Conditions: Age-Related Macular Degeneration
Keywords: Wet AMD choroidal neovascularization Fovista® E10030 Avastin® Eylea®
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 645
Healthy volunteers: no

Brief summary:
The objectives of this study are to evaluate the safety and efficacy of intravitreal administration of Fovista® administered in combination with either Avastin® or Eylea® compared to Avastin® or Eylea® monotherapy in subjects with subfoveal choroidal neovascularization secondary to age-related macular degeneration (AMD).

Detailed description:
Subjects will be randomized in a 1:1 ratio to the following two arms per study design:

* Fovista® 1.5 mg/eye + Avastin® 1.25 mg/eye or Eylea® 2 mg/eye
* Fovista® sham + Avastin® 1.25 mg/eye or Eylea® 2 mg/eye

Subjects will be treated for up to 24 months with active Fovista® or sham, in combination with either Avastin® or Eylea® with the primary endpoint at 12 months.

Approximately 622 subjects will be randomized into one of the two treatment groups (311 patients per dose group), and the efficacy analysis will be based on the data from these two groups as per the SAP

Arms:
arm 1: E10030 1.5 mg intravitreal injection + bevacizumab 1.25 mg intravitreal injection or aflibercept 2 mg intravitreal injection arm 2: E10030 sham injection + bevacizumab 1.25 mg intravitreal injection or aflibercept 2 mg intravitreal injection

Interventions: intervention 1: E10030 intervention 2: bevacizumab or aflibercept intervention 3: E10030 sham injection
Intervention descriptions: intervention 1: None intervention 2: Patients are randomized to receive either bevacizumab or aflibercept intervention 3: Pressure on the eye with a syringe with no needle

Protocol document:
Prot_000.pdf: 
A PHASE 3 RANDOMIZED, DOUBLE-MASKED, CONTROLLED TRIAL 
TO ESTABLISH THE SAFETY AND EFFICACY OF INTRAVITREOUS 
ADMINISTRATION OF FOVISTATM (ANTI PDGF-B  PEGYLATED 
APTAMER) ADMINISTERED IN COMBINATION WITH EITHER 
AVASTIN® OR EYLEA® COMPARED TO AVASTIN® OR EYLEA® 
MONOTHERAPY IN SUBJECTS WITH SUBFOVEAL NEOVASCULAR 
AGE-RELATED MACULAR DEGENERATION  
 
 
PROTOCOL NO:  OPH1004B 
(Supersedes Protocol No: OPH1004A) 
 
 
 
Final Version Date:  6 March 2014 
 
 
 
SPONSOR: 
OPHTHOTECH CORP. 
One Penn Plaza – 19th Floor 
New York, NY 10119 
 
FOR MEDICAL EMERGENCIES REFER TO THE 
“SAFETY CONTACT LIST” PROVIDED SEPARATELY 
    
 
 
EudraCT No. 2013-003018-42 
Confidentiality Statement 
 
The information in this document is confidential and will not be disclosed to others without written authorization 
from Ophthotech Corp., except to the extent necessary to obtain informed consent from persons receiving the 
investigational drug or their legal guardians, or for discussions with local regulatory authorities, institutional 
review boards (IRB), or persons participating in the conduct of the trial. 
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TABLE OF CONTENTS 
1 
GLOSSARY OF ABBREVIATIONS ...................................................................... 4 
2 
SUMMARY OF PROTOCOL OPH1004B ............................................................. 5 
3 
STUDY ASSESSMENTS ..................................................................................... 7 
4 
INTRODUCTION .................................................................................................. 9 
4.1 
Age-Related Macular Degeneration (AMD) .............................................. 9 
4.2 
Vascular Endothelial Growth Factor (VEGF), Platelet Derived Growth 
Factor (PDGF) and Neovascular AMD .................................................... 10 
4.3 
Fovista™ (E10030) ................................................................................. 12 
4.4 
Clinical Data ............................................................................................ 13 
4.5 
Trial Rationale ......................................................................................... 15 
5 
TRIAL OBJECTIVES .......................................................................................... 18 
5.1 
Objectives ............................................................................................... 18 
5.2 
Endpoints ................................................................................................ 18 
6 
TRIAL DESIGN .................................................................................................. 19 
7 
PROCEDURES .................................................................................................. 19 
7.1 
Procedures for Refraction and Vision Testing ......................................... 19 
7.2 
Tonometry ............................................................................................... 20 
7.3 
Ophthalmologic Examination .................................................................. 20 
7.4 
Fundus Photography and Fluorescein Angiography ............................... 20 
7.5 
Optical Coherence Tomography ............................................................. 21 
7.6 
Laboratory Tests ..................................................................................... 21 
7.7 
Vital Signs, Physical Examination and Performance Status (ECOG) ..... 21 
7.8 
12-Lead ECG .......................................................................................... 22 
7.9 
Visual Function Questionnaire-25 ........................................................... 22 
8 
SUBJECT POPULATION ................................................................................... 22 
8.1 
Sample Size ............................................................................................ 22 
8.2 
Inclusion Criteria ..................................................................................... 22 
8.3 
Exclusion Criteria .................................................................................... 23 
9 
TRIAL MEDICATION .......................................................................................... 26 
9.1 
Drug Supply ............................................................................................ 26 
9.2 
Dose and Administration ......................................................................... 27 
9.3 
Previous or Concomitant Therapy .......................................................... 29 
10  TRIAL CONDUCT .............................................................................................. 29 
10.1 
Subject Enrollment .................................................................................. 29 
10.2 
Trial Assessments .................................................................................. 30 
10.3 
Withdrawal from Trial .............................................................................. 45 
10.4 
Trial Discontinuation ............................................................................... 45 
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11  STATISTICAL METHODS .................................................................................. 46 
11.1 
Experimental Design ............................................................................... 46 
11.2 
Endpoints ................................................................................................ 47 
11.3 
Number of Subjects ................................................................................ 48 
11.4 
Randomization Procedure ...................................................................... 48 
11.5 
Masking Procedures ............................................................................... 48 
11.6 
Analytical Considerations ........................................................................ 50 
12  ADVERSE  EVENTS .......................................................................................... 52 
12.1 
Definition of Adverse Events ................................................................... 52 
12.2 
Assessment and Reporting of Adverse Events ....................................... 53 
12.3 
Definition of Serious Adverse Events ...................................................... 54 
12.4 
Assessment and Reporting of Serious Adverse Events .......................... 56 
12.5 
Independent Data Monitoring Committee (IDMC) ................................... 56 
12.6 
Exposure in Utero ................................................................................... 56 
12.7 
Abnormal Laboratory Results ................................................................. 56 
13  RESPONSIBILITIES .......................................................................................... 57 
13.1 
Emergency Equipment ............................................................................ 57 
13.2 
Case Report Forms and Trial Documentation ......................................... 57 
13.3 
Drug Accountability/Storage Conditions .................................................. 58 
13.4 
Protocol Compliance ............................................................................... 58 
13.5 
Ethical Aspects ....................................................................................... 58 
13.6 
Institutional Review Board (IRB) or Ethics Committee (EC) Approval and 
Informed Consent ................................................................................... 59 
13.7 
Clinical Trial Insurance ............................................................................ 59 
13.8 
Trial Report and Publications .................................................................. 59 
14  MONITORING .................................................................................................... 60 
15  REFERENCES ................................................................................................... 61 
16  SIGNATURE  PAGE .......................................................................................... 65 
17  APPENDICES .................................................................................................... 66 
17.1 
Method for Evaluating Anterior Chamber Inflammatory Activity .............. 66 
17.2 
Method for Evaluating Vitreous Inflammatory Activity ............................. 67 
 
 ......................................... 68 
17.4 
ECOG/WHO Performance – Karnofsky Performance Status Scales ...... 79 
 
 ...................................................... 80 
17.6 
NYHA Functional Classifications ............................................................ 86 
 


1 GLOSSARY OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AMD 
Age-Related Macular Degeneration 
AST 
Aspartate aminotransferase 
BUN 
Blood Urea Nitrogen 
CATT 
Comparison of AMD Treatments Trials 
CNV 
Choroidal Neovascularization 
CRF 
Case Report Form 
DA 
Disc Area 
DNA 
Deoxyribonucleic Acid 
EC 
Ethics Committee 
EC 
Endothelial Cell 
ECG 
Electrocardiography 
ECOG 
Eastern Cooperative Oncology Group 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EW 
Early Withdrawal 
FA 
Fluorescein Angiography 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl-Transferase 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
NLP 
No Light Perception 
NV 
Neovascular 
NYHA 
New York Heart Association 
OCT 
Optical Coherence Tomography 
OU 
Both eyes 
PDGF 
Platelet Derived Growth Factor 
PDT 
Photodynamic Therapy 
RC 
Reading Center 
RPE 
Retinal Pigment Epithelium 
SAE 
Serious Adverse Event 
SE 
Study Eye 
SGOT 
Serum Glutamic Oxaloacetic Transaminase  
SGPT 
Serum Glutamic Pyruvic Transaminase  
SHRM 
Subretinal Hyper-Reflective Material 
TLP 
Thermal Laser Photocoagulation 
ULN 
Upper Limit of Normal 
VA 
Visual Acuity 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 
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2 SUMMARY OF PROTOCOL OPH1004B 
 
SYNOPSIS 
TITLE: 
A phase 3 randomized, double-masked, controlled trial to establish 
the safety and efficacy of intravitreous administration of Fovista™ (Anti 
PDGF-B pegylated aptamer) administered in combination with either 
Avastin® or Eylea® compared to Avastin® or Eylea®  monotherapy in 
subjects with subfoveal neovascular age-related macular 
degeneration. 
OBJECTIVES: 
The objectives of this study are to evaluate the safety and efficacy of 
Fovista™ (E10030) intravitreous administration when administered in 
combination with either Avastin® or Eylea® compared to Avastin®   or 
Eylea® monotherapy in subjects with subfoveal choroidal 
neovascularization secondary to age-related macular degeneration 
(AMD). 
STUDY DESIGN: 
 
 
 
 
Subjects will be randomized in a 1:1 ratio to the following dose 
groups: 
• 
Fovista™ 1.5 mg/eye + Avastin® 1.25 mg/eye or Eylea® 2 
mg/eye 
• 
Fovista™ sham + Avastin® 1.25 mg/eye or Eylea® 2 mg/eye 
Within each of the above dose groups, subjects will be randomized in 
a 1:1 ratio to either Avastin® 1.25 mg/eye or Eylea® 2 mg/eye. 
 
