Conditions: Neovascular Age Related Macular Degeneration
Keywords: brolucizumab 6 mg prefilled syringe PFS open label study neovascular age related macular degeneration intravitreal injection IVT observation
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 34
Healthy volunteers: no

Brief summary:
This was a multicenter, open label study that is designed to evaluate the safety of brolucizumab 6 mg in a prefilled syringe in subjects with neovascular age related macular degeneration and to support collection of observations of the prefilled syringe use for intravitreal injection.

Detailed description:
The primary objective of this study was to evaluate the safety of brolucizumab 6 mg delivered in a pre-filled syringe (PFS) in subjects with neovascular age-related macular degeneration (nAMD) with the primary endpoint being the incidence of ocular and non-ocular adverse events (AEs). There were no other objectives for this study.

Arms:
arm 1: brolucizumab 6 mg in a prefilled syringe

Interventions: intervention 1: RTH258
Intervention descriptions: intervention 1: 6 mg in prefilled syringe

Protocol document:
Prot_000.pdf: 
Novartis Research and Development
RTH258
Clinical Trial Protocol CRTH258A2308 / NCT03930641
An Open-Label, Single-Arm, Multicenter, Phase IIIb Study in 
Patients With Neovascular Age-Related Macular 
Degeneration to Evaluate the Safety of Brolucizumab 6 mg 
in Prefilled Syringe 
Document type:
Amended Protocol Version
EUDRACT number:
NA
Version number:
01 (Clean)
Clinical Trial Phase:
IIIb
Release date:
11-Apr-2019
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template version 1.0 dated 01-Dec-2017


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................7
Amendment 1 ......................................................................................................................9
Protocol summary..............................................................................................................11
1
Introduction .......................................................................................................................13
1.1
Background............................................................................................................13
1.2
Purpose ..................................................................................................................14
2
Objectives and endpoints...................................................................................................14
3
Study design ......................................................................................................................14
4
Rationale............................................................................................................................15
4.1
Rationale for study design .....................................................................................15
4.2
Rationale for dose/regimen and duration of treatment ..........................................15
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................15
4.4
Purpose and timing of interim analyses/design adaptations..................................15
4.5
Risks and benefits..................................................................................................16
5
Population..........................................................................................................................16
5.1
Inclusion criteria ....................................................................................................16
5.2
Exclusion criteria...................................................................................................16
6
Treatment...........................................................................................................................18
6.1
Study treatment......................................................................................................18
6.1.1
Investigational and control drugs..........................................................18
6.1.2
Treatment arms/group ...........................................................................18
6.1.3
Treatment duration................................................................................18
6.2
Other treatment(s)..................................................................................................18
6.2.1
Concomitant therapy.............................................................................18
6.2.2
Prohibited medication ...........................................................................18
6.3
Subject numbering, treatment assignment, randomization....................................19
6.3.1
Subject numbering ................................................................................19
6.3.2
Treatment assignment, randomization ..................................................19
6.4
Treatment masking ................................................................................................19
6.5
Dose escalation and dose modification..................................................................19
6.6
Additional treatment guidance...............................................................................19


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6.6.1
Treatment compliance...........................................................................19
6.6.2
Emergency breaking of assigned treatment code..................................19
6.7
Preparation and dispensation.................................................................................19
6.7.1
Handling of study treatment and additional treatment..........................20
6.7.2
Instruction for prescribing and taking study treatment .........................20
7
Informed consent procedures ............................................................................................21
8
Visit schedule and assessments .........................................................................................21
8.1
Screening ...............................................................................................................23
8.1.1
Information to be collected on screening failures.................................23
8.2
Subject demographics/other baseline characteristics.............................................23
8.3
Efficacy..................................................................................................................23
8.4
Safety.....................................................................................................................23
8.4.1
Pregnancy and assessments of fertility .................................................24
9
Study discontinuation and completion ..............................................................................24
9.1
Discontinuation......................................................................................................24
9.1.1
Discontinuation of study treatment .......................................................24
9.1.2
Withdrawal of informed consent...........................................................24
9.1.3
Lost to follow-up...................................................................................25
9.1.4
Early study termination by the sponsor.................................................25
9.2
Study completion and post-study treatment ..........................................................25
10 Safety monitoring and reporting........................................................................................25
10.1
Definition of adverse events and reporting requirements......................................25
10.1.1
Adverse events ......................................................................................25
10.1.2
Serious adverse events ..........................................................................27
10.1.3
SAE reporting........................................................................................28
10.1.4
Pregnancy reporting ..............................................................................28
10.2
Additional Safety Monitoring................................................................................28
11 Data Collection and Database management......................................................................29
11.1
Data collection.......................................................................................................29
11.2
Database management and quality control............................................................29
11.3
Site monitoring ......................................................................................................29
12 Data analysis and statistical methods ................................................................................30
12.1
Analysis sets ..........................................................................................................30
12.2
Subject demographics and other baseline characteristics......................................30
12.3
Treatments .............................................................................................................30
12.4
Analysis of the primary endpoint(s) ......................................................................31
12.4.1
Definition of primary endpoint(s).........................................................31


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12.4.2
Statistical model, hypothesis, and method of analysis..........................31
12.4.3
Handling of missing values/censoring/discontinuations.......................31
12.4.4
Sensitivity and Supportive analyses......................................................31
12.5
Analysis of secondary endpoints ...........................................................................32
12.6
Interim analyses.....................................................................................................32
12.7
Sample size calculation..........................................................................................32
12.7.1
Primary endpoint(s)...............................................................................32
13 Ethical considerations and administrative procedures ......................................................32
13.1
Regulatory and ethical compliance........................................................................32
13.2
Responsibilities of the investigator and IRB/IEC..................................................32
13.3
Publication of study protocol and results...............................................................32
13.4
Quality Control and Quality Assurance.................................................................33
14 Protocol adherence ............................................................................................................33
14.1
Protocol Amendments ...........................................................................................33
15 References .........................................................................................................................34
16 Appendices ........................................................................................................................36


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List of tables
Table 2-1
Objectives and related endpoints ..........................................................14
Table 6-1
Investigational and control drug............................................................18
Table 6-2
Prohibited medication ...........................................................................19
Table 8-1
Assessment Schedule ............................................................................22
List of figures
Figure 3-1
Study design..........................................................................................15


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List of abbreviations
AE
adverse event
AMD
age related macular degeneration
Anti-
VEGF
anti-vascular endothelial growth factor
ATC
Anatomical Therapeutic Chemical
CFR
Code of Federal Regulation
CMO&PS
chief medical officer & patient safety
CNV
choroidal neovascularization
CRA
clinical research associate
CRO
Contract Research Organization
DDE
direct data entry
eCRF
electronic case report form
EDC
electronic data capture
EU
European Union
FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
IB
investigator brochure
ICH
International Council for Harmonization of Technical Requirements for Registration for 
Pharmaceuticals for Human Use
IEC
independent ethics committee
IFU
instruction for use
IN
investigator notification
IOP
intraocular pressure
IRB
institutional review board
IUD
intra-uterine device
IUS
intra-uterine system
IVT
intravitreal injection
MedDRA
Medical dictionary for regulatory activities
nAMD
neovascular age related macular degeneration
PFS
prefilled syringe
QMS
quality management system
RPE
retinal pigment epithelium
SAE
serious adverse event
ScFv
single-chain fragment variable
SD card
secure digital card
SMQ
standardized MedDRA query
SUSAR
Suspected Unexpected Serious Adverse Reactions
USA
United States of America
VEGF
vascular endothelial growth factor
WHO
World Health Organization
WOCBP
women of child bearing potential


