjects 
will be randomized per treatment arm.
Key words
Neovascular 
Age-related 
Macular 
Degeneration 
(AMD), 
intravitreal 
injection, 
brolucizumab, aflibercept, double-masked


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1
Introduction
1.1
Background
Age-related macular degeneration (AMD) is the leading cause of severe vision loss affecting 
10%-13% of people over the age of 65 in North America, Europe, and Australia 
(Smith et al 2001, Rein et al 2009, Kawasaki et al 2010).
There are few data on the epidemiology of AMD in the Asian population. In a Shihpai Eye 
Study (Hsu et al 2004), a population-based cross-sectional study of an elderly Chinese 
population 65 years or older in Taiwan, AMD was the cause of visual impairment in 10.4% of 
the subjects. In the epidemiological study in Shanghai China, it was reported that the prevalence 
of AMD (dry and wet combination) was 15.5% of the overall population that were more than 
50 years old (Li X 2013). The prospective Hisayama study in a Japanese population aged 50 
years or older reported for AMD prevalence of 19.5% in men and of 14.9% in women 
(Miyazaki et al 2003). Considering an aging population and socioeconomic development, it is 
expected that the incidence of visual impairment due to AMD will increase over time in China 
(Wong et al 2008).
AMD is classified into 2 clinical subtypes: the non-neovascular (atrophic) or dry form and the 
neovascular (exudative) or wet form (Ferris 1983, Lim et al 2012, Miller 2013). Neovascular 
AMD is characterized by the growth of abnormal new blood vessels (neovascularization) under 
the retinal pigment epithelium (RPE) or subretinal 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 anti-vascular endothelial growth factor (anti-VEGF) treatments 
(Ferris 1983, Sommer et al 1991, Wong et al 2008).
Anti-VEGFs and unmet medical need in treatment of nAMD VEGF has been shown to be 
elevated in patients with neovascular AMD (nAMD), and is thought to play a key role in the 
neovascularization 
process 
(Spilsbury et al 2000). 
The 
use 
of 
intravitreal 
(IVT) 
pharmacotherapy targeting VEGF has significantly improved visual outcomes in patients with 
neovascular AMD (Bloch et al 2012, Campbell et al 2012). Anti-VEGF treatments, such as 
ranibizumab (Lucentis ®) and aflibercept (Eylea ®), inhibit VEGF signaling pathways and have 
been shown to halt the growth of neovascular lesions and resolve retinal edema. However, the 
patient monitoring and treatment burden remain high with approved anti-VEGF therapies.
Currently, three anti-VEGFs are approved for treatment of nAMD in China: ranibizumab 
(Lucentis®), conbercept (Lumitin®) and aflibercept (Eylea®). The Chinese prescribing 
information recommends a loading phase for all anti-VEGFs in nAMD, followed by less 
frequent injections in a comparable range as in other countries. Lucentis® is dosed monthly for 
the first three months, followed by 4 – 5 injections per year or by injections every 3 months, 
but with reduced efficacy compared to monthly dosing. Eylea® is dosed monthly for the first 
three months followed by injections every 2 months (8 weeks), and Lumitin®  is dosed monthly 


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for the first three months followed by injections every 3 months, while both efficacies compared 
to Lucentis® have not been established.
Physicians have responded to the treatment burden in nAMD by exploring different regimens 
with fewer injections (Gupta et al 2011). In the real-world setting, patients with nAMD may not 
achieve the best possible long-term outcomes (Tufail et al 2014, Holz et al 2014, Chong 2016), 
as vision continues to decline despite anti-VEGF treatment often due to the underutilization of 
treatment and monitoring (Holz et al 2015). Some patients undergo treatment fatigue with anti-
VEGF therapies and choose to discontinue treatment. (Boulanger-Scemama et al 2015). This 
can result in recurrent disease and permanent vision loss (Essex et al 2016). Therefore, unmet 
medical needs for effective and more durable anti-VEGF therapies still exist for patients with 
nAMD (Freund et al 2013).
Brolucizumab development program in nAMD Brolucizumab (RTH258, formerly 
ESBA1008) is a humanized single-chain Fv (scFv) antibody fragment inhibitor of vascular 
endothelial growth factor A with a molecular weight of ~26 kDa. Brolucizumab is an inhibitor 
of VEGF-A and works by binding to the receptor binding site of the VEGF-A molecule, thereby 
preventing the interaction of VEGF-A with its receptors VEGFR1 and VEGFR2 on the surface 
of endothelial cells.
The smaller molecular size of the scFv delivers a higher molar dose, which prolongs the 
therapeutic effect and enables better tissue penetration at the retina, compared to whole 
antibodies and larger antibody fragments. A low molecular weight and high concentration 
gradient between the vitreous and the retina should increase drug distribution into the target site 
of action, ensuring rapid and effective control of anatomical disease activity.Safety, efficacy, 
and pharmacokinetics of brolucizumab in subjects with nAMD were evaluated in the following 
completed clinical studies:

Single ascending dose study of brolucizumab (0.5, 3.0, 4.5 and 6 mg) versus ranibizumab 
0.5 mg (Alcon protocol C-10-083, SEE),

56-week multiple dose study of brolucizumab 6 mg versus aflibercept 2 mg (Alcon 
protocol C-12-006, OSPREY),

Proof-of concept study of two concentrations of brolucizumab (120 mg/mL and 60 
mg/mL) applied as a microvolume injection (10 μL) or infusion (8.3 μL) (Alcon protocol 
C-13-001, OWL),

3 dose study of brolucizumab at 6mg or 3mg in patients of Japanese and non-Japanese 
ancestry (Alcon protocol RTH258-E003 also referred to as CRTH258A2201, SHRIKE).
Two pivotal, two-year, randomized, double-masked, multicenter phase III studies of 
brolucizumab were completed in patients with nAMD: RTH258-C001 (HAWK) and RTH258-
C002 (HARRIER). The primary objective of both studies was to demonstrate noninferiority of 
brolucizumab to aflibercept. Analysis of data up to Week 48 demonstrated noninferiority of 
brolucizumab 3 mg and 6 mg versus aflibercept in mean change in BCVA from Baseline to 
Week 48. A majority of subjects, 56% (HAWK) and 51% (HARRIER), were maintained 
exclusively on a q12w interval following the loading phase through Week 48. Brolucizumab 
was generally well tolerated with overall adverse event rates comparable to aflibercept.
In general, brolucizumab was demonstrated to be safe and well tolerated with an ocular and 
systemic safety profile similar to ranibizumab and aflibercept and non-inferior efficacy as 
compared to ranibizumab and aflibercept. 


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Since the initial marketing authorization approval in October 2019 for the treatment of nAMD, 
adverse events of retinal vasculitis and/or retinal vascular occlusion, that may result in severe 
vision loss and typically in the presence of intraocular inflammation, have been reported from 
post-marketing experience with brolucizumab (Beovu®). Results of the mechanistic study 
BASICHR0049 on blood samples from nAMD patients exposed to brolucizumab and having 
subsequently developed retinal vasculitis and/or retinal vascular occlusion, taken together with 
accumulated data from HAWK, HARRIER and CRTH258AUS04 (MERLIN), regarding the 
association of treatment-emergent immunogenicity and IOI, indicate a causal link between the 
treatment-emergent immune reaction against brolucizumab and the brolucizumab-related 
retinal vasculitis and/or retinal vascular occlusion, typically in the presence of IOI. Considering 
the incidence of these events is uncommon, the overall risk/benefit assessment remains positive. 
Please refer to the Brolucizumab Investigator’s Brochure (IB) for further details.
1.2
Purpose
The purpose of the study is to evaluate the efficacy and safety of brolucizumab 6 mg versus 
aflibercept 2 mg in Chinese patients with nAMD.
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 demonstrate that brolucizumab 6 mg is not 
inferior to aflibercept 2 mg with respect to the 
change in BCVA after 48 weeks of treatment

Change in BCVA from Baseline to Week 48

Average change in BCVA from Baseline over the 
period Week 36 to Week 48
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To estimate the proportion of q12w subjects (1 
injection every 12 weeks) up to Week 48 in the 
brolucizumab 6 mg treatment arm

q12w treatment status at Week 48 (for subjects 
randomized to brolucizumab 6 mg only)

To estimate the predictive value of the first q12w 
cycle for maintenance of q12w treatment up to 
Week 48 in the brolucizumab 6 mg treatment arm

q12w treatment status at Week 48 within the 
subjects with no q8w need during the first q12w 
cycle (Week 16 and Week 20) (for subjects 
randomized to brolucizumab 6 mg only)

To evaluate the efficacy of brolucizumab 6 mg 
relative to aflibercept 2 mg over the time period 
up to Week 48 by assessing changes in BCVA

Change in BCVA from Baseline to each 
postbaseline visit

Average change in BCVA from Baseline over the 
period Week 4 to Week 48

Average change in BCVA from Baseline over the 
period Week 12 to Week 48

Gain in BCVA of 15/10/5 letters or more from 
Baseline at each postbaseline visit

Number and percentage of subjects with BCVA 
of 73 letters or more at each visit

Loss in BCVA of 15/10/5 letters or more from 
Baseline at each postbaseline visit

To evaluate the efficacy of brolucizumab 6 mg 
relative to aflibercept 2 mg over the time period 
up to Week 48 by assessing changes in 
anatomical parameters of disease activity

Change in CSFTtot from Baseline to each 
postbaseline visit

Average change in CSFTtot from Baseline over 
the period Week 36 through Week 48

Average change in CSFTtot from Baseline over 
the period Week 4 to Week 48


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Objective(s)
Endpoint(s)

Change in CSFTns from Baseline to each 
postbaseline visit

Change in area of CNV lesion from Baseline at 
Weeks 12 and 48

Presence of subretinal and/or intraretinal fluid 
(central subfield) at each postbaseline visit (and 
specifically Week 16 and Week 48)

Number of visits with simultaneous absence of 
subretinal and intraretinal fluid (central subfield) 
during Week 36 to Week 48

Presence of subretinal fluid (central subfield) at 
each postbaseline visit

Presence of intraretinal fluid (central subfield) at 
each postbaseline visit

Presence of sub RPE fluid (central subfield) at 
each postbaseline visit

To evaluate the efficacy of brolucizumab 6 mg 
relative to aflibercept 2 mg at the end of the 
matched treatment phase

Change in CSFTtot from Baseline at Week 16

Presence of subretinal and/or intraretinal fluid 
(central subfield) at Week 16 

q8w treatment need identified at Week 16

To 
assess 
the 
safety 
and 
tolerability 
of 
brolucizumab 6 mg relative to aflibercept 2 mg

Incidence and characteristics of treatment-
emergent adverse events

Treatment-emergent changes in ocular and 
systemic parameters

Presence of fibrosis from color fundus 
photography by assessment visit

To assess visual function-related subject reported 
outcomes following treatment with brolucizumab 6 
mg relative to aflibercept 2 mg

Change in subject reported outcomes (VFQ-25) 
total and subscale scores from Baseline to 
Weeks 24 and 48

To assess immunogenicity of brolucizumab 6 mg

ADA status at Baseline (enrollment), Weeks 4, 
12, 24, 36, and 48 (End of Study)

To assess systemic PK of brolucizumab at 6 mg 
following a single IVT injection

PK parameters after first brolucizumab 6 mg 
dose in a subset of subjects
3
Study design
This is a randomized, double-masked, multicenter, parallel-group, active-controlled study. The 
study includes 14 scheduled visits over 48 weeks. A screening period of 2 weeks will be used 
to assess eligibility.


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After confirmation of eligibility at Baseline, patients will be randomized in a 1:1 ratio to one of 
the two treatment arms:

Brolucizumab 6 mg: three monthly intravitreal injections of brolucizumab 6 mg in the 
loading treatment period (q4w regimen) up to Week 8 followed by injections every 12 
weeks (q12w regimen) or 8 weeks (q8w regimen) up to Week 40 or Week 44, depending 
on disease activity status.

Aflibercept 2 mg: three monthly intravitreal injections of aflibercept 2 mg in the loading 
treatment period (q4w regimen) up to Week 8 followed by injections every 8 weeks 
(q8w regimen) up to Week 40.
Only one eye fulfilling all eligibility criteria will be selected/ treated and will be defined as the 
study eye.
There are no stratification factors in this study.
For an overview of the study design please see Figure 3-1 below:
Figure 3-1
Study design
q4w - injection every 4 weeks; q8w - injection every 8 weeks; q12w - injection every 12 weeks
4
Rationale
4.1
Rationale for study design
This study is designed as a randomized, multi-center, double-masked, 2 arm, active controlled, 
prospective study to demonstrate the safety and efficacy of brolucizumab 6 mg against the 
active control, aflibercept 2 mg, used per approved label in China. Since the treatment schedule 
is different between arms, to ensure masking, the following will apply:


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
subjects will receive active or sham injection at each protocol visit except Week 12 and 
Week 48 visits (no scheduled treatment for any arm),

disease activity assessment (DAA) will be performed for both arms at protocol specified 
visit,

to fulfill the double-masking requirement, the investigational site will have masked and 
unmasked staff.
Non-inferiority testing related to the primary efficacy parameter Best-corrected visual acuity 
(BCVA) will be based on a margin of 4 letters. This non-inferiority margin provides assurance 
that any proof of non-inferiority only occurs if the observed treatment differences are of no 
clinical relevance.
The patient population will be described in more detail in Section 5.
4.2
Rationale for dose/regimen and duration of treatment
The dose and regimen for brolucizumab are based on:

The performed analysis of data up to Week 48 from the two phase III brolucizumab 
studies (HAWK and HARRIER) in nAMD, brolucizumab 6 mg and 3 mg doses showed 
comparable efficacy and safety profiles to aflibercept 2 mg.

The numerical differences between the 3 mg and 6 mg dose seen in the functional and 
anatomical endpoints, in the proportion of subjects on a q12w dosing regimen and in the 
control of disease activity consistently favor the 6 mg dose. Overall, the safety of
brolucizumab 6 mg was comparable to the 3mg dose. Hence, brolucizumab 6 mg dose will 
be used in this study.
Aflibercept will be administered as per the approved label in China.
Route of administration is intravitreal injection as for all anti-VEGF treatments currently 
approved for treatment of nAMD.
Study duration of 48 weeks is deemed sufficient to assess efficacy and safety of brolucizumab 
6 mg administered at the target q12w dosing regimen. The 2 year data of the aflibercept studies 
(View 1 and View 2) showed that the mean BCVA change from Baseline reaches a plateau 
during the first year of treatment, which to a large degree is sustained during the second year 
(Schmidt-Erfurth et al 2014). Similar results were observed in the ranibizumab study 
(Li et al 2016) with Chinese population that BCVA improvement in the first year was 
maintained during the second year. Also the brolucizumab Phase III studies (HAWK and 
HARRIER) used the time point of 48 weeks for the primary endpoint and also showed that 
BCVA reached a plateau during the first year of treatment.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Aflibercept 2 mg is an established standard of care anti-VEGF treatment for nAMD in US and 
EU, which has been recently approved in China in May 2018.
Aflibercept has been chosen as a comparator in two recently completed global brolucizumab 
Phase III studies RTH258-C001 (HAWK) and RTH258-C002 (HARRIER) due to the 
consistency of the approved dose and posology of aflibercept in most countries worldwide. 


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Using the same comparator as in the global pivotal studies will support the comparison of the 
results between China and global study populations.
Due to the well-established efficacy of anti-VEGF treatments in the indication of nAMD, an 
internal validation of this study via a placebo arm is ethically not acceptable.
4.4
Purpose and timing of interim analyses/design adaptations
Not applicable.
4.5
Risks and benefits
The risk to subjects in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring, and periodic review of safety data 
by an independent program level data monitoring committee (DMC).
Women of childbearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study, and agree that in order to participate in the study they must adhere to the contraception 
requirements outlined in the exclusion criteria. If there is any question that the patient will not 
reliably comply, they should not be entered or continue in the study.
Brolucizumab is an inhibitor of VEGF with a mechanism of action similar to ranibizumab or 
aflibercept with a smaller molecular size (26 kDa and 48 kDa or 115 kDa, respectively). 
Ranibizumab and aflibercept (both approved inhibitors of VEGF-A) have consistently 
demonstrated efficacy in VEGF-driven retinal pathologies, including nAMD, with benefits 
outweighing the risks. Assuming a corresponding class-effect, it is justified to expect that 
brolucizumab (having the same MoA as ranibizumab and aflibercept) will likewise be 
efficacious and have a similar safety profile in the nAMD indication. 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 were achieved while a 
majority of patients 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. Retinal vasculitis and/or retinal vascular occlusion, typically in the 
presence of IOI has been reported following brolucizumab injection. These immune mediated 
adverse events may occur following the first intravitreal injection. Discontinuation of study 
treatment is required in subjects who develop these events. In addition, subjects who 
experience IOI may be at risk of developing retinal vasculitis and/or retinal vascular occlusion 
and should be closely monitored.
Based on clinical studies, IOI related adverse events, including retinal vasculitis and retinal 
vascular occlusion, were reported more frequently in female patients treated with 
brolucizumab than male patients (e.g. 5.3% females vs. 3.2% males in HAWK and 
HARRIER, Novartis data on file).
Overall, brolucizumab was well tolerated in clinical studies with nAMD subjects when 
treatment interval is not less than every 8 weeks after the first 3 monthly initial doses (loading 
phase). The risk/benefit assessment for brolucizumab remains positive.


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Further details of the known and potential risks and benefits associated with brolucizumab are 
presented in the IB.
5
Population
The study population will consist of male and female Chinese patients (≥50 years of age) with 
untreated active CNV secondary to AMD in the study eye. Approximately 488 patients will be 
screened (20% screening failure rate expected) and approximately 390 patients will be 
randomized (195 per arm) in approximately 30 sites in China.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Male or female Chinese patient ≥ 50 years of age at the time of screening.
3. Active choroidal neovascularization (CNV) lesions secondary to AMD that affect the 
central subfield (including retinal angiomatous proliferation [RAP] lesions with a CNV 
component) in the study eye at screening and confirmed by the Central Reading Center 
(CRC).
4. Total area of CNV (including both classic and occult components) must comprise > 50% 
of the total lesion area in the study eye at screening and confirmed by the CRC.
5. Intra and/or subretinal fluid affecting the central subfield of the study eye at screening and 
confirmed by the CRC.
6. BCVA between 78 and 23 letters, inclusive, in the study eye at screening and Baseline 
using Early Treatment Diabetic Retinopathy Study (ETDRS) testing.
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
1. Any active intraocular or periocular infection or active intraocular inflammation (e.g. 
infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis, uveitis) 
in study eye at Baseline.
2. Central subfield of the study eye affected by fibrosis or geographic atrophy assessed by 
color fundus photography at screening and confirmed by the CRC.
3. Total area of fibrosis ≥ 50% of the total lesion in the study eye at screening and confirmed 
by the CRC.
4. Subretinal blood affecting the foveal center point and/or ≥50% of the lesion of the study 
eye at screening and confirmed by the CRC.
5. Previous treatment with any approved or investigational drugs for neovascular AMD in 
the study eye (other than vitamin supplements).
6. Any history or evidence of a concurrent intraocular condition in the study eye, including 
retinal diseases other than neovascular AMD, that, in the judgment of the Investigator, 
could require medical or surgical intervention during the course of the study to prevent or 
treat visual loss that might result from that condition, or that limits the potential to gain 
visual acuity upon treatment with the investigational product (IP).
7. Retinal pigment epithelium (RPE) rip/tear in the study eye at screening.


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8. Current vitreous hemorrhage or history of vitreous hemorrhage in the study eye within 4 
weeks prior to Baseline.
9. History or evidence of the following in the study eye:

intraocular or refractive surgery within the 90 day period prior to Baseline

previous penetrating keratoplasty or vitrectomy

previous panretinal photocoagulation

previous submacular surgery, other surgical intervention or laser treatment for AMD
10. Uncontrolled glaucoma in the study eye defined as intraocular pressure (IOP) > 25 mmHg 
on medication or according to Investigator’s judgment at screening and Baseline.
11. Aphakia and/or absence of the posterior capsule in the study eye at screening.
12. Use of dexamethasone intravitreal implant (Ozurdex) or fluocinolone acetonide 
intravitreal implant (Iluvien) in study eye at any time. Intra- or periocular use of 
corticosteroids in the study eye during the 6 month period prior to Baseline.
13. Any history of uveitis in either eye.
14. Previous treatment with any anti-VEGF drugs in the study eye. 
15. Use of systemic corticosteroids for 30 or more consecutive days within the 90 days prior 
to Baseline, with the exception of low stable doses of corticosteroids (defined as ≤ 10 mg 
prednisolone or equivalent dose used for 90 days or more prior to Baseline). Inhaled, nasal 
or dermal steroids are permitted.
16. Previous therapeutic radiation near the region of the study eye.
17. Treatment with any anti-VEGF within the 4 week period prior to Baseline in the nonstudy 
eye.
18. History of a medical condition (disease, metabolic dysfunction, physical examination 
finding, or clinical laboratory finding) that, in the judgment of the Investigator, would 
preclude scheduled study visits, completion of the study, or a safe administration of 
investigational product.
19. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes.
20. Pregnant or nursing (lactating) women.
21. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 3 months after stopping of investigational medication. Highly 
effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient). 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 
investigational drug. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject

Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 


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(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 investigational drug.
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she considered 
not of child bearing potential.
22. Use of other investigational drugs within 5 half-lives of enrollment, or [within 30 days 
/until the expected pharmacodynamic effect has returned to Baseline], whichever is 
longer.
23. Systemic anti-VEGF therapy during the 3 month period prior to Baseline.
24. Stroke or myocardial infarction in the 6 month period prior to Baseline.
25. Uncontrolled blood pressure defined as a systolic value ≥ 160 mmHg or diastolic value 
≥100 mmHg at screening and Baseline.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible subjects.
In cases where both eyes are eligible, the eye with the worse BCVA at Baseline will be selected 
as the study eye. If both eyes have the same BCVA, it is recommended to select the right eye 
as the study eye.
6
Treatment
6.1
Study treatment
6.1.1
Investigational and control drugs
Table 6-1
Investigational and control drug
Investigational/ 
Control Drug
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply type
Sponsor 
(global or local)
Brolucizumab 6 mg
Sterile solution 
for injection
Intravitreal 
injection
Open label supply in Sterile 
glass vial. Masking at the 
clinical site by unmasked site 
personnel
Sponsor global
Aflibercept 2 mg
Sterile solution 
for injection
Intravitreal 
injection
Open label supply in Sterile 
glass vial. Masking at the 
clinical site by unmasked site 
personnel
Sponsor global
Brolucizumab study kits will consist of a carton that contains 1 single use, sterile glass vial containing 
approximately 0.2 mL of the brolucizumab solution to allow the administration of a single dose (50 μL). 
The content of the vial must not be split. The formulation does not contain any preservative; it is to be 
used for single-dose administration only.
Novartis will provide sufficient supplies of brolucizumab for treatment use to allow for 
completion of the study.


