Clinical trial NCT03386474
Conditions: Neovascular Age-related Macular Degeneration
Keywords: double-masked, extension study neovascular age-related macular degeneration intravitreal injection brolucizumab aflibercept
Sponsor: Novartis Pharmaceuticals
Start date: 2018-01-15; Completion date: 2018-09-06
Enrollment: 151 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this extension study was to assess the safety and efficacy of the new formulation of brolucizumab 6 mg ophthalmic solution when given to the same patients who received brolucizumab in the core trial CRTH258A2301 (also known as CRTH258-C002). The medical condition treated in the core and extension trials was neo-vascular age-related macular degeneration (nAMD).

Detailed description:
Subjects in the United States who had completed the 96 week core trial, CRTH258A2301 (also referred as CRTH258-C002), were eligible to participate in the extension trial provided the core trial Visit 26 at week 96, was less than or equal to 12 weeks from the Baseline Visit in the extension trial, CRTH258A2301E1.

Subjects who were treated with aflibercept during the core trial and met the eligibility requirements of this extension trial continued to receive aflibercept in this extension trial in order to maintain the masking during the extension trial. No hypothesis testing or descriptive analyses were planned.

Subjects who were treated in the core trial with brolucizumab 3mg or brolucizumab 6 mg, and met the eligibility requirements of this extension trial, received the new formulation of brolucizumab 6 mg solution in the extension trial.

Enrolled subjects were to receive three intravitreal (IVT) ophthalmic injections. The study eye was the same eye that received the treatment in the core study. The extension trial consisted of 7 study visits at 4 week intervals over a period of 24 weeks.

Assessment of the efficacy and safety of brolucizumab 6 mg was based on a within-patient comparison with the last 6 months of corresponding core-study efficacy and safety data serving as the reference. Neither the patient selection process nor expected sample sizes supported a valid comparison between aflibercept and brolucizumab. The aflibercept arm was included only to maintain the masking in the extension trial. Data was presented descriptively for only brolucizumab in line with the study objective. No formal hypothesis testing was planned.

Arms: arm 1: Brolucizumab 6 mg solution for IVT injection, single injection at Day 1 (baseline), Week 8, and Week 16 or Week 20 arm 2: Aflibercept 2 mg solution for IVT injection, single injection at Day 1 (baseline), Week 8 and Week 16 to maintain the masking of the extension trial only.
Interventions: intervention 1: Brolucizumab 6 mg intervention 2: Aflibercept 2 mg
Intervention descriptions: intervention 1: Administered as opthalmic solution for an intravitreal injection to the study eye intervention 2: Administered as an opthalmic solution for intravitreal injection to the study eye

Protocol documents:
Prot_001.pdf: 
Global Clinical Development - General Medicine 
RTH258/Brolucizumab
Clinical Trial Protocol [CRTH258A2301E1] / NCT03386474
A 24-week, double-masked, multicenter, two-arm extension 
study to collect safety and efficacy data on brolucizumab 6 
mg drug product intended for commercialization in patients 
with neovascular age-related macular degeneration who 
have completed the CRTH258A2301 study
Document type:
Clinical Trial Protocol
EUDRACT number:
Not applicable
Version number:
00
Clinical trial phase:
III
Release date:
05-Dec-2017
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.4 (May 2017)


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................8
Protocol summary................................................................................................................9
1
Introduction .......................................................................................................................12
1.1
Background............................................................................................................12
1.2
Purpose ..................................................................................................................13
2
Study objectives and endpoints .........................................................................................14
2.1
Objectives and related endpoints...........................................................................14
3
Investigational plan ...........................................................................................................14
3.1
Study design...........................................................................................................14
3.2
Rationale for study design .....................................................................................15
3.3
Rationale for dose/regimen, route of administration and duration of treatment....15
3.4
Rationale for choice of comparator .......................................................................16
3.5
Purpose and timing of interim analyses/design adaptations..................................16
3.6
Risks and benefits..................................................................................................16
4
Population..........................................................................................................................17
4.1
Inclusion criteria ....................................................................................................17
4.2
Exclusion criteria...................................................................................................17
5
Treatment...........................................................................................................................18
5.1
Study treatment......................................................................................................18
5.1.1
Investigational and control drugs..........................................................18
5.1.2
Additional treatment..............................................................................19
5.2
Treatment arms......................................................................................................19
5.3
Treatment assignment and randomization.............................................................19
5.4
Treatment masking ................................................................................................19
5.5
Treating the patient................................................................................................21
5.5.1
Patient numbering .................................................................................21
5.5.2
Dispensing the study drug.....................................................................21
5.5.3
Handling of study and additional treatment..........................................21
5.5.4
Instructions for prescribing and taking study treatment........................22
5.5.5
Permitted dose adjustments and interruptions of study treatment ........23
5.5.6
Rescue medication ................................................................................24


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5.5.7
Concomitant medication .......................................................................24
5.5.8
Prohibited medication ...........................................................................24
5.5.9
Emergency breaking of assigned treatment code..................................24
5.6
Study completion and discontinuation...................................................................25
5.6.1
Study completion and post-study treatment..........................................25
5.6.2
Discontinuation of study treatment .......................................................25
5.6.3
Withdrawal of informed consent...........................................................26
5.6.4
Loss to follow-up ..................................................................................26
5.6.5
Early study termination by the sponsor.................................................27
6
Visit schedule and assessments .........................................................................................27
6.1
Information to be collected on screening failures..................................................29
6.2
Patient demographics/other baseline characteristics .............................................29
6.3
Treatment exposure and compliance .....................................................................29
6.4
Efficacy..................................................................................................................29
6.4.1
Visual acuity assessment.......................................................................29
6.4.2
Optical Coherence Tomography ...........................................................30
6.4.3
Appropriateness of efficacy assessments..............................................30
6.5
Safety.....................................................................................................................30
6.5.1
Ophthalmic examination.......................................................................30
6.5.2
Color Fundus Photography ...................................................................31
6.5.3
Vital signs..............................................................................................31
6.5.4
Laboratory evaluations..........................................................................32
6.5.5
Pregnancy and assessments of fertility .................................................32
6.5.6
Appropriateness of safety measurements..............................................32
6.6
Other assessments..................................................................................................33
6.6.1
Anti-drug antibodies (immunogenicity)................................................33
33
7
Safety monitoring..............................................................................................................33
7.1
Adverse events.......................................................................................................33
7.2
Serious adverse events...........................................................................................35
7.2.1
Definition of SAE .................................................................................35
7.2.2
SAE reporting........................................................................................36
7.3
Liver safety monitoring .........................................................................................36
7.4
Renal safety monitoring.........................................................................................37
7.5
Reporting of study treatment errors.......................................................................37
7.6
Pregnancy reporting...............................................................................................37


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8
Data review and database management.............................................................................38
8.1
Site monitoring ......................................................................................................38
8.2
Data collection.......................................................................................................38
8.3
Database management and quality control............................................................39
8.4
Data Monitoring Committee..................................................................................39
8.5
Adjudication Committee........................................................................................39
9
Data analysis......................................................................................................................39
9.1
Analysis sets ..........................................................................................................40
9.2
Patient demographics and other baseline characteristics.......................................40
9.2.1
Demographics .......................................................................................40
9.2.2
Baseline characteristics.........................................................................40
9.2.3
Medical history......................................................................................40
9.3
Treatments .............................................................................................................40
9.3.1
Study treatment exposure......................................................................40
9.3.2
Prior medications ..................................................................................41
9.3.3
Prior surgical and medical procedures ..................................................41
9.3.4
Concomitant medications......................................................................41
9.3.5
Concomitant surgical and medical procedures .....................................42
9.4
Analysis of safety and efficacy variable(s)............................................................42
9.4.1
Safety and efficacy variable(s)..............................................................42
9.4.2
Statistical model, hypothesis, and method of analysis..........................42
9.4.3
Handling of missing values/censoring/discontinuations.......................45
9.4.4
Sensitivity analyses ...............................................................................45
9.5
Analysis of secondary variables ............................................................................45
9.5.1
Efficacy variables..................................................................................46
9.5.2
Safety variables .....................................................................................46
9.5.3
Resource utilization...............................................................................46
9.5.4
Pharmacokinetics ..................................................................................46
9.5.5
DNA......................................................................................................46
9.5.6
Biomarkers............................................................................................46
9.5.7
PK/PD ...................................................................................................46
9.6
Analysis of exploratory variables ..........................................................................46
9.7
Interim analyses.....................................................................................................46
9.8
Sample size calculation..........................................................................................46
10 Ethical considerations........................................................................................................47
10.1
Regulatory and ethical compliance........................................................................47


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10.2
Informed consent procedures.................................................................................47
10.3
Responsibilities of the investigator and IRB/IEC..................................................47
10.4
Publication of study protocol and results...............................................................48
10.5
Quality Control and Quality Assurance.................................................................48
11 Protocol adherence ............................................................................................................48
11.1
Protocol amendments.............................................................................................48
12 References .........................................................................................................................49
List of tables
Table 2-1
Objectives and related endpoints ..........................................................14
Table 5-1
Prohibited medication ...........................................................................24
Table 6-1
Assessment schedule.............................................................................28
Table 7-1 
Guidance for capturing the study treatment errors................................37
List of figures
Figure 3-1
Study design..........................................................................................15
Figure 5-1
Dosing schedule ....................................................................................23


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List of abbreviations
ADA
Anti-drug antibodies
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical (classification system)
BCVA
Best Corrected Visual Acuity
BP
Blood pressurelocal
BUN
Blood urea nitrogen
CF
Color fundus
CFR
US Code of Federal Regulations 
CNV
CRA
Choroidal neovascularization
Clinical Research Associate
CRF
Case Report/Record Form (paper or electronic)
CPO
Country Pharma Organization
CRO
Contract Research Organization
CSFT
Central subfield thickness
CSM
Clinical Site Management
CTM
Clincial Trial Management
EDC
EMA
Electronic Data Capture
European Medicines Agency
ETDRS
Early Treatment Diabetic Retinopathy Study
EOS
End of study
eSource
Electronic Source
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
Gamma glutamyl transminase
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICF
Informed consent form
IEC
IFU
Independent Ethics Committee
Instructions for use
IOP
Intraocular pressure
IP
Investigational product
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
IUS
Intrauterine device
intrauterine system
IVT
Intravitreal injection
LDH
Lactate dehydrogenase
LFT
Liver function test 
LOCF
Last observation carried forward
MedDRA
Medical dictionary for regulatory activities 
nAMD
Neovascular Age-Related Macular Degeneration


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OCT
Optical coherence tomography
PD
Protocol deviation
PK
Pharmacokinetics 
RBC
Red blood cell
RPE
Retinal pigment epithelium
SAE
Serious Adverse Event
scFv
Single-chain variable fragment
SoC
Standard of care
SUSAR
Suspected Unexpected Serious Adverse Reactions
TD
Study Treatment Discontinuation
VA
Visual Acuity
VEGF
Vascular endothelial growth factor
WBC
White blood cell
WHO
World Health Organization 
WoC
Withdrawal of Consent


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Glossary of terms
Dosage
Dose of the study treatment given to the patient in a time unit (e.g. 100 
mg once a day, 75 mg twice a day)
Electronic Data Capture 
(EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces.
EDC includes the use of Electronic Case Report Forms (eCRFs) which 
are used to capture data transcribed from paper source forms used at 
the point of care.
Enrollment
Point/time of patient entry into the study at which informed consent 
must be obtained (e.g. prior to starting any of the procedures 
described in the protocol)
Investigational drug
The 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.”
Medication pack number
A unique identifier on the label of each investigational drug package
Subject ID 
A unique number assigned to each patient upon signing the informed 
consent 
Source Data/Document
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a 
dataset, a spreadsheet or even hard-coded data, such as paper or 
eSource.
Study drug/ treatment
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug (s), 
placebo/comparator active drug run-ins or background therapy
Study Treatment 
Discontinuation (TD)
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date 
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 is defined as when a patient 
does not want to participate in the study any longer, and does not want 
any further visits or assessments, and does not want any further study 
related contact, and does not allow analysis of already obtained 
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Protocol summary
Protocol number
RTH258A2301E1
Full Title
A 24-week, double-masked, multicenter, two-arm extension study to 
collect safety and efficacy data on brolucizumab 6 mg drug product 
intended for commercialization in patients with neovascular age-
related 
macular 
degeneration 
who 
have 
completed 
the 
CRTH258A2301 study
Brief title
Study of safety and efficacy of brolucizumab 6 mg drug product 
intended for commercialization in patients with nAMD.
Sponsor and Clinical 
Phase
Novartis; Phase 3
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this study is to collect data on safety and efficacy of 
the brolucizumab 6 mg drug product intended for commercialization 
in patients with nAMD and to support comparability to the 6 mg drug 
product used in Phase III.
Primary Objective(s) 
The objective of this study is to collect data on safety and efficacy 
of the brolucizumab 6 mg drug product intended for 
commercialization in patients with nAMD previously treated in 
CRTH258A2301 study to support comparability to the 6 mg drug 
product used in Phase III.
Secondary Objectives
Not applicable
Study design
This is a 24-week, double-masked, multicenter, two-arm extension 
study. 
Patients from the United States who have completed the 96-week 
core study CRTH258A2301 are eligible to participate provided Visit 
26/ Week 96 in the core study is ≤ 12 weeks from Baseline visit in 
the extension study. During the study, patients will receive either 
brolucizumab 6 mg (if they were treated with brolucizumab 3 mg or 
6 mg in the core) or aflibercept (if they were treated with aflibercept 
in the core). Total study duration is 24 weeks.
Population
The study population will consist of male and female patients who 
have completed the CRTH258A2301 core study. Approximately 75 
to 100 patients are expected to be enrolled in approximately 70 
centers in the United States.
Key Inclusion criteria

Written informed consent must be obtained before any 
assessment is performed. 


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
The patient completed the core study, as defined by providing 
assessments at the Visit 26/ Week 96, within ≤ 12 weeks of 
Baseline visit of the extension study.
Key Exclusion criteria
1. Patient discontinued the treatment or the core study prematurely 
at any time.
2. Patient received standard of care treatment for nAMD after 
completion of the core study.
3. Any of the following treatments received after completion of the 
core study:

investigational treatment for nAMD in the study eye,

intraocular or periocular injections of steroids in the 
study eye,

systemic anti-VEGF therapy.
4. Patient has a systemic or ocular medical condition or personal 
circumstance which precludes study participation or compliance 
with study procedures, as assessed by the investigator.
5. Stroke or myocardial infarction within the 3 months of Baseline 
visit of the extension study. 
6. Participation in an investigational drug, biologic, or device study 
within 30 days or the duration of 5 half-lives of the 
investigational product (whichever is longer) prior to Baseline 
visit in the extension study.
7. Pregnant or nursing (lactating) women and 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 weeks after 
stopping of study medication.
Study treatment

Brolucizumab 6 mg

Aflibercept 2 mg 
Efficacy assessments

BCVA

Optical coherence tomography
Key safety 
assessments

Adverse event monitoring

Ophthalmic examination (intraocular pressure, slit-lamp and 
fundus examination)

Color fundus photography

Vital signs


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
Laboratory parameters (hematology, chemistry and urinalysis)
Other assessments

Anti-drug antibodies

Data analysis
The assessment of the brolucizumab outcome of this study will be 
based on a within-patient comparison with corresponding core-study 
data serving as reference. Neither the patient selection process nor 
the expected sample sizes support a valid comparison between 
aflibercept and brolucizumab. 
Analyses of brolucizumab data will be performed on the Extension 
Safety Set which is defined as all patients who enter this extension 
study and receive at least one injection of study treatment. Data will 
be presented descriptively. No formal hypothesis testing is planned 
for this study. Data for the aflibercept treatment group will be 
presented in listings.
The final analysis will be conducted on all subject data at the time 
the trial ends. An interim analysis may be conducted when at least 
50 patients are treated with brolucizumab 6 mg for 6 months to 
support a brolucizumab Biologic License Application Submission at 
the earliest possible time point, currently planned for end of 2018.
Key words
double-masked, extension study; neovascular age-related macular 
degeneration; intravitreal injection; brolucizumab; aflibercept.