Subjects randomized to receive Avastin will be treated with active 
Fovista™ or sham in combination with Avastin® monthly for 24 
months. 
 
Subjects randomized to receive Eylea will be treated with active 
Fovista™ or sham in combination with Eylea® every month for the first 
3 doses (Day 1, Month 1, and Month 2) and every other month 
thereafter (i.e., Months 4, 6, 8, 10, 12, 14, 16, 18, 20, and 22). 
 
 
Therefore, subjects randomized to receive Avastin® will be treated 
with active Fovista™ or sham in combination with Avastin® for a total 
of 24 administrations.  Subjects randomized to receive Eylea® will be 
treated with active Fovista™ or sham in combination with Eylea® for a 
total of 13 administrations. 
 
 
All subjects will have a final follow-up visit at Month 24. 
ENDPOINTS: 
Primary Efficacy Endpoint: 
The primary efficacy endpoint is the mean change in visual acuity 
(ETDRS letters) from baseline at the Month 12 visit. 
 
 
 
Safety Endpoints: 
Safety endpoints include adverse events, vital signs, ophthalmic 
variables [ophthalmic examination, intraocular pressure (IOP), 
fluorescein angiogram (FA), optical coherence tomography (OCT)], 
ECG, and laboratory variables. 
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4 INTRODUCTION 
4.1 
Age-Related Macular Degeneration (AMD) 
Age-related macular degeneration is a disease characterized by progressive 
degenerative abnormalities in the macula of the eye, a small area in the central 
portion of the retina. It is characteristically a disease of individuals >50 years of age 
and is the leading cause of visual loss in developed countries.  In the United States, 
it is estimated that approximately 6% of individuals 65-74 years of age, and 20% of 
those older than 75 years of age are affected with AMD [1].  Because of the 
increasing life expectancy in developed and developing countries, the elderly sector 
of the general population is expected to rise at a greater rate in the coming 
decades.  While 1 of 8 Americans was considered to be elderly in 1994, it is 
expected that 1 of 5 will fall into this category in 2030.  Using U.S. Census Bureau 
projections, the number of Americans over 65 years of age will more than double to 
80 million by the middle of this century [2].  In the absence of adequate prevention 
or treatment measures, the number of cases of AMD with visual loss is expected to 
grow accordingly. 
Age-related macular degeneration is classified into one of two general subgroups: 
the non-neovascular (non-exudative or dry) form of the disease and the 
neovascular (exudative or wet) form of the disease.  The non-neovascular form of 
AMD is more prevalent, accounting for approximately 90% of all AMD cases, and is 
often characterized by a slow degeneration of the macula resulting in atrophy of the 
central retina with gradual vision loss over a period of years.  By contrast, 
neovascular AMD, although less prevalent, commonly causes sudden, often 
substantial, loss of central vision and is responsible for most cases of severe loss of 
visual acuity in this disease [3]. This type of AMD results when abnormal blood 
vessels (neovascularization) proliferate under and/or within the retina.  These blood 
vessels leak blood and fluid into the retina, which results in rapid vision loss.  The 
end stage of the disease is scarring with irreversible destruction of the central 
retina.   
The current FDA approved pharmacologic therapies for wet AMD target and inhibit 
Vascular Endothelial Growth Factor (VEGF). VEGF is an endothelial cell survival 
factor and a mitogen. Endothelial cells are a key component of neovascular tissue. 
All approved anti-VEGF agents for wet AMD are administered by the intravitreal 
route of administration. These include Lucentis® (ranibizumab), Eylea® (aflibercept), 
and Macugen® (pegaptanib sodium) [4, 5, 6, 7] 


 
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In addition, although not labeled by the FDA for the treatment of neovascular AMD, 
the anti-VEGF agent Avastin® (bevacizumab) is currently used to treat the ~50% of 
eyes with neovascular AMD in the United States. A multicenter, prospective, 
randomized trial, funded by the US National Eye Institute, “The Comparison of Age-
Related Macular Degeneration Treatments Trials” (CATT) demonstrated that 
monthly dosing with Avastin® 1.25 mg (0.05 mL) was non-inferior to monthly dosing 
of Lucentis® for eyes with neovascular AMD [8].  
Avastin®, Lucentis®, and Eylea®, on average, all improve the visual outcomes in 
eyes with neovascular AMD. The primary mechanism of action of these anti-VEGF 
agents is to decrease the intraretinal and subretinal fluid associated with abnormal 
blood vessels. Despite maximal therapy with intravitreal monotherapy anti-VEGF 
agents, majority of subjects do not achieve significant visual gain (≥ 15 letters of 
vision), and approximately 20% to 30% lose additional vision from baseline. 
Neovascular proliferation is the key step in wet AMD development. These abnormal 
vessels consist of endothelial cells, pericytes, and inflammatory cells. Two factors 
that play important roles in proliferation and maintenance of abnormal blood vessels 
are VEGF and Platelet Derived Growth Factor (PDGF). VEGF is an endothelial cell 
survival factor and a key mediator in the process of neovascularization. It is also 
one of the most potent inducer of vascular permeability in biologic systems.  
PDGF is a growth factor responsible for pericyte survival, maturation and 
regulation.   
The neovascularization process is complex and anti-VEGF resistance may result 
from multiple mechanisms including endothelial cell protection by pericytes. 
Simultaneous and selective inhibition of both VEGF and PDGF has the potential to 
have significantly more impact on abnormal vessels than inhibition of the VEGF 
alone [9]. 
 
4.2 
Vascular Endothelial Growth Factor (VEGF), Platelet Derived 
Growth Factor (PDGF) and Neovascular AMD 
A number of distinct cytokine growth factors are known to be involved in the 
complex process of angiogenesis [10].  Of those factors, VEGF, a homodimeric 
protein, has high specificity for vascular endothelium and its major tyrosine kinase 
receptors are selectively expressed on vascular endothelium. VEGF stimulates 
endothelial cells to proliferate, migrate and protect them from apoptosis [11].   


 
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PDGF is another growth factor which has been implicated in ocular 
neovascularization.  A total of four different genes encode four different PDGF 
polypeptide chains (PDGF-A, PDGF-B, PDGF-C, and PDGF-D). Each of these bind 
to their receptors as a homodimer i.e. PDGF-AA, PDGF-BB, PDGF-CC, and PDGF-
DD. In addition, a heterodimer PDGF AB is also encoded [12, 13]. Neovascular 
endothelial cells secrete Platelet Derived Growth Factor B (PDGF-BB), which binds 
to its PDGF receptor β (PDGFR- ββ) on pericytes (mural cells). PDGF-BB signaling 
is critical for pericyte survival, maturation and regulation. 
PDGF plays a major role during embryonic development, where they are of crucial 
importance for the development of certain types of mesenchymal cell types 
(muscle, blood, connective tissue, vascular system, heart, much of the kidney and 
dermis of the skin).  In the adult, PDGF stimulates wound healing and regulates the 
interstitial fluid pressure in tissues.  Overactivity of PDGF has been implicated in 
certain malignancies, as well as in other diseases involving excessive cell growth, 
including atherosclerosis and fibrotic conditions and ocular neovascularization [13, 
14].  The sequence homology of PDGF is highly conserved across species.  Rat 
and rabbit PDGF sequences bear remarkable similarities to the human cytokine 
[15, 16].  This is important in the extrapolation of animal data to humans. 
PDGF upregulation has been demonstrated in the chick chorioallantoic membrane 
assay [17], the mouse corneal pocket assay [18] and in tumors [19].  It is also well 
established that PDGF plays a role in pericyte recruitment [20].  
Pericyte recruitment is part of the maturation process in blood vessel development. 
Pericytes intimately cover the endothelial cells and lead to a mature blood vessel 
phenotype.  Once the pericyte cell population is well established, the effectiveness 
of anti-VEGF agents at destabilizing blood vessels is greatly reduced. This anti-
VEGF resistance is imparted by pericytes being a major source of survival factors 
(i.e. VEGF-A) to the endothelial cells. PDGF-B, secreted at high levels specifically 
by the growth of endothelial cells in neo-vessels, leads to the recruitment of 
pericytes to the newly formed vessels.  The primary receptor for PDGF-B in the eye, 
PDGFR-β, is expressed on recruited pericytes.  Disruptions of the PDGF-
B/PDGFR-β receptor system by either blocking agents or gene knock-out result in 
pericyte loss along with extensive vascular defects that include microaneurysms, 
vascular permeability and non-functional vessels. In addition, it has been shown 
that the interruption of the PDGF-B/PDGFR-β receptor system in combination with 
anti-VEGF strategies result in vessel regression [9].  Whereas disruption of the 








 
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Combination therapy was well tolerated.  The most common ocular adverse events 
were, as expected in intravitreal studies, related to the intravitreal preparation and 
injection procedure and not drug-related, e.g., conjunctival hemorrhage, punctate 
keratitis, and eye pain.  There were no events of endophthalmitis, retinal 
detachment, retinal tear or iatrogenic traumatic cataract after a total of 4431 
intravitreal injections (1776 administrations of Fovista™ and 2655 administrations of 
Lucentis®).  As expected, the mean IOP increased after each intravitreal injection 
consistent with the volume effect.   However, mean IOP in all arms returned to pre-
injection level at the next visit, including at the end of the study.  The systemic 
safety profile of Fovista™/Lucentis® was similar to that of Lucentis® monotherapy. 
Additional information regarding the clinical data for Fovista™ is described in detail 
in the Investigator Brochure (IB). 
 
