A Single-Arm, Open-Label, Multicenter, Phase IIIb Study to Collect Safety and Electrocardiogram Data on Brolucizumab 6 mg Intravitreal Treatment in Patients With Neovascular Age-Related Macular Degeneration
Phase: PHASE3
Conditions: Age-Related Macular Degeneration, Macular Degeneration, Wet Macular Degeneration, Retinal Degeneration, Retinal Diseases, Eye Diseases
Sponsor: Novartis Pharmaceuticals

Novartis Institutes for BioMedical Research
RTH258/brolucizumab
Clinical Trial Protocol CRTH258A2309
A Single-Arm, Open-Label, Multicenter, Phase IIIb Study to 
Collect Safety and Electrocardiogram Data on 
Brolucizumab 6 mg Intravitreal Treatment in Patients with 
Neovascular Age-Related Macular Degeneration
Document type:
Clinical Trial Protocol
EUDRACT number:
N/A
Version number:
00 (Original Protocol)
Clinical trial phase:
IIIb
Release date:
13-Mar-2019
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 2.0 (01-Aug-2018)

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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................4
List of figures ......................................................................................................................4
List of abbreviations............................................................................................................5
Glossary of terms.................................................................................................................8
Protocol summary..............................................................................................................10
1
Introduction .......................................................................................................................12
1.1
Background............................................................................................................12
1.2
Purpose ..................................................................................................................13
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 ..........................................16
4.3
Rationale for choice of control drugs ....................................................................16
4.4
Purpose and timing of interim analyses/design adaptations..................................16
4.5
Risks and benefits..................................................................................................16
4.5.1
Blood sample volume............................................................................16
5
Population..........................................................................................................................17
5.1
Inclusion criteria ....................................................................................................17
5.2
Exclusion criteria...................................................................................................17
6
Treatment...........................................................................................................................19
6.1
Study treatment......................................................................................................19
6.1.1
Investigational drug...............................................................................19
6.1.2
Additional study treatments ..................................................................19
6.1.3
Treatment arms/group ...........................................................................19
6.2
Other treatment(s)..................................................................................................19
6.2.1
Concomitant therapy.............................................................................19
6.2.2
Prohibited medication after Screening..................................................20
6.2.3
Restriction for study subjects................................................................20
6.3
Subject numbering, treatment assignment, randomization....................................21
6.3.1
Subject numbering ................................................................................21
6.3.2
Treatment assignment, randomization ..................................................21
6.4
Treatment blinding.................................................................................................22
6.5
Dose escalation and dose modification..................................................................22

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6.6
Additional treatment guidance...............................................................................22
6.6.1
Treatment compliance...........................................................................22
6.6.2
Recommended treatment of adverse events..........................................22
6.6.3
Emergency breaking of assigned treatment code..................................22
6.7
Preparation and dispensation.................................................................................23
7
Informed consent procedures ............................................................................................23
8
Visit schedule and assessments .........................................................................................24
8.1
Screening ...............................................................................................................26
8.1.1
Information to be collected on screening failures.................................26
8.2
Subject demographics/other baseline characteristics.............................................26
8.3
Efficacy..................................................................................................................26
8.4
Safety.....................................................................................................................26
8.4.1
Laboratory evaluations..........................................................................27
8.4.2
Electrocardiogram (ECG) .....................................................................28
8.4.3
Pregnancy and assessments of fertility .................................................28
8.4.4
Ophthalmic examination.......................................................................28
8.4.5
Appropriateness of safety measurements..............................................29
8.5
Additional assessments..........................................................................................29
9
Study discontinuation and completion ..............................................................................30
9.1
Discontinuation......................................................................................................30
9.1.1
Discontinuation of study treatment .......................................................30
9.1.2
Withdrawal of informed consent...........................................................30
9.1.3
Lost to follow-up...................................................................................31
9.1.4
Early study termination by the sponsor.................................................31
9.2
Study completion and post-study treatment ..........................................................31
10 Safety monitoring and reporting........................................................................................32
10.1
Definition of adverse events and reporting requirements......................................32
10.1.1
Adverse events ......................................................................................32
10.1.2
Serious adverse events ..........................................................................33
10.1.3
SAE reporting........................................................................................34
10.1.4
Pregnancy reporting ..............................................................................35
10.1.5
Reporting of study treatment errors including misuse/abuse................35
10.2
Additional Safety Monitoring................................................................................36
11 Data collection and database management........................................................................36
11.1
Data collection.......................................................................................................36
11.2
Database management and quality control............................................................37

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11.3
Site monitoring ......................................................................................................37
12 Data analysis and statistical methods ................................................................................38
12.1
Analysis sets ..........................................................................................................38
12.2
Subject demographics and other baseline characteristics......................................38
12.3
Treatments .............................................................................................................38
12.4
Analysis of the primary endpoint(s) ......................................................................38
12.4.1
Definition of primary endpoint(s).........................................................38
12.4.2
Statistical model, hypothesis, and method of analysis..........................38
12.4.3
Handling of missing values/censoring/discontinuations.......................39
12.4.4
Sensitivity and Supportive analyses......................................................39
12.5
Analysis of secondary endpoints ...........................................................................39
12.5.1
Safety endpoints....................................................................................39
12.6
Interim analyses.....................................................................................................39
12.7
Sample size calculation..........................................................................................39
12.7.1
Primary endpoint(s)...............................................................................39
13 Ethical considerations and administrative procedures ......................................................40
13.1
Regulatory and ethical compliance........................................................................40
13.2
Responsibilities of the investigator and IRB/IEC..................................................40
13.3
Publication of study protocol and results...............................................................40
13.4
Quality Control and Quality Assurance.................................................................40
14 Protocol adherence ............................................................................................................41
14.1
Protocol amendments.............................................................................................41
15 References .........................................................................................................................42
List of tables
Table 2-1
Objectives and endpoints ......................................................................14
Table 6-1
Investigational drug...............................................................................19
Table 6-2
Prohibited medication ...........................................................................20
Table 6-3
Blinding and unblinding plan................................................................22
Table 8-1
Assessment Schedule ............................................................................24
Table 8-2
Assessments and Specifications............................................................27
Table 8-3
Laboratory Assessments........................................................................27
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................36
List of figures
Figure 3-1
Study Design .........................................................................................15

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List of abbreviations
ADA
anti-drug antibodies
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AMD
age related macular degeneration
anti-VEGF
antivascular endothelial growth factor
AST
aspartate aminotransferase
AV
atrioventricular
BCVA
best corrected visual acuity
bpm
beats per minute
CFR
code of federal regulations
CMO & PS
Chief Medical Office and Patient Safety
CNV
choroidal neovascularization
CRA
clinical research associate
CrCL
creatinine clearance
CRF
case report form
CRO
clinical research organization
e.g.
for example
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EMA
European Medicines Agency
EOS
end of study
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FU
follow up
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
h
hour
HDL
high-density lipoprotein

