Clinical trial NCT02130024
Conditions: Age-Related Macular Degeneration
Keywords: Age-related macular degeneration AMD wet AMD ranibizumab aflibercept geographic atrophy inject and extend
Sponsor: Novartis Pharmaceuticals
Start date: 2014-04-11; Completion date: 2017-11-15
Enrollment: 281 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to compare the development of new geographic atrophy in patients with wet Age-related Macular Degeneration (AMD) when treated with either ranibizumab or aflibercept over 24 months. Geographic atrophy is an advanced form of AMD that can result in the progressive and irreversible loss of visual function over time.

Detailed description:
In each arm, patients underwent three monthly loading doses (at Baseline, Week 4, and Week 8). From Week 8, after the patient had received their third injection of study treatment, the visit intervals were determined by the patient's disease activity. If any of the protocol-specified signs of disease activity were present in the study eye, the subsequent injection visit interval was kept at 4 weeks. If none of the signs were present, the subsequent injection interval was extended by 2-week increments up until a maximum of 12-weekly intervals was reached. If there were any signs of disease activity in the study eye, the treatment interval was reduced as specified in the protocol. The planned individual duration of study participation was 24 months.

Arms: arm 1: 3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity \[treat and extend\] arm 2: 3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity \[treat and extend\]
Interventions: intervention 1: Ranibizumab 0.5 mg intervention 2: Aflibercept 2.0 mg
Intervention descriptions: intervention 1: Administered as an intravitreal injection intervention 2: Administered as an intravitreal injection

Protocol documents:
Prot_000.pdf: 
Clinical Development 
RFB002/ranibizumab 
Clinical Trial Protocol CRFB002AAU17 / NCT02130024
Development of new geographic atrophy in patients with 
neovascular (wet) age-related macular degeneration: a 
comparison of ranibizumab and aflibercept. 
Authors: 
 
Document type: 
Clinical Trial Protocol  
EUDRACT number: 
n/a 
Version number: 
02 
Development phase: 
IV  
Release date: 
19-JAN-2015
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
NCDS Template Version 03-Feb-2012 


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Table of contents 
List of tables ...................................................................................................................... 4 
List of figures .................................................................................................................... 4 
List of abbreviations .......................................................................................................... 5 
Glossary of terms .............................................................................................................. 7 
Protocol synopsis .............................................................................................................. 8 
1 
Introduction ..................................................................................................................... 16 
1.1 
Background ......................................................................................................... 16 
1.2 
Purpose ............................................................................................................... 16 
2 
Study objectives .............................................................................................................. 18 
2.1 
Primary and key secondary objectives ................................................................ 18 
2.2 
Additional secondary objectives .......................................................................... 18 
3 
Investigational plan ......................................................................................................... 18 
3.1 
Study design ....................................................................................................... 18 
3.2 
Rationale for Study Design ................................................................................. 19 
3.3 
Rationale for dose, duration and method of administration ................................. 19 
3.4 
Rationale for choice of comparator ..................................................................... 20 
3.5 
Purpose and timing of analyses / design adaptations ......................................... 20 
3.6 
Risks and Benefits .............................................................................................. 21 
4 
Population ....................................................................................................................... 21 
4.1  
Inclusion criteria .................................................................................................. 21 
4.2  
Exclusion criteria ................................................................................................. 22 
5 
Treatment ....................................................................................................................... 24 
5.1 
Protocol requested treatment .............................................................................. 24 
5.1.1 
Investigational treatment ...................................................................... 24 
5.1.2 
Additional study treatment ................................................................... 24 
5.2 
Treatment Arms .................................................................................................. 24 
5.3 
Treatment Assignment, Randomisation .............................................................. 25 
5.4 
Treatment blinding/Masking ................................................................................ 25 
5.5 
Treating the patient ............................................................................................. 25 
5.5.1 
Patient numbering ................................................................................ 25 
5.5.2 
Dispensing the investigational treatment ............................................. 26 
5.5.3 
Handling of Treatment Medication ....................................................... 26 
5.5.4 
Instructions for prescribing and taking treatment ................................. 26 
5.5.4.1  
Treatment Regimens ........................................................................... 26 
5.5.4.2  
Treatment of the fellow eye .................................................................. 27 
5.5.4.3  
Permitted dose adjustments and interruptions of study treatment ....... 28 
5.5.5 
Rescue Medication .............................................................................. 28 
5.5.6 
Concomitant Medication ...................................................................... 28 
5.5.7 
Prohibited Treatment ........................................................................... 28 
5.5.8 
Discontinuation of study treatment and premature patient withdrawal 29 
5.5.9 
Emergency breaking/ Unmasking of treatment assignment ................ 30 


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5.5.10 
Study completion and post-study treatment ......................................... 30 
5.5.11 
Early Study Termination ....................................................................... 30 
6 
Visit Schedule and Assessments .................................................................................... 30 
6.1 
Information to be collected on screening failures ................................................ 33 
6.2 
Patient demographics/other baseline characteristics .......................................... 33 
6.3 
Treatment Exposure and Compliance ................................................................. 33 
6.4 
Efficacy ................................................................................................................ 34 
6.4.1 
Colour fundus photography and fluorescein angiography (FA) ........... 34 
6.4.2 
Visual Acuity ........................................................................................ 34 
6.4.3 
Autofluorescence ................................................................................. 35 
6.4.4 
Optical Coherence Tomography (OCT) ............................................... 35 
6.4.5 
Appropriateness of Efficacy Assessments ........................................... 35 
6.5 
Safety .................................................................................................................. 35 
6.5.1  
Ophthalmologic Exams ........................................................................ 35 
6.5.2  
Fellow eye ............................................................................................ 36 
6.5.3  
Physical Exam ..................................................................................... 36 
6.5.4  
Vital Signs ............................................................................................ 36 
6.5.5  
Laboratory Investigations ..................................................................... 36 
6.5.6  
Electrocardiogram (ECG) ..................................................................... 36 
6.5.7  
Pregnancy ............................................................................................ 36 
6.5.8  
Appropriateness of Safety Measurements ........................................... 37 
6.6  
Other Assessments ............................................................................................. 37 
6.6.1  Plasma VEGF ..................................................................................................... 37 
7 
Safety monitoring ............................................................................................................ 38 
7.1 
Adverse Events ................................................................................................... 38 
7.2 
SAE reporting ...................................................................................................... 39 
7.3 
Pregnancy Reporting .......................................................................................... 40 
8 
Data review and Database Management ....................................................................... 40 
8.1 
Site Monitoring .................................................................................................... 40 
8.2 
Data Collection .................................................................................................... 41 
8.3 
Database Management and Quality Control ....................................................... 41 
8.4 
Data Monitoring Committee ................................................................................ 41 
8.5 
Adjudication Committee ...................................................................................... 41 
9 
Data analysis .................................................................................................................. 41 
9.1 
Analysis sets ....................................................................................................... 42 
9.2 
Patient demographics and other baseline characteristics ................................... 42 
9.3 
Treatments .......................................................................................................... 43 
9.4 
Analysis of the primary and key secondary variable(s) ....................................... 43 
9.4.1 
Key variable(s) ..................................................................................... 43 
9.4.2 
Statistical model, hypothesis, and method of analysis ......................... 44 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 44 
9.4.4 
Supportive analyses ............................................................................. 44 
9.5 
Analysis of secondary variables .......................................................................... 44 
9.5.1 
Efficacy variables ................................................................................. 44 
9.5.1.1  
Visual acuity ......................................................................................... 44 


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9.5.1.2  
Injection Frequency .............................................................................. 45 
9.5.1.3 Central Retinal Thickness ................................................................................... 45 
9.5.1.4 Newly Developed Geographic Atrophy at 12 Months ......................................... 45 
9.5.1.6 Proportion of patients showing no intraretinal and subretinal fluid at 2, 12 and 24 
months ............................................................................................................................ 45 
9.5.1.8 
Plasma VEGF ...................................................................................... 46 
9.5.1.9 Retinal nerve fibre analysis ................................................................................. 46 
9.5.1.10 Safety variables ................................................................................................ 46 
9.6 
12 Month Data Analysis ...................................................................................... 47 
9.7 
Sample size calculation ....................................................................................... 48 
9.8 
Power analysis of key secondary variables ........................................................ 48 
10 Ethical Considerations .................................................................................................... 48 
10.1 
Regulatory and Ethical Compliance .................................................................... 48 
10.2 
Informed Consent Procedures ............................................................................ 48 
10.3 
Responsibilities of the Investigator and IRB/IEC ................................................. 49 
10.4 
Publication of Study Protocol and Results .......................................................... 49 
11 Protocol Adherence ........................................................................................................ 49 
11.1 
Protocol Amendments ......................................................................................... 49 
12 References ..................................................................................................................... 50 
 
List of tables 
Table 5-1 
Prohibited Treatment .......................................................................... 29 
Table 6-1 
Assessment schedule ......................................................................... 32 
 
 
List of figures 
Figure 3-1 
Study design ....................................................................................... 19 


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List of abbreviations 
AE 
 
 
 Adverse event 
AMD  
 
Age-related macular degeneration 
BCVA  
 
Best-corrected visual acuity 
BRB 
 
 
Blood retinal barrier 
BRVO  
 
Branch retinal vein occlusion 
CF 
 
 
Colour fundus photography 
CFR 
 
 
Code of Federal Regulations 
CMH  
 
Cochran-Mantel-Haenszel 
CNV 
 
 
Choroidal neovascularisation 
CRC 
 
 
Central reading centre 
CRO  
 
Contract Research Organisation 
CRVO  
 
Central retinal vein occlusion 
CRT 
 
 
Central retinal thickness 
CS 
 
 
Contrast sensitivity 
CSFT  
 
Central subfield thickness 
CSFV  
 
Central subfield volume 
CSR 
 
 
Clinical Study Report 
DME  
 
Diabetic macular edema 
DS&E  
 
Drug Safety and Epidemiology 
eCRF  
 
electronic Case Report Form 
EDC 
 
 
Electronic data capture 
EOS 
 
 
End of study 
EOT 
 
 
End of treatment 
ETDRS 
 
Early Treatment Diabetic Retinopathy Study 
EU SmPC 
 
European Union summary of product characteristics 
FA 
 
 
Fluorescein angiography 
FAS 
 
 
Full Analysis Set 
FAZ 
 
 
Foveal avascular zone 
GCP 
 
 
Good Clinical Practice 
 
GA 
 
 
Geographic Atrophy 
IB 
 
 
Investigator’s brochure 
ICG 
 
  
Indocyanine Green [angiography] 


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ICH 
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IEC 
 
 
Independent ethics committee 
IOP 
 
 
Intraocular pressure 
IRB 
 
 
Institutional review board 
IRF 
 
 
Intraretinal Fluid 
IS 
 
 
Inner Segment 
IUD 
 
 
Intrauterine device 
IUS 
 
 
Intrauterine system 
IWRS  
 
Interactive Web Response System 
LOCF  
 
Last observation carried forward 
logMAR 
 
Logarithm of the minimum angle of resolution 
MacTSQ 
 
Macular Disease Treatment Satisfaction Questionnaire 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
NEI-VFQ-25  
National Eye Institute Visual Function Questionnaire-25 
OCT 
 
 
Optical coherence tomography 
OS 
 
 
Outer segment 
PCV 
 
 
Polypoidal choroidal vasculopathy 
PPS 
 
 
Per Protocol Set 
PRN 
 
 
Pro re nata, as required 
RMP  
 
Risk Management Plan 
RPE 
 
 
Retinal Pigment Epithelium 
RVO 
 
 
Retinal vein occlusion 
SAE 
 
 
Serious Adverse Event 
SAP 
 
 
Statistical Analysis Plan 
SD/HD-OCT  
Spectral domain/ high-definition optical coherence tomography 
SDV 
 
 
Source Document Verification 
SRF 
 
 
Subretinal Fluid 
TD-OCT 
 
Time domain optical coherence tomography 
VA 
 
 
Visual acuity 
VEGF  
 
Vascular endothelial growth factor 
wAMD  
 
Neovascular (wet) age-related macular degeneration 
WHO  
 
World Health Organization 
 


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Glossary of terms 
 
Assessment 
A procedure used to generate data required by the study 
Enrolment 
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol) 
Epoch  
The planned stage of the subjects’ participation in the study. Each epoch 
serves a purpose in the study as a whole. Typical epochs are: 
determination of subject eligibility, wash-out of previous treatments, 
exposure of subject to treatment or to follow-up on subjects after treatment 
has ended 
Fellow eye 
The contralateral eye to the study eye which may either be treated prior to 
patient entering the study (named first eye/non-study) or treated 
subsequent to the patient entering the study (second eye/non-study)  
Investigational drug 
The drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product” 
Investigational treatment 
All investigational drug(s) whose properties are being tested in the study 
as well as their associated treatment controls.  
Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed by 
the protocol when used within approved indication/dosage 
Masking 
A term that is interchangeable with the term “blinding” but is more typically 
used in studies relating to visual loss   
Medication number 
A unique identifier on the label of each investigational/study drug package 
in studies that dispense medication using an IRT system 
Subject Number  
A number assigned to each patient who enrols into the study  
Part  
A subdivision of a single protocol into major design components. These 
parts often are independent of each other and have different populations or 
objectives. For example, a single dose design, a multiple dose design that 
are combined into one protocol, or the same design with different patient 
populations in each part 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all investigational/study treatment administration and all 
assessments (including follow-up) 
Randomisation number 
A unique identifier assigned to each randomised patient, corresponding to 
a specific treatment arm assignment 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or when 
study/investigational treatment was discontinued whichever is later 
Study drug/ treatment 
Any single drug or combination of drugs administered to the patient as part 
of the required study procedures; includes investigational drug (s), active 
drug run-ins or background therapy  
Study/investigational treatment 
discontinuation 
Point/time when patient permanently stops taking study/investigational 
treatment  for any reason; may or may not also be the point/time of 
premature patient withdrawal 
Variable 
Information used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified time points 
 
 
 
 


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Amendment 2 – 19 Jan 2015 
Amendment rationale 
A protocol amendment was released on 19 January 2015 pertaining to specific sections of 
the protocol as shown in the track change version of the protocol using strike through red font 
for deletions and red underlined for insertions. 
 
The major changes made to the protocol are summarised in this section. Other minor 
administrative changes are incorporated directly into the protocol. The major changes include 
the following: 
 
Change to primary endpoint: The Steering Committee agreed a continuous variable is 
a more valid way to assess Geographic Atrophy than a dichotomous variable, as a 
dichotomous variable would miss patients with clinically significant Geographic 
Atrophy that it is considered under the 250µm definition cutoff (There is no uniformity 
in the cutoff point with 175µm also commonly used). For example a patient with no 
Geographic Atrophy at baseline but 240µm at year 2 would be considered to have no 
Geographic Atrophy for the whole study. However a patient with 230µm at baseline 
and 260µm at year 2 would be considered to have had a significant increase in 
Geographic Atrophy under a dichotomous assessment. This change to the primary 
endpoint will also align with two ongoing landmark Geographic Atrophy studies 
underway, the CHROMA (NCT02247479) and SPECTRI (NCT02247531) studies 
sponsored 
by 
Hoffmann-La 
Roche. 
Modifying 
the 
primary 
endpoint 
for 
CRFB002AAU17 will allow a larger pool of trials and evidence reporting with a 
common endpoint. The subsequent change in statistical analysis and modelling 
reflects the change from a dichotomous primary endpoint to a continuous variable.   
 
A change in the 12 and 24 month visit window from +/- 14 days to +/-6 days to reduce 
the possibility of the key secondary endpoint of injection number being biased by the 
decision of the unmasked investigator deciding to combine a variable visit and 12 or 
24 month assessment visit. 
 
The addition of enhanced depth imaging to Table 6-1- Assessment schedule. This is 
a specific OCT technique to image the deeper layers of the eye. It is already in the 
Central Reading Centre manual but to maximize collection of this data it is added as a 
reminder within the protocol. 
 
The addition of text ‘week 8’ to section 6.4.1, to align  with the assessment schedule 
table 6-1, 
 
Formal allowance of the use of the ranibizumab pre-filled syringe. 
 
Update of patient discontinuation criteria to the updated International Vitreomacular 
Traction Study (IVTS) Group Classification 2013 for Macular Holes nomenclature. 
 
 
 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs). The changes described in this amended 
protocol require IRB/IEC approval prior to implementation. 
The changes herein do not affect the Informed Consent, sites are not required to update the 
patient Informed Consent that is currently in use. 


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Amendment 1 – 12 December 2013 
Amendment rationale 
A protocol amendment was released on 12th December 2013 pertaining to specific sections 
of the protocol as shown in the track change version of the protocol using strike through red 
font for deletions and red underlined for insertions. 
 
The major changes made to the protocol are summarised in this section. Other minor 
administrative changes are incorporated directly into the protocol. The major changes include 
the following: 
 
For the VEGF sampling the wording ‘Serum’ is replaced with ‘Plasma’ VEGF. 
 
Inclusion of AutoFluoresence image at Week 4 and Week 8 to make allowance for the 
first image to be obstructed by haemorrhage. The CRC may use the clearest of the 3 
initial readings as the baseline image.  
 
Optional test for Colour Fundus Photography at all visits if there is presence of 
haemorrhage so it may be confirmed by the blinded CRC. 
 
Inclusion of prohibited treatments to exclusion criteria 19-20 as per existing table 5-1 
Prohibited Medications 
 
Exclusion criterion of patients with total non contiguous area of Geographic Atrophy is 
amended to patients with one or more patches > 250µm of Geographic Atrophy in 
either eye. This change is based on the recent CATT publication (Grunwald 2014) to 
minimise any bias of pre-existing Geographic Atrophy on the primary end point. 
 
Additional angiographic assessment at week 8 to allow for obstruction of the first 
image by haemorrhage. The CRC may use the clearer of the 2 initial readings as the 
baseline image. 
 
Removal of pseudoexfoliation as an exclusion criterion to bring in line with clinical 
practice. There is no safety or data quality reason to exclude these patients from the 
trial. 
 
Allowance of 3 failed extensions before the break point treatment interval is set for the 
rest of the study, which brings the protocol in line with clinical practice. This allows 
subjects not to be unnecessarily restricted to 4 weekly treatments for the two year 
study period, if they were to fail the first two extensions. 
 
Removal of Data Monitoring Committee as this will not be required for this study 
based on the recent VIEW 96 weeks (Schmidt-Erfurth 2014) publication which found 
no significant differences in safety or efficacy when both were used on a PRN 
regimen. 
 
 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs). The changes described in this amended 
protocol require IRB/IEC approval prior to implementation. 
In addition, as the changes herein affect the Informed Consent, sites are required to update 
and submit for approval a revised Informed Consent that takes into account the changes 
described in this amended protocol. 


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Protocol synopsis 
  
Protocol number 
CRFB002AAU17 
Title 
Development of new geographic atrophy in patients with neovascular (wet) 
age-related macular degeneration: a comparison of ranibizumab and 
aflibercept 
Brief title 
Geographic atrophy: a comparison of ranibizumab and aflibercept  
Sponsor and Clinical 
Phase 
Novartis Pharmaceuticals Australia Pty Ltd. Phase IV 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
With the increasing use of targeted anti-VEGF therapies for the treatment 
of age-related macular degeneration (AMD), there has been a rising 
concern related to the risk of progression of geographic atrophy with 
intensive and long term use of these agents. 
The association is thought to stem from the prolonged inhibition of VEGF-
A, which is known to act as a vascular survival factor in the adult eye 
(Hoffman et al, 2000), and VEGF-B, which is known to confer 
neuroprotective properties in the eye (Zhang et al, 2009; Dhondt et al, 
2011).  
The two most commonly used anti-VEGF therapies for the treatment of 
wet AMD, ranibizumab and aflibercept, have differing mechanisms of 
action in terms of their receptor inhibition profiles. These different biologic 
characteristics may have varying clinical consequences in terms of the risk 
of progression of geographic atrophy within the retina. Ranibizumab is a 
recombinant, humanised, monoclonal antibody that neutralises all forms of 
VEGF-A, while aflibercept is a recombinant fusion protein which 
neutralises all VEGF-A isoforms, VEGF-B and placental growth factor 
(PlGF). Aflibercept by its ability to inhibit VEGF-B (in addition to VEGF-A 
and PlGF) may confer a greater risk for the development of geographic 
atrophy in patients. 
The aim of the present study is to compare the development of new 
geographic atrophy in patients treated with 0.5 mg ranibizumab “inject and 
extend” versus those treated with 2.0 mg aflibercept “inject and extend” 
over 24 months. 
 