4.5 
Trial Rationale 
There is widespread acceptance that the main therapeutic benefit of anti-VEGF 
mono-therapy is its potent anti-permeability property. This is consistent with VEGF 
being the most potent inducer of permeability [24]. The current clinically available 
anti-VEGF agents (Lucentis®, Avastin® and Eylea®) have all demonstrated similar 
therapeutic benefit in multiple clinical studies [4, 5, 6, 8].  However, despite maximal 
anti-VEGF therapy (e.g. increased dosage/regimen), additional efficacy has not 
been observed [25].  Based on this, it appears that a “ceiling” of anti-VEGF effect 
has been reached and an unmet need persists. Furthermore, anti-VEGF 
monotherapy does not lead to the regression of the pathologic neovascular (NV) 
tissue. Therefore, stability of the NV complex ensues despite continued treatment, 
which may limit significant visual gain in majority of treated subjects. Hence, 
targeted pharmacotherapeutic strategies inducing NV regression coupled with 
resolution of permeability in wet AMD may result in enhanced visual outcome.  
Neovascularization is a normal process involved in embryonic development and 
tissue repair but becomes pathological when blood vessels proliferate into 
abnormal tissues (i.e. tumors), avascular cornea, or the subretinal space. The 


 
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proliferation, invasion, and migration of the NV vessels are coordinated by a 
complex molecular mechanism involving growth factors, cytokines, and their 
associated receptors. The diverse set of signaling pathways involved in wet AMD 
indicate the need for a multi-targeted pharmacotherapy approach for its treatment.  
The NV tissue consists of endothelial cells (EC), pericytes, and inflammatory cells 
(i.e. occasional macrophages). Based on current understanding, the NV process 
involves the formation of angiogenic sprouts from existing capillaries growing into 
the avascular space. These sprouts are led by tip cell filopodia. VEGF is a master 
switch for NV involved in the activation, survival, and proliferation of EC and has 
been found at the tip of the angiogenic sprout. Following the formation of the EC 
angiogenic sprout, the newly formed vessels attract and are coated by pericytes 
leading to NV maturation.  
Pericytes are derived via differentiation of mural cells. Their presence on capillaries 
leads not only to NV support and stabilization but also promotes endothelial cell 
survival through chemical signaling and physical interactions including pericyte 
production of VEGF [26]. The endothelial survival signaling by integrated pericytes 
is critical and may explain the resistance of the NV tissue to VEGF withdrawal, i.e. 
lack of NV regression to monotherapy anti-VEGF treatment [26]. Therefore, 
stripping of pericytes combined with anti-VEGF therapy may lead to regression of 
NV vessels and further improvement of visual outcome.  
The coating of the NV endothelial cells by pericytes is initiated by endothelial cell 
expression of the paracrine platelet derived growth factor B (PDGF-B), which forms 
the homo dimer PDGF-BB. The EC expressed PDGF-B is retained proximally by 
heparin sulfate proteoglycan with the highest concentration in the cells at the tip of 
the angiogenic sprout. The recognition of the proximally retained PDGF-BB by the 
PDGFR-β receptor on pericytes initiates the proliferation and migration of the 
pericytes along the growing neovascularization. The importance of PDGF-
B/PDGFR-β interaction in the pericyte recruitment and capillary maturation has 
been demonstrated through gene knockout, ectopic delivery of competing PDGF-B, 
blocking the PDGF-B/PDGFR-β interaction by external agents, or deletion of the 
PDGF-B heparin sulfate proteoglycans binding motif [27,28].  At the angiogenic 
sprout, the attachment and maturation of pericytes follows the proliferation of 
endothelial cells (both in time and space) [28,29]. 
The importance of the PDGF–B/PDGFR-β interaction in pericyte recruitment, 
maturation, and resistance to anti-VEGF mediated regression has been 


 
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demonstrated in animal models [9]. These studies show that blocking the PDGF–
B/PDGFR-β interaction leads to lack of pericyte coverage, abnormal/leaking blood 
vessels, inhibition of NV capillary maturation, and neonatal lethality [30,31]. 
Specifically, animal injury models of corneal and choroidal neovascularization 
(CNV) have demonstrated that administration of agents that block the PDGF-
B/PDGFR-β interaction leads to pericyte stripping from the pathological 
neovasculature [9].  Further, co-administration of anti-VEGF and anti-PDGF agents 
leads to a greater NV inhibition than either agent alone.  More importantly, such 
combination induces NV regression as well. 
Established mature, non-pathological vascularization is unaffected with inhibitors of 
the PDGF-B/PDGFR- β interaction. A decreased PDGF-B dependency on pericytes 
residing on mature host vessels may be related to differential PDGFR-β receptor 
expression on these cells or the nature of pericyte-EC associations in each 
situation. In the mature host vascular bed (non-pathologic vascular tissue), 
Sphingosine-1-phosphate (SP1) mediated N-Cadherin and Gap junction activated 
TGF-β1 leads to a stabilized pericyte-EC interaction and mural cell differentiation 
[32]. In addition, in the mature host vasculature, the pericytes and EC share a 
common basement membrane with individual pericytes contacting multiple 
endothelial cells. Conversely, pericytes involved in pathological neovascularization 
appear to have an abnormal morphology with a looser association to the underlying 
EC vasculature [33].  
Fovista™ (E10030) is a PDGF-B antagonist with high specificity and affinity in the 
form of a pegylated oligonucleotide (aptamer).  In vitro and in vivo studies using this 
compound in combination with an anti-VEGF agent have demonstrated its 
effectiveness at preventing the formation of NV vessels as well as stripping of 
pericytes leading to regression of established NV vessels [28]. 
The Phase 2 Fovista™ study demonstrated superiority of Fovista™ (1.5mg) 
/Lucentis® combination therapy compared to Lucentis® monotherapy. At the 
commencement of this phase 2b trial, Eylea was not available in the market and 
was therefore not included as an anti-VEGF agent. In addition, the data from the 
CATT trial establishing the non-inferiority of Avastin® to Lucentis® was not available. 
Well powered, randomized, controlled, prospective comparative trials of 
monotherapy anti-VEGF agents in wet AMD have failed to show superiority of any 
of the anti-VEGF agents. Fovista’s pharmaceutical activity as measured via the 
level of gene expression, using real-time PCR, as a function of binding to the 


 
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cellular receptors reveal that the specific anti-VEGF in the combination does not 
affect its individual activities.  
 
5 TRIAL OBJECTIVES 
5.1 
Objectives 
The objectives of this study are to evaluate the safety and efficacy of Fovista™ 
intravitreous administration when administered in combination with either Avastin® 
or Eylea® compared to Avastin® or Eylea® monotherapy in subjects with subfoveal 
choroidal neovascularization secondary to age-related macular degeneration 
(AMD). 
 
5.2 
Endpoints 
Primary Efficacy Endpoint: 
The primary efficacy endpoint is the mean change in visual acuity (ETDRS letters) 
from baseline at the Month 12 visit. 
 
Secondary Efficacy Endpoints: 
Refer to Statistical Methods (Section 11) for enumeration of the secondary efficacy 
parameters. 
 
Safety Endpoints: 
• Adverse events (AEs) 
• Vital signs (pulse, systolic and diastolic blood pressure) 
• Ophthalmic variables (IOP, ophthalmic examination, fluorescein angiograms 
and OCT) 
• ECG (12-lead) 
• Laboratory variables (blood:  hematology, renal function, hepatic function, 
and electrolytes; urinalysis) 
 
 


 
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6 TRIAL DESIGN 
Subjects will be randomized in a 1:1 ratio to the following dose groups: 
• Fovista™ 1.5 mg/eye + Avastin® 1.25 mg/eye or Eylea® 2 mg/eye 
• Fovista™ sham + Avastin® 1.25 mg/eye or Eylea® 2 mg/eye 
Within each of the above dose groups, subjects will be randomized in a 1:1 ratio to 
either Avastin® 1.25 mg/eye or Eylea® 2 mg/eye. 
Subjects randomized to receive Avastin will be treated with active Fovista™ or 
sham in combination with Avastin® monthly for 24 months. 
Subjects randomized to receive Eylea will be treated with active Fovista™ or sham 
in combination with Eylea® every month for the first 3 doses (Day 1, Month 1 and 
Month 2) and every other month thereafter (i.e., Months 4, 6, 8, 10, 12, 14, 16, 18, 
20, and 22). 
Therefore, subjects randomized to receive Avastin® will be treated with active 
Fovista™ or sham in combination with Avastin® for a total of 24 administrations.  
Subjects randomized to receive Eylea® will be treated with active Fovista™ or sham 
in combination with Eylea® for a total of 13 administrations. 
All subjects will have a final follow-up visit at Month 24. 
 
7 PROCEDURES 
7.1 
Procedures for Refraction and Vision Testing 
Refraction and Vision Testing will be performed at all time points specified in 
Section 10.2 “Trial Assessments”.  Retroilluminated modified Ferris-Bailey ETDRS 
(Early Treatment Diabetic Retinopathy Study) charts are used starting at 4 meters 
(see Appendix 17.3). 
When protocol refraction and best-corrected visual acuity measurement is required 
by the trial protocol, this will be performed only by certified visual acuity examiners 
masked to the previous visual acuity measurement and to whether or not the 
subject has been assigned to active treatment or control.  The examiner will be 
supplied with the previous protocol refraction only.   
 


