Conditions: Neovascular Age-related Macular Degeneration
Keywords: Macular degeneration age-related macular degeneration (ARMD) vision loss macula damage retina damage dry macular degeneration wet macular degeneration AMD
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 103
Healthy volunteers: no

Brief summary:
AMD (Age Related Macular Degeneration) is the leading cause of severe visual loss and blindness registration in the UK . It is a disease which affects the retina (the nerve and blood vessel network at the back of the eye responsible for vision). Patients can suffer with severe visual loss and have difficulties with every day tasks such as recognising faces, reading \& driving.

There are two variations of the disease, a 'dry' type \& a 'wet' type also known as neovascular AMD (nAMD). In wet/nAMD new vessels grow from the blood supply underneath the retina, in part due to higher than normal levels of a protein called Vascular Endothelial Growth Factor (VEGF). Since the introduction of drugs which block VEGF, visual outcomes for patients with wAMD have dramatically improved.

There are 2 widely used treatments; ranibizumab and aflibercept. Whilst the majority of patients have a successful outcome with treatment, many patients experience suboptimal response. This study evaluated if these patients experience a benefit from a switch to a different antiVEGF drug treatment.

In this study nAMD patients who are showing no or poor to response to treatment with aflibercept were switched to ranibizumab to assess if there is any benefit in terms of treatment outcomes.

Patients visited the hospital clinic 8 times over the 7 - 8 month study period. Monthly ranibizumab injections were given for the first 3 months, then monthly as required for the next 3 months.

Detailed description:

Arms:
arm 1: All patients received 3 monthly intraveal injections of 0.5mg ranibizumab followed by monthly injections of ranibizumab 0.5mg for a further 3 months on a prn (as required) basis, as determined by the study doctor.

Interventions: intervention 1: Ranibizumab
Intervention descriptions: intervention 1: Intraveal injections of 0.5mg ranibizumab

Protocol document:
Prot_000.pdf: 
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Protocol No. CRFB002AGB17
Clinical Development
Ranibizumab; Lucentis®
Clinical Trial Protocol CRFB002AGB17 / NCT02161575
A Phase IV, prospective, open-label, uncontrolled, European
Study in patients with neovascular Age-related macular 
degeneration (nAMD), evaluating the efficacy and safety of 
switching From intravitreal Aflibercept to RanIbizumab 0.5mg: 
the SAFARI study
Authors:
 
Document type:
Amended Protocol Version
EUDRACT number:
2014-001085-10 
Version number:
02 (Clean)
Development phase:
Document status:
IV
Final
Release date:
11 May 2016
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations...................................................................................................................6
Glossary of terms........................................................................................................................8
Protocol summary.......................................................................................................................9
History of Amendments............................................................................................................13
Amendment 1 ....................................................................................................................13
Amendment 2 ....................................................................................................................13
1
Introduction .......................................................................................................................15
1.1
Background............................................................................................................15
1.2
Purpose ..................................................................................................................16
2
Study objectives.................................................................................................................16
2.1
Primary objective...................................................................................................16
2.2
Secondary objectives .............................................................................................17
17
3
Investigational plan ...........................................................................................................18
3.1
Study design...........................................................................................................18
3.2
Rationale of study design.......................................................................................21
3.3
Rationale of dose/regimen, route of administration and duration of treatment.....21
3.4
Rationale for choice of comparator .......................................................................21
3.5
Purpose and timing of interim analyses/design adaptations..................................22
3.6
Risks and benefits..................................................................................................22
4
Population..........................................................................................................................22
4.1
Inclusion criteria ....................................................................................................22
4.2
Exclusion criteria...................................................................................................24
5
Treatment...........................................................................................................................26
5.1
Protocol requested treatment .................................................................................26
5.1.1
Investigational treatment.......................................................................26
5.1.2
Additional study treatment....................................................................26
5.2
Treatment arms......................................................................................................26
5.3
Treatment assignment, randomization...................................................................27
5.4
Treatment masking ................................................................................................27
5.5
Treating the patient................................................................................................27
5.5.1
Subject numbering ................................................................................27


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5.5.2
Dispensing the investigational treatment ..............................................28
5.5.3
Handling of study treatment..................................................................28
5.5.4
Instructions for prescribing and taking study treatment........................29
5.5.5
Permitted dose adjustments and interruptions of study treatment ........31
5.5.6
Rescue medication ................................................................................31
5.5.7
Concomitant treatment..........................................................................31
5.5.8
Prohibited Treatment.............................................................................31
5.5.9
Discontinuation of study treatment .......................................................32
5.5.10
Withdrawal of consent ..........................................................................33
5.5.11
Loss to follow-up ..................................................................................33
5.5.12
Emergency breaking of assigned treatment code..................................33
5.5.13
Study completion and post-study treatment..........................................34
5.5.14
Early study termination.........................................................................34
6
Visit schedule and assessments .........................................................................................34
6.1
Information to be collected on screening failures..................................................38
6.2
Patient demographics/other baseline characteristics .............................................38
6.3
Treatment exposure and compliance .....................................................................38
6.4
Efficacy..................................................................................................................39
6.4.1
Optical Coherence Tomography ...........................................................39
6.4.2
Color Fundus Photography, Fluorescein and Indocyanine Green 
Angiography..........................................................................................40
6.4.3
Fundus autofluorescence.......................................................................41
6.4.4
ETDRS Best-Corrected Visual Acuity..................................................41
6.4.5
Appropriateness of efficacy assessments..............................................41
6.5
Safety.....................................................................................................................41
6.5.1
Ophthalmic examinations......................................................................42
6.5.2
Fellow eye .............................................................................................42
6.5.3
Physical Examination............................................................................42
6.5.4
Vital signs..............................................................................................42
6.5.5
Height and weight .................................................................................43
6.5.6
Laboratory evaluations..........................................................................43
6.5.7
Electrocardiogram (ECG) .....................................................................43
6.5.8
Pregnancy and assessments of fertility .................................................43
6.5.9
Appropriateness of safety measurements..............................................44
44
44


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7
Safety monitoring..............................................................................................................45
7.1
Adverse events.......................................................................................................45
7.2
Serious adverse events...........................................................................................47
7.2.1
Definition of SAE .................................................................................47
7.2.2
SAE reporting........................................................................................48
7.3
Pregnancy reporting...............................................................................................49
8
Data review and database management.............................................................................50
8.1
Site monitoring ......................................................................................................50
8.2
Data collection.......................................................................................................50
8.3
Database management and quality control............................................................51
8.4
Data Monitoring Committee..................................................................................51
8.5
Adjudication Committee........................................................................................51
9
Data analysis......................................................................................................................52
9.1
Analysis sets ..........................................................................................................52
9.2
Patient demographics and other baseline characteristics.......................................53
9.3
Treatments .............................................................................................................53
9.4
Analysis of the primary variable(s) .......................................................................54
9.4.1
Variable(s).............................................................................................54
54
9.4.3
Handling of missing values/censoring/discontinuations.......................54
9.4.4
Supportive analyses...............................................................................55
9.5
Analysis of secondary variables ............................................................................55
9.5.1
Efficacy variable ...................................................................................55
9.5.2
Safety variables .....................................................................................57
9.6
Interim analyses.....................................................................................................58
58
10 Ethical considerations........................................................................................................59
10.1
Regulatory and ethical compliance........................................................................59
10.2
Informed consent procedures.................................................................................59
10.3
Responsibilities of the Investigator and the IEC ...................................................60
10.4
Publication of study protocol and results...............................................................60
11 Protocol adherence ............................................................................................................61
11.1
Protocol Amendments ...........................................................................................61
12 References .........................................................................................................................62
13 Appendix 1: Clinically notable laboratory values and vital signs.....................................63


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List of tables
Table 5-1  Prohibited treatment................................................................................................32
Table 6-1   Assessment schedule (Eligibility criteria, demographics & baseline characteristics, 
imaging procedures) ..............................................................................................36
Table 6-2   Assessment schedule (peri-injection procedures, safety assessments and venous 
blood sample collection)........................................................................................37
59
Table 13-1 Clinically notable abnormal vital signs..................................................................63
List of figures
Table 5-1
Prohibited treatment..............................................................................32
Table 6-1
Assessment schedule (Eligibility criteria, demographics & baseline 
characteristics, imaging procedures) ........................................................................................36
Table 6-2 Assessment schedule (peri-injection procedures, safety assessments and 
venous blood sample collection) .........................................................................................37
59
Table 13-1 Clinically notable abnormal vital signs ...........................................................63
Figure 3-1   Study design..........................................................................................................18


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List of abbreviations
AE
Adverse event
AMD
Age-related macular degeneration
BCVA
Best-corrected visual acuity
CF
Color fundus photography
CNV
Choroidal neovascularization
CRC
Central reading center
CRT
Central retinal thickness
CSRT
Central subfield retinal thickness
CSRV
Central subfield retinal volume
DS&E
Drug Safety and Epidemiology
eCRF
electronic Case Report/Record Form
EOS
End of Study
ETDRS
Early Treatment Diabetic Retinopathy Study
EU
European Union
EWV
Early withdrawal visit
FA
Fluorescein angiography
FAF
Fundus autofluorescence
FAS 
Full Analysis Set 
GCP
Good Clinical Practice 
IB
Investigator’s Brochure
ICGA
Indocyanine green angiography
ICH
International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
IEC
Independent ethics committee
IN
Investigator notification
IOP
Intraocular pressure
IRC
Intra-retinal cysts
IUD
Intra-uterine device
IVT
Intravitreal
MedDRA
Medical Dictionary for Regulatory Activities
nAMD
neovascular (wet) age-related macular degeneration
OCT
Optical Coherence Tomography
PCV
Polypoidal choroidal vasculopathy


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PED
Pigment epithelial detachment
PFS
Pre-filled syringe
PRN
Pro re nata/administer as required
RAP
Retinal angiomatous proliferation
RPE
Retinal pigment epithelium
SAE
Serious adverse event
SD/HD-OCT
Spectral domain/high definition optical coherence tomography
SF
Sub-retinal fluid
SmPC
Summary of Product Characteristics
SRT
Subfoveal retinal thickness
SUSAR
Suspected Unexpected Serious Adverse Reaction
UK
United Kingdom
VA
Visual acuity
VEGF
Vascular endothelial growth factor
WHO
World Health Organisation


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Glossary of terms
Assessment
A procedure used to generate data required by the study
End of Study Visit
Point/time at which the patient came in for a final evaluation visit 
or when study drug was discontinued whichever is later
Enrollment
Point/time of patient entry into the study at which informed 
consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol)
ETDRS - standards
Early Treatment Diabetic Retinopathy Study-standards became 
the standard for all subsequent ophthalmological clinical trials; 
they include specific guidelines and requirements on how BCVA 
is being assessed and the equipment to be used for this 
assessment
Fellow treated eye
The fellow eye treated with ranibizumab
Patient withdrawal
Point/time when the patient exits from the study before the 
planned completion of all study drug administration and 
assessments; at this time all study drug administration is 
discontinued and no further assessments are planned
Period
A minor subdivision of the study timeline; divides phases into 
smaller functional segments such as Screening, Baseline, 
Monthly treatment, and PRN treatment
Protocol
A written account of all the procedures to be followed in a trial, 
which describes all the administrative, documentation, analytical 
and clinical processes used in the trial.
Study drug
A drug administered to the patient as part of the required study 
procedures; includes investigational drug, active drug run-ins or 
background therapy 
Study eye
The study eye is the eye selected by the Investigator at Baseline 
(according to the protocol) to receive the study treatment
Subject number
A number assigned to each patient who enrolls in the study. 
When combined with the center number, a unique identifier is 
created for each patient in the study
Variable
A measured value or assessed response that is determined in 
specific assessments and used in data analysis to evaluate the 
drug being tested in the study


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Protocol summary
Protocol number
CRFB002AGB17
Title
A Phase IV, prospective, open-label, uncontrolled, European Study in 
patients with neovascular Age-related macular degeneration (nAMD), 
evaluating the efficacy and safety of switching From intravitreal 
Aflibercept to RanIbizumab 0.5mg: the SAFARI study
Brief title
Study of efficacy and safety of ranibizumab in patients with wet age 
related macular degeneration that have previously been treated with 
aflibercept.  
Sponsor and Clinical 
Phase
Novartis Phase 4
Investigation type
Drug
Study type
Interventional 
Purpose and rationale
There are limited prospective data regarding the potential benefit and 
risks associated with switching between anti-VEGF therapies in patients 
with nAMD who have either failed to achieve a clinical response to the 
first anti-VEGF therapy used, or who initially achieved a favorable
response but subsequently have evidence of increasing disease activity
despite continuation of therapy. Furthermore the retinal morphology 
characteristics of patients who respond favorably or unfavorably to an 
anti-VEGF switch strategy have not been previously reported.   
The purpose of this study is to determine, in patients with nAMD treated 
with aflibercept and where there is evidence of persistent or increasing 
disease activity, whether switching treatment to ranibizumab reduces 
disease activity over a 6 month period as assessed by a variety of 
measures including retinal imaging parameters and BCVA.
 
 
Primary Objective(s) 
The primary objective is to evaluate whether treatment with intravitreal 
ranibizumab is associated with improvement (i.e. reduction at Day 90 
from Baseline) in central subfield retinal thickness (CSRT) as determined 
by spectral domain/high definition optical coherence tomography (SD/HD-
OCT) after 3 monthly injections of ranibizumab.
The CSRT represents the average retinal thickness (µm) of the circular 
area within 1 mm diameter around the foveal center.
Secondary Objectives
To evaluate whether treatment with intravitreal ranibizumab is associated 
with improvements in various retinal morphology parameters as 
determined by SD/HD-OCT at various time points over a period of 6 
months and evaluated by the Central Reading Centre (CRC) including:

The change in subfoveal retinal thickness (SRT), central subfield 
retinal thickness (CSRT) and central subfield retinal volume 
(CSRV).

The proportion of patients with subretinal fluid (SF), intra-retinal 
cystoid changes (IRC), pigment epithelial detachments (PEDs), 


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or dry retina.

The change in size (height or volume as appropriate) of various 
anatomical parameters including SF, IRC, and PEDs.
To evaluate changes from Baseline BCVA at various time points over a 
period of 6 months including changes in BCVA between 3 and 6 months.
To evaluate ocular and systemic safety by determining the incidence of 
ocular and systemic adverse events (AEs) up to Day 180.
Study design
This is a 6-month, phase IV, unmasked, uncontrolled, single arm, 
multicenter study.  The study includes 8 study visits over a minimum of 6 
months.  All patients with nAMD and eligible to enter the study will 
receive 3 monthly intravitreal (IVT) ranibizumab 0.5mg injections followed 
thereafter by monthly IVT injections of ranibizumab 0.5mg on a PRN 
basis.
Population
The study will include 124 patients diagnosed with visual impairment due 
to nAMD who have been treated with aflibercept and where either no 
treatment response has been achieved or where there is suboptimal 
treatment response. 
Key inclusion criteria
Inclusion criteria for patient

Age ≥50 years. 

BCVA ≥23 ETDRS letters in study eye

Evidence of active CNV involving the center of the fovea in study 
eye
Patient subgroup specific inclusion criteria
Patients need to meet all the criteria for one of the following two groups:
Group 1. Primary treatment failure 

Initiated treatment with aflibercept <130 days prior to the 
Screening Visit.