 


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Primary Objective(s) 
and Key Secondary 
Objectives 
The primary objective for the study will be the mean change in area of 
geographic atrophy in the study eye from baseline to month 24 as 
measured by multimodal imaging assessed by an independent reading 
centre masked (blinded) to the treatment arms. 
Key secondary objectives include assessment of: 
 
the number of injections from baseline to month 12 
 
the mean change in BCVA (logMAR) from baseline to month 12 
Secondary Objectives 
 
Secondary objectives will include: 
 
the mean change in area of existing and newly developed 
geographic atrophy from baseline to month 12 
 
the proportion of patients showing geographic atrophy from 
baseline to month 12 
 
the number of injections from baseline to month 24 
 
the mean change in BCVA (logMAR) from baseline to month 24 
 
the mean change in central retinal thickness (CRT) from baseline 
to months 12 and 24 
 
the proportion of patients showing no intraretinal fluid (IRF) and 
subretinal fluid (SRF) at months 2, 12 and 24 
 
the proportion of patients showing greater than and equal to a 15 
letters (logMAR) gain from baseline to months 12 and 24 
 
the proportion of patients showing less than and equal to a 15 
letters (logMAR) loss from baseline to months 12 and 24 
 
the number of times a patient needed to return to monthly 
treatments during the 24 months 
 
retinal nerve fibre analysis at baseline and month 24 
 
the concentration of plasma VEGF at baseline and 7 days post-
injection following Week 4 and Week 8 mandated intravitreal 
injections in full population and treatment naïve patients 
 
ocular and systemic adverse events at all visits 
 
ocular inflammation at baseline and 7 days post-injection 
following 3rd mandated intravitreal injection 
Study design 
This is a phase IV, randomised, controlled, masked study recruiting 
patients with one treatment-naïve eye presenting with subfoveal choroidal 
neovascularisation (CNV) secondary to wet AMD. At screening, following 
the informed consent process, patients will be assessed for study eligibility 
by assessment of visual acuity using logarithm of the minimum angle of 
resolution (logMAR), stereoscopic biomicroscopic slit-lamp fundus 
examination (78 D or similar lens); fluorescein angiogram (FA); colour 
fundus photography; fundus autofluorescence and optical coherence 
tomography (OCT). 
Eligible patients will be enrolled and then randomised to one of two  
arms: 
Arm 1: 0.5 mg ranibizumab using an inject and extend regimen 


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Arm 2: 2.0 mg aflibercept using an inject and extend regimen 
Since the study will recruit patients who are either treatment-naïve in both 
eyes or, alternatively, treatment naïve in only one eye (i.e. the first/fellow 
[non-study] eye may be treated with any anti-VEGF), the patients will be 
stratified at randomisation to ensure an even distribution across the two 
study groups to account for any potential contralateral effect of the 
first/fellow eye medication on the study eye. Randomisation will occur 
within three strata: two treatment naïve eyes, one eye (first/fellow non-
study eye) being treated with ranibizumab, and one eye (first/fellow non-
study eye) being treated with an anti-VEGF other than ranibizumab. 
Population 
This will be a multi-centre study conducted in approximately 21 sites 
across Australia and New Zealand. Each site will recruit approximately 15 
patients. A total of approximately 278 patients will be recruited to this 
study, with approximately 139 randomised to each study arm. This 
accounts for an expected 15% drop out rate over 24 months. 
Assuming an average 20% screen failure rate, approximately 333 patients 
will need to be screened to have approximately 278 patients found eligible 
and commencing treatment in the trial. 
Inclusion criteria 
Inclusion criteria for patient: 
1. 
Written informed consent must be obtained before any study-related 
assessment is performed. 
2. 
Male or female patients ≥50 years of age.  
Inclusion criteria for study eye: 
3. 
Diagnosis of active subfoveal CNV secondary to wet AMD without 
restriction of lesion size, with visual impairment being exclusively due 
to an active wet AMD lesion. Active lesions will be characterised by 
any of the following: abnormal retinal thickness, with evidence of 
intraretinal, subretinal or sub-pigment epithelial fluid accumulation, 
confirmed by OCT; presence of intraretinal or subretinal haemorrhage; 
leakage shown on a FA unless solely due to dry, fibrotic staining; 
visual acuity deterioration considered likely to represent CNV. 
4. 
BCVA score at both Screening and Baseline must be 23 letters or 
more as measured by the 3 metre Early Treatment Diabetic 
Retinopathy Study (ETDRS)-like charts, inclusively (or approximate 
Snellen equivalent to 3/60+3). 
If both eyes are eligible at Screening and Baseline, the investigator will 
decide the study eye based on clinical judgment. Only one eye needs to 
meet the study entry criteria. 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in 
this study.  
Exclusion criteria for patient: 
1. Inability to comply with study or follow-up procedures.  
2. Pregnant or nursing (lactating) women. 
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 


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lifestyle of the subject). Periodic abstinence (e.g., calendar, 
ovulation, 
symptothermal, 
post-ovulation 
methods) 
and 
withdrawal are not acceptable methods of contraception 
 
Female sterilisation (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 sterilisation (at least 6 m prior to screening). For female 
subjects on the study, the vasectomised 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.  
 
Exclusion criteria for systemic medical history and conditions:  
4. 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. 
5. Stroke or myocardial infarction less than 3 months prior to 
Screening.  
6. Uncontrolled blood pressure defined as systolic value of >160 mm 
Hg or diastolic value of >100 mm Hg at Screening or Baseline.  
7. Known hypersensitivity to ranibizumab or aflibercept or any 
component of the ranibizumab or aflibercept formulation, or 
fluorescein.  
Exclusion criteria for ocular medical history and conditions: 
For both eyes:  
8. Any active periocular or ocular infection or inflammation (e.g., 
blepharitis, 
conjunctivitis, 
keratitis, 
scleritis, 
uveitis, 
endophthalmitis) at the time of Screening or Baseline.  
9. 1 or more patches of geographic atrophy > 250µm in longest linear 
dimension. 


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10. Uncontrolled glaucoma (intraocular pressure [IOP] ≥30 mm Hg on 
medication or according to investigator’s judgment) at the time of 
Screening or Baseline. 
11. Neovascularisation of the iris or neovascular glaucoma at the time 
of Screening or Baseline. 
12. Inability of obtaining multimodal images of sufficient quality to be 
analysed.  
For study eye: 
13. Visually significant cataract (likely to require surgery within the 
next 12 months), aphakia,  severe vitreous haemorrhage, 
rhegmatogenous 
retinal 
detachment, 
proliferative 
diabetic 
retinopathy or CNV of any  cause other than wet AMD (e.g., ocular 
histoplasmosis, pathologic myopia macular hole) at the time of 
Screening and Baseline.  
14. Structural damage within 0.5 disc diameter of the centre of the 
macula (e.g., vitreomacular traction, epiretinal membrane, scar, 
laser burn, foveal atrophy) at the time of screening that in the 
investigator’s opinion could preclude visual function improvement 
with treatment. 
Exclusion criteria for prior or current systemic medication:  
15. Use of other investigational drugs within 30 days or 5 half-lives 
from baseline, whichever is longer. 
16. Current or planned use of systemic medications known to be toxic 
to the lens, retina or optic nerve as outlined in the Lucentis and 
Eylea Product Information.  
Exclusion criteria for prior or current ocular treatment: 
For study eye: 
17. Treatment with any anti-angiogenic drugs (including any anti-
VEGF agents) prior to Baseline in eye.    
18. Any intraocular procedure (including Yttrium-Aluminium-Garnet 
capsulotomy) within 2 months prior to Baseline or anticipated 
within 
the 
next 
6 
months 
following 
Baseline. 
 
Exclusion criteria of prohibited treatments (study eye): 
19. Intra or periocular corticosteroids (including sub tenon but 
excluding topical formulations) 
20. Intraocular corticosteroid implants 
PLEASE NOTE REGARDING TREATMENT FOR FELLOW EYE: 
Treatment with any anti-angiogenic drug (including any anti-VEGF agents) 
is allowed prior to Baseline in fellow eye. 
Investigational 
therapies 
Aflibercept 2.0mg intraocular injections. 
Ranibizumab 0.5mg intraocular injections. 
 
 


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Efficacy assessments 
 
Ophthalmic examination 
 
Colour fundus photography and fluorescein angiography 
 
BCVA measured by logMAR 
 
Autofluorescence 
 
Optical Coherence Tomography 
Safety assessments 
The safety assessments selected for this study are standard for the 
indication and patient population and will include the results of ophthalmic 
examinations, IOP, vital signs, and laboratory results if reported as an 
adverse event. In addition, systemic adverse events at all visits and ocular 
inflammation at baseline and 7 days post-injection following 3rd mandated 
intravitreal injection will be assessed. 
Other assessments 
 
Vital signs 
 
Serum pregnancy test 
 
Plasma VEGF 
Data analysis 
The primary objective of this study is to compare the risk of the study eye 
developing new geographic atrophy after receiving either 0.5 mg 
ranibizumab or 2.0 mg aflibercept. The primary endpoint is the mean 
change in area of geographic atrophy in the study eye from baseline to 
month 24. 
Key secondary endpoints are the number of injections from baseline to 
month 12 and the mean change in BCVA from baseline to month 12.  
These will be analysed ahead of the primary endpoint when 12 month data 
are available to explore the inject and extend treatment algorithm for anti-
VEGF therapy described specifically in this study since it represents a 
novel approach to patient management not previously explored in a 
randomised, controlled trial as an alternative to monthly or prn regimens. 
The primary endpoint and all of the secondary endpoints will be analysed 
and requested at the end of the study. 
The primary analysis will be performed on the Full Analysis Set fitting a 
mixed model. The number of injections will be analysed using Poisson or 
negative binomial regression. BCVA will be analysed using a mixed model 
approach. This approach takes into account the repeated measures nature 
of the data; it allows all results to be included and does not require 
imputation of missing data if the missing observations can be assumed to 
be missing at random. 
Other secondary endpoints that will be analysed using the mixed model 
approach include mean change in area of new and existing geographic 
atrophy at 12 and 24 months, mean change in BCVA at 24 months, mean 
change in CRT. Secondary endpoints of resolution of intraretinal fluid (IRF) 
and subretinal fluid (SRF), the achievement of at least a 15 letter 
improvement and less than a 15 letter loss will be analysed using logistic 
regression. Descriptive statistics such as n, mean, standard deviation, 
minimum and maximum will be provided by treatment and visit for all 
continuous endpoints and n and percent for categorical endpoints.
Key words 
Age-related macular degeneration, ranibizumab, aflibercept, geographic 
atrophy, inject and extend 
 


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1 
Introduction 
1.1 
Background 
Age-related macular degeneration (AMD) is the leading cause of severe loss of vision in the 
elderly population. Genetic, environmental and health factors play an important role in the 
pathogenesis of the disease. Among the clinical features, the cumulative deposition of 
acellular, polymorphous debris between the retinal pigment epithelium and Bruch’s 
membrane, known as drusen, at the central region of the macula is considered a main 
predictor of the establishment of a progressive and degenerative process, in which an 
advanced AMD, defined as the presence of choroidal neovascularisation (CNV) and/or 
geographic atrophy, can be the final result. 
In recent years, the earlier diagnosis, precise and close monitoring of patients with 
neovascular (wet) age-related macular degeneration (wAMD), in association with efficacious 
medications with a well-characterised safety profile such as ranibizumab, have contributed to 
a decrease of cases of blindness as well as improved quality of life of the patients with this 
chorioretinal degenerative disease.  
1.2 
Purpose 
The advent of intravitreal anti-vascular endothelial factors (anti-VEGF) has revolutionised the 
treatment of neovascular age-related macular degeneration (AMD). The first of these 
therapies to be registered and reimbursed in Australia, ranibizumab is a recombinant, 
humanised, monoclonal antibody that neutralises all forms of VEGF-A, a key mediator of the 
neovascular process in AMD. While the pivotal phase III trials for ranibizumab, ANCHOR and 
MARINA, demonstrated previously unseen increases in visual acuity with a monthly dosing 
regimen (Rosenfeld et al, 2006; Brown et al, 2009), subsequent clinical trials demonstrated 
that similar visual outcomes could be achieved with less than monthly dosing. Two such 
studies, in which a ranibizumab prn arm was incorporated, were the CATT and HARBOR 
studies (Martin et al, 2012; Busbee et al, 2013). Patients in CATT treated with 0.5 mg 
ranibizumab prn experienced a 6.8 letter gain in visual acuity with 6.9 injections by 12 
months. Similarly, patients in HARBOR treated with 0.5 mg ranibizumab prn experienced an 
8.2 letter gain in visual acuity with 7.7 injections by 12 months. These injection frequencies 
are comparable to that cited in the Pharmaceutical Benefit Advisory Committee (PBS) Drug 
Utilisation Sub-Committee (DUSC) report which stated that, in real clinical practice, 
Australian patients are receiving an average of 7.42 injections in the first year of treatment. 
The second of the wet AMD therapies to be registered and reimbursed in Australia, 
aflibercept, is a recombinant fusion protein which neutralizes all VEGF-A isoforms, VEGF-B 
and placental growth factor (PlGF). The pivotal phase III trials for aflibercept, the VIEW I and 
VIEW II studies, demonstrated that the 2 mg dose administered for three consecutive months 
followed by 8 weekly injections thereafter was non-inferior to monthly 0.5 mg ranibizumab in 
terms of visual acuity benefit by 12 months (Heier et al, 2012). 
The injection of anti-VEGF medications into the vitreous cavity has the potential for both 
ocular adverse events (such as endophthalmitis, lens trauma and retinal detachment) and 
systemic adverse events (arterial thromboembolic events including myocardial infarction, 
cerebrovascular events and death). Thus limiting the number of injections is desirable if the 
same visual acuity result can be achieved. An additional consequence of greater injection 
frequency is the potential for progression of geographic atrophy, which has been 
hypothesised as being exacerbated over time with intensive, long-term anti-VEGF therapy. 


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VEGF-A is known to act as a vascular survival factor in the adult eye and has been 
suggested to be involved in the paracrine signalling between the RPE and choriocapillaris 
(Hoffman et al, 2000). This is consistent with findings that VEGF-A (121) and VEGF-A (165) 
isoforms are most abundantly expressed in the choroid, RPE, retina and iris tissue (Bhisitkul 
et al, 2006). Studies have shown that inactivation of VEGF-A in the RPE (in VEGF-/- 
knockout mice) results in RPE degeneration and, specifically, that the absence of the 
diffusible VEGF-A isoforms 120 and 164 leads to an age-dependent degeneration of the 
RPE-CC that is similar in many respects to dry/atrophic AMD. RPE loss, choroidal 
remodelling, and increased photoreceptor apoptosis lead to a decline in visual acuity as 
detected by ERG (Saint-Geniez et al, 2009). In the CATT study, the development of 
geographic atrophy was more common in eyes receiving a greater number of injections by 2 
years, i.e. 25.8% of eyes treated with monthly ranibizumab and 17.9% of eyes treated with 
monthly bevacizumab compared to 15.2% treated with ranibizumab prn and 12.9% treated 
with bevacizumab prn. By correlation, the patient groups treated with more injections of either 
ranibizumab or bevacizumab showed a greater reduction in presence of fluid compared to 
those patient groups in which a prn regimen was used (Martin et al, 2012). Therefore, one 
possible consequence of prolonged VEGF-A inhibition in the eye, as observed with monthly 
dosing, is an increased risk of geographic atrophy. 
VEGF-B, which is inhibited by aflibercept but not ranibizumab, is known to confer 
neuroprotective properties in the eye. It has been shown to be involved in retinal recovery 
processes and plays a potent role of neuroprotection in mouse retinal ganglion cells after 
optic nerve crush (Zhang et al, 2009). Studies in VEGF-B-deficient mice suggest that VEGF-
B, instead of acting as an angiogenic factor, exerts direct neuroprotective effects through its 
neuronal receptor FLT1 (Dhondt et al, 2011). Therefore again, one possible consequence of 
VEGF-B inhibition in the eye is an increased risk of geographic atrophy. Indeed, aflibercept 
by its ability to inhibit VEGF-B (in addition to VEGF-A and PlGF) may confer a greater risk for 
the development of geographic atrophy in patients.  
 
The aim of the present study is to compare the rate of progression of geographic atrophy in 
the study eye of patients treated with 0.5 mg ranibizumab “inject and extend” versus those 
treated with 2.0 mg aflibercept “inject and extend” over 24 months. The primary objective for 
the study will be the mean change in area of geographic atrophy in the study eye from 
baseline to month 24 as measured by multimodal imaging assessed by an independent 
reading centre masked (blinded) to the treatment arms. This change to the primary endpoint 
will also align with two ongoing landmark Geographic Atrophy studies underway, the 
CHROMA (NCT02247479) and SPECTRI (NCT02247531) studies sponsored by Hoffmann-
La Roche. Modifying the primary endpoint for CRFB002AAU17 will allow a larger pool of 
trials and evidence reporting with a common endpoint.  
 
Since the study will recruit patients who are either treatment-naïve in both eyes or, 
alternatively, treatment naïve in only one eye (i.e. the first/fellow [non-study] eye may be 
treated with any anti-VEGF), the patients will be stratified at randomisation to ensure an even 
distribution across the two study groups to account for any potential contralateral effect of the 
first/fellow eye medication on the study eye. Randomisation will occur within three strata: two 
treatment naïve eyes, one eye (first/fellow non-study eye) being treated with ranibizumab, 
and one eye (first/fellow non-study eye) being treated with an anti-VEGF other than 
ranibizumab. 
 


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2 
Study objectives 
2.1 
Primary and key secondary objectives 
The primary objective is to investigate the difference between the development of new 
geographic atrophy in the study eye following intravitreal ranibizumab relative to aflibercept in 
patients with wet AMD. The primary endpoint for the study will be the mean change in area of 
geographic atrophy from baseline to month 24 (as measured by OCT and autofluorescence 
images assessed by an independent masked reading centre). 
The key secondary endpoints will be:  
 
the number of injections from baseline to month 12 
 
the mean change in BCVA (logMAR) from baseline to month 12 
2.2 
Additional secondary objectives 
Additional secondary endpoints will include: 
 
the mean change in area of existing and newly developed geographic atrophy from 
baseline to month 12 
 
the proportion of patients showing geographic atrophy from baseline to month 12 
 
the number of injections from baseline to month 24 
 
the mean change in BCVA (logMAR) from baseline to month 24 
 
the mean change in central retinal thickness (CRT) from baseline to months 12 and 
24 
 
the proportion of patients showing no intra-retinal and sub-retinal fluid at months 2, 
12 and 24 
 
the proportion of patients showing greater than and equal to 15 letters (logMAR) gain 
from baseline to months 12 and 24 
 
the proportion of patients showing less than or more than and equal to 15 letters 
(logMAR) loss from baseline to months 12 and 24 
 
the number of times a patient needed to return to monthly treatments during the 24 
months 
 
retinal nerve fibre analysis at baseline and month 24 
 
the concentration of plasma VEGF at baseline and 7 days post-injection following 
week 4 and week 8 mandated intravitreal injections in full population and treatment 
naïve patients ocular and systemic adverse events at all visits 
 
ocular inflammation at baseline and 7 days post-injection following 3rd mandated 
intravitreal injection. 
3 
Investigational plan 
3.1 
Study design 
This is a randomised, multi-centre trial investigating the risk of developing new geographic 
atrophy in the study eye of patients treated with aflibercept relative to patients treated with 
ranibizumab. After consenting to participate in the study, patients will participate in a 
screening period lasting up to 2 weeks to evaluate patient eligibility. After eligibility 
confirmation at the Baseline Visit, patients will be randomised in a 1:1 ratio to one of the two 
treatment arms i.e. 2.0 mg aflibercept or 0.5 mg ranibizumab within the appropriate stratum 


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depending on the treatment at baseline for the non-study eye i.e. none, ranibizumab or other 
anti-VEGF therapy. Only one eye will be selected/treated as the study eye. Ranibizumab and 
aflibercept will be administered monthly for the first 3 injections followed by an individual 
treatment interval determined by disease activity (described in section 5.5.4.1). 
Patients withdrawn from the study prior to completion of the 24 month assessment visit will 
be asked to return for an Early Discontinuation evaluation 30 days +/- 7 days following their 
last study visit. 
 