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i.e.
that is
ICF
informed consent form
ICH
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IOP
intraocular pressure
IRB
Institutional Review Board
IVT
intravitreal
kDa
kilodalton
LAMA
long-acting muscarinic antagonist
LDH
low-density lipoproteins
LABA
long-acting beta adrenergic
mAbs
monoclonal antibodies
MDRD
modification of diet in renal disease study
MedDRA
medical dictionary for regulatory activities 
μL
microliter(s)
mg
milligram(s)
mL
milliliter(s)
mmHg
millimeters of mercury
ms
millisecond
OU 
both eyes
PMDA
Pharmaceuticals and Medical Devices Agency
q4w
every 4 weeks
RBC
red blood cell
RPE
retinal pigment epithelium
SAE
serious adverse event
SAP
statistical analysis plan
scFv
single-chain Fv
SE
study eye
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SOM
study operations manual

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SUSAR
suspected unexpected serious adverse reaction
US
United States
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of child bearing potential

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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study subject 
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
End of the clinical trial
The end of the clinical trial is defined as the last visit of the last subject or 
at a later point in time as defined by the protocol
Enrollment
Point/time of subject entry into the study at which informed consent must 
be obtained 
Investigational drug/
treatment
The drug whose properties are being tested in the study
Medication number
A unique identifier on the label of medication kits
Other treatment
Treatment that may be needed/allowed during the conduct of the study 
(i.e. concomitant or rescue therapy)
Patient
An individual with the condition of interest for the study
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and 
will be used in clinical trial database setup and eventually in analysis
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. 
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this 
time all study drug administration is discontinued and no further 
assessments are planned
Screen Failure
A subject who did not meet one or more criteria that were required for 
participation in the study
Study operational 
manual (SOM)
SOM provides additional operational guidance/details for study 
procedures and is not part of the Clinical Study Report
Source 
Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource
Start of the clinical trial
The start of the clinical trial is defined as the signature of the informed 
consent by the first subject
Study treatment
Any single drug or combination of drugs or intervention administered to 
the subject as part of the required study procedures
Study treatment 
discontinuation
When the subject permanently stops taking any of the study drug(s) prior 
to the defined study treatment completion date (if any) for any reason; 
may or may not also be the point/time of study discontinuation 
Subject
A trial participant 

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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.
Withdrawal of study 
consent (WoC)
Withdrawal of consent from the study occurs only when a subject does not 
want to participate in the study any longer and does not allow any further 
collection of personal data 

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Protocol summary
Protocol number
CRTH258A2309
Full Title
A Single-Arm, Open-Label, Multicenter, Phase IIIb Study to Collect Safety 
and Electrocardiogram Data on Brolucizumab 6 mg Intravitreal Treatment 
in Patients with Neovascular Age-Related Macular Degeneration
Brief title
Study to collect safety and ECG data on Brolucizumab 6 mg Intravitreal 
Treatment in Patients with wet AMD
Sponsor and Clinical 
Phase
Novartis/IIIb
Investigation type
Biologic
Study type
Interventional
Purpose and rationale
The purpose of this study is to collect ECG data after a single IVT injection 
of brolucizumab 6 mg in patients with neovascular age-related macular 
degeneration (nAMD).
Primary Objective(s) 
The primary objective of this study is to collect information on ECG after 
intravitreal injection of brolucizumab 6 mg in patients with nAMD. 
Secondary Objectives
The secondary objective is to collect safety data after intravitreal injection 
of brolucizumab 6 mg in patients with nAMD. 
Study design
This is a single-arm, open-label, multicenter study to collect ECG data 
after a single IVT injection of brolucizumab 6 mg in patients with nAMD.
Total study duration for each patient is up to 8 days.
Population
The study population will consist of male and female patients with nAMD. 
Approximately 10-15 patients ≥ 50 years old are expected to be enrolled 
in the US and Puerto Rico.
Key Inclusion criteria

Signed informed consent MUST be obtained prior to 
participation in the study

Study eye is diagnosed with nAMD and deemed to be eligible 
for intravitreal injection at the discretion of the Investigator

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Key Exclusion criteria

Treatment with any ocular intravitreal injection in the study eye 
within the past 7 half-lives prior to Baseline

Diagnosis of ECG abnormalities including:

Clinically significant cardiac arrhythmias, e.g., atrial 
fibrillation, sustained ventricular tachycardia, and clinically 
significant second or third degree AV block without a 
pacemaker

Familial long QT syndrome or known family history of 
Torsades de Pointes

Resting heart rate < 50 or > 90 bpm at screening

Resting QTcF ≥450 ms (male) or ≥460 ms (female) at 
screening

Use of concomitant medications that are classified as known 
risk, conditional risk or possible risk to prolong QT/QTc interval 
within 7 half-lives of the drug prior to baseline

History of stroke (including transient ischemic attack, reversible 
ischemic neurological deficit, prolonged reversible ischemic 
neurological deficit) or myocardial infarction (ST or non-ST 
elevation myocardial infarction) at any time prior to baseline

Chronic kidney disease as determined as a CrCL at screening 
of < 60 ml/min/1.73 m2 as determined by the MDRD formula

Uncontrolled high blood pressure defined as a systolic value 
≥140 mmHg or diastolic value ≥90 mmHg at screening or 
baseline

Systemic anti-VEGF therapy during the 6-month period prior to 
baseline

Electrolyte disturbances determined as out of normal range 
sodium, potassium or calcium serum concentrations at 
screening 
Study treatment
RTH258 (brolucizumab)
Efficacy assessments
Not applicable
Key safety 
assessments
Electrocardiogram (ECG), Holter ECG Monitoring, Vital Signs, Ophthalmic 
Exam 
(including 
Intraocular 
Pressure, 
Biomicroscopy, 
and 
Ophthalmoscopy), Physical Exam, Screening Labs (Hematology, Clinical 
Chemistry, and Pregnancy)
Data analysis
There are no formal hypotheses in this study. Incidences between 20 
and 24 h post-injection of clinically relevant treatment emergent changes 
in HR, PR, QRS, and QTc interval will be listed by patient. The 
frequency and proportion of patients with QTcF > 450, 480, and 500 ms 
between 20 and 24 h post-injection will be summarized. 
Key words
neovascular age-related macular degeneration, AMD, nAMD, wet AMD, 
RTH258, brolucizumab, ECG, open-label