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Glossary of terms
Additional 
treatment
Medicinal products that may be used during the clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g. any background 
therapy).
Assessment
A procedure used to generate data required by the study
Dosage
Dose of the study treatment given to the subject 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 subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol)
eSource
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines 
source documents and case report forms (eCRFs) into one application, allowing 
for the real time collection of clinical trial information to sponsors and other 
oversight authorities, as appropriate.
Investigational 
Drug
The study drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with 
"investigational new drug" or "test substance"
Medication 
number
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IRT system.
Observational 
Study Participant
Qualified ophthalmologist and assistants who may perform the preparation 
steps, to prepare and administer the PFS injection and to follow the IFU.
Patient
An individual with the condition of interest
Period
A minor subdivision of the study timeline; divides phases into smaller functional 
segments such as screening, baseline, titration, washout, etc.
Personal Data
Subject information collected by the Investigator that is transferred to Novartis 
for the purpose of the clinical trial. This data includes subject identifier 
information, study information and biological samples.
Screen Failure
A subject who is screened but is not treated or randomized
Source Data
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource.
Study completion
Point/time at which the subject came in for a final evaluation visit or when study 
drug was discontinued whichever is later.
Study treatment
Any drug (or combination of drugs) administered to the study participants as 
part of the required study procedures; includes investigational drug(s), control(s) 
or non-investigational medicinal product(s)
Subject
An individual who has consented to participate in this study. The term Subject 
may be used to describe either a healthy volunteer or a patient.
Subject number
A unique number assigned to each subject upon signing the informed consent. 
This number is the definitive, unique identifier for the subject and should be 
used to identify the subject throughout the study for all data collected, sample 
labels, etc.
Variable
Information used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints.


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Withdrawal of 
consent (WoC)
Withdrawal of consent from the study is defined as when a subject 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 
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Amendment 1
Amendment rationale
Based on Food and Drug Administration (FDA) feedback there was a need to change the sample 
size from the initially planned 10 subjects to 30. In addition, the exclusion criterion regarding 
prior intravitreal treatment was clarified, taking into account that available clinical evidence 
suggests that most of the subjects with neovascular age-related macular degeneration (nAMD) 
may need more frequent anti-vascular endothelial growth factor (anti-VEGF) injections, 
compared to other intravitreal treatments options. In addition, minor changes were made to the 
protocol language to provide clarity.
Changes to the protocol
5: population - page 14:
Change from:
The study population will be male and female subjects ≥ 50 years old who are diagnosed with 
nAMD. A minimum of 10 subjects are expected to be injected at approximately 3 sites in the 
United States of America.
Change to:
The study population will be male and female subjects ≥ 50 years old who are diagnosed with 
nAMD. Approximately 30 subjects are expected to be injected in approximately 3 sites at the 
United States of America.
5.1 Inclusion Criteria:
Add: definition of study population into sequence numbering; Inclusion # 3: Subjects ≥ 50 years 
of age at Baseline.
5.2 Exclusion Criteria:
Change Exclusion # 5 from:
Treatment with any intravitreal injection in the study eye within the past three months prior to 
enrollment. (Study eye is the eye eligible for intravitreal injection. If both eyes are eligible, one 
eye should be selected for injection at the discretion of the Investigator and according to clinical 
practice).
Change (split) to:
Treatment with anti-VEGF intravitreal injection in the study eye within one month prior to 
enrollment. (Study eye is the eye eligible for intravitreal injection. If both eyes are eligible, one 
eye should be selected for injection at the discretion of the Investigator and according to clinical 
practice).
Use of intraocular corticosteroids in the study eye during the 3-month period prior to enrollment.
These changes to the protocol are also reflected in the Summary on page 11 and 12.


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IRB Section
Institutional Review Board (IRB) approval for this protocol amendment will be requested and 
needs to be received prior to implementation of the amendment at the sites.


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Protocol summary
Protocol 
number
RTH258A2308
Full Title
An Open-Label, Single-Arm, Multicenter, Phase IIIb Study in Patients With 
Neovascular Age-Related Macular Degeneration to Evaluate the Safety of 
Brolucizumab 6 mg in Prefilled Syringe
Brief title
Study of the Safety of brolucizumab 6 mg in Prefilled Syringe in Patients with 
neovascular age related macular degeneration
Sponsor and 
Clinical Phase
Novartis Phase IIIb
Investigation 
Type
Drug
Study type
Interventional
Purpose and 
rationale
This is a multicenter, open label study that is designed to evaluate the safety of 
brolucizumab 6 mg in a prefilled syringe in subjects with neovascular age related 
macular degeneration and to support collection of observations of the prefilled 
syringe use for intravitreal injection. The use of the prefilled syringe will be 
observed by evaluating the ability of observational study participants, including 
qualified ophthalmologists and assistants who may perform the preparation 
steps, and to administer brolucizumab 6 mg in prefilled syringe via intravitreal 
injections to subjects and to follow the instructions for use.
Primary 
Objective(s) 
To evaluate the safety of brolucizumab 6 mg delivered in prefilled syringe in 
subjects with neovascular age related macular degeneration
Study Design
This is an open-label, single-arm, multicenter, phase IIIb study in subjects with 
neovascular age related macular degeneration
The Screening and Baseline Visit may be combined in one visit with one follow up 
visit after 7 days ± 2.
Each enrolled subject will receive one injection of brolucizumab 6 mg in a prefilled 
syringe.
Population
Approximately 30 subjects (males and females of at least 50 years of age) 
diagnosed with neovascular age related macular degeneration will be enrolled in 
the study in approximately 3 sites in the United States of America.
Key Inclusion 
criteria
1.
Written informed consent must be obtained before any assessment is 
performed.
2.
Study eye is diagnosed with neovascular age related macular degeneration 
and deemed to be indicated for intravitreal injection at the discretion of the 
retina specialist.
3.
Subjects ≥50 years of age at Baseline.
Key Exclusion 
criteria
1.
Any active intraocular or periocular or systemic infection or active intraocular 
inflammation in either eye at Baseline.
2.
Uncontrolled glaucoma in the study eye
3.
Participants legally blind in one or both eyes.
4.
History of a medical, ocular or non-ocular conditions, that in the judgment of 
the Investigator, would preclude a safe administration of investigational 
product.
5.
Treatment with anti-VEGF intravitreal injection in the study eye within one 
month prior to enrollment.