Figure 3-1 
Study design 
 
Group-1, aflibercept 2.0 mg; N=139 
N=278 
 
 
 
  Group-2, ranibizumab 0.5 mg; N=139  
Week -2 Day 0             Week 8                      Week 52 
 
Week 104 
 
   
     SCN    BSL INITIAL 3 TR.                FLEXIBLE INTERVAL TR.              Pr. EP EOS   
                                                                     
(12 month IA)                
SCN = Screening, BSL = baseline, INITIAL 3 TR. = Initial 3 treatments at 4 weekly intervals both arms, 
Flexible interval Tr = treatment intervals will differ based on arm and disease activity, Pr. EP = Primary 
Endpoint, EOS= End of study, IA = 12 Month Data analysis. 
3.2 
Rationale for Study Design 
The current design will test whether aflibercept, via its inhibitory action on VEGF-B (in 
addition to VEGF-A), exacerbates progression of geographic atrophy in wet AMD patients 
relative to ranibizumab, which inhibits VEGF-A only. This will be tested by comparing 2.0 mg 
aflibercept with 0.5 mg ranibizumab using an inject and extend regimen (as defined in section 
5.5.4.1) in a parallel group study using a primary endpoint of mean change in area of 
geographic atrophy from baseline to 24 months. 
Stratification of patients at randomisation will ensure an even distribution across the two 
study groups to account for any potential contralateral effect of the first/fellow eye medication 
on the study eye. There will be no stratification based on photodynamic therapy with 
verteporfinin in the fellow eye as only treatment with anti-VEGF therapies may have any 
potential, should the phenomenon exist, for exerting a contralateral effect on the study eye. 
3.3 
Rationale for dose, duration and method of administration 
The current approved doses of 0.5 mg ranibizumab by intravitreal injection and 2.0 mg 
aflibercept by intravitreal injection will be used in this study. The current recommended 
administration for ranibizumab is monthly or, if this is not feasible, quarterly, and for 


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aflibercept it is monthly for the first 3 months then bi-monthly thereafter (Lucentis Product 
Information; Eylea Product Information). In practice, ophthalmologists use a more 
conservative approach based on a prn or inject and extend regimen in which frequency of 
injections is guided by disease activity (Deloitte Access Economics, 2011). This approach is 
supported by a number of clinical trials including the PrONTO, CATT and HARBOR 
ranibizumab studies (Spaide, 2007; Lalwani et al, 2009; Frampton, 2013; Oubraham et al, 
2011; Martin et al. 2011; 2012; Busbee et al, 2013) and the 2nd year of the VIEW I and II 
aflibercept studies (Browning et al, 2012; Stewart, 2012). 
This practice will be used for the current study. 
Historical data from a number of clinical trials demonstrate that 0.5 mg ranibizumab and 2.0 
mg of aflibercept offers the most favourable risk/benefit profile and these are the licensed 
doses for the treatment of wet AMD in Australia. 
Both ranibizumab and aflibercept are administered as intravitreal injections to maximise the 
bioavailability of the drug at the site of pathology whilst minimising systemic exposure. The 
‘inject and extend treatment’ approach has been demonstrated to yield similar efficacy 
outcomes to the monthly injection regimen (as referenced above). 
The 24 month duration of the study is necessary for a treatment of this type to determine any 
clinically significant differences or outcomes between the two treatment groups. The CATT 
study demonstrated that, by 2 years of treatment, there was a statistically significant 
difference in the number of patients newly developing geographic atrophy based on type of 
anti-VEGF therapy used (ranibizumab or bevacizumab) and treatment regimen (monthly or 
prn) (Martin et al, 2012). Further, as yet unpublished clinical observation by the Steering 
Committee of retinal specialists for this study is that geographic atrophy changes of any 
clinical significance are not apparent before a minimum of 2 years of anti-VEGF therapy and 
that a reported mean enlargement rate of geographic area of 2.07 mm2/ year (Moussa et al, 
2013) equating to a change of >4 mm2 over 2 years has the clinical consequence of 
negatively impacting visual acuity in patients over the longer term (>3 years and beyond).  
A parallel group design for this study is acceptable as the therapies being used are both well 
established for the treatment of wet AMD. It will allow patient responses to be measured over 
time as is required to assess the development of geographic atrophy over 24 months. 
3.4 
Rationale for choice of comparator 
Aflibercept is the comparator therapy for this study. The rationale for the choice of aflibercept 
is that it is currently the only registered and reimbursed alternative medication to ranibizumab 
that shows comparable visual gains for the treatment of wet AMD in Australia. It is therefore 
the only appropriate comparator available at present. 
3.5 
Purpose and timing of analyses / design adaptations 
An analysis of the two key secondary endpoints will be conducted after all patients have had 
12 months of treatment to explore the treatment algorithm for anti-VEGF therapy described 
specifically in this study. The question of the inject and extend regimen and subsequent 
injection frequency between ranibizumab and aflibercept is of great clinical interest in the 
ophthalmology community (medical retina subspecialty) since a randomised, controlled trial 
has not been previously performed to investigate outcomes using an inject and extend 
regimen for either drug (published treatment regimens for ranibizumab are limited to monthly 
and prn, and for aflibercept 3 monthly followed by 8 weekly in year 1 followed by prn in year 
2). The analysis will explore specifically the number of injections and mean change in BCVA 
from baseline to month 12. While no power analysis was undertaken directly for these early 


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measurements, the sample size estimated for the primary endpoint was assessed as to its 
adequacy for addressing the question of number of injections at 12 months. As the study is 
masked at the level of the central reading centre only, it will be possible to analyse these two 
endpoints when 12 month data are available without compromising the ongoing conduct of 
the study. This is the only analysis that will occur before the end of the study. The primary 
endpoint and all other secondary endpoints will only occur at the conclusion of the study. 
3.6 
Risks and Benefits 
The main risks of the study relate to the actual intravitreous injection itself. In the first 
instance, injections of drug into the vitreous cavity have inherent risks, both ocular (such as 
endophthalmitis, lens trauma and retinal detachment) and systemic (arterial thromboembolic 
events) so that limiting the number of injections would be desirable if the same visual acuity 
result could be achieved. The ocular and systemic risk profile for ranibizumab has been 
clearly described for monthly injections (up to 24 months) in the pivotal ANCHOR and 
MARINA studies (Lucentis Product Information), and for less than monthly injections in the 
CATT and HARBOR studies (Martin et al, 2012; Busbee et al, 2013) so no new risks are 
anticipated as a result of this present study. The ocular and systemic risk profile for 
aflibercept has been clearly described for monthly injections and for three consecutive 
monthly injections followed by bi-monthly (both treatment arms for 12 months) followed by 
capped (at 12 weeks) prn (Heier et al, 2012; Eylea Product Information) so no new risks are 
anticipated as a result of this present study. 
The risk to subjects in this trial will be minimised by compliance with the inclusion/exclusion 
criteria and close clinical monitoring for any adverse effects as a result of the treatment. 
4 
Population 
This will be a multi-centre study conducted in approximately 21 sites across Australia and 
New Zealand, recruiting patients diagnosed with visual impairment due to wet AMD. Each 
site will recruit approximately 15 patients. A total of 278 will be recruited to this study, with 
139 patients randomised to each arm. This accounts for a drop-out rate of 15% over 2 years. 
Assuming an approximate 20% screen failure rate, approximately 333 patients will need to 
be screened to have 278 patients found eligible and commencing treatment in the trial. 
4.1  
Inclusion criteria 
Patients eligible for inclusion in this study have to fulfil all of the following criteria: 
Inclusion criteria for patient: 
1. 
Written informed consent must be obtained before any study-related assessment is 
performed. 
2. 
Male or female patients ≥50 years of age. 
Inclusion criteria for study eye: 
3. 
Diagnosis of active subfoveal CNV secondary to wet AMD without restriction of lesion 
size, with visual impairment being exclusively due to an active wet AMD lesion. Active 
lesions will be characterised by any of the following: abnormal retinal thickness, with 
evidence of intraretinal, subretinal or sub-pigment epithelial fluid accumulation, 
confirmed by OCT; presence of intraretinal or subretinal haemorrhage; leakage shown 


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on a FA unless solely due to dry, fibrotic staining; visual acuity deterioration considered 
likely to represent CNV. 
4. 
BCVA score at both Screening and Baseline must be 23 letters or more as measured 
by the 3 metre Early Treatment Diabetic Retinopathy Study (ETDRS)-like charts, 
inclusively (or approximate Snellen equivalent to 3/60+3). 
If both eyes are eligible at Screening and Baseline, the investigator will decide the study eye 
based on clinical judgment. Only one eye needs to meet the study entry criteria. 
4.2  
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study.  
Exclusion criteria for patient: 
1. Inability to comply with study or follow-up procedures. 
2. Pregnant or nursing (lactating) women. 
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 sterilisation (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 sterilisation (at least 6 m prior to screening). For female subjects on the study, 
the vasectomised 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. 
 
Exclusion criteria for systemic medical history and conditions: 
4. 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. 


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5. Stroke or myocardial infarction less than 3 months prior to Screening.  
6. Uncontrolled blood pressure defined as systolic value of >160 mm Hg or diastolic 
value of >100 mm Hg at Screening or Baseline.  
7. Known hypersensitivity to ranibizumab or aflibercept or any component of the 
ranibizumab or aflibercept formulation, or fluorescein. 
Exclusion criteria for ocular medical history and conditions: 
For both eyes: 
8. Any active periocular or ocular infection or inflammation (e.g., blepharitis, 
conjunctivitis, keratitis, scleritis, uveitis, endophthalmitis) at the time of Screening or 
Baseline. 
9. 1 or more patches of geographic atrophy > 250µm in longest linear dimension. 
10. Uncontrolled glaucoma (intraocular pressure [IOP] ≥30 mm Hg on medication or 
according to investigator’s judgment) at the time of Screening or Baseline. 
11. Neovascularisation of the iris or neovascular glaucoma at the time of Screening or 
Baseline. 
12. Inability to obtain multimodal images of sufficient quality to be analysed. 
For study eye: 
13. Visually significant cataract (likely to require surgery within the next 12 months), 
aphakia, severe vitreous haemorrhage, rhegmatogenous retinal detachment, 
proliferative diabetic retinopathy or CNV of any cause other than wet AMD (e.g., 
ocular histoplasmosis, pathologic myopia macular hole) at the time of Screening and 
Baseline. 
14. Structural damage within 0.5 disc diameter of the centre of the macula (e.g., 
vitreomacular traction, epiretinal membrane, scar, laser burn, foveal atrophy) at the 
time of screening that in the investigator’s opinion could preclude visual function 
improvement with treatment. 
Exclusion criteria for prior or current systemic medication:  
15. Use of other investigational drugs within 30 days or 5 half-lives from baseline, 
whichever is longer. 
16. Current or planned use of systemic medications known to be toxic to the lens, retina 
or optic nerve as outlined in the Lucentis and Eylea Product Information. 
Exclusion criteria for prior or current ocular treatment: 
For study eye:  
17. Treatment with any anti-angiogenic drugs (including any anti-VEGF agents) prior to 
Baseline in eye. 
18.  Any intraocular procedure (including Yttrium-Aluminium-Garnet capsulotomy) within 
2 months prior to Baseline or anticipated within the next 6 months following Baseline. 
Exclusion criteria of prohibited treatments (study eye): 
19. Intra or periocular corticosteroids (including sub tenon but excluding topical 
formulations) 
20. Intraocular corticosteroid implants 


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PLEASE NOTE REGARDING TREATMENT FOR FELLOW EYE: 
Treatment with any anti-angiogenic drug (including any anti-VEGF agents) is allowed prior to 
Baseline in fellow eye. 
5 
 Treatment 
5.1 
Protocol requested treatment 
5.1.1 
Investigational treatment 
The investigational treatment/study drugs in this study are 2.0 mg aflibercept and 0.5 mg 
ranibizumab. 
Aflibercept is available for use in Australia and New Zealand for the treatment of wet AMD. In 
Australia, it is reimbursed and thus available on the Pharmaceutical Benefits Scheme (PBS); 
it is not reimbursed in New Zealand and thus will be supplied for patients by the study 
sponsor. Aflibercept is supplied as a solution for injection in a single use glass vial providing 
0.05 ml of 40 mg/mL for intravitreal injection. 
Ranibizumab is available for use in Australia and New Zealand for the treatment of wet AMD. 
In Australia, it is reimbursed and thus available on the PBS; it is not reimbursed in New 
Zealand and thus will be supplied for patients by the study sponsor. Ranibizumab solution for 
injection is commercially supplied in vials with each vial containing ranibizumab in the 
concentration of 10 mg/ml (0.5 mg/0.05 ml, corresponding to a 0.5 mg dose level) and as 
0.165 mL sterile solution in a pre-filled syringe. Vials and pre-filled syringes of ranibizumab 
are for single use only.  
5.1.2 
Additional study treatment 
No additional treatment beyond the investigational and reference treatments is requested for 
this trial. 
5.2 
Treatment Arms 
Patients will be assigned to one of the following treatment groups (=arms) in a ratio of 1:1: 
Arm 1.  2.0 mg aflibercept – administered monthly for the first three injections, followed by an 
individualised treatment interval determined by disease activity as described in section 
5.5.4.1. 
Arm 2. 0.5 mg ranibizumab – administered monthly for the first three injections, followed by 
an individualised treatment interval determined by disease activity as described in section 
5.5.4.1. 
Please see Section 5.5.4.1 for detailed description of the inject and extend treatment 
regimen.  


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5.3 
Treatment Assignment, Randomisation 
At Visit 2, all eligible patients will be randomised via Interactive Web-based Response 
System (IWRS) to one of the treatment arms. The investigator or his/her delegate will confirm 
that the patient fulfils all the inclusion/exclusion criteria and identify to which stratum they 
belong. The IWRS will link the patient to a treatment arm. 
At subsequent visits after randomisation, the decision to administer treatment to the patient 
will be made according to the treatment regimen (as described in Section 5.5.4.1) and in line 
with the treatment group assignment at randomisation. 
5.4 
Treatment blinding/Masking 
Due to logistical difficulties of masking at the investigator site (requiring two independent 
ophthalmologists to act as assessor and injector) and to avoid introduction of investigator 
bias in retreatment decisions, a central reading centre will be employed to mask the study for 
the primary endpoint and for secondary endpoints which rely on imaging of the eye. The 
central reading centre will be masked to the randomisation and treatment of the patient. All 
images collected during the study (OCT, FA, AF & Colour Fundus), will be sent to the 
masked central reading centre. During the inject and extend phase of the protocol (Week 8 
onwards), the investigator will review the patient results so as to determine the appropriate 
treatment interval per section 5.5.4.1. However, prior to the next scheduled visit for the 
patient, the central reading centre will communicate to the investigator a recommendation of 
when this next visit should occur based on analysis of the images. The investigator should 
adjust the visit schedule in line with the central reading centre recommendation. Information 
sent to the central reading centre will be de-identified and will include confirmation of disease 
activity criteria per section 5.5.4.1 to allow this assessment. The sponsor of the trial, through 
the monitoring process, will be able to review protocol compliance based on the 
recommendations provided by the masked central reading centre and the visit schedule as 
captured in the eCRF during the study. 
So as to ensure that the measurement of BCVA scores is not influenced by bias, it is the 
investigator’ responsibility to ensure that a qualified person is appointed for assessment of 
BCVA scores and that this person is masked to the treatment assignment. The initials of the 
BCVA assessor will be captured  to enable an in study review of compliance in this respect. 
On site monitoring by Novartis will confirm that adequate measures have been taken to 
maintain the masking of the BCVA assessor. 
The patient should be kept masked to their treatment allocation by the investigator. 
5.5 
Treating the patient 
5.5.1 
Patient numbering 
Each patient is uniquely identified in the study by a combination of his/her centre number and 
patient number. The centre number is assigned by Novartis to the investigative site. Upon 
signing the informed consent form, the patient is assigned a patient number by the 
investigator. At each site, the first patient is assigned patient number 00001, and subsequent 
patients are assigned consecutive numbers (e.g. the second patient is assigned patient 
number 00002, the third patient is assigned patient number 00003). 
Once assigned to a patient, the patient number will not be reused. If the patient fails to be 
randomised for any reason, the IWRS should be notified that the patient was not randomised. 


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The reason for not being randomised will be entered on the electronic case report form 
(eCRF). 
5.5.2 
Dispensing the investigational treatment 
In Australia, ranibizumab and aflibercept are commercially available through prescription by 
the treating ophthalmologist. Medication will be prescribed and dispensed following standard, 
Australian clinical practice complying to regulatory and reimbursement requirements. Since 
ranibizumab and aflibercept are not reimbursed in New Zealand, the drug will be provided by 
the Sponsor specifically for New Zealand patients. 
5.5.3 
Handling of Treatment Medication 
Both ranibizumab and aflibercept should be kept in a secure location and the vials should be 
kept in the outer carton to protect from light until needed. Ranibizumab and aflibercept should 
be stored at 2°C to 8°C (refrigerate - do not freeze) as per the approved product information 
(Lucentis Product Information, Eylea Product Information). 
5.5.4 
Instructions for prescribing and taking treatment 
For the entire trial, regardless of randomisation, the following rule applies: ranibizumab or 
aflibercept should be administered in the study eye on the day of the study visit or, if this is 
not possible, within 7 days after the occurrence of the study visit. In any case, study 
treatment has to occur within the visit window as indicated in table 6.1. 
Instructions on how to prepare and administer ranibizumab or aflibercept for intravitreal 
injection should follow the approved Prescribing Information for each medication. 
5.5.4.1  Treatment Regimens  
Screening Period: Week -2 to Baseline Visit 
At Screening (Visit 1 to occur up to 2 weeks before Baseline [Visit 2]), after signing the 
informed consent, patients are enrolled into the study and procedures are performed to allow 
assessment of the study eligibility criteria. Patients will be assessed for study eligibility by 
assessment of visual acuity using logMAR, stereoscopic biomicroscopic slit-lamp fundus 
examination (78 D or similar lens), FA and OCT.  
Once eligibility is confirmed they will be randomised to one of two arms: 
Arm 1: 2.0 mg aflibercept  OR  
Arm 2: 0.5 mg ranibizumab 
Initial Treatment Period: Baseline to Week 8 (Visit 2,3,4) 
Regardless of the treatment arm to which the patient is randomised, all patients will have 
three monthly injections of either 2.0 mg aflibercept or 0.5 mg ranibizumab in the elected 
study eye, according to the treatment arm to which the patient is assigned, at Baseline, Week 
4 and Week 8. 
 
 


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Treatment Period: Week 8 (Visit 4) to Week 104 (Month 24) 
The patient will receive either 2.0 mg aflibercept or 0.5 mg ranibizumab in the elected study 
eye, according to the treatment arm to which they are assigned, at each treatment visit.  
At Week 8 (Visit 4), the patient will be treated and the interval before the next treatment visit 
will be determined by their disease activity as defined below. 
At Week 8 (Visit 4), the patient will receive their third injection of study treatment and the 
central reading centre will assess for disease activity in the study eye as defined by: 
 
a loss of VA of ≥5 letters than the best VA recorded since treatment started (Where 
VA loss is considered, by the investigator, to be due to disease activity);  
 
new retinal haemorrhage;  
 
the presence of any IRF or SRF on OCT. 
If any of these signs of disease activity are present in the study eye, either singularly or in 
combination, the subsequent injection visit interval is kept at 4 weeks (i.e. 28 day interval; no 
increase in the treatment interval). If none of these signs of disease activity are present, the 
subsequent injection interval is extended to 6 weeks. This process occurs with a 2 week 
extension until 12 weekly intervals are reached; there is no increase past 12 weekly. 
If there are any signs of disease activity in the study eye at any given interval, then the 
subsequent injection interval is not increased. 
Once treatment interval extension has occurred, the presence of disease activity in the study 
eye will require a reduction in the treatment interval as follows: 
 
If one (1) sign of disease activity, as defined above, is seen then the interval is 
reduced by 2 weeks. 
 