No increase in BCVA (≥5 letters) since commencing treatment 
with aflibercept.

Disease activity has never been controlled in the study eye after 
initiating aflibercept as defined by at least one of the following: 
evidence of unchanged or increasing retinal* or sub-retinal fluid; 
new PED; unchanged or increasing size of pre-existing PED. 
Group 2. Suboptimal treatment response

Aflibercept commenced ≥6 months prior to the Screening Visit.

Received ≥3 aflibercept injections into the study eye within 6 
months of the Screening Visit.

Evidence of previous reduced disease activity (as defined by 
reduction of ≥50µm in CSRT on OCT) noted in the study eye 
after initiating aflibercept.

At Screening Visit, disease activity has worsened (as defined by 
increasing retinal* or sub-retinal fluid, or new or increasing size of 
PED) in the study eye compared to prior visits.


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*Evidence of increasing retinal fluid may include increased number, size 
or total volume of IRCs, or increased central retinal or foveal thickness, or 
similar quantitative retinal imaging data recorded within the individual 
patient record.
Key exclusion criteria
Exclusion criteria for systemic medical history and conditions

History of cerebrovascular accident, transient ischemic attack or 
myocardial infarction within 3 months of the Screening visit.

Uncontrolled blood pressure
Exclusion criteria for ocular medical history and conditions for 
either eye

Evidence of bilateral active CNV during the Screening Period or 
at Baseline requiring bilateral anti-VEGF injections*.

Prior intravitreal injection of ranibizumab or bevacizumab into the 
study eye and/or prior intravitreal injection of bevacizumab into 
the fellow eye.
*Patients with active CNV in the study eye with quiescent CNV in the 
fellow eye who may have received IVT aflibercept or ranibizumab 
injections into the fellow eye >40 days prior to Screening, are not 
excluded from the Study. However, should the fellow eye require anti-
VEGF treatment during the study, only ranibizumab may be utilized.
Study eye exclusion criteria 

Cataract (if causing significant visual impairment), aphakia, 
severe vitreous hemorrhage, rhegmatogenous retinal 
detachment, proliferative retinopathy or choroidal 
neovascularization of any other cause than wet AMD (e.g. ocular 
histoplasmosis, pathologic myopia (≥-6 dioptres)) at the time of 
Screening and Baseline.

Irreversible structural damage involving the center of the fovea 
(e.g. advanced fibrosis or geographic atrophy) which in the 
opinion of the Investigator is sufficient to irreversibly impair visual 
acuity. 

Polypoidal choroidal vasculopathy (PCV), RPE tear, central 
serous retinopathy (CSR), or significant vitreomacular traction 
identified during Screening period or within 4 months of Baseline 
visit. Note that small vitreomacular adhesions that do not result in 
deformity of the retina are permitted.

Unable to obtain at Screening OCT images of sufficient quality to 
be analyzed. 
Investigational and 
reference therapy
Investigational and reference therapy:
The investigational treatment in this study is 0.5 mg ranibizumab. There 
is no reference therapy.
Efficacy assessments
Efficacy assessments will include both anatomical and functional 
evaluations. The methods of evaluation and the parameters to be 
assessed are listed below.

Spectral-domain/High definition Optical Coherence Tomography 


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
ETDRS Best-Corrected Visual Acuity
Safety assessments

Ophthalmic examinations

Vital signs

Adverse events
Other assessments

Color fundus photography

Fluorescein angiography

Fundus autofluorescence

Indocyanine green angiography
Data analysis
The primary objective is to demonstrate that the mean change from 
baseline in CSRT (as determined by SD/HD-OCT) at Day 90 is less than 
zero.  
 
 
 
The primary analysis will be performed on the Full Analysis Set.
Key words
Prospective, uncontrolled study, ranibizumab 0.5 mg, neovascular
age-related macular degeneration, PRN, OCT, suboptimal treatment 
response, primary treatment failure


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History of Amendments
Amendment 1
Amendment rationale
The main purpose for the current amendment is to update the requirements for historical OCT 
images during aflibercept treatment and add these to the inclusion criteria for further clarity.
In addition, references are included in the safety sections to the Investigator’s Brochure as the 
Reference Safety Information, and minor corrections and clarifications have been made to the 
previous version of the study protocol.
The study started enrolment in the UK on 28th August 2014 and in Germany on 28th January 
2015.
Changes to the Protocol
Major changes made to the protocol:

Amendment to Sections 3.1, 4.1 (Inclusion criteria) and 6.4.1 to extend the time 
period for collection of pre-treatment historical OCT images from ≤ 14 days to ≤ 28 
days before the date of first injection of aflibercept

Amendment to Section 4.2: Study Eye Exclusion Criterion number 15 of the 
pathological myopia definition from ≥ 8 dioptres to ≥ 6 dioptres

Clarification in Sections 3.6, 5.5.4, 7.1 and 7.2.2 that the Reference Safety Information
for the study is the Investigator’s Brochure for ranibizumab, rather than the SmPC
Additional minor and typographical changes (Sections  4.2: Exclusion Criterion number 12; 
Section 5.5; Section 6, Section 6.1, Section 6.4.1; Section 8.3; Section 9; Section 9.4.2)
Amendment 2
Amendment rationale
The main purpose for the current amendment is to re-assess the sample size calculation in the 
light of new information provided by a further literature search.


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Changes to the Protocol
Major changes made to the protocol:

Amendment to Protocol summary - Population, reducing the sample size from 162 to 
124.

Amendment to Section 4 (Population), reducing the sample size from 162 to 124 and 
consequently, the approximate number needing to be screened from 200 to 155.

Amendment to Section 9.7 (Sample size calculation) reducing the estimated standard 
deviation of differences from 117 µm to 102 µm resulting in a reduction of the sample 
size from 162 to 124.  Details regarding the justification of this change are also 
provided in this section.  


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1
Introduction
1.1
Background
Age-related macular degeneration (AMD) is the commonest cause of severe visual loss in 
people aged over 50 years in the UK and other European countries (Owen 2012). The 
prevalence of late AMD standardized to the UK population aged 50 years or more has been 
estimated to be 2.4%, increasing to 4.8% in those aged 65 years or more and 12.2% in those 
aged 80 years or more (Owen 2012).  Given the demographic trend for an increasing 
proportion of elderly people in the European population, the prevalence of AMD will likely 
increase dramatically over the next decades (Klein 2004), resulting in significant morbidity 
and socioeconomic burden.
Two distinct forms of AMD exist, namely geographic atrophy (dry form) and choroidal 
neovascularization (wet or neovascular form, nAMD). Although nAMD accounts for only 10% 
of all AMD, 90% of people with severe visual loss have nAMD (Veritti 2012). The 
underlying processes and factors contributing to the etiology of nAMD are not entirely clear, 
although vascular endothelial growth factor (VEGF) has been identified as a key stimulus for 
angiogenesis, increase capillary permeability and disease progression for nAMD (Chong 
2012).  
The management of nAMD in Europe has been transformed since the availability of anti-
VEGF therapies administered locally via intravitreous injection.  Although pegaptanib was the 
first anti-VEGF available in 2006, many opthalmologists switched to using ranibizumab 
following regulatory approval in Switzerland in 2006 and European Commission approval in 
2007. Unlike pegaptanib, ranibizumab demonstrated clinically and statistically significant 
improvements from baseline in visual acuity and patients’ quality of life; improvements in 
visual acuity were rapid often occurring 7 days after the first intravitreous injection and 
sustained for at least 2 years (Rosenfeld 2006).  Changes in visual acuity were also superior to 
the standard of care treatment at that time (verteporfin photodynamic therapy) and were also 
associated with significant improvements in the morphological characteristics of nAMD
(Brown 2006). 
Aflibercept is an anti-VEGF that was approved in 2012 by European competent authorities for 
use in nAMD.  Two Phase 3 studies that supported approval of aflibercept for nAMD,
evaluated changes in visual acuity with aflibercept as compared to ranibizumab (Heier 2012).  
Aflibercept 2mg treatment every 8 weeks after the initial 3 monthly doses, was demonstrated 
to be non-inferior and clinically equivalent to monthly ranibizumab 0.5mg with regards to 
improvement in visual acuity at 52 weeks (Heier 2012). Intravitreal aflibercept was generally 
well tolerated and had a profile of ocular treatment-emergent adverse events, including 
serious ocular adverse events, similar to those for monthly ranibizumab.  


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Despite the widespread use of intravitreal anti-VEGF therapies and evidence for improvement 
and stabilization of visual acuity for many patients, a minority of individuals experience rapid, 
continued worsening clinical status without ever having achieved an adequate clinical 
response (primary treatment failures), whilst in others there is evidence of persisting or 
worsening disease activity following an initial response to treatment (suboptimal treatment 
response). In these cases, repeated intravitreal injections may fail to stabilize either symptoms, 
visual acuity or other evidence of disease activity (CATT Research Group 2011; Fung 2012). 
Tachyphylaxis, where repeat administration of a drug leads to decreased therapeutic responses, 
has also been reported (Schaal 2008; Gasperini 2012). In all these cases, ophthalmologists are 
increasingly considering switching to an alternative anti-VEGF therapy.  
 
1.2
Purpose 
The purpose of this study is to determine, in patients with nAMD treated with aflibercept and 
where there is evidence of persistent or increasing disease activity, whether switching 
treatment to ranibizumab 0.5mg reduces disease activity over a 6 month period as assessed by 
a variety of measures.
2
Study objectives
2.1
Primary objective
The primary objective is to evaluate whether treatment with intravitreal ranibizumab 0.5mg is 
associated with improvement (i.e. reduction at Day 90 from Baseline) in central subfield 
retinal thickness (CSRT) as determined by optical coherence tomography (OCT) after 3 
monthly injections of ranibizumab.


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2.2
Secondary objectives

To evaluate whether treatment with intravitreal ranibizumab 0.5mg is associated with 
improvements in various retinal morphology parameters as determined by OCT at 
various time points over a period of 6 months and evaluated by a Central Reading 
Centre (CRC), including:
o
The change in subfoveal retinal thickness (SRT), central subfield retinal 
thickness (CSRT) and central subfield retinal volume (CSRV).
o
The proportion of patients with subretinal fluid (SF), intra-retinal cystoid 
changes (IRC), pigment epithelial detachments (PEDs), or dry retina.
o
The change in size (height or volume as appropriate) of various anatomical 
parameters including SF, IRC, and PEDs.

To evaluate changes from Baseline BCVA at various time points over a period of 6 
months including changes in BCVA between 3 and 6 months.

To evaluate ocular and systemic safety by determining the incidence of ocular and 
systemic adverse events (AEs). 


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3
Investigational plan
3.1
Study design
This is a 6-month, phase IV, unmasked, uncontrolled, single arm, multicenter study.  The 
study includes 8 study visits over a minimum of 6 months.  All patients with nAMD and 
eligible to enter the study will receive 3 monthly intravitreal (IVT) ranibizumab 0.5mg 
injections followed thereafter by monthly IVT injections of ranibizumab 0.5mg on a PRN 
basis (Figure 3-1).  
Figure 3-1
Study design
There will be 3 periods in this study;

Screening period: from Day -70 to Day 0

Monthly Treatment period: from Baseline (Day 1) to Day 60

PRN Treatment period: from Day 61 to Day 180 


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Screening Period: Day -70 to Day 0
At the Screening visit, patient informed consent will be obtained and eligibility criteria will be 
assessed. The informed consent process will also include providing consent for prior medical 
and treatment history, as well as for pseudo-anonymized historical retinal images to be 
reviewed by a Central Reading Centre (CRC). 
 
 
  
After signing the informed consent, several procedures will be performed to assess eligibility
(patient and study eye). For the study eye eligibility, BCVA, ophthalmic examination, 
SD/HD-OCT, color fundus photography (CF), fluorescein angiography (FA), indocyanine 
green angiography (ICGA) and fundus autofluorescence (FAF) will be performed.  The study
eye will be selected at the discretion of the Investigator to be used for the primary, secondary 
 based on the eligibility criteria defined in Section 4.  Various 
retinal and choroidal imaging assessments for the study eye should be completed and 
transferred to the CRC (Figure 3-1 and Table 6-1). 
 
  In addition, pseudo-anonymized historical retinal OCT 
images acquired after a minimum of 2 aflibercept injections indicating either no change or 
worsening disease activity (primary treatment failure subgroup) or an improvement in retinal 
morphology (suboptimal treatment response subgroup) will also be collected and transferred 
to the CRC.  Patients that do not meet the eligibility criteria on the first occasion may undergo 
rescreening on 1 more occasion only. Eligibility for inclusion within the study will be 
performed at a site level and not by the CRC.   
For patients meeting the eligibility criteria for primary treatment failure to aflibercept (see 
Section 4.1 for definitions), a minimum of 28 days but no more than 40 days should have 
passed since the last IVT injection of aflibercept before the Baseline Visit (Day 1) occurs. The 
source data will need to verify the patient fulfils eligibility criteria for this subgroup.
For patients meeting the eligibility criteria for suboptimal treatment response to aflibercept 
(see Section 4.1 for definition), a minimum of 28 days but no more than 70 days should have 
passed since the last IVT injection of aflibercept before the Baseline Visit (Day 1) occurs. The 
source data will need to verify the patient fulfils eligibility criteria for this subgroup.  
                                                
 
 


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Monthly Treatment period: Day 1 to Day 60
Eligibility criteria will be confirmed by the Investigator at Baseline and BCVA, retinal and
choroidal imaging, and pre-therapy adverse events will be evaluated before the first IVT
injection of ranibizumab 0.5mg.  
Repeat efficacy and safety assessments
(see Table 6-1) and IVT ranibizumab injections will occur at Day 30 and Day 60 visits.
Injections of IVT ranibizumab to the study eye should occur on the same day as the scheduled 
study visit.
All subjects will attend Scheduled Study Visits every 30 (±7) days.
PRN treatment period: Day 61 to Day 180
Efficacy and safety assessments will be repeated (see Table 6-1) at Day 90, 120, 150 and 180.  
All subjects will attend Scheduled Study Visits every 30 (±7) days. The primary endpoint will 
be evaluated when patients have completed assessments at the Day 90 visit.  
Between the Day 90 and Day 150 visits inclusive, the decision to administer ranibizumab 
0.5mg will be at the discretion of the Investigator and driven either by persistent or worsening 
visual symptoms attributed by the Investigator to nAMD, or worsening visual acuity (>1 letter 
decline since last Study Visit) or by the presence of persistent or worsening disease activity on 
OCT.  Source documentation must provide evidence for one or more of these retreatment 
criteria.  Injections of IVT ranibizumab to the study eye, where required, should occur on the 
same day as the scheduled study visit. 
Final efficacy and safety assessments will be conducted at Day 180.
                                                
Persistent or worsening disease activity on OCT includes the presence of sub-retinal fluid, persistent or 
increased number, size or total volume of IRCs, or increased central retinal or foveal thickness, or similar 
quantitative retinal imaging data recorded within the individual patient record.