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6.
Use of intraocular corticosteroids in the study eye during the 3-month period 
prior to enrollment.
7.
Any invasive intraocular surgery, prior long-acting therapeutic agent, or 
ocular drug release device implantation (approved or investigational) in the 
study eye any time during the past 3 months.
8.
Receipt of any systemic anti-vascular endothelial growth factor within the 
last 6 months prior to enrollment.
9.
Uncontrolled hypertension.
Study 
treatment
Brolucizumab 6 mg in a prefilled syringe.
Key safety 
assessments
Incidence of ocular and non-ocular AEs are considered primary endpoints.
Other 
assessments 
Observation of the preparation and the injection using the prefilled syringe.
Data analysis
All safety analyses will be performed using the full analysis set.
Key words
Open label study, neovascular age related macular degeneration, intravitreal 
injection, brolucizumab prefilled syringe, observation.


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1
Introduction
1.1
Background
Age-related macular degeneration (AMD) is the leading cause of severe vision loss, affecting 
10% to 13% of individuals over the age of 65 in North America, Europe, and Australia 
(Kawasaki et al 2010, Rein et al 2009, Smith et al 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 (geographic atrophy) or dry 
form and the neovascular (exudative) or wet form (Ferris et al 1984, Lim et al 2012, 
Miller 2013). Neovascular AMD (nAMD) is characterized by the growth of abnormal new 
blood vessels (neovascularization) under the retinal pigment epithelium (RPE) or subretinal 
space 
from 
the 
subjacent 
choroid, 
termed 
choroidal 
neovascularization 
(CNV) 
(Ferris et al 1984). These newly formed vessels have an increased likelihood to leak blood and 
serum, damaging the retina by stimulating inflammation and scar tissue formation. This damage 
to the retina results in progressive, severe, and irreversible vision loss
(Shah and Del Priore 2007, Shah and Del Priore 2009). Without treatment, most affected eyes 
will have poor central vision (20/200) within 12 months (Blinder et al 2003). Although the 
neovascular form of the disease is only present in about 10% of all AMD cases, it accounted 
for approximately 90% of the severe vision loss from AMD prior to the introduction of anti-
vascular endothelial growth factor (anti-VEGF) treatments (Ferris 1983, Sommer et al 1991, 
Wong et al 2008, Spilsbury et al 2000, Bloch et al 2012, Campbell et al 2012).
Brolucizumab (RTH258, formerly ESBA1008) is a humanized single-chain (scFv) antibody 
fragment inhibitor of vascular endothelial growth factor with a molecular weight of ~26 kDa. 
Brolucizumab is an inhibitor of vascular endothelial growth factor - A (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 safety and efficacy of brolucizumab 6 mg in subjects with nAMD was evaluated in two 
pivotal studies (CRTH258A2301 [HAWK] and CRTH258A2302 [HARRIER]), with the 
primary objective of noninferiority in best corrected visual acuity of brolucizumab compared 
to aflibercept. Brolucizumab was demonstrated to be safe and well tolerated with an ocular and 
systemic safety profile similar to aflibercept and non-inferior efficacy as compared to 
aflibercept.
In these studies brolucizumab 6 mg was administered as an injection into the eye, and was 
available in a vial from which medication needed to be withdrawn using a standard syringe with 
a filter needle. The filter needle was then replaced by a smaller gauge needle for the intravitreal 
injection. Prefilled syringe eliminates the need for withdrawing medication from a vial and 
changing needles prior to use.
The Food and Drug Administration (FDA) recommended to evaluate the ability of intended 
users (qualified ophthalmologists and their assistants who may perform the preparation steps) 
the use of brolucizumab 6 mg prefilled syringe (PFS) formulation by following the Instructions 
for Use (IFU) in a certain number of subjects.


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Therefore, the current study will be performed for safety purposes and will support a sub-study 
type for collection of observations on PFS use for intravitreal injection. There will be two 
separate protocols as follows:

Current clinical protocol is designed to collect safety data obtained from the IVT 
injections conducted with the use of the PFS.

The observational study protocol
(provided separately, 
 
 
 is designed to evaluate the ability of observational study participants, including 
qualified ophthalmologists and assistants who may perform the preparation steps, to prepare 
and administer to subjects IVT injection using brolucizumab 6 mg PFS and to follow the 
IFU.
1.2
Purpose
This is a multicenter, open label study designed to evaluate the safety of brolucizumab 6 mg 
PFS in subjects with nAMD. This protocol describes the collection of safety data resulting from 
the use of brolucizumab 6 mg PFS.
Based on this study, a separate sub-study type protocol will collect observations of PFS use for 
intravitreal injection (IVT). The use of PFS will be observed by evaluating the ability of 
observational study participants, including qualified ophthalmologists and assistants who may 
perform the preparation steps, to prepare and administer to subjects an IVT injection using 
brolucizumab 6 mg PFS and to follow the IFU. These observations and evaluations will be 
performed according to observational study protocol 
 
. The results will be described in a separate 
report.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To evaluate the safety of brolucizumab 6 mg 
delivered in PFS in subjects with nAMD.

Incidence of ocular and non-ocular 
Adverse Events (AEs).
3
Study design
This study is an open-label, single arm, multicenter, phase IIIb study. Screening and Baseline 
visits may be performed on the same day. The Follow-up, which is End of Study is 7 days ± 2 
days after Baseline.
Subjects who consent will undergo all screening activities to evaluate their eligibility based on 
the Inclusion and Exclusion Criteria. Subjects who meet all criteria will receive:

Brolucizumab 6 mg in PFS, one injection.


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Figure 3-1
Study design
4
Rationale
4.1
Rationale for study design
This study is to evaluate the safety of the drug product in PFS where in addition under a separate 
observational protocol, the ability to follow the IFU and giving the brolucizumab injection in 
PFS to subjects with nAMD is observed. 
4.2
Rationale for dose/regimen and duration of treatment
Each subject who enters the study will be given one injection of brolucizumab 6 mg in PFS. 
Previously performed studies in this indication suggest that brolucizumab 6 mg dose is effective 
and safe. One injection will be given in order to support the observation of the successful use 
of the device (PFS). After this injection, the follow up visit at Day 8 will be performed and there 
will be a safety follow-up phone call at Day 31. Subjects will be considered to have completed 
the study after the evaluations at Visit 2. The investigator will recommend the appropriate 
follow-up medical care, as needed and according to the clinical practice, for all subjects who 
completed the study.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Control drugs (comparator/placebo) or combination drugs are not planned in this study.
4.4
Purpose and timing of interim analyses/design adaptations
An interim analysis is not planned for this study. 