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1
Introduction
1.1
Background 
Age-related macular degeneration (AMD) is the leading cause of severe vision loss in people 
affecting 10%-13% of individuals over the age of 65 in North America, Europe, and Australia 
(Kawasaki 2010, Rein 2009, Smith 2001). Genetic, environmental and health factors play an 
important role in the pathogenesis of the disease. 
AMD is classified into 2 clinical subtypes: the non-neovascular (atrophic) or dry form and the 
neovascular (exudative) or wet form (Ferris 1984, Lim 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, 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 2007, Shah 2009). Without treatment, most affected eyes will 
have poor central vision (20/200) within 12 months (TAP 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 1991, Wong 2008).
VEGF has been shown to be elevated in patients with neovascular AMD, and is thought to play 
a key role in the neovascularization process (Spilsbury 2000). The use of intravitreal (IVT) 
pharmacotherapy targeting VEGF has significantly improved visual outcomes in patients with 
neovascular AMD (Bloch 2012, Campbell 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.
Brolucizumab development program in nAMD
Brolucizumab (RTH258, formerly ESBA1008) is a humanized single-chain Fv (scFv) antibody 
fragment inhibitor of vascular endothelial growth factor 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 pharmacological characteristics of brolucizumab (a relatively small molecule formulated 
at high concentrations of 120 mg/mL) allow delivery of a much higher molar dose via 
intravitreal injection compared to other VEGF-inhibitors. A 6 mg dose of brolucizumab delivers 
a molar dose which is approximately 11 and 22 times higher than aflibercept 2 mg and 
ranibizumab 0.5 mg, respectively. These attributes are expected to confer advantages in the 
treatment of retinal diseases. 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 patients with nAMD were evaluated 
in the following completed clinical studies:


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
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),

56-week multiple dose study of brolucizumab 6 mg versus aflibercept 2 mg (Alcon 
protocol C-12-006),

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),

3 dose study of brolucizumab 6 mg or 3 mg in patients of Japanese and non-Japanese 
ancestry (Alcon protocol RTH258-E003 also referred to as CRTH258A2201).
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. Please refer to the Investigator’s Brochure (IB) for further details 
Two pivotal, two-year, randomized, double masked, multicenter phase III studies of 
brolucizumab are ongoing in patients with nAMD: CRTH258A2301 (HAWK) and 
CRTH258A2302 (HARRIER). The primary objective of both studies is to demonstrate 
noninferiority of brolucizumab to aflibercept. Please refer to the study protocols for additional 
details. In a recently performed analysis of data up to Week 48 non-inferiority of brolucizumab 
3 mg and 6 mg versus aflibercept 2 mg in mean change in best-corrected visual acuity (BCVA)
from baseline to Week 48 was demonstrated. The non-inferiority in BCVA occurred while the 
majority of patients on 6 mg brolucizumab (57% (HAWK) and 52% (HARRIER) were 
maintained exclusively on a q12 regiment immediately following the loading phase through 
week 48 versus q8 regimen for aflibercept. Brolucizumab was generally well tolerated with 
overall ocular and non-ocular (systemic) adverse event rates comparable to aflibercept.
Drug substance and drug product manufacturing changes have been implemented for 
brolucizumab in order to scale-up the manufacturing process and to modify the brolucizumab 
formulation intended for commercialization, respectively.
During the Type C meeting with FDA on September 20, 2017, the FDA recommended to 
include into the Biologic License Application clinical data of at least 50 patients (who were 
previously treated with brolucizumab in ongoing HAWK and/or HARRIER studies) treated for 
additional 6 months with the brolucizumab product intended for commercialization to support 
comparability. 
This study, CRTH258A2301E1, is an extension of the CRTH258A2301 (HAWK) study. 
Patients from US completing Visit 26/ Week 96 of HAWK will be eligible to participate. All 
enrolled patients will receive either brolucizumab 6 mg (if previously treated with brolucizumab 
3 mg or 6 mg) or aflibercept 2 mg (if previously treated with aflibercept 2 mg) over a study 
period of 24 weeks. At least 50 patients previously treated with brolucizumab will be enrolled
into the extension study.
1.2
Purpose
The purpose of this study is to collect information on safety and efficacy of the brolucizumab 6 
mg drug product intended for commercialization in patients with nAMD to support
comparability to the brolucizumab 6 mg drug product used in Phase III clinical studies. 


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2
Study objectives and endpoints
2.1
Objectives and related endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)

To collect data on safety and efficacy of the 
brolucizumab 6 mg drug product intended 
for commercialization in patients with nAMD 
previously treated in CRTH258A2301 study
to support comparability to the brolucizumab 
6 mg drug product used in Phase III clinical 
studies

Incidence and characteristics of treatment 
emergent adverse events

Loss in BCVA of 15 letters or more from 
Baseline at each post-baseline visit

Change in BCVA from Baseline at each 
post-baseline visit

q12 treatment status at Week 20

Change in CSFT from Baseline at each 
post-baseline visit

ADA status at Baseline, Week 8, Week 16 
and Week 24. 
3
Investigational plan
3.1
Study design
This is a double-masked, multicenter, two-arm extension study (Figure 3-1). Subgroup of 
patients who have completed the 96-week core study CRTH258A2301, regardless of the 
treatment group (brolucizumab 3 mg, brolucizumab 6 mg or aflibercept 2 mg) are eligible for 
inclusion in the extension provided Visit 26/ Week 96 in the core study is ≤ 12 weeks from 
Baseline visit in the extension study. Patients who were treated with aflibercept during the core 
study will continue to receive aflibercept in the extension study. Patients who were treated with 
brolucizumab 3 mg or 6 mg in the core study will receive brolucizumab 6 mg in the extension 
study.
At the Baseline visit, patients will sign an informed consent and will be evaluated for study 
eligibility based on inclusion/exclusion criteria. 
Baseline visit 
Baseline visit of the extension study must occur no later than 12 weeks after Visit 26/ Week 96 
of the core study.
If the patient can directly rollover from the core to the extension study, Baseline visit of the 
extension study can occur on the same day as the Visit 26/Week 96 of the core study. 
If the patient already completed Visit 26/Week 96 in the core study, Baseline visit of the 
extension study should occur as soon as possible and no later than 12 weeks after Visit 26/Week 
96 of the core study.


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Enrolled patients will receive three intravitreal injections of either brolucizumab 6 mg or 
aflibercept 2 mg according to dosing schedule described in Section 5.5.4. This extension study 
consists of 7 study visits at 4-week intervals, labeled Visit 1/ Baseline to Visit 7/ EoS over a 
period of 24 weeks. 
The study eye will be the same eye that received brolucizumab or aflibercept study treatment 
in the core study.
Figure 3-1
Study design 
3.2
Rationale for study design 
This multicenter extension study is designed to collect data on safety and efficacy of the 
brolucizumab 6 mg drug product intended for commercialization in nAMD patients. Enrollment 
of patients who were treated with aflibercept in the core study ensures that the conduct of both 
studies (core and extension) remains double-masked in a seamless fashion and until the end of 
each study. Study design, study duration and patient population were assessed as adequate to 
gain safety and efficacy experience with brolucizumab 6 mg drug product intended for 
commercialization.
The patient population will be described in more detail in Section 4 below.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment 
Analysis of the data up to Week 48 from the ongoing CRTH258A2301 and CRTH258A2302 
studies demonstrated non-inferiority in BCVA for brolucizumab as compared to aflibercept
while the overall ocular and non-ocular (systemic) adverse events were comparable between 
the two treatments.
Patients entering this extension study who were treated with brolucizumab 3 mg or 6 mg in the 
core study will receive three brolucizumab 6 mg IVT injections: at Baseline, Week 8 and, 
depending on the disease activity status, at Week 16 (q8 interval) or Week 20 (q12 interval).
This is to ensure that patients, regardless of treatment regimen in the core study (i.e., q12 or q8) 


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are not under-treated. Patients entering this extension study who were treated with aflibercept 
2 mg in the core study will continue to receive aflibercept 2 mg every 8 weeks as per approved 
label. Since patients have been previously treated in HAWK study at maintenance treatment 
frequencies of q12 or q8, treatment initiation within this extension study starting with fixed 
treatment at Baseline and Week 8 is considered adequate.
3.4
Rationale for choice of comparator 
In the CRTH258A2301 core study, efficacy and safety of brolucizumab was compared with 
aflibercept.
This is an extension to the CRTH258A2301 study and patients who were randomized to the 
aflibercept arm in the core will continue receiving aflibercept in order to ensure that both studies 
(core and extension) remain double-masked in a seamless fashion and until the end of the 
extension study.
For the assessment of the outcome of this extension study, the core study data for patients 
participating in this extension study will be used as a reference.
3.5
Purpose and timing of interim analyses/design adaptations 
An interim analysis might be conducted when 50 patients are treated with brolucizumab 6 mg 
for 6 months to support a brolucizumab Biologic License Application submission at the earliest 
possible time point, which is currently planned for Dec 2018.
3.6
Risks and benefits 
Brolucizumab is an inhibitor of VEGF with a mechanism of action similar to ranibizumab with 
a smaller molecular size (26 kDa and 48 kDa, respectively).
Comprehensive analytical drug substance comparability studies and ongoing analytical testing 
of the drug product, demonstrate comparability between drug substance/product used in 
ongoing Phase III clinical studies and the drug substance intended for commercialization.
Results from this study will support comparability between brolucizumab 6 mg drug product 
intended for commercialization and used in Phase III studies.
In a recently performed analysis of data up to Week 48, non-inferiority of brolucizumab 3 mg 
and 6 mg versus aflibercept 2 mg in mean change in BCVA from baseline to Week 48 was 
demonstrated. The non-inferiority in BCVA occurred while the majority of patients on 6 mg 
brolucizumab, 57% (HAWK) and 52% (HARRIER), were maintained exclusively on a q12 
regiment immediately following the loading phase through week 48 versus q8 regimen for 
aflibercept.
Further details of the known and potential risks and benefits associated with brolucizumab are 
presented in the Investigator’s Brochure.
The risk to subjects in this trial will be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring.


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4
Population
The study population will consist of male and female patients who have completed the core 
study (CRTH258A2301). Approximately 75 to 100 patients are expected to be enrolled in 
approximately 70 centers in the United States.
4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. The patient completed the core study, as defined by providing assessments at the Visit 26/ 
Week 96, within ≤ 12 weeks of Baseline visit of the extension study.
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
1. Patient discontinued the treatment or the core study prematurely at any time.
2. Patient received standard of care treatment for nAMD after completion of the core study.
3. Any of the following treatments received after completion of the core study:
a.
investigational treatment for nAMD in the study eye,
b. intraocular or periocular injections of steroids in the study eye,
c.
systemic anti-VEGF therapy.
4. Patient has a systemic or ocular medical condition or personal circumstance which 
precludes study participation or compliance with study procedures, as assessed by the 
investigator.
5. Stroke or myocardial infarction within the 3 months of Baseline visit of the extension study. 
6. Participation in an investigational drug, biologic, or device study within 30 days or the 
duration of 5 half-lives of the investigational product (whichever is longer) prior to Baseline 
visit in the extension study.
Note: observational clinical studies solely involving
over-the-counter vitamins, 
supplements, or diets are not exclusionary.
7. Pregnant or nursing (lactating) women and 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 weeks after stopping of study 
medication. Highly effective contraception methods include:
a.
Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception


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b. 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
c.
Male sterilization (at least 6 m prior to screening in the core study). For female 
subjects on the study, the vasectomized male partner should be the sole partner for 
that subject
d. Use of oral, (estrogen and progesterone), injected or implanted hormonal methods 
of contraception or other forms of hormonal contraception that have comparable 
efficacy (failure rate <1%), for example hormone vaginal ring or transdermal 
hormone contraception or placement of an intrauterine device (IUD) or intrauterine 
system (IUS) 
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.
In case local regulations deviate from the contraception methods listed above, local regulations 
apply and will be described in the ICF.
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.
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs

Brolucizumab 6 mg

Aflibercept 2 mg
Brolucizumab 6 mg drug product intended for commercialization is used in this study. Changes 
to the excipients within the drug product were made, namely change to the pH (increase from 
app. 6.8 to app. 7.2) and change to the polysorbate concentration (decreased in concentration 
from 0.05% to 0.02%). Although drug substance remains unchanged, an optimized 
manufacturing scale for brolucizumab drug substance was introduced.
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) and a single filter needle. 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. The proposed commercial instructions for use (IFU) of the brolucizumab kit are provided 
in the Operational Manual.


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Novartis will provide sufficient supplies of brolucizumab for treatment use to allow for 
completion of the study.
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.
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.
5.1.2
Additional treatment
No additional treatment beyond investigational drug is included in this trial.
5.2
Treatment arms 
Depending on the treatment arm assignment in the core study, patients will be assigned at Visit 
1/ Baseline to one of the two treatment arms:

Arm 1: brolucizumab 6 mg – patients treated with brolucizumab 3 mg or brolucizumab 
6 mg in the core study. All patients will receive IVT injection at Baseline and Week 8 
and, depending on disease activity as assessed by the investigator, at Week 16 or Week 
20.

Arm 2: aflibercept 2 mg – patients treated with aflibercept 2 mg in the core study. All 
patients will receive IVT injection at Baseline, Week 8 and Week 16.
5.3
Treatment assignment and randomization 
At Visit 1/ Baseline, the investigator or his/her delegate will access the IRT after confirming 
that the patient fulfills all the inclusion/exclusion criteria. IRT will specify a unique medication 
number for the package of study drug to be dispensed to the patient.
5.4
Treatment masking 
This is a double-masked study. The patients, investigators and site staff (except for the 
unmasked site personnel and unmasked injecting physician), Sponsor clinical site management 
(except for those who have been delegated responsibility for working with the study drug), the 


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statisticians and clinicians who are directly involved in the conduct of the study (i.e. involved 
in patient level discussions or direct interaction with sites) will remain masked to treatment
assignments while the study is in progress using the following methods: 

Sponsor personnel who has access to treatment codes (e.g., unmasked Programming 
personnel directly involved in bioanalysis of serum samples, unmasked monitors 
performing study drug accountability, Clinical Supplies personnel, members of the
HAWK study team having access to week 48 subject level data) will not divulge the 
codes to subjects, Investigators, site staff, Sponsor Clinical Trial Management (CTM), 
or Sponsor Clinical Site Management (CSM).

Treatment allocation data will be kept strictly confidential until the time of unmasking, 
and will not be accessible by anyone else involved in the study.

Study drug injections will be performed by unmasked injecting physician.