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3.2
Rationale of study design
This study can be considered exploratory in nature as there are no published data describing 
the efficacy of switching treatment from aflibercept to ranibizumab in patients with nAMD
where either no treatment response has been achieved or where there is suboptimal treatment 
response.  It is recognized that there are potential patient and Investigator derived sources of 
bias in this study due to the unmasked design, but these are acceptable bearing in mind the 
exploratory nature of the study.  A parallel group design to include either a sham injection 
group or continued injection of aflibercept cannot be justified at this stage as the patient 
population most likely to benefit from a switch from aflibercept to ranibizumab is unknown 
and there are insufficient data to assist in the development of sample size calculations that 
allow robust statistical conclusions to be achieved on potential between group differences.
The design of the study also reflects current clinical practice where patients who achieve 
suboptimal treatment responses with one anti-VEGF therapy will be switched to an alternative 
anti-VEGF therapy.  The 6 month duration of the study is also reflective of the timeframe 
used in clinical practice to assess whether patients are likely to achieve a meaningful clinical 
response to an anti-VEGF therapy.
3.3
Rationale of dose/regimen, route of administration and duration 
of treatment
In this study, ranibizumab will be administered at the SmPC and other product labels
approved dose of 0.5mg and the dosing regimen is consistent with current clinical practice 
where re-treatment decisions are based not only on changes in VA but also on retinal 
morphology changes that may be indicative of disease activity (Myolonas 2009).  Historical 
data from a number of clinical trials demonstrate that 0.5mg ranibizumab offers a favorable
benefit-risk profile. Ranibizumab is administered as an IVT injection to maximize the 
bioavailability of the drug at the site of pathology while minimizing systemic exposure.
The posology section of the SmPC for ranibizumab recommends monthly injections until 
maximum visual acuity is achieved with additional injections thereafter in the event of a loss
of visual acuity due to nAMD. In this study, this re-treatment criterion will be applied 
although in addition re-treatment will occur based on measures of increasing or persistent 
retinal disease activity as these are commonly used in clinical practice. The permitted interval 
between ranibizumab injections will be 23 to 37 days during the Monthly Treatment period 
and 23 days or greater during the PRN Treatment period.  This study design is in keeping with 
the posology used in other prospective studies with ranibizumab in nAMD.
3.4
Rationale for choice of comparator
No comparator will be used in this study.


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3.5
Purpose and timing of interim analyses/design adaptations
An interim analysis will be conducted after the first 50 patients complete the 90 day study 
visit. The primary objective for this analysis is to provide preliminary safety data in the 
proposed population of patients with nAMD. The secondary objective is to provide 
preliminary efficacy data.
3.6
Risks and benefits
The risk to subjects in this trial will be minimized by compliance with the eligibility criteria 
and study procedures and close clinical monitoring.  The management and monitoring of 
patients in this study reflects both the recommendations within the IB, SmPC, other 
international product labelling, and current clinical practice; there are no clinically relevant 
disadvantages from participating in this study. The risks associated with use of ranibizumab 
are well described in the IB, product labelling and patient information leaflet. 
Patients who provide informed consent and enter this study, are currently not achieving 
optimal treatment response with aflibercept.  The potential benefit to participants is that 
disease activity may be stabilized or improved with ranibizumab.  
4
Population
The study will include patients diagnosed with visual impairment due to nAMD who have 
been treated with aflibercept and where either no treatment response has been achieved or 
where there is suboptimal treatment response.  Assuming an approximate 20% screen failure 
rate, approximately 155 patients will need to be screened to have 124 eligible patients 
commencing treatment in the trial.  Approximately 40 ophthalmology centers in Western 
European countries will be initiated.
It is anticipated that patients with primary treatment failure to aflibercept (see Section 4.1 for 
definition) are likely to achieve small responses to treatment with ranibizumab.  In order to 
minimize potential risks to these patients, a maximum of 30 patients will be recruited in this 
subgroup.
4.1
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
Inclusion criteria for patient
1. Written informed consent must be obtained before any assessment is performed.
2. Age ≥50 years. 
3. BCVA ≥23 ETDRS letters, at both the Screening Visit and Baseline Visit in the Study 
eye. 
4. Active, angiographically documented CNV lesion in study eye (e.g. leakage on 
fluorescein angiography plus intraretinal, subretinal or sub-retinal pigment epithelium 
(RPE) fluid on SD/HD-OCT) secondary to AMD at Screening.


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5. Evidence of active CNV involving the center of the fovea in the study eye (e.g. 
pigment epithelium detachment, subretinal or sub-RPE hemorrhage, macular edema, 
or subretinal, sub-RPE or intraretinal fluid) at Baseline.
6. The total area of fibrosis in the study eye comprising less than 50% of the lesion area.
Patient subgroup specific inclusion criteria
Patients need to meet all the criteria for one of the following two groups:
Group 1. Primary treatment failure
7. No prior anti-VEGF treatment prior to initiating aflibercept.
8. Received no more than 3 injections of aflibercept into the study eye prior to the 
Screening Visit.
9. Historical OCT volume scan acquired ≤28 days before the first aflibercept injection 
was administered to the study eye.
10. Initiated treatment with aflibercept <130 days prior to the Screening Visit.
11. Last injection of aflibercept was ≥28 days but ≤40 days prior to the Baseline visit. 
12. No increase in BCVA (≥5 letters) since commencing treatment with aflibercept.
13. Disease activity has never been controlled in the study eye after initiating aflibercept 
as defined by at least one of the following observed on a historical OCT volume scan 
acquired after a minimum of 2 aflibercept injections: evidence of unchanged or 
increasing retinalor sub-retinal fluid; new PED; unchanged or increasing size of pre-
existing PED. 
Group 2. Suboptimal treatment response
14. No prior anti-VEGF treatment prior to initiating aflibercept.
15. Aflibercept commenced ≥6 months prior to the Screening Visit.
16. Received ≥3 aflibercept injections into the study eye within 6 months of the Screening 
Visit.
17. Historical OCT volume scan acquired ≤28 days before the first aflibercept injection 
was administered to the study eye.
18. Evidence of previous reduced disease activity in the study eye after initiating 
aflibercept as defined by reduction of ≥50µm in central subfield retinal thickness
observed on a historical OCT volume scan acquired after a minimum of 2 aflibercept 
injections.
19. Last injection of aflibercept was ≥28 days but ≤70 days prior to the Baseline visit.
20. At Screening Visit, disease activity has worsened (as defined by increasing retinalor 
sub-retinal fluid, or new or increasing size of PED) in the study eye compared to prior 
visits.
                                                
Evidence of increasing retinal fluid may include increased number, size or total volume of IRCs, or increased 
central retinal or foveal thickness, or similar quantitative retinal imaging data recorded within the individual 
patient record


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4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the Investigator, in order to ensure that the study 
population will be representative of all eligible patients.
Exclusion criteria for patient
1. Inability to comply with study or follow-up procedures.
2. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
hCG laboratory test.
3. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during 
dosing of study treatment. Effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of 
the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. 
In case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment.

Male sterilization (at least 6 months prior to screening). For female subjects in 
the study, the vasectomized male partner should be the sole partner for that 
subject.

Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.

Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone 
contraception.

Placement of an intrauterine device (IUD) or intrauterine system (IUS).
In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking 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) 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.


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Exclusion criteria for systemic medical history and conditions
4. History of cerebrovascular accident, transient ischemic attack or myocardial infarction 
within 3 months of the Screening visit.
5. Any type of systemic disease or its treatment, including any medical condition 
(controlled or uncontrolled) that could be expected to progress, recur, or change to such 
an extent that it may bias the assessment of the clinical status of the patient to a 
significant degree or put the patient at special risk.
6. Uncontrolled blood pressure defined as a persistent systolic value of >160 mm Hg or 
persistent diastolic value of >100 mm Hg at Screening or Baseline.
7. Simultaneous participation in any other clinical study for the duration of this study.
8. Use of other investigational drugs (excluding vitamins and minerals) or participation in 
any other clinical study within 90 days or 5 half-lives of the Screening visit, or until the 
expected pharmacodynamic effect has resolved, whichever is longer.
9. History of hypersensitivity to either ranibizumab (or any component of the ranibizumab 
formulation), or fluorescein, or indocyanine green, or to drugs of similar chemical 
classes.
Exclusion criteria for ocular medical history and conditions
For either eye
10. Any active periocular or ocular infection or inflammation (e.g., blepharitis, conjunctivitis,
keratitis, scleritis, uveitis, endophthalmitis) at the time of Screening or Baseline.
11. Uncontrolled glaucoma (intraocular pressure [IOP] ≥30 mm Hg on medication or 
according to Investigator’s judgment) at the time of Screening or Baseline.
12. Evidence of bilateral active CNV during the Screening Period or at Baseline requiring 
bilateral anti-VEGF injections. Patients with active CNV in the study eye with quiescent 
CNV in the fellow eye who may have received IVT aflibercept or ranibizumab injections 
into the fellow eye >40 days prior to the Screening visit are not excluded from the study; 
however, should the fellow eye require anti-VEGF treatment during the study only 
ranibizumab may be utilized.
13. Prior intravitreal injection of ranibizumab or bevacizumab into the study eye and/or prior 
intravitreal injection of bevacizumab into the fellow eye
Study eye exclusion criteria 
14. At Baseline, intraocular surgery was performed within the previous 28 days or 
intraocular surgery is planned at any time during the 6 month study period.
15. Cataract (if causing significant visual impairment), aphakia, severe vitreous hemorrhage, 
rhegmatogenous retinal detachment, proliferative retinopathy or choroidal 
neovascularization of any other cause for CNV other than wet AMD (e.g., ocular 
histoplasmosis, pathologic myopia (≥-6 dioptres)) at the time of Screening and Baseline.
16. Irreversible structural damage involving the center of the fovea (e.g. advanced fibrosis or 
geographic atrophy) which in the opinion of the Investigator is sufficient to irreversibly 
impair visual acuity.


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17. Polypoidal choroidal vasculopathy (PCV), RPE tear, central serous retinopathy (CSR), 
or significant vitreomacular traction identified during Screening period or within 4 
months of Baseline visit. Note that small vitreomacular adhesions that do not result in 
deformity of the retina are permitted.
18. Any other ocular abnormality unrelated to AMD that is in the Investigator’s opinion is 
likely to contribute to progressive deterioration in visual acuity over the next 6 months.
19. Prior laser therapy or use of verteporfin photodynamic therapy.
20. Prior use of intra- or peri-ocular corticosteroids within 6 months of Screening. 
21. Unable to obtain at Screening SD/HD-OCT images of sufficient quality to be analyzed.
5
Treatment
5.1
Protocol requested treatment
5.1.1
Investigational treatment
The investigational treatment/study drug in this study is ranibizumab 0.5mg (Lucentis®).
Ranibizumab solution for injection will be supplied in either pre-filled syringes (PFS) or vials
according to local availability.  Each PFS or vial contains ranibizumab in a concentration of 
10mg/ml (labeled as RFB002 0.5mg/0.05ml, corresponding to a 0.5mg dose). 
Study medication will be supplied in commercially available packaging. Each vial or PFS will 
be labeled with the appropriate information. Medication labels will comply with the legal 
requirements and be printed in the local language. The storage conditions will be described on 
the label. 
Ranibizumab is formulated as a sterile solution aseptically filled in a sterile glass vial or PFS. 
Each vial/PFS contains ranibizumab in an aqueous solution (pH 5.5) with histidine, trehalose 
and polysorbate 20. The vial/PFS contains no preservatives. It is suitable for single use only 
and the content of the vial/PFS must not be split. Ranibizumab must be stored according to 
label instructions and it must be kept in a secure locked facility.
5.1.2
Additional study treatment
No additional treatment beyond investigational treatment is requested for this trial.
5.2
Treatment arms
All eligible patients will be assigned to active treatment with ranibizumab.


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5.3
Treatment assignment, randomization
This is not a randomized study.  Patients will meet eligibility criteria for either the primary 
treatment failure subgroup or the secondary suboptimal response subgroup (see Section 4.1).  
Recruitment of patients into the primary treatment failure subgroup will be up to a maximum 
of 30 patients. Recruitment to this subgroup will be closed once this number of patients has 
been allocated to the primary treatment failure subgroup, and have both successfully 
completed the Screening assessments and confirmation of eligibility has been entered into the 
eCRF.
At the Baseline Visit (Day 1), all eligible patients will receive IVT injection of ranibizumab 
0.5mg into the study eye.  Repeat ranibizumab injections will only occur at scheduled study 
visits; i.e. at Day 30 (±7) and Day 60 (±7).  Repeated ranibizumab injections may also occur 
according to the protocol defined re-treatment criteria (see Section 5.5.4) at Day 90 (±7) and 
Day 120 (±7). After each visit has been performed the eCRF needs to be updated with the 
details of whether an injection has been administered or not.  
5.4
Treatment masking
This is an open-label study and neither Investigators nor patients are masked.
5.5
Treating the patient
5.5.1
Subject numbering
Each patient is uniquely identified in the study by a combination of his/her center number and 
subject number. The center number is assigned by Novartis to the investigative site. Upon 
signing the informed consent form, the patient is assigned a subject number by the 
Investigator. At each site, the first patient is assigned subject number 01, and subsequent 
patients are assigned consecutive numbers (e.g. the second patient is assigned subject number
02, the third patient is assigned subject number 03).  Once assigned to a patient, the subject 
number will not be reused. This also applies to the situation in which a patient has initially 
failed screening but at a later stage meets all eligibility criteria.  It is then possible to re-screen 
the same patient but a new subject number has to be assigned. As long as the recruitment 
phase has not yet ended, re-screening (on one occasion only) is possible.
The site should enter the data into the eCRF for that patient using the individual subject
number.  Only the assigned subject number should be entered in the field labeled “Patient ID” 
on the eCRF data entry screen (e.g. enter ‘01’, ‘02’, etc.). If the patient undergoes screening 
but fails to meet the eligibility criteria, the reason(s) will be entered on the Screening Log and 
the Demography eCRF should be completed.
If the patient is eligible for treatment but fails to be treated at the Baseline visit for any reason, 
the reason(s) for not being treated should be entered on the Screening Log and the 
Demography eCRF should be completed.    Re-screening (on one occasion only) may be 
possible for these patients.


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5.5.2
Dispensing the investigational treatment
Within each participating country, each study site will be supplied by Novartis with 
investigational treatment (study drug) in commercially available packaging, labelled 
according to local legal requirements. The decision to administer study drug to the patient is 
made according to the protocol specified treatment regimen.  
5.5.3
Handling of study treatment
5.5.3.1
Handling of investigational treatment
Investigational treatment (study drug) must be received by a designated person at the study 
site, handled and stored safely and properly, and kept in a secured location to which only the 
Investigator and designees have access.  Upon receipt, all investigational treatment should be
stored according to the instructions specified on the labels. Clinical supplies are to be 
dispensed only in accordance with the protocol. Technical complaints are to be reported to the 
respective Novartis CPO Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the investigational treatment but no 
information about the patient.
The Investigator must maintain an accurate record of the shipment and dispensing of 
investigational treatment in a drug accountability log. All used vials/PFS packaging should be 
kept until monitoring of drug accountability has been completed by the field monitor. 
Monitoring of drug accountability will be performed by the field monitor during site visits and 
at the completion of the trial.
At the conclusion of the study, and as appropriate during the course of the study, the 
Investigator will return all unused investigational treatment, packaging, drug labels, and a 
copy of the completed drug accountability log to the Novartis monitor or to the Novartis 
address provided in the Investigator folder at each site.
5.5.3.2
Handling of other study treatment
Not applicable.