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4.5
Risks and benefits
Brolucizumab is an inhibitor of VEGF with a mechanism of action similar to ranibizumab 
(LUCENTIS) 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 the 
ongoing Phase III studies (HAWK and HARRIER) and the drug substance intended for 
commercialization.
Further details of the known and potential risks and benefits associated with brolucizumab are 
presented in the Investigator Brochure.
The risks to subjects in this trial will be minimized by compliance with the eligibility criteria as 
well as close monitoring.
Women of child bearing potential (WOCBP) and sexually active males must be informed that 
taking the study treatment may involve unknown risks to the fetus if pregnancy were to occur 
during the study, and agree that in order to participate in the study they must adhere to the 
contraception requirements outlined in the exclusion criteria. If there is any question that the 
subject will not reliably comply, they should not be entered or continue in the study.
The intended commercial formulation has (only in vial) been used in the HAWK extension 
study (CRTH258A2301E1).
5
Population
The study population will be male and female subjects ≥ 50 years old who are diagnosed with 
nAMD. Approximately 30 subjects are expected to be injected at approximately 3 sites in the 
United States of America.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Study eye is diagnosed with nAMD and deemed to be indicated for intravitreal injection at 
the discretion of the retina specialist.
3. Subjects ≥50 years of age at Baseline.
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
1. Any active intraocular or periocular infection or active intraocular inflammation in either 
eye at Baseline.
2. Uncontrolled glaucoma in the study eye defined as intraocular pressure (IOP) > 25 mmHg 
on medication or according to Investigator’s judgment.
3. Participants legally blind in one or both eyes.
4. History of a medical conditions, ocular or non-ocular, that, in the judgment of the 
Investigator, would preclude a safe administration of investigational product.


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5. Treatment with anti-VEGF intravitreal injection in the study eye within one month prior to 
enrollment. (Study eye is the eye eligible for intravitreal injection. If both eyes are 
eligible, one eye should be selected for injection at the discretion of the Investigator and 
according to clinical practice).
6. The use of intraocular corticosteroids in the study eye during the 3-month period prior to 
enrollment.
7. Any invasive intraocular surgery, prior long-acting therapeutic agent, or ocular drug 
release device implantation (approved or investigational) in the study eye any time during 
the past 3 months.
8. Receipt of any systemic anti-VEGF within the last 6 months prior to enrollment.
9. Intolerance or known reaction to prior biological therapies.
10. Uncontrolled hypertension (systolic > 160 mmHg and/or diastolic > 100 mmHg) while 
sitting.
11. Current systemic infectious disease or a therapy for active infectious disease.
12. Pregnant or nursing (lactating) women or women of child-bearing potential (WOCBP) is 
defined as all women less than 1 year postmenopausal or less than 6 weeks since 
sterilization at Baseline, unless they are using highly effective methods of contraception 
during dosing of study treatment.
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, unless they are using highly effective methods of contraception while taking study 
treatment. Highly effective contraception methods include:

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.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study 
treatment. In case of oophorectomy alone, only when the reproductive status of the woman 
has been confirmed by follow up hormone level assessment.

Male sterilization (at least 6 months prior to screening). For female subjects on the study, 
the vasectomized male partner should be the sole partner for that subject.

Use of oral (estrogen and progesterone), injected, or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), 
or other forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example, hormone vaginal ring or transdermal hormone contraception.
In case of use of oral contraception, women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment No additional exclusions may be applied 
by the investigator, in order to ensure that the study population will be representative of all 
eligible subjects.
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 (eg 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 


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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.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible subjects.
6
Treatment
6.1
Study treatment
All subjects will receive one intravitreal injection of brolucizumab 6 mg PFS. A brolucizumab 
PFS kit will consist of a carton with a sterile sealed blister pack PFS. The IFU will be provided 
in the carton.
6.1.1
Investigational and control drugs
Table 6-1
Investigational and control drug
Investigational/
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor (global 
or local)
Brolucizumab 6 
mg
solution for 
injection
intravitreal 
injection
PFS
Novartis
6.1.2
Treatment arms/group
This is an open-label study where all subjects will receive one injection of brolucizumab 6 
mg PFS at Baseline.
6.1.3
Treatment duration
One injection of brolucizumab 6 mg PFS per subject will be administered at Baseline, with one 
End of Study follow up visit after 7 days (± 2 days).
6.2
Other treatment(s)
6.2.1
Concomitant therapy
All medications, procedures and significant non-drug therapies administered after the subject 
was enrolled into the study must be recorded on the appropriate electronic Case Report Forms 
(eCRF). As needed, treatment of the fellow eye will be performed according to clinical practice 
and the used medication or procedure should be reported in the eCRF.
6.2.2
Prohibited medication
Use of the treatments displayed in the below table is NOT allowed at the start of the 
investigational drug.


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Table 6-2
Prohibited medication
Medication
Prohibition period
Action taken
Anti-VEGF therapy other than 
IP in study eye
At Baseline
Discontinue study
Intraocular or periocular 
injections of corticosteroids
(except if treatment for AE) in 
study eye
At Baseline
Discontinue study
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
Each subject is identified in the study by a Subject Number (Subject No.) that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential subject 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the subject is assigned to the next sequential Subject 
No. available.
6.3.2
Treatment assignment, randomization
Treatment assignment and randomization is not applicable for this open-label study.
6.4
Treatment masking
This is an open-label study, therefore treatment will be open to subjects, investigator staff, and 
observational study participants including qualified ophthalmologists and their assistants and 
representatives of the sponsor.
6.5
Dose escalation and dose modification
Dose escalation and modification is not permitted in this study.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
The subject will receive only one intravitreal injection of brolucizumab 6 mg PFS performed 
by a qualified ophthalmologist. For this injection the appropriate eCRF will be completed.
6.6.2
Emergency breaking of assigned treatment code
Emergency breaking of assigned treatment code is not applicable, since this is an open label 
study, where each subject receives one injection of brolucizumab 6 mg via PFS.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs Section 6.1.1.


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A unique medication number is printed on the study medication label.
The study medication has a 2-part label (base plus tear-off label). Immediately before the IVT 
is performed, site personnel will detach the outer part of the label from the package and affix it 
to the subject’s source document.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the Investigator’s Brochure (IB). Clinical supplies are 
to be dispensed only in accordance with the protocol. Technical complaints are to be reported 
to the respective Novartis Country Organization Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Subjects will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment.
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
6.7.2
Instruction for prescribing and taking study treatment
The IVT injection will be carried out under controlled, aseptic conditions per local clinical 
practice. 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 subjects with active ocular-or periocular infections and in subjects with 
active intraocular inflammation; therefore, the investigator should verify that these conditions 
are not present in either eye (study and fellow eyes) prior to the injection.
All kits of study treatment will be recorded/databased. Date and time of every injection 
administered to the subject will be recorded in the eCRF.
Additionally, the conduct of IVT injections brolucizumab 6 mg PFS will be observed by an 
external team under observational protocol 
 
.