 
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7.2 
Tonometry  
Tonometry will be performed at all time points specified in Section 10.2 “Trial 
Assessments”.  Tonometry should be performed before the first injection and at 
least 30 minutes after each injection.  For the post-injection tonometry, proper care 
should be taken to minimize the risk of contamination. 
Goldmann applanation tonometry must be performed at Screening.  Tonopens may 
be used at all other timepoints, but Goldmann applanation tonometry must be used 
to verify IOP for a post-injection reading of ≥ 30 mm Hg occurring more than 30 
minutes post-injection, or for a reading of ≥ 30 mm Hg at any other time.  
 
7.3 
Ophthalmologic Examination 
The following examinations will be performed at all time points specified in Section 
10.2 “Trial Assessments”. 
• Inspection of the eyelids 
• Examination of the extra-ocular muscle movement  
• Inspection of the cornea 
• Examination of the anterior chamber for inflammation (Appendix 17.1) 
• Examination of the pupils 
• Examination of the iris 
• Inspection of the lens 
• Inspection of the vitreous body (Appendix 17.2) 
• Inspection of the retina and optic disc 
 
7.4 
Fundus Photography and Fluorescein Angiography 
Color fundus photographs and fluorescein angiography (FA) will be performed at all 
time points specified in Section 10.2 “Trial Assessments”.  A  Reading Center (RC) 
will confirm eligibility of subjects prior to enrollment.  All color fundus photos and 
FAs that are collected at protocol-specified times must be sent to the RC as 
specified in the RC procedure manual.  The RC will provide instructions for the 
color fundus photographs and FA procedures.  
 


 
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7.5 
Optical Coherence Tomography 
Optical Coherence Tomography (OCT) will be performed at all time points specified 
in Section 10.2 “Trial Assessments”.  The RC will provide instructions for the OCT 
procedures, including which OCT reports must be sent to the RC. 
 
7.6 
Laboratory Tests 
The following laboratory tests will be performed as specified in Section 10.2 “Trial 
Assessments”: 
• Hematology: hemoglobin, platelet count, WBC and differential 
• Coagulation profile:  PT, PTT (baseline only) 
• Renal Function: serum creatinine and BUN 
• Hepatic function: serum bilirubin, alkaline phosphatase, GGT, SGOT/AST 
and SGPT/ALT 
• Electrolytes: sodium, potassium, chloride, bicarbonate, calcium and 
phosphate 
• HbA1c (baseline only) 
• Complete Urinalysis (including specific gravity, protein, blood, etc.) 
• Serum pregnancy test (if of child-bearing potential) 
If a laboratory value outside of the normal range is judged as clinically significant by 
the Investigator, the Investigator will repeat the laboratory determination as judged 
appropriate to ensure the validity of the abnormal result.  If any clinically significant 
abnormal results are noted, the tests are to be repeated until the results are normal, 
are no longer considered clinically significant by the investigator, or an explanation 
for the change is obtained. 
 
7.7 
Vital Signs, Physical Examination and Performance Status 
(ECOG) 
A physical examination will be performed at Screening and at the Investigators’ 
discretion thereafter.  Assessment of vital signs will be performed at all time points 
specified in Section 10.2 “Trial Assessments”.   
Performance Status (ECOG) will be assessed at Screening in accordance with 
Appendix 17.4.  


 
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7.8 
12-Lead ECG 
A 12-lead ECG will be performed at all time points specified in Section 10.2 “Trial 
Assessments”.   
 
7.9 
Visual Function Questionnaire-25 
The Visual Function Questionnaire (or VFQ-25) is a 25-question quality of life 
questionnaire created by the National Eye Institute to measure the influence of 
visual disability on general health and functioning.  The VFQ-25 will be 
administered by site personnel and performed at all time points specified in Section 
10.2 “Trial Assessments”. 
 
8 SUBJECT POPULATION 
8.1 
Sample Size 
Approximately 311 subjects will be enrolled in each cohort, for a total of 622 
subjects in the study. 
  
8.2 
Inclusion Criteria  
Subjects must meet the following criteria to be eligible to participate in this study. 
 


 
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8.2.2 General Inclusion Criteria 
8.2.2.1 
Subjects of either gender aged ≥ 50 years. 
8.2.2.2 
Performance Status ≤ 2 according to Eastern Cooperative Oncology 
Group (ECOG) / World Health Organization (WHO) scale (Appendix 
17.4). 
8.2.2.3 
Women must agree to be using two forms of effective contraception, be 
post-menopausal for at least 12 months prior to trial entry, or surgically 
sterile; if of child-bearing potential, a serum pregnancy test must be 
performed within 14 days prior to the first injection with a negative result.  
The two forms of effective contraception must be implemented during the 
trial and for at least 60 days following the last dose of test medication. 
8.2.2.4 
Provide written informed consent. 
8.2.2.5 
Ability to comply with study and follow-up procedures and return for all 
trial visits. 
 
8.3 
Exclusion Criteria 
Subjects will not be eligible for the trial if any of the following criteria are present 
in the study eye or systemically: 
8.3.1 Ophthalmic Exclusion Criteria 
8.3.1.1 
Any prior treatment for AMD in the study eye prior to the Day 1 visit, 
except oral supplements of vitamins and minerals. 
8.3.1.2 
Any prior intravitreal treatment in the study eye prior to the Day 1 visit, 
regardless of indication (including intravitreal corticosteroids). 


 
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8.3.1.3 
More than 50% of the total lesion size made up of scarring or atrophy as 
determined by fundus photography with or without fluorescein 
angiography, with or without OCT.  Subjects with any subfoveal scar or 
subfoveal atrophy directly below the center of the fovea are excluded.  
8.3.1.4 
More than 50% of the total lesion size consisting of subretinal 
hemorrhage.  
8.3.1.5 
Presence of retinal angiomatous proliferation (RAP). 
8.3.1.6 
Presence of significant serous pigment epithelial detachments (PEDs), 
such as large PEDs that constitute greater than 50% of the total lesion or 
have a vertical height of ≥ 400 µm.  Presence of pure PED without 
subretinal hyper-reflective material. 
8.3.1.7 
Presence of pigment epithelial tears or rips. 
8.3.1.8 
Presence of intraocular inflammation (≥ trace cell or flare), significant 
epiretinal membrane (causing distortion of macular anatomy and/or 
opacification), significant vitreomacular traction (causing distortion of 
macular anatomy), macular hole (full or partial thickness) or vitreous 
hemorrhage. 
8.3.1.9 
Aphakia or absence of the posterior capsule.  Absence of an intact 
posterior capsule is allowed if it occurred as a result of YAG laser 
posterior capsulotomy in association with prior posterior chamber IOL 
implantation. 
8.3.1.10 History of idiopathic or autoimmune-associated uveitis in either eye. 
8.3.1.11 Significant media opacities, including cataract, which might interfere with 
visual acuity, assessment of toxicity, or fundus photography in the study 
eye.  Subjects should not be entered if there is likelihood that they will 
require cataract surgery in the study eye in the next 12 months. 
8.3.1.12 Presence of other causes of choroidal neovascularization, including 
pathologic myopia (spherical equivalent of -8 diopters or more, or axial 
length of 25mm or more), the ocular histoplasmosis syndrome, angioid 
streaks, choroidal rupture, and multifocal choroiditis. 
8.3.1.13 Any intraocular surgery or thermal laser within three (3) months of trial 
entry.  Any prior thermal laser in the macular region, regardless of 
indication. 


 
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8.3.1.14 Any ocular or periocular infection in the past twelve (12) weeks. 
8.3.1.15 History of any of the following conditions or procedures in the study eye: 
Rhegmatogenous retinal detachment, pars plana vitrectomy, filtering 
surgery (e.g. trabeculectomy), glaucoma drainage device, corneal 
transplant. 
8.3.1.16 Previous therapeutic radiation in the region of the study eye.  
 
8.3.2 General Exclusion Criteria 
8.3.2.1 
Any of the following underlying conditions or diseases including: 
• 
A definitive diagnosis of diabetes mellitus or diabetic retinopathy 
(regardless of HbA1c level) 
• 
HbA1c value of ≥6.5%*   
*If the HbA1c value is ≥ 6.5% and ≤ 6.9%, and the patient has no 
signs or symptoms of diabetes mellitus, has a normal creatinine, 
has no diabetic retinopathy and no glycosuria, then the patient 
may have an oral glucose tolerance test (OGTT) at the discretion 
of the investigator.  If the 2-hour glucose value on OGTT is <200 
mg/dL (<11.1mmol/L), then the patient may be enrolled.1 
• History of other disease, metabolic dysfunction, physical 
examination finding or clinical laboratory finding giving reasonable 
suspicion of a disease or condition that contraindicates the use of 
an investigational drug or that might affect interpretation of the 
results of the study or render the subject at high risk for treatment 
complications. 
• History or evidence of severe cardiac disease (e.g., NYHA 
Functional Class III or IV - see Appendix 17.6), history or clinical 
evidence of unstable angina, acute coronary syndrome, 
myocardial infarction or coronary artery revascularization within 6 
                                                 
 
 
1 The OGTT will be performed at a local laboratory as follows:  (1) A fasting baseline plasma glucose is drawn; 
(2) the patient is administered 75 gm oral dextrose; (3) a 2-hour plasma glucose level is drawn.  FDA form 1572 
must be amended to include the local laboratory, and the local laboratory certification and OGTT normal values 
must be collected and appropriately filed by the site. 


 
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months, or ventricular tachyarrythmias requiring ongoing 
treatment. 
• Stroke (within 12 months of trial entry). 
• Any major surgical procedure within one month of trial entry. 
8.3.2.2 
Any treatment with an investigational agent in the 60 days prior to 
randomization for any condition. 
8.3.2.3 
Known serious allergies to the fluorescein dye used in angiography (mild 
allergy amenable to treatment is allowable), or to the components or 
formulation of either Fovista™ or Avastin® or Eylea®. 
 