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5.5.4
Instructions for prescribing and taking study treatment 
For the entire trial, ranibizumab should be administered in the study eye on the day of the 
scheduled study visit. In the event that a protocol specified ranibizumab injection into the 
study eye is delayed for more than 7 days following the scheduled study visit, a protocol 
deviation will be recorded but the patient may continue in the study.  The assessments 
required as part of an Unscheduled Visit should be conducted and recorded in the eCRF (see 
Section 6).  The Investigator should make every effort to resume the protocol specified 
timings for scheduled study visits and simultaneous ranibizumab injections to the study eye.  
Repeat ranibizumab injection into the study eye may not be administered sooner than 23 days 
after the last ranibizumab injection into the study eye.
Instructions on how to prepare and administer ranibizumab for IVT injection using the PFS or 
vial should follow the locally approved product information leaflet. Details of all PFS and 
vials administered will be recorded in the eCRF.  Standard local practice should be applied in 
the peri-injection management of patients and should be consistent with the local labelling
and/or IB.  
The injection procedure should be carried out under aseptic conditions, which includes the use 
of surgical hand disinfection, sterile gloves, a sterile drape and a sterile eyelid speculum (or 
equivalent) and the availability of sterile paracentesis (if required).  Adequate anesthesia and a 
broad-spectrum topical microbicide to disinfect the periocular skin, eyelid and ocular surface 
may be administered prior to the injection, in accordance with local practice.  The injection 
needle should be inserted 3.5-4.0 mm posterior to the limbus into the vitreous cavity, avoiding 
the horizontal meridian and aiming towards the center of the globe. The injection volume of 
0.05 ml is then delivered; a different scleral site should be used for subsequent injections.
Both intraocular pressure and the perfusion of the optic nerve head must be monitored and 
managed appropriately following IVT injection of ranibizumab.  
5.5.4.1
Monthly Treatment Period: Day 1 to Day 60
After eligibility confirmation at Baseline (Day 1), all patients will receive IVT injection of
ranibizumab into the study eye.  Re-treatment with IVT injection of ranibizumab will occur 
on Day 30 and Day 60.


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5.5.4.2
PRN Treatment Period: Day 90 to Day 180
All patients will have monthly assessments of BCVA and disease activity assessed by OCT.  
These assessments, together with an assessment of the patient’s visual symptoms, will be used 
for the decision of potential re-treatment with ranibizumab.  This PRN regimen, will permit 
re-treatment with ranibizumab at Day 90, Day 120 and/or Day 150 if in the opinion of the 
Investigator persistent or worsening visual symptoms are attributed to nAMD, and/or if there 
is evidence of worsening ETDRS best corrected visual acuity (>1 letter decline since last 
Study Visit) and/or the presence of persistent or worsening disease activity on OCT.  Source 
documentation must provide evidence for one or more of these retreatment criteria.
5.5.4.3
Treatment of the Fellow Eye
Patients who develop visual impairment due to nAMD in the fellow eye (non-study eye)
during the study that, in the Investigator’s opinion, qualifies for and requires treatment, may
be treated at the Investigator’s discretion according to the standard of care, including ocular
administration with ranibizumab. This eye is then called the fellow treated eye.
Ranibizumab will be provided by the Sponsor (supplied for investigational treatment) and
should be administered according to the SmPC or local labelling. Details of all PFS and vials 
administered will be recorded on drug accountability forms and a record of the administration 
also included in the eCRF.
Treatment of the fellow eye must be scheduled in a way not to disturb the schedule for visits
and treatments of the study eye. Ideally injection of the fellow eye should occur on the same 
day as a scheduled study visit in order to minimize the total number of clinic visits required 
by the patient.  Bilateral IVT injections of ranibizumab may occur at any scheduled study visit 
between Day 30 and Day 150.  The fellow treated eye must be monitored according to routine 
practice and AE(s) and SAE(s) must be captured in the eCRF. Should injection of the fellow 
eye occur at a visit other than a scheduled study visit, this should be recorded in the eCRF as 
an unscheduled study visit and all protocol specified procedures for an unscheduled visit 
should be completed (see Section 6).
If in the Investigator’s opinion, the fellow eye requires further treatment with ranibizumab, 
this should not occur more frequently than monthly in accordance with the posology section 
of the SmPC.  A protocol deviation will be recorded should the patient receive a repeat 
ranibizumab injection into the fellow eye less than 23 days after the previous injection into the 
fellow eye.  However, the patient will not be withdrawn from the study. 
At the time when treatment of the fellow eye is being initiated, the BCVA assessment for the 
fellow eye should be repeated and recorded in the eCRF.
Treatment with other anti-VEGF medication other than ranibizumab is prohibited in either eye
at any time during the study.
                                                
Persistent or worsening disease activity on OCT includes the presence of sub-retinal fluid, persistent or 
increased number, size or total volume of IRC, or increased central retinal or foveal thickness, or similar 
quantitative retinal imaging data recorded within the individual patient record.


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Treatment for non-nAMD indications with anti-angiogenic drugs including ranibizumab in the 
fellow eye is prohibited.
5.5.5
Permitted dose adjustments and interruptions of study treatment
Dose adjustments, i.e., adjustments of the injection volume of ranibizumab dose solution, are 
not permitted. Adjustments of the PRN dosing regimen of ranibizumab that is described as 
part of the study treatment administration in Section 3.1, and Section 5.5.4 are not permitted.
Ranibizumab treatment should be withheld and treatment should not be resumed earlier than 
the next scheduled treatment in the event of:

an IOP of ≥30 mm Hg,

an untreated retinal tear is diagnosed,

active or suspected ocular or periocular infections,

active severe intraocular inflammation.
5.5.6
Rescue medication 
No rescue medication is permitted in this study.
5.5.7
Concomitant treatment
The Investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications (including for non-
ophthalmic conditions), procedures and significant non-drug therapies (including physical 
therapy and blood transfusions) administered after the patient was enrolled into the study must 
be recorded in the eCRF.
Medications that may be used as part of the protocol specified retinal image acquisition (e.g., 
mydriatic drops, fluorescein dyes) and pre- and post-injection medications (e.g., topical 
anesthetics, topical antimicrobials) used by a patient during the study, are not considered 
concomitant medications.
If a patient requires intraocular surgery on the study eye during the course of the study, the 
patient should be withdrawn from the study. 
5.5.8
Prohibited Treatment
Use of treatments, as displayed in Table 5-1 is NOT allowed after the Screening visit and for 
the duration of the study. In addition, there are certain wash-out periods to be respected as 
outlined in the list of exclusion criteria.
Please see Table 5-1 below for actions to be taken, apart from stopping the prohibited
medication taken.


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Table 5-1
Prohibited treatment
Medication
Action to be taken
Anti-VEGF drugs other than ranibizumab (ocular or systemic)
Withdraw patient from study
Intra- or periocular corticosteroids (including sub-tenon but 
excluding topical formulations) – study eye only
Withdraw patient from study
Intra-ocular corticosteroid implants – study eye only
Withdraw patient from study
Investigational drugs and interventions of any type
Withdraw patient from study
5.5.9
Discontinuation of study treatment
Patients may voluntarily discontinue study treatment for any reason at any time. 
The study and treatment completion dates will be determined by the last visit the patient came 
to the clinic.
The Investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. Patients who are 
prematurely withdrawn from the study will not be replaced by an equal number of newly 
enrolled patients.
Patients can discontinue study treatment because of the appearance of a new health condition 
suspected to require appropriate care or require medications prohibited by the protocol 
(Section 5.5.8), unacceptable AEs, refusal to continue treatment, or at the Investigator’s 
discretion based on his or her clinical judgment.
The Investigator should discontinue study treatment for a given patient or withdraw the 
patient from study if, on balance, he/she believes that continuation would be detrimental to the 
patient’s well-being.
Study treatment must be discontinued under the following circumstances:

Withdrawal of informed consent

Emergence of the following AEs:
o
Stage 3 or 4 macular hole
o
Stroke or transient ischemic attack
o
Rhegmatogenous retinal detachment

Pregnancy

Use of prohibited treatment in Table 5-1

Two sequential ranibizumab injections to the study eye should have occurred 
according to the protocol specified monthly/PRN treatment period criteria but were 
withheld (see Section 5.5.5) or missed. 


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
Any other protocol deviation that results in a significant risk to the patient’s safety.
Patients who permanently discontinue study treatment and start a prohibited non-study 
treatment (see Section 5.5.8) should be withdrawn from the study and undergo all assessments 
for End of Study visit as described in Table 6-1 and Table 6-2.
Patients who discontinue study treatment but do not receive prohibited treatment should not 
be considered withdrawn from the study and may continue their scheduled follow-up 
assessments until End of Study.
The Completion/Withdrawal eCRF page should be completed, providing the primary reason 
for stopping study treatment.
5.5.10
Withdrawal of 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 want any further visits or assessments and does not want any further 
study related contacts and does not allow analysis of already obtained biologic material.
If a patient withdraws consent, the Investigator must make every effort (e.g. telephone, e-mail, 
letter) to determine the primary reason for this decision and record this information in the 
eCRF. Study treatment must be discontinued and no further assessments conducted. All 
biological material that has not been analyzed at the time of withdrawal must not be used. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
The Completion/Withdrawal eCRF page should be completed, providing the primary reason 
for stopping study treatment.
5.5.11
Loss to follow-up
For patients who are lost to follow-up (i.e., those patients whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the Investigator should 
show due diligence by documenting in the source documents the steps taken to contact the 
patient (e.g., dates of telephone calls, registered letters).
The Completion/Withdrawal eCRF page should be completed, providing the primary reason 
for stopping study treatment.
5.5.12
Emergency breaking of assigned treatment code 
Not applicable as all patients will receive ranibizumab 0.5mg


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5.5.13
Study completion and post-study treatment 
Patients who already have entered the Screening Period should not enter the Treatment Period 
once the planned number of patients has been found eligible to commence treatment in the 
study.
The Investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.
Patients who successfully complete all study assessments of the study through to Day 180 will 
be considered to have completed the study.
The study is considered as completed once, according to the study protocol, all protocol
required activities have been executed in all treated patients.
No extension study has been planned.
Following completion of the study, all patients will be provided with appropriate ongoing care 
according to the Investigator’s or treating ophthalmologist’s judgment. 
5.5.14
Early study termination 
The study can be terminated at any time and for any reason by Novartis.  Should this be 
necessary, the patient should be seen as soon as possible and treated as described in Section 6 
for 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 will be responsible for informing the 
local IEC of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 and Table 6-2 list all the assessments and procedures to be performed by study 
visits.
All data obtained from these assessments must be supported in the patient’s source 
documentation. Assessments are indicated with an “X” when they need to be performed.
A planned study visit schedule will be established at the time of Baseline visit (Day 1) for all 
patients. Study assessments will be performed at the Screening visit, Baseline (Day 1), and at 
Day 30, Day 60, Day 90, Day 120, Day 150 and Day 180, ± 7 days to allow for flexibility in 
scheduling. In addition, the Screening visit may be performed over a maximum of 2 
consecutive days; if this occurs, the last day must be entered as the visit date in the eCRF
Should a deviation from the study visit schedule occur, all efforts should be made to return to 
the planned visit schedule taking into consideration the restrictions on the minimum treatment 
interval between ranibizumab treatments which should be ≥ 23 days.
At a minimum, patients will be contacted and reviewed in the clinic for safety evaluations 
either at Day 180 (±7) days, or during the 30 days following the last administration of study 
treatment. Documentation of attempts to contact the patient should be recorded in the source 
documentation. 


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Should unscheduled study visits occur, the Investigator will ask the patient for information 
regarding the use of concomitant medications and new or ongoing adverse events, which will 
be recorded in source documentation and in the eCRF. BCVA for both eyes, vital signs and 
ranibizumab injections that occur at unscheduled study visits will also be recorded in the 
eCRF.  


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Table 6-1
Assessment schedule (Eligibility criteria, demographics & baseline characteristics, imaging procedures)
Screening
V1
Baseline
V2
V3
V4
PEV
V5
V6
V7
EOS or 
EWV
V8
UNSCHED V
Days relative to Day 1
(permitted time window)
Primary treatment 
failure≤40 days
Suboptimal treatment 
response≤70 days 
prior to Baseline visit
1
30±7
60±7
90±7
120±7
150±7
180±7
Informed consent
X
Review of 
inclusion/exclusion criteria
X
X
Diagnosis
X
Demography
X
Medical History
X
X
Prior/concomitant meds
X
X
X
X
X
X
X
X
X
Serum pregnancy test
X
BCVA score (ETDRS)
X*
X*
X
X
X*
X
X
X*
X*
Historical retinal images 
collected
X
Ophthalmic examination
X
X
X
X
X
X
X
X
OCT (retina and choroid)
X
X
X
X
X
X
X
X
Color fundus photography
X
X
Fluorescein angiography
X
X
Fundus autofluorescence
X
X
Indocyanine green 
angiography 
X
PEV: Primary Endpoint Visit.  EOS: End of Study visit also incorporates the Early Withdrawal Visit (EWV).   UNSCHED V: Unscheduled visit
* Assessment to be performed also on fellow-eye; where ranibizumab treatment is initiated in the fellow-eye BCVA is to be repeated and recorded in the eCRF prior to injection.


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Table 6-2 Assessment schedule (peri-injection procedures, safety assessments and venous blood sample collection)
Screening
V1
Baseline
V2
V3
V4
PEV
V5
V6
V7
EOS or 
EWV
V8
UNSCHED V
Dispense topical 
antibiotic medication
according to local 
practice
(X)
(X)
(X)
(X)
(X)
(X)
Ranibizumab injection
X
X
X
(X)
(X)
(X)
Post-injection 
assessments
X
X
X
(X)
(X)
(X)
Vital signs
X
X
X
X
X
X
X
X
X
Height and Weight
X
Adverse events
X
X
X
X
X
X
X
X
X
PEV: Primary Endpoint Visit.  EOS: End of Study visit also incorporates the Early Withdrawal Visit (EWV). UNSCHED V: Unscheduled visit
(X) Indicates that local standard practice should be applied or in the case of ranibizumab injection, that Investigator judgment is used to determine whether repeat injection is required.