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7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (eg all of 
the procedures described in the protocol). The subject will also need to consent that the injection 
procedure and observation is video recorded. The process of obtaining informed consent must 
be documented in the subject source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with ICH/GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification (IN) 
or an aggregate safety finding. New information might require an update to the informed 
consent and then must be discussed with the subject.
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
8
Visit schedule and assessments
The Assessment Schedule (Table 8-1) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the subject's source document.
Subjects should be seen for all visits/assessments as outlined in the Assessment Schedule 
(Table 8-1) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. Subjects who prematurely discontinue the study 
for any reason should be scheduled for a visit as soon as possible, at which time all of the 
assessment of the final visit will be performed. At this final visit, the adverse event and 
concomitant medications should be recorded on the eCRF.


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Table 8-1
Assessment Schedule
Period
Open Label Treatment
Post-Treatment Follow-Up
Follow up
Visit Name
Baseline
End of Study
Follow up
Days
1
8
31
Informed consent
X
Inclusion / Exclusion criteria
X
Demography
X
Medical history/current medical 
conditions
X
Concomitant medications
X
X
Intraocular Pressure (IOP)
X
X
Vital Signs
X
X
Pregnancy Test
S
Study drug administration
X
Observation of PFS injection
S
Adverse Events
X
X
S
Ocular Assessments (slitlamp, 
ophthalmoscopy)
S
S
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only


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8.1
Screening
Subjects who sign an informed consent form, meet all of the inclusion and exclusion criteria, 
will receive one injection of Brolucizumab 6 mg PFS in the study eye at Baseline.
The conduct of the IVT injection and preparation will be observed and videotaped by 2 
observers and will follow observational study protocol
 
, which aims to assess the ability of 
observational study participants, including qualified ophthalmologists and assistants who may 
perform the preparation steps, to prepare and administer to subjects an IVT injection using 
brolucizumab 6 mg PFS and to follow the IFU.
Re-screening is not allowed in this protocol.
8.1.1
Information to be collected on screening failures
There is no separate screening period planned for this study. Subject's Eligibility will be 
assessed at the Baseline Visit. 
Subjects who sign an informed consent but do not receive the IVT injection will be considered 
a screen failure. The demographic information, informed consent, and Inclusion/Exclusion data 
must be completed in the eCRF and also be kept in the source documents for screen failure 
subjects. No further data will be entered into the clinical database for subjects who are screen 
failures, except if subject experienced a serious adverse event (see SAE section for reporting 
details).
8.2
Subject demographics/other baseline characteristics
The following data will be documented in the source document: age, sex, race, ethnicity, vital 
signs, study eye, IOP, date of nAMD diagnosis, concomitant medications, medical history, and 
current medical conditions.
8.3
Efficacy
Efficacy is not measured in this study. The usability assessments of PFS conducted within this 
study are specified in observational study protocol 
 
8.4
Safety
Safety evaluation will include ocular and non-ocular assessments (eg vital signs, IOP, slitlamp 
and ophthalmoscopy) and will be performed according to the clinical practice. Any clinically 
significant changes should be reported as AEs.
For details on AE collection and reporting, refer to Section 10.1.1.
The End of Study visit after 7 days (± 2) will be done at the site. The ocular assessments like 
slitlamp and ophthalmoscopy will be recorded in the source document and IOP will be entered 
in the eCRF. The non-ocular assessment (vital signs) will be recorded in the eCRF.


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Additionally, a follow-up phone call 30 days after the End of Study Visit will be performed for 
subjects with any ongoing AEs at the End of Study Visit. Any occurred adverse events in this 
period should be collected in the source, and SAEs must be reported to Novartis safety 
according instructions in Section 10.1.3.
8.4.1
Pregnancy and assessments of fertility
A urine pregnancy test will be conducted for all women of childbearing potential to assess 
pregnancy before inclusion in the study.
Additional pregnancy testing may be performed if requested by local requirements. 
9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
This is a single dose study, therefore discontinuation of study treatment is not applicable.
Subjects who decide they do not wish to participate in the study further should NOT be 
considered withdrawn from the study UNLESS they withdraw their consent (see withdraw of 
informed consent Section 9.1.2). Where possible, they should return for the assessments 
indicated in the assessment schedule. If they fail to return for these assessments for unknown 
reasons, every effort (eg telephone, e-mail, and letter) should be made to contact the subject/pre-
designated contact as specified in the lost to follow-up section. This contact should preferably 
be done according to the study visit schedule.
If the subject cannot or is unwilling to attend the follow up visit at Day 8, the site staff should 
maintain regular telephone contact with the subject, or with a person pre-designated by the 
subject. This telephone contact should preferably be done according to the study visit schedule.
9.1.2
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (eg telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.


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Novartis will continue to keep and use collected study information (including any data resulting 
from analysis of a subject's samples until the time of withdrawal) according to the applicable 
law.
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, eg dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed or until the end of the study.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety. Should early termination be 
necessary, subjects must be seen as soon as possible (provide instruction for contacting the 
subject, when the subject should stop taking drug, when the subject should come for a final 
visit) and treated as a prematurely withdrawn subject. The investigator may be informed of 
additional procedures to be followed in order to ensure that adequate consideration is given to 
the protection of the subject’s interests. The investigator or sponsor depending on the local 
regulation will be responsible for informing IRBs / IECs of the early termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes their End of Study Visit, and any 
repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the date 
of that decision.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (eg, 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. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.


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The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information (as far as possible) 
(if the event is serious refer to Section 10.1.2):
1. The severity grade includes the following: 
mild: usually transient in nature and generally not interfering with normal activities
moderate: sufficiently discomforting to interfere with normal activities
severe: prevents normal activities
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (ie progression of the study indication) the assessment of causality 
will usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single subject.
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported.
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met.
5. action taken regarding with study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

no action taken (further observation only)

Concomitant medication or non-drug therapy given.
6. its outcome 
a. not recovered/not resolved;
b. recovered/resolved;
c. recovering/resolving,
d. recovered/resolved with sequelae;
e. fatal; or unknown
Conditions that were already present at the time of informed consent should be recorded in 
medical history source document of the subject.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 30 days, following the injection.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (eg continuing at the end of the study), and assessment must be made at each visit 


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(or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator Brochure (IB).
10.1.2
Serious adverse events
A serious adverse event (SAE) is defined as any adverse event [appearance of (or worsening of 
any pre-existing)] undesirable sign(s), symptom(s) or medical conditions(s) which meets any 
one of the following criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, eg defined as an event that jeopardizes the subject or may require 
medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse. (Please refer to the ICH-
E2D Guidelines).
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
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All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.
10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis safety within 24 hours of learning of its occurrence. 
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a chief medical officer & patient 
safety (CMO & PS) Department associate may urgently require further information from the 
investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with European Union 
(EU) Guidance 2011/C 172/01 or as per national regulatory requirements in participating
countries.
Safety events occurring during the study will be reported as AEs in the eCRF. Device 
malfunction observations are to be reported to the respective Novartis Country Organization 
Quality Assurance.
10.1.4
Pregnancy reporting
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded and reported by the investigator to the Novartis CMO&PS. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment and any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported.
10.2
Additional Safety Monitoring
No additional safety monitoring is planned in this study.