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The aflibercept trial kits will consist of a masked, numbered carton containing the following 
items depending on the source of the aflibercept:

Novartis-sourced aflibercept: one package of aflibercept in its commercial presentation 
and one post-injection label containing the same kit number as the carton mentioned 
above. The post-injection label will be placed on the vial of aflibercept after injection. 
Novartis will provide sufficient supplies of aflibercept for treatment use to allow for 
completion of the study.

Site-sourced aflibercept: One post-injection label containing the same kit number as the 
carton mentioned above. The post-injection label will be placed on the vial of aflibercept 
after injection. The labeled vial and the commercial carton will be placed inside the 
numbered carton mentioned above.
All aflibercept for this study will be sourced using only one of the two options outlined above. 
Sourcing the aflibercept using both options will not be allowed.
Sham injections refer to an imitation of an intravitreal injection procedure using an empty sterile 
syringe without a needle. There will be no sham vials.
All trial kits should be stored at 2º to 8ºC (35.6º to 46.4ºF); do not freeze. To ensure proper 
conditions are maintained, a daily (7 days/week) temperature log will be maintained 
documenting appropriate investigational product storage conditions.
6.1.2
Additional study treatments
No additional treatment beyond investigational drug and control drug are included in this trial.
6.1.3
Treatment arms/group
Patients will be assigned at Baseline visit to one of the following two treatment arms in 1:1 
ratio:

Brolucizumab 6 mg: 3 x q4w up to Week 8 followed by q12w / q8w up to Week 40 or 
Week 44, depending on disease activity status.

Aflibercept 2 mg: 3 x q4w up to Week 8 followed by q8w up to Week 40.
6.1.4
Treatment duration
The planned study duration is 48 weeks with the last aflibercept treatment at Week 40 and the 
last brolucizumab treatment at Week 40 or Week 44, depending on dosing regimen (q8w or 
q12w, respectively). Subjects may be discontinued from treatment earlier due to unacceptable 
toxicity, disease progression and/or treatment is discontinued at the discretion of the 
investigator or the subject. For subjects who in the opinion of the investigator are still deriving 
clinical benefit from the study drug, every effort will be made to continue provision of study 
treatment.
6.2
Other treatment(s)
Not applicable.


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6.2.1
Concomitant therapy
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after signing the study informed consent. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the patient was enrolled into the study must be recorded in the appropriate electronic case 
report form (eCRF) page.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started. If the subject is already 
enrolled, contact Novartis/sponsor to determine if the subject should continue participation in 
the study.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
Non-investigational treatment for fellow eye is permitted at the discretion of the investigator 
and in accordance with the administration procedures established at the study center. Such 
treatment must be recorded on the appropriate Case Report/Record Form (CRF).
Administration of topical ocular corticosteroids are permissible in the study eye during the 
course of the study. If the subject is planning to receive a COVID-19 vaccine that is authorized 
by local regulation, it is recommended to receive the vaccine at least 7 days before or after the 
study treatment visit including Baseline (Day 1) visit.
6.2.2
Prohibited medication
Use of the treatments displayed in the below table are not allowed after screening. 
Table 6-2
Prohibited medication
Medication
Prohibition period
Action taken
Study eye
Anti-VEGF therapy other than study medication
Any time
Discontinue study treatment
Intra- or periocular corticosteroids (except if needed 
as short term treatment of AE)
Any time
Discontinue study treatment 
(except if for treatment of AE)
Any Laser treatment for nAMD
Any time
Discontinue study treatment
Any other investigational drug, biologic or device
Any time
Discontinue study treatment
Fellow eye
Unapproved or Investigational treatment
Any time
None
Systemic
Anti-VEGF therapy
Any time
Discontinue study treatment
Any investigational drug, biologic or device (with the 
exception of over-the-counter vitamins, supplements 
or diets)
Any time
Discontinue study treatment
6.2.3
Rescue medication
Subjects who received rescue therapy (standard of care) per investigator’s discretion will be 
required to discontinue with the study treatment but may continue with the study follow-up 
procedures.


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Use of rescue medication (standard of care) in the study eye will be documented in the source 
documents and recorded in the eCRF.
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient 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 (3 digit number) suffixed to it, so that each subject is numbered 
uniquely across the entire database.
Upon signing the informed consent form, the patient is assigned to the next sequential Subject 
No. available in electronic data capture (EDC) system. The investigator or her/his staff will 
contact the Interactive Response Technology (IRT) and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned to a patient, the patient 
number will not be reused for another patient. If the patient fails to be randomized for any reason, 
the IRT must be notified within 2 days that the patient was not randomized. The reason for not 
being randomized will be entered on the Screening Log, and the Demography eCRF should be 
completed. Patients who have been screen failures but are re-screened (see Section 8.1) will be 
assigned a new Subject No.
6.3.2
Treatment assignment, randomization
At Baseline visit, all eligible patients will be randomized via Interactive Response Technology 
(IRT) to one of the treatment arms, in a ratio of 1:1. There are no stratification factors in this 
study.
The investigator or her/his delegate will contact the IRT, after it was confirmed that the patient 
fulfills all the inclusion and none of the exclusion criteria. The IRT will assign a randomization 
number to the patient, which will link the patient to a treatment arm.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of patient numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms. A separate medication list will be produced 
by or under the responsibility of Novartis Global Clinical Supply using a validated system that 
automates the random assignment of medication numbers to packs containing the study 
treatment.
The randomization scheme for patients will be reviewed and approved by a member of the 
Randomization Group.
6.4
Treatment masking
The intent of masking is to limit the occurrence of conscious and unconscious bias in the 
conduct and interpretation of the clinical study. Bias could arise from the influence that the 


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knowledge of a specific treatment assignment may have on the recruitment and allocation of 
subjects, their subsequent care, the assessment of end points, the handling of withdrawals, and 
so on. The essential aim of masking, therefore, is to prevent identification of the treatments by 
the investigator, subject, and others associated with the conduct of the study until all such 
opportunities for bias have passed.
This study will be double-masked, with patients randomized to be treated with brolucizumab 6 
mg or aflibercept 2 mg. All members of the Sponsor team will be masked to treatment 
assignments while the study is in progress. In addition, the biostatistician who is directly 
involved in the conduct of the study (i.e. involved in subject level discussions or direct 
interaction with sites) will remain masked to treatment assignments while the study is in 
progress. Sponsor personnel who have access to treatment codes will not divulge the codes to 
subjects, investigators, site staff or Sponsor.
Unmasking of investigators and personnel directly involved in the conduct of the study will 
only occur in the case of subject emergencies (Section 6.6.2), and then at the time of the final 
analysis (Section 11), at the conclusion of the study.
In the event of a medical emergency or an adverse event (AE) during the study where the 
knowledge of subject treatment is required (e.g. in case of Suspected Unexpected Serious 
Adverse Reactions (SUSAR)), an individual investigator will have the ability to unmask the 
treatment assignment for a specific subject. The investigator should notify the Sponsor prior to 
unmasking a subject, if there is sufficient time. Further, the Sponsor must be informed whenever 
the randomization code is broken and be informed about the reasons for unmasking.
Each site must have both masked and unmasked investigators available. The investigator who 
performs the injection will be unmasked to the treatments as will any other site personnel who 
have been delegated responsibility for working with the IP. The unmasked site personnel and 
unmasked injecting investigator must not perform BCVA, complete ophthalmic examination, 
disease activity assessments or administer the VFQ-25. Also, the unmasked site personnel and 
unmasked injecting physician must not perform assessment of any ocular or non-ocular safety 
parameters, or assess causality AEs for subjects during the course of the study except an event 
reported immediately following IVT injection.
The unmasked investigator/site personnel should, however, assess subject safety immediately 
following injection. Once the designated roles are determined, the unmasked investigator/site 
personnel not be switched at any time after randomization to masked role. Every effort must be 
made to limit the number of unmasked study personnel to ensure the integrity of this masked 
study.
Treatment masking of individual subjects will remain intact until the final database lock has 
occurred by ensuring: Randomization data are kept strictly confidential until the time of 
unmasking and will not be accessible by anyone else involved in the study except the 
unmasked/treating investigator. During and after database lock at Week 48, the masked 
personnel and subjects will remain masked to the treatment assignment until the conclusion of 
the study.
Unmasked monitors will be available to perform study medication accountability and to deal 
with study issues involving the unmasked investigator or unmasked site staff.


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An independent, masked review of fundus photography, fluorescein angiography and optical 
coherence tomography (OCT) images for subjects enrolled in the study will be performed at a 
Central Reading Center (CRC).
The randomization codes associated with subjects from whom PK and ADA samples are taken 
will be disclosed to PK analysts who will keep PK results confidential until database lock.
Unmasking will occur in the case of subject emergencies and at the conclusion of the study.
Table 6-3
Masking levels
Role
Time or Event
Randomization list 
generated
Treatment allocation 
& dosing
Safety event (single 
subject unmasked)
Subjects/Patients
B
B
B
Site staff
B
B
B
Unmasked site staff (see text for 
details) 
B
UI
UI
Global Clinical Supply and 
Randomization Office
UI
UI
UI
Unmasked sponsor staff (see 
text for details)
B
UI
UI
Statistician/statistical 
programmer/data analysts
B
B
B
All other sponsor staff not 
identified above
B
B
B
B Remains masked
UI Allowed to be unmasked on individual patient level
6.5
Dose escalation and dose modification
Investigational treatment dose adjustments are not permitted.
If based on investigator’s judgement, safe administration of the study drug is contraindicated 
(e.g. subject experiences an AE), investigational treatment can be administered within 7 days 
after the scheduled visit (per allowed visit window) or temporarily interrupted.
6.5.1
Dose modifications
Treatment dose adjustments and/or interruptions are not permitted unless interruptions are 
warranted by an AE.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
Every time the study treatment is to be administered, IRT needs to be accessed for the 
medication (kit) number. 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 
unmasked investigator staff or by unmasked field monitor on the appropriate study treatment 
dispensing form.


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Exposure to the study treatment will be based on the number of injections administered. 
Compliance with the study treatment will be assessed by the unmasked field monitor at each 
visit using vial counts and information provided by the pharmacist or by the investigator.
The type, reason for use, start and stop dates (or “ongoing”) of all concomitant medications 
administered during the study will be collected on the Concomitant medications CRF.
6.6.2
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a subject, he/she must provide 
the requested subject identifying information and confirm the necessity to break the treatment 
code for the subject. The investigator will then receive details of the investigational drug 
treatment for the specified subject and a fax or email confirming this information. The system 
will automatically inform the Novartis monitor for the site and the study team that the code 
has been broken.
If the treatment code needs to be broken in the interest of subject safety, the investigator is 
encouraged to contact an appropriate Sponsor representative prior to unmasking if there is 
sufficient time.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide:

protocol number

study drug name (if available)

subject number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that unmasking 
can be performed at any time.
The appropriate personnel from the site and Sponsor will assess whether study treatment should 
be discontinued for any subject whose treatment code has been broken for any reason.
6.7
Preparation and dispensation
Each study site will be supplied with study drug.
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label. Unmasked study staff will identify the study drug package(s) to dispense to 
the patient by contacting the IRT and obtaining the medication number(s). Immediately before 
dispensing the medication kit to the patient, investigator staff will detach the outer part of the 
label from the packaging and affix it to the source document (Drug Label Form) for that 
patient’s unique patient number.


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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 unmasked investigator and 
designated site personnel have access. Upon receipt, all study treatment must be stored 
according to the instructions specified on the labels and in the IB. Clinical supplies are to be 
dispensed only in accordance with the protocol. Technical complaints are to be reported to the 
respective Novartis Country Organization (CO) Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number.
The unmasked investigator designated 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 unmasked monitors during site visits or remotely and at the 
completion of the trial. Study site will be asked to return all unused study drug and packaging.
At the conclusion of the study, and as appropriate during the course of the study (eg. at the time 
of discontinuation of study treatment), the investigator will return all unused study treatment, 
packaging, drug labels, and a copy of the completed drug accountability log to the Novartis 
unmasked monitor or to the Novartis address provided in the investigator folder at each site.
6.7.1.2
Handling of additional treatment
6.7.2
Instruction for prescribing and taking study treatment
All kits of study treatment assigned by the IRT will be recorded/databased in the IRT.
There will be two treatment phases for IVT injections with different timing for brolucizumab 
and aflibercept treatment arms (loading phase and maintenance phase).
Brolucizumab 6 mg will be administered by IVT injection in accordance with supplied 
instructions for use. Subjects in the brolucizumab 6 mg arm will receive loading doses at 
Baseline, Week 4 and Week 8. After the loading doses, subjects will receive q12w treatment 
unless there is disease activity as assessed by the investigator during one of the scheduled DAA 
visits. If disease activity is identified, the subject will be assigned to receive injections q8w 
thereafter, up to Week 44.
Aflibercept 2 mg will be administered by IVT injection in accordance with instructions for use 
specified in the label. Subjects in the aflibercept 2 mg arm will receive loading doses at Baseline, 
Week 4 and Week 8. After the loading doses, subjects will receive q8w treatment starting at 
Week 16 and up to Week 40. DAAs will be conducted by the evaluating/masked investigator 
for masking purposes and will not influence the treatment interval.
The IVT injection procedure for brolucizumab and aflibercept, including aseptic and 
antimicrobial requirements, will be performed according to local clinical practice. 
The sham injection should mimic an IVT injection including the aseptic and antimicrobial 


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requirements. The tip of the sham injection syringe (the hub without a needle) will be placed 
on the eye for the approximate amount of time it would take to perform an IVT injection. 
In both treatment arms, there will be no treatment injection administration on Week 12 and 48.
Figure 6-1
Dosing schedule
Disease activity assessment (DAA)
The concept of the brolucizumab q12w/q8w regimen is to allocate subjects according to their 
individual treatment needs to either a q12w or a q8w treatment schedule. The initial schedule is 
q12w and a subject will remain on q12w as long as the masked investigator does not identify 
disease activity which in his opinion requires more frequent anti-VEGF treatment.
Disease activity will be assessed by the masked Investigator for all subjects in order to maintain 
masking. The assessment will only be performed at the prespecified DAA visits at:

Week 16 and Week 20, during the first q12w treatment interval (i.e. for brolucizumab 
subjects 8 and 12 weeks after the last loading injection) to make sure that subjects with a 
high treatment need are identified early on,

Week 32, following second q12w treatment interval

Week 44, to document the adequacy of the q12w treatment schedule at the end of 
treatment (EOT) period (without having impact on the subject's treatment schedule).
The assessment of the disease activity is at the discretion of the masked investigator. He/she 
should apply their own expert judgement when assessing q8w treatment need. Disease activity 
criteria outlined below might be considered as guidance.
Disease activity criteria at Week 16:

Decrease in BCVA of ≥ 5 letters compared with Baseline

Decrease in BCVA of ≥ 3 letters and CSFT increase ≥ 75μm compared with Week 12

Decrease in BCVA of ≥ 5 letters due to nAMD disease activity compared with Week 12


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
New or worse intraretinal cysts (IRC) / intraretinal fluid (IRF) compared with Week 12
Disease Activity Criterion at Weeks 20, 32 and 44:

Decrease in BCVA of ≥ 5 letters due to nAMD disease activity compared with Week 12
If DAA reveals a need for q8w treatment the subject will be assigned to receive injections q8w 
thereafter, up to the end of the study. Only DAA at the scheduled DAA visits have an impact 
on the subject’s treatment schedule (except Week 44).
The outcome of the DAA will be captured in the IRT system. The IRT system will make the 
necessary changes to the dosing schedule as per the masked investigator’s assessment of disease 
activity.
A subject randomized to brolucizumab 6 mg who misses Week 16 will undergo disease activity 
assessment at Week 20 as he/she would have done if the visit had not been missed. If, however, 
subject misses Week 20 or Week 32 visit, then the subject will be assumed to have had a q8w 
treatment need at this missed visit and will be assigned to a q8w schedule at the next visit (i.e. 
at the next visit the subject will receive an active injection) up to study exit. The IRT system 
will make the necessary changes once the missed visit is registered.
Intravitreal injection
The IVT injection will be carried out under controlled, aseptic conditions per local clinical 
practice and in accordance with supplied instructions for use (brolucizumab 6 mg) or 
instructions for use specified in the label (aflibercept 2 mg).
The study eye will be assessed before and after intravitreal injection to ensure that the procedure 
and/or the study treatment had not endangered the health of the eye.
An IVT injection is contraindicated in patients with active ocular or periocular infections and 
in patients with active intraocular inflammation (IOI); therefore, the investigator must verify 
that these conditions are not present in study eye prior to every injection.
If any signs of intraocular inflammation is present, then an IVT injection must not be performed. 
Additional ophthalmic examination and imaging should be performed to evaluate IOI (see 
Section 8.4.3).
If IOI is confirmed, subjects should be treated for IOI according to clinical practice and closely 
monitored since they may be at risk of developing retinal vasculitis and/or retinal vascular 
occlusion. If subject develops retinal vasculitis and/or retinal vascular occlusion based on the 
investigator’s evaluation, the study treatment must be discontinued.
All kits of study treatment assigned by the IRT will be recorded in the IRT system.
Date and time of every injection administered to the subject will be recorded in the CRF.
Sham injection
At all applicable visits from Week 16 to Week 44, inclusive, a sham treatment will be performed
to maintain subject masking. For the sham treatment the tip of an injection syringe (the hub 
without a needle) will be used.


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7
Informed consent procedures
Eligible patients may only be included in the study after providing (witnessed, where required 
by law or regulation), IEC approved informed consent.
If applicable, in cases where the patient's representative(s) gives consent (if allowed according 
to local requirements), the patient must be informed about the study to the extent possible given 
his/her understanding. If the patient is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the patient source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the patient informed consent and should 
be discussed with the subject during the study as needed. Any new information regarding the 
safety profile of the investigational drug that is identified between IB updates will be 
communicated as appropriate, for example, via an investigator notification (IN) or an aggregate 
safety finding. As new information becomes available, informed consent to be updated and then 
must be discussed with the subject.
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
Male patients must be informed that if a female partner becomes pregnant while he is enrolled 
in the study, contact with the female partner will be attempted to request her consent to collect 
pregnancy outcome information.
A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval. 
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 informed consent forms (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 subject will be back at the trial sites.


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8
Visit schedule and assessments
Assessment schedule lists all of the assessments and indicates with an “X”, the visits when they 
are performed. All data obtained from these assessments must be supported in the subject’s 
source documentation.
Subjects should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. Subjects who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible, at which time all of the assessments listed 
for the final visit will be performed. At this final visit, all dispensed investigational product 
should be reconciled, and the adverse event and concomitant medications recorded on the CRF.
If the COVID-19 pandemic limits or prevents on-site study visits, study treatment could not be 
administered and other study assessments may not be performed. Alternative methods of safety 
monitoring may be implemented. Depending on local regulations, site capabilities and patient’s 
visit status in the study, phone calls or virtual contacts (e.g. teleconsult) can be performed for 
safety follow-up for the duration of the pandemic, until it is safe for the participant to visit the 
site again.