Sham injections will be administered to establish identical injection schedule in both 
treatment arms.
To maintain the masking and data integrity at least two investigators (and corresponding study 
staff) will be involved in the study at each site: one masked (evaluating) investigator performing 
all assessments and capturing data in the EDC and one unmasked (treating) investigator 
administering study treatment according to the protocol. The investigators will maintain the 
same role throughout the study. The unmasked investigator in the core study cannot resume 
responsibilities of the masked investigator in the extension study and vice versa.
The Masked Investigator is masked to the treatment assignment and performs the monthly 
clinical assessments. All other site staff involved in performing study assessments and 
procedures (e.g. BCVA, ophthalmic examination, disease activity assessments, upload of data 
in eCRF) must be also masked to the treatment assignment. The only exception is the 
administration of study treatment and post-injection assessment (see below).
The Unmasked Investigator performs the injections and will be unmasked to the treatments 
as will any other site personnel who have delegated responsibility for working with the study 
drug. The unmasked physician and other site personnel must not perform any other roles after 
randomization except the assessment of safety immediately following IVT injection.
The masked/evaluating Investigator will be responsible for all aspects of the study, excluding 
the injection procedures. The unmasked/treating Investigator will only perform all 
treatment/sham injections and must not be involved in any other aspects of the study and must 
not divulge the patient treatment assignment to anyone (masked site personal, the patient and 
the masked Sponsor representative). Once the designated roles are determined, the roles cannot 
be switched at any time during the conduct of the study. Every effort must be made to limit the 
number of unmasked study personnel to ensure the integrity of this masked study.
VA examiner (masked to the treatment assignment)
A trained and certified (by Novartis designated VA Certifier) site clinical staff with 
optometrical training. The VA examiner will not perform any tasks which may unmask him or 
her to patient’s treatment.


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The detailed list of study tasks performed by masked and unmasked Investigators and Site 
Personnel is provided in the Operation Manual.
Unmasked sponsor personnel will include unmasked monitors performing study treatment 
accountability and reporting protocol deviations requiring knowledge of treatment allocation. 
Unmasked CTM and unmasked statistician will be involved in assessment of those unmasked 
PDs.
Unmasking will only occur in the case of patient emergencies (see Section 5.6), at the time of 
the interim analysis if performed (see Section 3.5) and at the conclusion of the study. Interim 
analyses will be performed with an unmasking of specified individuals from the sponsor who 
are not directly involved in the conduct of the trial (see Section 9.7).
5.5
Treating the patient 
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
5.5.1
Patient numbering
Each patient is uniquely identified by a Subject Number assigned by Novartis. The subject 
number is composed of a site number and a sequential number.
The same Subject Number assigned to the patient in the core study will be used in the extension 
study.
Upon signing the informed consent form, the investigator or his/her staff will access the IRT 
and provide the requested identifying information for the patient to register them into the IRT. 
This information includes subject number that was assigned to the patient in the core study.
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the appropriate 
Screening period CRF.
5.5.2
Dispensing the study drug 
Each study site will be supplied with investigational and control drug in packaging of identical 
appearance.
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label. Investigator staff will identify the study drug package(s) to dispense to the 
patient by accessing the IRT and obtaining the medication number(s). Immediately before 
administration of the IVT injection 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 subject number.
5.5.3
Handling of study and additional treatment 
5.5.3.1
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designees 


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have access. Upon receipt, all study treatment must be stored according to the instructions 
specified on the labels. Clinical supplies are to be dispensed only in accordance with the 
protocol. Technical complaints are to be reported to the respective Novartis CPO 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 patient except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits and at the completion of the trial. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
5.5.3.2
Handling of additional treatment 
Not applicable.
5.5.4
Instructions for prescribing and taking study treatment
Brolucizumab will be administered via intravitreal injection (in accordance with supplied 
proposed commercial instructions for use as described in the Operational Manual) at Visit 1/
Baseline, Visit 3/ Week 8, and, depending on the disease activity as assessed by the investigator, 
at Visit 5/ Week 16 or Visit 6/ Week 20. 
Aflibercept will be administered via intravitreal injection at Visit 1/ Baseline, Visit 3/ Week 8, 
and Visit 5/ Week 16.
Sham injection will be administered at Visit 5/ Week 16 to patients on brolucizumab 6 mg q12 
interval (without disease activity at Week 16 as assessed by the investigator) and at Visit 6/ 
Week 20 to patients on aflibercept 2 mg or patients on brolucizumab 6 mg q8 interval (with 
disease activity at Week 16 as assessed by the investigator).


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Figure 5-1
Dosing schedule
Disease activity assessment
Disease activity will be assessed by the investigator at Visit 5/ Week 16 and Visit 6/ Week 20.
The investigators should apply their own expert judgement when assessing disease activity i.e., 
q8 treatment need. Decrease in BCVA of ≥ 5 letters due to nAMD disease activity compared 
with Week 12 might be considered as guidance. 
Intravitreal injection 
The IVT injection will be carried out under controlled, aseptic conditions per local clinical 
practice and following the processes provided in core study.
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; therefore, the investigator should verify that 
these conditions are not present in either eye (study and fellow eyes) prior to every injection.
All kits of study treatment assigned by the IRT will be recorded/ databased in the IRT.
Date and time of every injection administered to the patient will be recorded in the CRF.
At selected sites, the conduct of IVT injections will be observed by an external study team 
member to ensure compliance with the proposed commercial instruction for use. 
Sham injection
At Visit 5/ Week 16 or Visit 6/ Week 20, sham injection will be administered to maintain 
masking. For the sham injection, the tip of an injection syringe (the hub without a needle) will 
be used.
5.5.5
Permitted dose adjustments and interruptions of study treatment 
Investigational treatment dose adjustments are not permitted. 


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If based on investigator’s judgement, safe administration of the study drug is contraindicated 
(e.g., patient experiences an AE), investigational treatment can be administered within 7 days 
after the scheduled visit or temporarily interrupted. 
5.5.6
Rescue medication
Rescue medication in the study eye is not permitted in this study.
Treatment with medications approved for nAMD is permitted in the fellow eye 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 CRF.
5.5.7
Concomitant medication 
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the patient was enrolled into the study must be recorded in the appropriate CRF.
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 
enrolling a patient or allowing a new medication to be started.
5.5.8
Prohibited medication
Use of the treatments displayed in the below table is NOT allowed after the start of 
investigational drug. 
Table 5-1
Prohibited medication
Medication
Prohibition period
Action taken
Study eye
Anti-VEGF therapy other than IP
Any time
Discontinue study treatment
Intraocular or periocular injections of 
corticosteroids (except if treatment for AE)
Any time
Discontinue study treatment
Laser treatment for AMD
Any time
Discontinue study treatment
Fellow eye
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
5.5.9
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to treat the patient safely. 
Most often, study treatment discontinuation and knowledge of the possible treatment 


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assignments are sufficient to treat a study patient 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 patient, he/she must provide the requested patient 
identifying information and confirm the necessity to break the treatment code for the patient. 
The investigator will then receive details of the investigational drug treatment for the specified 
patient 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.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide:

protocol number

study drug name (if available)

patient 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. 
After treatment unmasking the patient cannot continue to receive the assigned treatment and if 
applicable will be given standard of care as per investigator judgement.
5.6
Study completion and discontinuation 
5.6.1
Study completion and post-study treatment 
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol.
The investigator and/or referring physician will recommend the appropriate follow-up medical 
care, if needed, for all patients who completed the study or prematurely withdrawn from the 
study.
5.6.2
Discontinuation of study treatment 
Discontinuation of study treatment for a patient occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by either the patient or the investigator. 
The investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation.
Study treatment must be discontinued under the following circumstances: 

Patient wish 

Pregnancy (see Section 6.5.6 and Section 7.6)

Use of prohibited treatment as per recommendations in Table 5-1

Any situation in which study participation might result in a safety risk to the patient

At the investigator’s discretion based on his/her clinical judgement the patient requires 
rescue medication


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If discontinuation of study treatment occurs, the patient should NOT be considered withdrawn 
from the study. The investigator should encourage the patient to continue in the study and to 
return for the remaining visits up to and including Visit 7/ EoS. Otherwise, the patient should 
return to the clinic as soon as possible, after discontinuation of study drug, for an EoS visit. EoS 
visit assessments detailed in Table 6-1 should be completed and recorded in the CRF. 
The investigator must determine the primary reason for the patient’s premature discontinuation 
of study treatment and record this information on the appropriate CRF. 
The investigator must also access the IRT to register the patient’s discontinuation from study 
treatment.
5.6.3
Withdrawal of informed consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent from the study is defined as when a patient:

Does not want to participate in the study anymore
and

Does not want any further visits or assessments
and

Does not want any further study related contacts
and

Does not allow analysis of already obtained biologic material
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’s decision to withdraw his/her consent and record 
this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
assessment table below.
5.6.4
Loss 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 patient cannot be considered as lost to follow-up until the time 
point of his/her planned end of study visit has passed.


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5.6.5
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the patient 
must be seen as soon as possible and treated as a prematurely discontinued patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator will 
be responsible for informing the Institutional Review Board/Independent Ethics Committee 
(IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed.
Patients must be seen for all visits on the designated day, or as close to it as possible. Patients 
with missed visits should have them re-scheduled as soon as possible. Missed or rescheduled 
visits should not lead to automatic discontinuation. Patients 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 reconciled on the CRF.


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Table 6-1
Assessment schedule
Visit number
1/ Baselinea
2
3
4
5
6
7/ EoSl
Week
Day 1
4
8
12
16
20
24
Visit window (days)
+/- 7
+/- 7
+/- 7
+/- 7
+/- 7
+/- 7
Informed consentb
X
Inclusion/Exclusion Criteria
X
Demographics
X
Medical History
Xc
Urine Pregnancy Testd
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
Adverse Events
Xn
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
Chemistry/ Hematology/ Urinalysisef
X
X
Anti-Drug Antibodies (ADA)
X
X
X
X
BCVAh
X
X
X
X
X
X
X
Slit-lamp and Fundus Examf
Xo
X
X
X
X
X
Xo
Intraocular Pressure (IOP)
Xo
X
X
X
X
X
Xo
Optical Coherence Tomographyi
Xo
X
X
X
X
X
Xo
Color Fundus Photographyfi
X
X
Access IRT
X
X
X
X
Disease Activity Assessment
X
X
IVT injectionm and post-injection 
assessmentfg
X
X
Xj
Xk
a – Visit 1/ Baseline of CRTH258A2301E1 can occur on the same day as the patient’s last visit in CRTH258A2301 (Visit 26/
Week 96) but no later than 12 weeks after Visit 26/ Week 96 of CRTH258A2301
b – ICF must be obtained prior to any study specific procedure
c – When Baseline visit of the extension study does not occur on the same day as the last visit in the core study, medical 
conditions which started and/or ended after the last visit in the core and before the baseline visit in the extension study will be 
recorded 
d – Women of childbearing potential only. Urine pregnancy tests will be performed unless local regulations require a serum 
pregnancy test
e – All blood draws should be performed prior to receiving the IVT injection
f – These assessments are source documentation only and will not be entered into the CRF
g – The study eye will be evaluated within 5 minutes and approximately 30 minutes post injection to ensure that the injection 
procedure and/or the investigational product have not endangered the health of the eye
h – Both eyes at all visits
i – Local assessments (no central reading center)
j – Only if patient assigned to q8
k – Only if patient assigned to q12
l – All procedures should be followed, regardless of when the patient exits the study
m – At selected sites, the conduct of IVT injections will be observed by an external study team member to ensure compliance 
with the proposed commercial instruction for use
n – Adverse Events which are ongoing at the patient’s last visit in CRTH258A2301 and at the baseline visit in the extension 
study must be recorded and entries in the extension study database should match those in the core study database as 
appropriate
o – Both eyes; all other assessments are study eye only


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6.1
Information to be collected on screening failures 
There is no separate screening visit/ screening period planned in this study. Patient’s eligibility 
will be assessed at Visit 1/ Baseline.
All patients who have signed informed consent but not entered into the extension study will be 
considered screen failures. The following information will be collected for screen failure 
patients: demographics, inclusion/exclusion, and serious adverse event (SAE). Adverse events 
that are not SAEs will be followed by the investigator and collected only in the source data.
6.2
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristic data to be collected on all patients include: age, 
sex, race, ethnicity, and Japanese ancestry, study eye, iris color and history of primary diagnosis. 
With the exception of age, entries in the extension study database should match those in the 
core study database.
Additionally, the following data will be collected for all patients at baseline: vital signs, BCVA, 
IOP, and concomitant medications.
For patients whose baseline visit of the extension study does not occur on the same day as the 
last visit in the CRTH258A2301 core study, medical condition which started and/or ended after 
the last visit in the core study and before the baseline visit in the extension study will be 
collected.
6.3
Treatment exposure and 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 recorded in the CRF 
Dosing Log and/or will be captured by the unmasked field monitor.
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.
6.4
Efficacy 
Efficacy assessment will include BCVA with ETDRS-like chart at 4 meters and Optical 
Coherence Tomography (OCT). 
The BCVA will be conducted in both eyes at every study visit. BCVA testing should precede 
any examination requiring administration of eye drops to dilate the eye or any examination 
requiring contact with the eye, or administration of study treatment.
6.4.1
Visual acuity assessment 
Best-corrected visual acuity will be tested at all study visits in a sitting position using the 
ETDRS visual acuity testing protocol at an initial testing distance of 4 meters. 


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If it is not possible to perform a subjective refraction or VA testing at 4 meters because VA is 
too poor for the patient to read at least 4 letters on the EDTRS chart at this distance, the 
refraction/VA testing should be attempted at 1 meter. Further details on refraction technique 
and VA testing will be described in the Operational Manual, which will be provided to all sites.
Certificates from the core study will be extended for investigators and/or their designated study 
staff performing VA assessments as well as all the equipment. New staff will be certified for 
this trial by Novartis designated VA certifiers.
The total BCVA score derived according to the Operational Manual captured in the VA 
Assessment Worksheet will be recorded in the CRF.
6.4.2
Optical Coherence Tomography 
Optical Coherence Tomography will be assessed in the study eye at every study visit and in 
both eyes at Visit 1/ Baseline and Visit 7/ EoS.
The assessment will be performed by qualified technician or investigator prior to study drug 
administration. The investigator should evaluate the images according to their standard clinical 
practice and capture Central Subfield Thickness (CSFT) in the CRF. No other qualitative or 
quantitative parameters will be collected. Any new clinically significant abnormalities after 
Baseline will be recorded on the adverse event page of the CRF.
All OCT images will be retained in source documents. The sponsor may request OCT images 
to be submitted for the central review, if standardized evaluation is deemed necessary.
6.4.3
Appropriateness of efficacy assessments 
BCVA and OCT are standard assessments for this indication and patient population, and well 
established in the field of ophthalmologic clinical research.
6.5
Safety 
Safety assessments will be done based on ophthalmic examinations, color fundus photography, 
vital signs, laboratory results and the type, frequency, and severity of AEs.
Safety assessments are performed according to the schedule in Table 6-1.
6.5.1
Ophthalmic examination 
The ophthalmic exam will be performed in the study eye at every study visit and in both eyes 
at Visit 1/ Baseline and Visit 7/ 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 eye.
The ophthalmic exam will consist of the following:

Slit-lamp examination (Bimicroscopy) – includes evaluation of the lids/lashes, 
conjunctiva, cornea, anterior chamber aqueous reaction (cells and flare), iris, lens and 
anterior part of the vitreous body. Slit-lamp examination will be performed before study 
treatment. The test results will be recorded in the source documents only and any clinically 
significant findings must be documented on the CRF.