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11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the eCRF. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
CFR Part 11 requirements, Investigator site staff will not be given access to the electronic data 
capture (EDC) system until they have been trained. Automatic validation programs check for 
data discrepancies in the eCRFs, allow modification and/or verification of the entered data by 
the investigator staff.
The investigator/designee is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. The Investigator must 
certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
11.2
Database management and quality control
Novartis personnel or designated Contract Research Organization (CRO) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated investigator 
site staff are required to respond promptly to queries and to make any necessary changes to the 
data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical (ATC) classification system. Medical history/current medical conditions 
and adverse events will be coded using the Medical dictionary for regulatory activities 
(MedDRA) terminology.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for data analysis. Any changes to 
the database after that time can only be made after written agreement by Novartis development 
management.
11.3
Site monitoring
Before study initiation, at a site initiation visit a Novartis representative will review the protocol 
and data capture requirements (ie eSource direct data entry (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 subject records, the accuracy of data capture/data 
entry, the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, 
and to ensure that study treatment is being stored, dispensed, and accounted for according to 


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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 subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments, including the secure digital (SD) card, properly labelled with the subject number, 
containing the video taken from the injection procedure. All information on eCRFs must be 
traceable to these source documents in the subject’s file. The investigator must also keep the 
original informed consent form signed by the subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria,
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed.
12
Data analysis and statistical methods
12.1
Analysis sets
The Full Analysis Set (FAS) includes all enrolled subjects who receive a dose of study 
treatment.
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data will be listed and summarized descriptively for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. Relevant medical 
histories and current medical conditions at baseline will be summarized by system organ class 
and preferred term for all subjects.
12.3
Treatments
Descriptive summary statistics for exposure to study treatment will be provided for the FAS. 
The cumulative number of IVT injections will be presented for the period baseline to Day 8.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system for all subjects.


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12.4
Analysis of the primary endpoint(s)
12.4.1
Definition of primary endpoint(s)
Incidence of ocular and non-ocular AEs are considered primary endpoints.
12.4.2
Statistical model, hypothesis, and method of analysis
No formal hypothesis tests will be performed in this study. All safety analyses will be performed 
using the FAS.
Adverse events
The number (and percentage) of subjects with treatment-emergent adverse events (events 
started after the single dose of study treatment or events present prior to start of study treatment 
but which increased in severity based on preferred term) will be summarized in the following 
ways:

by treatment, primary system organ class and preferred term

by treatment, primary system organ class, preferred term and maximum severity

by treatment, Standardized MedDRA Query (SMQ) and preferred term
Separate summaries will be provided for study treatment related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation of the study. Separate 
presentations will be provided related to ocular events in the study eye and fellow eye and 
systemic events. Additional summaries will be provided by severity and causality (separately 
assessed for the injection procedure and the drug). Subject listings of all adverse events will be 
provided. Deaths and other serious or clinically significant non-fatal adverse events will be 
listed separately.
A subject with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.
Ophthalmic examinations
Pre-injection and post-injection IOP measurements will be listed.
Vital signs
All vital signs data will be listed by subject and, if ranges are available, abnormalities will be 
flagged with thresholds representing clinical relevant abnormality.
12.4.3
Handling of missing values/censoring/discontinuations
This is a single dose, open-label study with two scheduled visits over the period of one week. 
Therefore, missing data will not be imputed. Analysis of the primary endpoint will include all 
subjects in the FAS as defined in Section 12.1.
12.4.4
Sensitivity and Supportive analyses
This section is not applicable.


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12.5
Analysis of secondary endpoints
Based on the study design, analysis of secondary endpoints is not applicable.
12.6
Interim analyses
No interim analysis is planned for this study.
12.7
Sample size calculation
12.7.1
Primary endpoint(s)
No formal statistical power calculations to determine sample size were performed for this study.
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (eg, 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis/ Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (eg Clinicaltrials.gov, EudraCT etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the initiation visit.


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13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.
14.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


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15
References
References are available upon request
Blinder KJ, Bradley S, Bressler NM, et al (2003) Effect of lesion size, visual acuity, and 
lesion composition on visual acuity change with and without verteporfin therapy for choroidal 
neovascularization secondary to age-related macular degeneration: TAP and VIP report no. 1. 
Am. J. Ophthalmol. p. 407-18.
Bloch SB, Larsen M, Munch IC (2012) Incidence of legal blindness from age-related macular 
degeneration in denmark: year 2000 to 2010. Am. J. Ophthalmol. p. 209-213.e2.
Campbell JP, Bressler SB, Bressler NM (2012) Impact of availability of anti-vascular 
endothelial growth factor therapy on visual impairment and blindness due to neovascular age-
related macular degeneration. Arch. Ophthalmol. p. 794-5.
Ferris FL (1983) Senile macular degeneration: review of epidemiologic features. Am. J. 
Epidemiol. p. 132-51.
Ferris FL, Fine SL, Hyman L (1984) Age-related macular degeneration and blindness due to 
neovascular maculopathy. Arch. Ophthalmol. p. 1640-2.
Kawasaki R, Yasuda M, Song SJ, et al (2010) The prevalence of age-related macular 
degeneration in Asians: a systematic review and meta-analysis. Ophthalmology p. 921-7.
Lim LS, Mitchell P, Seddon JM, et al (2012) Age-related macular degeneration. Lancet p. 
1728-38.
Miller JW (2013) Age-related macular degeneration revisited--piecing the puzzle: the LXIX 
Edward Jackson memorial lecture. Am. J. Ophthalmol. p. 1-35.e13.
Rein DB, Wittenborn JS, Zhang X, et al (2009) Forecasting age-related macular degeneration 
through the year 2050: the potential impact of new treatments. Arch. Ophthalmol. p. 533-40.
Shah AR, Del Priore LV (2009) Natural history of predominantly classic, minimally classic, 
and occult subgroups in exudative age-related macular degeneration. Ophthalmology p. 1901-
7.
Shah AR, Del Priore LV (2007) Progressive visual loss in subfoveal exudation in age-related 
macular degeneration: a meta-analysis using Lineweaver-Burke plots. Am. J. Ophthalmol. p. 
83-89.
Smith W, Assink J, Klein R, et al (2001) Risk factors for age-related macular degeneration: 
Pooled findings from three continents. Ophthalmology p. 697-704.
Sommer A, Tielsch JM, Katz J, et al (1991) Racial differences in the cause-specific 
prevalence of blindness in east Baltimore. N. Engl. J. Med. p. 1412-7.
Spilsbury K, Garrett KL, Shen WY, et al (2000) Overexpression of vascular endothelial 
growth factor (VEGF) in the retinal pigment epithelium leads to the development of choroidal 
neovascularization. Am. J. Pathol. p. 135-44.


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


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16
Appendices
Appendices are not applicable for this study.