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1
Introduction
1.1
Background
Age-related macular degeneration (AMD) is a chronic eye disease characterized by progressive 
degenerative abnormalities in the central retina (macula) and is the leading cause of severe 
vision loss in people affecting 10%-13% of individuals over the age of 65 years 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 (Wong et al 2014).
AMD is classified into 2 clinical subtypes: the non-neovascular (atrophic) or dry form and the 
neovascular (exudative) or wet form (Ferris et al 1984; Lim et al 2012; Miller 2013). 
Neovascular AMD 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). 
VEGF has been shown to be elevated in patients with neovascular AMD, and is thought to play 
a key role in the neovascularization process (Spilsbury et al 2000). The use of intravitreal (IVT) 
pharmacotherapy targeting VEGF has significantly improved visual outcomes in patients with 
neovascular AMD (Bloch et al 2012; Campbell et al 2012). Anti-VEGF treatments, such as 
ranibizumab (LUCENTIS®) and aflibercept (EYLEA®), inhibit VEGF signaling pathways and 
have been shown to halt the growth of neovascular lesions and resolve retinal edema.
Brolucizumab
Brolucizumab (RTH258, formerly ESBA1008) is a humanized single-chain Fv (scFv) antibody 
fragment inhibitor of vascular endothelial growth factor with a molecular weight of ~26 kDa. 
Brolucizumab is an inhibitor of VEGF-A and works by binding to the receptor binding site of 
the VEGF-A molecule, thereby preventing the interaction of VEGF-A with its receptors 
VEGFR1 and VEGFR2 on the surface of endothelial cells.
A low molecular weight (a surrogate for hydrodynamic radius) should increase drug distribution 
into the target site of action, ensuring effective control of anatomical disease activity. This could 
potentially translate into a more durable efficacy and a reduced treatment burden (number of 
injections) for the patient and health care professional.
Brolucizumab in nAMD
In a single ascending dose Phase I study (C-10-083), the median time until patients fulfilled 
protocol defined criteria for receipt of standard of care treatment was 30 days longer for 
brolucizumab 6 mg (P = 0.036) versus ranibizumab, with the maximum effect on best-corrected 
visual acuity (BCVA) and central subfield thickness (CSFT) reached at Week 6 for 
brolucizumab versus Week 4 for ranibizumab. In a separate repeat dosing Phase II study 

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(C-12-006, OSPREY) comparing brolucizumab 6 mg (n = 44) every 8 weeks (q8w), then every 
12 weeks (q12w) administration, i.e. administration every q8w and q12w, respectively, against 
aflibercept (q8w administration, n = 45), brolucizumab achieved comparable visual outcome 
during the loading and q8w phase, with a lower number of patients requiring additional rescue 
treatments (5 out of 44 versus 10 out of 45, respectively). Brolucizumab demonstrated a trend 
for greater improvements and more stability in retinal anatomy during the 4 cycles of q8w 
dosing (up to Week 40).
In the Phase III Studies RTH258-C001 (HAWK) and RTH258-C002 (HARRIER), 
brolucizumab demonstrated non-inferiority to aflibercept in mean change in BCVA from 
baseline to Week 48 in both trials using a non-inferiority margin (NIM) of 4 letters. In both 
studies, the treatment effect observed at Week 48 was largely maintained up to the end of the 
study (Week 96) in all treatment arms and results for BCVA-related secondary endpoints at 
Week 96 were overall comparable with those at Week 48. These results were achieved while a 
majority of patients on brolucizumab 6 mg – 56% in HAWK and 51% in HARRIER – were 
maintained on a q12w (every 12 weeks) dosing interval following the loading phase (baseline 
to Week 8) through Week 48. Patients in the brolucizumab 6 mg treatment group who were on 
q12w at Week 44 revealed probabilities of 81.5 % and 75.4% to remain on q12w up to week 92 
in HAWK and HARRIER, respectively. Brolucizumab 6 mg achieved superior reductions in 
CSFT versus aflibercept in both the head-to-head and maintenance phases (P = 0.0016 and 
P = 0.0023 at Week 16 and Week 48, respectively, in HAWK; P < 0.0001 at both Week 16 and 
Week 48 in HARRIER). The greater reductions in CSFT observed at Week 48 with 
brolucizumab 6 mg or 3 mg compared to patients treated with aflibercept 2 mg were maintained 
through Week 96. Brolucizumab safety was comparable to aflibercept, with the overall 
incidence of adverse events (AEs) balanced across all treatment groups in both studies.
This study, CRTH258A2309, is an ECG collection study on request of the Pharmaceuticals and 
Medical Devices Agency (PMDA) of Japan. Patients from US and Puerto Rico, 50 years old or 
greater, diagnosed with nAMD will be eligible to participate. All enrolled patients will receive 
one (1) intravitreal dose of brolucizumab 6 mg at baseline and will be observed over a study 
period of 8 days with a follow up phone call on day 31. 
1.2
Purpose
The purpose of this study is to collect ECG data after a single IVT injection of brolucizumab 
6 mg in patients with neovascular age-related macular degeneration (nAMD).

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2
Objectives and endpoints
Table 2-1
Objectives and endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)
Endpoint(s) for primary objective(s) 

To collect information on ECG after 
intravitreal injection of brolucizumab 6 mg 
in patients with nAMD

Incidence between 20 and 24 h post-injection 
of clinically relevant treatment emergent 
changes in HR, PR, QRS, and QTc (heart rate 
corrected QT using Fridericia’s formula, 
QTcF) interval (ms)
Secondary Objective(s)
Endpoint(s) for secondary objective(s)

To collect safety data after intravitreal 
injection of brolucizumab 6 mg in patients 
with nAMD

Any ocular and non-ocular AEs (including 
clinically relevant ECG abnormalities) until the 
end of the study 
3
Study design
This is a single-arm, open-label, multicenter study to collect ECG data after a single IVT 
injection of brolucizumab 6 mg in patients with nAMD.
All patients must provide informed consent before any study-specific procedure is performed. 
At the Screening and Baseline visits, patients are evaluated for study eligibility based on the 
inclusion/exclusion criteria. Patients who meet all the inclusion and none of the exclusion 
criteria will receive one single intravitreal injection (IVT) of brolucizumab 6 mg during the 
treatment phase of the study.
Triplicate 12-lead ECG recording will be performed at screening to determine eligibility. 
A second triplicate 12-lead ECG recording will be collected approximately 2h prior to the 
brolucizumab IVT injection on Day 1. Holter ECG recording will start approximately 1 h prior 
to the brolucizumab IVT injection and will end approximately 48h after the IVT injection. 
A third triplicate 12-lead ECG recording will be performed after the conclusion of Holter 
monitoring on Day 3.
The final study assessments will be performed at end of study (EOS) visit on Day 8, i.e. 1 week 
after injection. The EOS visit will be performed via a telephone call. Total study duration for 
each patient is up to 8 days. Additionally, a safety follow-up phone call will be performed on 
Day 31. Any AEs starting between Day 9 and Day 31 are collected in the source documents. 
All SAEs MUST be reported to Novartis safety according to instructions in Section 10.1.3 SAE 
reporting.