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Table 8-1
Assessment Schedule
Period
Screening
Treatment
End of Treatment/Study
Visit Name
Screening 
/ Visit 0
Baseline 
/ Visit 1
Visit 
1b/ 
6h 
post 
dose 2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
EOS2
Days
-14 to -1
1
1
2
8
±1
15
±1
22
±3
29
±3
57
±3
85
±7
113
±7
141
±7
169
±7
197
±7
225
±7
253
±7
281
±7
309
±7
337
±7
Weeks
-2 to -1
1
1
1
2
3
4
4
8
12
16
20
24
28
32
36
40
44
48
Time (post-dose)
-
-
6h
±1
24h
±4
168h
±24
336h
±24
504h
±72
672h
±72
-
-
-
-
-
-
-
-
-
-
-
Informed consent3
X
Demography
X
Medical history/current 
medical conditions
X
Physical Examination4
X
Concomitant medications
X
X
X5
X5
X5
X5
X5
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X5
X5
X5
X5
X5
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion / Exclusion 
criteria
X
X
Visual Function 
Questionnaire-25
X
X
X
Vital Signs
X6
X6
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test (urine)7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetics 
Informed Consent
X
PK blood collection5,8
X
X
X
X
X
X
X15
anti-drug antibody in 
blood
X
X
X
X
X
X
Hematology8
X
X
X


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Period
Screening
Treatment
End of Treatment/Study
Visit Name
Screening 
/ Visit 0
Baseline 
/ Visit 1
Visit 
1b/ 
6h 
post 
dose 2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
EOS2
Days
-14 to -1
1
1
2
8
±1
15
±1
22
±3
29
±3
57
±3
85
±7
113
±7
141
±7
169
±7
197
±7
225
±7
253
±7
281
±7
309
±7
337
±7
Weeks
-2 to -1
1
1
1
2
3
4
4
8
12
16
20
24
28
32
36
40
44
48
Time (post-dose)
-
-
6h
±1
24h
±4
168h
±24
336h
±24
504h
±72
672h
±72
-
-
-
-
-
-
-
-
-
-
-
Clinical Chemistry8
X
X
X
Urinalysis8
X
X
X
Best corrected visual 
acuity
X9
X9
X
X
X9
X
X
X9
X
X
X9
X
X
X9
Intraocular Pressure 
(IOP)
X9
X
X
X
X
X
X
X
X
X
X
X
X
X9
Ophthalmic Exam10,1
X9
X
X
X
X
X
X
X
X
X
X
X
X
X9
Spectral Domain Optical 
Coherence Tomography1
X9
X
X
X
X
X
X
X
X
X
X
X
X
X9
Fluoroscein angiography1 X9
X
X9
Color fundus photo1
X9
X
X9
Disease activity 
assessment
X
X
X
X
Contact IRT
X
X13
X
X
X
X
X
X
X
X
X
X
Administration of study 
drug or sham14
X
X
X
X
X
X
X
X
X
X
X
X Assessment to be recorded in the clinical database or received electronically from a vendor
1 Additional ophthalmic examinations and images will be performed in case of any signs of intraocular inflammation.


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Period
Screening
Treatment
End of Treatment/Study
Visit Name
Screening 
/ Visit 0
Baseline 
/ Visit 1
Visit 
1b/ 
6h 
post 
dose 2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
EOS2
Days
-14 to -1
1
1
2
8
±1
15
±1
22
±3
29
±3
57
±3
85
±7
113
±7
141
±7
169
±7
197
±7
225
±7
253
±7
281
±7
309
±7
337
±7
Weeks
-2 to -1
1
1
1
2
3
4
4
8
12
16
20
24
28
32
36
40
44
48
Time (post-dose)
-
-
6h
±1
24h
±4
168h
±24
336h
±24
504h
±72
672h
±72
-
-
-
-
-
-
-
-
-
-
-
2 All exit procedures should be followed, regardless of when the subject exits the study. Visit should be at least 4 weeks from last dose of study treatment. Patient report 
outcome (PRO) will not be administered on EOS if different from Week 48 visit.
3 Must be signed/dated prior to performing any study procedures, including screening procedures.
4 All clinically significant findings will be recorded as medical history or adverse events, as appropriate. Includes height and weight.
5 If PK Consent was provided (in subset of PK subjects).
6 In case there is an elevated blood pressure measurement as specified in the exclusion criteria the blood pressure measurement should be repeated after 20 minutes. If 
the repeat measurement is elevated, then the patient is not eligible to be enrolled into the study.
7 Required for all female subjects of childbearing potential. Urine pregnancy test will be performed unless local regulations require a serum pregnancy test.
8 All blood draws and collection of urine should be performed prior to receiving the IVT or sham injection and prior to injection of fluorescein dye.
9 Both eyes
10 Includes fundus and slit lamp examination. Pupil dilation for the fundus examination is at the discretion of the Investigator.
13 Patients will be randomized to brolucizumab 6 mg/50 µL or aflibercept 2 mg/50 µL.
14 Beginning at Week 16, when subjects do not receive an active injection, they will receive a sham injection. The injection may be performed at a later time, as long as it 
is within 7 days of the scheduled visit and within the visit window.
15 No need to additionally collect PK blood at visit 6 for PK consent participants. The blood drawn for anti-drug antibody in blood could also be used for PK analysis at the 
same visit.


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8.1
Screening
Screening
A screening period of up to 2 weeks will be used to assess eligibility. The screening period 
starts with the signing of the ICF.
One time rescreening of patients will be allowed, except for the purpose of capturing new 
BCVA or imaging assessments that previously failed to qualify the patient. As long as testing 
can be repeated within 14 days of the first screening, the other screening assessments do not 
need to be repeated. If rescreening is to occur beyond 14 days from the original screening visit 
date, then all screening procedures must be repeated.
Medical judgement should be exercised to ensure that treatment is not withheld in order for a 
patient to participate in the study.
8.1.1
Information to be collected on screening failures
All patients who have signed informed consent but not entered into the next period will have 
the study completion eCRF pages for the screening period, demographics, inclusion/exclusion, 
and serious adverse event (eSAE) data collected. Adverse events that are not SAEs will be 
followed by the investigator and collected only in the source data.
Patients who are randomized and fail to start treatment, e.g. patients randomized in error, will 
be considered an early terminator. The reason for early termination will be recorded on the 
appropriate CRF.
8.2
Subject demographics/other baseline characteristics
The following information will be collected/documented at screening/Baseline visit for each 
patient:

Age

Gender

Race

Physical Exam

Vital signs

Study eye

Visual acuity

Optical Coherence Tomography (OCT)

Fluoroscein angiography (FA)

Color Fundus Photo

Visual Function Questionnaire (VFQ-25)

Intraocular pressure (IOP)

Laboratory test results including urinalysis, ADA and PK

Concomitant medications

Past medical history and current medical condition


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Investigators will have the discretion to record abnormal test findings on the medical history 
CRF 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 and 
aflibercept on visual function, retinal structure and vascular leakage:

Best-corrected visual acuity with ETDRS-like chart at initial testing distance of 4 meters,

Optical Coherence Tomography,

Color Fundus Photography and Fluorescein Angiography.
8.3.1
Visual acuity
Visual acuity will be assessed at every study visit using best correction determined from 
protocol refraction (BCVA). BCVA measurements will be taken in a sitting position using Early 
Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. The details of the 
procedure and training materials are provided in the applicable manual. Certification of the 
assessment procedures and assessors will occur prior to any evaluation of study patients.
8.3.2
Optical coherence tomography
Spectral Domain Optical Coherence Tomography (SD-OCT) will be assessed in the study eye 
at every study visit and in both eyes at screening and EOS.
These assessments will be performed by certified technician or investigator at the sites and 
should be performed prior to any study drug administration. Certification of the equipment and 
examiners at each investigative site will occur prior to evaluation of study patients. Masked 
evaluating investigators will evaluate the SD-OCT to assess the status of disease activity. The 
SD-OCT machine used for an individual patient should not change for the duration of the study.
The images will be reviewed by a Central Reading Center (CRC) to ensure a standardized 
evaluation. At screening, SD-OCT images will be submitted to the CRC for determination of 
eligibility. For further procedural details, the investigator should refer to applicable manual 
provided by the CRC.
8.3.3
Color fundus photography and fluorescein angiography
Color fundus photography and fluorescein angiography (FA) will be performed in both eyes at 
screening and EOS and in the study eye only at Week 12.
These assessments will be performed by certified technician or investigator at the sites and 
should be performed prior to any study drug administration. Certification of the equipment and 
examiners at each investigative site will occur prior to evaluation of study patients.
The images will be reviewed by a CRC to ensure a standardized evaluation. At screening, retinal 
images will be submitted to the CRC for determination of eligibility. FA images from previous 
routine evaluations may be used for the screening FA as long as they were performed within 14 
days of the screening visit using CRC-certified equipment and examiners. For further 
procedural details, the investigator should refer to applicable manual provided by the CRC.


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Additional images will be taken in case of any signs of intraocular inflammation. Optical 
coherence tomography, color fundus photography and fluorescein angiography (preferably 
wide-field or with peripheral sweeps) should be performed for safety evaluation as described in 
Section 8.4.3.
 
 
 
 
 
 
8.3.5
Appropriateness of efficacy assessments
The selected efficacy assessments are the ones used in the clinical practice to assess the 
functional and anatomical changes of the affected macular area due to nAMD. BCVA as a 
measure of retinal function and SD-OCT images to analyze anatomical changes are standard 
assessments to monitor nAMD and potential treatment effects in routine practice and clinical 
trials. Likewise established FA is used to assess the type of CNV lesion and determine the 
vascular leakage; and Color Fundus that helps classifying potential presence of retinal 
pathology such as fibrosis or geographic atrophy.
8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 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 
subject´s health status, until the subject can again visit the site.
For details on AE collection and reporting, refer to AE section.
Assessment
Specification
Physical examination
A complete physical examination will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities, vascular and neurological. The 
examination will be performed at screening and at EOT/EOS visit.
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are present prior to
signing informed consent must be included in the eCRF capturing Medical History. 
Significant findings made after signing informed consent which meet the definition of 
an Adverse Event must be recorded on the appropriate AE eCRF page.
Vital signs
Sitting blood pressure and pulse rate will be collected at all visits before treatment. 
Vital signs include assessment of sitting blood pressure (systolic and diastolic 
pressure in mm Hg) and pulse (beats per minute). In case there is an elevated blood 
pressure measurement as specified in the exclusion criteria, at the screening or 
Baseline visits, the blood pressure measurement should be repeated after 20 
minutes. If the repeat measurement is elevated, then the patient is not eligible to be 
enrolled into the study.


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Assessment
Specification
On days when study drug is administered, vital signs will be measured before 
administration of study medication. The results will be recorded in the eCRF.
Height and weight
Height and weight will be measured at the screening visit only as part of the physical 
examination.
Height in centimeters (cm) and body weight (to the nearest 0.1 kg, in indoor clothing 
but without shoes) will be measured at screening only. The results will be recorded 
in the eCRF.
8.4.1
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected at applicable visits. 
Details on the collections, shipment of the samples and reporting of the results by the central 
laboratory are provided to investigators in the laboratory manual.
Clinically significant abnormalities must be recorded on the relevant section of the medical 
history/current medical conditions/AE eCRF page as appropriate.
The following laboratory evaluations will be performed:

Hematology: hematocrit, hemoglobin, red blood cell (RBC) count, white blood cell 
(WBC) count with differential (absolute and percentage of neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils), and quantitative platelet count.

Clinical chemistry: Blood urea nitrogen (BUN), serum creatine, BUN/Creatinine ratio, 
uric acid, cholesterol, triglycerides, albumin, total globulin, albumin/globulin (A/G) ratio, 
total serum iron, total protein, serum electrolytes (sodium, potassium, bicarbonate, 
chloride, calcium, magnesium), phosphate, glucose and the following liver function tests 
(LFTs): serum aspartate transaminase [AST (SGOT)], serum alanine transaminase [ALT 
(SPGT)], alkaline phosphatase, gamma glutamyl transminase (GGT), total bilirubin, direct 
bilirubin, indirect bilirubin, and lactate dehydrogenase (LDH).

Urinalysis: specific gravity, pH, color, glucose, blood, ketones, bilirubin, and microscopic 
examination (WBC, RBC, epithelial cells, bacteria, mucus, casts, and crystals).
If the COVID-19 pandemic limits or prevents on-site study visits, the method of collection of 
samples may be modified by Novartis if applicable and if modified, will be communicated to 
the Investigator.
8.4.2
Pregnancy and assessments of fertility
High effective contraception is required for women of childbearing potential during the study 
and for 3 months after stopping the investigational medication.
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.
In the absence of the above medical documentation, FSH testing is required of any female 
patient, regardless of reported reproductive/menopausal status at screening/Baseline.


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All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements.
A urine pregnancy test will be conducted for all women of childbearing potential to assess 
pregnancy before inclusion into the study at screening visit and then at EOT/EOS visit. During 
study, monthly urine pregnancy testing will be performed and results captured in the source 
documents.
8.4.3
Ophthalmic examination
The ophthalmic exam will be performed in the study eye at every study visit and in both eyes 
at screening and EOT/EOS. If study visit assessments and a corresponding treatment occur on 
separate days, ophthalmic examinations should be performed as safety check-up before 
treatment of the study eye.
The ophthalmic exam will consist of the following:
Anterior biomicroscopy (slit lamp examination ) will be completed at every visit (scheduled 
and unscheduled) to examine the anterior segment structures (e.g., eyelids/lashes, conjunctiva, 
cornea, anterior chamber, iris, lens and anterior part of the vitreous) of the study eye (Additional 
examination of the fellow eye will be done at the discretion of the investigator). The outcome 
of the examination will be recorded in the source documents.
Slit lamp examination must be carefully performed before study treatment for signs of IOI. If 
there is any signs of IOI, severity of anterior chamber cells and flare should be assessed 
according to the standardization uveitis nomenclature (SUN) working group grading 
system.(Jabs et al., 2005). The test results will be recorded in the source documents (e.g., 
ophthalmic examination tool) and captured in the appropriate eCRF as applicable. 
Measurement of Intraocular pressure measurement (IOP) will be conducted according to 
the routine clinical practice (using an applanation tonometer, non-contact tonometer, or 
Tonopen). The same method should be used throughout the study for each patient. If dilation is 
required, IOP must be measured prior to the use of dilating drops. The IOP will be assessed in 
the study eye, pre-dose and post-dose at every scheduled visit. The values recorded in mmHg 
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 procedure is not 
recommended unless normalization of the IOP has been achieved. Post dose IOP should be 
assessed after every IVT injection, within 60 minutes after injection and if ≥25 mmHg, 
assessment should be repeated until back to normal.
Monitoring of optic nerve head perfusion may be appropriate within 30 minutes after injection, 
at the discretion of the investigator and/or according to the local requirements/practices. Results 
of these procedures will be recorded in the source documents, only if the findings constitute an 
AE they have to be recorded in the eCRF.
Posterior segment (indirect fundus) examination will be conducted by the investigator at the 
screening visit for both eyes. An examination of the peripheral retina must also be conducted 
to ensure that the intravitreal injection can be safely performed. Posterior segment examination 
must be performed carefully before each study treatment. The results of the examination 


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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. 
Instruct the patient to contact the site for any changes in vision or any symptoms of 
inflammation between scheduled visits. Every effort should be made to bring the subject 
for immediate examination. When IOI, retinal vasculitis, and/or retinal artery occlusion (RAO) 
is present or suspected during a visit, investigators must perform thorough ophthalmic 
examination, and conduct optical coherence tomography, 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. If subject develops retinal vasculitis 
and/or retinal vascular occlusion based on the investigator’s evaluation, the study treatment 
must be discontinued. In addition, as some of the subjects who experience IOI may be at risk 
of developing retinal vasculitis and/or retinal vascular occlusion, the subject should be closely 
monitored and managed according to clinical practice.
8.4.4
Other safety evaluations
8.4.5
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/patient population. If there are 
any signs of IOI, additional assessment will be performed as described in Section 8.4.3.
8.5
Additional assessments
8.5.1
Clinical Outcome Assessments (COAs)
8.5.1.1
Patient Reported Outcomes (PRO)
The impact of brolucizumab on subject visual function will also be assessed by a visual function 
questionnaire using the National Eye Institute VFQ-25 which is a validated instrument that has 
been used in many studies of patients with nAMD. The VFQ-25 was developed to address the 
need to measure a patient’s subjective assessment of vision-related QoL (Mangione et al 2001). 
This is part of the 51-item NEI-VFQ which was developed based on feedback from patients to 
measure vision-targeted functioning and the impact of vision problems on HealthRelated 
Quality of Life (HRQL) across a number of common eye conditions. This allowed the 
developers to identify the content areas and aspects of visual disability that were most important 
and relevant to AMD patients.
At Baseline and Weeks 24 and EOS the VFQ-25 will be completed and captured by masked 
site staff on behalf of the subjects, at sites where local language versions are available, validated, 
and approved by the IEC/IRB. All these questionnaires should be completed before subjects see 
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A detailed training manual relating to the administrative procedures of the questionnaires will 
be provided to the sites.
Completed questionnaires will be reviewed and examined by the masked/evaluating 
investigator, before the clinical examination, for responses that may indicate potential AE or 
SAE. If AEs or SAEs are confirmed, then the physician must record the events as per 
instructions given in Section 10.1.1 and Section 10.1.2.
8.5.2
Pharmacokinetics
Systemic brolucizumab exposure will be assessed in approximately 24 consented subjects 
(approximately 12 subjects per treatment arm to maintain masking). Serum samples will be 
taken (according to manual provided by lab) at Day 1 prior to the first injection and at the 
following time points after the first injection: 6h post-injection on Day 1, Day 2, Day 8, Day 
15, Day 22, and Day 29 prior to the second injection.
Further details on sample collection, numbering, processing and shipment can be found in the 
central lab manual.
8.5.3
Other Assessments
Anti-drug antibodies (immunogenicity) 
Collection of blood for ADA assessment will be done at screening, Weeks 4, 12, 24, 36, 48 and 
exit/premature discontinuation in brolucizumab treatment arm (collection of ADA sample will 
be done in both treatment arms to maintain masking). Systemic exposure of brolucizumab will 
be measured concomitantly with ADA levels for interpretation purposes, no pharmacokinetic 
parameters will be determined from brolucizumab exposure measured at the above-mentioned 
timepoints (except, at visit 6 the blood drawn for anti-drug antibody in blood would also be 
used for PK analysis at the same visit, for the PK consent participants.). Additional 
pharmacodynamic assessment may be conducted on the samples wherever permitted by local 
regulation. Blood draws should take place prior to the injection/sham. A standardized 
procedure for the collection, processing, storage and shipment of these blood samples is 
provided by the central laboratory. Further details on sample collection, numbering, processing 
and shipment can be found in the central lab manual.
9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration, and can be initiated by either the subject or the investigator.
The investigator should discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being.
Study treatment must be discontinued under the following circumstances:

Subject/guardian decision


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
Pregnancy 

Use of prohibited treatment as per recommendations in Table 6-2

Any situation in which study participation might result in a safety risk to the subject

Subject develops a retinal vasculitis and/or a retinal vascular occlusion event

Unsatisfactory therapeutic effect

Patient's condition no longer requiring study treatment
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information.
Subjects who discontinue study treatment should NOT be considered withdrawn from the study 
UNLESS they withdraw their consent (see withdraw of informed consent section,). The 
investigator must determine the primary reason for the patient’s premature discontinuation of 
study treatment and record this information on the appropriate eCRF page. Where possible, 
they should return for the assessments indicated in the assessment schedule. 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 subject/pre-designated contact as specified in the lost to follow-
up section. This contact should preferably be done according to the study visit schedule.
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

new / concomitant treatments

adverse events/Serious Adverse Events
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment.
If discontinuation occurs because treatment code has been broken, please refer to Section 6.6.2.
9.1.2
Withdrawal of informed consent /Opposition to use data/biological 
samples
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent/opposition to use data/biological samples occurs only when a subject:

Explicitly requests to stop use of their biological samples and/or data (opposition to use 
subject’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 subject’s decision to withdraw his/her consent 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 subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.
Discontinued subjects will not be replaced.
Novartis will continue to keep and use all research results (data) that have already been collected 
for the study evaluation, including processing of biological samples that has already started at 
time of consent withdrawal/opposition. No new Personal Data (including biological samples) 
will be collected following withdrawal of consent/opposition.
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed 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 for any reason.
Reasons for early termination:

Unexpected, significant, or unacceptable safety risk to subjects 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 the subject welfare and safety. 
Should early termination be necessary, subjects must be seen as soon as possible (provide 
instruction for contacting the subject, when the subject should stop taking drug, when the 
subject should come for a final visit) and treated as a prematurely withdrawn subject. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the subject’s interests. The investigator or 
sponsor depending on the 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 subject finishes their Study Completion visit (e.g. 
LPLV), 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 (e.g. Each subject will be required to complete the study in 
its entirety and thereafter no further study treatment will be made available to them).
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation patient after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Adverse events must be recorded in the Adverse Events CRF 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 subject
3. its relationship to the study procedure
4. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported.


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5. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
6. action taken regarding study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Drug interrupted/withdrawn
7. its outcome 
a. not recovered/not resolved;
b. recovered/resolved;
c. recovering/resolving,
d. recovered/resolved with sequelae;
e. fatal; or unknown.
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued 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 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 subjects 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


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Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life-threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after last study visit must be reported to 
Novartis/safety within 24-hours of learning of its occurrence.
1. SAEs occurring after the patient has provided informed consent until the time the patient 
is deemed a Screen Failure must be reported to Novartis/
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the 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 


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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 (EC) in accordance with EU Guidance 
2011/C172/01 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.
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 subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment.
Any SAE experienced during pregnancy must be reported.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
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, subject or 
consumer (EMA definition).
Misuse/ abuse is not applicable to this study as IVT injection is performed by the investigator.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded in 
the dose administration record (DAR) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE.