If two (2), or more, signs of disease activity, as defined above, are seen then the 
interval of injections is reverted back to 4 weekly injections. 
The interval is further decreased (if not at 4 weeks) at the subsequent visit(s) if signs of 
activity are detected using this approach. 
The minimum injection interval for both medications is 4 weeks. 
Extension will again occur at a subsequent visit if there are no signs of disease activity. 
However, on the fourth extension, or any extension thereafter, the maximum interval will be 2 
weeks less than the maximum interval at which disease activity previously occurred in any of 
the three previous extensions (referred to as the break point). The patient will continue at the 
break point treatment interval for the rest of the study unless they have signs of disease 
activity listed above. 
Follow-up Period: Month 24 
Where a patient has had their last study injection prior to the Month 24 visit window the 
patient will return for final efficacy and safety assessments at Month 24. Week 103 is the last 
possible visit in the study at which a patient may receive an injection. If a patient requires an 
injection at week 104 (Month 24), the visit assessments will be performed as part of the study 
then the injection may be administered subsequently but not as part of the study. 
5.5.4.2  Treatment of the fellow eye 
Patients that develop visual impairment due to wet AMD in the fellow eye (non-study eye) 
during the study that, in the investigator’s opinion, qualifies for and requires treatment may be 
treated with any medication in accordance with the country’s standard of care. This eye is 


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then called the fellow treated eye. 
Treatment of the fellow eye must be scheduled in a way so as not to disturb the schedule for 
visits and treatments of the study eye. It must be recorded in the eCRF each time treatment 
has been administered to the fellow eye. 
5.5.4.3  Permitted dose adjustments and interruptions of study 
treatment 
Dose adjustments, i.e., adjustments of the injection volume of ranibizumab or aflibercept 
dose solution, are not permitted. 
Adjustments of the dosing regimen of ranibizumab or aflibercept outside of that described as 
part of the study treatment administration in Section 5.5.4.1 are not permitted. 
Ranibizumab or aflibercept 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. 
If study medication is withheld, the reason for the interruption of treatment and date of 
interruption should be appropriately documented in the source documents as well as in the 
eCRF. 
5.5.5 
Rescue Medication 
No rescue medication is permitted in this study. 
5.5.6 
Concomitant Medication 
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, 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. 
Protocol specific medications (e.g., dilating drops, fluorescein dyes) and pre- and post-
injection medications (e.g., topical anaesthetics, topical antimicrobials) used by a patient 
during the study are not considered concomitant medications.  
5.5.7 
Prohibited Treatment 
Use of treatments, as displayed in Table 5-1are NOT allowed after the start of study i.e., 
screening. Use of these treatments after the start of the study require that the patient be 
withdrawn from the study (See 5.5.8). 
 
 


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Table 5-1 
Prohibited treatment 
Medication 
Action to be taken 
Anti-VEGF drugs other than ranibizumab & aflibercept (ocular or 
systemic) - study eye 
Study withdrawal 
Intra- or periocular corticosteroids (including sub Tenon but excluding 
topical formulations) – study eye 
Study withdrawal 
Intraocular corticosteroid implants – study eye 
Study withdrawal 
Investigational drugs and interventions - any type 
Study withdrawal 
5.5.8 
Discontinuation of study treatment and premature patient 
withdrawal 
Patients may voluntarily withdraw from the study for any reason at any time. Patients may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason. If premature withdrawal occurs for any reason, the 
investigator must make every effort to determine the primary reason for a patient’s premature 
withdrawal from the study and record this information on the relevant study completion page 
in the eCRF. Study treatment must be discontinued. 
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 study and treatment completion dates will be determined by the last clinic visit by the 
patient. 
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. 
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 5.5.7), unacceptable AEs, refusal to continue treatment, or at the 
investigator’s discretion based on 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 any of the following AEs: 
o Full thickness macular hole (Gass stages 2,3 or 4) 
o Stroke or transient ischemic attack 
o Rhegmatogenous retinal detachment 
o Pregnancy 
o Unsatisfactory therapeutic effect 
- 
Any other protocol deviation that results in a significant risk to the patient’s safety 


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- 
Use of prohibited treatment in Table 5-1 
- 
Patient’s condition no longer requires study treatment 
- 
Administrative problems (e.g. patient’s non-compliance) 
Patients who permanently discontinue study treatment and start a prohibited non-study 
treatment (see Section 5.5.7) should be withdrawn from the study and undergo all 
assessments for Month 24/Early Discontinuation Visit as described in Table 6-1. 
In addition to scheduled visits, patients who discontinue study drug due to adverse events or 
abnormalities on safety monitoring tests must be followed up with additional visits as needed 
in order to confirm the resolution of abnormalities. 
A treatment period completion form in the eCRF should be completed, providing the primary 
reason for stopping study treatment. 
Patients who are prematurely withdrawn from the study will not be replaced by an equal 
number of newly enrolled patients.  
5.5.9 
Emergency breaking/ Unmasking of treatment assignment 
Not applicable to this study as investigators are not masked to treatment assignment.  
5.5.10 
Study completion and post-study treatment 
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 Month 24 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. 
No extension study has been planned. 
5.5.11 
Early Study Termination 
The study can be terminated at any time for any reason by Novartis. Should this be 
necessary, the patient should be seen as soon as possible and undergo assessments as 
described in Table 6-1 for an Early Discontinuation Visit. 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 
IRB/EC of the early termination of the trial. 
6 
Visit Schedule and Assessments 
Table 6-1 lists all of the assessments and procedures to be performed at each study visit. 
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 0) for all 
patients. Study assessments will be performed at Screening (Visit 1), Baseline (Day 0, Visit 
2) and at Visits 3 and 4 as per the study schedule. After Visit 4 and then through to Month 24 
(Week 104), the visit intervals will be determined by the patient’s disease activity as per 
section 5.5.4.1. Visit windows are applied as indicated in table 6-1 to allow for flexibility in 
scheduling for all visits. 


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However, it is essential that the treatment period be strictly adhered to during the period of 
the first three consecutive doses. Further, it is essential that the shortest interval between 
ranibizumab doses be ≥28 days. 
An unscheduled visit may occur at any time throughout the study due to an AE or any other 
reasons. All information obtained from any assessments performed during an unscheduled 
visit must be also supported in the patient’s source documentation and recorded in the 
eCRF.  
 
 
 


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Table 6-1 Assessment schedule 
Key: n = number of visits as required per protocol section 5.5.4.1 
v = variable. The number of visits will differ dependent on treatment interval as per protocol section 5.5.4.1 
Xf = Procedures to be which performed for both eyes (study and fellow eye)  
e
 = Enhanced Depth Imaging (EDI). To be collected by sites with the Heidelberg OCT machine. 
^ = To determine eligibility BCVA score at Screening must be 23 letters or more as measured by the 3 metre Early Treatment 
Diabetic Retinopathy Study (ETDRS)-like charts, inclusively or approximate Snellen equivalent to 3/60+3 
s = serum 
u = urine  
* =Optional if haemorrhage is present in study eye and Colour Fundus is required 
** = Fluorescein angiography and colour fundus photography images that were performed under normal clinical practice will be 
accepted if performed no more than 14 days prior to the baseline visit. For all other visits the protocol as described in the 
manual provided by the central reader, should be followed. 
If there is no more than 48 hours between the screening and baseline visit, and the screening BCVA was measured by the 3 
metre Early Treatment Diabetic Retinopathy Study (ETDRS)-like charts there is no requirement to repeat BCVA for the baseline 
visit.  
r = Visual Assessments requiring refraction 
†= If patient is not due for another injection within the visit window of the Month 12 the patient should attend a visit and have all procedures 
except ranibizumab or aflibercept injection.  
Period 
Screen 
Initial Treatment 
Treatment Period 
Visit 
1 
2 
3 
Visit 
3+ 
7days 
4 
Visit 
4+ 
7days 
n 
 
Month 
12† 
 
n 
Month 24 
or Early 
Discontin
-uation 
Weeks (relative to 
Baseline, Day 0) 
-2 to 0 
Baseline 
4 
5 
8 
9 
v 
52 
v 
104 
Visit window 
(days) 
 
 
±3 
±3 
±3 
±3 
±7 
± 6 
± 7 
±6 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Assign Patient 
Number 
X 
 
 
 
 
 
 
 
 
 
Review of 
inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
 
Review of 
withdrawal criteria 
 
X 
X 
 
X 
 
X 
X 
X 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medication 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
Pregnancy test 
Xs 
 
 
 
 
 
 
 
 
Xs or u 
Randomisation 
 
X
 
 
 
 
 
 
 
 
 
Plasma VEGF 
X 
 
 
X 
 
X 
 
 
 
 
Vital signs 
X 
X 
 
 
 
 
 
X 
 
X 
BCVA 
score(logMAR) 
Xf & r^ 
Xf & r** 
X 
 
X& r 
 
X 
Xf & r 
X 
Xf & r 
Ophthalmic 
examination 
Xf 
Xf 
X 
 
X 
 
X 
Xf 
X 
Xf 
Optical coherence 
tomography 
Xf 
Xfe 
Xe 
 
Xe 
 
Xe 
Xfe 
X 
Xfe 
Autofluorescence 
Xf 
Xf 
Xf 
 
Xf 
 
 
Xf 
 
Xf 
Colour fundus 
photography 
Xf** 
Xf** 
X* 
 
X* 
 
X* 
Xf 
X* 
Xf 
Fluorescein 
angiography 
Xf** 
Xf** 
 
 
Xf 
 
 
Xf 
 
Xf 
Nerve Fibre 
Analysis 
 
X 
 
 
 
 
 
X 
 
X 
Intraocular 
Inflammation 
 
X 
 
 
 
X 
 
 
 
 
Study Treatment 
 
X 
X 
 
X 
 
X 
X
† 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IWRS entry 
X 
X 
 
 
 
 
 
 
 
X 


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6.1 
Information to be collected on screening failures 
Patients will undergo screening procedures after providing written informed consent (See 
10.2). 
Patients who are screened but determined not eligible for treatment are considered 
screening failures. The reason for screening failures will be documented on the Screening 
Log. In addition, the demography information and serious adverse event (SAE) data will be 
collected for all screening failures in the eCRF.  
For screen failure patients, adverse events that are not SAEs will be followed by the 
investigator and collected only in the source data. SAEs will be reported immediately as per 
7.2. 
For all patients who have signed informed consent and are randomised into the next period 
of the study, all AEs occurring after informed consent is signed will be recorded on the 
relevant AE eCRF. 
Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF whenever in their judgment, the test abnormality occurred before the informed consent 
signature. 
6.2 
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristics to be collected for randomised patients 
include:  
 
Demography: date of birth, gender, race, ethnicity 
 
Relevant medical history/current medical condition data includes data until the 
informed consent is signed. Where possible, diagnoses and not symptoms will be 
recorded 
 
Study eye selection 
 
Baseline characteristics 
Other assessments performed at Screening to determine eligibility are listed in Table 6-1. 
6.3 
Treatment Exposure and Compliance 
Treatment exposure to ranibizumab or aflibercept will be assessed for both study eye and 
fellow treated eye. Information regarding study treatment administration (ranibizumab or 
aflibercept) in the study eye will be collected on the drug administration record of the eCRF. 
Treatment of the fellow eye will be captured on a separate eCRF page. 
In instances of missed doses, the reason will be described on the drug administration record 
of the eCRF for the corresponding eye or eyes. 
Compliance to treatment regimen 
The evaluation of the investigator’s assessments will be compared to treatment decision – 
i.e. if injections were administered to the study eye in line with the regimen of the assigned 
treatment group. An independent review of fundus photography, FA, OCT and 
autofluorescence images for patients enrolled in the study will be performed at a masked 
central reading centre. During the inject and extend phase of the study, the decision 
regarding the interval of time to the next injection will be made by the investigator as per 
5.5.4.1. However, the central reading centre, which will be masked to the treatment, will 
confirm the investigator’s decision or mandate an alternative interval based on the 


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assessment of the fundus photography, OCT and autofluorescence images  and specified 
retreatment criteria for both arms of the study. 
6.4 
Efficacy 
All efficacy assessments are to be done on the study eye and recorded in the relevant eCRF. 
Efficacy assessments will include both functional and anatomical evaluations. The methods 
of evaluation and the parameters to be assessed are described below. 
The CRC will provide sites with a Study Manual and training materials for the specified study 
ocular images. All images will be obtained by trained site personnel at the study sites and 
forwarded to the CRC for independent standardized analysis and storage. 
These assessments are performed according to the schedule in Table 6-1 
Study eye selection: 
If both eyes are eligible for the study the investigator will designate the study eye at his/her 
discretion at the screening visit and will confirm his/her decision at the baseline visit. This 
decision and confirmation needs to be documented in the relevant eCRF and in the source 
documents of the patient. The study eye should be naïve to previous therapy and is the one 
treated with the study treatment and assessed according to protocol requirements as outlined 
in the assessment schedule (Table 6-1). Data collected on the study eye are used for the 
evaluation of efficacy objectives of the study. At visits when ranibizumab or aflibercept 
treatment is administered, an ocular examination and efficacy assessments must be 
conducted prior to administration of that treatment. 
6.4.1 
Colour fundus photography and fluorescein angiography 
(FA) 
Macular colour fundus photography will be performed in both the study and fellow eye at 
Screening/Baseline, Month 12 and 24. If a new haemorrhage is found in the study eye, then 
colour fundus photograph should be taken at the relevant visit to confirm presence. FA will be 
performed in both the study and fellow eye at Screening/Baseline, Week 8, Month 12 and 24. 
The images will be evaluated by a central reading centre to determine the presence and the 
type of AMD and area of leakage. There will be no requirement for central reading centre 
confirmation of patient eligibility to study sites before patient enrolment in the study. 
Photography and FA performed within 14 days before the Baseline Visit will be accepted as 
the baseline examination (will not need to be repeated unless clinically indicated). 
6.4.2 
Visual Acuity  
Visual acuity will be performed by an assessor (masked to the randomisation and treatment 
of the patient) using a logMAR chart at all visits. BCVA with refraction will be performed in the 
study eye at Screening/Baseline, Week 8, and Months 12 and 24, and in the fellow eye at 
Screening/Baseline and Months 12 and 24. If it is not possible to perform a subjective 
refraction or visual acuity testing due to any reason, including visual acuity is too poor for the 
patient to read at least 3 letters on the refraction/visual acuity chart, the refraction/visual 
acuity testing should be attempted at 1 metre. 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 by an 
accredited vendor chosen by the sponsor prior to any study assessments taking place. The 


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total BCVA score (derived according to the BCVA testing manual captured in the BCVA 
Assessment Worksheet) will be recorded in the relevant eCRF. 
6.4.3 
Autofluorescence 
Autofluorescence will be performed for the study and fellow eye to measure the presence of 
existing geographic atrophy at Screening/Baseline, Week 4 & 8 and the expansion of existing 
geographic atrophy and newly developed geographic atrophy at Month 12 and 24. A masked 
central reading centre will evaluate geographic atrophy for the primary endpoint. As the initial 
image may be obstructed by haemorrhage, the CRC may use the clearest of the initial 3 
readings as the baseline value. 
6.4.4 
Optical Coherence Tomography (OCT)  
OCT images are to be taken using High Definition (HD)/Spectral Domain (SD) (OCT) 
equipment to assess central retinal thickness and the presence of IRF and/or SRF. Patients 
must be assessed using the same machine throughout the course of the study. 
The investigator will perform OCT at all visits as indicated in Table 6-1. The information 
collected will be used by the investigator to assess the status of disease activity i.e., 
decisions with regard to treatment extension are based on investigator evaluation and 
confirmed by the central reading centre in accordance with the retreatment criteria outlined in 
sections 5.5.4.1 and the reading centre procedures as outlined in section 5.4. 
There will be centralised reading of all OCT images collected throughout the study. Details of 
this will be recorded in an OCT manual provided by the central reading centre. 
Enhanced Depth Imaging (EDI) images should be taken by sites using the Heidelberg OCT 
machines as per the CRC manual. 
6.4.5 
Appropriateness of Efficacy Assessments 
Evaluations described in this protocol are standard ophthalmic assessments in this indication 
and are required to enable 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. Methods 
applied for the evaluation of safety include ophthalmic examinations and vital signs. These 
assessments are performed according to the schedule in Table 6-1. 
Significant findings that are present prior to signature of the informed consent must be 
included in the Relevant Medical History/Current Medical Conditions eCRF. Significant 
findings made after the signature of the informed consent which meet the definition of an 
Adverse Event must be recorded on the Adverse Event eCRF. 
All ocular assessments enabling identification of possible adverse events will be performed 
on both the study and fellow eye. 
6.5.1  
Ophthalmologic Exams 
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 or 


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aflibercept. In the study eye, tonometry should be conducted at every study visit in both 
treatment groups to assess IOP, regardless of treatment administration afterwards, based on 
investigator discretion. On visits when ranibizumab or aflibercept treatment is administered, 
also post-injection tonometry may be performed as per investigator discretion between 15 
and 60 minutes after treatment in the study eye. It is recommended that reference is made to 
the TGA approved Lucentis Product Information and Eylea Product Information. 
If study visit assessments and a corresponding treatment occur on separate days, a repeat 
ophthalmoscopy should be performed as a safety check before treatment of the study eye. 
6.5.2  
Fellow eye 
In order to characterise the patient and collect safety data, ophthalmic examination, FA, 
BCVA, OCT, colour fundus photography and autofluorescence will be performed in the 
fellow-eye (treated or not treated) at Baseline, Month 12 and Month 24/Early Discontinuation 
Visit. Data will be documented in the source documents and also recorded in the eCRF as 
applicable. 
If the fellow eye presents with wet AMD it may be treated according to the country’s standard 
of care, at the discretion of the investigator. The fellow eye treated is then labelled the fellow 
treated eye. At the time when treatment of the fellow eye is being initiated, the BCVA 
assessment should be repeated. 
6.5.3  
Physical Exam 
No physical examination will be performed except for Vital Signs.  
6.5.4  
Vital Signs 
This includes assessment of the sitting blood pressure (systolic, diastolic) at screening, 
baseline and Month 24/Early discontinuation visit. The results will be recorded in the relevant 
eCRF. 
6.5.5  
Laboratory Investigations 
No laboratory evaluations to assess blood or urine parameters will be performed – with the 
exception of pregnancy assessments as described in Section 6.5.7. Plasma VEGF 
assessments will be performed as described in Section 6.6.1. 
6.5.6  
Electrocardiogram (ECG) 
No ECG will be performed 
6.5.7  
Pregnancy 
During the study period, all women of child-bearing potential, defined as all women 
physiologically capable of becoming pregnant, must use an effective method of 
contraception. 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 sterilisation (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 


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 
Male sterilisation (at least 6 months prior to screening). For female subjects on the 
study, the vasectomised 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. 
All pre-menopausal women who are not surgically sterile will have a serum pregnancy test at 
the screening visit and results will be recorded in the source documents and on the eCRF. 
Where possible, a local laboratory will be used for analysis of the serum. Where not possible, 
the sponsor may enlist a central laboratory. A positive result will exclude the patient from 
participation in the study. If a patient becomes pregnant between Screening and Month 24, 
they will be discontinued from study treatment and followed until completion of the pregnancy 
and the outcome will be reported. A urine or serum pregnancy test, as is most convenient for 
the site, will be done at Month 24. Any instances of pregnancy will be reported as per section 
7.3. 
6.5.8  
Appropriateness of Safety Measurements 
The safety assessments selected for this study are standard for this indication and patient 
population. In addition, intraocular inflammation will be measured at baseline and 7 days 
post-injection following the 3rd mandated intravitreal injection to determine if there is a 
difference in the risk of inflammation with either aflibercept or ranibizumab. 
6.6  
Other Assessments 
6.6.1  
Plasma VEGF 
Blood for plasma VEGF is being collected at Screening and again at 7 days (+/- 3 days) after 
the injection at Week 4 (Visit 3) and 7 days (+/- 3 days) after the injection at Week 8 (Visit 4). 
The purpose of the plasma VEGF measurements is to determine if aflibercept and 
ranibizumab inhibit systemic VEGF levels to a differing degree by virtue of their distinct 
difference in systemic half-life post-intravitreal injection. This has consequences potentially 
on the rates of systemic adverse events, particularly arterial thromboembolic events, which 
have been described for both aflibercept and ranibizumab. A venous blood sample will be 
collected from each patient using a central lab facility and stored for subsequent 
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7 
Safety monitoring 
7.1 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavourable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of 
a medicinal (investigational) product. 
The 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. All adverse events must be recorded on the Adverse 
Events eCRF with the following information: 
1 
the severity grade (mild, moderate, severe) 
2 
its relationship to the study drug(s) (suspected/not suspected) 
3 
its duration (start and end dates or if continuing at final exam) 
4 
whether it constitutes a serious adverse event (SAE) 
5 
site (non-ocular, left eye, right eye, study eye, fellow eye, both eyes). 
An SAE is 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 hospitalisation or prolongation of existing hospitalisation, unless 
hospitalisation is for: 
o routine treatment or monitoring of the studied indication, 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 
- 
is medically significant, i.e. defined as an event that jeopardises the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2. 
All adverse events should be treated appropriately. Treatment may include one or more of 
the following: no action taken (i.e. further observation only); study drug dosage 
adjusted/temporarily interrupted; study drug permanently discontinued due to this adverse 
event; concomitant medication given; non-drug therapy given; patient hospitalised/patient’s 
hospitalisation prolonged. The action taken to treat the adverse event should be recorded on 


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the Adverse Event eCRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent. 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 for ranibizumab already known about the 
investigational drug can be found in the Product Information leaflet or will be communicated 
in the form of Investigator Notifications. Information about common side effects for aflibercept 
already known about the investigational drug can be found in the product information leaflet. 
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 
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. 
Information about all SAEs (either initial or follow up information) is collected and recorded on 
the 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 Investigator’s Brochure or 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 


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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 local regulatory requirements. 
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 outcomes must be 
collected for the female partners of any males who took investigational product in this study. 
Consent to collect information regarding these pregnancy outcomes should be obtained from 
the mother. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
8 
Data review and Database Management 
8.1 
Site Monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and the eCRF with the investigators and their staff. 
During the study, the field monitor will visit the site regularly to check the completeness of 
patient records, the accuracy of entries on the relevant recording method chosen, the 
adherence to the protocol and to Good Clinical Practice, the progress of enrolment, and to 
ensure that study drug is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, and the results of any other tests or assessments. All 
information on the relevant 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 relevant eCRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion 
criteria, documentation of SAEs, and the recording of data that will be used for all primary 
and safety variables. Additional checks of the consistency of the source data with the 
relevant eCRFs are performed according to the study-specific monitoring plan. No 
information in source documents about the identity of the patients will be disclosed. 