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
Intraocular pressure measurement (IOP) – a measurement of IOP will be conducted 
using an applanation 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 pre-dose and post-dose at every scheduled visit. 
The values recorded in mmHg will be entered into the CRF.
In case of any abnormal rise of intraocular pressure (≥25 mmHg), if not transient, for any 
reason and at any time during the study period, treatment and closer monitoring of IOP 
should be performed by the investigator in order to achieve similar values to the baseline 
measurement. In this case, intravitreal procedure is not recommended unless normalization 
of the IOP has been achieved. The investigator should treat appropriately the increased IOP 
in order to allow the patient to continue in the study.
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 AE CRF.

Fundus exam – includes ophthalmoscopic assessments of the vitreous, retina, macular, 
choroid, and optic nerve. The retina will also be assessed for detachment/tear and 
hemorrhage and the vitreous will be evaluated for hemorrhage and vitreal cells. Dilation for 
the fundus exam is at the discretion of the investigator. Fundus examination will be 
performed before study treatment and recorded in source documentation. Any clinically 
significant findings must be documented on the CRF.
6.5.2
Color Fundus Photography
Color Fundus (CF) photography will be assessed in the study eye at Visit 1/ Baseline and Visit 
7/ EoS.
The assessment will be performed by qualified technician or investigator prior to study drug 
administration. The investigator should evaluate the images according to their standard clinical 
practice and record any clinically significant abnormalities on the adverse event page of the 
CRF.
A copy of the photographs will be retained in the source documents. The sponsor may request 
CF photographs to be submitted for the central review, if standardized evaluation is deemed 
necessary.
6.5.3
Vital signs 
Vital signs include blood pressure (BP) and pulse measurements. After the patient has been 
sitting for approximately five minutes (in case of ‘white coat syndrome’ the patient should be 
given sufficient time to calm down), with back supported and both feet placed on the floor, 
systolic and diastolic BP will be measured three times using an automated validated device, 
with an appropriately sized cuff. The repeat sitting measurements will be made at approximately 
1 - 2 minute intervals and the mean of the three measurements will be used. In case the cuff 
sizes available are not large enough for the patient's arm circumference, a sphygmomanometer 
with an appropriately sized cuff may be used. 


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On days when study drug is administered, vital signs will be measured before administration of 
study medication.
6.5.4
Laboratory evaluations
Local or central laboratory will be used for analysis of all specimens collected at the visits 
indicated in Table 6-1. The results of the laboratory examinations should be recorded in the 
source documents only. Any clinically significant abnormalities will be recorded on the adverse 
event page of the CRF.
Whether action needs to be taken to address notable laboratory values will be decided by the 
study investigator, taking into account the overall status of the patient. No specific action is 
foreseen as part of the study protocol.
6.5.4.1
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 will be measured.
6.5.4.2
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) will be measured.
6.5.4.3
Urinalysis 
Specific gravity, pH, color, glucose, blood, ketones, bilirubin, and microscopic examination 
(WBC, RBC, epithelial cells, bacteria, mucus, casts, crystals) will be performed.
6.5.5
Pregnancy and assessments of fertility 
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 (Visit 1/ Baseline) and at Visit 7/ EoS. During the 
study, monthly urine pregnancy testing will be performed.
6.5.6
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population.


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6.6
Other assessments 
6.6.1
Anti-drug antibodies (immunogenicity) 
Collection of blood for ADA assessment will be performed at Visit 1/ Baseline, Visit 3/ Week 
8, Visit 5/ Week 16 and Visit 7/ EoS. Blood draws should take place prior to the study drug
administration. 
Further details on sample collection, numbering, processing, storage and shipment can be found 
in the Central Laboratory Manual.
7
Safety monitoring 
7.1
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 subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.
The occurrence of adverse events must be sought by non-directive questioning of the patient at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the patient during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
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 patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. 


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Adverse events must be recorded in the appropriate CRF capturing AEs under the signs, 
symptoms or diagnosis associated with them, accompanied by the following information:

the severity AE 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

its relationship to 

the study treatment

the ocular injection procedure 

its duration (start and end dates or actual duration if AE was shorter than 24 hours) or if 
the event is ongoing an outcome of not recovered/not resolved must be reported.

whether it constitutes a serious adverse event (SAE - See Section 7.2 for definition of 
SAE) and which seriousness criteria have been met.

action taken regarding [investigational] treatment 

for ocular AEs, the eye the AE occurred in
All adverse events must be treated appropriately. Treatment may include one or more of the
following: 

no action taken (e.g. further observation only) 

investigational treatment interrupted/withdrawn

concomitant medication or non-drug therapy given 

non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition of 
SAE)

its outcome (not recovered/not resolved; recovered/resolved; recovered/resolved with 
sequelae; fatal; or unknown)
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent, and assessment must be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions required 
to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any new 
information regarding the safety profile of the medicinal product that is identified between IB 
updates will be communicated as appropriate, for example, via an Investigator Notification or 
an Aggregate Safety Finding. New information might require an update to the informed consent 
and has then to be discussed with the patient.
The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the investigator’s 


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source documents; however, if the AE meets the criteria of an SAE, it must be reported to 
Novartis.
7.2
Serious adverse events 
7.2.1
Definition of SAE 
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:

is fatal or life-threatening 

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 (specify what this includes)

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

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 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (please refer to Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.


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7.2.2
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit / following the last 
administration of study treatment whichever is later must be reported to Novartis safety within 
24 hours of learning of its occurrence. Any SAEs experienced after the 30 day period after the 
last study visit / following the last administration of study treatment should only be reported to 
Novartis safety if the investigator suspects a causal relationship to study treatment.
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.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to each specific 
component of study treatment, (if study treatment consists of several components) complete the 
SAE Report Form in English, and submit the completed form within 24 hours to Novartis. 
Detailed instructions regarding the submission process and requirements for signature are to be 
found in the investigator folder provided to each site.
Follow-up information is submitted as instructed in the investigator folder. Each re-occurrence, 
complication, or progression of the original event must be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not, and 
whether the patient continued or withdrew from study participation.
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 Drug Safety and Epidemiology 
Department associate may urgently require further information from the investigator for health 
authority reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries.
Note: SAEs must be reported to Novartis within 24 hours of the investigator learning of its 
occurrence/receiving follow-up information.
7.3
Liver safety monitoring 
Due to the extremely low systemic exposure following IVT administration and the lack of 
systemic toxicity following repeated IVT injections of brolucizumab up to 6 mg observed in 
pre-clinical studies, no clinical liver toxicity studies were considered necessary. In addition, 
clinical experience with other intravitreally administered VEGF-inhibitors did not identify any
liver safety concern.


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Laboratory assessments will be performed at Visit 1/ Baseline and Visit 7/ EoS. Please refer to 
Section 6.5.4 and Section 6.5.4.2 for details and list of laboratory parameters that will be 
measured.
7.4
Renal safety monitoring 
Due to the extremely low systemic exposure following IVT administration and the lack of 
systemic toxicity following repeated IVT injections of brolucizumab up to 6 mg observed in 
pre-clinical studies, no clinical renal toxicity studies were considered necessary. In addition, 
clinical experience with other intravitreally administered VEGF-inhibitors did not identify any 
renal safety concern.
Laboratory assessments will be performed at Visit 1/ Baseline and Visit 7/ EoS. Please refer to 
Section 6.5.4 and Section 6.5.4.2 and 6.5.4.3 for details and list of laboratory/urine parameters 
that will be measured.
7.5
Reporting of study treatment errors 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (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 collected in 
the Dosing CRF (date and time of the injection) and in the Dispensing Log at the Study site, 
irrespective of whether or not associated with an AE/SAE and reported to Safety only if 
associated with an SAE. 
Table 7-1 
Guidance for capturing the study treatment errors 
Treatment error 
type
Document in 
CRF (Yes/No)
Dispensing Log 
(Yes/No)
Document in 
AE eCRF
Complete SAE 
form
Unintentional 
study treatment 
error
Yes (only date 
and time of 
injection)
Yes (misallocation, 
e.g. patient received 
wrong medication)
Only if 
associated with 
an AE
Only if 
associated with 
an SAE
7.6
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. 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.


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Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
8
Data review and database management 
8.1
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of patient records, the accuracy 
of data capture / data entry, the adherence to the protocol and to 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 clinical research associate (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 patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, and the results of any other tests or assessments. All information 
on CRFs must be traceable to these source documents in the patient's file. [Data not requiring a 
separate written record will be defined before study start and will be recorded directly on the 
CRFs.] The investigator must also keep the original informed consent form signed by the patient 
(a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients/subjects will be disclosed.
8.2
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRFs) using fully validated secure web-enabled software that conforms 
to US CFR 21 Part 11 requirements. Designated investigator site staff will not be given access 
to the system until they have been trained.
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 


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database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.
8.3
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 is required to respond 
promptly to queries and to make any necessary changes to the data.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Randomization codes and data about all study drug(s) dispensed to the patient 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).
8.4
Data Monitoring Committee 
Not required.
8.5
Adjudication Committee 
Not required.
9
Data analysis 
The assessment of the brolucizumab outcome of this study will be based on a within-patient 
comparison with corresponding core-study data serving as reference. Neither the patient 
selection process nor the expected sample sizes support a valid comparison between aflibercept 
and brolucizumab. Analyses of brolucizumab data will be performed on the Extension Safety
Set which is defined as all patients who enter this extension study and receive at least one 
injection of study treatment. Data will be presented descriptively. No formal hypothesis testing 
is planned for this study. Data for the aflibercept treatment group will be presented in listings.
Continuous variables will be summarized using the number of observations, mean, standard 
deviation, standard errors, 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 frequency and percent.
All analyses will be presented for the brolucizumab 6 mg treatment group. Selected analyses 
may be presented stratified by core study treatment group (brolucizumab 6 mg, brolucizumab 
3 mg). Data for aflibercept patients will be presented in separate listings.


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The final analysis will be conducted on all subject data at the time the trial ends. Any data 
analysis carried out independently by the investigator should be submitted to Novartis before 
publication or presentation.
9.1
Analysis sets 
All analyses will be performed on the Extension Safety Set, being defined as all patients who 
enter this extension study and receive at least one injection of study treatment in this extension 
study.
9.2
Patient demographics and other baseline characteristics 
9.2.1
Demographics
Age (< 50, 50-64, 65-74, 75-84, ≥ 85 years), gender, ethnicity and Japanese ancestry will be 
summarized using the number of observations, the number of observations for each category 
and the corresponding frequency and percent.
Age will also be summarized as a continuous variable.
9.2.2
Baseline characteristics
The summary of baseline ocular characteristics will be presented separately for the study eye 
and the fellow eye and will include: primary diagnosis of AMD, time since diagnosis of AMD 
(months), whether AMD is unilateral or bilateral, BCVA (both as a continuous variable and 
using categories (≤ 55, 56-70, ≥ 71 letters)) and CSFT (both as a continuous variable and using 
categories (< 400, ≥ 400µm)).
A summary of length of time (weeks) between the last visit of the core study and first visit of 
extension study will be presented.
9.2.3
Medical history
Medical history (ocular and non-ocular) will be described based on:

the medical history as documented in the core study

all treatment emergent SAEs/AEs as documented in the core study

all new medical conditions occurring between the end of core study and enrollment into
the extension study
Tabulations will be based on primary system organ class and preferred term according to the 
MedDRA dictionary.
9.3
Treatments 
9.3.1
Study treatment exposure
The extent of exposure to study treatment is calculated using the number of injections. The 
following summaries will be presented:


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
Overall number of treatments will be presented separately (active and sham, active only, 
sham only) during the following time periods:

Extension baseline to Week 8

Week 12 to Week 24

Extension baseline to Week 24

Treatment exposure by visit: The number and percent of patients who received active 
injections, sham injections, missed a treatment (active and sham) and missed visits will be 
presented by visit and by treatment status (q8, q12)

Frequency of all observed dosing patterns from extension baseline to Week 24 
differentiating between active and sham treatments, missed treatments and wrong 
treatments will be presented

brolucizumab q12/q8 allocation by visit: Number and percent of patients on q12 and q8 at 
each visit
9.3.2
Prior medications
Prior medications (ocular and non-ocular) will be summarized using number and percent of 
patients by ATC class and preferred term according to the WHO Drug reference list dictionary.
Prior medications are those that have a start date prior to the date of the first injection of study 
treatment in this extension study.
Prior ocular medications will be summarized separately for the study eye and fellow eye.
9.3.3
Prior surgical and medical procedures
Prior surgical and medical procedures (ocular and non-ocular) will be summarized using 
number and percent of patients by primary system organ class and preferred term according to 
the MedDRA dictionary.
Prior surgical and medical procedures are those that have a start date prior to the date of the first 
injection of study treatment in this extension study.
Prior ocular surgical and medical procedures will be summarized separately for the study eye 
and fellow eye.
9.3.4
Concomitant medications
Concomitant medications (ocular and non-ocular) will be summarized using number and 
percent of patients by ATC class and preferred term according to the WHO Drug reference list 
dictionary.
A concomitant medication is defined as any medication taken at least once after the first 
injection of study treatment in this extension study.
Concomitant ocular medications will be summarized separately for the study eye and fellow 
eye.


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9.3.5
Concomitant surgical and medical procedures
Concomitant surgical and medical procedures (ocular and non-ocular) will be summarized 
using number and percent of patients by primary system organ class and preferred term 
according to the MedDRA dictionary.
Concomitant surgical and medical procedures are those that occurred after the date of the first 
injection of study treatment in this extension study.
Concomitant ocular surgical and medical procedures will be summarized separately for the 
study eye and fellow eye.
9.4
Analysis of safety and efficacy variable(s)
The objective of this study is to collect data on the safety and efficacy of the brolucizumab 6 
mg drug product intended for commercialization in patients with nAMD previously treated in 
the CRTH258A2301 study to support comparability to the drug product used in Phase III. The 
aflibercept 2 mg treatment arm is included in this study to maintain the masking. 
Correspondingly, the analysis will focus on brolucizumab patients only. Data of aflibercept 
patients will be presented in separate listings.
9.4.1
Safety and efficacy variable(s)
Safety and efficacy variables:

Treatment emergent Adverse Events

Best-corrected visual acuity

q12 treatment status at Week 20

ADA status including drug exposure

CSFT

Intraocular pressure

Vital signs
9.4.2
Statistical model, hypothesis, and method of analysis
Formal hypothesis testing is not planned for this study.
Treatment emergent Adverse Events
Treatment emergent AEs are defined as AEs which start on or after the time of the first injection 
of study treatment in this extension study and until the patient exits the study.
The number and percentage of patients who report treatment emergent AEs will be summarized 
by primary system organ class and preferred term according to the MedDRA dictionary.  
Separate summaries will be produced for ocular and non-ocular events. Ocular AEs will be 
presented for the study eye and fellow eye separately. 
In addition, the following treatment emergent AE summaries will be produced:


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
SAEs by primary system organ class and preferred term

AEs by maximum severity, primary system organ class and preferred term

AEs resulting in treatment and/or study discontinuation by primary system organ class 
and preferred term

AEs (as defined in the case retrieval strategy) by safety topic of interest and preferred 
term

AEs by causal relationship to study treatment and ocular injection procedure 
AEs which start prior to the date/time of the first injection of study treatment in this extension 
study will be listed only.
Treatment emergent AEs occurring during the last 6 months of the core study, for the same set 
of patients included in the extension study safety set will be presented.
Best-Corrected Visual Acuity
The change from extension baseline in BCVA to each post-baseline visit will be summarized 
descriptively by visit.
The number and percentage of patients with a loss of BCVA of 15 letters or more from extension 
baseline to each post baseline visit will be presented.
The extension baseline BCVA value is defined as the BCVA value at Day 1.
Last observation carried forward (LOCF) will be used to impute missing BCVA values (see 
Section 9.4.3 for further details).
BCVA over 96 weeks in the core study, for the same set of patients included in the extension 
safety set, will be displayed graphically alongside BCVA over 24 weeks for patients in the 
extension safety set.
q12 treatment status at Week 20
The proportion of patients with a positive q12 treatment status at Week 20 will be presented. 
Patients without an identified q8 need (according to the investigators disease activity 
assessment) at Week 16 and Week 20 are considered to have a positive q12 status at Week 20.
The estimate for the proportion of patients with a positive q12 treatment status at Week 20 will 
be derived from Kaplan Meier time-to-event analyses for the event ‘first q8-need’ applying a 
‘q8-need’ allocation in case of missing or confounded data attributable to lack of efficacy and/or 
lack of safety. Remark: Patients without any relevant valid disease activity assessment are 
considered censored at extension baseline.
The proportion of patients with a positive q12 treatment status will be derived as follows 
requiring duration of effect (as assessed by q8 need) together with ‘sufficient efficacy and 
safety’:

For the ‘duration of effect’ requirement patients will need to have the status of ‘q8 need = 
no’ at Week 16 and Week 20 unless the ‘q8 need = yes’ is confounded by reasons other than 
lack of efficacy and/or safety (see censoring details below).