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Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dose Administration 
(DAR) eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE 
form
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated 
with an SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.
10.2
Additional Safety Monitoring
10.2.1
Data Monitoring Committee
The RTH258 program level Data Monitoring Committee (DMC) will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will assess at defined intervals the progress 
of a clinical trial, safety data, and critical efficacy variables and recommend to the sponsor 
whether to continue, modify or terminate a trial.
Specific details regarding composition, responsibilities, data monitoring and meeting frequency, 
and documentation of DMC reports, minutes, and recommendations will be described in a 
separate charter that is established between the sponsor and the DMC.
The DMC charter will include the DMC membership and responsibilities, the timing of DMC 
meetings, the content of the analysis report for the DMC meetings, and the communications 
with the Sponsor. The DMC will only make recommendations for changes in study conduct.
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff.
The investigator/designee is responsible for assuring that the data (entered into eCRF) is 
complete, accurate, and that entry and updates are performed in a timely manner. The 
Investigator must certify that the data entered are complete and accurate
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.


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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 
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.
Randomization codes and data about all study treatment (s) dispensed to the subject and all 
dosage changes 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.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis.
The occurrence of relevant protocol deviations will be determined. Once all the necessary 
actions have been completed and the database has been declared to be complete and accurate, 
it will be locked and the treatment codes will be unmasked and made available for data 
analysis/moved to restricted area to be accessed by independent programmer and statistician. 
Any changes to the database after that time can only be made after written agreement by 
Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis (or 
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 subject records, the accuracy 
of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis (or 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 subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, retinal imaging, and the results of any other tests or assessments. 
All information on CRFs must be traceable to these source documents in the subject’s file. The 
investigator must also keep the original informed consent form signed by the subject (a signed 
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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 
subjects will be disclosed.
12
Data analysis and statistical methods
The primary efficacy and safety analysis will be based on data up to and including Week 48. 
This will be performed once all subjects complete the EOS visit or discontinue from the study. 
Summary statistics will be presented by treatment group unless otherwise specified. For 
continuous variables, summary statistics will generally include: n, mean, standard deviation, 
median, quartiles, minimum, and maximum. For categorical variables, these will generally 
include: n, frequency and percentage in each category. 
 
 
Further technical details and discussions of the statistical considerations will be provided in the 
SAP.
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
The Randomized Analysis Set (RAS) consists of all randomized patients. Patients are 
considered randomized when they had been deemed eligible for randomization by the 
investigator and given a randomization number. Subjects will be analyzed according to the 
treatment assigned to at randomization.
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned 
by randomization and who receive at least one IVT injection of the study treatment. The full 
analysis set will serve as the primary analysis set for all efficacy analyses. According to the 
intent to treat principle, subjects will be analyzed according to the treatment they have been 
assigned to during the randomization procedure.
The Safety Set includes all subjects who received at least one dose of study treatment. Subjects 
will be analyzed according to the study treatment arm from which they received majority of 
treatments up to and including Week 44.
Supportive analyses of the primary and key secondary efficacy endpoints will include analysis 
using the Per-Protocol Set (PPS). PPS is a subset of the Full Analysis Set and will exclude 
subjects with protocol deviations (PDs) and analysis restrictions (ARs) that are expected to 
majorly affect the validity of the assessment of efficacy at Week 48 including for e.g. lack of 
compliance (including missed treatments and treatment misallocation), missing data, prohibited 
concomitant medication and deviation from inclusion/exclusion criteria. Confounded data or 


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discontinuation from treatment due to lack of efficacy and/or safety do not constitute a reason 
for exclusion from the PPS.
Before the database lock, the relevant protocol deviations will be identified at the subject level 
in the database. After the database lock, analysis restrictions will be derived in the analysis 
database. Censoring applied in relation to the specific PDs / ARs will be specified as well.
The FAS will be the analysis set for the primary estimand as defined in Table 12-1. However, 
when assessing the robustness of the overall efficacy conclusions, considerations will be given 
to the analysis based on the primary estimand using FAS and the supplementary estimand (see 
Table 12-1) using PPS, i.e., similar conclusions on non-inferiority based on both estimands are 
expected. Inconsistencies in key efficacy study results between the FAS and PPS will be 
examined and discussed in the clinical study report (CSR).
The Pharmacokinetic analysis set includes all subjects who provide an evaluable PK profile for 
brolucizumab. A profile is considered evaluable if all of the following conditions are satisfied:

Subject receives the planned first dose of brolucizumab

Subject provides at least one primary PK parameter of brolucizumab (Cmax and AUC)
12.2
Subject demographics and other baseline characteristics
Demographic and Baseline characteristics will be summarized for all analysis sets. All 
summaries will be presented by the treatment group and overall.
The demographic parameters are age category (50 to 64, 65 to 74, 75 to 84, and ≥ 85), gender 
and race. Age will also be summarized as a continuous variable.
Baseline characteristics will include: primary diagnosis of neovascular AMD, time since 
diagnosis of neovascular AMD (days), whether neovascular AMD is unilateral or bilateral, 
BCVA (both as a continuous variable and as a categorical variable (≤ 55, ≥56-≤70, ≥ 71 letters)), 
lesion type (predominantly classic, minimally classic, pure occult), foveal involvement 
(subfoveal, extrafoveal, undeterminable), CNV lesion size, presence of subretinal fluid, 
presence of intraretinal fluid/cyst, presence of sub RPE fluid, neurosensory retinal thickness, 
CSFT (both as a continuous variable and as a categorical variable (< 400 ≥ 400 μm)).
12.3
Treatments
The Safety set will be used for the analyses below.
The extent of treatment exposure will be presented based on the overall number of injections, 
the number of subjects injected per visit, and frequency of the different treatment patterns.
Relevant medical history (ocular and non-ocular) will be tabulated by system organ class and 
preferred term of the MedDRA dictionary. Ocular events will be presented by study and non-
study eye.
The number and percentage of subjects taking concomitant therapies will be summarized by 
preferred term according to the WHO Drug Reference List dictionary. Ocular therapies will be 
presented by study and non-study eye.


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12.4
Analysis of the primary endpoint(s)
12.4.1
Definition of primary endpoint(s)
The primary endpoint is the change from Baseline in BCVA at Week 48. The first key 
secondary endpoint is average change in BCVA from Baseline over the period Week 36 through 
Week 48. For each subject, this endpoint is defined as the average of the changes from Baseline 
to Week 36, 40, 44 and 48. The primary analysis of the primary and first key secondary 
endpoints will be based on the FAS.
12.4.2
Statistical model, hypothesis, and method of analysis
The statistical hypothesis for the primary endpoint and first key secondary endpoint is non-
inferiority of brolucizumab 6 mg to aflibercept 2 mg within a margin of 4 letters.
The following 2 hypotheses will be tested in the pre-specified hierarchical sequence according 
to their numbering (HAn, n=1,2). Consequently, confirmatory testing of the second hypothesis 
requires rejection of the first null hypothesis. In this setting, each hypothesis will be assessed at 
a one-sided significance level of 0.05, while keeping the global type I error rate at 0.05.
Hypotheses: The following noninferiority hypotheses are related to a noninferiority margin of 
4 letters.
48 = Week 48, 36-48 = Week 36 through 48, R= brolucizumab 6 mg, A= aflibercept 2 mg
H01: μ48R - μ48A ≤ -4 letters vs HA1: μ48R - μ48A > -4 letters
μ48R and μ48A being the corresponding unknown true mean BCVA changes from Baseline to 
Week 48.
H02: μ36-48R - μ36-48A ≤ -4 letters vs HA2: μ36-48R - μ36-48A > -4 letters
μ36-48R and μ36-48A being the corresponding unknown true mean values for the average change 
in BCVA from Baseline over the period Week 36 through 48.
For the test of non-inferiority, a two-sided 90% CI for the treatment difference will be derived 
from an analysis of variance (ANOVA) model with treatment, Baseline BCVA categories (≤55, 
≥56-≤70, ≥ 71 letters) and age categories (< 75, ≥ 75 years) as factors. In order to demonstrate 
non-inferiority, the lower limit of the two-sided 90% CI for the treatment difference 
(brolucizumab 6 mg – aflibercept 2 mg) must be greater than -4 letters representing the 
noninferiority margin. 
The primary estimand and supplementary estimand of interest are described in Table 12-1
below, together with their key attributes, and will be discussed in further detail in the SAP.


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Table 12-1
Primary and supplementary estimands
Estimand
Estimand definition
Analysis set
Statistical methods 
(Including strategy for 
imputation/replacement 
of missing/censored 
data)
Primary estimand
Difference in change 
from baseline in BCVA at 
Week 48 excluding the 
effect of switching to 
alternative nAMD 
medication in the study 
eye
FAS
Analysis of variance 
(ANOVA) model including 
terms for treatment, 
baseline BCVA (≤55, 
≥56-≤70, ≥ 71 letters) 
and age category (<75, 
≥75 years), and using 
LOCF 
imputation/replacement 
for missing/censored 
data.
Supplementary estimand
Difference in change 
from baseline in BCVA at 
Week 48 for patients 
adhering to the protocol 
as per the PPS definition
PPS
ANOVA model as per the 
primary estimand.
LOCF 
imputation/replacement 
for missing/censored 
data
12.4.3
Handling of missing values/censoring/discontinuations
Missing BCVA values will be imputed by LOCF (Last Observation Carried Forward) as a 
primary approach. For subjects with no post-Baseline BCVA value, the Baseline value will be 
carried forward. Data collected after start of alternative nAMD treatment in the study eye (e.g. 
other anti-VEGF treatment, as further detailed in the SAP) will be censored for the primary 
analysis. All non-missing post-Baseline values including assessments done at unscheduled 
visits will be used when implementing the LOCF imputation. From an estimand perspective, 
the main focus is to adequately reflect in the analysis unfavorable study outcome related to the 
treatment (e.g. lack of efficacy, safety problems).
The LOCF approach is expected to be sensitive to an early study termination due to lack of 
efficacy assuming that such lack of efficacy is reflected in the last observed BCVA 
measurement. In case of the use of alternative treatment for the underlying disease, data 
collected after the start of such a treatment would be censored. LOCF will then be based on the 
last value prior to the start of this treatment, again expecting that this value would reflect the 
negative BCVA outcome under study treatment. In case of missing data due to lack of 
safety/tolerability with impairment of the function of the study eye the LOCF method would 
also provide a sensitive approach to capture such an unfavorable outcome.
In case of missing data occurring independently of the response to study treatment, the LOCF 
approach assumes stability which seems to be adequate based on historical data both for the 
maintenance treatment phase (i.e. stabilization of BCVA) and also in case of the absence of any 
treatment effect. In case of an early study termination during the loading phase, the LOCF 
method will result in a conservative estimate potentially underestimating the true outcome. 
LOCF is an established method within the assessment of efficacy of anti-VEGF treatments in 
terms of BCVA outcome. It is important to note that non-inferiority studies should follow the 
main design features (primary variables, the dose of the active comparator, eligibility criteria, 


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etc.) as the previously conducted superiority trials in which the active comparator demonstrated 
clinically relevant efficacy. 
Other methods of handling missing or confounded data within sensitivity analyses will be 
performed, as detailed in the SAP.
12.4.4
Sensitivity and Supportive analyses
Sensitivity and supportive analysis to explore the robustness of the primary efficacy results with 
respect to protocol deviations will use the PPS with LOCF imputation of missing values using 
the same model and factors as in the primary efficacy analysis model.
Sensitivity analyses to explore the robustness of the primary and first key secondary efficacy 
analysis results related to missing values will be performed on the observed data in the FAS 
applying the specified ANOVA model and a mixed model repeated measures (MMRM) 
assuming missing at random.
The following subgroups will be analyzed for the primary and first key secondary efficacy 
endpoints using the primary analysis approach:

Age category (< 75 years and ≥75 years)

Gender (male and female) 

Baseline BCVA categories (≤ 55, ≥56-≤70, ≥ 71 letters)

Baseline CSFT category (< 400, ≥ 400)

Baseline lesion type (predominantly classic, minimally classic, pure occult)
12.5
Analysis of secondary endpoints
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
Secondary endpoints will be analyzed based on FAS.
Key secondary efficacy endpoints related to dosing regimen:

q12w treatment status at Week 48 for subjects randomized to brolucizumab 6 mg

q12w treatment status at Week 48 within the subjects randomized to brolucizumab 6 mg 
and with no q8w need during the first q12w cycle (Week 16 and Week 20)
The key secondary endpoints will be analyzed based on the FAS with a negative q12 treatment 
status at Week 48 in case of incomplete active treatment up to Week 48.
The q12w treatment status at Week 48 in brolucizumab 6 mg treatment arm will be presented 
descriptively together with exact 90% confidence intervals for the proportion of subjects with 
a positive status: For the (overall) proportion of subjects with a positive q12w treatment status 
at Week 48, the denominator is all FAS subjects in the brolucizumab 6 mg group, and the 
numerator is the corresponding number of subjects with no identified q8w-need at Week 16, 20, 
32 and 44 (while missing the Week 16 assessment is considered as no q8w treatment needed). 
For the predictability of the adequacy of q12w treatment based on the absence of disease activity 
during the first q12w cycle, the denominator is all FAS subjects in the brolucizumab 6 mg group 
with no identified q8w-need at Week 16 and Week 20 (while missing the Week 16 assessment 
is considered a no-q8w treatment needed), and the numerator is the corresponding number of 


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subjects with a positive q12w treatment status at Week 48 (i.e. with no identified q8w-need at 
Week 16, 20, 32 and 44).
Secondary efficacy endpoints based on BCVA:

Change in BCVA from Baseline to each post-Baseline visit

Average change in BCVA from Baseline over the period Week 4 to Week 48

Average change in BCVA from Baseline over the period Week 12 to Week 48

Gain in BCVA of 15/10/5 letters or more from Baseline to each post-Baseline visit
Note: Subjects with BCVA value of 84 letters or more at a post-Baseline visit will be considered 
as responders for the corresponding endpoint. This is to account for a ceiling effect, e.g. for the’ 
≥15-letter gain’ endpoint, for those subjects with BCVA values at Baseline ≥ 70 letters.

Absolute BCVA of 73 letters or more at each visit

Loss in BCVA of 15/10/5 letters or more from Baseline to each post-Baseline visit 
Secondary efficacy endpoints related to anatomy or disease activity:

Change in CSFTtot from Baseline to each post-Baseline visit

Average change in CSFTtot from Baseline over the period Week 36 through Week 48

Average change in CSFTtot from Baseline over the period Week 4 to Week 48

Change in CSFTns from Baseline to each post-Baseline visit

Change in area of CNV within the lesion from Baseline to Weeks 12 and 48

Presence of subretinal and/or intraretinal fluid (central subfield) at each post-Baseline visit 
(and specifically Week 16 and Week 48)

Number of visits with simultaneous absence of subretinal and intraretinal fluid (central 
subfield) during Week 36 to Week 48

Presence of subretinal fluid (central subfield) at each post-Baseline visit

Presence of intraretinal fluid (central subfield) at each post-Baseline visit

Presence of sub RPE fluid (central subfield) at each post-Baseline visit
Secondary efficacy endpoints related to efficacy at the end of the matched treatment phase:

Change in CSFTtot from Baseline at Week 16

Presence of subretinal and/or intraretinal fluid (central subfield) at Week 16

q8w treatment need identified at Week 16
12.5.2
Safety endpoints
There are no formal safety hypotheses in this study. All safety analyses will be performed using 
the Safety Set.
Adverse events
Only treatment-emergent adverse events will be presented in the summary tables.
Adverse events will be coded using the MedDRA dictionary and presented by system organ 
class (SOC) and preferred term (PT). Treatment-emergent AEs will be analyzed based on the 
number and percentage of subjects with at least one AE in the category of interest. Separate 
presentations will be provided related to ocular events in the study eye and fellow eye and 
systemic events. Additional summaries will be provided by severity and causality (separately 


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assessed for the injection procedure and the drug). Serious adverse events and adverse events 
leading to discontinuation of study treatment will also be summarized separately.
Subject listings of all adverse events will be provided. Deaths and other serious or clinically 
significant non-fatal adverse events will be listed separately.
An adverse event of special interest (ESI) is one of scientific and medical interest to the Sponsor 
and include, but is not limited to, the following:

Endophthalmitis

Uveitis: all cases of anterior, posterior, or panuveitis

≥30 letter decrease in BCVA compared with Baseline visual acuity

New retinal tear or detachment

New diagnosis of geographic atrophy
The number (and proportion) of subjects with adverse events related to identified and potential 
risks, including AEs of special interest will be summarized by treatment
Ophthalmic examinations
Pre-injection IOP measurements will be presented descriptively (absolute values and change 
from Baseline). Post-injection IOP measurements will be listed. Presence of fibrosis from color 
fundus photography by assessment visit will be summarized.
Laboratory tests, vital signs, and special tests
Laboratory data and vital signs will be summarized by presenting shift tables using extended 
normal ranges (as provided by the central laboratory) with thresholds representing clinical 
relevant abnormality and by presenting descriptive statistics of raw data and change from 
Baseline. Values outside the extended normal range will be listed by subject and treatment arm 
and flagged in data listings.
12.5.3
Pharmacokinetics
Pharmacokinetic parameters will be determined using Phoenix WinNonlin (Version 6.4 or later-
Certara L.P) using non-compartmental method(s) for the subjects who had full PK sampling (7 
blood sampling points after first dose). PK parameters will be listed by treatment and subject. 
Descriptive summary statistics will include mean (arithmetic and geometric), SD, and CV 
(arithmetic and geometric), median, minimum and maximum. An exception to this is Tmax 
where median, minimum and maximum will be presented. For calculation of PK parameter, 
Concentrations below LLOQ will be treated as missing.
Serum concentrations will be summarized by treatment and time point for the subjects who had 
full PK sampling following first dose. Summary statistics will include n (number of values to 
be reported), arithmetic and geometric mean, median, SD, CV, and geometric CV, minimum 
and maximum. For the purpose of calculating descriptive statistics for serum concentrations, 
post-injection concentrations below the LLOQ will be treated half of LLOQ in summary 
statistics. If the mean was less than the LLOQ, it was reported as being BLQ within the summary 
tables.


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Table 12-2
Non-compartmental pharamcokinetic parameters
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time 
x volume-1)
AUCinf
The AUC from time zero to infinity (mass x time x volume-1)
AUC0-t
The AUC calculated from time zero to the defined time point t (eg.648h)(massx time x volume-1)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration 
after single dose administration (mass x volume-1)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration 
after single dose administration (time)
T1/2
The elimination half-life associated with the terminal slope (lz) of a semi logarithmic 
concentration-time curve (time).
12.5.4
DNA
Not applicable 
12.5.5
Biomarkers
Not applicable
12.5.6
PK/PD relationships
Not applicable.
12.5.7
Patient reported outcomes
The VFQ-25 questionnaires will be scored (total and subscale scores) at Baseline and Weeks 
24 and 48. Absolute scores and the absolute changes from Baseline will be calculated and 
summarized descriptively.
Further details on the scoring algorithm and analysis will be provided in the SAP.
12.5.8
Anti-drug antibody
Collection of blood for ADA assessment will be done at screening, weeks 4, 12, 24, 36 and 48 
prior to the injection/sham, and exit/premature discontinuation. Number and percent of 
subjects according to their ADA status (negative, positive without boost, treatment-induced, 
treatment-boosted) will be presented for brolucizumab arm. Patient listings of all ADA titer 
values will be presented for subjects in brolucizumab arm.
 


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12.7
Interim analyses
Not Applicable.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
In the spirit of bridging concept under ICH E5, a sample size of 175 subjects per treatment arm 
is sufficient to demonstrate noninferiority (margin = 4 letters) of brolucizumab 6 mg versus 
aflibercept 2 mg with respect to the BCVA change from Baseline to Week 48 at a one-sided 
alpha level of 0.05 with a power of approximately 80% assuming equal efficacy and a common 
standard deviation of 15 letters. A power of at least 80% can be expected for the first key 
secondary endpoint assuming that averaging BCVA change from Baseline over the 4 time 
points will not lead to an increase in the standard deviation. To account for a drop-out rate of 
10%, a total of 195 subjects will be randomized per treatment arm.
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g. 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 


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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 as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk-based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case-by-case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.