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Figure 3-1
Study Design
4
Rationale
4.1
Rationale for study design
This multicenter study is designed to meet the request of the Pharmaceuticals and Medical 
Devices Agency (PMDA) of Japan to provide ECG data on approximately 10-15 patients  at 
the time at which maximum systemic concentration is reached (Tmax) after a single injection 
of brolucizumab 6 mg. The study design, study duration, and patient population were assessed 
as adequate to meet the agency’s request. The study is NOT a thorough QT study. The patient 
population is described in Section 5 Population below. 
Furthermore, monoclonal antibodies (mAbs) are not expected to directly inhibit the function of 
ion channels responsible for cardiac repolarization; therefore, thorough QT studies are generally 
not required for biotherapeutics (Malik et al 2010). There are no known preclinical 
cardiovascular safety signals with brolucizumab. The systemic exposure was confirmed to be
very low in human with a median AUCinf (Area under the concentration-time curve from time 
zero to infinity) of 5580 ng*h/mL (Investigator’s Brochure). 
Approximately 1 h before a single injection of brolucizumab, a Holter monitor will provide 
continuous ECG monitoring for 48h; capturing the approximate time at which maximum 
systemic concentration is reached (median Tmax was approximately 24 hours post dose). 
A single injection is deemed sufficient because it was previously shown in the RTH258A2201 
study that brolucizumab does not accumulate in the systemic circulation after repeated monthly 
injections (SHRIKE, RTH258E003). 
Additionally long-term ECG data is being collected in an ongoing large Phase III study of 
brolucizumab 3 mg or 6 mg in Japanese patients with diabetic macular edema, CRTH258B2301.
ECG data for the CRTH258B2301 study is collected at baseline and after 52 and 100 weeks of 
first treatment with brolucizumab 3 mg, 6 mg or aflibercept.

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4.2
Rationale for dose/regimen and duration of treatment
The dose and regimen for brolucizumab are based on the following considerations:

Brolucizumab is well tolerated at a dose of 6 mg, based on the previous clinical Phase III 
program in which 1088 patients with nAMD received brolucizumab.

Brolucizumab 6 mg is the maximum feasible dose for a 50 μL IVT injection based on 
brolucizumab physico-chemical properties and is the highest dose that has been tested. 
Brolucizumab 6 mg provides the higher systemic exposure after IVT injection as 
compared to the different dose strengths previously investigated in patients and is foreseen 
as the therapeutic dose. Thus, the proposed dose and route are appropriate to generate 
ECG data in its target population with brolucizumab.
4.3
Rationale for choice of control drugs
Not applicable. 
4.4
Purpose and timing of interim analyses/design adaptations
Not applicable.
4.5
Risks and benefits
Intravitreal brolucizumab 6 mg has been administered to 1355 patients with nAMD for up to 
2 years treatment. Further details of the known and potential risks and benefits associated with 
brolucizumab are presented in the RTH258/brolucizumab Investigator’s Brochure.
All intravitreal injection procedures carry the risk of endophthalmitis, retinal detachment, 
vitreous or retinal hemorrhage, cataract, elevated intraocular pressure, and ocular inflammation. 
These conditions are apparent on eye exam and most cause symptoms that prompt the patient
to seek immediate evaluation. With respect to endophthalmitis, current best clinical practices 
are used to reduce the risk of endophthalmitis. Despite these practices, endophthalmitis rates 
may approximate 1 in 1,000 to 1 in 20,000.
As with any antibody, brolucizumab may carry the risk of anaphylaxis or hypersensitivity 
reactions and may also elicit the formation of human anti-drug antibodies (ADA).
The risk to patients in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring.
4.5.1
Blood sample volume
Approximately 6 mL of blood is planned to be collected over a period of up to 14 days 
(during Screening), from each patient as part of study screening. Additional samples may be 
required for safety monitoring.
The timing of blood sample collection is outlined in the Assessment Schedule (Table 8-1).
A summary blood log is provided in the Site Operations Manual (SOM).

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5
Population
The study population will consist of male and female patients with nAMD. 
Approximately 10-15 patients ≥ 50 years old are expected to be enrolled in the US and 
Puerto Rico.
5.1
Inclusion criteria
Patients eligible for inclusion in this study must meet all of the following criteria at screening:
1. Signed informed consent MUST be obtained prior to participation in the study
2. Study eye is diagnosed with nAMD and deemed to be eligible for intravitreal injection at 
the discretion of the Investigator
5.2
Exclusion criteria
Patients meeting any of the following criteria are NOT eligible for inclusion in this study.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
1. Concomitant conditions or ocular disorders in the study eye at screening which may cause 
safety concerns on the judgement of the investigator
2. Any active intraocular or periocular or systemic infection or active intraocular 
inflammation at Baseline
3. Treatment with any ocular intravitreal injection in the study eye within the past 
7 half-lives prior to Baseline
4. 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 prior to Baseline
5. Diagnosis of ECG abnormalities including:

Clinically significant cardiac arrhythmias, e.g., atrial fibrillation, sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker

Familial long QT syndrome or known family history of Torsades de Pointes

Resting heart rate < 50 or > 90 bpm at screening

Resting QTcF ≥450 ms (male) or ≥460 ms (female) at screening
6. Use of concomitant medications that are classified as known risk, conditional risk or 
possible risk to prolong QT/QTc interval within 7 half-lives prior to Baseline
7. History of stroke (including transient ischemic attack, reversible ischemic neurological 
deficit, prolonged reversible ischemic neurological deficit) or myocardial infarction (ST or 
non-ST elevation myocardial infarction) at any time prior to baseline
8. Chronic kidney disease as determined as a CrCL at screening of < 60 ml/min/1.73 m2 as 
determined by the MDRD formula
9. Uncontrolled high blood pressure defined as a systolic value ≥140 mmHg or diastolic 
value ≥90 mmHg at screening or baseline
10. Systemic anti-VEGF therapy during the 6-month period prior to baseline

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11. Electrolyte disturbances determined as out of normal range sodium, potassium or calcium 
serum concentrations at screening 
12. Concomitant intake of long-acting muscarinic antagonist (LAMA)/ long-acting beta 
adrenergic (LABA) combination therapy
13. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
classes as assessed by the investigator
14. Use of systemic or ocular (including intravitreal) investigational drugs within 7 half-lives 
of baseline, (or within 30 days/until the expected pharmacodynamic effect has returned to 
baseline), whichever is longer or longer if required by local regulations (observational 
clinical studies solely involving over-the-counter vitamins, supplements, or diets are not 
exclusionary)
15. Pregnant or nursing (lactating) women
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 patient. 
Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 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 patients on the study, 
the vasectomized male partner should be the sole partner for that patient

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 the case of use of oral contraception, women must be stable on the same pill for a minimum 
of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks ago. 
In the case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child-bearing 
potential.
If local regulations deviate from the contraception methods listed above to prevent pregnancy, 
local regulations apply and is described in the informed consent form (ICF).