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6.1
Information to be collected on screening failures
All patients who have signed informed consent but not initiated study treatment at Baseline 
will be considered Screen Failures. For these patients demographics, inclusion/exclusion
fulfillment, and adverse event (AE) data will be collected. The Completion/Withdrawal page 
in the eCRF will be completed.
6.2
Patient demographics/other baseline characteristics
Patient demographic and baseline characteristics to be collected on screened patients
include:

Demography: year of birth, gender, race, ethnicity

Relevant medical history/current medical condition data includes data until the 
informed consent form is signed. Where possible, diagnoses and not symptoms will be 
recorded. Investigators will have the discretion to record abnormal test findings on the 
medical history eCRF whenever the test abnormality occurred before the informed 
consent signature

Study eye selection

Baseline characteristics

Prior utilization of aflibercept (number and dates of injections into one or both eyes)

Other assessments performed at Screening to determine eligibility are listed in Table 
6-1.
At the Baseline visit and after review of eligibility criteria, patients will be allocated to either 
the primary treatment failure subgroup or to the suboptimal treatment response subgroup.
6.3
Treatment exposure and compliance
Treatment exposure
Treatment exposure to ranibizumab will be assessed for both study eye and fellow treated eye
as well as total exposure (study eye and fellow eye). Information regarding study treatment 
administration (ranibizumab) in the study eye will be collected on the drug administration 
record eCRF. Treatment of the fellow eye with ranibizumab will be captured on a separate 
eCRF.
The reason for dosing of ranibizumab or the reason for dose/no dose will be described on the
drug administration record eCRF for the study eye.
At every visit, it needs to be reported within the eCRF if treatment or no treatment with study 
drug has been administered to the patient both for the study eye and the fellow eye.
In addition, confirmation of disease activity as assessed by the Investigator through functional
and anatomical parameters detected by BCVA and OCT will be captured for the study eye 
(please see Section 5.5.4.2).


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Compliance to treatment regimen
The evaluation of compliance will assess whether ranibizumab injections were administered 
according to the protocol specified regimen during the monthly treatment period and 
according to the Investigator’s assessment of disease activity during the PRN treatment period.
6.4
Efficacy
All efficacy assessments are to be performed on the study eye and recorded in the eCRF. 
Efficacy assessments will include both functional and anatomical evaluations. The methods of 
evaluation and the parameters to be assessed are described below.
These assessments are performed according to the schedule in Table 6-1 and Table 6-2.
Study eye selection:
The Investigator will designate the study eye based on the pre-specified eligibility criteria at 
the Screening visit and will confirm his/her decision at the Baseline visit. As described in 
Section 4.2, patients are ineligible to participate in the study if there is evidence of bilateral 
active CNV at Baseline requiring bilateral anti-VEGF treatment. The decision as to the 
selection of the study eye needs to be documented in the eCRF and in the source documents
of the patient. The study eye is the one treated with the study treatment, assessed according to
protocol requirements and as outlined in the assessment schedule (Table 6-1 and Table 6-2)
and data collected on the study eye are used for the evaluation of efficacy objectives of the
study. At visits when ranibizumab treatment is administered, efficacy assessments must be
conducted prior to administration of ranibizumab.
At all visits where efficacy assessments are conducted, BCVA should be assessed first before 
mydriatic drops are applied to the study eye in order to acquire ophthalmic images.
6.4.1
Optical Coherence Tomography
Optical Coherence Tomography (OCT) images are to be taken using High Definition 
(HD)/Spectral Domain (SD) optical coherence tomography (OCT) equipment. Patients must 
be assessed using the same machine throughout the course of the study. 
The Investigator will perform OCT at visits indicated in Table 6-1 according to a standardized 
imaging protocol as specified in the Procedure Manual. The information collected will be 
used by the Investigator to assess the status of disease activity; i.e., decisions on subject 
eligibility as well as decisions on PRN treatment are based on his/her own evaluation. 
The Investigator will send the digital raw images taken monthly from Screening to Day 180 to 
the Central Reading Center (CRC) as soon as possible after the Scheduled Study Visit; the 
images will be transferred electronically using the dedicated SD/HD-OCT software format. 
No transmission of imaging data on print-outs will be accepted. The captured images will 
contain quantitative parameters (i.e., the Subfoveal Retinal Thickness (SRT), the Central 
Subfield Retinal Thickness (CSRT), Central Subfield Retinal Volume (CSRV), PED height, 
SRF volume, IRC volume, and the subfoveal choroidal thickness), as well as the presence or 
absence of qualitative parameters (IRC, intraretinal fluid, SRF, hemorrhage, dry retina, or 
other). The CRC will evaluate the images and the results of the CRC assessments will be 
transferred to the CRO responsible for data management. 


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The CSRT represents the average retinal thickness (µm) of the circular area within 1 mm 
diameter around the foveal center. The CSRV represent the total retinal volume (µm3) of the 
circular area within 1mm around the foveal center. Both CSRT and CSRV are based on the 
automatically determined values from the dedicated SD/HD-OCT software. Before accepting 
the values provided by the dedicated SD/HD-OCT software, the OCT image acquisition 
technician must ensure adequate image quality for the assessment of the CSRT. Specifically 
the technician must exclude any artifacts of the automated segmentation. If artifacts are 
identified, a manual correction of segmentation lines must be done. 
The SRT represents the retinal thickness (µm) measured at the focal center point (center of the 
anatomical fovea). It is determined on the single most central B-scan with the vitreo-retinal 
interface as the upper boundary and the lower border of band 4 (presumably RPE/Bruch’s 
membrane) as the lower boundary. 
The CRC will provide each site with a manual giving instructions and guidance on how to
acquire, export and transfer OCT images. All investigational site personnel performing OCT
assessments will be certified by the CRC prior to any study assessments taking place.
Historical OCT images for individual patients will also be evaluated by the CRC.  Pseudo-
anonymized historical retinal images (including one OCT volume scan acquired no greater 
than 28 days before the first IVT injection of aflibercept was administered to the study eye) 
will be collected and electronically transferred to the CRC.  In addition, pseudo-anonymized 
historical retinal OCT images acquired after a minimum of 2 aflibercept injections indicating 
either no change or worsening disease activity (primary treatment failure subgroup) or an 
improvement in retinal morphology as defined by a reduction of ≥50µm in CSRT (suboptimal 
treatment response subgroup) will also be collected and transferred to the CRC. The data (i.e.,
copies of OCT images with relevant written Investigator interpretation) supporting these 
requirements should be recorded within the source documentation.
6.4.2
Color Fundus Photography, Fluorescein and Indocyanine Green 
Angiography
Fluorescein angiography (FA) is to be done in conjunction with color fundus photography 
(CF) at visits indicated in Table 6-1.  Indocyanine green angiography (ICGA) is to be 
performed at Screening in all patients in order to determine eligibility for participation in the 
study. Imaging systems used in the study must be registered at the CRC, however individual 
certification by the CRC of site personnel to conduct FA, CF and ICGA imaging will not be 
required.
The Investigator will electronically send FA and CF images taken at Screening and Day 180, 
to the CRC. The ICGA images taken at Screening will also be transferred to the CRC. No 
print-outs will be accepted.
 
 and 
presence/absence of PCV and RAP.   The results of the CRC assessments will be transferred 
to the CRO responsible for data management.
The CRC will provide each site with a manual giving instructions and guidance on how to 
acquire and transfer FA, CF and ICGA images as applicable.


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6.4.3
Fundus autofluorescence
Fundus autofluorescence (FAF) is to be done at visits indicated in Table 6-1. Imaging systems 
used in the study must be registered at the CRC and will include systems utilizing either 
confocal scanning laser ophthalmoscopy or fundus camera FAF.  Individual certification by 
the CRC of site personnel to conduct FAF imaging will not be required.
The Investigator will electronically send FAF images taken at the Screening and Day 180 to 
the CRC. 
 
 
 As applicable, the CRC data will be used for the 
evaluation of the objectives having anatomical parameters as endpoints.
The CRC will provide each site with a manual giving instructions and guidance on how to 
take and transfer FAF images.
6.4.4
ETDRS Best-Corrected Visual Acuity
Best-corrected visual acuity (BCVA) will be assessed in the study eye (and separately in the 
fellow eye where indicated) in a sitting position using subjective refraction and ETDRS-like 
visual acuity testing charts at an initial testing distance of 4 meters.
If it is not possible to perform subjective refraction or visual acuity testing at 4 meters because 
visual acuity is too poor for the patient to read at least 4 letters on the refraction/visual acuity 
chart at this distance, the refraction/visual acuity testing should be attempted at 1 meter. 
Further details on refraction technique and visual acuity testing will be described in the 
BCVA testing manual which will be provided to the sites.
All investigational site personnel performing BCVA assessments will be certified prior to any 
study assessments taking place. The total BCVA score derived according to the BCVA testing 
manual captured in the BCVA Assessment Worksheet will be recorded in the eCRF.
6.4.5
Appropriateness of efficacy assessments 
Evaluations described in this protocol are standard ophthalmic assessments in this indication 
and are required for a comparative evaluation of the results of this trial with the existing 
evidence from other trials.
6.5
Safety
Safety will be assessed by the type, frequency and severity of Adverse Events, ophthalmic 
examinations and vital signs. These assessments are performed according to the schedule in 
Table 6-1 and Table 6-2.


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Significant findings that are present prior to signature of the informed consent must be 
included in the Relevant Medical History/Current Medical Conditions Screening page on the 
patient’s eCRF. Significant findings that occur after the signature of the informed consent 
which meet the definition of an Adverse Event must be recorded as AEs in the patient’s eCRF.  
These include significant findings identified by the CRC during the review of imaging data 
which will be communicated directly to Investigators.
All ocular assessments enabling identification of possible adverse events will be performed on 
both eyes.
6.5.1
Ophthalmic examinations
The standard ophthalmic examinations include slit lamp examination, anterior chamber 
examination, direct and indirect ophthalmoscopy of the macular and peripheral retina, and 
tonometry.
Slit lamp and fundus examinations will be performed prior to treatment with ranibizumab. In 
the study eye, tonometry is conducted at every study visit in both treatment groups to assess 
IOP, regardless of treatment administration afterwards. On visits when ranibizumab treatment 
is administered, post-injection tonometry may be performed as per Investigator discretion 
between 15 and 60 minutes after treatment in the study eye.
If study visit assessments and a corresponding treatment occur on separate days, a repeat 
ophthalmoscopy should be performed as safety check-up before treatment of the study eye. 
Results will be documented in the source documents but not in the eCRF. If any concern 
arises, treatment needs to be cancelled and a re-evaluation needs to take place.
6.5.2
Fellow eye
In order to characterize the patient and collect safety data, the assessment of BCVA will be 
performed in the fellow-eye (treated or not treated with ranibizumab) at Screening, Baseline 
(Day 1), Day 90 and Day 180. AEs and SAEs for the fellow eye will be recorded at every visit.  
Data will be recorded in the eCRF.
At the time when treatment of the fellow eye occurs, the BCVA assessment should be 
repeated prior to injection of ranibizumab and the data recorded in the eCRF.
6.5.3
Physical Examination
No physical examination will be performed.
6.5.4
Vital signs 
At every study visit at least 3 separate measurements of the sitting blood pressure (systolic, 
diastolic) and pulse rate after at least 5 minutes rest, should be recorded in source 
documentation. At visits when ranibizumab treatment is administered, vital signs will be 
measured prior to the administration of ranibizumab.
The results from the final measurements of vital signs for each visit will be recorded in the 
eCRF.


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6.5.5
Height and weight 
Height (cm) and body weight (to the nearest kg, in indoor clothing but without shoes) will be 
measured at Screening. The results will be recorded in the eCRF.
6.5.6
Laboratory evaluations 
No safety laboratory evaluations to assess blood or urine parameters will be performed with 
the exception of evaluation of pregnancy in women of child bearing potential as described in 
Section 6.5.8.
6.5.7
Electrocardiogram (ECG) 
No ECG will be performed.
6.5.8
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have a serum pregnancy test 
performed at Screening. A central laboratory approved by the Sponsor will be used for 
analysis of the serum. All results will be recorded in the eCRF.  If positive, the patient must 
be discontinued from the study.


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6.5.9
Appropriateness of safety measurements 
The safety assessments selected for this study are standard for this indication and patient 
population.


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7
Safety monitoring
7.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.


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The occurrence of adverse events should 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, laboratory test, or 
other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy. 
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. These include significant abnormal findings identified by the CRC during 
the review of imaging data which will be communicated directly to Investigators.  
Investigators have the responsibility for managing the safety of individual patient and 
identifying adverse events. Alert ranges for labs and other test abnormalities are included in 
Appendix 1.
Adverse events should be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information:

the severity grade
o
mild: usually transient in nature and generally not interfering with normal 
activities
o
moderate: sufficiently discomforting to interfere with normal activities
o
severe: prevents normal activities

its relationship to the study treatment (no/yes)

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported.

whether it constitutes a serious adverse event (SAE - See section 7.2 for definition of 
SAE)

action taken regarding study treatment.

Its site (non-ocular, left eye, right eye, both eyes).
All adverse events should be treated appropriately. Treatment may include one or more of 
the following: 
o
no action taken (i.e. further observation only) 
o
study treatment temporarily interrupted 
o
study treatment permanently discontinued due to this adverse event 
o
concomitant medication given 


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o
non-drug therapy given 
o
patient hospitalized/patient’s hospitalization prolonged 
o
its outcome (not recovered/not resolved; recovered/resolved; 
recovering/resolving, recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the IB or local labelling/package insert. This information will be included in the 
patient informed consent and should be discussed with the patient during the study as needed.
The Investigator should also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information should be recorded in the 
Investigator’s source documents, however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
7.2
Serious adverse events
7.2.1
Definition of SAE 
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the 
following criteria:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:
o
routine treatment or monitoring of nAMD, not associated with any 
deterioration in condition 
o
elective or pre-planned treatment for a pre-existing condition that is unrelated 
to the indication under study and has not worsened since signing the informed 
consent
o
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 
o
social reasons and respite care in the absence of any deterioration in the 
patient’s general condition


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
is medically significant, i.e. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe (see Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or
development of dependency or abuse (see Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the eCRF, SAEs also require individual 
reporting to DS&E as per section 7.2.2.
7.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the
patient has provided informed consent and until 30 days after the patient has stopped study
participation (defined as time of last dose of study drug taken or last visit whichever is later)
must be reported to Novartis within 24 hours of learning of its occurrence.
Any SAEs experienced after this 30 day period should only be reported to Novartis if the
Investigator suspects a causal relationship to the study drug.
Recurrent episodes, complications, or progression of the initial SAE must be reported as
follow-up to the original episode, regardless of when the event occurs. This report must be
submitted within 24 hours of the Investigator receiving the follow-up information. An SAE
that is considered completely unrelated to a previously reported one should be reported
separately as a new event.


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Information about all SAEs (either initial or follow up information) is collected and recorded
on the paper Serious Adverse Event Report Form. The Investigator must assess the 
relationship of any SAE to study drug, complete the SAE Report Form in English, and send 
the completed, signed form by fax within 24 hours after awareness of the SAE to the local
Novartis Drug Safety and Epidemiology Department. The telephone and fax number of the 
contact persons in the local department of Drug Safety and Epidemiology, specific to the site, 
are listed in the Investigator folder provided to each site. The original copy of the SAE Report 
Form and the fax confirmation sheet must be kept with the case report form documentation at 
the study site. Follow-up information should be provided using a new paper SAE Report 
Form stating that this is a follow-up to a previously reported SAE.
Follow-up information provided should describe whether the event has resolved or continues,
if and how it was treated, whether the treatment code was broken or not and whether the 
patient continued or withdrew from study participation. Each re-occurrence, complication, or
progression of the original event should be reported as a follow-up to that event regardless of
when it occurs.
If the SAE is not previously documented in the IB or local labelling/package insert
(new occurrence) and is thought to be related to the investigational treatment a Drug Safety
and Epidemiology Department associate may urgently require further information from the
Investigator for Health Authority reporting. Novartis may need to issue an Investigator
Notification (IN) to inform all Investigators involved in any study with the same
investigational 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 Directive 2001/20/EC or as per national
regulatory requirements in participating countries.
7.3
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
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 on the Pharmacovigilance Pregnancy Form and reported by the 
Investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.