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8.2 
Data Collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the eCRF system 
until they have been trained. Automatic 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 Electronic Case Report Forms are complete and 
accurate. After database lock, the investigator will receive a CD-ROM or paper copies of the 
patient data for archiving at the investigational site. 
8.3 
Database Management and Quality Control 
Novartis staff, or 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. 
Data queries are created, issued to the sites, and tracked through the eCRF system. They 
are either generated automatically, via programmatic edit checks, or manually generated by 
the Monitor during source document verification (SDV) or Data Management during data 
review and reconciliation activities. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
FA, OCT and autofluorescence readings will be processed centrally and the results will be 
sent electronically to Novartis and the CRO working on behalf of Novartis. 
8.4 
Data Monitoring Committee 
A Data Monitoring Committee (DMC) will not be required for this study. The recent VIEW 96 
weeks (Schmidt-Erfurth 2014) publication found no significant differences in safety or efficacy 
when both were used on a PRN regimen at 2 years. 
8.5 
Adjudication Committee 
Central reading of OCT, autofluorescence and other assessments will occur in a masked 
fashion. This blinded assessment will be used for data analysis of primary and secondary 
endpoints as well as to assess compliance with the treatment intervals requirement in each 
treatment group. 
9 
Data analysis 
All analyses will be performed by a designated CRO. 
One analysis is planned when all patients randomised in the study have completed the 
Month 12 visit (see 9.6, 12 Month Data Analysis). 
All other endpoint analyses are planned when all patients randomised in the study have 
completed the Month 24 visit (or a final visit before or at Month 24) and the Month 24 
database has been locked. 
Based on this Month 24 database lock, the primary endpoint analysis and remaining 


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secondary endpoints analyses (i.e. including safety) will be conducted. 
Descriptive statistics (n, mean, standard deviation, median, minimum and maximum values 
and, where appropriate, confidence intervals for continuous variables; frequencies and 
percentages for categorical variables) 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 but who do not enter the treatment period data will 
only be listed. 
Further technical details and discussions of the following statistical considerations will be 
provided in the Statistical Analysis Plan (SAP). 
9.1 
Analysis sets 
The Randomised Population will consist of all randomised patients. 
The Full Analysis Set (FAS) compromises all subjects randomised and who have at least 
one post-baseline efficacy value for the primary endpoint. Following the intent-to-treat 
principle, subjects will be analysed according to the treatment regimen they were assigned to 
at randomisation. 
The Per Protocol Set (PPS) will consist of all patients in the FAS who followed the treatment 
regimen as randomised and completed the study without clinically significant protocol 
deviations. 
Clinically significant protocol deviations will be identified and documented prior to the 
database lock. 
The Safety Set will consist of all patients who received at least one application of study 
treatment and had at least one post-baseline safety assessment. The statement that a 
patient had no adverse events also constitutes a safety assessment. Subjects will be 
analysed according to the treatment regimen they received. 
All efficacy evaluations will be carried out on the FAS. The analysis for the primary efficacy 
evaluation will be carried out on both the FAS and the PPS population. All safety evaluations 
will be carried out on the Safety population. 
 
Additional analysis sets maybe added and will be detailed in the SAP.  
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 summarised as appropriate 
with descriptive statistics. 
Analyses will be based on Randomised Population. 
 
 


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9.3 
Treatments 
Study Treatment 
Descriptive statistics will be provided for exposure to study treatment using the Safety Set. 
The number of ranibizumab and aflibercept injections will be presented by treatment group in 
frequency tables by visit and cumulatively. Summaries will be presented for the injections in 
the study eye and the fellow treated eye as appropriate. 
Analyses of the treatment exposure and treatment patterns of the two alternative treatments 
over 24 months include: treatment frequency (total number of injections), reason for 
treatment (as defined within disease activity for each arm), the interval between treatments 
(the first, second and third intervals) and the number of times the patient returns to monthly 
treatments. Details of the analysis methods will be provided in the SAP. 
Concomitant therapies 
The number and percentage of patients taking concomitant therapies will be summarised 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 and key secondary variable(s) 
The primary objective is to evaluate the difference in the mean change in area of geographic 
atrophy in the study eye between two treatments from baseline to 24 months. 
Key secondary endpoints include assessment of the mean change in BCVA from Baseline to 
Month 12 and the number of injections from Baseline to Month 12 that will be assessed. A 
mixed model (see below) utilising all data will be the primary analysis to assess these 
endpoints in the one analysis with no imputation for missing data. Sensitivity analyses will be 
conducted as described below.. 
All significance tests will be 2-sided and differences will be declared statistically significant if 
p<0.05. 
The assessment of injection frequency and BCVA when 12 month data are available for all 
subjects will have no impact on the powering of the primary endpoint.  
9.4.1 
Key variable(s) 
The primary efficacy variable is: 
 
the mean change in area of geographic atrophy from Baseline to 24 months.  
The key secondary variables are:  
 
the number of injections from Baseline to Month 12 
 
the mean change in BCVA from Baseline to Month 12. 
 
All data will be summarised by timepoint and treatment group using descriptive statistics. Full 
details of allocation of assessments to timepoints will be provided in the SAP. All data will be 
listed. 


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9.4.2 
Statistical model, hypothesis, and method of analysis 
The primary analysis will be conducted using the FAS. 
A mixed model will be fitted with treatment as a factor. Using a modelling approach allows 
other variables of interest to be included in the model if required, for example age or time 
since diagnosis of AMD. Details of additional covariates, if any, will be defined in the SAP. 
The null hypothesis is that there is no difference between the treatments in the development 
of new geographic atrophy from Baseline to 24 months. The two treatments will be declared 
different if the p-value for the treatment effect is <0.05. Ranibizumab will be assessed against 
aflibercept and found superior if the mean area of geographic atrophy is less than that for 
aflibercept. 
Handling of missing values/censoring/discontinuations 
For the primary analysis there will be no imputation for missing data. For secondary and 
sensitivity analysis, the area of geographic atrophy at the last on-study visit will be used for 
patients who withdraw prior to the 12 or 24 month visit. A sensitivity analysis will be 
undertaken using time-to-event techniques where the time to geographic atrophy for patients 
who withdraw or complete the study prior to developing geographic atrophy will be censored 
at the time they left the study. 
There will be no imputation for missing data for analyses of secondary efficacy variables. 
Most analyses will consist of using the mixed model approach where all values recorded for 
each patient up to the time of withdrawal (or completion) are used. This is an appropriate 
model for data missing at random. Sensitivity analyses may be conducted to explore the 
robustness of the data to the methods of dealing with missing data. These methods may 
include LOCF and multiple imputations. The full details of these analyses will be documented 
in the SAP. 
9.4.3 
Supportive analyses 
. Sensitivity analyses will be described in the SAP. In addition the primary model will be fitted 
to the per protocol population as a supporting analysis. 
9.5 
Analysis of secondary variables 
9.5.1 
Efficacy variables 
Secondary efficacy variables include the number of injections from Baseline to Month 12 and 
24, mean change in BCVA from Baseline to Month 12 and 24, the change in area of 
geographic atrophy at Month 12, the change in CRT from Baseline to Month 12 and Month 
24, IRF and SRF at Months 2, 12 and 24, the proportion of patients gaining more than 15 
letters or losing less than 15 letters from Baseline to Month 12 and Month 24 and the number 
of times a participant needed to return to monthly treatments during the 24 months. 
All variables will be summarised by time point and treatment group using descriptive 
statistics. Full details of allocation of assessments to time points will be provided in the SAP. 
All data will be listed. 
9.5.1.1 
Visual acuity 
The model to analyse BCVA will be an expansion of the model used to analyse BCVA from 
Baseline to 12 months for the 12 month data analysis. 


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A mixed model will be fitted with BCVA at each visit as the outcome variable and treatment 
as a class variable. All results for BCVA will be included. Visit will be included as a class 
variable in order to estimate the mean BCVA at each time and an interaction term to 
determine if the mean BCVA at each time differs between treatments. The change in BCVA 
between Baseline and Month 12 or Month 24 for each treatment and the difference between 
ranibizumab and aflibercept will be obtained along with 95% confidence limits. Subject will be 
included as a random term and the repeated nature of the data modelled by fitting the 
appropriate correlation structure. Other factors may be included in the model, such as centre. 
The decision on the correlation structure and additional factors will be fully detailed in the 
SAP. 
Ranibizumab will be found to be statistically significantly better at increasing BCVA if the 
change from Baseline is more than that for aflibercept and p <0.05. 
9.5.1.2 
Injection Frequency 
The number of injections over the 24 month period will be analysed in a similar fashion to 
that for the 12 month data analysis using a Poisson or Negative Binomial model as 
appropriate for count type data. The number of injections in the 24 months will be the 
outcome variable and treatment as a class variable. The length of time each subject is in the 
study up to their 24 month visit will be used as an offset variable. The injection frequency (per 
24 months) and the difference between injection frequencies will be obtained for each 
treatment group along with the corresponding 95% confidence intervals and p-values. The 
model may be expanded to cater for other time points. Details will be provided in the SAP. All 
data will be listed. 
9.5.1.3 
Central Retinal Thickness 
The mean change in CRT from Baseline to Month 24 will be analysed as described for visual 
acuity above. All data will be listed. 
9.5.1.4 
Newly Developed Geographic Atrophy at 12 Months 
A mixed model will be fitted as for the primary endpoint. In addition, a model fitting the 
development of geographic atrophy in the first 12 month period or the second 12 month 
period may be fitted to provide one analysis of the newly developed GA over time. This 
analysis would be undertaken using the method of generalised estimating equations. Full 
details will be provided in the SAP. 
9.5.1.5 
Proportion of patients showing no intraretinal and subretinal 
fluid at 2, 12 and 24 months 
At each assessment the patient is examined for the presence/absence of IRF and SRF as 
per the definitions for their treatment arm (5.5.4.1). The number (and percentage) of patients 
in category (present/absent) for each assessment (IRF, SRF) will be presented by treatment 
group at each time point. 
The presence/ absence of IRF classification of each patient at each timepoint will be 
modelled using logistic regression. Output will include prespecified comparisons of 
proportions between treatments at each visit and between treatments over all visits. A similar 
approach will be used for the presence/absence of SRF. Full details of the approach will be 
provided in the SAP. 
All data will be listed. 


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9.5.1.6 
Proportion of patients showing greater than 15 letters 
(logMAR) gain and less than 15 letters loss from Baseline to 
Months 12 and 24 
The patient’s BCVA at Month 12 (or the closest visit to Month 12) and Month 24 (or the 
closest visit to Month 24) will be compared with the baseline assessment. Patients will be 
classified as having >15 letters improvement (i.e. Month 12/24 – Baseline >15) or otherwise. 
The percentage of patients in each category at each timepoint will be presented by treatment 
group. A generalised estimating equation model will be fitted as described above for IRF. 
Patients will also be classified as having a ≤ 15 letters loss or otherwise at each visit with the 
responses modelled using the generalised estimating equations approach. 
9.5.1.7 
Plasma VEGF 
Blood for plasma VEGF is being collected at Baseline and again at 7 days after the injection 
at Week 4 (Visit 3) and 7 days after the injection at Week 8 (Visit 4). Descriptive statistics will 
be used to summarise plasma VEGF at these time points. 
The concentration of VEGF will be compared between treatments using the mixed model 
approach as described for BCVA. All data will be listed. 
9.5.1.8 
Retinal nerve fibre analysis 
Retinal nerve fibre analysis will be undertaken at Baseline and Month 24. All data will be 
listed. The proportion of patients with retinal nerve fibre damage will be provided by visit and 
treatment. Shift tables will present the change in nerve fibre status. 
9.5.1.9 
Safety variables 
Safety parameters will include adverse events, the results of ophthalmic examinations, IOP, 
vital signs, and laboratory results if reported as AE, in addition to post-injection ocular 
inflammation at baseline and 7 days post-injection following 3rd mandated intravitreal 
injection. 
All safety analyses will be conducted within 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 together with all other adverse events. Pre-treatment and treatment-emergent adverse 
events will be summarised separately. 
Adverse events will be summarised by presenting for each treatment group the number and 
percentage of patients having any adverse event, having a study-eye-related adverse event, 
having a fellow-eye 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 
experience multiple adverse events for a preferred term will be counted once, similarly for 
patients with multiple adverse events per system organ class. 
All the AEs after the first on-study treatment will be listed with relation to the date of the study 
treatment. 
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. 


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Deaths, serious adverse events, and adverse events leading to discontinuation of study 
treatment will be listed separately and, if appropriate, summarised by primary system organ 
class and preferred term. 
Vital signs and special tests 
Vital signs will be summarised by presenting shift tables using extended normal ranges with 
thresholds representing clinical relevant abnormality and by presenting descriptive statistics 
of raw data and change from baseline. Values outside the extended normal range will be 
listed by patient and treatment group and flagged in data listings. IOP measurements will be 
presented descriptively (absolute values and change from Baseline). 
Ocular inflammation is being assessed at Baseline and 7 days post the third injection and will 
be summarised using descriptive statistics only. The proportion of patients with each grade of 
inflammation will be presented by treatment group for each visit. Shift tables will present the 
change in inflammation status between visits by treatment group. All results will be listed. 
9.6 
12 Month Data Analysis 
One analysis is planned at 12 months for the key secondary endpoints of the number of 
injections and mean change in BCVA from Baseline to Month 12. The rationale for this 
analysis of the key secondary endpoints is outlined in 3.5. 
No power analysis was undertaken directly for the 12 month data analysis. However, the 
sample size estimated for the primary endpoint was assessed as to its adequacy for 
addressing the question of injection frequency at 12 months.  
Assuming the 2-sided test for percentage developing geographic atrophy and a sample size 
of 121 per group, the sample size is also suitable for detecting a difference in injection 
frequency between ranibizumab and aflibercept at 12 months of: 
• 
0.7 injections if the standard deviation is 2, 
• 
0.9 injections if the standard deviation is 2.5 
• 
1.1 injections if the standard deviation is 3.0, and 
• 
1.3 injections if the standard deviation is as large as 3.5. 
Power is 80%, alpha is 0.05, test is a two-sided t-test and no adjustment has been made to 
alpha, the type I error rate for assessing multiple endpoints. These assumptions are based 
on the CATT study (Martin et al, 2012). 
The mean number of injections over the first 12 month period will be analysed using a 
Poisson or Negative Binomial model as appropriate for count type data. The number of 
injections in the first 12 months will be the outcome variable and treatment as a class 
variable. The length of time each subject is in the study up to their 12 month visit will be used 
as an offset variable. The injection frequency (per year) and the difference between injection 
frequencies will be obtained for each treatment group along with the corresponding 95% 
confidence intervals and p-values. The model may be expanded to cater for other time points 
once the study is completed. Details will be provided in the SAP. 
The model to analyse mean change in BCVA from Baseline to 12 months will be a mixed 
model with BCVA at each visit as the outcome variable and treatment as a class variable. All 
results for BCVA from Baseline to Month 12 will be included. Visit will be included as a class 
variable in order to estimate the mean BCVA at each time and an interaction term to 
determine if the mean BCVA at each time differs between treatments. The change in BCVA 
between baseline and month 12 for each treatment and the difference between ranibizumab 
and aflibercept will be obtained along with 95% confidence limits. Subject will be included as 


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a random term and the repeated nature of the data modelled by fitting the appropriate 
covariance/correlation structure. Other factors may be included in the model, such as centre. 
The decision on the correlation structure and additional factors will be fully detailed in the 
SAP. 
Ranibizumab will be found to be statistically significantly better at increasing BCVA if the 
change from Baseline is more than that for aflibercept and p <0.05.All data will be listed. 
9.7 
 Sample size calculation 
The sample size for the difference in the change in area of patients developing geographic 
atrophy is based on a two-sided z-test with α=0.05 and 80% power. Ranibizumab will be 
assessed against aflibercept and considered superior if the p-value for the z-test is <0.05 and 
the  mean area of geographic atrophy is less for those on ranibizumab. A 95% two sided 
confidence interval for the difference in means will also be estimated. This is based on an 
assumption that a meaningful difference to detect is 20%. 278 patients should be able to 
detect a 20% difference in geographic area between the two groups based on expected 
change in Geographic Atrophy of 2mm/year with a sigma of 1.5.  
9.8 
Power analysis of key secondary variables 
The key secondary variables are those addressed in the 12 month data analysis section 
above and the power of these analyses is addressed there. 
No other power analyses were undertaken for any other secondary endpoints. 
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 Code of Federal Regulations Title 
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), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative 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. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested 
by the investigator must be agreed to by Novartis before submission to the IRB/IEC and a 


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copy of the approved version must be provided to the Novartis monitor after IRB/IEC 
approval. 
Women of child bearing potential should be informed that taking the study treatment may 
involve unknown risks to the foetus 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. 
10.3 
Responsibilities of the Investigator and IRB/IEC 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC) before study start. A signed and dated statement that the protocol 
and informed consent have been approved by the IRB/IEC must be given to Novartis before 
study initiation. 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 Clinical Quality Assurance 
representatives, designated agents of Novartis, IRBs/IECs, and regulatory authorities as 
required. If an inspection of the clinical site is requested by a regulatory authority, the 
investigator must inform Novartis immediately that this request has been made. 
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. In addition, upon study completion and 
finalisation of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results. 
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. Under no circumstances should an investigator collect additional data 
or conduct any additional procedures for any research related purpose involving any 
investigational drugs. 
If the 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 it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 
11.1 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment 
that must be approved by Novartis, Health Authorities where required, and the IRB/IEC. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC 
approval. 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 


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included in this study, even if this action represents a deviation from the protocol. In such 
cases, Novartis should be notified of this action and the IRB/IEC at the study site should be 
informed within 10 working days or less, if required by local regulations. 
12 
References  
 
Browning et al. Aflibercept for Age-Related Macular Degeneration: A Game-Changer or Quiet 
Addition? Am J Ophthalmol 2012;154:222–226. 
 
Bhisitkul et al. Vascular endothelial growth factor biology: clinical implications for ocular 
treatments. Brit J Ophthalmol 2006; 90 (12) 1542-47. 
 
Brown et al. Ranibizumab versus Verteporfin Photodynamic Therapy for Neovascular 
Age-Related Macular Degeneration: Two-Year Results of the ANCHOR Study. 
Ophthalmology 2009;116:57–65. 
 
Busbee et al. Twelve-Month Efficacy and Safety of 0.5 mg or 2.0 mg Ranibizumab in Patients 
with Subfoveal Neovascular Age-Related Macular Degeneration. Ophthalmology 2013; 
120:1046–1056. 
 
ClinicalTrials.gov. A Study Investigating the Efficacy and Safety of Lampalizumab Intravitreal 
Injections in Patients With Geographic Atrophy Secondary to Age-Related Macular 
Degeneration (CHROMA) http://clinicaltrials.gov/show/NCT02247479 
 
ClinicalTrials.gov. A Study Investigating the Safety and Efficacy of Lampalizumab Intravitreal 
Injections in Patients With Geographic Atrophy Secondary to Age-Related Macular 
Degeneration (SPECTRI) http://clinicaltrials.gov/show/NCT02247531 
Deloitte Access Economics. Eyes on the future: A clear outlook on Age-related Macular 
Degeneration. Macular Degeneration Foundation, 2011. Available at 
www.mdfoundation.com.au/LatestNews/MDFoundationDeloitteAccessEconomicsReport2011
.pdf. Accessed 15 November 2011. 
 
Dhondt J et al. Neuronal FLT1 receptor and its selective ligand VEGF-B protect against 
retrograde degeneration of sensory neurons. FASEB J 2011;25:1461–73. 
 
Eylea Product Information. 05 April 2013. 
 
Frampton, J. E. Ranibizumab: A Review of Its Use in the Treatment of Neovascular Age-
Related Macular Degeneration. ADIS drug evaluation Journal: Drugs and Aging. 2013.  DOI 
10.1007. Published online 29 March 2013. 
 