SAP_001.pdf: 
Clinical Development
RTH258/brolucizumab
RTH258A2308 / NCT03930641
An Open-Label, Single-Arm, Multicenter, Phase IIIb Study in 
Patients With Neovascular Age-Related Macular 
Degeneration to Evaluate the Safety of Brolucizumab 6 mg 
in Prefilled Syringe 
Statistical Analysis Plan (SAP)
Author:
, 
Document type:
SAP Documentation
Document status:
Amendment 1
Release date:
9-Aug-2019
Number of pages:
13
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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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome of update
Section and title impacted 
(Current)
9 Aug 
2019
Prior 
to 
DBL
Data is coded with 
MedDRA V21.1
References 
to 
“most 
recent version at the time 
of 
DBL” 
changed 
to 
reflect Version 21.1 is 
used
S2.3.2 Subject demographics 
and baseline characteristics
S2.4.2 Prior, concomitant and 
post therapies
S2.8.1 Adverse events
9 Aug 
2019
Prior 
to 
DBL
Sites have entered 
events prior to IFC 
on the eCRF
Text updated to reflect 
prior non-drug therapies 
and 
procedures
are 
included in the listing
S2.4.2 Prior, concomitant and 
post therapies
9 Aug 
2019
Prior 
to 
DBL
Criteria 
changed 
from increase ≥ 20 
mmHg from pre-
injection 
IOP 
to 
post-injection IOP 
within a visit to an 
increase 
≥ 
10 
mmHg
Text stating the criteria is 
updated
Section 
2.8.3.1 Intraocular 
pressure (IOP) (mmHg)
9 Aug 
2019
Prior 
to 
DBL
Imputation 
of 
partial 
dates 
for 
medications is not 
required for
any 
analyses
Section 5.1.2 removed
S5.1.2 
Concomitant 
medication date imputation


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Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
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
2.2.1
Subgroup of interest ................................................................................7
2.3
Subject disposition, demographics and other baseline characteristics ....................8
2.3.1
Subject disposition ..................................................................................8
2.3.2
Subject demographics and baseline characteristics.................................8
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)..............................................................................................................8
2.4.1
Study treatment / compliance..................................................................8
2.4.2
Prior, concomitant and post therapies.....................................................8
2.5
Analysis of the primary objective............................................................................8
2.5.1
Primary endpoint.....................................................................................8
2.5.2
Statistical hypothesis, model, and method of analysis............................9
2.5.3
Handling of missing values/censoring/discontinuations.........................9
2.5.4
Supportive analyses.................................................................................9
2.6
Analysis of the key secondary objective .................................................................9
2.7
Analysis of secondary efficacy objective(s)............................................................9
2.8
Safety analyses.........................................................................................................9
2.8.1
Adverse events ........................................................................................9
2.8.2
Deaths....................................................................................................10
2.8.3
Other safety data ...................................................................................10
2.9
Other Exploratory analyses....................................................................................11
2.10
Interim analysis......................................................................................................11
3
Sample size calculation .....................................................................................................11
4
Change to protocol specified analyses ..............................................................................11
5
Appendix ...........................................................................................................................12
5.1
Imputation rules.....................................................................................................12
5.1.1
AE date imputation ...............................................................................12
5.2
Statistical models...................................................................................................13


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5.3
Rule of exclusion criteria of analysis sets..............................................................13
6
Reference...........................................................................................................................13


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List of abbreviations
AE
Adverse event
ATC
Anatomical Therapeutic Classification
CM
Concomitant medication
CSR
Clinical Study report
DBL
Database Lock
eCRF
Electronic Case Report Form
FAS
Full Analysis Set
IOP
Intraocular pressure
MedDRA
Medical Dictionary for Drug Regulatory Affairs
nAMD
Neovascular Age-Related Macular Degeneration
PFS
Prefilled Syringe
PT
Preferred Term
SAP
Statistical Analysis Plan
SOC
System Organ Class
WHO
World Health Organization


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1
Introduction
This document contains details of the statistical analyses planned in Section 12 of the protocol
that will be presented in the clinical study report (CSR). It also contains details of the analyses 
to be performed for CT.gov which will not be presented in the CSR.
This statistical analysis plan (SAP) is based Protocol version number 01 (amended protocol) 
dated 11th April 2019
1.1
Study design
This study is an open-label, single arm, multicenter, phase IIIb study. Screening and Baseline 
visits may be performed on the same day. The Follow-up, which is End of Study is 7 days ± 2 
days after Baseline.
Subjects who consent will undergo all screening activities to evaluate their eligibility based on 
the inclusion and exclusion criteria. Subjects who meet all inclusion criteria and none of the 
exclusion criteria will receive:

Brolucizumab 6 mg prefilled syringe (PFS), one injection.
The study population will be male and female subjects ≥ 50 years old who are diagnosed with 
neovascular age-related macular degeneration (nAMD). Approximately 30 subjects are 
expected to be injected at approximately 3 sites in the United States of America.
Randomization is not applicable for this open-label study.
The primary analysis will be conducted after database lock (DBL).
No interim analyses are planned.
1.2
Study objectives and endpoints
The primary objective and endpoint is given in Table 1-1 below:
Table 1-1
Objectives and related endpoints
Objective
Endpoints
Primary objective
Endpoints for primary objective

To evaluate the safety of brolucizumab 6 mg 
delivered in PFS in subjects with nAMD.

Incidence of ocular and non-ocular 
Adverse Events (AEs).
There are no secondary endpoints.
2
Statistical methods
2.1
Data analysis general information
The final analysis will be performed by Novartis using SAS Version 9.4.
Categorical variables will be presented as frequencies and percentages. For continuous data, the 
mean, standard deviation, median, lower quartile, upper quartile, minimum and maximum will 
be presented.


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2.1.1
General definitions
The term ‘study treatment’ refers to brolucizumab 6 mg (PFS).
2.1.1.1
Study day
Study day is defined as the number of days since the date of the injection of study treatment. 
The date of the injection of study treatment will be defined as Day 1 and the day before the 
injection of study treatment will be defined as Day −1.
Therefore, for a particular date, study day will be calculated as follows: 

For dates on or after the date of the injection of study treatment,
Study day = Visit/Assessment date −date of injection of study treatment + 1

For dates prior to the date of the injection of study treatment,
Study day = Visit/Assessment date −date of injection of study treatment
2.1.1.2
Baseline definition
Baseline is defined as the last measurement/value before the injection of study treatment.  
2.1.1.3
Post-baseline definition
Post-baseline measurements are defined as assessments after the injection of study treatment.
When change from baseline is of interest the following formula will be used for each scheduled 
visit where baseline and post-baseline values are both available:
Change from baseline = post-baseline value −baseline value
2.1.1.4
End of study/treatment
The end of study date for a subject is the date when a subject completes or discontinues the 
study. 
2.1.1.5
Missing dates
Details on handling missing dates are shown in Section 5.
2.2
Analysis sets
The only analysis set defined is the Full Analysis Set (FAS) which will include all enrolled 
subjects who receive an injection of study treatment. 
The FAS will be used for the analysis of all variables.
2.2.1
Subgroup of interest
No subgroup analyses will be conducted.