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14.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to
implementation.
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


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15
References
References are available upon request
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. p. 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. p. 209-213.e2.
Boulanger-Scemama E, Querques G, About F, et al (2015) Ranibizumab for exudative age-
related macular degeneration: A five year study of adherence to follow-up in a real-life 
setting. J Fr Ophtalmol. p. 620-7.
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. p. 794-5.
Chong V (2016) Ranibizumab for the treatment of wet AMD: a summary of real-world 
studies: Eye (Lond). p. 1526.
Essex RW, Nguyen V, Walton R, et al (2016) Treatment Patterns and Visual Outcomes 
during the Maintenance Phase of Treat-and-Extend Therapy for Age-Related Macular 
Degeneration: Ophthalmology. p. 2393-2400.
Ferris FL (1983) Senile macular degeneration: review of epidemiologic features. Am. J. 
Epidemiol. p. 132-51.
Ferris FL, Fine SL, Hyman L (1984) Age-related macular degeneration and blindness due to 
neovascular maculopathy: Arch. Ophthalmol. p. 1640-2.
Freund KB, Mrejen S, Gallego-Pinazo R (2013) An update on the pharmacotherapy of 
neovascular age-related macular degeneration: Expert Opin Pharmacother p. 1017-28.
Gupta B, Adewoyin T, Patel SK, et al (2011) Comparison of two intravitreal ranibizumab 
treatment schedules for neovascular age-related macular degeneration: Br J Ophthalmol p. 
386-90.
Holz FG, Schmitz-Valckenberg S, Fleckenstein M (2014) Recent developments in the 
treatment of age-related macular degeneration: J. Clin. Invest. p. 1430-8.
Holz FG, Tadayoni R, Beatty S, et al (2015) Multi-country real-life experience of anti-
vascular endothelial growth factor therapy for wet age-related macular degeneration: Br J 
Ophthalmol p. 220-6.
Hsu WM, Cheng CY, Liu JH, et al (2004) Prevalence and causes of visual impairment in an 
elderly Chinese population in Taiwan: the Shihpai Eye Study. Ophthalmology p. 62-9.
Jabs DA, Nussenblatt RB, Rosenbaum JT(2005), Standardization of uveitis nomenclature 
(SUN) Working Group Standardization of uveitis nomenclature for reporting clinical data. 
Results of the first international workshop. Am J Ophthalmol 140(3).p.509-16. 


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Kawasaki R, Yasuda M, Song SJ, et al (2010) The prevalence of age-related macular 
degeneration in Asians: a systematic review and meta-analysis: Ophthalmology p. 921-7.
Li X (2013) Clinical Pathway of Age-related Macular Degeneration in China. The Clinical 
Guideline and Clinical Pathway Development Committee of Age-Related Macular 
Degeneration. Chin J Ocul Fundus Dis. p. 343-355.
Li X, Zhu A, Egger A, et al (2016) Ranibizumab 0.5 mg for nAMD: monthly versus PRN 
dosing in the DRAGON study.
Lim LS, Mitchell P, Seddon JM, et al (2012) Age-related macular degeneration: Lancet p. 
1728-38.
Mangione CM, Lee PP, Gutierrez PR, et al (2001) Development of the 25-item National Eye 
Institute Visual Function Questionnaire: Arch. Ophthalmol. p. 1050-8.
Miller JW (2013) Age-related macular degeneration revisited--piecing the puzzle: the LXIX 
Edward Jackson memorial lecture. Am. J. Ophthalmol. p. 1-35.e13.
Miyazaki M, Nakamura H, Kubo M, et al (2003) Risk factors for age related maculopathy in a 
Japanese population: the Hisayama study: Br J Ophthalmol p. 469-72.
Nussenblatt RB, Palestine AG, Chan CC et al (1985) Standardizatlon of vitreal inflammatory 
activity in intermediate and posterior uveitis.Ophthalmology; 92(4):467-71.
Rein DB, Wittenborn JS, Zhang X, et al (2009) Forecasting age-related macular degeneration 
through the year 2050: the potential impact of new treatments: Arch. Ophthalmol. p. 533-40.
Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al (2014) Intravitreal aflibercept injection 
for neovascular age-related macular degeneration: ninety-six-week results of the VIEW 
studies: Ophthalmology p. 193-201.
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. p. 
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 p. 1901-
7.
Smith W, Assink J, Klein R, et al (2001) Risk factors for age-related macular degeneration: 
Pooled findings from three continents: Ophthalmology p. 697-704.
Sommer A, Tielsch JM, Katz J, et al (1991) Racial differences in the cause-specific 
prevalence of blindness in east Baltimore: N. Engl. J. Med. p. 1412-7.
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. p. 135-44.
Tufail A, Xing W, Johnston R, et al (2014) The neovascular age-related macular degeneration 
database: multicenter study of 92 976 ranibizumab injections: report 1: visual acuity: 
Ophthalmology p. 1092-101.


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Wong T, Chakravarthy U, et al (2008) The natural history and prognosis of neovascular age-
related macular degeneration: a systematic review of the literature and meta-analysis: 
Ophthalmology p. 116-26.


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16
Appendices
Not Applicable.

SAP_001.pdf: 
Clinical Development 
RTH258/Brolucizumab/Beovu® 
CRTH258A2307 / NCT04047472
A Twelve-Month, Randomized, Double-Masked, Multicenter, Phase III, 
Two-Arm Study Comparing the Efficacy and Safety of Brolucizumab 6 
mg versus Aflibercept in Chinese Patients with Neovascular Age-Related 
Macular Degeneration (HOBBY) 
Statistical Analysis Plan (SAP)  
Document type: 
SAP Documentation 
Document status: 
Amendment V2 
Release date: 
25-Mar-2024
Number of pages: 
45 
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 
 
CRTH258A2307 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time point 
Reason for 
update 
Outcome for update 
Section and title 
impacted (Current) 
13-Apr-
2021 
Prior to DB 
lock 
Creation 
of 
final version 
N/A - First version 
NA 
25-Mar-
2024 
Prior to DB 
lock 
Creation 
of 
amendment 1 
Update the list of 
abbreviations 
 
 
 
 
Update the version of 
protocol 
Section 1 
 
 
 
Population sample size 
and significance level 
alpha for data analysis are 
updated 
Section 1.1, Section 
2.1, Section 2.5.4.1, 
Section 3 
 
 
 
Add footnote in Table 1-1 
Section 1.2 
 
 
 
Clarify the study drug and 
study treatment 
Section 2.1.1 
 
 
 
Update unscheduled visits 
Section 2.1.1 
 
 
 
Modify the definition of 
PK set 
Section 2.2 
 
 
 
Add other subgroups of 
interest 
Section 2.2.1 
 
 
 
 
 
 
 
 
 
 
 
Update disposition tables 
Section 2.3.1 
 
 
 
Update demographics and 
baseline characteristics 
Section 2.3.2 
 
 
 
Specify CNV, fibrosis, 
foveal involvement 
Section 2.3.2, 
2.7.1,2.8 
 
 
 
Add medical history 
Section 2.3.3 
 
 
 
 
 
 
 
 
 
 
 
Update the alternative 
nAMD treatment list 
Section 2.5.3 


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SAP 
 
CRTH258A2307 
 
Date 
Time point 
Reason for 
update 
Outcome for update 
Section and title 
impacted (Current) 
 
 
 
Add listing for imaging 
parameters 
Section 2.8.4.4 
 
 
 
 
 
 
 
 
 
 
 
Clarify primary and 
supplementary estimands 
and analyses based on 
estimands 
Sections 2.5.1, 
2.5.2, 2.5.4 
 
 
 
Modify table of  
 nAMD treatments 
Section 2.5.3 
 
 
 
Delete “as observed” 
approach 
Section 2.6.4 
 
 
 
  
 
 
 
 
 
 
Specify AESIs and AE 
reporting for safety 
disclosure 
Section 2.8.1.1 and 
Section 2.8.1.2 
 
 
 
Add shift tables of 
laboratory data 
Section 2.8.3 
 
 
 
Add analyses on presence 
of fibrosis  
Section 2.8.4.2 
 
 
 
Move up the imaging 
parameters section 
Section 2.8.4.5 
 
 
 
Specify tables and plots of 
PK endpoints 
Section 2.9 
 
 
 
Modify titer value 
threshold of ADA 
Section 2.10 
 
 
 
Specify tables, plots and 
listings of ADA endpoints 
Section 2.10 
 
 
 
Update listing of “change 
to protocol specified 
analyses” 
Section 4 


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SAP 
 
CRTH258A2307 
 
Date 
Time point 
Reason for 
update 
Outcome for update 
Section and title 
impacted (Current) 
 
 
 
Modify concomitant 
medication/procedure 
imputation 
Section 5.1.3 
 
 
 
Update the important PD 
table 
Section 5.5 


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SAP 
 
CRTH258A2307 
 
Table of contents 
Table of contents ................................................................................................................. 5 
List of abbreviations ............................................................................................................ 7 
1 
Introduction ......................................................................................................................... 9 
1.1 
Study design............................................................................................................. 9 
1.2 
Study objectives and endpoints ............................................................................. 10 
2 
Statistical methods ............................................................................................................. 12 
2.1 
Data analysis general information ......................................................................... 12 
2.1.1 
General definitions ................................................................................ 12 
2.2 
Analysis sets .......................................................................................................... 13 
2.2.1 
Subgroup of interest .............................................................................. 14 
2.3 
Subject disposition, demographics and other baseline characteristics .................. 15 
2.3.1 
Subject disposition ................................................................................ 15 
2.3.2 
Demographics and baseline characteristics ........................................... 15 
2.3.3 
Medical history ...................................................................................... 16 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 16 
2.4.1 
Study treatment exposure ...................................................................... 16 
2.4.2 
Prior medications and concomitant therapies ....................................... 17 
2.5 
Analysis of the primary objective .......................................................................... 17 
2.5.1 
Primary endpoint and first key secondary endpoint .............................. 17 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 18 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 20 
2.5.4 
Sensitivity and supportive analyses ...................................................... 21 
2.6 
Analysis of additional key secondary objectives ................................................... 23 
2.6.1 
Additional key secondary endpoints ..................................................... 23 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 23 
2.6.3 
Handling of missing values/censoring/discontinuations ....................... 24 
2.6.4 
Supportive analyses ............................................................................... 24 
2.7 
Analysis of secondary efficacy objectives ............................................................. 25 
2.7.1 
Secondary endpoints ............................................................................. 25 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 26 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 26 
2.8 
Safety analyses ....................................................................................................... 27 
2.8.1 
Adverse events (AEs) ............................................................................ 27 
2.8.2 
Deaths .................................................................................................... 29 
2.8.3 
Laboratory evaluations .......................................................................... 29 


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2.8.4 
Other safety data ................................................................................... 29 
2.9 
Pharmacokinetic endpoints .................................................................................... 31 
2.10 
Anti-drug antibodies (ADA) .................................................................................. 32 
2.11 
Patient-reported outcomes ..................................................................................... 32 
 
34 
2.13 
Interim analysis ...................................................................................................... 34 
3 
Sample size calculation ..................................................................................................... 34 
4 
Change to protocol specified analyses .............................................................................. 35 
5 
Appendix ........................................................................................................................... 35 
5.1 
Imputation rules ..................................................................................................... 35 
5.1.1 
Study drug ............................................................................................. 35 
5.1.2 
AE date imputation ............................................................................... 36 
5.1.3 
Concomitant medication/procedure date imputation ............................ 37 
5.1.4 
Medical history date of diagnosis imputation ....................................... 38 
5.2 
AEs coding/grading ............................................................................................... 39 
5.3 
Laboratory parameters and vital signs derivations ................................................ 39 
5.4 
Statistical models ................................................................................................... 40 
5.4.1 
Primary and first key secondary analysis .............................................. 40 
5.4.2 
Other secondary efficacy analysis ......................................................... 40 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 41 
5.6 
Censoring rules for analysis................................................................................... 44 
6 
Reference ........................................................................................................................... 45 


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List of abbreviations 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse events of special interest 
AMD 
Age-Related Macular Degeneration 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of Variance 
AR 
Analysis restriction 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
BCVA 
Best Corrected Visual Acuity 
BID 
Bis in diem/twice a day 
BLQ 
Below the Quantization Limit 
CI 
Confidence interval 
Cmax 
Maximum concentration 
CNV 
Choroidal neovascularization 
COVID-19 
Coronavirus disease 2019 
CS 
Compound symmetry  
CSFT 
Central Subfield Thickness 
CSFTns 
Central Subfield Thickness-neurosensory retina 
CSFTtot 
Central Subfield Thickness Total 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAA 
Disease activity assessment 
DMC 
Data Monitoring Committee  
eCRF 
Electronic Case Report Form 
eCRS 
Electronic case retrieval strategy 
EOS 
End of Study 
EOT 
End of Treatment 
ESI 
Event of Special Interest 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAS 
Full Analysis Set 
FP 
Fundus Photography (FP)  
ICF 
Informed consent form 
IOP 
Intraocular pressure 
IRF 
Intraretinal fluid 
IVR 
Interactive Voice Response 
IVT 
Intravitreal 
IWR 
Interactive Web Response 
KM 
Kaplan-Meier 
LLOQ 
Lower limit of quantification 
LOCF 
Last Observation Carried Forward 
 


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LSM 
Least square means 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
MMRM 
Mixed model repeated measures 
nAMD 
Neovascular Age-related Macular Degeneration 
NCI 
National Cancer Institute 
OCT 
Optical coherent tomography 
o.d. 
Once Daily 
OS 
Overall Survival 
 
 
PD 
Protocol deviation 
PDS 
Programming Data Specifications 
PDT 
Photodynamic therapy 
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
PRO 
Patient-reported Outcomes 
PT 
Preferred term 
q4w 
Every 4 weeks 
q8w 
Every 8 weeks 
q12w 
Every 12 weeks 
QoL 
Quality of Life 
RAP 
Report and Analysis Process 
RAS 
Randomized analysis set 
RECIST 
Response Evaluation Criteria in Solid Tumors  
RPE 
Retinal pigment epithelium 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SRF 
Subretinal fluid 
TEAE 
Treatment-emergent adverse event 
TFLs 
Tables, Figures, Listings 
TOEP 
Toeplitz  
UWF-C 
Ultra-wide field Color Fundus Photography 
VC 
Variance components 
VEGF 
Vascular endothelial growth factor 
VFQ-25 
Visual Function Questionnaire-25 
WBC 
White blood cell(s) 
WHO 
World Health Organization 
 
 
 
 
 


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1 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to describe the implementation of 
statistical analysis planned in the study protocol, and to provide detailed statistical methods that 
will be used for the Clinical Study Report (CSR) of study CRTH258A2307. 
Data will be analyzed according to the data analysis Section 12 of the study protocol (Clinical 
Trial Protocol CRTH258A2307 v04 dated 14-Jun-2022) which will be available in Appendix 
16.1.1 of the CSR. Important information is given in the following sections and details will be 
provided, as applicable, in Appendix 16.1.9 of the CSR. 
The SAP will be finalized before treatment unmasking. Any changes to the SAP after approval 
will be documented in CREDI. 
1.1 
Study design 
This is a randomized, double-masked, multicenter, parallel-group, active-controlled study. The 
study includes 14 scheduled visits over 48 weeks. A screening period of 2 weeks will be used 
to assess eligibility. 
After confirmation of eligibility at baseline, approximately 390 subjects will be randomized in 
a 1:1 ratio to one of the two treatment arms (approximately 195 subjects per arm): 
• Brolucizumab 6 mg: three monthly intravitreal injections of brolucizumab 6 mg during the 
loading treatment period (q4w regimen) up to Week 8 followed by injections every 12 
weeks (q12w regimen) or 8 weeks (q8w regimen) up to Week 40 or Week 44, depending 
on the status of disease activity. 
• Aflibercept 2 mg: three monthly intravitreal injections of aflibercept 2 mg during the 
loading treatment period (q4w regimen) up to Week 8 followed by injections every 8 weeks 
(q8w regimen) up to Week 40. 
Only one eye fulfilling all eligibility criteria will be selected/ treated and will be defined as the 
study eye. 
Novartis Interactive Response Technology will be used for randomization.  
There are no stratification factors in this study. 
There are no interim analyses in this study. 


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Figure 1-1 
Study design 
 
q4w - injection every 4 weeks; q8w - injection every 8 weeks; q12w - injection every 12 weeks 
 
1.2 
Study objectives and endpoints 
Table 1-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To demonstrate that brolucizumab 6 mg is not 
inferior to aflibercept 2 mg with respect to the 
change in BCVA after 48 weeks of treatment 
• 
Change in BCVA from Baseline to Week 48┼ 
• 
Average change in BCVA from Baseline over the 
period Week 36 to Week 48# 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To estimate the proportion of q12w subjects (1 
injection every 12 weeks) up to Week 48 in the 
brolucizumab 6 mg treatment arm 
• 
q12w treatment status at Week 48 (for subjects 
randomized to brolucizumab 6 mg only) 
• 
To estimate the predictive value of the first q12w 
cycle for maintenance of q12w treatment up to 
Week 48 in the brolucizumab 6 mg treatment arm 
• 
q12w treatment status at Week 48 within the 
subjects with no q8w need during the first q12w 
cycle (Week 16 and Week 20) (for subjects 
randomized to brolucizumab 6 mg only) 
• 
To evaluate the efficacy of brolucizumab 6 mg 
relative to aflibercept 2 mg over the time period 
up to Week 48 by assessing changes in BCVA 
• 
Change in BCVA from Baseline to each 
postbaseline visit 
• 
Average change in BCVA from Baseline over the 
period Week 4 to Week 48 
• 
Average change in BCVA from Baseline over the 
period Week 12 to Week 48 
• 
Gain in BCVA of 15/10/5 letters or more from 
Baseline at each postbaseline visit 


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Objective(s) 
Endpoint(s) 
• 
Number and percentage of subjects with BCVA 
of 73 letters or more at each visit 
• 
Loss in BCVA of 15/10/5 letters or more from 
Baseline at each postbaseline visit 
• 
To evaluate the efficacy of brolucizumab 6 mg 
relative to aflibercept 2 mg over the time period 
up to Week 48 by assessing changes in 
anatomical parameters of disease activity 
• 
Change in CSFTtot from Baseline to each 
postbaseline visit 
• 
Average change in CSFTtot from Baseline over 
the period Week 36 through Week 48 
• 
Average change in CSFTtot from Baseline over 
the period Week 4 to Week 48 
• 
Change in CSFTns from Baseline to each 
postbaseline visit 
• 
Change in area of CNV lesion from Baseline at 
Weeks 12 and 48 
• 
Presence of subretinal and/or intraretinal fluid 
(central subfield) at each postbaseline visit (and 
specifically Week 16 and Week 48) 
• 
Number of visits with simultaneous absence of 
subretinal and intraretinal fluid (central subfield) 
during Week 36 to Week 48 
• 
Presence of subretinal fluid (central subfield) at 
each postbaseline visit 
• 
Presence of intraretinal fluid (central subfield) at 
each postbaseline visit 
• 
Presence of sub RPE fluid (central subfield) at 
each postbaseline visit 
• 
To evaluate the efficacy of brolucizumab 6 mg 
relative to aflibercept 2 mg at the end of the 
matched treatment phase  
• 
Change in CSFTtot from Baseline at Week 16 
• 
Presence of subretinal and/or intraretinal fluid 
(central subfield) at Week 16  
• 
q8w treatment need identified at Week 16 
• 
To assess the safety and tolerability of 
brolucizumab 6 mg relative to aflibercept 2 mg 
• 
Incidence and characteristics of treatment-
emergent adverse events 
• 
Treatment-emergent changes in ocular and 
systemic parameters 
• 
Presence of fibrosis from color fundus 
photography by assessment visit  
• 
To assess visual function-related subject reported 
outcomes following treatment with brolucizumab 6 
mg relative to aflibercept 2 mg 
• 
Change in subject reported outcomes (VFQ-25) 
total and subscale scores from Baseline to 
Weeks 24 and 48 
• 
To assess immunogenicity of brolucizumab 6 mg 
• 
ADA status at Baseline (enrollment), Weeks 4, 
12, 24, 36, and 48 (End of Study) 
• 
To assess systemic PK of brolucizumab at 6 mg 
following a single IVT injection 
• 
PK parameters after first brolucizumab 6 mg 
dose in a subset of subjects  


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Objective(s) 
Endpoint(s) 
┼ Change in BCVA from Baseline to Week 48 in the study eye is the primary endpoint, corresponding to the 
primary objective, which is consistent with pivotal studies (HAWK & HARRIER). 
# Average change in BCVA from Baseline over the period Week 36 to Week 48 in the study eye is the first key 
secondary endpoint, considered also of clinical importance and therefore corresponds to the primary objective 
of the study. 
 
2 
Statistical methods 
2.1 
Data analysis general information 
The primary analysis will be performed after all subjects completed or discontinued the study 
by Novartis using SAS 9.4 or above.  
Continuous variables will be summarized using the number of observations, mean, standard 
deviation, standard errors (SE), median, quartiles, minimum and maximum values. Categorical 
variables will be summarized with number of observations, the number of observations for each 
category and the corresponding percent. Where appropriate, 2-sided 90% confidence intervals 
(CIs) for point estimates of the mean or proportion will be provided. For the treatment difference 
brolucizumab – aflibercept, point estimates with 90% CIs will be provided as appropriate unless 
otherwise specified. 
 
 
2.1.1 
General definitions  
Study drug and study treatment 
Study drug refers to both Brolucizumab 6 mg and Aflibercept 2 mg via intravitreal (IVT) 
injections. 
Study treatment refers to study drug or sham injections. 
Study day 
Day 1 is defined as the date of the first study treatment.  Study day is defined as the number of 
days since the date of first dose of study treatment (Day 1). 
Therefore, for a particular date, study day will be calculated as follows: 
• for dates on or after the date of first administration of study treatment: 
Study day = Assessment date – Date of first study treatment + 1; 


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• for dates prior to the date of first administration of study treatment: 
Study day = Assessment date – Date of first study treatment. 
 