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8
Data review and database management
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a Novartis 
representative will review the protocol and 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 entries on the eCRFs, 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 CRA organization.   Additionally, a central analytics organization may analyze data 
and 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 eCRFs 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 eCRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed.
8.2
Data collection
Designated Investigator staff will enter the data required by the protocol into the eCRF using 
fully validated software that conforms to US CFR 21Part 11 requirements. Designated 
Investigator site staff will not be given access to the eCRF system until they have been trained. 
Automatic and manual validation programs check for data discrepancies and, by generating 
appropriate error messages, allow the data to be confirmed or corrected before transfer of the 
data to the CRO working on behalf of Novartis. The Investigator must certify that the data 
entered into the eCRF are complete and accurate. After database lock, the Investigator will 
receive copies of the patient data from the CRO for archiving at the investigational site. 


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8.3
Database management and quality control 
Novartis staff and staff at a CRO working on behalf of Novartis will review the data entered 
into the eCRFs by investigational staff for completeness and accuracy and instruct the site 
personnel to make any required corrections or additions. Queries are sent to the 
investigational site using an electronic data query. Designated Investigator site staff are
required to respond to the query and confirm or correct the data. All relevant comments 
should be added to the eCRF using the Investigator Comment feature.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical (ATC) classification 
system. Medical history/current medical conditions and adverse events will be coded using 
the Medical dictionary for regulatory activities (MedDRA) terminology.
Data about the study drug dispensed to the patient will be tracked using the eCRF. The eCRF 
system will be supplied by a CRO, who will also manage the database. 
OCT, color fundus photographs, fluorescein angiograms, ICGA and fundus autofluorescence
images will be processed centrally by the CRC and the results will be sent electronically to a
designated CRO for incorporation into the master database. Data management staff will 
perform a reconciliation of the data entered into the eCRF versus what is received from the 
CRC. At a minimum, this reconciliation will include header reconciliation, visit window 
checks, duplicate record checks, out-of-range checks as defined by the Clinical Trial Team 
and checks to address missing reading center data.
 
 
 
 
 
 
 
At the conclusion of the study, the occurrence of any protocol deviations will be determined. 
After these actions have been completed and the database has been declared to be complete 
and accurate, it will be locked. Following database lock, the database will be sent 
electronically to Novartis (or a designated CRO). Any changes to the database after that time 
can only be made by joint written agreement by the Clinical Trial Leader, the Trial Statistician, 
the Data Manager and the Quality Manager.
8.4
Data Monitoring Committee
Not applicable.
8.5
Adjudication Committee
Not applicable


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9
Data analysis 
The statistical analysis will be performed by staff at a CRO working on behalf of Novartis.
There will be one interim analysis after the first 50 patients have completed all visits up to 
Day 90 (see section 9.6) and the final analysis after all patients have completed the study.
Descriptive statistics include n (the number of non-missing values), mean, standard deviation, 
median, minimum, maximum and, where appropriate, confidence intervals for continuous 
variables and frequencies and percentages for categorical variables and will be provided 
where applicable for patients and study eye. All data will be listed by patient, and where 
applicable, by eye.
For statistical purposes, baseline will be defined as the last available non-missing value 
collected just prior to the start of treatment in the study eye.
For patients with screening assessments who do not enter the treatment period, data will only 
be listed. For patients who do not enter the treatment period due to a study eye specific 
exclusion criterion, descriptive statistics as described above will be provided.
Unless otherwise specified, all statistical tests will be two-sided and use the 0.05 level of 
significance.
Further technical details and discussion of the following statistical considerations will appear 
in the Statistical Analysis Plan, which will be finalized prior to database lock and the analysis.
9.1
Analysis sets
For all patients only one eye will be considered as the study eye, but efficacy and safety 
parameters will be recorded for both eyes. In the event that a subject develops visual 
impairment due to nAMD in the fellow eye (non-study eye) during the study which is treated 
at the Investigator’s discretion according to the standard of care, any additional data (except 
for BCVA, ranibizumab injections and AEs and SAEs that occur in the fellow eye) collected 
according to routine practice will not be recorded on the eCRF. Data presentations will 
distinguish study and fellow eye values.
The Full Analysis Set (FAS) will consist of all patients who received at least one application
of study treatment in the study eye, have baseline and have at least one post-baseline 
assessment for CSRT. Following the intent-to-treat principle, patients will be analyzed 
according to the treatment assigned. No data will be excluded from the FAS analyses because 
of protocol deviations.
The Per Protocol Set (PPS) will consist of all patients in the FAS who followed the assigned 
treatment and completed the study without clinically significant protocol deviations.
Clinically significant protocol deviations will be defined in the Statistical Analysis Plan. If 
deviations do occur, then the data from specific patients, visits, or evaluations may be 
excluded from the PPS. The criteria and determination of clinically relevant protocol 
deviations and patient specific identification of data to be excluded from the PPS will be 
databased and finalized prior to database lock.


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The Safety Set (SAF) will consist of all patients who received at least one application of 
study treatment in the study eye and had at least one post-baseline safety assessment. The 
statement that a patient had no adverse events also constitutes a safety assessment.
All efficacy evaluations will be carried out on the Full Analysis Set and all safety evaluations
will be carried out on the Safety Set.
For sensitivity purposes, the primary analysis will be repeated using the Per Protocol Set. Any
major discrepancies in the results across analyses will be investigated as necessary.
Defined subgroups
Two subgroups of the FAS are defined for exploratory analyses (see section 4.1 for full 
definitions):
1) Group 1. Primary treatment failure (PTF)
2) Group 2. Suboptimal treatment response (STR)
Analyses to be presented for subgroups in addition to the main analysis sets (FAS or SAF) are 
indicated below.
9.2
Patient demographics and other baseline characteristics 
Descriptive statistics will be provided for patient demographics and all baseline characteristics 
(including the baseline values of the main efficacy endpoints). 
Relevant medical history (ocular and non-ocular) and current medical conditions will be 
tabulated by system organ class and preferred term of the MedDRA dictionary. Separate 
tables will be provided for ocular (in study eye and fellow eye) and non-ocular histories and 
conditions. Other relevant baseline information will be listed and summarized as appropriate 
with descriptive statistics.  Data will be summarized for the FAS and also for the subgroups
PTF and STR.
9.3
Treatments 
Study treatment
Descriptive statistics will be provided for exposure to study treatment using the Safety Set, 
PTF and STR subgroups. The number of ranibizumab injections will be presented by visit and 
cumulatively. Summaries will be presented for the injections in the study eye and the fellow 
treated eye as appropriate. Other data related to the application procedure will be summarized
as appropriate.


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The proportion of patients who received bilateral injections of ranibizumab (both the study 
eye and fellow eye injected at the same visit) will be summarized by visit.
Analyses of the treatment exposure will include:

Treatment frequency (total number of injections and number of injections by visit)

Reason for PRN treatment (patient symptoms, BCVA decline, or OCT criteria)

Compliance to treatment regimen (if treatment given monthly per protocol or as a 
response to changes in patient symptoms, BCVA or OCT)
Reasons for discontinuation from the study will be summarized.
Concomitant therapies
The number and percentage of patients taking concomitant therapies will be summarized by
preferred term according to the WHO Drug Reference List dictionary using the Safety Set.
Summaries will be presented over two time periods: therapies received prior to the start of
study treatment and therapies received after the start of study treatment.
9.4
Analysis of the primary variable(s)
The primary objective is to demonstrate that the mean change from baseline in CSRT (as 
determined by OCT) at Day 90 is less than zero.
9.4.1
Variable(s)
The primary variable will be the difference from baseline to Day 90 in CSRT.
9.4.3
Handling of missing values/censoring/discontinuations
In the event that CSRT is missing for Day 90, the analysis will follow an LOCF (Last 
Observation Carried Forward) approach for the Full Analysis Set. This will only be done for 
the primary outcome.


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9.4.4
Supportive analyses
For sensitivity purposes, the primary analysis will be repeated using the PPS. Any major 
discrepancies in the results across analyses will be investigated as necessary. For the PPS, it is 
assumed that a complete set of valid observations for the efficacy endpoints will be available. 
Therefore, no general rules for handling of missing values are specified. In case missing 
values occur, details regarding their handling will be described in a Statistical Analysis Plan.
9.5
Analysis of secondary variables
9.5.1
Efficacy variable
Secondary variables are:
From Optical Coherence Tomography (OCT): 

Mean change from baseline to visits up to Day 180 in Subfoveal Retinal Thickness (SRT), 
Central Subfield Retinal Thickness (CSRT), and Central Subfield Retinal Volume 
(CSRV).

Presence or absence of qualitative OCT parameters (intra-retinal cystoid changes (IRCs), 
subretinal fluid (SF), pigment epithelial detachments (PEDs), or dry retina).

Mean change from baseline to visits up to Day 180 in PED height, SF volume, and IRC 
volume.
From visual acuity:

Mean change in best corrected visual acuity (BCVA) from Baseline to visits up to Day 
180.

Mean change in BCVA from Day 90 to Day 180.

Proportions of patients gaining ≥5, ≥10 and ≥15 ETDRS letters from Baseline at visits up 
to Day 180.

Proportion maintaining vision (<15 ETDRS letters lost from baseline) at visits up to Day 
180.
The analysis of the secondary efficacy objectives will focus on the FAS. At all time-points 
assessed, each efficacy variable will be presented graphically and descriptive statistics 
provided based on absolute values and changes from baseline.


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9.5.2
Safety variables
Safety parameters will include adverse events, the results of ophthalmic examinations, 
intraocular pressure (IOP), vital signs, and laboratory results if reported as AE.
All safety analyses will be performed using the Safety Set.
Adverse Events
Adverse events will be deemed treatment emergent if the onset date is on or after the date of 
first study treatment. Any adverse events recorded prior to the start of study treatment will be 
listed as prior medical conditions. Only treatment-emergent adverse events will be 
summarized.
Adverse events will be summarized by presenting the number and percentage of patients 
having any adverse event, having an eye-related adverse event, having an adverse event in 
each primary system organ class and having each individual adverse event based on the 
preferred term. Patients who experienced multiple adverse events for a preferred term will be 
counted once, similarly for patients with multiple adverse events per system organ class.
All the ocular AEs after the first treatment of the fellow eye will be listed according to 
whether they occurred in the study eye or fellow treated eye.
All other information collected (e.g., severity or relationship to study treatment) will be 
tabulated and listed as appropriate. Summary tables will also be presented for the subset of 
adverse events suspected to be treatment related.
Deaths, serious adverse events, and adverse events leading to discontinuation of study 
treatment will be listed separately and, if appropriate, summarized by primary system organ 
class and preferred term.
Vital signs and special tests
Vital signs will be summarized by presenting shift tables using clinically notable abnormal 
ranges with thresholds representing clinical relevant abnormality and by presenting 
descriptive statistics of raw data and change from Baseline. Values outside the clinically 
notable range will be listed by patient and treatment group and flagged in data listings. IOP 
measurements will be presented descriptively (absolute values and change from baseline).


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9.6
Interim analyses
An interim analysis will be conducted after the first 50 patients have completed visits up to 
Day 90. This will be used primarily to provide preliminary data on the safety of ranibizumab 
in patients with nAMD with either primary treatment failure or suboptimal treatment response 
to aflibercept.  Descriptive analyses will be carried out on the main safety and efficacy 
variables. The results from this Day 90 analysis will be submitted for publication. As no 
hypothesis tests will be carried out, no statistical adjustments are required.


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10
Ethical considerations
10.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US CFR 21, and Japanese Ministry of 
Health, Labor, and Welfare), and with the ethical principles laid down in the Declaration of 
Helsinki.
10.2
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IEC-approved informed consent, or, if incapable of doing so, 
after such consent has been provided by a legally acceptable representative(s) of the patient. 
In cases where the patient’s representative gives consent, the patient should be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. Informed consent must be obtained before 
conducting any study-specific procedures (i.e. all of the procedures described in the protocol). 
The process of obtaining informed consent should be documented in the patient source 
documents. 


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Novartis will provide to Investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the Investigator must be agreed to by Novartis before submission to the IEC, and a copy of the 
approved version must be provided to the Novartis monitor after IEC approval.
Women of child bearing potential should be informed that taking the study drug may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirement for the duration 
of the study. If there is any question that the patient will not reliably comply, they should not 
be entered in the study.
In the event that Novartis wants to perform testing on the samples that are not described in 
this protocol, additional IEC approval will be obtained.
10.3
Responsibilities of the Investigator and the IEC
Before initiating a trial, the Investigator/institution should obtain approval/favorable opinion 
Independent Ethics Committee (IEC) for the trial protocol, written informed consent form, 
consent form updates, subject recruitment procedures (e.g., advertisements) and any other 
written information to be provided to 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 and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Quality Assurance representatives, designated agents of Novartis, 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.
10.4
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. Efficacy and safety data will be presented at 
both national and international scientific meetings.  In addition, upon study completion and 
finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results. Future authorship will be 
determined according to published ICMJE criteria (http://www.icmje.org/).


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11
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the Investigator contact Novartis or its agents, if any, monitoring the 
trial to request approval of a protocol deviation, as requests to approve deviations will not be 
granted.
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 should an 
Investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs.
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. All significant protocol deviations will be recorded and reported in the clinical 
study report.
11.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately provided the Health Authorities are 
subsequently notified by protocol amendment and the reviewing 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, the reporting 
requirements identified in section 7 Safety Monitoring should be followed.