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
The requirement regarding ‘sufficient efficacy and safety’ will be addressed by considering 
patients – even without an explicit ‘q8 need = yes’ – as having a negative q12 status in case 
any of the following confounding factors is attributable to lack of efficacy and/or lack of 
safety of the study treatment (assessed based on a masked medical review): early 
treatment/study discontinuation, use of forbidden concomitant medications/procedures 
and/or other deviation from treatment schedule (e.g. due to a missed visit/treatment).  The 
corresponding q8 need will be allocated to the next disease activity assessment visit at Week 
20 following the occurrence of such a confounding factor.
In case the missing or confounded data regarding the q12 treatment status are attributable 
to reasons other than lack of efficacy and/or safety, the patient is censored within the q12 
treatment status according to the following specifications:

Early treatment/study discontinuation: Censoring at the last valid disease activity 
assessment.

Single missed visit with a relevant disease activity assessment: Censoring at the last 
valid disease activity assessment prior to the missed visit.

Prohibited concomitant medications/procedures: Censoring at the last valid disease 
activity assessment prior to the corresponding application.

Discrepancy between disease activity assessment by investigator and the actual 
treatment received.

Other treatment allocations/applications deviating from the concept of ‘disease 
activity’. Censoring at the last valid disease activity assessment.
Using number and percent of patients, q12 treatment status at Week 20 in the extension safety 
set will be displayed by q12 treatment status at Week 96 in the core study and core study 
treatment group (brolucizumab 6 mg, brolucizumab 3 mg).
Anti-drug antibodies
The number and percent of patients according to their ADA status (ADA negative, ADA 
positive without boost, induced, boosted) will be presented.
The ADA tier pattern and shift table showing ADA titer at extension baseline relative to each 
post-baseline assessment, relative to the last visit and to any visit with most extreme increase 
in ADA titer will be presented.
Extension baseline is defined as the ADA measurement at Day 1.
 
 
Central Subfield Thickness
The change in CSFT from extension baseline to each post-baseline visit will be summarized 
descriptively by visit.
The extension baseline CSFT value is defined as the CSFT value at Day 1. 


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LOCF will be used to impute missing CSFT values (see Section 9.4.3 for further details).
CSFT over 96 weeks in the core study, for the same set of patients included in the extension 
safety set, will be displayed graphically alongside CSFT over 24 weeks for patients in the 
extension safety set.
Intraocular pressure
Pre-injection IOP values and post-injection IOP values will be summarized by visit.  Change 
from extension baseline IOP values will also be summarized by visit.
The number and percentage of patients with an IOP > 30mmHg will be presented separately for 
pre- and post-injection by visit.  In addition, the number and percentage of patients with IOP > 
30 mmHg at any visit and at the last visit will be presented.
Vital signs
Vital signs will be summarized for each visit.  Changes from extension baseline will be 
summarized by visit. The number and percentage of patients with clinically notable findings 
from extension baseline will be presented by visit.
Extension baseline is defined as the last measurement before the injection given at Day 1.
9.4.3
Handling of missing values/censoring/discontinuations
Missing BCVA data will be imputed using LOCF. Observed values from both scheduled and 
unscheduled visits will be used for the LOCF imputation. For patients with no post baseline 
value, no imputation will be performed. 
The details regarding handling of missing/ confounded data within the time-to-event analysis 
for the 'first q8 need' are specified in Section 9.4.2.
Missing CSFT data will be imputed using LOCF. Observed values from both scheduled and 
unscheduled visits will be used for the LOCF imputation. For patients with no post baseline 
value, no imputation will be performed. 
All other data will be analyzed as observed, i.e. without imputation of missing data. 
9.4.4
Sensitivity analyses 
Best-Corrected Visual Acuity
Analyses of the BCVA variables described in Section 9.4.2 will be performed using observed 
data.
Central Subfield Thickness
Analyses of the CSFT variables described in Section 9.4.2 will be performed using observed 
data.
9.5
Analysis of secondary variables
Not applicable


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9.5.1
Efficacy variables 
Not applicable
9.5.2
Safety variables
Not applicable
9.5.3
Resource utilization 
Not applicable
9.5.4
Pharmacokinetics 
Not applicable
9.5.5
DNA
Not applicable
9.5.6
Biomarkers 
Not applicable
9.5.7
PK/PD 
Not applicable
9.6
Analysis of exploratory variables 
Not applicable
9.7
Interim analyses
An interim analysis might be conducted when 50 patients are treated with brolucizumab 6 mg 
for 6 months to support a brolucizumab Biologic License Application submission at the earliest 
possible time point, which is currently planned for end of 2018.
The interim analysis will be performed with an unmasking of specified individuals from the 
sponsor who are not involved in the direct conduct of the trial.
Treatment masking of individual subjects will remain intact for all subjects, Investigators and 
staff from the sponsor who have contact with subjects or investigators or those who are involved 
with the direct conduct of the study until the final database lock has occurred.
9.8
Sample size calculation
Approximately 75 to100 patients who completed study CRTH258A2301 are expected to be 
enrolled in this study. This sample size is not based on a power calculation and depends on the 
number of patients in the core study fulfilling the eligibility criteria of the extension study (see 
Section 4).


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10
Ethical considerations 
10.1
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 Japanese 
Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the 
Declaration of Helsinki.
10.2
Informed consent procedures 
Eligible patients/subjects may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if applicable after such 
consent has been provided by a legally acceptable representative(s) of the patient. 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.
For trials using an Electronic Informed Consent system where a date/timestamp is automatically 
generated, the system-generated date/timestamp is sufficient; additional input of the date at the 
time of consent is not required by the patient.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guideline and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC approval.
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 requirement for the duration of 
the study. If there is any question that the patient will not reliably comply, they must not be 
entered in the study.
10.3
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, 
informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to patients/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 requested by a regulatory authority, the investigator must inform Novartis immediately that 
this request has been made.


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10.4
Publication of study protocol and results 
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results.
10.5
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance, a group 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.
11
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of patients/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, 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.
11.1
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 intended to eliminate an apparent immediate hazard 
to patients/subjects may be implemented immediately provided the health authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 


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study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed.
12
References 
References are available upon request.
Bloch SB, Larsen M, Munch IC (2012) Incidence of legal blindness from age-related macular 
degeneration in Denmark: Year 2000 to 2010. Am J Ophthalmol; 153:209-13.
Campbell JP, Bressler SB, Bressler NM (2012) Impact of availability of anti-vascular 
endothelial growth factor therapy on visual impairment and blindness due to neovascular age-
related macular degeneration. Arch Ophthalmol;130:794-5.
Ferris FL (1983) Senile macular degeneration. Review of epidemiologic features. Am J 
Ophthalmol; 118:132-51.
Ferris FL, Fine SL, Hyman L (1984) Age-related macular degeneration and blindness due to 
neovascular maculopathy. Arch Ophthalmol; 102:1640-42.
Kawasaki R, Yasuda M, Song S, et al. (2010) The prevalence of age-related macular 
degeneration in Asians: A systematic review and meta-analysis. Ophthalmology; 117:921-27.
Lim LS, Mitchell P, Seddon JM, et al. (2012). Age-related macular degeneration. 
Lancet;379:1728-38.
Miller JW (2013) Age-Related Macular Degeneration Revisited – Piecing the Puzzle: The 
LXIX
Edward Jackson Memorial Lecture. Am J Ophthalmol;155:1-35.
Rein DB, Wittenborn BS, Zhang X, et al. (2009) Vision Health Cost-Effectiveness Study 
Group. Forecasting age-related macular degeneration through the year 2050. Arch 
Ophthalmol; 127:533-40.
Shah AR, Del Priore L V (2007) Progressive visual loss in subfoveal exudation in age-related 
macular degeneration: a meta-analysis using Lineweaver-Burke plots. Am J Ophthalmol; 
143:83-89.
Shah AR, Del Priore LV (2009) Natural history of predominantly classic, minimally classic 
and occult subgroups in age-related macular degeneration. Am J Ophthalmol; 116:1901-07.
Smith W, Assink J, Klein R, et al. (2001) Risk factors for age-related macular degeneration: 
Pooled findings from three continents. Ophthalmology; 108:697-704.
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; 14:1412-17.
Spilsbury K, Garrett KL, Shen WY, et al. (2000) Over expression of vascular endothelial 
growth factor (VEGF) in the retinal pigment epithelial leads to the development of choroidal 
neovascularization. Am J Pathol; 157:135-44.
TAP and VIP Therapy Study Groups (2003) Effect of lesion size, visual acuity and lesion 
composition on visual acuity change with and without verteporfin therapy for choroidal 
neovascularization secondary to age-related macular degeneration: TAP and VIP Report No.1. 
Am J Ophthalmol; 136:407-18.


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Wong TY, Chakravarthy U, Klein R, et al. (2008) The natural history and prognosis of 
neovascular age-related macular degeneration: a systemic review of the literature and meta-
analysis. Ophthalmology; 115:116-26.

SAP_000.pdf: 
Clinical Development
RTH258/Brolucizumab
CRTH258A2301E1 / NCT03386474
A 24-week, double-masked, multicenter, two-arm extension 
study to collect safety and efficacy data on brolucizumab 6 
mg drug product intended for commercialization in patients 
with neovascular age-related macular degeneration who 
have completed the CRTH258A2301 study
Statistical Analysis Plan (SAP)
Author:
Document type:
SAP Documentation
Document status:
Amendment 1.0
Release date:
27 Sep 2018
Number of pages:
32
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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SAP Amendment
CRTH258A2301E1
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted (Current)
27Sep2018
Before 
CDBL
Consistency 
with 
final 
analysis
of 
core study
Reflect 
all 
changes 
discussed during dry run
See below
A summary of revisions to this SAP includes:

Changes in wording to simplify and distinguish between extension Baseline/Week and 
core Baseline/Week (coBL/coWeek vs exBL/exWeek),

Other baseline characteristics: changes in some categories and addition of some 
variables reflecting the treatment interval related to the transition period,

BCVA and CSFT: 
o
Changes in categories and baseline values considered for the shift tables
o
Removal of sensitivity analysis based on observed data without imputation and 
without censoring of assessments after start of alternative anti-VEGF treatment 
in the study eye, due to the low number of cases observed during the study 
conduct,

Use of “q12 treatment status at Week 24” instead of Week 20 for consistency with the 
core study (q12 treatment status at Week 48/96),

Adverse Events:
o
For summary tables, addition of the number and percentage of patients 
presenting AEs both during the extension study and during the last 6 months of 
the core study
o
Removal of table listing categories of AEs of potential relevance to t intravitreal 
anti-VEGF class but reference to the RTH258 nAMD electronic case retrieval 
strategy (eCRS) at the time of the core study CRTH258-C001 clinical database 
lock

ADA: change in analysis to reflect what has been done in the core study

ARs/PDs: as stated in the initial SAP, the list of ARs and PDs with their impact on the 
statistical analysis was added


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CRTH258A2301E1
Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................4
1
Introduction .........................................................................................................................5
1.1
Study design.............................................................................................................5
1.2
Study objectives and endpoints ...............................................................................6
2
Statistical methods...............................................................................................................6
2.1
Data analysis general information ...........................................................................6
2.1.1
General definitions..................................................................................7
2.2
Analysis sets ............................................................................................................7
2.3
Patient disposition, demographics and other baseline characteristics .....................8
2.3.1
Patient disposition...................................................................................8
2.3.2
Demographics .........................................................................................8
2.3.3
Baseline Characteristics ..........................................................................8
2.3.4
Medical history........................................................................................9
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................10
2.4.1
Study treatment / compliance................................................................10
2.4.2
Prior, concomitant and post therapies...................................................10
2.5
Analysis of safety and efficacy variables ..............................................................12
2.5.1
Safety and efficacy variables ................................................................12
2.5.2
Statistical hypothesis, model, and method of analysis..........................12
2.5.3
Handling of missing values/censoring/discontinuations.......................19
2.5.4
Sensitivity analyses ...............................................................................19
2.6
Interim analysis......................................................................................................20
3
Sample size calculation .....................................................................................................20
4
Change to protocol specified analyses ..............................................................................20
5
Appendix ...........................................................................................................................21
5.1
Imputation rules.....................................................................................................21
5.1.1
AE date imputation ...............................................................................21
5.1.2
Concomitant medication date imputation .............................................22
5.2
Rules for exclusion from the Extension Safety Set ...............................................24
5.3
Censoring rules for analysis of q12 treatment status at exWeek 24......................25


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CRTH258A2301E1
List of abbreviations
ADA
Anti-drug antibodies
AE
Adverse event
AR
Analysis Restriction
ATC
Anatomical Therapeutic Classification
BCVA
Best Corrected Visual Acuity
BLA
Biologic Licence Application
coBL
Core Study Baseline
coWeek
Core Study Week
CM
Concomitant Medication
CSFT
Central Subfield Thickness
CSR
Clinical Study report
DAA
Disease Activity Assessment
DBL
Database Lock
eCRF
Electronic Case Report Form
eCRS
Electronic Case Retrieval Strategy
EoS
End of Study
exBL
Extension Study Baseline
exWeek
Extension Study Week
IA
Interim Analysis
IOP
Intraocular Pressure
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary for Drug Regulatory Affairs
nAMD
Neovascular Age-related Macular Degeneration
PD
Protocol deviation
PT
Preferred Term
q8
Treatment every 8 weeks
q12
Treatment every 12 weeks
SAP
Statistical Analysis Plan
SE
Standard Error
SOC
System Organ Class
WHO
World Health Organization


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CRTH258A2301E1
1
Introduction
This Statistical Analysis Plan (SAP) describes the analyses to be conducted after Database Lock 
(DBL).
This SAP describes the analysis according to Section 9 of the study protocol along with any 
additional analyses, specifications or deviations from the protocol.  
1.1
Study design
This is a double-masked, multicenter, two-arm extension study. Patients recruited at US sites 
who completed the 96-week core study CRTH258A2301 (also referred to as RTH258-C001), 
regardless of the treatment group (brolucizumab 3 mg, brolucizumab 6 mg or aflibercept 2 mg) 
are eligible for inclusion in the extension study provided Visit 26/Week 96 in the core study is 
≤ 12 weeks from the Baseline visit in the extension study. The time period between the End of 
Study visit (EoS) of the core study and the first visit of the extension study is referred to as the 
transition period. Patients who were treated with aflibercept during the core study will continue 
to receive aflibercept in the extension study. Patients who were treated with brolucizumab 3 mg 
or 6 mg in the core study will receive brolucizumab 6 mg in the extension study.
Enrolled patients receive three intravitreal injections of either brolucizumab 6 mg or aflibercept 
2 mg according to the protocol specified dosing schedule. This extension study consists of 7 
study visits at 4-week intervals, labeled Visit 1/Baseline to Visit 7/EoS over a period of 24 
weeks. 
The study eye will be the same eye that received brolucizumab or aflibercept study treatment 
in the core study.
Approximately 75 to100 patients who completed study CRTH258A2301 are expected to be 
enrolled in this study. This sample size is not based on a power calculation but depends on the 
number of patients in the core study fulfilling the eligibility criteria of the extension study.
The final analysis will be conducted on all enrolled patient data at the time the trial ends. Any 
data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.