9 TRIAL MEDICATION 
9.1 
Drug Supply  
9.1.1 Fovista™  
Fovista™ (E10030) drug substance is a pegylated aptamer 
 




 
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injection kit) and a new 1-mL sterile syringe (supplied) to withdraw about 0.2 mL of 
Fovista™ from the glass vial using aseptic technique. Remove the filter needle and 
replace it with the sterile 27 gauge injection needle (supplied).  Expel any air 
bubbles and adjust the injection volume to 0.05 mL (50 μL).  The procedure for 
sham Fovista™ injection is described in Section 17.5. 
Avastin® injection is a preservative-free, clear to slightly opalescent, colorless to 
pale brown, sterile, pH 6.2 solution supplied in a single-use glass vial containing 
100 mg in 4 mL, of which 0.05 mL will be administered for intravitreal injection. The 
100 mg product is formulated in 240 mg α,α-trehalose dihydrate, 23.2 mg sodium 
phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, 
anhydrous), 1.6 mg polysorbate 20, and Water for Injection, USP.   Using aseptic 
technique, 0.2 mL of the Avastin® injection vial contents are withdrawn through a 5-
micron 19-gauge filter needle attached to a 1-cc tuberculin syringe. The filter needle 
should be discarded after withdrawal of the vial contents and should not be used for 
intravitreal injection. The filter needle should be replaced with a sterile 30-gauge × 
1/2-inch needle for the intravitreal injection. The contents should be expelled until 
the plunger tip is aligned with the line that marks 0.05 mL on the syringe. 
The Avastin vial is for single use.  Any Avastin remaining in the vial is non-
sterile and may not be used to treat any additional study subjects or non-
study patients. 
Eylea® is a sterile, clear, and colorless pale yellow solution.  Eylea® is supplied as a 
preservative-free, sterile, aqueous solution in a single-use, glass vial designed to 
deliver 0.05 mL (50 microliters) of Eylea® (40 mg/mL in 10 mM sodium phosphate, 
40 mM sodium chloride, 0.03% polysorbate 20, and 5% sucrose, pH 6.2).  Using 
aseptic technique, all (0.28 mL) of the aflibercept injection vial contents are 
withdrawn through a 5-micron 19-gauge filter needle attached to a 1-cc syringe. 
The filter needle should be discarded after withdrawal of the vial contents and 
should not be used for intravitreal injection. The filter needle should be replaced 
with a sterile 30-gauge × 1/2-inch needle for the intravitreal injection. The contents 
should be expelled until the plunger tip is aligned with the line that marks 0.05 mL 
on the syringe. 
 


 
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9.2.2 Treatment Regimen and Duration 
Subjects randomized to active drug will receive 18-24 injections of Fovista™ 1.5 
mg/eye. 
 
9.2.3 Administration of Trial Drug 
The method for intravitreous administration of Fovista™, Avastin® and Eylea® is 
described in detail in Appendix 17.5.  
 
9.2.4 Storage 
The investigator, or an approved representative (e.g. pharmacist), will ensure that 
all trial drugs are stored in a secured area, under recommended storage conditions 
and in accordance with applicable regulatory requirements. Store Fovista™, Eylea® 
and Avastin® under standard refrigeration conditions (2-8°C; 36-46°F); do not 
freeze.  All vials should be protected from light and stored in the original carton or 
clinical kit, as provided, until the time of use.  Avastin® vials should not be shaken. 
 
9.3 
Previous or Concomitant Therapy 
Previous treatment for AMD in the study eye prior to Day 1 is not permitted except 
for oral supplements of vitamins and minerals.  
Any treatment with any investigational agent for any condition in the 60 days prior to 
Screening, or treatment with an investigational agent for any condition during the 
trial, is not permitted.   
Treatment for AMD in the fellow eye during the study with an approved product is 
permitted at any time.  Although not labeled for the treatment of wet AMD, 
bevacizumab (Avastin®) is also allowed in the fellow eye at the discretion of the 
investigator. 
 
10 TRIAL CONDUCT 
10.1 Subject Enrollment 
Before recruitment of subjects into the trial, written Institutional Review Board (IRB) 
or Ethics Committee (EC) approval of the protocol and informed consent must be 
obtained. 


 
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Subjects who meet the eligibility criteria and have provided written informed 
consent will be enrolled in the trial.  If any inclusion or exclusion criteria are not met, 
treatment with trial drug should not commence without prior written approval from 
Ophthotech Corp. or its designee. 
 
10.2 Trial Assessments 
Written informed consent must be obtained before any of the Screening procedures 
listed below are performed.  However, if a routine office procedure (e.g. FA, OCT) is 
performed to diagnose AMD independent of this clinical trial, and subsequently the 
subject provides informed consent for this study, these procedures performed prior 
to informed consent may be used as screening assessments for this study, 
provided the 14-day period of screening evaluations is respected and provided the 
assessments are acceptable to the standards of the study, including the Reading 
Center. An explanation of the trial and discussion of the possible risks and 
discomforts will be given by the investigator.  Only those subjects who fulfill all 
eligibility criteria will be entered into the trial.  
Ocular assessments performed at Screening, Month 6, Month 12, Month 18 and 
Month 24 (and at an Early Withdrawal visit if performed) should be performed on 
both eyes (OU).  Ocular assessments at all other study visits are performed on the 
study eye (SE) only. 
The following assessments will be performed during the study.   
 
10.2.1 Screening Assessments  
The following Screening evaluations, as outlined in the Study Assessments Chart 
(see Section 3), will be performed within 14 days prior to Day 1.  Screening 
assessments can be broken into 2 days if necessary.    
• Informed consent 
• Medical history 
• Ophthalmologic history (OU) 
• Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• Ophthalmologic Examination and Goldmann Applanation Tonometry 
(OU) 
• Vital Signs /Physical Examination/Performance Status (ECOG) 


 
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• ECG 
• Color fundus photographs (OU)  
• Fluorescein Angiograms (FA) (OU, transit study eye) 
• Optical Coherence Tomography (OCT) (OU)  
• Laboratory Tests 
• Serum pregnancy test within 14 days of first injection (if applicable) 
• Concomitant Medication Assessment 
 
10.2.2 On-Trial Assessments 
The following evaluations, as outlined in the Study Assessments Chart (see 
Section 3), will be performed on the days specified below.     
Note:  
• Concomitant Medications should be assessed at every study visit. 
• Adverse events (AEs) should be assessed starting at Day 1 after the 
first dose of trial drug.   
 
10.2.2.1 
Reconfirmation of Eligibility at Day 1 
To remain eligible for randomization on Day 1, the following two criteria must be 
met: 
1. There is NO SIGNIFICANT ANATOMICAL CHANGE by clinical examination 
between the Screening visit and Day 1 (i.e. large subretinal hemorrhage, 
RPE rip, pigment epithelial detachment).  
 
2. VISUAL ACUITY at Day 1 is WITHIN INCLUSION CRITERIA (Snellen 
equivalent 20/63 to 20/200) and WITHIN 5 LETTERS (better or worse) of the 
SCREENING VA.   
 
*OR* 
 
VISUAL ACUITY at Day 1 is WITHIN INCLUSION CRITERIA (Snellen 
equivalent 20/63 to 20/200) and WITHIN 6-10 LETTERS (better or worse) of 
the SCREENING VA, and repeat clinical examination and OCT imaging – 
both as judged and documented by the investigator – does NOT reveal: 


 
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• A significant anatomical change since the Screening visit (for example, 
large subretinal hemorrhage, RPE rip, pigment epithelial detachment), or   
• An increase in central retinal thickness on OCT of ≥ 50 microns, or 
• Any increase in “intraretinal” foveal fluid 
If the patient is randomized, the repeat OCT (and FA, if taken) must be 
submitted to the Reading Center to be used as the new study baseline. 
If the clinical examination and OCT imaging reveal any of the above findings, 
the patient must NOT be randomized. 
 
If the Snellen VA equivalent at Day 1 is GREATER THAN 10 ETDRS LETTERS 
(better or worse) different from the SCREENING VA, the patient must NOT be 
randomized. 
 
If the Snellen VA equivalent at Day 1 is NO LONGER WITHIN THE INCLUSION 
CRITERIA (Snellen equivalent 20/63 to 20/200), the patient must NOT be 
randomized. 
 
10.2.2.2 
Day 1 Visit  
Pre-injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• Tonometry and Ophthalmologic Examination (SE) 
• Vital Signs 
• Visual Function Questionnaire-25 
• 
Randomization 
• 
Avastin® or Eylea® Treatment  
• 
FovistaTM/Sham Treatment 
Post-injection 
• 
Tonometry - at least 30 minutes after each injection (SE) 
• 
Ophthalmologic Exam - at least 30 minutes after the second injection  (SE) 
 
10.2.2.3 
Day 3 (±1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 


 
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10.2.2.4 
Month 1 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
Avastin® or Eylea® Treatment  
• 
FovistaTM/Sham Treatment 
Post-injection 
• 
Tonometry - at least 30 minutes after each injection (SE) 
• 
Ophthalmologic Exam - at least 30 minutes after the second injection (SE) 
 
10.2.2.5 
Month 1 + 3 Days (±1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.2.6 
Month 2 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
Avastin® or Eylea® Treatment  
• 
FovistaTM/Sham Treatment 
Post-injection 
• 
Tonometry - at least 30 minutes after each injection (SE) 
• 
Ophthalmologic Exam - at least 30 minutes after the second injection (SE) 
 
10.2.2.7 
Month 2 + 3 Days (±1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.2.8 
Month 3 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
Optical Coherence Tomography (OCT) (SE) 


 
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vastin® 
tment 
ho received Avastin + FovistaTM/Sham Only
• 
Visual Function Questionnaire-25 
Subjects Randomized to Receive A
• 
Avastin® Treatment  
• 
FovistaTM/Sham Trea
• 
 
Post-injection – Subjects w
 
d injection (SE) 
10.2.2.9 
Month 3 + 3 Days (±1 day) – Subjects who received Avastin + 
TM/
10.2.2.10 Month 4 (±7 days) 
• 
Tonometry - at least 30 minutes after each injection (SE) 
• 
Ophthalmologic Exam - at least 30 minutes after the secon
 
Fovista
Sham Only  
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
Avastin® or Eylea® Treatment  
• 
FovistaTM/Sham Treatment 
Post-injection 
• 
Tonometry - at least 30 minutes after each injection (SE) 
d injection (SE) 
10.2.2.11 Month 4 + 3 Days (±1 day) 
there are no signs or symptoms of retinal 
10.2.2.12 Month 5 (±7 days) 
• 
Ophthalmologic Exam - at least 30 minutes after the secon
 
• 
Telephone call to subject to ensure 
detachment or endophthalmitis. 
 