Grunwald et al. Risk of Geographic atrophy in the comparison of age-related macular 
degeneration treatments trials. Ophthalmology 2014; 121: 150-61 
 
Heier et al. Intravitreal Aflibercept (VEGF Trap-Eye) in Wet Age-related Macular 
Degeneration. Ophthalmology 2012;119:2537–2548. 
 
Hoffmann et al: Selective killing of RPE with a vascular endothelial growth factor chimeric 
toxin. Invest Ophthalmol Vis Sci 2000, 41:2389–2393. 
 


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Protocol No. CRFB002AAU17 
 
Lalwani et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular age 
related macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol. 
2009;148(1):43–58.e1. 
 
Lucentis Product Information. 05 October 2012. 
 
Maneros et al. Vascular endothelial growth factor expression in the retinal pigment epithelium 
is essential for choriocapillaris development and visual function. Am J Pathol 2006; 
167(5):1451-9. 
 
Martin et al. Ranibizumab and bevacizumab for neovascular age-related macular 
degeneration. N Engl J Med. 2011;364(20):1897–908. 
 
Martin et al. Ranibizumab and Bevacizumab for Treatment of Neovascular Age-related 
Macular Degeneration. Two-Year Results. Ophthalmology 2012; 119:1388–1398 
 
Moussa et al, 2013. Spectral domain optical coherence tomography-determined morphologic 
predictors of age-related macular degeneration-associated geographic atrophy progression. 
Retina 2013. E-pub.  
 
Oubraham et al. Inject and extend dosing versus dosing as needed: a comparative 
retrospective study of ranibizumab in exudative age-related macular degeneration. Retina. 
2011;31(1):26–30. 
 
Rosenfeld et al. Ranibizumab for Neovascular Age-Related Macular Degeneration. N Engl J 
Med 2006; 355:1419-31. 
 
Saint-Geniez et al. An essential role for RPE-derived soluble VEGF in the maintenance of the 
choriocapillaris. Proc Natl Acad Sci USA 2009;106(44):18751–18756. 
 
Schmidt-Erfurth U et al. Intravitreal Aflibercept injection for neovascular age-related macular 
degeneration: Ninety-six-week results of the VIEW studies. Ophthalmology 2014; 121: 193-
201. 
 
Schmitz-Valckenberg et al. Evaluation of autofluorescence imaging with the scanning laser 
ophthalmoscope and the fundus camera in age-related geographic atrophy. Am J 
Ophthalmol 2008: 146:183–192. 
 
Spaide R. Ranibizumab according to need: a treatment for age-related macular 
degeneration. Am J Ophthalmol. 2007;143(4):679-80 
 
Stewart. Clinical and differential utility of VEGF inhibitors in wet age-related macular 
degeneration: focus on aflibercept. Clinical Ophthalmology 2012:6   
 
Zhang SH et al. Effect of VEGF-B on neuroprotection in mouse retinal ganglion cells. Zhonghua 
Yan Ke Za Zhi 2009;45:38–42 
 

SAP_001.pdf: 
Clinical Development 
RFB002/ranibizumab / NCT02130024 
Development of new geographic atrophy in patients with 
neovascular (wet) age-related macular degeneration: 
 a comparison of ranibizumab and aflibercept
End of Study deliverables 
Detailed Statistical Methodology 
Author(s): 
 Statistician 
Document type: 
MAP Module 3 
Document status: 
Version 2.0 
Release date: 
04-May-2018
Number of pages: 
33 
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 ................................................................................................................. 3 
List of tables and figures ..................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
1 
Introduction ......................................................................................................................... 7 
2 
Project standards .................................................................................................................. 8 
2.1 
Analysis sets ............................................................................................................ 9 
2.2 
Subgroup definitions .............................................................................................. 10 
2.3 
Assessment windows, baseline and post baseline definitions, missing data 
handling ................................................................................................................. 10 
2.3.1 
Baseline and post-baseline definitions: ................................................. 11 
2.3.2 
Study observation period ....................................................................... 12 
2.3.3 
Missing and implausible dates .............................................................. 12 
2.4 
Subject disposition, background and demographic characteristics ....................... 15 
2.4.1 
Subject disposition ................................................................................ 15 
2.4.2 
Protocol deviations ................................................................................ 16 
2.4.3 
Background and demographic characteristics ....................................... 16 
2.4.4 
Eligibility............................................................................................... 16 
2.4.5 
Baseline Characteristics ........................................................................ 16 
2.4.6 
Medical history ...................................................................................... 18 
2.5 
Study medication ................................................................................................... 19 
2.5.1 
Exposure ................................................................................................ 19 
2.5.2 
Treatment patterns ................................................................................. 19 
 
 20 
2.6 
Prior and Concomitant medication ........................................................................ 21 
2.7 
Efficacy evaluation ................................................................................................ 21 
2.7.1 
Variables ............................................................................................... 21 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 22 
2.8 
Safety evaluation ................................................................................................... 29 
2.8.1 
Adverse events ...................................................................................... 29 
2.8.2 
Laboratory data ..................................................................................... 30 
2.8.3 
Vital signs.............................................................................................. 30 
2.8.4 
Electrocardiogram (ECG) ..................................................................... 31 
2.8.5 
Intra-Ocular Pressure (IOP) .................................................................. 31 
2.8.6 
Ophthalmologic Examination ............................................................... 31 
2.8.7 
Retinal nerve fibre analysis at Baseline and Month 24 ......................... 31 
2.8.8 
Ocular Inflammation ............................................................................. 31 
2.8.9 
Meta-analysis ........................................................................................ 32 
2.9 
Interim analyses (12 Month Data Analysis) .......................................................... 32 


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2.10 
Data monitoring committee (DMC) ...................................................................... 33 
2.11 
Sample size and power considerations .................................................................. 33 
2.12 
Pharmacokinetic analyses ...................................................................................... 33 
3 
References ......................................................................................................................... 33 
 
 
 


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List of tables and figures 
Table 1-1 
Studies covered in the MAP .................................................................... 7 
Table 2-1  
Analysis set exclusion summary ............................................................. 9 
Table 2.3-3 
Study Assessment Windows ................................................................. 10 
Table 2.7.2-1 
Primary and Key Secondary Efficacy Analyses ................................... 22 
Table 2.7.2-2 
Remaining Secondary Efficacy Analyses ............................................. 23 
Table 2.7.2.5-1 
Mixed Models ....................................................................................... 25 
Table 2.7.2.8-1 
Logistic Regression Models .................................................................. 28 
 
 
 


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List of abbreviations 
 
AE 
 
 
 
 
Adverse Event 
ANCOVA 
 
 
 
Analysis of Covariance 
AMD  
 
 
 
Acute Macular Degeneration 
APTC  
 
 
 
Antiplatelet Trialists' Collaboration 
ATE 
 
 
 
 
Arterial Thromboembolic Event 
BCVA  
 
 
 
Best Corrected Visual Acuity 
CI 
 
 
 
 
Confidence Interval 
CNV  
 
 
 
Choroidal Neovascularisation 
CRC  
 
 
 
Central Reading Center 
eCRF  
 
 
 
electronic Case Report Form 
GA 
 
 
 
 
Geographic Atrophy 
IOP 
 
 
 
 
Intraocular Pressure 
IRF 
 
 
 
 
Intra-Retinal Fluid 
LOCF  
 
 
 
Last Observation Carried Forward 
logMAR 
 
 
 
Logarithmic Minimum Angle of Resolution  
OCT  
 
 
 
Optical Coherence Tomography 
SAE 
 
 
 
 
Serious Adverse Event 
SAP 
 
 
 
 
Statistical Analysis Plan 
SE 
 
 
 
 
Standard Error 
SRF 
 
 
 
 
Sub-Retinal Fluid 
VA 
 
 
 
 
Visual Acuity 
 


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1 
Introduction 
The purpose of this document is to outline the statistical analyses planned for End of Study 
(EOS) deliverables. This document will also include 12 month interim analysis. The 
accompanying mock shells, will be compiled at a later date, prior to EOS data base lock. 
Studies covered are listed in Table 1-1. The study design, objective, treatment duration, and 
efficacy variables for this indication may be different from other related studies due to 
different indications and phases of clinical development so that almost every study is unique.  
The main purpose is to provide project-level standards for the statistical analyses of efficacy 
and safety data which are common or similar across studies. This MAP can be used as a 
reference or guidance of statistical methods for future studies not listed in Table 1-1. 
Table 1-1 
Studies covered in the MAP 
Indication
/Study 
Phase/ 
Duration 
Treatment/ dose 
Primary objective 
AMD / 
RFB002 
IV/ 
24 
Month 
(1) Aflibercept/  
2.0 mg 
(2) Ranibizumab/ 
0.5 mg 
The primary objective is to investigate the 
difference between the development of new 
geographic atrophy in the study eye following 
intravitreal ranibizumab relative to aflibercept in 
patients with wet AMD. The primary endpoint 
for the study will be the mean change in area of 
geographic atrophy from Baseline to Month 24 
(as measured by multimodal imagining assessed 
by an independent reading centre masked to the 
treatment arms). 
 
This is a randomized, multi-centre trial investigating the risk of developing new geographic 
atrophy in the study eye of patients treated with aflibercept relative to patients treated with 
ranibizumab. After consenting to participate in the study, patients will participate in a 
screening period lasting up to 2 weeks to evaluate patient eligibility. After eligibility 
confirmation at the Baseline Visit, patients will be randomized in a 1:1 ratio to one of the two 
treatment arms i.e. 2.0 mg aflibercept or 0.5 mg ranibizumab within the appropriate stratum 
depending on the treatment at Baseline for the non-study eye i.e. none, ranibizumab or other 
anti-VEGF therapy. Only one eye will be selected/treated as the study eye. Ranibizumab and 
aflibercept will be administered monthly for the first 3 injections followed by an individual 
treatment interval determined by disease activity. 
 
Patients withdrawn from the study prior to completion of the 24 Month assessment visit will 
be asked to return for an Early Discontinuation evaluation 30 days +/- 7 days following their 
last study visit. 
 
 


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Figure 3-1 Study design 
 
 
SCN = Screening, BSL = baseline, INITIAL 3 TR. = Initial 3 treatments at 4 weekly intervals both arms, 
Flexible interval Tr = treatment intervals will differ based on arm and disease activity, Pr. EP = Primary 
Endpoint, EOS= End of study, IA = 12 Month Data Interim analysis. 
2 
Project standards 
Treatment groups for the analysis 
The investigational treatment/study drugs in this study are 0.5 mg ranibizumab and 2.0 mg 
aflibercept. 
 
2.1 General considerations 
Descriptive statistics (n, mean, standard deviation, median, minimum and maximum values 
and, where appropriate, confidence intervals for continuous variables; frequencies and 
percentages for categorical variables) will be provided where applicable for patients and study 
eye. All data will be listed by patient, and where applicable, by eye. 
The study eye is the eye identified by the investigator according to the protocol inclusion and 
exclusion criteria and recorded as such at the screening or Baseline visit in the electronic Case 
Report Form (eCRF). 
All efficacy assessments are to be done on the study eye and recorded in the relevant eCRF. 
For non-ocular, study eye, and fellow eye summary tables, figures, and listings will be based 
on all patients included in the analysis/set population under consideration. Unless otherwise 
specified, all confidence intervals (CIs) and p values will be two-sided and will be based on 
an alpha significance level of 0.05. 
 


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2.1 
Analysis sets 
The following are common analysis sets used across the project.  
Randomized Set: The Randomized Set will consist of all randomized patients. 
Full Analysis Set: The Full Analysis Set comprises all subjects randomized and who have at 
least one post-baseline efficacy value for the primary endpoint, defined as a Geographic 
Atrophy (GA) assessment as captured in the eCRF from Autofluorescence for the study eye. 
Following the intent-to-treat principle, subjects will be analysed according to the treatment 
regimen they were assigned to at randomization. 
Safety Set: The Safety Set will consist of all patients who received at least one application of 
study treatment and had at least one post-baseline safety assessment. The statement that a 
patient had no adverse events also constitutes a safety assessment. Subjects will be analysed 
according to the treatment regimen they received. 
Per-Protocol Set: The Per-Protocol Set will consist of all patients in the Full Analysis Set 
who followed the treatment regimen as randomized without clinically significant protocol 
deviations.  Clinically significant protocol deviations will be identified and documented prior 
to the database lock.  Refer to “Protocol Deviations” study document for further details. 3  
In order to derive the analysis set, protocol deviations (defined prior to DB lock; impact on 
analysis defined in this document) and non-protocol deviations (based on the definition of the 
analysis set/according to this document) need to be considered. 
The protocol deviations are mainly used in excluding entire patients or particular data within a 
patient from the Per-Protocol Set and are described in the Protocol Deviation Plan. 
Furthermore - to derive the analysis sets, non-protocol deviations will be used.  
Table 2-1  
Analysis set exclusion summary below gives a summary of the non-protocol 
deviations that exclude patients from each analysis set. 
Table 2-1  
Analysis set exclusion summary 
Analysis Set (to 
be excluded from) 
Non-Protocol Deviations 
Full Analysis Set 
Not in the Randomized set 
Did not record at least one post-baseline 
efficacy value for the primary endpoint 
(see details above) 
Per-Protocol Set 
Not in Full Analysis Set 
Clinically significant protocol 
deviation(s) 
Safety Set 
Did not receive at least one application 
of study treatment 
Did not record at least one post-baseline 
safety assessment 
All efficacy evaluations will be carried out on the Full Analysis Set. The analysis for the 
primary efficacy evaluation will be carried out on both the Full Analysis Set and the Per-


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Protocol Set. Analyses for secondary 
 evaluations will be carried out on the 
Full Analysis Set, and may also be carried out on the Per-Protocol Set as part of sensitivity 
analyses. 
All safety evaluations will be carried out on the Safety set. Within the safety set, patients will 
be analysed as treated. 
The number and percentage of patients in each analysis set will be summarized based on all 
randomized patients in the analysis set. 
In addition, a listing will be produced to show the patient inclusion/exclusion into each of the 
analysis sets with the corresponding reason(s) for exclusion. 
Note that additional analysis sets may be derived as part of sensitivity analyses. 
2.2 
Subgroup definitions 
Sub-groups analyses may be included in 
 sensitivity analyses. Potential 
sub-groups: 
 Randomization Strata: Two treatment naïve eyes, one eye (first/fellow non-study eye) 
being treated with ranibizumab, and one eye (first/fellow non-study eye) being treated 
with an anti-VEGF other than ranibizumab. 
 Baseline Best Corrected Visual Acuity (BCVA) 
 Baseline choroidal neovascularisation (CNV) lesion size 
 Baseline CNV lesion type 
 Baseline IRF and/or SRF 
Sub-group analyses may include descriptive analyses as well as forest plot(s) displaying 
treatment effects within each sub-group. 
2.3 
Assessment windows, baseline and post baseline definitions, 
missing data handling 
Assessment windows to be applied to this study are detailed in Table 2.3-3. 
Table 2.3-3 
Study Assessment Windows 
Period 
Screen 
Initial Treatment 
Treatment Period 
Visit 
1 
2 
3 
Visit 
3+ 
7days 
4 Visit 
4+ 
7days 
n Month 
12 † 
n 
Month 24 or Early 
Discontinuation 
Weeks (relative to 
Baseline, Day 0) 
 
-2 to 0 
 
Baseline 
4 
5 
8 
9 
 
v 
 
52 
 
v 
 
104 
Visit window (days) 
 
 
±3 
±3 ±3 ±3 
±7 
± 6 
± 7 
±6 
n = number of visits as required per study protocol section 5.5.4.1 
v = variable. The number of visits will differ dependent on treatment interval as per study protocol section 
5.5.4.1 
†= If patient is not due for another injection within the visit window of the Month 12 the patient should attend a 
visit and have all procedures except ranibizumab or aflibercept injection. 


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2.3.1 
Baseline and post-baseline definitions: 
2.3.1.1 
Baseline 
Baseline is defined as the last available non-missing value collected just prior to the start of 
treatment in the study eye.   
Where a patient parameter value is missing for Visit 2: 
1. If the patient has entered the treatment period (i.e. received at least one treatment), the 
Baseline value for that patient will be imputed with the patient’s Screening value.   
2. If the patient never entered the treatment period, the Baseline value will not be 
imputed.   
Furthermore, patients with screening assessments, who do not enter the treatment period data, 
will only be included in data listings. 
Note:  
If Baseline images i.e. Fluorescein Angiography, Autofluorescence, Optical Coherence 
Tomography (OCT), Colour Fundus - are missing or not of a sufficient quality for analysis, 
images from either Week 4 or Week 8 will be used as the baseline measurement. 
 
2.3.1.2 
Post-baseline 
All assessments obtained after the date of first dose of study drug are considered as 
post-baseline unless otherwise specified. Missing data for post-baseline values, for example 
due to discontinuation, loss to follow-up, or other types of censoring (e.g. due to rescue 
medication), will not be imputed.  Only subjects with measurements at any given time point 
will be included in the analysis for that given parameter and visit.  Refer to Section 2.3.3 for 
further details regarding the handling of missing dates. 
The study day for a Baseline or post-baseline scheduled or unscheduled visit is defined as: 
Study day = (Date of visit) - (date of First Dosing) + 1 
The study day for a scheduled or unscheduled visit before baseline is defined as: 
Study day = (Date of visit) - (date of First Dosing). 
Note: The first dosing day will be calculated as study day 1 according to CDISC standards. 
However, the protocol documented the first dosing day as Day 0. 
 
2.3.1.3 
Visit Windows 
Data listings presented by visit will use the eCRF nominal visit windows (using planned visit 
dates), as well as the derived visit window (calculated using the actual visit date). Visit names 
available will be 4-weekly for the first 12 weeks, and then fortnightly. For example: Week 4, 
Week 8, Week 12, Week 14, Week 16, Week 18, etc... 
For derived visit windows: the actual post-baseline visit’s study day (as determined in 2.3.1.2) 
will be allocated to a derived visit window as follows:  
 Week 4: if the actual visit’s study day is between Day 2 (inclusive) and Day 43 
(inclusive); 


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 Week 8: if the actual visit’s study day is between Day 44 (inclusive) to Day 71 
(inclusive); 
 Week 12: if the actual visit’s study day is between Day 72 (inclusive) to Day 92 
(inclusive); 
 Week 14, Week 16, etc.: if the actual visit’s study day is within ([Actual date’s Week 
number x 7] ± 7 days)+1, exclusive at lower bound and inclusive at upper bound. 
 
Any other outputs requiring presentation by visit (e.g. tables) will use eCRF nominal visit 
windows, unless specified otherwise in the respective sections of the SAP. 
 
2.3.1.4 
Early Discontinuation 
Early Discontinuation visits will be assigned to a derived visit window based on the date of 
termination. If the Early Discontinuation visit is assigned to a visit window that already exists, 
then the assigned visit number will be set to the next visit window. 
In data listings presented by visit, an Early Discontinuation visit will be labelled both as per 
the eCRF nominal visit number (i.e. “End of Study/M24”) and as per the corresponding 
derived visit number, as described above. 
Early Discontinuation visits may also be summarized as a separate distinct visit, in addition 
to, or in place of, the approach described in the paragraph above. 
There will be no imputation for missing data in the primary analysis of the primary and 
secondary endpoints for those patients who discontinued the study early. For supporting and 
sensitivity analysis of the primary endpoint, the area of geographic atrophy at the last on-
study visit will be used for patients who withdraw prior to the 12 or 24 month visit.  
Sensitivity analyses may be conducted to assess the impact of possible biases in endpoint 
analyses due to missing endpoint data for early withdrawal patients. These analyses may 
include Last Observation Carried Forward (LOCF), Baseline Observation Carried Forward 
(BOCF) and other imputation methods, as detailed further in Section 2.7.2.2. 
2.3.2 
Study observation period 
The study observation period for each patient will be defined as the period (in days) between 
the date of first treatment in the study eye (Day 1) and the date of the end of study visit + 1 
(day). 
2.3.3 
Missing and implausible dates 
The general approach to handling missing dates is shown below for dates of Adverse Events 
(AEs), medical history diagnosis and concomitant treatment.  
 
2.3.3.1 
Adverse event start date imputation 
AEs with completely missing onset dates will be considered to be treatment emergent. 
Adverse events with partially missing onset dates will also be included as treatment emergent 
when the month (if it exists) and the year occur on or later than the month and year of the 
initial study treatment date. 