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12
References
References are available upon request.
Amoaku W, Blakeney S, Freeman M, et al. (2012). Action on AMD. Optimizing patient 
management: act now to ensure current and continual delivery of best possible patient care. 
Eye (Lond).; 26(Suppl 1): S2-S21.
Aslankurt M, Aslan L, Aksoy A, et al. (2013). The results of switching between 2 anti-VEGF 
drugs, bevacizumab and ranibizumab, in the treatment of neovascular age-related macular 
degeneration. Eur J Ophthalmol.; 23(4): 553-557.
Bayer. (2012). Aflibercept SmPC. Retrieved April 30th, 2013, from Medicines Compendium
UK: 
http://www.medicines.org.uk/emc/medicine/27224/SPC/Eylea+40mg+ml+solution+for+inject
ion+in+a+vial/
Biomarkers Definitions Working Group. (2001) Biomarkers and surrogate endpoints: 
preferred definitions and conceptual framework. Clin Pharmacol Ther.; 69(3):89-95.
Brown DM, Kaiser PK, Mitchels M, et al. (2006). Ranibizumab versus verteporfin for 
neovascular age-related macular degeneration. N Engl J Med.; 355(14): 1432-1444.
CATT Research Group (2011). Ranibizumab and bevacizumab for neovascular age-related 
macular degeneration. N Engl J Med.; 364(20), 1897-1908.
Chang AA, Li H, Broadhead GK, et al. (2014) Intravitreal aflibercept for treatment resistant 
neovascular age-related macular degeneration.  Ophthalmology; 121(1):188-192
CHMP. (2012, September 20th). Eylea Assessment Report. Retrieved April 30th, 2013, from 
European Medicines Evaluation Agency: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Public_assessment_report/human/002392/WC500135744.pdf
Chong, V. (2012). Biological, Preclinical and Clinical Characteristics of Inhibitors of 
Vascular Endothelial Growth Factors. Ophthalmologica; 227(Suppl 1), 2-10.
Ehlers JP, Spirn MJ, Shah CP, et al. (2010). Ranibizumab for exudative age-related macular 
degeneration in eyes previously treated with alternative vascular endothelial growth factor 
inhibitors. Ophthalmic Surg Lasers Imaging; 41(2), 182-189.
Fung AT, Kumar N, Vance SK, et al. (2012). Pilot study to evaluate the role of high-dose 
ranibizumab 2.0 mg in the management of neovascular age-related macular degeneration in 
patients with persistent/recurrent macular fluid <30 days following treatment with intravitreal 
anti-VEGF therapy (the LAST Study). Eye (Lond).; 26(9), 1181-1187.
Gasperini JL, Fawzi AA, Khondkaryan A, et al. (2012). Bevacizumab and ranibizumab 
tachyphylaxis in the treatment of choroidal neovascularisation. Br J Ophthalmol.; 96(1), 14-20.
He L, Silva RA, Moshpeghi DM, et al. (2016). Aflibercept for the treatment of retinal pigment 
epithelial detachments, Retina; 0: 1-7


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Heier JS, Brown DM, Chong V, et al. (2012). Intravitreal aflibercept (VEGF trap-eye) in wet 
age-related macular degeneration. Opthalmology; 119(12), 2537-2548.
Ho VY, Yeh S, Olsen TW, et al. (2013) Short-term outcomes of aflibercept for neovascular 
age-related macular degeneration in eyes previously treated with other vascular endothelial 
growth factor inhibitors. Am J Ophthalmol.;156(1):23-28.
Kent JS, Iordanous Y, Mao A, et al. (2012). Comparison of outcomes after switching 
treatment from intravitreal bevacizumab to ranibizumab in neovascular age-related macular 
degeneration. Can J Ophthalmol.; 47(2), 159-164.
Klein R, Peto T, Bird A, et al. (2004). The epidemiology of age related macular degeneration. 
Am J Ophthalmol.; 137, 486-495.
Kumar N, Marsiglia M, Mrejen S, et al. (2013). Visual and anatomical outcomes of 
intravitreal aflibercept in eyes with persistent subfoveal fluid despite previous treatments with 
ranibizumab in patients with neovascular age-related macular degeneration. Retina; 33(8): 
1605-1612.
Mylonas G, Ahlers C, Malamos P, et al (2009) Comparison of retinal thickness measurements
and segmentation performance of four different spectral and time domain OCT devices in
neovascular age-related macular degeneration Br J Ophthalmol; 93(11):1453-60.
Owen CG, Jazzar Z, Wormauld R, et al. (2012). The estimated prevalence and incidence of 
late stage age related macular degeneration in the UK. Br J Ophthalmol.; 96(5), 752-756.
Rosenfeld PJ, Brown DM, Heier JS, et al. (2006). Ranibizumab for neovascular age-related 
macular degeneration. N Engl J Med; 355(14), 1419-1431.
Schaal S, Kaplan HJ, Texel TH. (2008). Is there tachyphylaxis to intravitreal anti-vascular 
endothelial growth factor pharmacotherapy in age-related macular degeneration? 
Ophthalmology; 115(12), 2199-2205.
Veritti D, Sarao V, Lanzetta P. (2012). Neovascular Age-Related Macular Degeneration. 
Ophthalmologica; 227((suppl 1)), 11-20.
Wolf A, Kook D, Kreutzer T, et al. (2008). How to treat recurrences after Avastin treatment 
for neovascular AMD: stick to Avastin or switch to Lucentis? Br J Ophthalmol.; 92(9), 1298-
1299.
13
Appendix 1: Clinically notable laboratory values and vital 
signs
The criteria for clinically notable abnormal vital signs are shown in. In order to be identified
as being potentially clinically notable abnormal, an on-treatment vital sign value would need
to meet the criterion value, and represent a change of at least the magnitude noted in the
critical values column. 
Table 13-1 Clinically notable abnormal vital signs


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Variable
Type of abnormality
Critical value
Pulse rate 
(bpm)
High
Low
Either >120 with an increase from baseline>25 or >130 
absolute
Either <50 with a decrease from baseline>30 or <40 absolute
Systolic blood 
pressure 
(mmHg)
High
Low
Either >180 with an increase from baseline>30 or >200 
absolute
Either<90 with a decrease from baseline>30 or <75 absolute
Diastolic blood 
pressure 
(mmHg)
High
Low
Either >105 with an increase from baseline>20 or >115 
absolute
Either <50 with a decrease from baseline>20 or <40 absolute

SAP_001.pdf: 
Clinical Development 
Ranibizumab; Lucentis® 
CRFB002AGB17 / NCT02161575
A Phase IV, prospective, open-label, uncontrolled, European Study in 
patients with neovascular Age-related macular degeneration (nAMD), 
evaluating the efficacy and safety of switching From intravitreal 
Aflibercept to RanIbizumab 0.5mg: the SAFARI study 
RAP Module 3 – Detailed Statistical Methodology 
Author: 
 
Document type: 
RAP Documentation 
Document status: 
Final 4.0 
Release date: 
12OCT2017 
Number of pages: 
19 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Table of contents 
Table of contents......................................................................................................................... 2 
List of abbreviations ................................................................................................................... 3 
1 
Statistical methods planned in the protocol and determination of sample size ................... 5 
2 
Statistical and analytical plans ............................................................................................. 6 
2.1 
Patients and treatments ............................................................................................ 6 
2.1.1 
Analysis sets ............................................................................................ 6 
2.1.2 
Disposition of patients............................................................................. 7 
2.1.3 
Protocol deviations .................................................................................. 7 
2.1.4 
Demographic and baseline characteristics .............................................. 8 
2.1.5 
Medical history...................................................................................... 10 
2.1.6 
Prior and concomitant medications ....................................................... 10 
2.1.7 
Treatment exposure ............................................................................... 10 
2.2 
Efficacy evaluation ................................................................................................ 11 
2.2.1 
Primary objective .................................................................................. 11 
2.2.2 
Secondary objectives ............................................................................. 12 
 
 13 
2.3 
Pharmacogenetic and biomarker evaluations ........................................................ 17 
2.4 
Safety evaluation ................................................................................................... 17 
2.4.1 
Adverse events ...................................................................................... 17 
2.4.2 
Vital signs.............................................................................................. 18 
2.4.3 
Intraocular pressure ............................................................................... 18 
2.5 
Interim analysis...................................................................................................... 18 
2.6 
Other topics............................................................................................................ 18 
 
 19 
3 
Appendices ........................................................................................................................ 19 
 
 
 19 
3.2 
Appendix 2 Latest version of the VAP Module 3 - Protocol Deviations .............. 19 
 


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List of abbreviations 
AE 
Adverse event 
AMD 
Age-related Macular Degeneration 
 
 
AREAATRS 
Area size of atrophy (total area)  
AREACNVS 
Area of macular CNV lesion  
AREALEKS 
Area of leakage 
AREATOTS 
Area of total lesion (including CNV, blood, scar)  
BCVA 
Best-corrected visual acuity 
BMI 
Body mass index 
CI 
Confidence interval 
CNV 
Choroidal neovascularization 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CSRT 
Central subfield retinal thickness 
CSRV 
Central subfield retinal volume 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAS 
Full Analysis Set 
IOP 
Intraocular pressure 
IRC 
Intra-retinal cysts 
IVT 
Intravitreal 
MedDRA 
Medication Dictionary for Regulatory Activities 
nAMD 
Neovascular Age-related Macular Degeneration 
OCT 
Optical Coherence Tomography 
OD 
Occulus Dexter 
ORT 
Outer Retinal Tubulations 
OS 
Occulus Sinister 
PD 
Protocol deviation 
PED 
Pigment epithelial detachment 
PT 
Preferred Term 
PPS 
Per Protocol Set 


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PRN 
Pro re nata/administer as required 
PTF 
Primary treatment failure 
RAP 
Report and Analysis Plan 
RETFL 
Intraretinal fluid 
RETIRC 
Intraretinal fluid (at least some intraretinal fluid of cystoid origin) 
RETSF 
Intraretinal/subretinal Fluid within the Central Subfield (diameter 1000 
microns) 
RPE 
Retinal Pigment Epithelium 
SAE 
Serious adverse event 
SAF 
Safety Set 
SF 
Subretinal fluid 
SOC 
System Organ Class 
 
 
SRT 
Subfoveal retinal thickness 
STR 
Suboptimal treatment response 
SUBCENT 
Change of Subretinal Fluid within the Central Subfield 
TEAE 
Treatment-emergent adverse event 
VEGF 
Vascular endothelial growth factor 
WHODrug 
World Health Organization Drug dictionary 
 


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1 
Statistical methods planned in the protocol and 
determination of sample size 
This document is based on protocol version 02 dated 11 May 2016 and annotated Case Report 
Form (CRF) version 05 dated 05Aug2014. All comments documented in the CRF will be 
listed. 
Data will be analyzed by 
 according to the data analysis section 9 of the 
study protocol which is available in Appendix 16.1.1 of the clinical study report (CSR). 
Important information is given in the following sections and details are provided, as 
applicable, in Appendix 16.1.9 of the CSR. 
Following are the changes from the protocol planned analysis: 
• 
• SF volume and IRC volume were mentioned in the protocol as secondary efficacy 
variables.  Due to technical limitations, there is no robust way in the reading center to 
assess these two parameters.  CSRT thickness and subfoveal retinal thickness will be 
used to assess SF volume, and maximum height of intra-retinal cysts (IRC) will be 
used to assess IRC volume.  
• ‘Intra-retinal cystoid changes’ was listed as a variable in the secondary objectives 
section.  This is being assessed by presence of intraretinal fluid and whether some of 
the intraretinal fluid is of cystoid origin. 
• 
This is a phase IV, unmasked, uncontrolled, single arm, and multicenter study in patients 
diagnosed with visual impairment due to nAMD who have been treated with aflibercept and 
where either no treatment response has been achieved or where there is suboptimal treatment 
response. The study will enroll 150 patients in 30 ophthalmology centers in Western European 
countries. Patients will be enrolled according to 2 subgroups: primary treatment failure 
subgroup (maximum of 30 patients) or suboptimal response subgroup.  
The study includes 8 study visits over a minimum of 6 months. All patients with nAMD and 
eligible to enter the study will receive 3 monthly intravitreal (IVT) ranibizumab 0.5mg 
injections followed thereafter by monthly IVT injections of ranibizumab 0.5mg on a pro re 
nata/administer as required (PRN) basis. There will be 3 periods in this study: Screening 
period from Day -70 to Day 0, Monthly Treatment period from Baseline (Day 1) to Day 60, 
and PRN Treatment period from Day 61 to Day 180. 


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All assessments will be performed according to the assessment schedule (see Table 6-1 and 
Table 6-2 in Section 6 of the protocol).  
The purpose of this study is to determine, in patients with nAMD treated with aflibercept and 
where there is evidence of persistent or increasing disease activity, whether switching 
treatment to ranibizumab 0.5mg reduces disease activity over a 6 month period as assessed by 
a variety of measures. 
2 
Statistical and analytical plans 
For all patients only one eye will be considered as the study eye, but efficacy and safety 
parameters will be recorded for both eyes. Data presentations will distinguish study and 
fellow eye values. 
Summary statistics for continuous variables will include n (the number of non-missing 
observations), 
mean, 
standard 
deviation, 
minimum, 
median, 
maximum, 
and, 
where 
appropriate, 95% confidence interval (CI). 
Summary statistics for categorical variables will include frequencies and percentages, and, 
where appropriate, 95% CI. 
Unless otherwise specified, all statistical tests will be two-sided and use the 0.05 level of 
significance. 
All data will be listed by patient, and where applicable, by eye, for all screened patients. 
Baseline will be defined as the last available non-missing value collected prior to the start of 
treatment in the study eye.  The protocol deviation review at the end of the study will identify 
any patients where the gap between the prior reading and the start of the study is too wide, i.e. 
> 3 days. 
For patients with screening assessments who do not enter the treatment period, data will only 
be listed. For patients who do not enter the treatment period due to a study eye specific 
exclusion criterion, descriptive statistics as described above will be provided. 
2.1 
Patients and treatments  
2.1.1 
Analysis sets 
Assignment of patients to analysis sets will be agreed between the study statistician and the 
Sponsor prior to database lock, once all study data are available and verified.  All efficacy 
analyses will be performed on the study eye.  For visual acuity tests, the results for the fellow 
eye (non-study eye) will also be summarized for reference. 
Full Analysis Set (FAS): The FAS consists of all patients who received at least one 
application of study treatment in the study eye, have baseline and have at least one post-
baseline assessment for CSRT. Following the intent-to-treat principle, patients will be 
analyzed according to the treatment assigned. No data will be excluded from the FAS 
analyses because of protocol deviations. 
Per Protocol Set (PPS): The PPS consists of all patients in the FAS who followed the 
assigned treatment and completed the study without clinically significant protocol deviations.  


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Safety Set (SAF): The SAF consists of all patients who received at least one application of 
study treatment in the study eye and had at least one post-baseline safety assessment.  
All efficacy evaluations will be carried out on the Full Analysis Set and all safety evaluations 
will be carried out on the Safety Set. For sensitivity purposes, the primary analysis will be 
repeated using the Per Protocol Set. Any major discrepancies in the results across analyses 
will be investigated as necessary. 
In addition, 2 subgroups of patients are defined: 
• Group 1. Primary treatment failure (PTF) 
• Group 2. Suboptimal treatment response (STR) 
2.1.2 
Disposition of patients 
The following patient disposition details will be summarized by subgroups and overall, and 
will include the number and percentage of patients: 
• screened 
• treated at V2 
• included in the each study population (FAS, PPS, SAF) 
• who completed the study 
• who prematurely withdrew, including a breakdown of the primary reasons for 
withdrawal 
All screened patients will be listed indicating their eligibility to each analysis set and reasons 
for exclusion from the analysis sets as appropriate. 
Eligibility details, individual reasons for withdrawal and protocol deviations details will be 
listed separately.   
2.1.3 
Protocol deviations 
Protocol deviations (PDs) are collected as per the latest version of the VAP Module 3 - 
Protocol Deviations (see Appendix 2). This document gives a full list of possible PDs, 
including 
whether 
they 
are 
programmatically 
or 
manually 
derived, 
as 
well 
as 
Severity/Analysis classification codes to be assigned to each PD. Rules for patient 
classification in the analysis sets based on PDs are as follows: 
Protocol deviations and impact on analysis  
Code 
VAP de-code 
Impact on analyses 
0 
Exclude from all efficacy analysis 
(including ITT) 
Exclude patient completely from the FAS and Per-
Protocol Sets. 
1 
Exclude from Per-Protocol analysis 
Exclude patient completely from Per-Protocol Set. 
2 
Exclude from data analysis from this 
date 
Data from this date/visit onwards excluded from per 
protocol analyses (patient not excluded from 
population).  