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CRTH258A2301E1
1.2
Study objectives and endpoints
The study objectives and endpoints are described in Table 1-1.
Table 1-1
Study objectives and related endpoints
Objective(s)
Endpoint(s)
To collect data on safety and efficacy of the 
brolucizumab 6 mg drug product intended for 
commercialization in patients with nAMD 
previously treated in CRTH258A2301 study to 
support comparability to the brolucizumab 6 mg 
drug product used in Phase III clinical studies

Incidence and characteristics of treatment 
emergent adverse events (AE)

Loss in Best Corrected Visual Acuity 
(BCVA) of 15 letters or more from Baseline 
at each post-baseline visit

Change in BCVA from Baseline at each 
post-baseline visit

q12 treatment status at Week 24

Change in Central Subfield Thickness 
(CSFT) from Baseline at each post-
baseline visit

Anti-drug antibody (ADA) status at
Baseline, Week 8, Week 16 and Week 24. 
2
Statistical methods
2.1
Data analysis general information
The final analysis will be performed by Novartis using SAS Version 9.4.  This SAP describes 
the analyses to be conducted after the final DBL.  
No formal hypothesis testing is planned for this study. Neither the patient selection process nor 
the expected sample size support a valid comparison between aflibercept and brolucizumab. 
Therefore, descriptive analyses will be presented for the brolucizumab treatment group with 
selected analyses presented stratified by core study treatment group (brolucizumab 6 mg, 
brolucizumab 3 mg). Data for the aflibercept treatment group will be presented in listings, no 
analyses will be performed for this treatment group.  
 
Continuous variables will be summarized using the number of observations, mean, standard 
deviation, standard errors, 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.


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2.1.1
General definitions
2.1.1.1
Baseline and post-baseline definitions
Extension baseline (Day 1) is defined as the date of the first study treatment in the extension 
study. The extension baseline value for efficacy and safety variables is the last available value 
collected  prior to the first study treatment.
All data collected after first study treatment are defined as post-baseline. 
The study day for an extension post-baseline scheduled or unscheduled visit is defined as:
Study day = (date of visit) – (date of first study treatment in the extension study) + 1
The study day for a scheduled or unscheduled visit before extension baseline is defined as:
Study day = (date of visit) – (date of first study treatment in the extension study)
2.1.1.2
End of study/end of treatment day mapping
The end of study date is the date when a patient completes or discontinues the study. The “Date 
of Last Exposure” is the date of the last study treatment. 
For reporting data by visit in outputs, the end of study/end of treatment visit will be allocated 
to the actual (reported) visit number. If 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.
2.1.1.3
Unscheduled visits
Data collected at unscheduled visits (with the exception of data collected at unscheduled visits
see Section 2.1.1.2) will not be used in ‘by-visit’ tabulations or graphs , but will be included in 
analyses based on all post-baseline values such as last observation carried forward (LOCF) 
imputation, summary of maximum decrease or increase from extension baseline for vital signs 
data and maximum letter loss in BCVA from extension baseline (exBL) at any visit.
All data collected at unscheduled visits will be included in listings.
2.1.1.4
Missing and implausible dates
The general approach to handling missing dates is shown in Section 5.1.
2.2
Analysis sets
The Extension Safety Set will include all patients who enter this extension study and receive at 
least one injection of study treatment in this extension study.
The Extension Safety Set will be used for the descriptive analyses and listings related to both 
efficacy and safety for the brolucizumab treatment group and for the listings for the aflibercept 
treatment group.
Patients will be reported under the treatment they were randomized to in the core study
(brolucizumab, aflibercept). Note: In the core study, patients in the safety set are analyzed 
according to the treatment group from which they received the majority of treatments up to and 


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including Week 44. All patients received the majority of their treatments according to the 
randomization during this time period in the core study.
2.3
Patient disposition, demographics and other baseline 
characteristics
Descriptive analyses and listings will be presented for the brolucizumab treatment group. Data 
for the aflibercept treatment group will be presented in listings.
2.3.1
Patient disposition
The following summaries will be included in the disposition table: Number and percent of 
patients who are enrolled into the study, treated, complete the study, discontinue the study 
(including reasons for discontinuation) and discontinue from study treatment (including reasons 
for discontinuation). In addition, disposition will be presented by core study treatment group 
(brolucizumab 3 mg, brolucizumab 6 mg).
The number and percent of patients who discontinue the study and who discontinue treatment 
will be presented by study visit.
The number and percent of patients treated by site will be presented.
A listing of patients who discontinue from the study and/or treatment early will be provided for 
both treatment groups. The listing will identify the visits completed and when the study or 
treatment was discontinued including the corresponding reasons.
Number and percent of patients with protocol deviations (PD) and analysis restrictions (AR) 
will be presented by deviation/restriction category for the broluzicumab treatment arm 
including corresponding listings.
2.3.2
Demographics
Age at extension baseline (both as a continuous variable and using categories (< 50, 50-64, 
65-74, 75-84, ≥ 85 years)), gender, race, and ethnicity will be summarized.
Demographic data will be listed for both treatment groups.  
2.3.3
Baseline Characteristics
The summary of baseline ocular characteristics will be presented separately for the study eye 
and the fellow eye and will include: primary diagnosis of nAMD, time since diagnosis of 
nAMD when entering the core study (months), whether nAMD is unilateral or bilateral when 
entering the core study, core and extension baseline BCVA (both as a continuous variable and 
using categories (≤ 55, 56-70, ≥ 71 letters)) and core and extension baseline CSFT (both as a 
continuous variable and using categories (< 400, ≥ 400µm)).
A summary of length of the transition period will be presented both as a continuous variable 
(weeks) and using categories (0 days, 1 day - ≤4 weeks, > 4 weeks - ≤8 weeks, > 8 weeks - ≤
12 weeks, > 12 weeks).
In addition, a summary of length of time between last active treatment in the study eye in the 
core study and extension baseline (= first active treatment in the study eye in the extension 


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study),  referred as the treatment interval related to the transition period, will be presented both 
as a continuous variable (weeks) and using categories (≤4 weeks, > 4 weeks - ≤8 weeks, > 8 
weeks - ≤12 weeks, > 12 weeks - ≤16 weeks, > 16 weeks).
Furthermore, the distribution of core treatment group (brolucizumab 3 mg, brolucizumab 6 mg) 
and final treatment status (q12, q8) in the core study (coWeek 96) will be displayed. 
The treatment interval based on final q12 (considering 84 days) /q8 (considering 56 days) status 
in core study versus the treatment interval related to the transition period will be summarized 
using categories (≤28 days, > 28 days).
Data will be listed for both treatment groups. In addition, a listing will display the treatment 
group under which the patient was analyzed for safety in the core study, the last active treatment 
received during the core study and, for the brolucizumab patients, final treatment status in the 
core study.
2.3.4
Medical history
The following describes the data to be recorded on the extension study eCRFs.
For patients where Core end of study visit date and Extension study first visit date occur on the 
same day the following data is recorded on the Medical History eCRF.
a) Medical histories which start before the core study and are ongoing at first visit of the 
Extension study
For patients where Core end of study visit date and Extension study first visit date do not occur 
on the same day the following data is recorded on the Medical History eCRF:
a) AEs which started during the core study and ended during the transition period
b) Medical conditions/events which start during the transition period and are ongoing at 
first visit of the Extension study
c) Medical conditions/events which start during the transition period and end during the 
transition period
d) Medical histories which start before the core study and end during the transition 
period
e) Medical histories which start before the core study and are ongoing at first visit of the 
Extension study
f)
Procedures occurring during the transition period
Medical history (ocular and non-ocular) will be described together with current medical 
conditions. Current medical condition will be summarized as well separately.
Ocular events will be presented separately for the study eye and fellow eye.
Data will be tabulated using primary system organ class (SOC) and preferred term (PT) 
according to the MedDRA dictionary V20.1.
Data collected on the Medical History eCRF for the extension study will be listed for both 
treatment groups. Columns will be included to identify if the event started before the core study,
during the core study, during the transition period or during the extension study and if the event 
is ongoing or ended during the transition period or during the extension study.


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2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
Descriptive analyses and listings will be presented for the brolucizumab treatment group. Data 
for the aflibercept treatment group will be presented in listings.
2.4.1
Study treatment / compliance
Extent of exposure to study treatment is calculated as the number of injections received.  The 
following summaries will be presented:

Overall number of treatments from extension baseline to exWeek 24 using the following 
categories: active and sham, active only, sham only 

Treatment exposure by visit: The number and percent of patients who received active 
injections, sham injections, missed a treatment (active and sham) and missed visits will be 
presented by visit and by treatment status (q8, q12)

Frequency of all observed dosing patterns from extension baseline to exWeek 24 
differentiating between active and sham treatments, missed treatments and wrong 
treatments 

brolucizumab q12/q8 allocation by visit: Number and percent of patients on q12 and q8 at 
each visit, including number of patients switched from q12 to q8
Exposure data will be listed for both treatment groups.
2.4.2
Prior, concomitant and post therapies
The following describes the data to be recorded on the extension study eCRFs.
Medications
For patients where Core end of study visit date and Extension study first visit date occur on the 
same day the following data is recorded on the Concomitant Medications eCRF:
a) Medications started on Core end of study visit date/Extension study first visit date
b) Medications taken at least once during the Extension Study
For patients where Core end of study visit date and Extension study first visit date do not occur 
on the same day the following data is recorded on the Concomitant Medications eCRF:
c) Medications started during the core study and stopped during the transition period
d) Medications started during the core study and ongoing at Extension study first visit 
date
e) Medications started and stopped during the transition period
f)
Medications started during the transition period and ongoing at Extension study first 
visit date
Procedures
For patients where Core end of study visit date and Extension study first visit date occur on the 
same day the following data is recorded on the Procedures eCRF:


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a) Procedures occurring on date of Core end of study visit date/Extension study first visit
date
b) Procedures occurring during the Extension Study
For patients where Core end of study visit date and Extension study first visit date do not occur 
on the same day, the following data is recorded on the Procedures eCRF:
a) Procedures occurring during the Extension Study
Note: Procedures occurring during the transition period are recorded on the Medical History 
eCRF.
2.4.2.1
Prior medications
Prior medications (ocular and non-ocular) will be summarized using number and percent of 
patients by ATC class and preferred term according to the WHO Drug reference list dictionary.
Prior ocular medications will be summarized separately for the study eye and fellow eye.
Prior medications are those that have a start date prior to the date of the first injection of study 
treatment in this extension study.
Prior medications will be listed for both treatment groups.
2.4.2.2
Prior surgical and medical procedures
Prior surgical and medical procedures (ocular and non-ocular) will be summarized using 
number and percent of patients by primary system organ class and preferred term according to 
the MedDRA dictionary V20.1.
Prior ocular surgical and medical procedures will be summarized separately for the study eye 
and fellow eye.
Prior surgical and medical procedures are those that have a start date prior to the date of the first 
injection of study treatment in this extension study.
Prior surgical and medical procedures will be listed for both treatment groups.
2.4.2.3
Concomitant medications
Concomitant medications (ocular and non-ocular) will be summarized using number and 
percent of patients by ATC class and preferred term according to the WHO Drug reference list
dictionary.   
Concomitant ocular medications will be summarized separately for the study eye and fellow 
eye.
A concomitant medication is defined as any medication taken at least once after the first 
injection of study treatment in this extension study.
Concomitant medications will be listed for both treatment groups.


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2.4.2.4
Concomitant surgical and medical procedures
Concomitant surgical and medical procedures (ocular and non-ocular) will be summarized 
using number and percent of patients by primary system organ class and preferred term 
according to the MedDRA dictionary V20.1.
Concomitant ocular surgical and medical procedures will be summarized separately for the 
study eye and fellow eye.
Concomitant surgical and medical procedures are those that occurred after the date of the first 
injection of study treatment in this extension study.
Concomitant surgical and medical procedures will be listed for both treatment groups.
2.5
Analysis of safety and efficacy variables
Analyses and listings will be presented for the brolucizumab treatment group. Data for the 
aflibercept treatment group will be presented in listings.
2.5.1
Safety and efficacy variables
Safety and efficacy variables are:

Treatment emergent Adverse Events

Best-corrected visual acuity

q12 treatment status at exWeek 24

Anti-drug antibodies, including drug exposure

Central Subfield Thickness 

Intraocular pressure

Vital signs
2.5.2
Statistical hypothesis, model, and method of analysis
Formal hypothesis testing is not planned for this study.
2.5.2.1
Efficacy variables
Best-Corrected Visual Acuity
BCVA will be analyzed for the study eye. BCVA data for both the study eye and fellow eye 
will be listed for both treatment groups.
The following summaries will be presented:

The number and percentage with a loss in BCVA ≥5, ≥10, ≥15, ≥ 30 letters from exBL to 
each post-exBL study visit 

The number and percentage with a gain in BCVA ≥5, ≥10, ≥15 letters from exBL to each 
post-exBL study visit 


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Note: Patients 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 patients with BCVA values at 
baseline ≥ 70 letters.