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Partial AE start dates are imputed with reference to the treatment start date (TRTSTD) as 
outlined in the Imputation table below. Completely missing start dates will not be imputed.  
For individual data listings, any missing or partial AE start dates will always be presented as 
recorded. 
The date value is split into day, month, year sections and referenced in the Imputation table as 
outlined below: 
 
 
Day 
Month 
Year 
Partial AE Start Date 
Not used 
MON 
YYYY 
Treatment Start Date 
(TRTSTD) 
Not used 
TRTM 
TRTY 
 
The following matrix explains the logic behind the imputation. 
Comparison of 
Month Section 
MON MISSING 
MON<TRTM 
MON=TRTM 
MON>TRTM 
YYYY 
MISSING 
NC 
NC 
NC 
NC 
YYYY<TRTY 
(D)=01JULYYY 
Before Treatment 
Start 
(C)=15MONYYYY 
Before Treatment 
Start 
(C)=15MONYYYY 
Before Treatment 
Start 
(C)=15MONYYYY 
Before Treatment 
Start 
YYYY=TRTY 
(B)=TRTSTD+1 
Uncertain 
(C)=15MONYYYY 
Before Treatment 
Start 
(A)=TRTSTD+1 
Uncertain 
(A)=01MONYYYY 
After Treatment Start 
YYYY=TRTY 
(E)=01JANYYYY 
After Treatment Start 
(A)=01MONYYYY 
After Treatment Start 
(A)=01MONYYYY 
After Treatment Start 
(A)=01MONYYYY 
After Treatment Start 
The following table is the legend to the logic matrix. 
Relationship 
Before Treatment Start 
Partial date indicates AE start date prior to 
Treatment Start Date  
After Treatment Start 
Partial date indicates AE start date after 
Treatment Start Date 
Uncertain 
Partial date insufficient to determine 
relationship of AE start date to Treatment 
Start Date 
Imputation Calculation 
NC / Blank Uncertain 
No convention 
(A) After Treatment Start or Uncertain 
MAX(01MONYYYY,TRTSTD+1) 
(B) Uncertain 
TRTSTD+1 


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(C) Before Treatment Start 
15MONYYYY 
(D) Before Treatment Start 
01JULYYYY 
(E) After Treatment Start 
01JANYYYY 
 
2.3.3.2 
Medical history date of diagnosis imputation 
Completely missing dates will not be imputed. Partial dates of diagnosis will be compared to 
the treatment start date. 
 If DIAG year < treatment start date year and DIAG month is missing, the imputed 
DIAG date is set to the mid-year point (01JULYYYY)  
o else if DIAG month is not missing, the imputed DIAG date is set to the mid-
month point (15MONYYYY) 
 If DIAG year = treatment start date year 
o and (DIAG month is missing OR DIAG month is equal to treatment start 
month), the imputed DIAG date is set to one day before treatment start date 
o else if DIAG month < treatment start month, the imputed DIAG date is set to 
the midmonth point (15MON YYYY) 
o else if DIAG month > treatment start month => data error 
 If DIAG year > treatment start date year => data error 
 
2.3.3.3 
Concomitant treatment date imputation 
In order to classify a medication as prior or prior/concomitant, it may be necessary to impute 
the start date. Concomitant treatments with partial start dates will have the date or dates 
imputed. Partial concomitant treatment start dates are imputed with reference to the treatment 
start date (TRTSTD) in accordance with the rules outlined below: 
Concomitant treatments with completely missing start dates will not be imputed. As a 
conservative approach, such treatments will be classified as prior/concomitant (i.e. as being 
received on or after the start of study treatment). 
 
Day 
Month 
Year 
Partial CMD Start Date 
Not used 
MON 
YYYY 
Treatment Start Date 
(TRTSTD) 
Not used 
TRTM 
TRTY 
 
 
 
 
 


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The following matrix explains the logic behind the imputation. 
Comparison of 
Month Section 
MON MISSING 
MON<TRTM 
MON=TRTM 
MON>TRTM 
YYYY 
MISSING 
(C)  
Uncertain 
(C)  
Uncertain 
(C)  
Uncertain 
(C)  
Uncertain 
YYYY<TRTY 
(D)=01JULYYY 
Before Treatment 
Start 
(A)=15MONYYYY 
Before Treatment 
Start 
(A)=15MONYYYY 
Before Treatment 
Start 
(A)=15MONYYYY 
Before Treatment 
Start 
YYYY=TRTY 
(C) 
Uncertain 
(A)=15MONYYYY 
Before Treatment 
Start 
(C) 
Uncertain 
(B)=01MONYYYY 
After Treatment Start 
YYYY=TRTY 
(E)=01JANYYYY 
After Treatment Start 
(B)=01MONYYYY 
After Treatment Start 
(B)=01MONYYYY 
After Treatment Start 
(B)=01MONYYYY 
After Treatment Start 
 
The following table is the legend to the logic matrix. 
Relationship 
Before Treatment Start 
Partial date indicates CMD start date prior to Treatment Start 
Date  
After Treatment Start 
Partial date indicates CMD start date after Treatment Start 
Date 
Uncertain 
Partial date insufficient to determine relationship of CMD 
start date to Treatment Start Date 
Imputation Calculation 
NC / Blank Uncertain 
No convention 
(A) Before Treatment Start 
15MONYYYY  
(B) After Treatment Start 
MAX(01MONYYYY,TRTSTD+1) 
(C) Uncertain 
IF CMDTYP1C IN (1, 3) THEN TRTSTD-1 ELSE IF 
CMDTYP1C IN (. 2) THEN TRTSTD+1 
(D) Before Treatment Start 
01JULYYYY 
(E) After Treatment Start 
01JANYYYY 
2.4 
Subject disposition, background and demographic 
characteristics 
2.4.1 
Subject disposition 
The number of subjects randomized and included in each of the analysis sets will be presented 
by treatment group. The number and percentage of subjects in the Randomized Set who 


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completed the study, who discontinued the study and the reason for discontinuation will be 
presented for each treatment group and for all subjects (Total). 
The number of subjects screened only will also be presented. In addition, the reasons for 
screen failures will be provided. 
2.4.2 
Protocol deviations  
All clinically significant protocol deviations will be summarized by number and percentage of 
patients with each deviation. Patients with multiple protocol deviations will only be counted 
once at each level of summarization. In addition, a listing of protocol deviations will be 
produced including the date and study day of the deviation occurrence with the accompanying 
deviation details. Deviations will be summarized for the Full Analysis Set. Refer to the 
protocol deviation plan for the Protocol Deviations / non-Protocol Deviations) defined for this 
study. 
Note that protocol deviations may lead to exclusion of data based on a per-patient, per-visit or 
per-variable basis, as described in the protocol deviation plan. 
2.4.3 
Background and demographic characteristics 
The following background and demographic variables will be analysed using the Randomized 
Set: 
Continuous variables (as per eCRF): 
 Age (years) 
Categorical variables (as per eCRF): 
 Gender (Male, Female) 
 Race (Caucasian, Black African, Asian, Aboriginal and Torres Strait Islander, Pacific 
Islander, Other, Not sure) 
 Ethnicity (Anglo Saxon, Northern European, Southern European, Asian Indian, Other, Not 
sure) 
For continuous variables, descriptive statistics (mean, median, standard deviation, minimum 
and maximum) will be presented for each treatment group and for all subjects (Total).  
For categorical variables, the number and percentage of subjects in each category will be 
presented for categorical variables for each treatment group and for all subjects (Total).   
2.4.4 
Eligibility 
All eligibility data, including inclusion and exclusion criteria, will be listed. 
2.4.5 
Baseline Characteristics 
The following Baseline characteristic variables will be analysed using the Randomized Set: 
Categorical Baseline variables (as per eCRF): 
 Study eye selection (L/R) 
 Prior wet AMD treatment for fellow eye (Yes/No) 
 Prior wet AMD Treatment (Lucentis, Eylea, Visudyne, Avastin, Steroids, Other) 
 Family history of AMD 


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 History of arterial thromboembolic events 
 Smoking history (“Never smoked”, “Current smoker”, “Smoked in the past”) 
 
Continuous Baseline efficacy variables: 
 Total BCVA score (as per eCRF) 
 GA assessments (as per Central Reading Centre)  
 Area of GA (mm2, Can’t grade, NA), as measured on Autofluorescence* 
 Longest linear dimension (µm), as measured on OCT 
 OCT assessments (as per Central Reading Centre): 
 Central subfield foveal thickness (CSFT) (The mean thickness values measured in 
1mm diameter between the internal limited membrane layer and the bruch’s 
membrane) 
 Subfoveal choroidal thickness (central Subfoveal choroidal thickness) 
 Nerve Fibre analysis (Mean thickness of the retinal nerve fibre layer on a circle scan of 
the optic nerve head) 
 Fluorescein Angiography assessments (as per Central Reading Centre): 
 Area of lesion (mm2) 
 Area of active CNV (mm2) 
 
Categorical Baseline efficacy variables: 
 Visual acuity >=70 letters (20/40) – as per eCRF 
 Visual acuity <70 letters – as per eCRF 
 GA assessments (as per Central Reading Centre)* 
 Presence on Color Fundus Photography (Present, Absent, Can’t grade) 
 Presence on Fluorescein Angiography (Present, Absent, Can’t grade) 
 Presence on OCT (Present, Absent, Can’t grade) 
 Present on Autofluorescence (Present, Absent, Can’t grade) 
 Overall determination of GA presence (Yes, No)* 
 Location of GA on Autofluorescence (N/A, Can’t grade, Central subfield, Inner 
subfield, Outer subfield), if overall determination of GA is present 
 GA – as per eCRF 
 If present, Linear dimension (≤ 249 µm, ≥ 250 µm) 
 OCT assessments (as per Central Reading Centre): 
 Intra-retinal fluid (Present, Absent, Can’t grade) 
 Intra-retinal fluid center involvement (Present, Absent, Can’t grade) [If IRF = 
present]  
 Sub-retinal fluid (Present, Absent, Can’t grade) 
 Sub-retinal fluid center involvement (Present, Absent, Can’t grade) [If SRF = 
present] 
 PED (Present, Absent, Can’t grade. Solid, Hollow, Mixed. Subfoveal: Yes/No. If yes, 
max height within 1mm diameter) 


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 Vitreoretinal Abnormalities (Present, Absent, Can’t grade. If present: Epiretinal 
membrane [if affecting fovea], vitreomacular adhesion, vitreomacular traction, 
macular hole, other) 
 Subretinal hyper reflective material (Present, Absent) 
 Fluorescein Angiography assessments (as per Central Reading Centre): 
 Evidence of CNV complex (lesion), Study Eye Only (Present, Absent, Can’t grade) 
 CNV leakage (Present, Absent) 
 Type of CNV (predominantly classic, minimally classic/occult, RAP lesion, Can’t 
grade, other) 
 CNV complex (lesion) location, Study Eye only (subfoveal, juxtafoveal, extrafoveal, 
Can’t grade) 
 Lesion components (CNV, Blood, Serous PED, RPE rip/tear, Can’t grade, Blockade, 
other) 
 Colour fundus assessments (as per Central Reading Centre): 
 Presence of Retinal Haemorrhage (Yes, No) (also as per eCRF) 
 AMD abnormality (drusen, hemorrhages, atrophy, fibrosis, PED, Pigmentary changes) 
(Present, Absent, Can’t grade) 
 Autofluorescence assessments (as per Central Reading Centre): 
 Evidence of Hyperfluorescence (Present, Absent, Can’t Grade) 
 Hyperfluorescence Type (Focal, Banded, Diffuse) 
 Evidence of Reticular Pseudodrusen – subretinal deposits (Present, Absent, Can’t 
Grade) 
 Evidence of RPE rip/tear (Present, Absent, Can’t Grade). 
 
* GA will be determined as present or absent based on definitions in the current Central 
Reading Centre Study Specification Worksheet. If deemed present, GA area will also be 
measured. Diagnosis of GA was confirmed if it is present in two of the imaging modalities, 
one of which had to be OCT or Autofluorescence. 
 
Note for the study 12-month interim analysis: no data was extracted from the Central 
Reading Centre. The only structural data to be described in the interim analysis were the CNV 
location and the CNV classification at baseline, as reported in the eCRF.  
 
Summary statistics will be presented for each treatment group and for all subjects (Total) in 
the Randomized Set, for all Baseline characteristics (including the Baseline values of the main 
efficacy endpoints). 
For continuous variables, descriptive statistics will be presented.   
For categorical variables, the number and percentage of subjects in each category will be 
presented for each treatment group and all subjects (Total). 
2.4.6 
Medical history 
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 (Version 
17). Separate tables will be provided for ocular (study eye and fellow eye) and ATE histories 


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and conditions.  The number and percentage of subjects with each medical condition will be 
provided by treatment group for the Randomized Set. 
Additionally, all information will be listed including the investigator reported term, and the 
diagnosis/surgery date. 
2.5 
Study medication 
2.5.1 
Exposure 
The following summaries will be presented for the injections in the study eye using the 
Safety Set: 
 The number and percentage of patients receiving study medication by treatment group 
and visit. 
 Duration of Exposure 
o Descriptive statistics (mean, median, standard deviation, minimum and 
maximum) will be presented using days as the unit.  
 The number of injections presented by treatment group in frequency tables by visit 
and cumulatively. The output will be presented by visit based on eCRF nominal visit 
windows, and may also be presented by visit based on derived visit windows. 
 
2.5.2 
Treatment patterns 
The following summaries of treatment patterns over 12 and 24 Months will be presented 
using the Full Analysis Set:  
 Treatment frequency 
 Total number of injections 
 Reason for interval decision (as defined within disease activity for each arm) 
 The interval between treatments (the first, second and third intervals 
extensions) 
 The number of times patients return to monthly treatments. 
 
The number of injections administered per patient for injections in the study eye will be 
summarized. Both the frequency distribution (number of patients with 1 injection, number of 
patients with 2 injections, and so on up to the maximum number of injections for any one 
patient for the given treatment period) and summary statistics for the number of injections per 
patient will be presented. 
Injections administered on, or after, the Month 12 visit, will count towards the 2nd year of 
treatment. 
The listing containing information on dose administration in the study eye, will also include  
total number of injections in the study eye. 


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2.6 
Prior and Concomitant medication 
The number and percentage of patients taking concomitant therapies will be summarized by 
preferred term according to the WHO Drug Reference List dictionary (September 2013) 
using the Safety Set. Summaries will be presented over two time periods, in separate tables: 
therapies received prior to the start of study treatment and therapies received after the start of 
study treatment. Categorization of the time period will be determined based on recorded or 
imputed start and end dates of medications. Rules for imputing incomplete (start and end) 
dates are described in Section 2.3.3.3. 
Medications will be presented in alphabetical order, by Anatomical Therapeutic Chemical 
(ATC) codes and Preferred Terms. Tables will also show the overall number and percentage 
of subjects receiving at least one drug of a particular Anatomical Therapeutic Chemical code 
and at least one drug in a particular anatomical main group. 
For concomitant medication, a separate summary will be provided for ocular (location of the 
condition treated).  
2.7 
Efficacy evaluation 
The primary objective is to investigate the difference between the development of new 
geographic atrophy in the study eye following intravitreal ranibizumab relative to 
aflibercept in patients with wet AMD. The primary endpoint for the study will be the mean 
change in area of geographic atrophy from Baseline to Month 24 (as measured by 
autofluorescence images assessed by an independent masked reading centre), based on 
square root transformed data (which decreases the dependency of GA growth on baseline GA 
size). Supportive and Sensitivity analyses will be conducted as described in Section 02. 
 
Other key secondary variables include the number of injections from Baseline to Month 12 
and the mean change in BCVA (logMAR) from Baseline to Month 12. 
2.7.1 
Variables 
The primary efficacy variable and key secondary variables are: 
 The mean change in area of geographic atrophy from Baseline to Month 24 
 The number of injections from Baseline to Month 12 
 The mean change in BCVA (logMAR) from Baseline to Month 12. 
 
The remaining secondary variables (efficacy and safety) are: 
 The mean change in area of existing and newly developed geographic atrophy from 
Baseline to Month 12 
 The proportion of patients showing new geographic atrophy from Baseline to Month 
12 
 The number of injections from Baseline to Month 24 
 The mean change in BCVA (logMAR) from Baseline to Month 24 
 The mean change in central subfield foveal thickness from Baseline to Months 12 and 
24 


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 The proportion of patients showing no intraretinal fluid (IRF) and subretinal fluid 
(SRF) at Months 2, 12 and 24 (Present/Absent) 
 Proportion of patients showing greater than and equal to a 15 letters (logMAR) gain 
from Baseline to Month 12 and 24 
 The proportion of patients showing less than and equal to 15 letters (logMAR) loss 
from Baseline to Months 12 and 24 
 
 The number of times a patient needed to return to monthly treatments during the 24 
months 
 
 Retinal nerve fibre analysis at Baseline and Month 24 
 
 
The concentration of plasma VEGF at Baseline and 7 days post-injection following 
Week 4 and Week 8 mandated intravitreal injections in full population and treatment 
naïve patients 
 
 
Ocular and systemic adverse events at all visits 
 
 
Ocular inflammation at Baseline and 7 days post-injection following 3rd mandated 
intravitreal injection. 
 
2.7.2 
Statistical hypothesis, model, and method of analysis 
Statistical methodologies for efficacy variables are detailed in Table 2.7.2-1 (Primary and Key 
Secondary efficacy) and Table 2.7.2-2 (Secondary efficacy). 
The null hypothesis is that there is no difference between the treatments in the development 
of new geographic atrophy from Baseline to 24 Months. The two treatments will be declared 
different if the p-value for the treatment effect is <0.05. Ranibizumab will be assessed against 
aflibercept and found superior if the mean change in area of geographic atrophy, based on 
square root transformed data, is less than that for aflibercept. 
 
Table 2.7.2-1 
Primary and Key Secondary Efficacy Analyses 
Study Endpoint 
Method of Analysis 
Primary: Mean change in area of 
geographic atrophy in the study eye from 
Baseline to Month 24, based on square root 
transformed data. 
1. Mixed Modelling (Refer to Section 2.7.2.5) 
2. Summary statistics of change from  
Baseline will be presented.  
 
Key Secondary: Number of injections 
from Baseline to Month 12 
 
1. Negative Binomial Regression Model (Refer 
to Section 2.7.2.7) 
 
Key Secondary: Mean change in BCVA 
(logMAR) from Baseline to Month 12 
 
1 Mixed Modelling (Refer to Section 2.7.2.5) 
2. Summary statistics of change from Baseline 
will be presented. 
 


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Table 2.7.2-2 Remaining Secondary Efficacy Analyses 
Study Endpoint 
Method of Analysis 
Mean change in area of geographic 
atrophy in the study eye from Baseline 
to Month 12. 
1. Mixed Modelling  
(Refer to Section 2.7.2.85) 
The proportion of patients with no GA 
at baseline who developed new 
geographic atrophy by Month 12 
 
The proportion of patients with no GA 
at Month 12 who developed new 
geographic atrophy by Month 24 
 
1.Logistic Regression Model 
(Refer to Section 2.7.2.8) 
The number of injections from 
Baseline to Month 24 
 
1. Negative Binomial Model (Refer to 
Section 2.7.2.7) 
 
 
The mean change in BCVA (logMAR) 
from Baseline to Month 24 
 
1.Mixed Modelling 
(Refer to Section 2.7.2.5) 
2. Summary statistics of change from 
Baseline will be presented 
The mean change in central subfield 
foveal thickness from Baseline to 
Months 12 and 24 
 
1.Mixed Modelling 
(Refer to Section 2.7.2.85) 
2. Summary statistics of change from 
Baseline will be presented 
The proportion of patients showing no 
intraretinal fluid (IRF) and subretinal 
fluid (SRF) at Months 2, 12 and 24 
(Present/Absent) 
 
1.Logistic Regression Model 
(Refer to Section 2.7.2.8) 
The proportion of patients showing 
greater than and equal to a 15 letters 
(logMAR) gain from Baseline to 
Months 12 and 24 
1. Logistic regression model  
(Refer to Section 2.7.2.8) 
The proportion of patients showing 
less than and equal to a 15 
letters (logMAR) loss from Baseline to 
Months 12 and 24 
1. Logistic regression model  
(Refer to Section 2.7.2.8) 
Plasma VEGF concentrations 
1.Mixed Modelling 
(Refer to Section 2.7.2.85) 
2. Summary statistics will be presented by 
time points 
 
 


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2.7.2.1 
Descriptive Summaries 
All data will be listed. 
All continuous data will be summarized by mandatory scheduled visit time point and 
treatment group using descriptive statistics, unless otherwise stated in the SAP. All categorical 
data will be summarized by mandatory scheduled visit time point (if appropriate) and 
treatment group by the number (and percentage) of patients in each category, unless otherwise 
stated in the SAP. 
NOTE: certain outputs, presented by visit, may in addition use derived visit windows. 
 