Pre-Injection 
l refract
• 
Protoco
ion and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Avastin  Treatment  
• 
Tonometry and Ophthalmologic examination (SE) 
®
Subjects Randomized to Receive Avastin  
®


 
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ho received Avastin + FovistaTM/Sham Only
• 
FovistaTM/Sham Treatment 
Post-injection– Subjects w
 
tes after each injection (SE) 
(SE) 
Fovista
/Sham Only 
inal 
re-Injection
• 
Tonometry - at least 30 minu
• 
Ophthalmologic Exam - at least 30 minutes after the second injection 
 
10.2.2.13 Month 5 + 3 Days (±1 day) – Subjects who received Avastin + 
TM
• 
Telephone call to subject to ensure there are no signs or symptoms of ret
detachment or endophthalmitis. 
 
10.2.2.14 Month 6 (±7 days) 
P
 
al acuity (4 meters) using ETDRS chart (OU) 
try and Ophthalmologic examination (OU) 
ngiograms (FA) (OU, transit study eye) 
(OCT) (OU) 
reatment  
• 
Protocol refraction and visu
• 
Tonome
• 
Vital Signs 
• 
Color fundus photographs (OU) 
• 
Fluorescein A
• 
Optical Coherence Tomography 
• 
Laboratory Tests 
• 
Visual Function Questionnaire-25 
®
®
• 
Avastin  or Eylea  T
TM
• 
Fovista
/Sham Treatment 
Post-injection 
• 
Tonometry - at least 30 minutes after each injection (SE) 
es after the second injection  (SE) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
10.2.2.16 Month 7 (±7 days) 
Pre-Injection
• 
Ophthalmologic Exam - at least 30 minut
 
10.2.2.15 Month 6 + 3 Days (±1 day) 
 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 


 
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mination (SE) 
• 
FovistaTM/Sham Treatment 
eceived Avastin + FovistaTM/Sham Only
• 
Tonometry and Ophthalmologic exa
Subjects Randomized to Receive Avastin® 
• 
Avastin® Treatment  
Post-injection – Subjects who r
 
try - at least 30 minutes after each injection (SE) 
) 
1
cts who received Avastin + 
e are no signs or symptoms of retinal 
itis. 
• 
Tonome
• 
Ophthalmologic Exam - at least 30 minutes after the second injection (SE
 
0.2.2.17 Month 7 + 3 Days (±1 day) – Subje
TM
Fovista
/Sham Only 
• 
Telephone call to subject to ensure ther
detachment or endophthalm
 
10.2.2.18 Month 8 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
ost-injection
• 
Tonometry and Ophthalmologic examination (SE) 
®
®
• 
Avastin  or Eylea  Treatment  
• 
FovistaTM/Sham Treatment 
P
 
utes after each injection (SE) 
mologic Exam - at least 30 minutes after the second injection (SE) 
ure there are no signs or symptoms of retinal 
• 
Tonometry - at least 30 min
• 
Ophthal
 
10.2.2.19 Month 8 + 3 Days (±1 day) 
• 
Telephone call to subject to ens
detachment or endophthalmitis. 
 
10.2.2.20 Month 9 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
T) (SE) 
 
• 
Optical Coherence Tomography (OC
• 
Visual Function Questionnaire-25 


 
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Subjects Randomized to Receive Avastin® 
/Sham Treatment 
• 
Avastin® Treatment  
• 
FovistaTM
Post-injection – Subjects who received Avastin + FovistaTM/Sham Only 
• 
Tonometry - at least 30 minutes after each injection (SE) 
ter the second injection (SE) 
10.2.2.21 Month 9 + 3 Days (±1 day) – Subjects who received Avastin + 
TM
e are no signs or symptoms of retinal 
hthalmitis. 
• 
Ophthalmologic Exam - at least 30 minutes af
 
Fovista
/Sham Only 
• 
Telephone call to subject to ensure ther
detachment or endop
 
10.2.2.22 Month 10 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
Avastin® or Eylea® Treatment  
TM
• 
Fovista
/Sham Treatment 
Post-injection 
• 
Tonometry - at least 30 minutes after each injection (SE) 
ast 30 minutes after the second injection (SE) 
ns or symptoms of retinal 
• 
Ophthalmologic Exam - at le
 
10.2.2.23 Month 10 + 3 Days (±1 day) 
• 
Telephone call to subject to ensure there are no sig
detachment or endophthalmitis. 
 
10.2.2.24 Month 11 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
Subjects Randomized to Receive Avastin® 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
Avastin® or Treatment  
• 
FovistaTM/Sham Treatment 


 
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ost-injection – Subjects who received Avastin + FovistaTM/Sham Only
P
 
tes after each injection (SE) 
mologic Exam - at least 30 minutes after the second injection (SE) 
o received Avastin + 
t to ensure there are no signs or symptoms of retinal 
• 
Tonometry - at least 30 minu
• 
Ophthal
 
10.2.2.25 Month 11 + 3 Days (±1 day) – Subjects wh
TM
Fovista
/Sham Only 
• 
Telephone call to subjec
detachment or endophthalmitis. 
 
10.2.2.26 Month 12 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
•
Tonometry and Ophthalmologic examination (OU) 
• 
Fluorescein Angiograms (FA) (OU, transit study eye) 
phy (OCT) (OU) 
ry Tests 
m Treatment 
 
• 
Vital Signs 
• 
ECG 
• 
Color fundus photographs (OU) 
• 
Optical Coherence Tomogra
• 
Laborato
• 
Visual Function Questionnaire-25 
• 
Avastin® or Eylea® Treatment  
• 
FovistaTM/Sha
Post-injection  
after each injection (SE) 
econd injection (SE) 
 days (±1 day)  
e are no signs or symptoms of retinal 
• 
Tonometry - at least 30 minutes 
• 
Ophthalmologic Exam - at least 30 minutes after the s
 
10.2.2.27 Month 12 + 3
• 
Telephone call to subject to ensure ther
detachment or endophthalmitis. 
 
10.2.2.28 Month 13 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 


 
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Optical Coherence Tomography (OCT) (SE) 
tin® 
ost-injection – Subjects who received Avastin + FovistaTM/Sham Only
• 
Subjects Randomized to Receive Avas
• 
Avastin® or Treatment  
• 
FovistaTM/Sham Treatment 
P
 
tes after each injection (SE) 
mologic Exam - at least 30 minutes after the second injection (SE) 
o received Avastin + 
e no signs or symptoms of retinal 
halmitis. 
• 
Tonometry - at least 30 minu
• 
Ophthal
 
10.2.2.29 Month 13 + 3 days (±1 day) – Subjects wh
FovistaTM/Sham Only 
• 
Telephone call to subject to ensure there ar
detachment or endopht
 
10.2.2.30 Month 14 (±7 days) 
Pre-Injection 
• 
•
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 
Tonometry and Ophthalmologic examination (SE) 
•
Optical Coherence Tomography (OCT) (SE) 
 
• 
Avastin® or Eylea® Treatment  
• 
FovistaTM/Sham Treatment 
Post-injection Tonometry - at least 30 minutes after each injection (SE) 
• 
Ophthalmologic Exam - at least 30 minutes after the second injection (SE) 
onth 14 + 3 Days (±1 day)   
inal 
 
10.2.2.31 M
• 
Telephone call to subject to ensure there are no signs or symptoms of ret
detachment or endophthalmitis. 
 
10.2.2.32 Month 15 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
Optical Coherence Tomography (OCT) (SE) 
 
 


 
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tin® 
ost-injection – Subjects who received Avastin + FovistaTM/Sham Only
Subjects Randomized to Receive Avas
• 
Avastin® or Treatment  
• 
FovistaTM/Sham Treatment 
P
 
tes after each injection (SE) 
mologic Exam - at least 30 minutes after the second injection (SE) 
o received Avastin + 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
ys) 
• 
Tonometry - at least 30 minu
• 
Ophthal
 
10.2.2.33 Month 15 + 3 days (±1 day) – Subjects wh
FovistaTM/Sham Only 
• 
10.2.2.34 Month 16 (±7 da
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
Optical Coherence Tomography (OCT) (SE)  
®
®
• 
Avastin  or Eylea  Treatment  
TM
• 
Fovista
/Sham Treatment 
Post-injection  
• 
Tonometry - at least 30 minutes after each injection (SE) 
• 
Ophthalmologic Exam - at least 30 minutes after the second injection (SE) 
1 day)   
ne call to subject to ensure there are no signs or symptoms of retinal 
 
10.2.2.35 Month 16 + 3 days (±
• 
Telepho
detachment or endophthalmitis. 
 
10.2.2.36 Month 17 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
gic examination (SE) 
 
• 
Tonometry and Ophthalmolo
• 
Optical Coherence Tomography (OCT) (SE) 
 


 
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Page 41                                                    6Mar2014 
Subjects Randomized to Receive Avastin® 
ed Avastin + FovistaTM/Sham Only
• 
Avastin® Treatment  
• 
FovistaTM/Sham Treatment 
Post-injection – Subjects who receiv
 