Baseline 
The baseline value is defined as the last assessment performed prior to administration of the 
first dose of study treatment.  
All data collected after the first study treatment are defined as post-baseline. 
End of study day mapping 
The end of the study day is the date when a subject completes or discontinues the study. 
For reporting data by visit in outputs, the end of study visit will be allocated to the actual 
(reported) visit number. If the end of study date is not on a scheduled visit, then the end of study 
visit will be allocated, based on study day, to the closest future scheduled study visit. 
Unscheduled visits 
Data collected at unscheduled visits will not be used in ‘by-visit’ tabulations or graphs but will 
be included in analyses based on all postbaseline values such as last observation carried forward 
(LOCF) imputation, and summary of maximum letter loss in BCVA from baseline. Only values 
at scheduled visits (observed or imputed by LOCF) will be considered to average BCVA change 
from baseline over a given period. These data will not be used in analyses with mixed model 
for repeated measures (MMRM). 
Moreover, given unscheduled visits will not be active treatment visits, IOP measurements at 
unscheduled visits will not be considered as pre-injection IOP measurements, hence will not be 
used to identify subjects with pre-injection IOP >30 mmHg. 
Missing and implausible dates 
The general approach to handling missing dates is shown in Section 5.1. 
2.2 
Analysis sets 
The All Enrolled Set includes all subjects who signed informed consent and are assigned with 
subject numbers. This analysis set will be used to summarize subject disposition. 
The Randomized Set (RAN) will consist of all randomized subjects. Subjects are considered 
randomized when they have been deemed eligible for randomization by the investigator and 
given a randomization number. Subjects will be analyzed according to the treatment assigned 
to at randomization. 
The Full Analysis Set (FAS) includes all randomized subjects who receive at least one IVT 
injection of the study treatment. The full analysis set will serve as the primary analysis set for 
all efficacy analyses. Following the intent-to-treat principle, subjects will be analyzed according 
to the treatment assigned to at randomization. 
Supportive analyses of the primary and key secondary endpoints will include analysis using the 
Per Protocol Set (PPS). PPS is a subset of the FAS and will exclude subjects with important 
protocol deviations (PDs) and analysis restrictions (ARs, i.e. non-protocol deviations) that are 


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expected to majorly affect the validity of the assessment of efficacy and/or safety at the end of 
study. Confounded data or discontinuation from treatment due to lack of efficacy and/or safety 
do not constitute a reason for exclusion from the PPS.  
PDs that may lead to exclusion from PPS are specified in Table 5-3. ARs that may lead to 
exclusion from PPS are specified in Table 5-4. Before the database locks, the relevant protocol 
deviations will be identified at the subject level in the database. After the database locks, 
analysis restrictions will be derived in the analysis database. Subject evaluability based on pre-
specified PDs and/or ARs and their impact on analysis sets will be determined prior to the 
database lock. Censoring applied in relation to the specific PDs/ARs will be specified as well. 
Details are specified in Section 5.5 and Section 5.6. 
The FAS will be the analysis set for the primary estimand as defined in  Table 2-1. However, 
when assessing the robustness of the overall efficacy conclusions, considerations will be given 
to the analysis based on the primary estimand using FAS and the supplementary estimand (see 
Table 2-1) using PPS. Inconsistencies in key efficacy study results between the FAS and PPS 
will be examined and discussed in the clinical study report (CSR). 
The Safety Analysis Set (SAF) will include all subjects who receive at least one study drug 
IVT injection. Subjects in the safety analysis set will be analyzed according to the treatment 
arm from which they received the majority of treatments. 
2.2.1 
Subgroup of interest 
The subgroups of interest are specified below: 
• Age category (< 75 years and ≥ 75 years) 
• Gender (male and female) 
• Baseline BCVA categories (≤ 55, ≥56-≤70, ≥ 71 letters) 
• Baseline CSFT category (< 400, ≥ 400 µm ) 
• Baseline type of CNV (predominantly classic, minimally classic, pure occult)  
 
Subgroup analysis will be performed on FAS for the primary and first key secondary efficacy 
endpoints, (as defined in Section 2.5.1), using the primary analysis approach. More details can 
be found in Section 2.5.4. 
 
 
  
 
 
 
 
 
 
 
  


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2.3 
Subject disposition, demographics and other baseline 
characteristics 
2.3.1 
Subject disposition 
The number of subjects enrolled in the study and with screen failures will be presented in the 
subject disposition table. The number and percentage of subjects who are randomized, are 
treated, complete the study, discontinue from the treatment prior to Week 44, and discontinue 
from study prior to Week 48 will be summarized by the treatment arm randomized, based on 
the all enrolled set. The reasons for discontinuation (from the study and/or treatment) will also 
be summarized.  
The number and percent of subjects who discontinue the study and who discontinue study 
treatment will be presented by study visit.  
A listing of subjects who discontinue from the study and/or treatment early will be provided by 
treatment. The listing will identify the visits completed and the date of study or treatment 
discontinuation including the corresponding reasons. 
A subject is considered to have completed the study period if he/she does not discontinue from 
the study prior to Week 48.  
Subjects who sign an informed consent form and who are subsequently found to be ineligible 
prior to randomization will be considered as screen failures. Appropriate table and listing of all 
screen failures with corresponding reason will be presented as necessary. 
Number and percentage of subjects who are excluded (i.e. not evaluable) from any of the SAF, 
FAS, and PPS will be presented using the randomized analysis set. A listing of subjects along 
with the analysis set that they are excluded from, and the corresponding reasons will also be 
presented. 
Number and percentage of subjects with important PDs and ARs will be presented by treatment 
arm and deviation/restriction category, including corresponding listings. 
Subjects who discontinue from the study and/or treatment early related to COVID-19 will be 
identified. To evaluate the PDs that occur related to COVID-19, the number and percentage of 
subjects with PDs that occur related to COVID-19 will also be provided by deviation category, 
relationship to COVID-19 and treatment arm. A listing of all ARs and PDs will be provided by 
treatment arm and subject, including the information if the AR/PD leads to the subject exclusion 
from an analysis set and the relationship to COVID-19. 
2.3.2 
Demographics and baseline characteristics 
Demographic and baseline characteristics will be summarized with descriptive statistics by 
treatment arm and overall based on FAS. The demographic characteristics include age, age 
category (50 to 64, 65 to 74, 75 to 84, and ≥ 85 years), gender and race.  
Baseline characteristics table will include: 
• Study eye selection (left eye/OS or right eye/OD) 
• Time since diagnosis of nAMD category (< 1 month, 1-3 months, >3 months) 
• Whether neovascular AMD is unilateral or bilateral 


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• BCVA (letters) 
• BCVA category (≤55, ≥56-≤70, ≥71 letters) 
• Type of CNV (predominantly classic, minimally classic, pure occult) from Color 
Fundus Photography (FP) / Ultra-wide field Color Fundus Photography (UWF-C)  
• Foveal involvement (subfoveal, juxtafoveal, extrafoveal) from FP/UWF-C 
• CNV lesion size from FP/UWF-C 
• Presence of subretinal fluid (central subfield) 
• Presence of intraretinal fluid/cyst 
• Presence of sub RPE fluid 
• Neurosensory retinal thickness (CSFTns) 
• CSFTtot 
• CSFTtot category (< 400, ≥ 400 μm) 
Pure occult in type of CNV is considered present if at least one of the 3 subtypes (Fibrovascular 
PED, Serous PED and Late Leakage) is present. “Predominantly classic” category in type of 
CNV includes both “Predominantly classic” and “Classic” subcategories. 
With regard to eye-level assessments, the baseline characteristics table will be presented for the 
study eye only and a corresponding listing will be provided separately for the study eye and the 
fellow eye. Other relevant baseline information will be listed and summarized with descriptive 
statistics as appropriate.  
Time since diagnosis of nAMD (months) will be derived as [(first dose date – diagnosis start 
date + 1)/(365.25/12)]. In case of partial dates, the imputation rule is specified in Section 5.1.4. 
No tests for differences in demographics and baseline characteristics between treatment arms 
will be performed. Potential differences will be assessed basen on clinical relevance. 
2.3.3 Medical history 
Medical history and current medical conditions will be summarized and listed for ocular (study  
eye) and non-ocular events based on SAF. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment exposure 
Extent of exposure to study drug is calculated as the number of IVT injections received. 
Descriptive statistics for exposure to study treatment will be provided for the Safety Analysis 
Set. 
The following summaries will be presented based on the Safety analysis set: 
• Number of injections will be presented separately (active and sham, active only, sham only) 
in the following time periods: 
o 
Baseline to Week 8 
o 
Week 12 to Week 44 


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o 
Baseline to Week 44 
• Treatment exposure by visit: The number and percentage of subjects who received active, 
sham injections, missed a treatment (active or sham) and missed visits will be presented 
separately by arm and visit. 
• Frequency of all observed dosing patterns up to and including Week 44 will be presented 
by treatment group, differentiating between active and sham treatments, missed treatments 
and wrong treatments. 
• Brolucizumab q12w/q8w allocation by visit: Number and percentage of subjects on q12w 
and q8w treatment regimen including the number of subjects switched from q12w to q8w 
with the reasons based on FAS. 
Dose administration records will be listed by each treatment arm. 
2.4.2 
Prior medications and concomitant therapies 
The Safety analysis set will be used for the analyses below. 
Prior medications are defined as treatments taken and stopped prior to the first dose of study 
treatment. Concomitant medications are defined as medications received after the start of study 
treatment including those already started prior to the start of the study treatment. 
Prior or concomitant medications will be coded according to the WHO Drug Reference List 
dictionary, with Anatomical Therapeutic Classification (ATC) class and preferred term (PT). 
Ocular and non-ocular prior and concomitant medications will be summarized and listed by 
ATC class and preferred term by each treatment arm. Ocular medications will be listed for the 
study eye and the fellow eye separately. 
Concomitant anti-VEGF medications will be summarized by ATC class and PT for the fellow 
eye by each treatment arm. 
Ocular significant non-drug therapies and procedures will be summarized for the study eye only. 
Both ocular (study eye and fellow eye) and non-ocular  significant non-drug therapies and 
procedures will be listed. 
In the summary tables, data collected after the subject discontinued study treatment and started 
alternative nAMD treatment in the study eye will be censored (from the day the subject started 
alternative nAMD treatment onwards). 
A listing of subjects who received alternative nAMD treatment in the study eye will be provided. 
2.5 
Analysis of the primary objective 
2.5.1 
Primary endpoint and first key secondary endpoint 
• The primary efficacy endpoint is change in BCVA from baseline to Week 48 in the study 
eye. 
• The first key secondary endpoint is average change in BCVA from baseline over the period 
Week 36 through Week 48 in the study eye. For each subject, this endpoint is defined as the 
average of the changes from baseline to Weeks 36, 40, 44 and 48. 


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The primary efficacy analyses of these two endpoints will be based on the FAS with LOCF 
imputation or replacement of missing or censored BCVA values. 
The primary estimand for the primary endpoint includes the following components: 
• Population: Chinese subjects with neovascular age-related macular degeneration as per the 
inclusion/exclusion criteria. 
• Endpoint: The primary endpoint is the change from baseline in BCVA at Week 48. BCVA 
will be assessed by the masked assessor using ETDRS-like charts at an initial distance of 4 
meters. 
• Treatment of interest: brolucizumab or aflibercept 
• The handling of the intercurrent events as follows: 
o 
Treatment discontinuation due to any reason: use the observed data, or impute using 
LOCF if missing 
o 
Data after the start of alternative nAMD treatment will be censored and replaced 
using LOCF 
• Summary measure: Difference in the change from baseline in BCVA at Week 48 between 
brolucizumab and aflibercept treatment arms. 
2.5.2 
Statistical hypothesis, model, and method of analysis  
The objective related to the primary and first key secondary endpoints is to demonstrate non-
inferiority of brolucizumab to aflibercept with respect to change from baseline in BCVA, 
considering a margin of 4 letters. 
Let:  
B = Brolucizumab 6 mg 
- 3 x q4w loading then q12w/q8w maintenance 
A = Aflibercept 2 mg    
- 3 x q4w loading then q8w maintenance 
The following non-inferiority hypotheses are related to a non-inferiority margin of 4 letters:  
 
H01: μB – μA 
≤ -4 letters 
vs. 
HA1: μB – μA 
> -4 letters 
 
H02: B – A 
≤ -4 letters 
vs. 
HA2: B – A 
> -4 letters 
where μB and μA are the corresponding unknown true mean changes from baseline in BCVA at 
Week 48; B and A are the corresponding unknown true mean changes from baseline in BCVA 
averaged over the period Week 36 to Week 48. 
Based on the FAS, the above hypotheses will be tested via an analysis of variance (ANOVA) 
model. The model will include treatment, baseline BCVA (≤ 55, ≥56-≤70, ≥ 71 letters) and age 
category (<75, ≥75 years) as factors. Two-sided 90% confidence interval (CI) for the least 
square means (LSM) difference (brolucizumab - aflibercept) will be presented. Non-inferiority 
will be considered established if the lower limit of the corresponding 90% CI is greater than -4 
letters. P-value for non-inferiority (4-letter margin) (1-sided) will be presented. 
The two hypotheses will be tested sequentially (HAn, n=1, 2), i.e. confirmatory testing of the 
second hypothesis requires rejection of the first null hypothesis.  


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In this setting, each hypothesis will be assessed at a one-sided significance level of 0.05, while 
keeping the global type I error rate at 0.05. 
The primary estimand and other supplementary estimands of interest are described in Table 2-
1 below, together with their key attributes. The same approach for non-inferiority assessment 
in change from baseline in BCVA at Week 48 and average change from baseline in BCVA over 
the period Week 36 through Week 48 will be applied to supplementary estimands. 
Table 2-1 
Primary and supplementary estimands 
Estimand 
Estimand definition 
Analysis 
set 
Data 
included in 
analysis 
Statistical methods 
(Including missing data 
strategy) 
Primary 
estimand 
Difference in change from 
baseline in BCVA at 
Week 48 excluding the 
effect of switching to 
alternative nAMD 
medication (treatment) in 
the study eye 
FAS 
All data 
captured until 
the start of 
alternative 
nAMD 
treatment(s) 
will be included 
Analysis of variance 
(ANOVA) model at one-sided 
significance level of 0.05, and 
including terms for treatment, 
baseline BCVA (≤ 55, ≥56-
≤70, ≥ 71 letters) and age 
category (<75, ≥75 years), and 
using LOCF 
imputation/replacement for 
missing/censored data. 
Supplementary 
estimand 1 
Difference in change from 
baseline in BCVA at 
Week 48 for subjects 
adhering to the protocol 
as per the PPS definition 
PPS 
All data 
captured until 
the start of 
alternative 
nAMD 
treatment(s) or 
relevant 
PDs/Ars will be 
included 
ANOVA model as per the 
primary estimand. 
LOCF imputation/replacement 
for missing/censored data 


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Estimand 
Estimand definition 
Analysis 
set 
Data 
included in 
analysis 
Statistical methods 
(Including missing data 
strategy) 
For additional information on data handling related to intercurrent events, see Section 5.5 and Section 
5.6. 
2.5.3 
Handling of missing values/censoring/discontinuations 
Missing BCVA values will be imputed using LOCF as a primary approach. Observed values 
from both scheduled and unscheduled visits will be used for the LOCF imputation. For subjects 
with no postbaseline BCVA value, the baseline value will be carried forward.  
LOCF is an established method within the assessment of efficacy of anti-VEGF treatments in 
terms of BCVA outcome. In case of missing data occurring independently of the response to 
study treatment, the LOCF approach assumes stability which seems to be adequate based on the 
nature of the disease progression and historical data. In case of missing data due to lack of 
efficacy or safety/tolerability with impairment of the function of the study eye, the LOCF 
method would be able to capture such an unfavorable outcomes as reflected in the last observed 
measurement. 
For subjects who discontinue treatment but continue in the study, data collected after switching 
to the alternative nAMD treatment in the study eye (see Table 2-2) will be censored for the 
primary analysis. Censored or missing data will be replaced or imputed using LOCF by the last 
observation collected prior to the start of alternative nAMD treatment in the study eye. Detailed 
alternative nAMD treatments will be listed in the Programming Data Specifications (PDS) 
documentation. If there are newly approved nAMD treaments, they will be reflected in the PDS. 


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Table 2-2 
Alternative nAMD treatment in the study eye that leads to censoring 
• 
Ranibizumab 
• 
Aflibercept  
• 
Bevacizumab (off-label use) 
• 
Conbercept 
• 
Faricimab 
• 
Visudyne/ photodynamic therapy (PDT) 
• 
Laser photocoagulation, previous standard of care still being used as mono- or combination 
therapy with anti-VEGF 
• 
Intraocularly/periocularly administered steroids: 
o 
Dexamethasone 
o 
Fluocinolone acetonide 
o 
Triamcinolone acetonide 
o 
Other intraocular/periocular steroids 
From the estimand perspective, the main purpose is to adequately reflect the unfavorable study 
outcome related to the treatment (e.g. lack of efficacy, safety problems) in the analysis.  
2.5.4 
Sensitivity and supportive analyses 
2.5.4.1 
Sensitivity analyses on the primary estimand 
Sensitivity to the statistical model and imputation assumptions from the primary estimand will 
be considered, using FAS only. 
An alternative method of handling missing values such as below will be considered to assess 
the robustness of the hypothesis testing in comparison to the results from the primary analysis: 
• Mixed model for repeated measures (MMRM) assuming missing at random (MAR) using 
observed data only. The MMRM will include treatment, visit, baseline BCVA category, age 
category and treatment by visit interaction as fixed effect terms and visit as a repeated 
measure. An unstructured covariance matrix will be used to model the within-patient error. 
For the MMRM analysis: 
• The treatment difference brolucizumab - aflibercept at Week 48 will be estimated using 
the LSM and 90% CI. 
• If an MMRM model with an unstructured covariance matrix does not converge, a more 
restricted covariance matrix can be considered in the following order until convergence 
is reached: Toeplitz (TOEP), first-order autoregressive (AR), compound symmetry 
(CS), and variance components (VC). 
In this analysis, data collected after the switch to alternative nAMD treatment in the study eye 
will be censored. 
For the endpoint of average change from baseline over the period Week 36 through Week 48, 
a SAS code using the ESTIMATE statement in PROC MIXED will be provided in the 
programming specification document to obtain the LSM estimate and 90% CI for the 
corresponding treatment difference. P-value for non-inferiority (1-sided) will be presented. 


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Other sensitivity analyses on the primary estimand might be considered. 
2.5.4.2 
Supportive analyses using different supplementary estimands 
Supplementary estimand 1 on the PPS: 
The target population, the primary endpoint, the treatment of interest and the summary measure 
of the supplementary estimand 1 are the same as for the primary estimand. Different from the 
primary estimand, the handling of the intercurrent events for the supplementary estimand 1 can 
be found in Table 5-6 for the PPS population. The supportive analysis on the supplementary 
estimand 1 will apply the same LOCF/ANOVA method as for the primary estimand. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 


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2.5.4.3 
Summary statistics and subgroup analysis 
Summary statistics: 
• Descriptive statistics of primary and first key secondary endpoints will use observed 
data and primary analysis set (FAS), with censoring data after use of alternative nAMD 
treatment in the study eye. 
Subgroup analyses will be conducted to assess the consistency of treatment effect across 
various subgroups described in Section 2.2.1. They will be conducted using the framework for 
the primary estimand only (FAS with censoring of data collected after use of alternative nAMD 
treatment in the study eye, and missing/censored values imputed/replaced using LOCF). 
• Subgroup analyses will be conducted using the same model and analysis strategies 
described for the primary and  first key secondary endpoint but fitted by category of 
each of the subgroups. Subgroup variables that are used as fixed effects in the model 
will be removed from the model statement for the subgroup analysis. 
• In case of analyses on subgroups with extremely imbalanced sample sizes, the subgroup 
levels can either be combined, if appropriate, or the extremely small subgroup will be 
excluded while fitting the analysis model. 
• The point estimate and 90% CI for the between treatment difference for each subgroup 
will be presented using forest plots. 
2.6 
Analysis of additional key secondary objectives 
2.6.1 
Additional key secondary endpoints 
Additional key secondary efficacy endpoints related to dosing regimen: 
• q12w treatment status at Week 48 for subjects randomized to brolucizumab 6 mg 
• q12w treatment status at Week 48 within the subjects randomized to brolucizumab 6 mg 
and with no q8w need during the first q12w cycle (Week 16 and Week 20) 
2.6.2 
Statistical hypothesis, model, and method of analysis 
No hypothesis will be tested for additional key secondary efficacy endpoints. The additional 
key secondary efficacy endpoints will be analyzed based on FAS in brolucizumab 6 mg group. 
The analysis approach described below (efficacy/safety approach) will be conducted. 
The estimate for the proportion of subjects with a positive q12w treatment status will be derived 
from Kaplan-Meier (KM) time-to-event analyses for the event ‘first q8w-need’, applying a 
‘q8w-need’ allocation in case of missing or confounded data attributable to lack of efficacy 
and/or lack of safety for the purpose of analysis. 
The proportion of subjects with a positive q12w treatment status will be derived as follows 
according to the ‘sufficient efficacy and safety’ approach: 