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6
Treatment
6.1
Study treatment
Investigational product (IP) must be stored at 2° to 8°C (35.6° to 46.4°F); DO NOT FREEZE; 
protect from light.
Details on the requirements for storage and management of study treatment, and instructions for 
patient numbering, prescribing/dispensing and taking study treatment are outlined in the SOM. 
6.1.1
Investigational drug
Table 6-1
Investigational drug
Investigational Drug
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor (global or 
local)
Brolucizumab 
(RTH258)
6 mg / 0.05 mL
Solution for injection
Intravitreal 
Injection
Glass Vials
(in open label 
patient kit)
Novartis (global)
Brolucizumab (RTH258) will be provided to the study sites in a single use, sterile glass vial 
containing sufficient brolucizumab to deliver a 6 mg dose when administering a volume of 0.05 
mL. The content of the study drug vials must not be split (single use vials). Novartis will provide 
sufficient supplies of brolucizumab for treatment use to allow for completion of the study.
6.1.2
Additional study treatments
No other investigational treatment beyond the single injection of brolucizumab 6 mg is included 
in this trial.
6.1.3
Treatment arms/group
All eligible patients enrolled in this trial will receive a single injection of brolucizumab 6 mg at 
the Baseline visit (Day 1). 
6.2
Other treatment(s)
Treatment after the completion of the study follows current standard of care or PI discretion. 
Standard of care includes non-investigational therapies that are used according to clinical 
practice for the treatment of nAMD in the US or Puerto Rico. Other treatments, including 
off-label use and other clinical interventional trials or managed access programs, are prescribed
or recommended under the responsibility of the investigator.
6.2.1
Concomitant therapy
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the patient was enrolled into the study must be recorded 
on the appropriate Case Report Forms (CRFs).

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Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started. If the patient is already 
enrolled, the investigator must contact Novartis to determine if the patient should continue 
participation in the study.
6.2.2
Prohibited medication after Screening
Use of the treatments displayed in the below table are NOT allowed after screening.
Table 6-2
Prohibited medication
Medication
Prohibition period
Action taken
QT prolonging agent*
From Screening to Day 8
(EOS) visit
Study 
discontinuation
Anti-VEGF therapy other than assigned 
study medication in both eyes†
From Screening to Day 8 
(EOS) visit
Study 
discontinuation
Systemic Anti-VEGF therapy
From Screening to Day 8 
(EOS) visit
Study 
discontinuation
Intraocular or periocular injections of 
corticosteroids (except if treatment for AE) 
in both eyes
From Screening to Day 8 
(EOS) visit
Study 
discontinuation
*Please refer to https://crediblemeds.org/pdftemp/pdf/CombinedList.pdf
†During the study, if the fellow eye develops visual impairment, it may also be treated with 
standard of care (i.e. treatment of the fellow eye with anti-VEGF medication other than 
brolucizumab) at the discretion of the investigator. If the fellow eye treatment is required before 
Day 8, then the patient will be early discontinued from the trial.
6.2.3
Restriction for study subjects
For the duration of the study, patients should be informed and reminded of the restrictions 
outlined in this section. The below advices are suggested guidelines. 
Nonconformity to these advices will NOT result in a protocol deviation.
6.2.3.1
Dietary restrictions and smoking
1. No alcohol for 24 hours before dosing until after the study evaluation on Day 3.
2. No cannabis or cannabidiol oil containing products for 24 hours before dosing until after 
the study evaluation on Day 3.
3. Intake of xanthine (e.g. caffeine) containing food or beverages (i.e., coffee, tea, soda, 
chocolate) must be limited to 4 cups/day or less 24 hours prior to dosing until after the study 
evaluation on Day 3. 
4. Patients should maintain adequate hydration 24 hours prior to dosing until after the study 
evaluation on Day 3. 

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6.2.3.2
Other restrictions
During Holter Monitoring:
1. No strenuous physical exercise (e.g. weight training, aerobics, football, etc.) 24 hours 
prior to the treatment visit and for the entire duration you are wearing the Holter Monitor 
(until removal on Day 3). At approximately 22-24 hours after the IVT injection, try to 
avoid activity by laying down and resting for 1-2 hours.
2. No bathing or swimming from the time the Holter Monitor electrodes are placed on Day 1 
until it is removed on Day 3. 
3. Try to avoid metal detectors, magnets, microwave ovens, electric blankets, electric razors 
and electric toothbrushes while wearing the Holter monitor. 
4. Try to keep cellphones, portable music players, and other devices that may exert an 
electric frequency at least 6 inches from the Holter monitor. 
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
The patient number assigned to a patient at screening remains the unique identifier for the 
patient throughout the study. For information on patient numbering, please see ‘Subject 
numbering’ section in the Site Operations Manual.
6.3.2
Treatment assignment, randomization
Treatment assignment and randomization are not applicable. This is a single-arm, open-label 
study and all eligible patients will receive the investigational treatment. 

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6.4
Treatment blinding
Treatment blinding is not applicable because this is a single arm, open-label study. All patients, 
trial site, and Sponsor staff will know the treatment provided to the patient. 
Table 6-3
Blinding and unblinding plan
Time or Event
Role
Randomization 
list generated
Treatment 
allocation & 
dosing
Safety event 
(single patient
unblinded)
Interim 
Analysis & 
dose 
escalation
Patients
N/A
UI
UI
N/A
Site staff
N/A
UI
UI
N/A
Global Clinical Supply 
and Randomization 
Office
N/A
UI
UI
N/A
Statistician/statistical 
programmer/ data 
analysts
N/A
UI
UI
N/A
All other sponsor staff 
not identified above 
(trial team, project 
team, management & 
decision boards, 
support functions)
N/A
UI
UI
N/A
Key:
UI: Allowed to be unblinded on individual patient level
B: Remains blinded
NA: Not applicable to this study
6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments are not permitted.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
The patient will receive one intravitreal injection of brolucizumab 6 mg performed by a 
qualified ophthalmologist. The injection must be recorded on the appropriate eCRF page.
6.6.2
Recommended treatment of adverse events
Medication used to treat adverse events (AEs) must be recorded on the appropriate CRF.
6.6.3
Emergency breaking of assigned treatment code
Emergency breaking of the assigned treatment code is not applicable because this is a single 
arm, open label study. 

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6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under the 
investigational drugs section. Drug preparation instructions are included in the SOM. 
7
Informed consent procedures
Eligible patients 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 patient's representative(s) gives consent (if allowed according 
to local requirements), the patient must be informed about the study to the extent possible given 
his/her understanding. If the patient is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the patient source documents.
Novartis will provide the investigators a separate document with a proposed informed consent 
form that complies with the ICH/GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the patient informed consent and should 
be discussed with the patient during the study as needed. Any new information regarding the 
safety profile of the investigational drug that is identified between IB updates will be 
communicated as appropriate, for example, via an investigator notification or an aggregate 
safety finding. New information might require an update to the informed consent and then must 
be discussed with the patient.
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.
Refer to the Site Operations Manual for a complete list of ICFs included in this study.