• 
Tonometry - at least 30 minutes after each injection (SE) 
ast 30 minutes after the second injection (SE) 
 
no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
1
• 
Ophthalmologic Exam - at le
 
10.2.2.37 Month 17 + 3 Days (±1 day) – Subjects who received Avastin +
FovistaTM/Sham Only 
• 
Telephone call to subject to ensure there are 
0.2.2.38 Month 18 (±7 days) 
Pre-Injection 
Protocol refraction and visual acuity
• 
Tonometry and Ophthalmolo
 (4 meters) using ETDRS chart (OU) 
gic examination (OU) 
• 
• 
FovistaTM/Sham Treatment 
• 
• 
Vital Signs 
• 
Color fundus photographs (OU) 
Fluorescein Angiograms (FA) (OU, transit study eye) 
• 
Optical Coherence Tomography (OCT) (OU) 
• 
Laboratory Tests 
• 
Visual Function Questionnaire-25 
• 
Avastin® or Eylea® Treatment  
Post-injection  
• 
Tonometry - at least 30 minutes after each injection (SE) 
) 
 18 + 3 days (±1 day)   
re there are no signs or symptoms of retinal 
 
 
• 
Ophthalmologic Exam - at least 30 minutes after the second injection (SE
 
10.2.2.39 Month
• 
Telephone call to subject to ensu
detachment or endophthalmitis. 


 
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10.2.2.40 Month 19 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
 examination (SE) 
phy (OCT) (SE) 
domized to Receive Avastin® 
ost-injection – Subjects who received Avastin + FovistaTM/Sham Only
• 
Tonometry and Ophthalmologic
• 
Optical Coherence Tomogra
Subjects Ran
• 
Avastin® or Treatment  
• 
FovistaTM/Sham Treatment 
P
 
ach injection (SE) 
10.2.2.41 Month 19 + 3 days (±1 day) – Subjects who received Avastin + 
FovistaTM/Sham Only 
ensure there are no signs or symptoms of retinal 
ent or endophthalmitis. 
• 
Tonometry - at least 30 minutes after e
• 
Ophthalmologic Exam - at least 30 minutes after the second injection (SE) 
 
• 
Telephone call to subject to 
detachm
 
10.2.2.42 Month 20 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Tonometry and Ophthalmologic examination (SE) 
• 
Optical Coherence Tomography (OCT) (SE) 
®
®
• 
Avastin  or Eylea  Treatment  
TM
• 
Fovista
/Sham Treatment 
Post-injection  
• 
Tonometry - at least 30 minutes after each injection (SE) 
•
Ophthalmologic Exam - at least 30 minutes after the second injection (SE) 
re there are no signs or symptoms of retinal 
detachment or endophthalmitis. 
 
 
10.2.2.43 Month 20 + 3 Days (±1 day)  
• 
Telephone call to subject to ensu
 
 


 
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10.2.2.44 Month 21 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
gic examination (SE) 
herence Tomography (OCT) (SE) 
• 
FovistaTM/Sham Treatment 
vastin + FovistaTM/Sham Only
• 
Tonometry and Ophthalmolo
• 
Optical Co
Subjects Randomized to Receive Avastin® 
• 
Avastin® Treatment  
Post-injection – Subjects who received A
 
0 minutes after the second injection (SE) 
10.2.2.45 Month 21 + 3 days (±1 day) – Subjects who received Avastin + 
ne call to subject to ensure there are no signs or symptoms of retinal 
Pre
• 
Tonometry - at least 30 minutes after each injection (SE) 
• 
Ophthalmologic Exam - at least 3
 
FovistaTM/Sham Only 
• 
Telepho
detachment or endophthalmitis. 
 
10.2.2.46 Month 22 (±7 days) 
-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
gic examination (SE) 
ost-injection
• 
Tonometry and Ophthalmolo
• 
Optical Coherence Tomography (OCT) (SE) 
®
®
• 
Avastin  or Eylea  Treatment  
TM
• 
Fovista
/Sham Treatment 
P
  
y)   
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
itis. 
• 
Tonometry - at least 30 minutes after each injection (SE) 
• 
Ophthalmologic Exam - at least 30 minutes after the second injection (SE) 
 
10.2.2.47 Month 22 + 3 days (±1 da
detachment or endophthalm
 
 


 
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10.2.2.48 Month 23 (±7 days) 
Pre-Injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
y and Ophthalmologic examination (SE) 
• 
Avastin® or Treatment  
• 
Tonometr
• 
Optical Coherence Tomography (OCT) (SE) 
Subjects Randomized to Receive Avastin® 
• 
FovistaTM/Sham Treatment 
Post-injection – Subjects who received Avastin + FovistaTM/Sham Only 
• 
Tonometry - at least 30 minutes after each injection (SE) 
• 
Ophthalmologic Exam - at least 30 minutes after the second injection (SE) 
1 day) – Subjects who received Avastin + 
staTM/Sham Only 
inal 
1
gic examination (OU) 
• 
Fluorescein Angiograms (FA) (OU, transit study eye) 
10.2.2.51 Early Withdrawal  
l acuity (4 meters) using ETDRS chart (OU) 
• 
Color fundus photographs (OU) 
 
10.2.2.49 Month 23 + 3 Days (±
Fovi
• 
Telephone call to subject to ensure there are no signs or symptoms of ret
detachment or endophthalmitis. 
 
0.2.2.50 Month 24 (±7 days) 
 (4 meters) using ETDRS chart (OU) 
• 
Protocol refraction and visual acuity
Tonometry and Ophthalmolo
• 
• 
Vital Signs 
• 
ECG 
• 
Color fundus photographs (OU) 
 
• 
Optical Coherence Tomography (OCT) (OU) 
• 
Laboratory Tests 
• 
Visual Function Questionnaire-25 
 
• 
Protocol refraction and visua
• 
Tonometry and Ophthalmologic examination (OU) 
• 
Vital Signs 
• 
ECG 


 
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ein Angiograms (FA) (OU, transit study eye) 
(OCT) (OU) 
 days after the last dose of study drug or 
ntil the last follow up visit of the trial, whichever comes later.  An adverse event 
p study visit is required to be followed up until the 
sor.  
icity, the follow-up period 
eturn to baseline status or until the condition has stabilized. 
e for any reason.  The 
 Sponsor also have the right to 
 trial in the event of concurrent illness, adverse events, 
procedure, 
protocol 
violations, 
cure, 
dministrative or other reasons. 
s 
initiated, the subject will no longer be evaluated according to this protocol. 
10.4 Trial Discontinuation 
ed immediately to the clinical monitor or his/her 
designated representative if it is due to a serious adverse event (SAE) (see Section 
• 
Fluoresc
• 
Optical Coherence Tomography 
• 
Laboratory Tests 
• 
Visual Function Questionnaire-25 
 
Adverse events are recorded up until 30
u
that is ongoing at the last follow-u
event resolves or stabilizes at a level acceptable to the Investigator and/or Spon
If the subject still presents with any treatment-related tox
will be extended until r
 
10.3 Withdrawal from Trial 
Subjects have the right to withdraw from the trial at any tim
Investigator (after consultation with the Sponsor) or
withdraw subjects from the
treatment-failure 
after 
a 
prescribed 
a
Final trial assessments as outlined in the Study Assessments Chart, Section 3, 
should be performed on all subjects who withdraw.  Subjects who withdraw due to 
an adverse event should be followed until resolution of the adverse event, or an 
adequate explanation for the event is obtained. 
Subjects who withdraw for any reason should have assessments performed 
according to the Early Withdrawal schedule.  If an alternative treatment for AMD i
 
The reason for a subject discontinuing from the trial will be recorded in the case 
report form.  A discontinuation occurs when an enrolled subject ceases participation 
in the trial, regardless of the circumstances, prior to completion of the protocol.  The 
investigator must determine the primary reason for discontinuation.  A 
discontinuation must be report


 
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S 
e treated with active Fovista™ or 
 Eylea will be treated with active Fovista™ or sham 
 combination with Eylea® every month for the first 3 doses (Day 1, Month 1, and 
ereafter (i.e., Months 4, 6, 8, 10, 12, 14, 16, 18, 
with active 
Fovista™ or sham in combination with Avastin
f r a total of 24 administrations.  
ovista™ or sham 
h 24. 
12.4).  The final evaluation required by the protocol will be performed at the time of 
trial discontinuation.  The investigator will record the reason for trial discontinuation, 
provide or arrange for appropriate follow-up (if required) for such subjects, and 
document the course of the subject’s condition. 
Premature termination of this clinical trial may occur because of a regulatory 
authority decision, change in opinion of the IRB/IEC, drug safety problems, or at the 
discretion of Ophthotech Corp. 
 
11 STATISTICAL METHOD
11.1 Experimental Design 
Subjects will be randomized in a 1:1 ratio to the following dose groups: 
• Fovista™ 1.5 mg/eye + Avastin® 1.25 mg/eye or Eylea® 2 mg/eye 
• Fovista™ sham + Avastin® 1.25 mg/eye or Eylea® 2 mg/eye 
Within each of the above dose groups, subjects will be randomized in a 1:1 ratio to 
either Avastin® 1.25 mg/eye or Eylea® 2 mg/eye. 
Subjects will be treated with active Fovista™ or sham in combination with Avastin®  
Subjects randomized to receive Avastin will b
sham in combination with Avastin® monthly for 24 months. 
 
Subjects randomized to receive
in
Month 2) and every other month th
20, and 22). 
 