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• The q8w-need assessment is imputed as “Yes” at the DAA visit following early 
treatment/study discontinuation due to lack of efficacy and/or lack of safety of the study 
treatment (applies to both missing and non-missing DAAs). 
Intercurrent events associated with missing or confounded data regarding the q12w treatment 
status that are attributable to reasons other than lack of efficacy and/or safety are described 
below, together with the corresponding data handling strategies: 
• Early treatment/study discontinuation: censoring at the last valid DAA visit while on 
treatment/study 
• Single missed visit with a relevant DAA: censoring at the last valid DAA prior to the missed 
visit 
• Prohibited concomitant medications/procedures: censoring at the last valid DAA prior to 
the corresponding application 
• Discrepancy between DAA by investigator and the actual treatment received: censoring at 
the corresponding visit 
• Other treatment allocations/applications deviating from the concept of ‘treatment allocation 
according to disease activity’: censoring at the last valid DAA at or prior to the deviating 
visit. 
Censoring rules related to the q12w treatment status analysis are described in Section 5.6. 
The proportion of subjects with a positive q12w treatment status at Week 48 will be presented 
together with two-sided 90% confidence intervals. 
The outcome of the Kaplan-Meier analysis will be presented graphically by the estimated q12w-
probability over time, i.e. at each DAA visit. 
The analysis of ‘q12w treatment status at Week 48 within the subjects randomized to 
brolucizumab 6 mg and with no q8w need during the first q12w cycle’ is based on the subset of 
FAS subjects randomized to brolucizumabe 6 mg with no identified q8w-need at Week 16 and 
Week 20. For this subset a valid Week 20 DAA is required while missing the Week 16 DAA is 
considered as no q8w-need. 
2.6.3 
Handling of missing values/censoring/discontinuations 
The details regarding handling of missing values and discontinuations, including the timing of 
censoring within the time-to-event analyses for the event ‘first q8w-need’, are specified in the 
previous Section 2.6.2.  
Subjects without any valid DAA are considered censored at baseline for the overall q12w 
proportion and for the analysis of the predictive value of the first q12w cycle. 
From the estimand perspective, the impact of failing study completion according to the protocol 
due to lack of efficacy/safety is considered adequately reflected by a negative q12w-status.  
2.6.4 
Supportive analyses 
Supportive analyses will be performed on the FAS using alternative methods of handling 
missing or confounded data: 


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• ‘Efficacy only’ approach: approach with ‘q8w-need’ allocation only in case the reason 
for a missing or confounded q12w status is attributable to lack of efficacy of the study 
treatment. In case of a corresponding safety reason the subject is censored at the last 
valid DAA.  
Additionally, analyses described in Section 2.6.2 conducted using the FAS will be repeated 
using the PPS to assess the consistency of the assessment of the q12w proportions when looking 
only at those subjects who adhere to the protocol. 
2.7 
Analysis of secondary efficacy objectives 
2.7.1 
Secondary endpoints 
Secondary efficacy endpoints are listed below. 
Secondary efficacy endpoints based on BCVA: 
• Change in BCVA from Baseline to each postbaseline visit 
• Average change in BCVA from Baseline over the period Week 4 to Week 48 
• Average change in BCVA from Baseline over the period Week 12 to Week 48 
• Number and percentage of subjects with a gain in BCVA of 15/10/5 letters or more from 
Baseline to each postbaseline visit 
Note: Subjects with BCVA value of 84 letters or more at a postbaseline visit will be 
considered as responders for the corresponding endpoint. This is to account for a ceiling 
effect, e.g. for the’ ≥15-letter gain’ endpoint, for those subjects with BCVA values at 
Baseline ≥ 70 letters. 
• Number and percentage of subjects with an absolute BCVA of 73 letters or more at each 
visit 
• Number and percentage of subjects with a loss in BCVA of 15/10/5 letters or more from 
Baseline to each postbaseline visit  
Secondary efficacy endpoints related to anatomical parameters of disease activity: 
• Change in CSFTtot from Baseline to each postbaseline visit 
• Average change in CSFTtot from Baseline over the period Week 36 through Week 48 
• Average change in CSFTtot from Baseline over the period Week 4 to Week 48 
• Change in CSFTns from Baseline to each postbaseline visit 
• Change in area of CNV within the lesion from Baseline to Weeks 12 and 48 from FP/UWF-
C 
• Number and percentage of subjects with presence of subretinal and/or intraretinal fluid 
(central subfield) at each postbaseline visit (and specifically Week 16 and Week 48) 
• Number of visits with simultaneous absence of subretinal and intraretinal fluid (central 
subfield) during Week 36 to Week 48 
• Number and percentage of subjects with presence of subretinal fluid (central subfield) at 
each postbaseline visit 
• Number and percentage of subjects with presence of intraretinal fluid (central subfield) at 
each postbaseline visit 
• Number and percentage of subjects with presence of sub RPE fluid (central subfield) at each 
postbaseline visit 


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Secondary efficacy endpoints related to efficacy at the end of the matched treatment phase: 
• Change in CSFTtot from Baseline at Week 16 
• Number and percentage of subjects with presence of subretinal and/or intraretinal fluid 
(central subfield) at Week 16 
• Number and percentage of subjects with q8w treatment need identified at Week 16 
2.7.2 
Statistical hypothesis, model, and method of analysis 
No hypothesis will be tested for the secondary efficacy endpoints listed in the above Section 
2.7.1. 
These endpoints will be summarized and presented descriptively, based on the FAS with LOCF 
imputation for missing or censored data if not otherwise specified. Details on data handling 
such as missing values are described in Section 2.7.3. 
Continuous endpoints: 
The continuous secondary endpoints will be analyzed using ANOVA models. The LSM 
estimates for each treatment and for the treatment difference (brolucizumab – aflibercept), 
including 90% CIs will be presented. 
For the ANOVA analysis of BCVA-related endpoints, baseline BCVA category (≤55, ≥56-≤70, 
≥71 letters) and age category (<75, ≥75 years) will be considered as a class variable. For the 
ANOVA analysis of CSFT-related endpoints, baseline CSFT category (<400, ≥400 µm ) will be 
used instead of baseline BCVA as a class variable. For the ANOVA analysis of CSFTns-related 
endpoints, baseline CSFTns category (< overall median value, ≥ overall median value) will be 
used instead of baseline BCVA as a class variable. For the ANOVA analysis of CNV-related 
endpoints, baseline type of CNV (predominantly classic, minimally classic, pure occult) will be 
used instead of baseline BCVA as a class variable. 
The line plot of change from baseline in CNV lesion size, CSFTtot and CSFTns on LSM (±SE) 
by visit will also be provided for each treatment arm. 
Binary endpoints: 
For binary endpoints, frequency tables (count and percentage) will be provided by visit. In 
addition, proportions and treatment differences in proportions along with 90% CIs will be 
presented for each time point using a logistic regression with treatment, the corresponding 
baseline status and age category (<75, ≥75 years) as fixed effects.  Bar chart of the endpoints 
related to fluid will be plotted by visit and treatment arm.  
2.7.3 
Handling of missing values/censoring/discontinuations 
Missing data for all the secondary efficacy endpoints will be imputed using the LOCF method 
unless specified otherwise.  
For the LOCF method, missing data will be imputed by the value of the last available non-
missing post-baseline observation. For subjects with no postbaseline values (scheduled or 
unscheduled), the baseline value will be carried forward, as a conservative approach. For 
subjects who discontinue treatment but continue in the study, data collected after start of 
alternative nAMD treatment in the study eye will be censored for the analysis. Censored data 


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will be replaced by the last available observation prior to the start of alternative nAMDtreatment. 
Missing baseline values will not be imputed.  
For endpoints related to presence of fluids, if baseline visit is reported as “Cannot Grade” or 
“Not Applicable”, then it will be considered as “Absent”; if postbaseline visit is reported as 
“Cannot Grade” or “Not Applicable”, then it will be considered as missing and LOCF method 
for imputation will be applied. 
2.8 
Safety analyses 
Safety endpoints include: 
• Extent of exposure (see Section 2.4.1) 
• Adverse events 
• Deaths 
• Laboratory evaluations 
• Ophthalmic examinations 
• Presence of fibrosis from color fundus photography / ultra-wide field color fundus 
photography 
• Loss in BCVA 
• Vital signs 
There are no formal safety hypotheses in this study. All safety analyses will be performed using 
the Safety Analysis Set. 
Except for imputation of partial dates for AEs, no imputations will be performed for missing 
values in the safety analyses. 
In all summary tables, unless otherwise specified, data collected after the subject discontinued 
study treatment and started alternative nAMD treatment in the study eye will be censored (data 
on the day the subject started alternative nAMD treatment will be included). 
2.8.1 
Adverse events (AEs) 
A treatment-emergent adverse event (TEAE) is defined as any adverse event that develops after 
initiation of the study treatment or any event already present that worsens following exposure 
to the study treatment. Only TEAE will be presented in the summary tables. 
Adverse events will be coded using the MedDRA dictionary and presented by system organ 
class (SOC) and preferred term (PT). TEAEs will be analyzed based on the number and 
percentage of subjects with at least one AE in the category of interest. 
The number and proportion of subjects with TEAEs will be summarized in the following ways 
by treatment arm: 
 
 


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Table 2-4 
TEAE summary 
TEAE summary 
AE categories 
Ocular AE 
in the 
study eye 
Ocular AE 
in the 
fellow eye 
Non-
ocular 
AE 
AEs by primary SOC and PT 
Y# 
 
Y# 
AEs by primary SOC and PT (including events with onset date 
after start of alternative nAMD treatment) 
Y 
Y 
Y 
Frequent AEs by PT┼  
Y 
 
Y 
AEs by maximum severity, SOC and PT  
Y 
 
Y 
AEs related to study treatment by SOC and PT 
Y 
 
Y 
AEs related to injection procedure by SOC and PT 
Y 
 
Y 
AEs leading to permanent discontinuation of study treatment by 
SOC and PT 
Y 
 
Y 
AEs leading to temporary interruption of study treatment by SOC 
and PT 
Y 
 
Y 
SAEs by SOC and PT  
Y# 
 
Y# 
SAEs by SOC and PT (including events with onset date after 
start of alternative nAMD treatment) 
Y 
Y 
Y 
SAEs related to study treatment by SOC and PT 
Y 
 
Y 
SAEs related to injection procedure by SOC and PT 
Y 
 
Y 
┼≥2 % (or other cutting point as appropriate) in any treatment group for a given PT.  
 
 
In all summary tables listed above, unless otherwise specified, data collected after the subject 
discontinued study treatment and started alternative nAMD treatment in the study eye will be 
censored.  
Subject listings of all adverse events will be provided. Deaths and other serious or clinically 
significant non-fatal adverse events will be listed separately. 
The MedDRA version used for reporting the AEs will be described in a footnote. 
2.8.1.1 
Adverse events of special interest / grouping of AEs 
An adverse events of special interest (AESI) is one of scientific and medical interest to the 
sponsor and include the following:  
• Endophthalmitis 
• Intraocular Inflammation 
• Retinal Vascular Occlusion 
  


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Incidence of adverse events of special interest will be tabulated by treatment arm. AESIs in 
study eye and other safety topics of interest will be identified via the RTH258 electronic case 
retrieval strategy (eCRS). The eCRS that is current at the time of database lock will be used and 
AESIs and other safety topics of interest will be identified where the flag Core safety topic risk 
(SP) = ‘Y’. 
2.8.1.2 
Adverse event reporting for clinical trial safety disclosure  
For the legal requirements of ClinicalTrials.gov, two required tables on TEAEs which are not 
serious adverse events with an incidence greater than X% and on treatment emergent AEs and 
SAEs suspected to be related to study treatment will be provided by SOC and PT on the safety 
analysis set. Ocular TEAEs for study eye and fellow eye will be considered separately. 
If for the same subject, 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 
For occurrence, the presence of at least one SAE (respectively non-SAE) has to be checked in 
a block e.g. among AEs in a ≤ 1 day gap block, if at least one SAE is occurring, then one 
occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment, and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
2.8.2 
Deaths 
A summary of treatment emergent deaths will be presented by primary SOC and PT.  
All deaths recorded in the clinical database will be listed. 
2.8.3 
Laboratory evaluations 
Laboratory data will be presented graphically using boxplots of absolute change from baseline 
values by treatment arm and visit. No summary by visit tables will be provided. 
A summary table with counts and percentage of subjects satisfying the criteria representing 
clinically notable values given in Section 5.3 at any visit will be presented. A listing of subjects 
satisfying at least one criterion in Table 5-1 at any visit will also be presented. 
2.8.4 
Other safety data 
2.8.4.1 
Ophthalmic examinations 
Intraocular pressure (IOP) values summarized and listed in safety analyses refer to assessments 
for study eye.  


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Descriptive summaries of pre-injection change from baseline in intraocular pressure (IOP) 
values for the study eye will be presented  at each study visit by treatment arm, considering line 
plots of the mean change in IOP values with error bars representing ± SE. The x-axis will be 
study visit and the y-axis will be the change from Baseline value. No summary by visit tables 
will be provided. 
The number and percentage of subjects with pre-injection IOP >30 mmHg at any visit will be 
summarized.  
Post-injection IOP is to be assessed within 60 minutes after injection and if ≥25 mmHg, the 
assessment should be repeated until back to normal. Summary tables with counts and percentage 
of subjects with an IOP increase of ≥10, ≥20 mmHg from pre-injection to post-injection at any 
visit for the study eye will be presented. A listing for subjects with any post-injection IOP 
increase of ≥10 mmHg from pre-injection IOP at any visit for the study eye will be presented. 
A summary table with counts and percentage of subjects with observed pre-injection IOP ≥ 21 
mmHg at 3 consecutive scheduled visits will be presented. A visit with missing pre-injection 
IOP is considered to meet the ≥ 21mmHg criterion if the proceeding and the following visits 
meet the criterion that pre-injection IOP ≥ 21mmHg. For example, if schedule visit X has 
missing pre-injection IOP and pre-injection IOP ≥ 21mmHg is observed for both visit X-1 and 
X+1, the subject is considered to meet the criteria at visit X as well. 
A listing of subjects with any IOP > 30 mmHg will be presented. 
The abnormal findings via slit-lamp and indirect fundus examinations deemed as clinically 
significant by the investigator and reported as AE/SAE will be included in the safety analysis 
on AE/SAE.   
2.8.4.2 
Presence of fibrosis 
A summary table with counts and percentage of subjects with presence of fibrosis (central 
subfield) in study eye from color fundus photography/ ultra-wide field color fundus photograph 
will be presented by visit. Fibrosis data will be presented in a subject listing. 
2.8.4.3 
Loss in BCVA 
The numbers and percentages of subjects with a loss in BCVA ≥15, ≥30 letters (study eye) from 
baseline to the last visit, and maximum loss at any postbaseline visit will be presented.  
2.8.4.4 
Vital signs 
Vital signs include assessment of sitting blood pressure (systolic and diastolic pressure in mm 
Hg) and pulse (beats per minute). 
A summary table with numbers and percentages of subjects satisfying the criteria given in Table 
5-2 of Section 5.3 at any visit will be presented. A listing of subjects satisfying at least one 
criterion in Table 5-2 will also be presented. 
A line plot of mean change from baseline in each vital sign parameter by study visit and 
treatment with error bars representing ±SE will be presented. The x-axis will be study visit and 
the y-axis will be the mean change from baseline value. 


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2.8.4.5 
Imaging parameters 
Pre-defined imaging parameters in the study eye associated with intraocular inflammation 
and/or retinal vascular occlusion as assessed by the CRC will be listed. 
2.9 
Pharmacokinetic endpoints   
PK parameters of brolucizumab in serum will be assessed in subgroup with  approximately 12 
PK consented subjects in brolucizumab arm. 
A PK profile is considered evaluable if all the following conditions are satisfied: 
• Subject receives the planned first dose of brolucizumab 
• Subject provides at least one primary PK parameter of brolucizumab (e.g. Cmax or AUC) 
Pharmacokinetic parameters including but not limited to those presented in Table 2-5 will be 
determined using Phoenix WinNonlin (Version 8.3 or higher) using non-compartmental 
method(s). Descriptive summary statistics for PK parameters will include n (number), mean 
(arithmetic and geometric), SD, SE (arithmetic and geometric), and CV (arithmetic and 
geometric), median, minimum and maximum. An exception to this is Tmax where median, 
minimum and maximum will be presented. In addition, half-life (T1/2) will be summarized 
using Harmonic mean along with the Jack-Knife estimate for standard deviation. 
For PK consented group in brolucizumab arm, line plots showing the mean serum concentration 
± standard error versus nominal sample collection time will be presented, and the individual 
line plots will also be presented. 
Descriptive statistics will be presented for serum concentration levels for all the subjects with 
PK sample collection at each sampling time. Serum concentration values will also be listed by 
treatment subject and time point. Summary statistics will include n (number of values to be 
reported), arithmetic and geometric mean, median, SD, SE, CV, and geometric SE, geometric 
CV, minimum and maximumSamples collected outside of the protocol defined visit window 
will be excluded from that visit/timepoint for the purpose of presenting descriptive summaries 
by time point.At each time point, one-half the lower limit of quantitation (LLOQ) will be used 
for analysis when a subject has a determined concentration value below the LLOQ. For the 
purpose of calculating descriptive statistics for serum concentrations, post-injection 
concentrations below the LLOQ will be treated as half of LLOQ in summary statistics. If the 
mean was less than the LLOQ, it was reported as being Below the Limit of Quantitation (BLQ) 
within the summary tables. 
Table 2-5 
Non-compartmental pharmacokinetic parameters 
AUClast 
The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time 
x volume-1) 
AUCinf 
The AUC from time zero to infinity (mass x time x volume-1) 
AUC0-t 
The AUC calculated from time zero to the defined time point t (eg.648h)(massx time x volume-1) 
Cmax 
The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration 
after single dose administration (mass x volume-1) 
Tmax 
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration 
after single dose administration (time) 
T1/2 
The elimination half-life associated with the terminal slope (lz) of a semi logarithmic 
concentration-time curve (time). 


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2.10 
Anti-drug antibodies (ADA) 
Collection of blood for ADA assessment will be done at screening, Weeks 4, 12, 24, 36, 48 and 
exit/premature discontinuation. Analyses will be performed only in brolucizumab treatment arm. 
ADA status is defined using the following criteria. The pre-dose is referring to screening 
assessment and the post-dose is referring to postbaseline assessment in the following definition: 
• ADA negative: 
- ADA negative at all time points (pre-dose and post-dose) 
- ADA negative at pre-dose and no titer values above 40 at all other time points 
- ADA titer of 40 at pre-dose but negative at all other time points 
• ADA positive without boost: 
- ADA positive at pre-dose, post-dose titer values do not increase from pre-dose by 
more than 3-fold (1 dilution) at any time point 
• Induced: 
- ADA negative at pre-dose, post-dose titer value of 120 or more increase 
• Boosted: 
- ADA positive at pre-dose, post-dose titer values increase from pre-dose by more 
than 3-fold (1 dilution) at any time point 
The number and percentage of subjects according to their integrated ADA status (ADA negative, 
ADA positive without boost, induced, boosted) will be presented. In addition, tabulations will 
be presented for ADA titer pattern.  
The number and percentage of subjects with positive neutralizing antibody (NAb) will be 
summarized by ADA assessment visit for subjects with ADA titer values (ADA positive). 
The line plots showing the BCVA change from baseline up to Week 48 for the study eye by 
ADA status (pre-existing and integrated status up to Week 48) and NAb status (pre-existing and 
integrated status up to Week 48) among all the subjects and the subjects without AESI in study 
eyewill be generated. 
The summary tables of the incidence of AESIs in study eye by ADA status (pre-existing, pre-
existing nAb, integrated ADA and integrated nAb status up to Week 48) will be presented. 
Subject listings of all ADA titer values and NAb status will be presented for all subjects in the 
brolucizumab arm. Samples collected at unscheduled visits will not be part of the analysis. 
Systemic exposure of brolucizumab will be measured concomitantly with ADA levels for 
interpretation purposes.   
2.11 
Patient-reported outcomes 
The Visual Function Questionnaires (VFQ-25) will be scored (total and subscale scores) at 
Baseline, Week 24 and EOS visits. Absolute scores and the absolute changes from baseline 
will be calculated and summarized descriptively using the FAS. PRO data at EOS which is 
different from Week 48 will be excluded. 
Further details on the scoring algorithm and analysis are provided below. 


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Each subscale score has a range of 0 to 100 inclusive and will be calculated from the re-scaled 
raw data as described in Table 2-6. A missing response will not be re-scaled (except for the 
response to question 15c, see below, which will be re-set to 0 if the response to question 15b is 
1). 
The answers to questions will be re-scaled as follows to calculate the composite and subscale 
scores. 
Table 2-6 
Rescaling of VFQ-25 questions 
Answer to 
question 
Rescaling for 
questions 1, 3, 4 
and 15c 
Rescaling for 
question 2 
Rescaling for 
questions 5-14, 
16 and 16a 
Rescaling for 
questions 17-25 
1 
100 
100 
100 
0 
2 
75 
80 
75 
25 
3 
50 
60 
50 
50 
4 
25 
40 
25 
75 
5 
0 
20 
0 
100 
6 
N/A 
0 
N/A 
N/A 
• Note that the answer to question 15c will subsequently be adjusted based on the answer to 
question 15b. 
o If the answer to 15b is 1 then the answer to 15c will be re-set to 0 
o If the answer to 15b is 2 or 3 then the answer to 15c will be re-set to missing  
The VFQ subscales and their corresponding questions are shown in Table 2-7. 
Table 2-7 
Questions contributing to VFQ subscales 
Subscale 
Questions 
General vision 
2 
Ocular pain 
4 and 19 
Near activities 
5, 6 and 7 
Distance activities 
8, 9 and 14 
Social functioning 
11 and 13 
Mental health 
3, 21, 22 and 25 
Role difficulties 
17 and 18 
Dependency 
20, 23 and 24 
Driving 
15c, 16 and 16a 
Color vision 
12 
Peripheral vision 
10 
Subscales will be calculated where at least one of the (re-scaled) questions contributing to that 
subscale is non-missing, and otherwise set to missing. 
The composite score is the average of the 11 subscales shown in Table 2-7. It will be set to 
missing if at least six of the subscales are missing. 
The general health score is the re-scaled answer to question 1. 