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8
Visit schedule and assessments
The Assessment Schedule (Table 8-1) lists all of the assessments and when they are performed. All data obtained from these assessments must 
be supported in the patient’s source documentation.
Patients 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 will not lead to automatic discontinuation. Patients who prematurely discontinue the study for any 
reason should be scheduled for a visit as soon as possible, at which time all of the assessments listed for the final visit will be performed. 
At this final visit, the adverse event and concomitant medications recorded on the CRF.
Additional details regarding the visit schedule and assessments are located in the SOM. 
Table 8-1
Assessment Schedule
Period
Screening
Treatment
Safety Follow-up (FU)
Visit Name
Screening
Day 1 (Baseline)
Day 3 (Visit 2)
End of Study (EOS)
Safety Follow-up (FU)
Days
-14 to -1
1
3
8
31
Visit Number
1
101
102
199
N/A
Informed consent
X
Inclusion / exclusion criteria
S
S
Demography
X
Medical history/current medical conditions
X
Prior/concomitant medications
X
X
X
X
Physical examination
S
Vital signs (Blood Pressure and Pulse Rate)
X
X2
X3
Electrocardiogram (ECG)
X
X2
X
Holter ECG Monitoring
X4
X5
Hematology
X
Clinical chemistry
X
Pregnancy and assessments of fertility1
X

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Period
Screening
Treatment
Safety Follow-up (FU)
Visit Name
Screening
Day 1 (Baseline)
Day 3 (Visit 2)
End of Study (EOS)
Safety Follow-up (FU)
Days
-14 to -1
1
3
8
31
Visit Number
1
101
102
199
N/A
Intraocular Pressure (IOP)
OU
SE6
Ophthalmic Exam
OU
SE6
Adverse Events
X
X
X
X
S
Telephone follow-up
X
S
Study drug administration
X
Study completion information
X
X = assessment to be recorded in the clinical database or received electronically from a vendor
OU = Both Eyes
S = assessment to be recorded in the source documentation only
SE = Study Eye
1 Women of childbearing potential only. Urine pregnancy tests will be performed unless local regulations require a serum pregnancy test.
2 Pre-Injection Procedure, performed before Holter monitoring start
3 Remove Holter Monitor before Performing Procedure(s)
4 Holter monitoring will start approximately 1 h pre dose
5 Holter monitoring will end approximately 48 h post dose
6 Assessment performed pre-dose at Baseline and performed post-dose, if required, at Baseline. Post-dose clinically significant abnormal findings should be recorded as 
an AE.

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8.1
Screening
Patients will be screened for eligibility for up to 14 days prior to the Baseline visit. It is 
permissible to re-screen a patient if s/he fails the initial screening; however, each must be 
discussed and agreed with by the Sponsor on a case-by-case basis. Information on what data 
must be collected for screening failures and further information on re-screening is outlined in 
the Site Operations Manual.
In the case where a safety laboratory assessment at screening indicates an electrolyte imbalance, 
the investigator should investigate if the electrolyte disturbance is due to a chronic underlying 
disease or if is the sequela of an intercurrent illness (e.g. such as vomiting or diarrhea due to a 
recent stomach virus or flu). If the electrolyte imbalance is due to a chronic underlying disease, 
then the patient must be excluded. If the electrolyte imbalance is due to an intercurrent illness 
and the investigator believes the intercurrent illness has adequately resolved, then the
investigator may repeat the test once prior to treatment. If the repeat value remains outside of 
the specified ranges, the patient must be excluded from the study.
8.1.1
Information to be collected on screening failures
Patients who sign an informed consent form and who are subsequently found to be ineligible,
prior to receiving the injection, will be considered a screen failure. Information on what data 
must be collected for screening failures is outlined in the Site Operations Manual.
8.2
Subject demographics/other baseline characteristics
Patient demographic and baseline characteristic data are to be collected on all patients. 
Relevant medical history/current medical condition present before signing the informed consent 
will be recorded. Investigators will have the discretion to record abnormal test findings on the 
appropriate CRF whenever, in their judgment, the test abnormality occurred prior to the 
informed consent signature. Details are outlined in the Site Operations Manual. 
8.3
Efficacy
Efficacy / Pharmacodynamics are not measured in this study.
8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. For details on adverse event (AE) collection and reporting, refer 
to the AE section (Section 10.1.1). The methods, assessment, specification, and recording for 
each assessment will be detailed in the SOM.

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Table 8-2
Assessments and Specifications
Assessment
Specification
Physical 
examination
A physical examination will be performed at Screening, as a general health 
check according to local clinical practice.
Clinically relevant findings that are present prior to signing informed consent 
must be included in the eCRF capturing Medical History. Significant findings 
identified after providing written informed consent which meet the definition of 
an Adverse Event must be recorded on the appropriate AE eCRF page.
Vital signs
Vital signs include BP (systolic and diastolic pressure in mmHg) and pulse rate 
(beats per minute) measurements (see SOM Section 3.2 Vital signs for details). 
In case there is an elevated blood pressure measurement as specified in the 
exclusion criteria, at the screening and baseline visits, the blood pressure 
measurement may be repeated up to two times within 30 minutes of the first 
measurement (i.e. 3 measurements maximum within 30 min of the first 
measurement). If the final repeat measurement is elevated, then the patient is 
not eligible to be enrolled into the study.
If the case there is an out of range heart rate at screening and baseline, two 
additional repeat readings can be obtained, so that a total of up to three 
consecutive assessments are made, with the subject seated quietly for 
approximately five minutes preceding each repeat assessment. The last 
reading must be within the ranges provided in the eligibility criteria in order for 
the subject to qualify.
On Day 1, vital signs will be measured before the administration of study 
medication. The results are recorded in the eCRF.
Ophthalmic Exam
Intraocular 
Pressure 
(IOP), 
Biomicroscopy 
(slit 
lamp 
examination), 
Ophthalmoscopy (funduscopy) will be performed (see protocol Section 8.4.4
for details). 
8.4.1
Laboratory evaluations
Local laboratories will be used for analysis of all specimens collected at screening that will be 
used to evaluate systemic status. Any additional samples may be taken for safety monitoring. 
Collection of these samples will be performed according to the local clinical practice. 
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate.
Table 8-3
Laboratory Assessments
Test Category
Test Name
Hematology
Hematocrit, hemoglobin, red blood cell (RBC) count, white blood cell (WBC) count 
with differential (absolute and percentage of neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils), and quantitative platelet count
Chemistry
Serum electrolytes (sodium, potassium, chloride, phosphorus, calcium, 
magnesium), uric acid, urea nitrogen, creatinine, albumin, glucose, total protein, 
total bilirubin and direct bilirubin, serum glutamic oxaloacetic transaminase 
(SGOT)/ aspartate aminotransferase (AST), serum glutamic pyruvic transaminase 
(SGPT)/ alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), 
alkaline phosphatase (ALP), lactate dehydrogenase (LDH), troponin, high-density 
lipoprotein (HDL), low-density lipoprotein (LDL)
Pregnancy Test
Urine pregnancy test for women of childbearing potential. If required by local 
regulations, serum testing is accepted