Descriptive statistics for change from exBL in BCVA to each post-exBL study visit and 
coWeek 96 visit.
BCVA assessments after start of alternative anti-VEGF treatment in the study eye will be 
censored and imputed by the last value prior to start of this alternative treatment.  See Section 
2.5.3 for further details of the last observation carried forward (LOCF) rules to be used to 
impute censored or missing BCVA values.  
See Section 2.5.4.1 for details of the sensitivity analyses which will be performed for the above 
BCVA endpoints.
Using the core study data, descriptive statistics for change from coBL in BCVA (LOCF) to each 
post-baseline study visit for patients included in the Extension Safety Set will be summarized 
by core study treatment group (brolucizumab 3 mg, brolucizumab 6 mg) and pooled. This will 
be repeated for BCVA without imputation with LOCF (with censoring) of BCVA data after 
start of alternative anti-VEGF treatment in the study eye.
Means and standard errors (SE) for change in BCVA (LOCF) for the study eye will be presented 
graphically by study visit for the 96 week core study treatment period and the 24 week extension 
study treatment period.  Core study data will be plotted together with extension study data by 
core study treatment group. 
Using the core study data, summary statistics will be displayed for the average change in BCVA
from core Week 68 (coWeek 68) to Week 84 through Week 96 in the core study, the average 
change in BCVA from exBL to Week 12 through Week 24 in the extension study and for the 
difference (with 95% confidence interval). In addition, average change in BCVA from coWeek 
68 to coWeek 84 through coWeek 96 vs the average change in BCVA from exBL to exWeek 
12 through exWeek 24 will be displayed using a shift table with categories: ≤ -15, >-15 to <-
10, ≥-10 to <10, ≥10 to <15, ≥ 15 letters. The analysis will be conducted 1) with censoring of 
BCVA assessments after start of alternative anti-VEGF treatment in the study eye and censored 
or missing BCVA values imputed with LOCF and 2) with censoring of BCVA assessments 
after start of alternative anti-VEGF treatment in the study eye but without imputation with 
LOCF of missing or censored values.
q12 treatment status at exWeek 24
The proportion of patients with a positive q12 treatment status at Week 24 will be presented. 
Patients without an identified q8 need (according to the investigator’s disease activity 
assessment (DAA)) at exWeek 16 and exWeek 20 are considered to have a positive q12 status 
at exWeek 24.
The estimate for the proportion of patients with a positive q12 treatment status at Week 24 will 
be derived from Kaplan Meier time-to-event analyses for the event ‘first q8-need’ applying a 
‘q8-need’ allocation in case of missing or confounded data attributable to lack of efficacy and/or 
lack of safety and censoring as described below.


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The proportion of patients with a positive q12 treatment status will be derived as follows 
requiring ‘duration of effect’ (as assessed by q8 need) together with ‘sufficient efficacy and 
safety’:

For the ‘duration of effect’ requirement patients will need to have the status of ‘q8 need = 
no’ at exWeek 16 and exWeek 20 unless the ‘q8 need = yes’ is confounded by reasons other 
than lack of efficacy and/or safety (see censoring details below).

The requirement regarding ‘sufficient efficacy and safety’ will be addressed by considering 
patients – even without an explicit ‘q8 need = yes’ – as having a negative q12 status in case 
any of the following confounding factors is attributable to lack of efficacy and/or lack of 
safety of the study treatment (assessed based on a masked medical review, see Section 5.3
for further details): early treatment/study discontinuation, use of forbidden concomitant 
medications/procedures and/or other deviation from treatment schedule (e.g. due to a missed 
visit/treatment).  The corresponding q8 need will be allocated to the next DAA visit
(according to the protocol) following the occurrence of such a confounding factor.
In case the missing or confounded data regarding the q12 treatment status are attributable 
to reasons other than lack of efficacy and/or safety, the patient is censored within the q12 
treatment status according to the following specifications:

Early treatment/study discontinuation: Censoring at the last valid DAA.

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 visit of the discrepancy (assuming the DAA is valid).

Other treatment allocations/applications deviating from the concept of ‘disease 
activity’. Censoring at the last valid DAA at or prior to the deviation.
Remark: Patients without any relevant valid DAA are considered censored at extension baseline.
The proportion of patients with a positive q12 treatment status at exWeek 24 will be displayed 
by q12 treatment status at coWeek 96 and by core study treatment group (brolucizumab 6 mg, 
brolucizumab 3 mg).
Central Subfield Thickness
The change in CSFT from exBL to each post-exBL study visit will be summarized descriptively 
for the study eye. CSFT assessments after start of alternative anti-VEGF treatment in the study 
eye will be censored and imputed by the last value prior to start of this alternative treatment.
See Section 2.5.3 for further details regarding the LOCF rules to be used to impute missing 
CSFT values.
CSFT data for the study eye and fellow eye will be listed for both treatment groups.
See Section 2.5.4.1 for details of the sensitivity analysis which will be performed for CSFT.


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Using the core study data, change in CSFT (LOCF) for the study eye for patients included in 
the Extension Safety Set will be summarized by study visit and core study treatment group 
(brolucizumab 3 mg, brolucizumab 6 mg) and pooled. This will be repeated for CSFT without 
imputation with LOCF of CSFT data after start of alternative anti-VEGF treatment in the study 
eye.
Means and SEs for change in CSFT (LOCF) for the study eye will be presented graphically by 
study visit for the 96 week core study treatment period and the 24 week extension study 
treatment period.  Core study data will be plotted together with extension study data by core 
study treatment group. 
Using the core study data, summary statistics will be displayed for the average change in CSFT
from coWeek 68 to coWeek 84 through coWeek 96, the average change in CSFT from exBL to 
exWeek 12 through exWeek 24 and for the difference (with 95% confidence interval).  In 
addition, average change in CSFT from coWeek 68 to coWeek 84 through coWeek 96 in the 
core study vs the average change in CSFT from exBL to exWeek 12 through exWeek 24 in the 
extension study will be displayed using a shift table with categories: ≤ -100, > -100 to < -50, ≥ 
-50 to <50, ≥ 50 to < 100, ≥ 100 µm.  These analyses will be conducted 1) with censoring of 
CSFT assessments after start of alternative anti-VEGF treatment in the study eye and censored 
or missing CSFT values imputed with LOCF and 2) with censoring of CSFT assessments after 
start of alternative anti-VEGF treatment in the study eye but without imputation with LOCF of 
missing or censored values.
2.5.2.2
Safety variables
Safety analyses will include all treatment emergent data, including data collected after the 
patient discontinued study treatment and started alternative anti-VEGF treatment.  See Section 
2.5.4.2 for details of the sensitivity analyses which will be performed for safety variables.
Ocular and non-ocular findings (e.g. AEs) will be presented separately. All results related to 
ocular assessments will be presented using data from the study eye only, except for AEs where 
summaries will be presented separately for both the study eye and fellow eye.
Treatment emergent Adverse Events
The following describes the data to be recorded on the extension study eCRFs.
For patients where Core end of study visit date and Extension study first visit date occur on the 
same day the following data are recorded on the Adverse Event eCRF:
a) Events started during the core study and and ongoing at Extension study first visit 
date
b) Events occurring during the Extension Study
For patients where Core end of study visit date and Extension study first visit date do not occur 
on the same day the following data is recorded on the Adverse Event eCRF:
a) Events started during the core study and ongoing at Extension study first visit date
b) Events occurring during the Extension Study


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Note that AEs which start during the core study and end during the transition period are recorded 
on the Medical History eCRF not the Adverse Event eCRF.  Therefore these events are not
included in any AE summaries or listings but will be included in Medical History listings.
The study protocol states that, for each patient, AEs are collected after written informed consent 
for participation in the study has been provided until the end-of-study visit.
Treatment emergent AEs are defined as AEs which start on or after the time of the first injection 
of study treatment in this extension study and until the patient exits the study.
For treatment emergent AE analyses, separate summaries will be produced for ocular and non-
ocular events. Ocular events will be presented for the study eye and fellow eye separately. 
MedDRA Dictionary V20.1 will be used.
The number and percentage of patients who report treatment emergent AEs will be summarized 
by primary SOC and PT.
In addition, the following treatment emergent AE summaries will be presented using number 
and percent of patients:

SAEs by primary SOC and PT

AEs by maximum severity, primary SOC and PT

AEs resulting in treatment and/or study discontinuation by primary SOC and PT

AEs of potential relevance to intravitreal anti-VEGF class PT (according to the RTH258 
nAMD electronic case retrieval strategy (eCRS) at the time of the core study CRTH258-
C001 clinical database lock)

AEs by causal relationship to study treatment and ocular injection procedure by primary 
SOC and PT
Treatment emergent AEs will be listed for both treatment groups.
See Section 2.5.4.2 for details of the sensitivity analyses which will be performed for treatment 
emergent AEs.
AEs which start prior to the date/time of the first injection of study treatment in this extension 
study will be summarized using number and percent of patients by primary SOC and PT.  Prior 
AEs will be listed for both treatment groups.
Treatment emergent deaths will be summarized using counts and percentages by primary SOC
and PT.
All deaths including date and cause of death will be listed for both treatment groups.
AEs occurring during the last 6 months of the core study (defined as events with a start date on 
or after the date of core study Visit 19 /Week 68), for the patients included in the Extension 
Safety Set will be presented by core study treatment group (brolucizumab 3 mg, brolucizumab 
6 mg) using number and percent of patients. CoWeek 68 was chosen to consider the period 
between coWeek 68 and coWeek 96 as the last 6 months of the core study (actually 28 weeks) 
in order to reflect a similar exposure between brolucizumab patients since all of them were 
planned to receive 3 active injections during the period coWeek 68 to coWeek 96.


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The number and percentage of patients presenting AEs during the extension study and during 
the last 6 months of the core study will be displayed as well. The following summaries will be 
presented:

AEs by primary SOC and PT

SAEs by primary SOC and PT

AEs by maximum severity, primary SOC and PT

AEs resulting in treatment and/or study discontinuation by primary SOC and PT

AEs of potential relevance to intravitreal anti-VEGF class by category of events
(according to the RTH258 nAMD eCRS at the time of the CRTH258-C001 clinical 
database lock)

AEs of potential relevance to intravitreal anti-VEGF class by category of events  by AE
status during the core study (present, absent, ongoing) vs AE status during the extension 
study (present, absent, ongoing).
Note: 
1. Core study AE status = “ongoing” means that the AE was ongoing at coWeek 68.  
However, if a patient has an AE which is ongoing at coWeek 68 and this AE 
subsequently ends during the core study but then occurs again during the last 6 
months of the core study, this patient is counted under AE status during core study 
= “present” (“present” status supersedes “ongoing” status).
2. Extension study AE status = “ongoing” means that the AE was ongoing on the date 
of first injection of study treatment in the extension study (exBL).  However, if a 
patient has an AE which is ongoing on the date of first injection of study treatment 
in the extension study and this AE subsequently ends during the extension study but 
then occurs again during the extension study, this patient is counted under AE status 
during the extension study = “present” (“present” status supersedes “ongoing” status.

AEs by causal relationship to study treatment and ocular injection procedure by primary 
SOC and PT
Best-Corrected Visual Acuity
Counts and percentages of patients with a loss in BCVA ≥5, ≥10, ≥15, ≥ 30 letters from exBL
to each post-exBL study visit, and maximum loss at any visit will be presented. 
A listing of all patients with a ≥15 letter loss in BCVA from extension baseline to any post-
baseline visit will be presented. 
Anti-drug antibodies 
ADA status is defined using the following criteria:

ADA negative:
- ADA negative at all time points (pre-dose and post-dose)
- ADA negative at pre-dose and no titer values above 10 at all other time points


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- ADA titer of 10 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 30 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 ADA titer value will be presented by visit. The number and percent of patients induced or 
boosted according to their integrated ADA status will be presented.
 
Intraocular pressure
Pre-injection IOP and changes from extension baseline will be summarized descriptively by 
study visit. Post-injection IOP will be summarized descriptively by study visit and by injection 
type (active, sham). 
Summary tables with counts and percentage of patients with an IOP increase of ≥10, ≥20mmHg 
from pre-injection to post-injection will be presented by study visit, at the last visit, and at any 
visit. In addition, the number and percentage of patients with a post-injection IOP > 30mmHg 
will be presented by study visit, at the last visit and at any visit.  The IOP assessment performed
at approximately 30 minutes post-injection will be used for these summaries. 
A summary table with counts and percentage of patients with a pre-injection IOP ≥21mmHg 
in 3 consecutive scheduled visits will be presented. This will be repeated for patients with a 
post-injection IOP ≥ 21mmHg in 3 consecutive visits. In addition, the number and percentage 
of patients with a pre-injection IOP > 30mmHg will be presented by study visit, at the last visit 
and at any visit. 
IOP data will be listed for both treatment groups. In addition, a listing for patients with any 
post-injection IOP increase of ≥10mmHg from pre-injection IOP and a listing of patients with 
any IOP > 30mmHg will be presented.
Vital signs
Descriptive summaries of observed values and change from extension baseline to each study
visit in each vital sign parameter will be presented. 
A summary table with number and percentage of patients with clinically notable findings (see 
Table 2-1) will be presented by study visit, at the last visit and at any visit.


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Table 2-1
Clinically notable changes in vital signs
Variable
Category
Critical values
Systolic blood
pressure (mmHg)
High
Either >180 with an increase from extension baseline >30 or 
>200 absolute
Low
Either <90 with a decrease from extension baseline >30 or
<75 absolute
Diastolic blood
pressure (mmHg)
High
Either >105 with an increase from extension baseline >20 or 
>115 absolute
Low
Either <50 with a decrease from extension baseline > 20 or
<40 absolute
Pulse rate (bpm)
High
Either >120 with an increase from extension baseline of >25 or 
> 130 absolute
Low
Either <50 with a decrease from extension baseline >30 or
<40 absolute
A line plot of mean change from extension baseline in the vital sign parameter by study visit
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 extension baseline value.
A listing of all vital sign parameters will be presented for both treatment groups. In addition, a 
separate listing for patients satisfying at least one criterion in Table 2-1 will also be presented.
2.5.3
Handling of missing values/censoring/discontinuations
For the efficacy variables, BCVA and CSFT, missing data will be imputed using LOCF.
Observed values from both scheduled and unscheduled study visits will be used for the LOCF 
imputation. For patients with no post-exBL value, no imputation will be performed.
For patients who discontinue treatment but continue in the study, the efficacy data will be 
censored at the time the patient started alternative anti-VEGF treatment in the study eye.  Start 
date of an alternative anti-VEGF treatment will be identified using the Concomitant Medication 
eCRF where Standardized Medication Name (SAS variable name = CMDECOD) = 
"RANIBIZUMAB", "AFLIBERCEPT", "BEVACIZUMAB" or "PEGAPTANIB".  No other 
censoring is applied. Censored or missing data will be imputed by the last observation prior to 
receiving alternative anti-VEGF treatment.
Details regarding handling of missing values and discontinuations including the timing of 
censoring within the time-to-event analysis of the proportion of patients with a positive q12 
treatment status at exWeek 24 are specified in Section 2.5.2.1.
2.5.4
Sensitivity analyses
2.5.4.1
Efficacy variables
Best-Corrected Visual Acuity
Descriptive statistics for change from exBL in BCVA to each post-exBL study visit (and 
coWeek 96 visit).

With censoring of BCVA assessments after start of alternative anti-VEGF treatment in the 
study eye. No imputation with LOCF will be applied.