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Descriptive summary statistics for change from baseline to post baseline VFQ assessments will 
be presented using the FAS for the composite and subscale scores. Mean changes from baseline 
to each post baseline VFQ assessments visits will be compared between the brolucizumab arm 
and the aflibercept arm. Appropriate statistical methods (e.g. ANCOVA model with treatment 
as a fixed effect factor and corresponding baseline value of the endpoint in the model) will be 
used for treatment group comparison. Additionally, descriptive statistics will also be presented 
for the general health score.   
The VFQ-25 composite score and subscale scores will not be listed. 
 
 
2.13 
Interim analysis 
Not applicable. 
3 
Sample size calculation 
A sample size of 175 subjects per treatment arm is sufficient to demonstrate noninferiority 
(margin = 4 letters) of brolucizumab 6 mg versus aflibercept 2 mg with respect to the BCVA 
change from Baseline to Week 48 at a one-sided alpha level of 0.05 with a power of 
approximately 80% assuming equal efficacy and a common standard deviation of 15 letters. A 
power of at least 80% can be expected for the first key secondary endpoint assuming that 
averaging BCVA change from Baseline over the 4 time points will not lead to an increase in 
the standard deviation. To account for a drop-out rate of 10%, a total of 195 subjects will be 
randomized per treatment arm. 
 


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4 
Change to protocol specified analyses 
 
Protocol 
section 
Protocol wording 
Change in SAP 
12.2 
Demographic and Baseline 
characteristics 
will 
be 
summarized for all analysis 
sets. 
Demographic based on FAS, but not on all 
analysis set. 
12.5.2 
Laboratory data and vital signs 
will 
be 
summarized 
by 
presenting shift tables using 
extended normal ranges (as 
provided 
by 
the 
central 
laboratory) with thresholds 
representing clinical relevant 
abnormality and by presenting 
descriptive statistics of raw 
data and change from Baseline. 
Section 2.8.3 
Laboratory data will be presented graphically 
using boxplots of absolute change from baseline 
values by treatment arm and visit. No summary 
by visit tables will be provided. 
A summary table with counts and percentage of 
subjects satisfying the criteria representing 
clinically notable values given in Section 5.3 at 
any visit will be presented. A listing of subjects 
with all laboratory data in Table 5-1 at any visit 
will also be presented. 
Section 2.8.4.4 
A summary table with numbers and percentages 
of subjects satisfying the criteria given in Table 
5-1 at any visit will be presented. A listing for 
subjects satisfying at least one criterion in Table 
5-1 will also be presented. 
A line plot of mean change from baseline in each 
vital sign parameter by study visit and treatment 
with error bars representing ±SE will be 
presented. 
 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
No imputation will be made to the start date and end date of study treatment. 


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5.1.2 
AE date imputation 
5.1.2.1 
AE start date imputation 
The following table explains the notation used in the logic matrix below. Please note that 
completely missing start dates will not be imputed. 
 
 
Day  
Month 
Year 
Partial Adverse Event 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) 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. 
5.1.2.2 
AE 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. 
4. If the imputed AE end date is less than the existing AE start date then use AE start date as 
AE end date. 
5.1.3 
Concomitant medication/procedure date imputation 
5.1.3.1 
Concomitant medication/procedure start date imputation 
In order to classify a medication/procedure 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 CM/PR 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  
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 concomitant medication (CM)/concomitant procedure (PR) start date year value is 
missing, the imputed CM/PR start date is set to one day prior to treatment start date. 


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2. If the CM/PR start date year value is less than the treatment start date year value, the CM/PR 
started before treatment. Therefore: 
a. If the CM/PR month is missing, the imputed CM/PR start date is set to the mid-year point 
(01JulYYYY). 
b. Else if the CM/PR month is not missing, the imputed CM/PR start date is set to the mid-
month point (15MONYYYY). 
3. If the CM/PR start date year value is greater than the treatment start date year value, the 
CM/PR started after treatment. Therefore: 
a. If the CM/PR month is missing, the imputed CM/PR start date is set to the year start 
point (01JanYYYY). 
b. Else if the CM/PR month is not missing, the imputed CM/PR start date is set to the month 
start point (01MONYYYY). 
4. If the CM/PR start date year value is equal to the treatment start date year value: 
a. And the CM/PR month is missing or the CM/PR month is equal to the treatment start 
date month, then the imputed CM/PR start date is set to one day prior to treatment start 
date. 
b. Else if the CM/PR month is less than the treatment start date month, the imputed CM/PR 
start date is set to the mid-month point (15MONYYYY). 
c. Else if the CM/PR month is greater than the treatment start date month, the imputed 
CM/PR start date is set to the month start point (01MONYYYY). 
If complete (imputed) CM/PR end date is available and the imputed CM/PR start date is greater 
than the (imputed) CM/PR end date, then imputed CM/PR start date should be set to the 
(imputed) CM/PR end date. 
5.1.3.2 
Concomitant medication/procedure end date imputation 
1. If the CM/PR end date year value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the CM/PR end year value is missing or ongoing, the imputed 
CM/PR end date is set to NULL. 
2. Else, if the CM/PR end date month is missing, the imputed end date should be set to the 
earliest of the (treatment end date, 31DECYYYY, date of death). 
3. If the CM/PR end date day is missing, the imputed end date should be set to the earliest of 
the (treatment end date, last day of the month, date of death). 
4. If the imputed CM/PR end date is less than the existing CM/PR start date, use the CM/PR 
start date as the imputed CM/PR end date. 
5.1.4 
Medical history date of diagnosis imputation 
Completely missing dates and partially missing end dates will not be imputed. Partial dates of 
diagnosis will be compared to the treatment start date. 
1. If DIAG year < treatment start date year  
a. and DIAG month is missing, the imputed DIAG date is set to the mid-year point 
(01JULYYYY) 


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b. else if DIAG month is not missing, the imputed DIAG date is set to the mid-month 
point (15MONYYYY) 
2. If DIAG year = treatment start date year 
a. and (DIAG month is missing OR DIAG month is equal to treatment start month), 
the imputed DIAG date is set to one day before treatment start date 
b. else if DIAG month < treatment start month, the imputed DIAG date is set to the 
midmonth point (15MON YYYY) 
c. else if DIAG month > treatment start month => data error 
3. If DIAG year > treatment start date year => data error 
5.2 
AEs coding/grading 
AEs are coded using the MedDRA terminology.  
AEs severity is assessed by investigators according to the following:  
• 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 and vital signs derivations 
Table 5-1 
Clinically notable laboratory values 
Test 
Conventio
nal Units 
Critical 
Low 
Critical 
High 
Standar
d Units 
Critical Low 
Critical High 
Non-
numeric 
Calcium 
mg/dL 
< 6.0 
> 13.0 
mmol/L 
< 1.50 
> 3.25 
 
Creatinine, 
Jaffe or 
Enzymatic 
mg/dL 
N/A 
>5.0 
umol/L 
N/A 
>442 
 
Glucose 
mg/dL 
< 40 
> 500 
mmol/L 
< 2.22 
> 27.75 
 
Sodium 
mEq/L 
< 120 
> 160 
mmol/L 
< 120 
> 160 
 
Hemoglobin 
g/dL 
< 6.0 
> 20.0 
g/L 
< 60 
> 200 
 
Magnesium 
mg/dL 
< 0.7 
> 6.1 
mmol/L 
< 0.30 
> 2.50 
 
Magnesium 
mEq/L 
< 0.6 
> 5.0 
mmol/L 
< 0.30 
> 2.50 
 
Phosphate 
(Phosphorus
) 
mg/dL 
< 1.0 
N/A 
mmol/L 
< 0.32 
N/A 
 
Platelet 
X10E3/uL 
< 50 
> 999 
X10E9/L 
< 50 
> 999 
 
Potassium 
mEq/L 
< 2.8 
> 6.5 
mmol/L 
< 2.8 
> 6.5 
 
WBC 
X10E3/uL 
< 2.0 
N/A 
X10E9/L 
< 2.0 
N/A 
 
 
Table 5-2 
Clinically notable vital signs 
Variable 
Category 
Critical values 
Systolic blood 
pressure (mmHg) 
High 
Either >180 with an increase from baseline >30 or >200 absolute 
Low 
Either <90 with a decrease from baseline >30 or <75 absolute 


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Variable 
Category 
Critical values 
Diastolic blood 
pressure (mmHg) 
High 
Either >105 with an increase from baseline >20 or >115 absolute 
Low 
Either <50 with a decrease from baseline > 20 or <40 absolute 
Pulse rate (bpm) 
High 
Either >120 with an increase from baseline of >25 or > 130 
absolute 
Low 
Either <50 with a decrease from baseline >30 or <40 absolute 
5.4 
Statistical models 
5.4.1 
Primary and first key secondary analysis 
The primary endpoint (change from baseline in BCVA at Week 48) and first key secondary 
endpoint (average change from baseline in BCVA over the period Week 36 through Week 48) 
will be analyzed using ANOVA models. 
 
Analysis of Variance (ANOVA) 
The following ANOVA model will be used for the primary and first key secondary efficacy 
endpoints: 
<change from Baseline in BCVA at Week 48> <average change from Baseline in BCVA 
from Week 36 to Week 48> = intercept + treatment + Baseline BCVA category + age 
category + error. 
For the above analysis, the data structure is one record per subject.  
The SAS Proc MIXED will be used to perform the ANOVA analyses. 
 
Mixed Model Repeated Measures (MMRM) 
The following MMRM model will be used for the supportive analysis of the primary and first 
key secondary efficacy variables: 
<change from Baseline in BCVA> = intercept + treatment + Baseline BCVA category 
+ age category + visit + treatment*visit + error. 
 
The SAS Proc MIXED will be used to perform the MMRM analyses. 
Note: For the above MMRM analysis, the data structure is one record per subject per scheduled 
visit. The data will include all subjects and have records for all scheduled visits, regardless of 
whether the assessment was missed or not at a given visit. Missing values will NOT be imputed 
using LOCF. Instead, the value will be passed to the model as missing. 
5.4.2 
Other secondary efficacy analysis 
5.4.2.1 
ANCOVA model for continuous variables 
The continuous efficacy variable (such as VQF-25 score change from baseline) will be analyzed 
using an ANCOVA model adjusted for treatment, age category, and the corresponding baseline 
VFQ-25 score. 
The SAS Proc MIXED will be used to perform the ANCOVA analyses. 


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5.4.2.2 
Logistic regression for proportion variables 
The binary efficacy variables will be analyzed using the logistic regression model adjusted for 
treatment, age category, corresponding baseline variables, and other covariates if necessary.  
The SAS Proc LOGISTIC will be used.  
Note: 
• For the above analyses, the data structure is one record per subject and visit. The least 
square mean estimates obtained from the above model are for the log-odds ratios. 
• The estimated difference in proportions and the corresponding 90% confidence intervals 
will be obtained by applying the bootstrap method. The pseudo SAS code to derive the 
treatment difference and 90% CI from the least square mean output of the fitted model 
will be provided in the programming specification document. 
5.4.2.3 
KM estimate for time to event variables 
Within the brolucizumab treatment arm, the proportion of subjects maintained at q12w up to 
Week 48 will be estimated from Kaplan Meier time-to-event analyses for the event ‘first q8w-
need’ applying event allocations (in case of lack of efficacy and/or lack of safety) and censoring 
as described in Section 2.6.2 and Section 2.6.3.  
A corresponding 90% CI will be derived from the LOGLOG transformation, using SAS Proc 
Lifetest, with CONFTYPE = LOGLOG. 
 
 
 
 
  
 
  
 
 
  
 
 
5.5 
Rule of exclusion criteria of analysis sets 
Important protocol deviations are defined in the Protocol Deviations Requirements Document.  
Table 5-3 includes the important protocol deviations which lead to exclusion of a subject from 
one or more analysis sets.  
Table 5-3 
Important Protocol deviations leading to exclusion from analysis 
Deviation ID 
Description of Deviation 
Exclusion from Analyses 
M_INCL01_ICF not 
obtained 
Written informed consent not obtained 
Exclude from all analysis 


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Deviation ID 
Description of Deviation 
Exclusion from Analyses 
P_INCL02_Age less than 
50 yrs 
Subject less than 50 years of age at 
screening 
Exclude from PP analysis 
M_INCL03_CNV eligibility 
criteria 
Subject without active choroidal 
neovascularization (CNV) lesions 
secondary to AMD affecting central 
subfield or total area of CNV comprising 
less than 50% of the total lesion area at 
screening 
Exclude from PP analysis  
P_INCL04_BCVA score 
outside limits 
Study Eye: Subject not meeting BCVA 
eligibility criteria between 78 and 23 letters, 
inclusive, at screening or baseline 
Exclude from PP analysis 
M_EXCL01_Condition with 
impact study eye 
Study Eye: Confounding ocular 
concomitant conditions or ocular disorders 
with impact on efficacy and/or safety 
Exclude from PP analysis 
M_EXCL03_Confounding 
treatment study eye with 
impact 
Study Eye: Confounding concomitant 
medications or procedures with impact 
Exclude from PP analysis 
M_EXCL06_Systemic 
cond/trt with impact 
Systemic: Confounding systemic conditions 
(including Blood Pressure) or systemic 
treatments with impact on efficacy and/or 
safety 
Exclude from PP analysis 
M_TRT01_Wrong IP 
administered 
Wrong IP administered during the study 
Exclude from PP analysis 
M_TRT02_Under-
treatment during loading 
phase 
Under-treatment during loading phase; 
missed active treatment (not due to any 
safety event) 
Exclude from PP analysis 
M_TRT03_Over treatment 
Over treatment, received active when 
schedule was for sham /no treatment 
Exclude from PP analysis  
M_TRT04_Under-
treatment after loading 
phase 
Under-treatment after loading phase; 
missed active treatment (not due to any 
safety event) 
Exclude from PP analysis if any 
missed active treatment between 
W36 and W44 inclusive or if at least 
2 missed consecutive active doses 
(not due to safety) 
Otherwise include in all analysis 
M_OTH01_Other PD with 
impact 
Any other protocol deviation with impact on 
the efficacy assessments or safety of the 
subject 
Exclude from PP analysis  
M_COMD01_Prohibited trt 
with impact 
Prohibited medication and/or procedure as 
per protocol with impact on efficacy and/or 
safety 
Exclude from PP analysis 
P_WITH01_Treatment but 
consent withdrawn 
Subject withdrew consent but continue to 
receive study medication 
Exclude from PP analysis 
Table 5-4 lists the non-protocol deviations (analysis restrictions) that may lead to exclusion 
from per-protocol analysis. Analysis restrictions (ARs) address limitations in the evaluability 
which result from missing or confounded 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. 


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Table 5-4 
Non-protocol deviations (analysis restrictions) 
AR ID 
Description of AR 
Category 
of reason 
Exclusion in Analyses 
AR_EST_01 
Early study termination due to lack of efficacy 
1 
Include in all analyses 
AR_EST_02 
Early study termination due to lack of safety 
2 
Include in all analyses 
AR_EST_03 
Early study termination due to reasons other than 
lack of efficacy/safety 
0 
Exclude from PP analysis 
if before week 36.  
Otherwise include in all 
analyses 
AR_ETD_0
1 
Early study treatment termination due to lack of 
efficacy 
1 
Include in all analyses 
AR_ETD_0
2 
Early study treatment termination due to lack of 
safety 
2 
Include in all analyses 
AR_ETD_0
3 
Early treatment termination due to reasons other 
than lack of efficacy/safety 
0 
Exclude from PP analysis 
if before week 36.  
Otherwise include in all 
analyses 
AR_MD_01 
No valid BCVA assessment between W36 and W48  
0 
Exclude from PP analysis 
AR_MD_02 
Missing DAA due to lack of safety 
2 
Include in all analyses 
AR_MD_03 
Missing DAA due to reasons other than lack of 
safety 
0 
Include in all analyses 
Subject evaluability is based on two components: 
• Exclusion from an analysis set  
• Censoring of specific data points from an analysis (see Section 5.6). 
The consequence of an AR on the evaluability depends on the underlying reason, while three 
different categories of reason are considered: 
• Lack of efficacy of the study treatment (=1) 
• Lack of safety / tolerability of the study treatment (=2) 
• Other (=0) 
Remark: Based on the concept of PD’s, their underlying reason will always be ‘0’. 
As a general rule, ARs with a reason of 1 or 2 do not lead to an exclusion from any analysis set, 
as a potential link between exclusion reason and treatment would constitute a source for 
systematic bias. 
Table 5-5 describes subject classification with regards to analysis sets: 
Table 5-5 
Subject classification 
Analysis 
Set 
PD ID that may cause subjects to be excluded 
Non-PD (AR) ID that cause subjects to 
be excluded 
RAN 
M_INCL01_ICF not obtained 
Not Randomized; 
FAS 
M_INCL01_ICF not obtained 
Not in the RAN; 
Did not receive at least one study injection 
SAF 
M_INCL01_ICF not obtained 
Did not receive at least one study injection 
PPS 
M_INCL01_ICF not obtained,  
Not in the FAS 


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Analysis 
Set 
PD ID that may cause subjects to be excluded 
Non-PD (AR) ID that cause subjects to 
be excluded 
P_INCL02_Age less than 50 yrs,  
M_INCL03_CNV eligibility criteria,  
P_INCL04_ BCVA score outside limits, 
M_EXCL01_Condition with impact study eye,  
M_EXCL03_Confounding treatment study eye with 
impact,  
M_EXCL06_Systemic cond/trt with impact, 
M_TRT01_Wrong IP administered,  
M_TRT02_Under-treatment during loading phase, 
M_TRT03_Over treatment,  
M_TRT04_Under-treatment after loading phase,  
M_OTH01_Other PD with impact, 
P_WITH01_Treatment but consent withdrawn 
AR_EST_03, 
AR_ETD_03, 
AR_MD_01 
5.6 
Censoring rules for analysis 
PDs and ARs that are considered to be critical for the subject evaluability regarding the primary 
and key secondary endpoints are described in Section 5.5. 
The focus of the ARs is the identification of censoring related to the analysis of BCVA and 
q12w proportion as derived from DAA and described in Section 2.6.3. Censoring is only applied 
in case the underlying reason for a confounded DAA is assessed as ‘0’. Censoring of BCVA 
and DAA applies both to FAS and PPS. 
Table 5-6 summarizes the concepts of censoring for the key parameters BCVA and q12w-status/ 
DAA applied to the two efficacy analysis sets, FAS and PPS, as well as the details for the timing 
of censoring for BCVA and DAA. 
In case a subject has multiple PDs/ARs with impact on subject’s evaluability the following rules 
are applied: 
• A subject is excluded from an analysis set if at least one PD or AR with this consequence 
was identified (see Table 5-5). This rule is built on the concept of the medical assessment 
of the ‘reason’ which considers the reason of an earlier event to potentially also be the 
reason for following PDs or ARs. 
• In case of multiple censoring time points censoring will be performed at the earliest. 
Table 5-6 
Censoring concepts for BCVA and DAA 
Analysis Set 
Censoring concept for BCVA 
Censoring concept for DAA 
FAS 
Censoring of BCVA data after 
switch to alternative nAMD 
treatment in the study eye: 
imputation using the last 
observation collected prior to the 
start of alternative nAMD treatment 
(see section 2.5.3) 
No other censoring related to PDs or 
ARs. 
M_TRT01_Wrong_IP_administered: censoring at the 
last valid DAA visit at or prior to the PD visit 
M_TRT02_Under-treatment during loading phase: 
censoring at baseline 
M_TRT03_Over treatment: censoring at the last valid 
DAA visit at or prior to the PD visit 
M_TRT04_Under-treatment 
after 
loading 
phase: 
censoring at the last valid DAA visit at or prior to the 
PD visit 


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Page 45 of 45 
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M_COMD01_Prohibited trt with impact: censoring at 
the last valid DAA prior to the start of the prohibited 
medication or procedure 
AR_ETD_03: censoring at the last valid DAA visit at or 
prior to the PD visit 
AR_EST_03: censoring at the last valid DAA visit at or 
prior to the PD visit 
AR_MD_03: censoring at the last valid DAA prior to the 
missed visit 
Remark: The analysis of the q12w proportion as 
derived from DAA and described in section 2.6.3 
applies censoring in case the underlying DAA is 
considered to be confounded by reasons other than 
lack of efficacy and/or safety. 
 
 
 
 
Censoring: subjects are considered no longer to be 
under risk for a q8w-need identification at later visits. 
Censoring at baseline if above PD/AR occurred prior to 
Week 16. 
Censoring at Week 48 visit if subjects completed Week 
48 without above PD/AR. 
PPS 
Censoring of BCVA data after switch 
to alternative nAMD treatment in the 
study eye: imputation using the last 
observation collected prior to the 
start of alternative nAMD treatment 
(see section 2.5.3) 
Similar to FAS 
6 
Reference