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8.4.2
Electrocardiogram (ECG)
Full details of all procedures relating to the ECG collection and reporting are contained in the
core reading center technical manual and in the Site Operations Manual.
Triplicate 12 lead ECGs (performed at Screening, Baseline pre-injection, and Day 3) and 12 
lead Holter ECGs will be collected with ECG machines supplied by the core ECG reading 
center. All ECGs will be sent to the central ECG reading center. Central ECG reading will be 
used to determine eligibility at Screening.
A monitoring or review process should be in place for clinically significant ECG findings 
throughout the study. Only clinically significant abnormalities must be reported as adverse 
events.
The Holter ECG recording is performed to capture comprehensive ECG data and should start 
approximately one hour before IVT injection. The recording will end approximately 48 h after 
injection.
In the event that a clinically significant ECG abnormality is identified at the site (e.g. severe 
arrhythmia, conduction abnormality of QTcF > 500 ms), a copy of the assessment is sent to the 
core laboratory for expedited review if applicable, and the ECG is repeated to confirm the diagnosis.
If the patient is hemodynamically compromised, the investigator or a medically qualified person must 
initiate appropriate safety procedures without delay (for example cardioversion).
Clinically significant abnormalities must be recorded on the eCRF as either medical 
history/current medical conditions or adverse events as appropriate.
8.4.3
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have pregnancy testing at 
Screening. Additional pregnancy testing might be performed if requested by local requirements.
Local pregnancy testing and associated results will not be collected on the eCRF.
Highly effective contraception is required for women of child-bearing potential during the study 
drug administration and for 3 months after the investigational medication is administered.
8.4.4
Ophthalmic examination
The ophthalmic examination (including IOP, Biomicroscopy, and Ophthalmoscopy) will be 
performed at Screening and Baseline (pre-dose and post-dose) as noted below:

Intraocular pressure (IOP) – IOP will be measured in mmHg and entered in the eCRF.

Screening: IOP is assessed in both eyes (OU) at Screening.

Baseline: IOP is assessed in the study eye (SE) ONLY; pre-dose and post-dose 
measurements are required at Baseline.

Post-dose IOP should be assessed, approximately 30 - 60 minutes after the IVT 
injection and, if ≥ 25 mmHg, the assessment should be repeated until back to normal. 

Treatment and close monitoring of an elevated IOP should be performed by the 
investigator according to clinical practice

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
Biomicroscopy (slit lamp examination) – The slit lamp examination will be completed 
to examine the structures of the study eye. The results of the examination must be 
recorded in the source documents.

Screening: Biomicroscopy is assessed in both eyes (OU).

Baseline: Biomicroscopy is assessed in the study eye (SE) ONLY; pre-dose and, if 
required, post dose examinations.

Ophthalmoscopy (funduscopy) – Ophthalmoscopy will be completed to examine the 
peripheral retina and confirm that an intravitreal injection can be safely performed. 
The results of the examination must be recorded in the source documents.

Screening: Ophthalmoscopy is assessed in both eyes (OU) at Screening.

Baseline: Ophthalmoscopy is assessed in the study eye (SE) ONLY; pre-dose and, if 
required, post-dose examinations 
Note: Pupil dilation for the slit lamp examination and ophthalmoscopy is optional according to 
local practice. 
Clinically significant abnormal findings (as judged by the masked investigator) from slit lamp 
or ophthalmoscopy observations should be recorded as an AE in the eCRF.
8.4.5
Appropriateness of safety measurements
Standard ECG intervals and morphology variables will be assessed, and QTcF and QTcB will 
be calculated. Cardiac assessments will be based on the QTcF, although QTcB will be used for 
comparative and historical control. ECG data is collected at several time points (Screening, 
Baseline and then continuously between Baseline 1h pre-injection through 48h, and on Day 3).
It is appropriate to explore the within- and between-patient exposure-effect relationship.
Laboratory samples will be drawn at Screening in order to identify a potential electrolyte 
imbalance (e.g. hypokalemia) that might affect ECG parameters and morphology.
The other safety assessments selected are standard for this indication/patient population.
8.5
Additional assessments
No additional tests will be performed on patients entered into this study.

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9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Since this is a single dose study, discontinuation of study treatment is not applicable.
Patients who decide they do not wish to participate in the study further after the single dose
should NOT be considered withdrawn from the study UNLESS they withdraw their consent 
(see Section 9.1.2 Withdrawal of informed consent). Where possible, they should return for 
the assessments indicated in the Assessment Schedule (Table 8-1). If they fail to return for 
these assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be 
made to contact the patient/pre-designated contact as specified in the lost to follow-up, 
see Section 9.1.3 Lost to follow-up. This contact should preferably be done according to the 
study visit schedule.
If the patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient. This telephone 
contact should preferably be done according to the study visit schedule.
9.1.1.1
Replacement policy
Patients will not be replaced on study. However, if a patient is considered as non-evaluable, 
enrollment of a new patient will be considered by Novartis if there are less than the required 
number of patients that complete the study. 
9.1.2
Withdrawal of informed consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the patient’s decision to withdraw his/her consent and 
record this information.
Study treatment must not be given (if not yet injected) and no further assessments conducted, 
and the data that would have been collected at subsequent visits will be considered missing.
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
Assessment Schedule (Table 8-1).
Novartis will continue to keep and use collected study information (including any data resulting from 
the analysis of a patient’s samples until the time of withdrawal) according to applicable law.

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All biological samples not yet analyzed at the time of withdrawal may still be used for further 
testing/analysis in accordance with the terms of this protocol and of the informed consent form.
9.1.3
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the patient, e.g. dates of telephone 
calls, registered letters, etc. A patient should not be considered as lost to follow-up until due 
diligence has been completed or until the end of the study.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination:

Unexpected, significant, or unacceptable safety risk to patients enrolled in the study

Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data

Discontinuation of study drug development
In taking the decision to terminate, Novartis will always consider patient welfare and safety. 
Should early termination be necessary, patients must be seen as soon as possible and treated as 
a prematurely withdrawn patient. The investigator may be informed of additional procedures to 
be followed in order to ensure that adequate consideration is given to the protection of the 
patient’s interests. The investigator or sponsor depending on 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 patient finishes their End of Study (EOS) visit and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or, in the event of an early study termination decision, the 
date of that decision.
All treated patients will have a safety follow-up call conducted on Day 31. The information 
collected during this call is kept as source documentation. All SAEs reported during this time 
period must be reported as described in Section 10.1.3 SAE reporting and SOM. Documentation 
of attempts to contact the patient are recorded in the source documentation.
Continuing care should be provided by the investigator and/or referring physician after the 
conclusion of the trial based on patient availability for follow-up. 
This care may include:

Enrollment in an extension study or managed access program, if any are available

Initiation of standard of care treatment (approved treatment for nAMD) or other treatment, 
under the responsibility of the investigator and/or referring physician

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Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation patient after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of the individual patient and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the patient at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the patient during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to
Section 10.1.2 Serious adverse events):
1. The severity grade:

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single patient
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not recovered/not 
resolved must be reported
4. Whether it constitutes an SAE (see Section 10.1.2 Serious adverse events for definition of 
SAE) and which seriousness criteria have been met
5. Action taken regarding with study treatment

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All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose reduced/increased

Drug interrupted/withdrawn
6. Its outcome
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the patient.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator’s Brochure (IB).
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
the underlying disease.
Follow the instructions found in the Site Operations Manual for data capture methodology 
regarding AE collection for patients that fail screening.
10.1.2
Serious adverse events
An SAE is defined as any adverse event appearance of (or worsening of any pre-existing)
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria:

Fatal

Life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines 2004).