2.7.2.2 
Supportive/Sensitivity Analyses 
 
1. The primary endpoint will be assessed using a mixed model (as described in 2.7.2.5) 
with no imputation for missing data, using the Full Analysis Set.   
As a supporting analysis, the primary model will also be fitted to the Per-Protocol Set.  
Sensitivity analyses may be carried out by re-fitting the model with missing data 
imputed (as detailed further in Section 2.7.2.3) using: 
 Last Observation Carried Forward (LOCF) in the following way: 
o Mixed model (as described above) 
o A cross-sectional analysis at Month 24 by using an ANCOVA model. 
 Non-transformed GA size (data provided by the Central Reading Centre) 
 Mixed model (as described above) 
 A cross-sectional analysis at Month 24 by using an ANCOVA model. 
 Multiple imputation.  
 The main analysis is based on a random effects mixed model (subject specific model). 
Different correlation structure between the repeated measured data could be 
considered. Therefore, a mixed model for repeated measures (MMRM, marginal 
model) could be used to assess the robustness of the conclusion based on the main 
analysis. In the MMRM, the variance-covariance structure of the repeated measures 
will be specified as ‘Unstructured’.   
2. Key secondary endpoints will be analysed with no imputation for missing data. As a 
supporting analysis, the key secondary endpoint models may also be fitted to the Per-
Protocol Set. 
For the mean change in BCVA from Baseline to Month 12 (interim analysis at Month 12), 
a sensitivity analyses may be conducted with missing data imputed using the LOCF 
imputation method (mixed model) and may be analysed cross-sectionally by an ANCOVA 
model and multiple imputation.  
3. The remaining secondary endpoints will be analysed with no imputation for missing data. 
In addition, the remaining secondary endpoint models may be fitted to the Per-Protocol 
Set as a supporting analysis. Sensitivity analyses may be conducted; including the re-
fitting of models with missing data imputed using the LOCF and multiple imputation.  


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2.7.2.3 
Handling of missing values/discontinuations in efficacy analyses 
For the primary analysis there will be no imputation for missing data. For supporting and 
sensitivity analysis, the area of GA at the last on-study visit will be used for patients who 
withdraw prior to the 12 or 24 month visit. 
The mixed model approach where all values at mandatory scheduled visits recorded for 
each patient up to the time of study completion (or withdrawal) are used, is an appropriate 
model for data missing at random. 
Sensitivity analyses will be conducted to explore the robustness of the data to the methods 
of dealing with missing data. These methods will include LOCF and multiple imputation, 
as applicable. 
 
2.7.2.4 
Center pooling 
Not Applicable 
 
2.7.2.5 
Mixed Modelling 
The mixed models to be fitted are detailed in Table 2.7.2.5-1. 
Table 2.7.2.5-1 
Mixed Models 
Model 
Number 
Outcome 
Variable 
Covariate/Predictor 
Class Variable 
Random 
Term 
Definite 
Optional 
Definite 
Optional 
MM_1 
Change in area 
of geographic 
atrophy in the 
study eye from 
Baseline to 
Months 12 and 
24, based on 
square root 
transformed 
data. 
 Baseline 
Area of GA in 
study eye 
(continuous) 
 Treatment 
 Visit 
(categorical) 
 Treatment 
by Visit 
interaction 
At Baseline: 
 Presence of any GA 
in fellow eye (Y/N) 
 Presence of any GA 
in study eye (Y/N) 
 Location of GA in 
study eye (categorical: 
central subfield, inner 
subfield, outer subfield) 
 Presence of IRF in 
study eye (Y/N) 
 Presence of SRF in 
study eye (Y/N) 
 BCVA (continuous) 
 Presence of Reticular 
Pseudodrusen in study 
eye (Y/N) 
 Presence of Reticular 
Pseudodrusen in fellow 
eye (Y/N) 
 Area of active CNV 
(continuous) 
 CNV lesion type 
(categorical: classic, 
minimally 
classic/occult, RAP) 
 Age (continuous) 
 Subfoveal choroidal 
thickness (continuous) 
Treatment 
Visit 
Subject 
Stratum 
Center 
 
Subject 


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 Presence of Retinal 
Haemorrhage (per 
CRC) (Y/N) [Note: 
AMD abnormalities = 
present] 
 Presence of 
Epiretinal Membrane 
(ERM) OCT (Y/N) 
[Note: AMD 
abnormalities = 
present] 
 
 
May also be carried 
out if deemed relevant: 
Baseline:  
 Past history of 
smoking (Y/N) 
 Any treatment ever 
given to the fellow eye 
prior to Screening? 
(Y/N) 
 Presence of Pigment 
Epithelium Detachment 
on OCT (Y/N) 
 Presence of 
Subretinal 
hyperreflective material 
on OCT (Y/N) 
MM_2 
Change in 
BCVA 
(logMAR) from 
Baseline to 
Months 12 and 
24 
 Baseline 
BCVA 
(continuous) 
 Treatment 
 Visit 
(categorical) 
 Treatment 
by Visit 
interaction 
Baseline: 
 Presence of IRF in 
study eye (Y/N) 
 Presence of SRF in 
study eye (Y/N) 
 Presence of Fibrosis 
in study eye (Y/N) 
 Presence of subfoveal 
GA in study eye (Y/N) 
[Note: Overall 
determination of GA 
presence = Yes and 
Location of GA central 
subfield = Yes] 
 Age (continuous) 
 Area of active CNV 
(continuous) 
 CNV Lesion type 
(categorical: 
categorical: classic, 
minimally 
classic/occult, RAP) 
 
May also be carried 
out if deemed relevant: 
Baseline:  
 Area of lesion 
(continuous) 
Treatment 
Visit 
Subject 
Stratum 
Center 
 
Subject 


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MM_3 
Change in 
central subfield 
foveal thickness 
from Baseline to 
Months 12 and 
24 
 Baseline 
central 
subfield foveal 
thickness 
(continuous) 
 Treatment 
 Visit 
(categorical) 
 Treatment 
by Visit 
interaction 
Baseline: 
 Presence of IRF in 
study eye (Y/N) 
 Presence of SRF in 
study eye (Y/N) 
 Presence of Fibrosis 
in study eye (Y/N) 
 Presence of subfoveal 
GA in study eye (Y/N) 
[Note: Overall 
determination of GA 
presence = Yes and 
Location of GA central 
subfield = Yes] 
 Age (continuous) 
 Area of active CNV 
(continuous) 
 CNV Lesion type 
(categorical: classic, 
minimally 
classic/occult, RAP) 
Treatment 
Visit 
Subject 
Stratum 
Center 
 
Subject 
MM_4 
Plasma VEGF 
concentrations at 
Weeks 5 and 9 
 Baseline 
plasma VEGF 
concentrations 
(continuous) 
 Treatment 
 Visit 
(categorical) 
 Treatment 
by Visit 
interaction 
Baseline: 
 Bilateral treatment 
(categorical) 
 
Treatment 
Visit 
Subject 
Stratum 
Center 
 
Subject 
 
Results from mandatory visits will be included for each model, unless otherwise indicated. The 
repeated nature of the data will be modelled by including subject as random effect. The 
Kenward-Roger (KR) correction will be used to compute the denominator degrees of freedom 
to test fixed effects. The least square (LS) mean estimate for “Ranibizumab”treatment 
group – “Aflibercept”treatment group will be obtained where treatment time = 24 Months and 
where treatment time = 12 Months, as appropriate. These will be obtained with 95% 
confidence limits. 
In regards to the BCVA key secondary endpoint, ranibizumab will be found to be statistically 
significantly better at increasing BCVA if the change from Baseline is more than that for 
aflibercept and p <0.05. 
 
2.7.2.6 
Generalised Estimating Equations 
In addition, a model fitting the development of new geographic atrophy in the first 12 month 
period or the second 12 month period may be fitted to provide one analysis of the newly 
developed GA over time. New geographic atrophy is defined as the change in diagnosis of 
GA from “No” to “Yes”. This analysis would be undertaken using a Generalised Estimating 
Equation logistic regression. The General Estimating Equations analysis includes repeatedly 
collected GA data from different visits into one model, and the correlation of the repeatedly 
collected data is accounted for by the model.  


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Absence/Presence of IRF and/or SRF may also be analysed using a Generalised Estimating 
Equation logistic regression at Months 2, 12 and 24. 
 
2.7.2.7 
Analysis of Binomial Data 
The mean number of injections over the 24 month period will be analysed in a similar fashion 
to that for the 12 Month data analysis using a Negative Binomial model for count type data. 
The number of injections in the 24 Months will be the outcome variable and treatment as a 
class variable. The logarithmic length of time each subject is in the study up to their 24 Month 
visit will be used as an offset variable. The injection frequency (per 12 months) and the 
difference between injection frequencies (ratio) will be obtained for each treatment group 
along with the corresponding 95% confidence intervals and p-values. The model may be 
expanded to cater for other time points once the study is completed. 
 
2.7.2.8 
Logistic regression 
The logistic regression models to be fitted are detailed in Table 2.7.2.8-1. 
Table 2.7.2.8-1 Logistic Regression Models 
Model 
Number 
Outcome Variable 
Predictor/Covariate 
Mandatory 
Optional 
LR_1 
The proportion of patients with no 
GA at baseline who developed 
new* GA by Month 12 (Yes/No) 
 
The proportion of patients with no 
GA at Month 12 who developed 
new* GA by Month 24 (Yes/No) 
Treatment 
Center 
Baseline: 
Presence of GA in the fellow eye (Y/N) 
CNV Lesion type (categorical: classic, minimally 
classic/occult, RAP) 
Presence of IRF in study eye (Y/N) 
Presence of SRF in study eye (Y/N) 
Presence of Reticular Pseudodrusen in study eye 
(Y/N) 
BCVA (continuous) 
Age (continuous) 
Area of active CNV (continuous) 
Subfoveal choroidal thickness (continuous) 
LR_2 
Proportion of patients with no 
intraretinal fluid (IRF) and 
subretinal fluid (SRF) at Months 2, 
12 and 24 
Treatment 
Center 
Baseline: 
Presence of IRF/SRF in study eye  
BCVA (continuous) 
Area of lesion (continuous) 
Area of active CNV (continuous) 
LR_3 
Proportion of patients showing ≥15 
letters gain from Baseline to 
Months 12, 24 (Yes/No)  
Treatment 
Center 
Baseline BCVA (continuous) 


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LR_4 
Proportion of patients showing ≤15 
letters loss from Baseline to 
Months 12, 24 (Yes/No) 
Treatment 
Center 
Baseline BCVA (continuous) 
* New GA is defined as diagnosis of GA change from “No” to “Yes”, as determined by the 
Central Reading Center using multimodal imaging (overall determination of GA presence). 
From each model the adjusted odds ratio for the outcome variable, for ranibizumab compared 
with aflibercept, will be obtained with 2-sided 95% confidence limits. 
Using PROC GENMOD to calculate the 95% confidence interval for the odds ratios assumes 
asymptotic normality of the Wald estimate for the regression coefficient. The 95% confidence 
interval for the regression parameter of ranibizumab treatment effect relative to aflibercept is 
calculated using an exponential transformation to create the 95% confidence interval for the 
odds ratio.  
All p-values reported on linear hypotheses about regression coefficients will be based on the 
Wald tests from Type III analyses. In the SAS procedure PROC GENMOD, a Type III 
analysis will be performed by adding the model options: TYPE3, DIST=BIN, and 
LINK=LOGIT. 
The repeated binary data for absence/presence of IRF and/or SRF may also be assessed using 
a random intercept logistic regression (under the frame work of generalized linear mixed 
model) with robust estimation of standard error (SE). 
 
2.7.2.9 
Time to Event 
Time to newly developed GA will be analysed by survival analysis. Kaplan-Meier survival 
function will be summarized and plotted. Cox proportional hazards model may also be used as 
deemed appropriate. The newly developed GA is defined as any reported post baseline GA 
for those subjects without GA at baseline. Subjects without newly developed GA will be 
censored at the last visit date or withdrawal date, whichever occurs first.  
2.8 
Safety evaluation 
Safety parameters will include adverse events, the results of ophthalmic examinations, IOP, 
vital signs, and laboratory results if reported as AE, in addition to post-injection ocular 
inflammation at baseline and 7 days post-injection following 3rd mandated intravitreal 
injection. 
All safety analyses will be conducted within the Safety Set. 
2.8.1 
Adverse events 
Adverse events (AEs) will be reported by primary system organ class and preferred term 
according to the Medical Dictionary for Regulatory Activities (MedDRA), Version 17. 
AEs will be deemed treatment emergent if the onset date is on or after the date of first study 
treatment. Any AEs recorded prior to the start of study treatment will be listed together with 
all other AEs. Pre-treatment and treatment-emergent adverse events will be summarized 
separately. If any event has an incomplete onset date, this will be handled as described in 
section 2.3.3.1 above. 
The incidence of treatment emergent AEs will be summarized separately for ocular AEs as 
follows: 


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 All AEs 
 AEs by maximum severity 
 AEs suspected to be related to study drug 
 Serious AEs 
 AEs leading to study treatment discontinuation 
 
In addition, arterial thromboembolic events (ATEs) will be summarized, including: overall 
ATEs and APTC ATEs.  
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 information pertaining to AEs noted during the study will be listed by patient, detailing 
AE (e.g., verbatim given by the investigator as well as the system organ class and preferred 
term according to MedDRA), date of starting and ending, severity, suspected relationship (by 
the investigator) to the study drug / ocular injection, and eye (for ocular events). The AE onset 
will also be shown relative (in number of days) to the day of (first) initial study treatment and 
relative (in number of days) to the Day 1. 
The following AE listings will be provided: 
 All adverse events 
 Ocular adverse events 
 Adverse events suspected to be related to study drug and/or ocular injection 
 Serious adverse events 
 Adverse events leading to treatment withdrawal 
 Adverse events leading to treatment interruption. 
2.8.2 
Laboratory data 
No laboratory evaluations to assess blood or urine parameters will be performed – with the 
exception of pregnancy assessments, if applicable. 
2.8.3 
Vital signs 
Vital signs will be listed with values outside the extended normal range flagged as: H (High) 
and L (Low). 
Vital signs (sitting systolic and diastolic blood pressure (mmHg)) will be summarized by 
treatment group using descriptive statistics for all time points assessed, including change from 
Baseline for all post-Baseline assessments. Shift tables from Baseline to all post-Baseline 
assessments will also be generated for each parameter with values of Within Normal Limits 
(WNL), High, and Low used for the shift categories. 
Categories for “High” and “Low” are defined as follows:  
 High  
o Systolic (mmHg): either >180 with increase from Baseline >30 or >200 
absolute 
o Diastolic (mmHg): either >105 with increase from Baseline >20 or >115 
absolute; 
 


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 Low  
o Systolic (mmHg): either <90 with decrease from Baseline >30 or <75 absolute 
o Diastolic (mmHg): either <50 with decrease from Baseline >20 or <40 
absolute. 
 
2.8.4 
Electrocardiogram (ECG) 
No ECG performed during this study. 
2.8.5 
Intra-Ocular Pressure (IOP) 
IOP measurements will be summarized by treatment group, for the study eye, using 
descriptive statistics for all time points assessed, including change from Baseline for all post-
Baseline assessments. 
2.8.6 
Ophthalmologic Examination 
Ophthalmic examination results for the study and fellow eye will be listed separately and will 
include: 
 Cornea (Normal, Abnormal) 
 Iris (Normal, Abnormal) 
 Vitreous (Normal, Abnormal) 
 Disc (Normal, Abnormal) 
 Retina other than wAMD (Normal, Abnormal) 
 Lens (Phakic, Aphakic, Pseudophakic) 
 AREDS grading; 1st, 2nd and 3rd criteria (Nuclear Sclerosis, Cortical, PSC) 
 Grade categorised as (<2=’none to mild’ or >2=’moderate to severe’). 
 
In addition, ophthalmic examination results will be summarized by treatment group, for the 
study eye, using descriptive statistics. 
2.8.7 
Retinal nerve fibre analysis at Baseline and Month 24 
Retinal nerve fibre analysis will be undertaken at Baseline and Month 24. The proportion of 
patients with retinal nerve fibre damage will be provided by visit and treatment. Shift tables 
will present the change in nerve fibre status. 
Categories for “Decrease”, “No Change” and “Increase” are defined as follows:  
 Decrease (i.e. a decrease of >10 µm from Baseline)  
 No change (i.e. within ±10 µm from Baseline) 
 Increase (i.e. an increase of >10 µm from Baseline). 
 
2.8.8 
Ocular Inflammation 
Ocular inflammation is being assessed at Baseline and 7 days post the third injection and will 
be summarized using descriptive statistics. The proportion of patients with each grade of 


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inflammation will be presented by treatment group for each visit. Shift tables will present the 
change in inflammation status between visits by treatment group. 
2.8.9 
Meta-analysis 
Not Applicable. 
2.9 
Interim analyses (12 Month Data Analysis) 
One analysis is planned at 12 Months for the key secondary endpoints of the number of 
injections and mean change in BCVA from Baseline to Month 12. AEs (Adverse Events) and 
SAEs (Serious Adverse Events) may be included descriptively. 
 
No power analysis was undertaken directly for the 12 Month data analysis. However, the 
sample size estimated for the primary endpoint was assessed as to its adequacy for addressing 
the question of injection frequency at 12 Months. Assuming the 2-sided test for percentage 
developing geographic atrophy and a sample size of 121 per group, the sample size is also 
suitable for detecting a difference in injection frequency between ranibizumab and aflibercept 
at 12 Months of: 
 
• 0.7 injections if the standard deviation is 2, 
• 0.9 injections if the standard deviation is 2.5, 
• 1.1 injections if the standard deviation is 3.0, and 
• 1.3 injections if the standard deviation is as large as 3.5. 
Power is 80%, alpha is 0.05, test is a two-sided t-test and no adjustment has been made to 
alpha, the type I error rate for assessing multiple endpoints. These assumptions are based on 
the CATT study (Martin et al, 2012). 
 
The mean number of injections over the first 12 month period will be analysed using a 
Negative Binomial model for count type data. The number of injections in the first 12 Months 
will be the outcome variable and treatment as a class variable. The logarithmic length of time 
each subject is in the study up to their 12 Month visit will be used as an offset variable. The 
injection frequency (per year) and the difference (ratio) between injection frequencies will be 
obtained for each treatment group along with the corresponding 95% confidence intervals (CI) 
and p-values. 
 
The model to analyse mean change in BCVA from Baseline to 12 Months will be a random 
effects mixed model. In the random effects mixed model, change in BCVA from Baseline at 
Week 4, Week 8 and Month 12 (mandatory visits) will be included in the model as the 
outcome (response) variable and treatment as a class variable. Visit will be included as a class 
variable in order to estimate the mean BCVA change from Baseline at Week 4, Week 8 and 
Month 12 and an interaction term to determine if the mean BCVA change from Baseline at 
Week 4, Week 8 and Month 12 differs between treatments. The model will also include 
baseline BCVA as a continuous variable for the purpose of baseline covariate adjustment. The 
change in BCVA between Baseline and Month 12 for each treatment and the difference 
between 
ranibizumab 
and 
aflibercept 
(least 
square 
(LS) 
mean 
estimate 
for 
“ R a n i b i z u m a b ” t r e a t m e n t  gr o u p  – “ A f l i b e r c e p t ” t r e a t m e n t  g r o u p )  will 
be obtained along with 95% confidence limits. The repeated nature of the data will be 
modelled by including subject as random effect. The Kenward-Roger (KR) correction will be 


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used to compute the denominator degrees of freedom to test fixed effects. Other factors may 
be included in the model, such as centre. 
 
The 12 Month pre-planned interim analysis was conducted for information purposes only, 
with no stopping rule set up at interim analysis. 
2.10 
Data monitoring committee (DMC) 
Not Applicable. 
2.11 
Sample size and power considerations 
The sample size for the difference in the change in area of patients developing geographic 
atrophy is based on a two-sided z-test with α=0.05 and 80% power. Ranibizumab will be 
assessed against aflibercept and considered superior if the p-value for the z-test is <0.05 and 
the mean area of geographic atrophy is less for those on ranibizumab. A 95% two sided 
confidence interval for the difference in means will also be estimated. This is based on an 
assumption that a meaningful difference to detect is 20%. 278 patients should be able to detect 
a 20% difference in geographic area between the two groups based on expected change in 
Geographic Atrophy of 2mm/year with a sigma of 1.5 (also see Section 2.9 Interim Analyses). 
2.12 
Pharmacokinetic analyses 
Not applicable. 
3 
References 
1.Clinical Study Protocol, Version 02, dated 19 January 2015. 
2.eCRF, Version 3.0, dated 04 November 2014. 
3. CRFB002AAU17 Protocol Deviation Plan Version 1 04 Jul 2014. 
4. CRFB002AAU17 SSW V5 23 Jun 2016.