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2.3
Subject disposition, demographics and other baseline 
characteristics
2.3.1
Subject disposition
The number of subjects screened and treated will be summarized.
The number and percentage of subjects who complete or discontinue from the study will be 
summarized including the reasons for discontinuation.
The number and percentage of subjects with protocol deviations will be summarized by 
deviation category (selection criteria not met, subject not withdrawn as per protocol, treatment 
deviation, prohibited concomitant medication, other). 
2.3.2
Subject demographics and baseline characteristics
Age at study entry (as a continuous variable), gender, race and ethnicity will be summarized
descriptively and listed.
The following baseline ocular characteristic will be summarized for the study eye:

primary diagnosis of nAMD
This baseline ocular characteric will be listed for the study eye and fellow eye.
Medical histories and current medical conditions will be coded with the Medical Dictionary for 
Regulatory Activities terminology (MedDRA) Version 21.1. All medical histories and current 
medical conditions will be listed.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
The total number of subjects who received an injection of study treatment will be presented.
2.4.2
Prior, concomitant and post therapies
Medications will be coded according to the Anatomical Therapeutic Chemical (ATC) 
classification system.
Non-drug therapies and procedures will be coded using MedDRA Version 21.1. 
Prior and concomitant medications and  non-drug therapies and procedures will be listed.
2.5
Analysis of the primary objective
2.5.1
Primary endpoint
The incidence of ocular and non-ocular AEs are the primary endpoints. The primary endpoints 
will be analyzed for the FAS.


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2.5.2
Statistical hypothesis, model, and method of analysis
No formal hypothesis testing will be performed in this study. 
See Section 2.8.1 for details of the analyses to be performed for AEs.
2.5.3
Handling of missing values/censoring/discontinuations
This is a single dose, open-label study with 2 scheduled visits over the period of 1 week. 
Therefore, missing data will not be imputed. 
2.5.4
Supportive analyses
Not applicable.
2.6
Analysis of the key secondary objective
No key secondary objectives are defined for this study. 
2.7
Analysis of secondary efficacy objective(s)
No secondary objectives are defined for this study. 
2.8
Safety analyses
All safety analyses will be performed for the FAS.
2.8.1
Adverse events 
AEs will be coded using MedDRA Version 21.1. 
All AEs will be listed. 
Summaries will include all treatment emergent AEs which are defined as AEs which start on or 
after the date of the injection of study treatment up until the patient discontinues or completes 
the study.
Analyses will be performed for ocular AEs for the study eye only and non-ocular AEs. Ocular 
and non-ocular AEs will be presented separately. Ocular AEs for the fellow eye will be listed 
only.
The number and percentage of subjects who reported treatment emergent AEs will be 
summarized by primary SOC and PT for:

all AEs

all AEs by maximum severity

all AEs by investigator causality assessment (relationship to study treatment and/or study 
treatment administration procedure)

AEs leading to study discontinuation

all serious adverse events (SAE)


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If a subject reports more than one AE with the same PT, the AE will be counted only once for 
that PT. If a subject reports more than one AE within the same primary SOC, the subject will 
be counted only once for that SOC.
2.8.1.1
Adverse event reporting for CT.gov 
For the legal requirements of clinicaltrials.gov, two required tables on treatment emergent AEs
which are not SAEs with an incidence greater than or equal to x% (default is 5% but a lower 
cut off may be applied and this will be determined based on the final data) and on treatment 
emergent SAEs will be provided by SOC and PT for the FAS.
If for the same subject, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:
a single occurrence will be counted if there is ≤1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE
more than one occurrence will be counted if there is > 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE/non SAE has to be checked in a block e.g. 
among AE's in a ≤1 day gap block, if at least one SAE is occurring, then one occurrence is 
calculated for that SAE.
2.8.2
Deaths
A summary of treatment emergent deaths will be presented by primary SOC and PT.
All deaths recorded in the clinical database will be listed.
2.8.3
Other safety data
2.8.3.1
Intraocular pressure (IOP) (mmHg)
All IOP measurements will be listed for subjects who fulfil at least one of the following criteria:

IOP > 30 mmHg

Increase ≥ 10 mmHg from pre-injection IOP to post-injection IOP within a visit
2.8.3.2
Vital signs
All vital signs measurements will be listed for subjects who fulfil at least one of the following 
clinically notable criteria:
Table 2-1
Clinically notable criteria for vital signs
Variable
Category
Critical Values
Systolic blood 
pressure (mmHg)
High
Either >180 with an increase from baseline >30 or >200 absolute
Low
Either <90 with a decrease from baseline >30 or
<75 absolute
Diastolic blood
pressure (mmHg)
High
Either >105 with an increase from baseline >20 or >115
absolute


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Variable
Category
Critical Values
Low
Either <50 with a decrease from baseline > 20 or
<40 absolute
Pulse rate (bpm)
High
Either >120 with an increase from baseline of >25 or >130
absolute
Low
Either <50 with a decrease from baseline >30 or
<40 absolute
2.9
Other Exploratory analyses
No exploratory objectives are defined for this study. 
2.10
Interim analysis
No interim analysis is planned for this study.
3
Sample size calculation
No formal statistical power calculations to determine sample size were performed for this study.
4
Change to protocol specified analyses
Protocol section 12.2 states that relevant medical histories and current medical conditions at 
baseline will be summarized.  Given the small sample size this data will be listed only.
Protocol section 12.3 states that descriptive statistics for exposure to study treatment and the 
cumulative number of injections will be presented. As subjects are only scheduled to receive a 
single injection of study treatment the total number of patients who received an injection will 
be presented.
Protocol section 12.3 states that concomitant medications and significant non-drug therapies 
prior to and after the start of the study treatment will be summarized. Given the small sample 
size this data will be listed only.
Protocol section 12.4.2 states that treatment emergent AEs will be summarized by SMQ and 
PT.  This summary will not be produced, treatment emergent AEs will be presented by SOC 
and PT only.
Protocol section 12.4.2 states that AE presentations will be presented for the fellow eye.  
Adverse events for the fellow eye will be listed only.  
Protocol section 12.4.2 states that pre-injection and post-injection IOP measurements will be 
listed. Instead, IOP measurements will only be listed for subjects who have at least IOP 
measurement meeting the criteria defined in SAP Section 2.8.3.1.
Protocol section 12.4.2 states that all vital signs data will be listed. Instead, vital signs 
measurements will only be listed for subjects who have at least one vital signs measurement 
meeting the criteria defined in SAP Section 2.8.3.2.


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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 
rational date. Therefore, if the AE year value is missing, the imputed AE start date is set
to NULL.


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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.
5.2
Statistical models
No hypothesis testing will be performed for this study.
5.3
Rule of exclusion criteria of analysis sets 
Only one analysis set is defined, the FAS. No protocol deviations are defined which lead to 
exclusion from the FAS.
6
Reference
Not applicable.