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
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 information 
consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

Is medically significant, e.g. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse (please refer to the 
ICH-E2D Guidelines 2004).
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days following the last administration of study 
treatment if there are post-treatment follow-up visits with no required procedures must be 
reported to Novartis safety within 24 hours of learning of its occurrence. Detailed instructions 
regarding the submission process and requirements are provided to each site.
Screen failures (e.g. a patient who is screened but is not treated)
SAEs occurring after the patient has provided informed consent until the time the patient is 
deemed a Screen Failure must be reported to Novartis. 

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Treated Patients
SAEs collected between time patient signs ICF until 30 days after the patient has discontinued 
or stopped study treatment must be reported to Novartis.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the Investigator’s Brochure (new occurrence) and 
is thought to be related to the study treatment, a CMO & PS Department associate may urgently 
require further information from the investigator for health authority reporting. Novartis may 
need to issue an Investigator Notification (IN) to inform all investigators involved in any study 
with the same study treatment that this SAE has been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 30 day period following the last administration of study 
treatment should only be reported to Novartis Safety if the investigator suspects a causal 
relationship to study treatment.
10.1.4
Pregnancy reporting
To ensure patient safety, each pregnancy occurring after signing the informed consent form 
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 Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the investigational 
treatment of any pregnancy outcome. Any SAE experienced during pregnancy must be reported.
10.1.5
Reporting of study treatment errors including misuse/abuse
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not it is associated with an AE/SAE and reported 
to Safety (only if associated with an SAE). 
Misuse or abuse will be collected and reported in the safety database irrespective of it being 
associated with an AE/SAE within 24 hours of Investigator’s awareness.

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Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.
10.2
Additional Safety Monitoring
Not applicable
11
Data collection and database management
11.1
Data collection
Data not requiring a separate written record will be defined in the protocol and the Assessment 
Schedule (Table 8-1) and can be recorded directly on the CRFs. All other data captured for this 
study will have an external originating source (either written or electronic) with the CRF not 
being considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
Designated investigator staff will enter the data required by the protocol into the electronic Case 
Report Forms (eCRF). The eCRFs are built using fully validated secure web-enabled software 
that conforms to 21 CFR Part 11 requirements. Automatic validation programs check for data 
discrepancies in the eCRFs, allow modification and/or verification of the entered data by the 
investigator staff. Investigator site staff will not be given access to the EDC system until they 
have been trained. 
The investigator/designee is responsible for assuring that the data recorded on CRFs (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 is complete and accurate.
After the final database lock, the investigator will receive copies of the patient data for archiving 
at the investigational site.
All data should be recorded, handled and stored in a way that allows accurate reporting, 
interpretation, and verification.

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11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values. Queries are sent 
to the investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) terminology.
Once all of 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/moved to restricted 
area to be accessed by the independent programmer and statistician. Any changes to the 
database after that time can only be made after written agreement by Novartis development 
management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis or 
delegated CRO representative will review the protocol and data capture requirements 
(i.e. eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of patient records, the accuracy 
of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis or delegated CRO/CRA organization. Additionally, a 
central analytics organization may analyze data & identify risks & trends for site operational 
parameters, and provide reports to Novartis clinical teams to assist with trial oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient’s file. The investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs and of data that will be used for all primary variables. Additional checks 
of the consistency of the source data with the CRFs are performed according to the study-
specific monitoring plan. No information in source documents about the identity of the patients 
will be disclosed.

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12
Data analysis and statistical methods
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
The safety analysis set will include all patients that received one (1) IVT injection of 
brolucizumab 6 mg. All analyses will be performed on the Safety Set unless otherwise specified.
12.2
Subject demographics and other baseline characteristics
Demographic and Baseline characteristics will be summarized descriptively. 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. Separate tables will be presented for ocular and 
non-ocular histories and conditions.
For selected characteristics, listings will be presented by patient.
12.3
Treatments
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.
12.4
Analysis of the primary endpoint(s)
The primary objective of this study is to collect information on ECG after intravitreal injection 
of brolucizumab 6 mg in patients with nAMD. 
12.4.1
Definition of primary endpoint(s) 
The primary endpoints include the following:

Incidence between 20 and 24 h post-injection of clinically relevant treatment emergent 
changes in HR, PR, QRS, and QTc (heart rate corrected QT using Fridericia’s formula, 
QTcF) interval (ms)
12.4.2
Statistical model, hypothesis, and method of analysis
There are no formal hypotheses in this study. 
Incidences between 20 and 24 h post-injection of clinically relevant treatment emergent changes 
in HR, PR, QRS, and QTc interval will be listed by patient. 
The frequency and proportion of patients with change from baseline in QTcF ≥ 30 ms and 
≥60 ms between 20 and 24 h post-injection will be summarized. Listings of patients with 
change from baseline in QTcF ≥ 30 ms and ≥ 60 ms between 20 and 24 h post-injection will be 
provided.

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The frequency and proportion of patients with QTcF > 450, 480, and 500 ms between 20 and 
24 h post-injection will be summarized. Listings of patients with QTcF > 450, 480, and 500 ms 
between 20 and 24 h post-injection will be provided separately.
Holter ECG data between 20 and 24 h post-injection will be plotted by patient, and 
abnormalities will be flagged. 
Further details on analyses of primary endpoints will be provided in the SAP.
12.4.3
Handling of missing values/censoring/discontinuations
There will be no imputation of missing data. Only observed data will be used for the analyses.
12.4.4
Sensitivity and Supportive analyses
There will be no sensitivity analyses.
12.5
Analysis of secondary endpoints
The secondary endpoints are ocular and non-ocular AEs (including clinically relevant ECG 
abnormalities) until the end of the study.
12.5.1
Safety endpoints
A treatment-emergent adverse event is defined as any adverse event that develops after 
initiation of the study treatment or any event already present that worsens following exposure 
to the study treatment, until the end of study. Only treatment-emergent adverse events will be 
presented in the summary tables.
Adverse events will be coded using the MedDRA dictionary and presented by system organ 
class (SOC) and preferred term (PT). AEs will be presented based on the number and percentage 
of patients with at least one AE in the category of interest. Separate tables will be provided for 
ocular events in the study eye and fellow eye and non-ocular events (including clinically 
relevant ECG abnormalities).
Patient listings of all adverse events will be provided. Deaths and other serious or clinically 
significant non-fatal adverse events will be listed separately.
12.6
Interim analyses
Not applicable.
12.7
Sample size calculation
12.7.1
Primary endpoint(s)
The PMDA of Japan requested a sample size of approximately 10 to 15 patients for this study. 
No sample size calculations were performed. 

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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, patient recruitment procedures 
(e.g., advertisements) and any other written information to be provided to patients. Prior to 
study start, the investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents, 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 and posted in a publicly 
accessible database of clinical trial results, such as the Novartis clinical trial results website and 
all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT, etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided at the trial investigator 
training.
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

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Protocol adherence
This protocol defines the study objectives, the study procedures, and the data to be collected on 
study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the 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 patient 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 patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.

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References
References are available upon request
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Wong WL, Su X, Li X, et al (2014) Global prevalence of age-related macular degeneration 
and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. 
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