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All BCVA values (as imputed, as observed, as censored) will be listed.
Central Subfield Thickness
The change in CSFT from extension baseline to each post-baseline study visit will be 
summarized descriptively for the study eye with censored CSFT assessments after start of 
alternative anti-VEGF treatment in the study eye. No imputation with LOCF will be applied.
All CSFT values (as imputed, as observed, as censored) will be listed.
2.5.4.2
Safety variables
Treatment emergent Adverse Events
The following sensitivity analyses, will be conducted, in which, for patients who discontinue 
treatment but continue in the study, with application of alternative anti-VEGF treatment, their 
safety data are censored at the time the patient starts alternative anti-VEGF treatment.  That is, 
only safety data collected prior to receiving alternative anti-VEGF treatment will be used for 
these analyses (see Section 2.5.3 for further details regarding the identification of start date of 
alternative anti-VEGF treatment). Using number and percentage of patients the following 
summaries will be presented:

Treatment emergent AEs by primary SOC and PT

Treatment emergent SAEs by primary SOC and PT
Separate summaries will be produced for ocular and non-ocular events. Ocular AEs will be 
presented for the study eye and fellow eye separately. 
Additionally, for patients who received alternative anti-VEGF treatment, a listing of treatment 
emergent AEs for AEs with a start date after the patient received alternative anti-VEGF 
treatment will be presented by primary SOC and PT.  This will be repeated for SAEs.
2.6
Interim analysis
This analysis plan assumes that no IA will be performed.
3
Sample size calculation
Approximately 75 to 100 patients who completed study CRTH258-C001 are expected to be 
enrolled in this study. This sample size is not based on a power calculation and depends on the 
number of patients in the core study fulfilling the eligibility criteria of the extension study.
4
Change to protocol specified analyses

The protocol defined extension baseline as the value at Day 1. The definition has been 
changed to be “the last available value collected prior to the first treatment”.

The protocol defined that AEs would be summarized by safety topic of interest and 
preferred term using the eCRS.  Text has been added into this SAP to clarify that the 
eCRS to be used is the RTH258 nAMD eCRS at the time of the CRTH258-C001 clinical 
database lock.


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
Overall number of treatments will be presented for the entire extension period but not by
time period
5
Appendix
5.1
Imputation rules
5.1.1
AE date imputation
5.1.1.1
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.
If the imputed AE end date is less than the existing AE start date then use AE start date as AE 
end date.
5.1.1.2
AE start date imputation
The following table explains the notation used in the logic matrix. Please note that completely 
missing start dates will not be imputed.
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


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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).
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
Concomitant medication date imputation
5.1.2.1
Concomitant medication (CM) end date imputation
1. If the CM end date year value is missing, the date uncertainty is too high to impute a
rational date. Therefore, if the CM end year value is missing or ongoing, the imputed CM
end date is set to NULL.
2. Else, if the CM end date month is missing, the imputed end date should be set to the
earliest of the (treatment end date, 31DECYYYY, date of death).
3. If the CM end date day is missing, the imputed end date should be set to the earliest of the
(treatment end date, last day of the month, date of death).


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If the imputed CM end date is less than the existing CM start date, use the CM start date as the
imputed CM end date.
5.1.2.2
Concomitant medication start date
In order to classify a medication as prior and prior/concomitant, it may be necessary to impute 
the start date.
Completely missing start dates will be set to one day prior to treatment start date. As a 
conservative approach, such treatments will be classified as prior and concomitant (and 
summarized for each output).
Concomitant treatments with partial start dates will have the date or dates imputed.
The following table explains the notation used in the logic matrix
Day 
Month
Year
Partial CMD Start Date
Not used
MON
YYYY
Treatment Start Date
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY
MISSING
(1) Uncertain
(1) Uncertain
(1) Uncertain
(1) Uncertain
YYYY < TRTY
(2.a) Before 
Treatment Start 
(2.b) Before 
Treatment Start 
(2.b) Before 
Treatment Start 
(2.b) Before 
Treatment Start 
YYYY = TRTY
(4.a) Uncertain
(4.b) Before 
Treatment Start
(4.a) Uncertain
(4.c) After 
Treatment Start
YYYY > TRTY
(3.a) After 
Treatment Start
(3.b) After 
Treatment Start
(3.b) After 
Treatment Start
(3.b) After 
Treatment Start
1. If the CM start date year value is missing, the imputed CM start date is set to one day prior
to treatment start date.
2. If the CM start date year value is less than the treatment start date year value, the CM
started before treatment. Therefore:
a. If the CM month is missing, the imputed CM start date is set to the mid-year point
(01JulYYYY).
b. Else if the CM month is not missing, the imputed CM start date is set to the mid-month
point (15MONYYYY).
3. If the CM start date year value is greater than the treatment start date year value, the CM
started after treatment. Therefore:
a. If the CM month is missing, the imputed CM start date is set to the year start point
(01JanYYYY).


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b. Else if the CM month is not missing, the imputed CM start date is set to the month
start point (01MONYYYY).
4. If the CM start date year value is equal to the treatment start date year value:
a. And the CM month is missing or the CM month is equal to the treatment start date
month, then the imputed CM start date is set to one day prior to treatment start date.
b. Else if the CM month is less than the treatment start date month, the imputed CM start
date is set to the mid-month point (15MONYYYY).
c. Else if the CM month is greater than the treatment start date month, the imputed CM
start date is set to the month start point (01MONYYYY).
If complete (imputed) CM end date is available and the imputed CM start date is greater than
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM end 
date.
5.1.2.3
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.
If DIAG year < treatment start date year and DIAG month is missing, the imputed
   DIAG date is set to the mid-year point (01JULYYYY)
else if DIAG month is not missing, the imputed DIAG date is set to the mid-month
   point (15MONYYYY)
If DIAG year = treatment start date year
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
else if DIAG month < treatment start month, the imputed DIAG date is set to the mid-
month point (15MON YYYY)
else if DIAG month > treatment start month => data error
If DIAG year > treatment start date year => data error
5.2
Rules for exclusion from the Extension Safety Set
Protocol deviations are defined in the Protocol Deviations Requirements Document.  Table 5-
1 includes the protocol deviations which lead to exclusion of a patient from the Extension 
Safety Set:
Table 5-1
Protocol deviations leading to exclusion from the extension safety set
Deviation ID
Description of Deviation
Exclusion in Analyses
TRT01
Enrolled but no study drug administered
during the extension study
Exclude from Extension Safety Set


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5.3
Censoring rules for analysis of q12 treatment status at exWeek 
24
For the analysis of q12 treatment status at exWeek 24, Analysis Restrictions (ARs) will address 
the limitations in the patient’s evaluability resulting from missing or confounded data with an 
underlying background not qualifying as a PD, i.e. early study terminations, early treatment 
discontinuations, missed visits /treatments /assessments.
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)
The focus of the ARs is the identification of censoring related to the analysis of the q12 
proportion as derived from DAA and described in Section 2.5.2.1. Censoring is only applied 
in case the underlying reason for a confounded DAA is assessed as ‘0’.
ARs will be identified at the patient level by masked team members before DBL.
The following rules apply for handling missed injections/visits during the study (Unmasked 
Clinical Scientific Expert will perform AR/PD review and will present in masked fashion to 
masked clinical team to ensure appropriate PD or AR allocation):
a.
If a patient missed sham injection → not a PD or AR.
b. If a patient missed active treatment due to an AE related to study drug or study procedure 
with action taken “drug interrupted” or “drug withdrawn” → not a PD but an AR.
c.
If a patient missed active treatment due to AE not related to study drug or study procedure 
(e.g. fall and fractured hip) but which prevented the study visit from occurring, or had an 
ocular AE determined unrelated to study treatment / procedure but which prohibited safe 
administration of study treatment (e.g. blepharitis) → not a PD but an AR.
d. If a patient missed active treatment due to any other reason → a PD. 
e.
Allocation of AR
codes for early treatment discontinuations and early study 
discontinuations will be based on a totality of available patient data.
The following tables specify for all relevant protocol specifications and study assessments the 
criteria to be used for establishing whether a protocol deviation or analyis restriction has 
occurred and, if applicable, whether the AR has an effect on analysis (censoring for DAA).


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The Table 5-3 also highlights whether the PD is identified by the masked or unmasked study 
personnel.


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Table 5-2
Analysis Restrictions (ARs)
Analysis 
restriction 
(AR) 
Description of AR code
Censoring of 
DAA
Reason 
0=other
1=LoE
2=LoS
Comment 
AR_EST_01 
Early study termination due to lack 
of efficacy 
0
1
Early termination reason = lack of efficacy. 
Temporal mapping: first corresponding missed visit
AR_EST_02 
Early study termination due to lack 
of safety 
0
2
Early termination reason= AE; AE reviewed by clinical regarding link to 
treatment (lack of efficacy / safety)
Temporal mapping: first corresponding missed visit
AR_EST_03
Early study termination due to 
reasons other than lack of efficacy 
/ safety
0
0
Temporal mapping: first corresponding missed visit
AR_ETD_01 
Early treatment  discontinuation 
due to lack of efficacy 
0
1
Early discontinuation reason = lack of efficacy. Temporal mapping: first visit 
following the decision to stop treatment.  Missed treatments at the visit of 
decision are captured via an AR_TRT05 code. 
Remark: regarding the final DA status see Section 2.5.2.1
AR_ETD_02 
Early treatment discontinuation 
due to lack of safety
0
2
Early discontinuation reason= AE; AE reviewed by clinical regarding link to 
treatment (lack of efficacy / safety)
Temporal mapping: first visit following the decision to stop treatment. 
Missed treatments at the visit of decision are captured via an AR_TRT05 
code.
Remark: regarding the final DA status see Section 2.5.2.1


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Analysis 
restriction 
(AR) 
Description of AR code
Censoring of 
DAA
Reason 
0=other
1=LoE
2=LoS
Comment 
AR_ETD_03
Early treatment discontinuation 
due to reasons other than lack of 
efficacy / safety
0
0
Temporal mapping: first visit following the decision to stop treatment.  
Missed treatments at the visit of decision are captured via an AR_TRT05 
code. 
Case by case: Based on potential treatment patterns including the ‘q8-
need’ status it is assessed up to which visit the patient at minimum is 
treated as per protocol. 
Remark: there are no DAA after treatment discontinuation.
AR_TRT_05
Missed active treatment for 
reasons other than lack of efficacy 
or related safety event or PD 
(=TRT05)
3
0
Temporal mapping: first corresponding missed visit
AR_TRT_05_S Missed active treatment for 
related safety event
0
2
Temporal mapping: first corresponding missed visit
AR_TRT_05_E Missed active treatment due to 
lack of efficacy
0
1
Temporal mapping: first corresponding missed visit
For Reason in above table: LoE = lack of efficacy; LoS = lack of safety
*Censoring: 0=no censoring, 1=exclusion of value at PD visit, 2=censoring at visit preceding PD visit (exclusion of values from all visits starting from PD visit), 
3=censoring at PD visit (exclusion of values from all visits following the PD visit)


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Table 5-3
Protocol Deviations (PDs)
PD ID 
(Code)
Description of the ID Code
PD Category Description
Censoring of DAA Reason
0=other
1=LoE
2=LoS
Comment
INCL01
Study ICF not obtained prior to study related 
procedure(s) performed 
Selection criteria not met
0
0
INCL02
Pregnancy ICF not obtained prior to study 
related procedure(s) performed 
Selection criteria not met
0
0
INCL03
Patient entered the study > 12 weeks after 
completion of the core study
Selection criteria not met
0
0
EXCL01
Patient discontinued the core study 
prematurely
Selection criteria not met
0
0
EXCL02
Patient discontinued the treatment in the 
core study prematurely
Selection criteria not met
0
0
EXCL03
Patient received standard of care medication 
for nAMD in the study eye after completion 
of the core study
Selection criteria not met
0
0
EXCL04
Patient received investigational treatment 
for nAMD in the study eye after completion 
of the core study
Selection criteria not met
0
0
EXCL05
Patient received intraocular or periocular 
injection of steroids in the study eye after 
completion of the core study
Selection criteria not met
0
0
EXCL06
Patient received systemic anti-VEGF therapy 
after completion of the core study
Selection criteria not met
0
0


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PD ID 
(Code)
Description of the ID Code
PD Category Description
Censoring of DAA Reason
0=other
1=LoE
2=LoS
Comment
EXCL07
Patient has a systemic or ocular  medical 
condition or personal circumstance 
precluding study participation or compliance 
with study procedures
Selection criteria not met
0
0
EXCL08
Patient had a stroke or myocardial infarction 
within 3 months of Baseline visit
Selection criteria not met
0
0
EXCL09
Patient participated in an investigational 
drug, biologic, or device study within 30 days 
or 5 half-lives of the investigational drug 
prior to entering the extension
Selection criteria not met
0
0
EXCL10
Female patient was pregnant or nursing 
(lactating) at Baseline
Selection criteria not met
0
0
EXCL11
Female patient of child bearing potential and 
not using an effective method of 
contraception
Selection criteria not met
0
0
TRT01
Patient enrolled but no study drug 
administered
Treatment allocation
0
0
TRT02
Patient received wrong study drug 
Treatment allocation
3
0
TRT03
Patient received active treatment when 
schedule was for sham
Treatment allocation
0/3 (3 in relation 
to the second 
TRT03)
0
TRT04
Patient did not have disease activity but 
received active treatment
Treatment allocation
3
0
Overtreatment
TRT05
Patient missed active treatment for reasons 
other than lack of efficacy or any safety 
event
Treatment allocation
3
0


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PD ID 
(Code)
Description of the ID Code
PD Category Description
Censoring of DAA Reason
0=other
1=LoE
2=LoS
Comment
TRT06
Patient received sham when schedule was 
for active treatment
Treatment allocation
3
0
Undertreatment
TRT07
Patient received over-dose of study 
treatment at a single visit
Treatment allocation
0
0
TRT08
Patient was injected in the wrong eye (i.e. 
not "study eye")
Treatment allocation
0
0
OTH02
Masked personnel unmasked to study 
treatment assignment without subsequent
involvement in efficacy assessments
(BCVA and/or DAA)
Other
0
0
OTH03
Patient potentially unmasked
Other
3
0
OTH04
Unmasked personnel performed efficacy 
assessments
Other
2
0
OTH05
BCVA in the study eye not performed 
correctly
Other
0
0
OTH06
Pregnancy testing not performed 
Other
0
0
OTH07
ADA and/or systemic RTH258 testing  not 
drawn prior to injection 
Other
0
0
OTH08
Sham injection given with a needle
Other
0
0
OTH09
Injection administered although subject had 
active ocular or periocular infection and/or 
active intraocular inflammation
Other
0
0
OTH10
Injection procedure performed with 
potential risk to patient 
Other
0
0
COMD0
1
Prohibited ocular medication and/or 
procedure in the study eye
Conc. medication
3
0


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PD ID 
(Code)
Description of the ID Code
PD Category Description
Censoring of DAA Reason
0=other
1=LoE
2=LoS
Comment
COMD0
2
Prohibited systemic medication 
Conc. medication
0
0
COMD0
3
Investigational treatment in nonstudy eye
Conc. medication
0
0
WITH01 Patient became pregnant during the study 
but study treatment was not discontinued
Withdrawal
0
0
WITH02 Patient received anti-VEGF therapy in the 
study eye other than the IP but study 
treatment was not discontinued
Withdrawal
0
0
WITH03 Patient received intraocular or periocular 
injections of corticosteroids in the study eye 
but study treatment was not discontinued
Withdrawal 
0
0
WITH04 Patient received laser treatment for AMD in 
the study eye but study treatment was not 
discontinued
Withdrawal
0
0
WITH05 Patient received systemic anti-VEGF but 
study treatment was not discontinued
Withdrawal
0
0
WITH06 Patient received any systemic investigational 
drug, biologic or device but study treatment 
was not discontinued
Withdrawal
0
0
WITH07 The emergency unmasking has been done 
but study treatment was not discontinued
Withdrawal
0
0
For Reason in above table: LoE = lack of efficacy; LoS = lack of safety
*Censoring: 0=no censoring, 1=exclusion of value at PD visit, 2=censoring at visit preceding PD visit (exclusion of values from all visits starting from PD visit), 
3=censoring at PD visit (exclusion of values from all visits following the PD visit)