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49 
Report relevant protocol deviation – 
include in all analyses 
Include in all analysis  
 
A protocol deviation meeting will be organized.  The criteria and determination of clinically 
relevant protocol deviations and patient specific identification of data to be excluded from the 
PPS following this meeting will be databased and finalized prior to database lock. 
All protocol deviations will be listed. All responses to the screening and baseline log will also 
be listed. 
2.1.4 
Demographic and baseline characteristics 
The following demographic and baseline characteristics, collected at screening, will be 
summarized by subgroup and overall for the FAS: age, sex, height, weight, body mass index 
(BMI), predominant race, and ethnicity. All demographic and baseline characteristics will be 
listed. 
Descriptive statistics of the baseline value for the following continuous efficacy endpoints 
will be provided by subgroup and overall for the FAS, including a count of the number of 
missing readings/records: 
• From optical coherence tomography (OCT):  
o Central subfield retinal thickness (CSRT) (GRADE: CSRTTHK)   
o Subfoveal Retinal Thickness (SRT) (GRADE: SUBFOVTK) 
o Central Subfield Retinal Volume (CSRV) (GRADE: CSRVVOL) 
o Subfoveal Choroidal Thickness (GRADE: SUBCHTK) 
o Maximum height of IRC (GRADE: IRCHEIGH) 
o Maximum 
height 
of 
pigment 
epithelial 
detachments (PED) (GRADE: 
PEDHEIGH) 
o Maximum diameter of PED (GRADE: PEDDIAM) 
• From visual acuity: best-corrected visual acuity (BCVA) for study eye and fellow eye 
separately 
Categorical summaries (Number and %) of the baseline results for the following efficacy 
endpoints will be provided by subgroup and overall for the FAS, including a count of the 
number of missing readings/records: 
• From OCT:  
o OCT quality (OS – Oculus sinister or left eye (GRADE: OCQUALOS) and 
OD oculus dexter or right eye (GRADE: OCQUALOD))  
o Acceptability of OCT submission ( GRADE: OCTSUB) 
o Presence of intraretinal fluid (GRADE: RETFL) 
o Presence of subretinal fluid (GRADE: RETFLSF) 


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o  Presence of intraretinal fluid (at least some intraretinal fluid of cystoid 
origin) (GRADE: RETIRC) 
o Presence of intraretinal/subretinal fluid within the central subfield (diameter 
1000 microns) (GRADE: RETSF) 
o  Presence of PED (GRADE: PEDDET)  
o Presence of central retinal pigment epithelium (RPE) atrophy (GRADE: 
RPEATRO)  
o  Presence of macular geographic atrophy (GRADE: MACARO) 
o Presence of outer retinal tubulations (ORT) (GRADE: ORTTUB) 
o Presence of vitreomacular traction (GRADE: VITTRAC) 
o Presence of dry retina. Dry retina is defined as eye without intraretinal fluid 
(RETFL from derived.grade) AND eye without subretinal fluid (RETFLSF 
from derived.grade) AND eye without intraretinal cysts (RETIRC from 
derived.grade) 
o Development of RPE rip (GRADE: RPETIP) 
o Is there atrophy outside the active choroidal neovascularization (CNV) 
lesion? (GRADE: ATROCNV) 
o CNV subtype (study eye) (GRADE: CNVTYPE) 
o Area of macular CNV lesion (standardized) (GRADE: AREACNVS) 
o Area of leakage (standardized) (GRADE: AREALEKS) 
o Area of total lesion (including CNV, blood, scar) (GRADE: AREATOTS) 
o Area size of atrophy (total area) (GRADE: AREAATRS) 
• From Indocyanine Angiography (ICG):  
o Presence of intraretinal/subretinal or sub-RPE hemorrhage (study eye) 
(GRADE: PRESHEM)  
• From General Image Grading: 
o Does the hemorrhage include the fovea (study eye) (GRADE: HEMFOV) 
o Presence of active leakage in the sense of a neovascular membrane (study 
eye) ( GRADE: LEAKNEO) 
Age is calculated in years as (year of drug administration - year of birth) 
BMI is calculated as (weight (kg) / [height (cm)/100]2)) 
All demographic and baseline characteristics details, including derived variables, will be 
listed. 
Age-related macular degeneration diagnosis details, pregnancy test details, historical retinal 
images details will be listed separately. 


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2.1.5 
Medical history 
Relevant medical history (ocular and non-ocular) and current medical conditions will be 
coded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 18.1 
or higher.  
Prior to database lock, a complete list of medical history events, as recorded on the eCRF, will 
be provided by 
 to Novartis in an Excel spreadsheet. Novartis will review the individual 
medical history events and classify them as ocular or non-ocular. 
The number and percentage of patients with ocular (in study eye and fellow eye) medical 
histories will be tabulated by system organ class (SOC) and preferred term (PT), by subgroup 
and overall for the FAS. SOCs will be ordered in decreasing frequency of the total number of 
patients with ocular medical histories and conditions reported in each SOC and PTs will be 
ordered within a SOC in decreasing frequency of the total number of patients with ocular 
medical histories and conditions.   
The same table will be provided for ocular current medical conditions, non-ocular medical 
histories and non-ocular current medical conditions. 
All relevant medical history (ocular and non-ocular) and current medical conditions details 
will be listed. 
2.1.6 
Prior and concomitant medications 
Prior and concomitant medications will be coded according to the World Health Organization 
Drug dictionary (WHODrug) (Standard) version of September 2015 or higher. 
Prior medications are defined as those for which the end date is prior to the date of first dose 
of study treatment. 
Concomitant medications are defined as those which are indicated as ‘Ongoing’ on the date of 
first dose of study treatment, or those which start on or after the date of first dose of study 
treatment, or those which start prior to date of first dose of study treatment and have an end 
date after the first dose of study treatment. 
If medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant. 
The number and percentage of patients who took any prior medications and the number and 
percentage of patients who took any concomitant medications will be presented separately by 
medication class and standardized medication names sorted alphabetically, by subgroup and 
overall for the SAF. 
All prior and concomitant medications will be listed by reported name, medication class, 
standardized medication name, indication, dose, dose unit, frequency, route of administration, 
start date and end date or ‘ongoing’ flag. 
2.1.7 
Treatment exposure 
Treatment exposure to ranibizumab will be summarized by subgroup and overall for the SAF, 
and will include:  


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• Duration of exposure to ranibizumab for both study eye and fellow treated eye, as well 
as total duration of exposure (study eye and fellow eye). Duration of exposure will be 
calculated as date of last ranibizumab injection – date of first ranibizumab injection 
+ 1, for study eye, fellow treated eye and both eyes together 
• Total number of injections overall the study course and number of injections by visit 
(including unscheduled visits), for both study eye and fellow treated eye 
• Number and percentage of patients who received bilateral injections of ranibizumab 
(both the study eye and fellow eye injected at the same visit) by visit 
• Reason for PRN treatment (BCVA decline, or OCT criteria) by visit during the PRN 
treatment period, for study eye 
• Reason for no dosing by visit, for study eye. Prior to database lock, a complete list of 
reasons for no dosing during the Monthly treatment period, as recorded on the eCRF, 
will be provided by 
 to Novartis in an Excel spreadsheet. Novartis will review 
them and classify them as ocular or non-ocular. 
• Compliance to treatment regimen, for study eye 
Compliance to treatment regimen will be assessed as follows 
• Monthly treatment period, compliance=100*(number of injections in study eye/3) 
• PRN treatment period, compliance=100*(number of injections done in study eye / 
number of required injections in study eye based on changes in patient symptoms, 
BCVA or OCT) 
An injection will be considered as required if: 
o in the opinion of the Investigator persistent or worsening visual symptoms are 
attributed to nAMD and/or  
o there is evidence of worsening early treatment diabetic retinopathy study 
(ETDRS) BCVA (>1 letter decline since last Study Visit) and/or  
o the presence of persistent or worsening disease activity on OCT (presence of 
sub-retinal fluid, persistent or increased number, size or total volume of IRC, 
or increased central retinal or foveal thickness) 
 
All treatment exposure to ranibizumab details, including derived variables, will be listed. 
2.2 
Efficacy evaluation 
2.2.1 
Primary objective 
The primary objective is to demonstrate that the mean change from baseline in CSRT as 
determined by OCT at Day 90 is less than zero. 
2.2.1.1 
Variables 
The primary variable will be the difference from baseline to Day 90 in CSRT. 


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2.2.1.2 
Descriptive analyses 
The change in CSRT from baseline to Day 90 will be summarized together with the 95% CI 
for the mean and absolute values of CSRT at baseline and at Day 90.  
In the event that CSRT is missing for Day 90, the analysis will follow an LOCF (Last 
Observation Carried Forward) approach for the FAS.  
The primary analysis will be performed on the FAS. 
For sensitivity purposes, the primary analysis will be repeated using the PPS. 
2.2.2 
Secondary objectives 
2.2.2.1 
Variables 
Secondary variables are:  
From OCT 
• Change from baseline to visits up to Day 180 in  
▪ Subfoveal Retinal Thickness (SRT) (GRADE: SUBFOVTK),  
▪ Central Subfield Retinal Thickness (CSRT) (GRADE: CSTTHK),  
▪ Central Subfield Retinal Volume (CSRV) (GRADE: CSRVVOL). 
• Presence or absence of qualitative OCT parameters: 
▪ Intraretinal fluid (GRADE: RETFL), 
▪ Intraretinal fluid of cystoid origin (GRADE: RETIRC) 
▪ Subretinal fluid (SF) (GRADE: RETFLSF) 
▪ Intraretinal/subretinal fluid within the central subfield (diameter 1000 
microns) (GRADE: RETSF) 
▪ Pigment epithelial detachments (PEDs) (GRADE: PEDDET), 


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▪  Dry retina. Dry retina is defined as eye without intraretinal fluid 
(RETFL 
from 
derived.grade) AND eye without subretinal fluid 
(RETFLSF from derived.grade) AND eye without intraretinal cysts 
(RETIRC from derived.grade) 
• Change from baseline to visits up to Day 180 in PED height (GRADE: PEDHEIGH) 
and diameter (GRADE: PEDDIAM) and IRC height (GRADE: IRCHEIGH). 
• Frequency of qualitative change OCT parameters: 
o Change from previous visit, each visit up to Day 180 in intraretinal fluid 
(GRADE: INTRAFL)  
o Change from previous visit, each visit up to Day 180 in subretinal fluid (SF) 
(GRADE: SUBRETFL) 
o Change from previous visit, each visit up to Day 180 in intraretinal/subretinal 
fluid within the central subfield (GRADE: SUBCENT) 
o Change from previous visit, each visit up to Day 180 in the pigment epithelium 
detachment (PED). (GRADE: CHAGPED) 
or  From visual acuity (for study eye and fellow eye) 
• Change in BCVA from baseline to visits up to Day 180. 
• Change in BCVA from Day 90 to Day 180. 
• 
Proportions of patients with change from baseline in ETDRS letters for the following 
categories:≤-15, >-15 to <0, ≤0 to <5,  ≥5 to <10, ≥ 10 to <15 and ≥15 ETDRS letters 
from baseline at visits up to Day 180. 
2.2.2.2 
Descriptive analyses 
The analysis of the secondary efficacy objectives will be performed on the FAS.  
No replacement of missing data will be done. 
Data from visual acuity will be summarized for study eye and fellow eye separately. 
Continuous secondary variables will be summarized presenting the absolute values and 
changes from baseline by visit, and will also be plotted over time. 
Waterfall plot for change in number of letters for BCVA will be presented. 
Qualitative secondary variables will be summarized presenting the number and percentage of 
patients for each modality by visit, and will also be presented graphically over time using bar 
charts. 
All secondary variables details, including derived variables, will be listed. 


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2.4 
Safety evaluation 
All safety analyses will be performed using the Safety Set, by subgroups and overall. 
2.4.1 
Adverse events 
Adverse events (AEs) will be coded according to MedDRA version 18.1 or higher. 
A treatment-emergent adverse event (TEAE) is defined as an AE with start date/time on or 
after the first dose of study treatment, or AEs with worsening severity on or after the first dose 
of study treatment.  
AEs with unknown start date/time will be assumed to be treatment-emergent unless the end 
date/time is known to be before the first dose of study treatment.   
An overview summary of TEAEs will be created, including the number of events and the 
number and percentage of patients reporting: TEAEs, serious TEAEs, eye-related TEAEs, 
TEAEs leading to study discontinuation, TEAEs leading to death, TEAEs by severity and 
TEAEs by relationship to study treatment.  
Summary tables of TEAEs presenting the number of events and the number and percentage of 
patients by SOC and PT will be created for: 
• All TEAEs 
• TEAEs by severity, patient will be counted once for each SOC and once for each PT at 
the maximum severity 
• Study treatment related TEAEs 
• Eye-related TEAEs 
• Serious TEAEs 
• Deaths 
• TEAEs leading to study discontinuation 


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• TEAEs leading to dose adjustment (including study treatment discontinuation) 
SOC and PT will be presented in decreasing frequency of the total number of patients with 
TEAEs. If a patient experienced more than one TEAE, the patient will be counted once for 
each SOC and once for each PT.  
All AEs details will be listed with a flag for TEAEs.   
Separate listings of all serious adverse events (SAEs) and of all eye-related AEs will also be 
presented with a flag for TEAEs. Eye-related AEs will be listed according to whether they 
occurred in the study eye, the fellow treated eye or both. 
2.4.2 
Vital signs 
Vital signs include pulse rate, systolic blood pressure, and diastolic blood pressure. 
Vital signs will be summarized by visit presenting shift tables using clinically notable 
abnormal ranges with thresholds representing clinical relevant abnormality and by presenting 
descriptive statistics of raw data and change from baseline.  
All vital signs data will be listed with a flag for values outside the clinically notable range. 
2.4.3 
Intraocular pressure 
Intraocular pressure (IOP) measurements will be summarized by visit including absolute 
values and change from baseline. 
All ophthalmic examination details will be listed. 
2.5 
Interim analysis 
An interim analysis will be conducted after the first 50 patients have completed visits up to 
Day 90. This will be used primarily to provide preliminary data on the safety of ranibizumab 
in patients with nAMD with either primary treatment failure or suboptimal treatment response 
to aflibercept. The results from this Day 90 analysis will be submitted for publication. As no 
hypothesis tests will be carried out, no statistical adjustments are required. 
Descriptive analyses will be carried out on the main safety and efficacy variables, as follows: 
• Demographics and baseline characteristics 
• Adverse events – All summary tables and listings mentioned in Section 2.4.1 
• Primary efficacy variable 
• Secondary efficacy variables – All summary tables and listings mentioned in Section 
2.2.2. 
• 
2.6 
Other topics  
None 


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3 
Appendices 
 
 
3.2 
Appendix 2 Latest version of the VAP Module 3 - Protocol 
Deviations 
CRFB002AGB17 
Final VAP M3 PDs V5