Therefore, subjects randomized to receive Avastin® will be treated 
® o   
Subjects randomized to receive Eylea® will be treated with active F
in combination with Eylea® for a total of 13 administrations. 
All subjects will have a final follow-up visit at Mont


 
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he primary efficacy endpoint is the mean change in visual acuity (ETDRS letters) 
• 
The proportion of subjects in each treatment group gaining 20 or more ETDRS 
sing 5 or more ETDRS 
y (ETDRS letters) from baseline at the Month 6 
visit. 
.2.3 Safety and Tolerability Endpoints 
emed related to the injection 
procedure or study treatment 
or not deemed related to the injection 
procedure or study treatment  
function, hepatic function, and 
electrolytes; urinalysis) 
mination, fluorescein angiograms and 
OCT) 
ign measurements 
ECG 
 
11.2 Endpoints 
11.2.1 Primary Efficacy Endpoint 
T
from baseline to the Month 12 visit. 
  
11.2.2 Secondary Efficacy Endpoints 
Secondary efficacy endpoints of the trial include: 
letters from baseline at the Month 12 visit. 
• 
The proportion of subjects in each treatment group gaining 25 or more ETDRS 
letters from baseline at the Month 12 visit. 
• 
The proportion of subjects in each treatment group lo
te
line at the Month 12 visit. 
let
rs from base
• 
The mean change in visual acuit
 
11
Safety and tolerability endpoints are: 
• 
All adverse events reported, whether or not de
• 
All serious adverse events (SAE), whether 
• 
Laboratory data (blood:  hematology, renal 
• 
Ophthalmic variables (IOP, ophthalmic exa
• 
Vital s
• 




 
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ed study personnel and the 
ent assignment of Fovista™ 1.5 
similar to those of The Comparison of 
l Institutes of Health.  There are 
different levels of masking within the study.  The Refractionist and Visual Acuity 
xaminer are masked to the treatment assignment of Fovista™ 1.5 mg/eye or 
ked injector (ophthalmologist) and designated 
ista™ sham. Additionally, the study staff 
not to discuss the assignment to Avastin® or 
ylea® with Visual Acuity Examiner prior to each examination. 
It is the responsibility of the Principal Investigator to ensure that the physician 
assessing adverse events, the VA examiner, all mask
subject remain masked to the subject’s treatm
™ 
mg/eye or Fovista
sham. 
The masking procedures for this protocol are 
Age-Related Macular Degeneration Treatments Trials (CATT) [8], sponsored by the 
National Eye Institute of the United States Nationa
E
Fovista™ sham. The unmas
unmasked assistant(s) (if needed) are unmasked to treatment assignment. The 
masked assessor (ophthalmologist) will perform all other physician assessments 
including the relationship of all adverse events to study drug, including those noted 
by the unmasked injector.  
 
11.5.1 Visual Acuity Assessments  
Since this is a double-masked study, subjects and staff at the investigational site, 
particularly the visual acuity examiners, will be masked to the subject’s treatment 
assignment of Fovista™ 1.5 mg/eye or Fov
and the patient should not inform the visual acuity examiner if the patient is being 
treated with Avastin® or Eylea®.  All visual acuity assessments will be performed by 
the trial refractionist/ophthalmologist, who will be masked to the subject’s treatment 
as 
well 
as 
previous 
visual 
acuity 
assessments. 
The 
trial 
refractionist/ophthalmologist will be supplied only with the subject’s most recent 
protocol refraction. 
To ensure that the visual acuity examiner remains masked to the assignment to 
Avastin® or Eylea®, an important task of the study coordinator is to remind the 
patient not to discuss the drug they are receiving with the visual acuity examiner.  
Similarly, clinic staff must be reminded 
E
 
11.5.2 Injections 
Each clinical site is required to have a minimum of 2 ophthalmologists – the 
unmasked injector and the masked assessor.  The unmasked injector will perform 


 
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nment.  Once the unmasked injector or unmasked assistant 
sessments including 
the relationship of all adverse events to study drug, including those noted by the 
nmasked injector. 
will not be made available to investigators or to individuals 
rectly involved in the conduct of the trial in order to preserve appropriate masking.   
dpoint is the mean change in visual acuity (ETDRS letters) 
from baseline to the Month 12 visit. 
the FovistaTM/Sham injection as well as the post-injection ophthalmic exam and 
tonometry measurements. Either ophthalmologist may perform the Avastin® or 
Eylea® injection. The unmasked injector and designated unmasked assistants (if 
needed) are not permitted to be involved in the conduct of the study in any other 
manner and are not to communicate with any other personnel or subjects regarding 
the treatment assig
breaks the seal on the masked drug kit, no masked study personnel can be present 
until after the injections are complete and the drug kit and components (vial, 
syringe, needles) have been disposed of by the unmasked injector/unmasked 
assistant; only the empty drug kit box and the tear-off part of the vial label are 
saved. The masked assessor will perform all other physician as
u
 
11.5.3 Statistical Analyses 
All statistical analyses will be performed by a statistical office independent of the 
study Sponsor. The Sponsor and the subjects will remain masked to treatments 
until the end of the study, except if safety considerations justify breaking the code 
for individual subjects. 
 
11.5.3.1 Analysis upon all Subjects Completing Month 12 
When all enrolled subjects have either completed 12 months of treatment or 
discontinued from the study, an analysis will be conducted to assess results for the 
primary and secondary endpoints (at the primary time point, Month 12). Results will 
be made available to select individuals within the sponsor organization to provide 
executive oversight and for regulatory and legal purposes, e.g., public 
dissemination of results as required by U.S. business law.  Individual patient 
treatment regimens 
di
 
11.6 Analytical Considerations 
11.6.1 Analytical Plan and Significance Levels 
The primary efficacy en


 
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he methods for imputation of post-baseline, missing data will be specified in the 
Observation Carried 
Forward (LOCF), all observed data, a mixed model repeated measure approach 
omparability, including demographic information, treatment administration, and 
 
points 
nalysis methodology for secondary endpoints will be specified in a separate 
will be conducted on all subjects who had at least one 
dministration of trial drug. 
ummarized using MedDRA terms. The incidence and 
 events will be listed and grouped by body system.  
T
Statistical Analysis Plan.  Among the approaches, Last 
(MMRM), multiple imputation and other analyses will be considered as deemed 
appropriate.  The Statistical Analysis Plan will specify the details of this approach.  
Additional details regarding analyses will be provided in a separate Statistical 
Analysis Plan. 
 
11.6.2 Descriptive Statistics 
Descriptive statistics will be provided to document baseline and on-trial 
c
protocol violations.   
 
11.6.3 Efficacy Analysis 
Primary Endpoint 
Comparisons of the mean change in visual acuity in ETDRS letters between 
Fovista™/Avastin® or Eylea® and Sham/Avastin® or Eylea® for the primary endpoint 
will be made using analysis of covariance with baseline visual acuity as a covariate, 
stratified by (blocking on) lesion subtype (>50% classic vs. ≤50% classic).  
Secondary End
A
Statistical Analysis Plan.  
 
11.6.4 Safety Analysis 
The safety analysis 
a
Adverse events will be s
severity of adverse


 
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um and 
aximum) will be presented for all continuous variables.  
ll be given on the number of subjects for whom the trial 
medication had to be permanently stopped. 
Subset Analyses 
test for the presence of treatment by subset interactions. 
Thus true treatment by subset interactions will likely be missed, unless they are 
erapy than the total population, this will not be taken as 
, exploratory 
:  Any untoward medical occurrence in 
 patient or subject including unfavorable and unintended signs, symptoms or 
ated with the use of a medicinal product and which does 
 addition, clinically significant changes in objective findings (e.g., laboratory, ECG, 
 should also be considered as to whether they are 
ing whether an objective finding should be 
2. Requires medical/surgical intervention; and/or 
All laboratory data will be listed and values falling outside normal ranges will be 
identified. Summary statistics (i.e., mean, median, standard deviation, minim
m
Summary statistics wi
 
11.6.5 
The trial is not sized to 
quite substantial. Conversely, should any particular subset of subjects seem to 
benefit more or less from th
evidence of a true treatment by subset interaction, given the likelihood that such an 
observation could be due to chance alone. With these caveats in mind
subset analyses may be performed. 
 
12 ADVERSE  EVENTS 
12.1 Definition of Adverse Events 
An Adverse Event (AE) is defined as follows
a
disease temporally associ
not necessarily have to have a causal relationship to this treatment. 
Adverse events include illnesses with onset during the trial, or exacerbations of pre-
existing illnesses. Exacerbation of pre-existing illness is defined as a significant 
increase in the severity of the illness as compared to the start of the trial, and 
should be considered when a subject requires new or additional treatment for that 
illness.  Lack of or insufficient clinical response or efficacy should not be recorded 
as an adverse event. 
In
X-ray, physical examination)
adverse events.  The criteria for determin
reported as an adverse event are as follows: 
1. Associated with accompanying symptoms; and/or 


 
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se or until the last follow-up visit 
An adverse event that is 
 followed up until the event 
, 
to trial treatment and determination of “serious”. 
urgery, 
as performed should be reported if it meets the definition of 
e event.  For example, an acute appendicitis that begins during the 
e adverse event. 
3. Leads to a change in trial dosing or discontinuation from the trial, significant 
additional concomitant drug treatment or other therapy; and/or
4. Leads to any of the outcomes included in the definition of a serious adverse 
event; and/or 
5. Is considered to be an adverse event by the investigator or Sponsor. 
Any abnormal test result that is determined to be an error does not require reporting 
as an adverse event. 
 
12.2 Assessment and Reporting of Adverse Events 
Adverse events will be recorded starting after the first dose of trial drug and 
continuing until 30 days after the last do
required by the protocol, whichever comes later.  
ongoing at the last follow up study visit is required to be
resolves or stabilizes at a level acceptable to the investigator and/or Sponsor. 
All adverse events spontaneously reported, elicited or observed by the investigators 
will be recorded. The events will be recorded in the source documents and onto the 
adverse event pages of the case report form, including date of onset and resolution
severity, relationship 
Diagnostic and therapeutic non-invasive and invasive procedures, such as s
should not be reported as adverse events.  However, the medical condition for 
which the procedure w
an advers
adverse event reporting period should be reported as the adverse event, and the 
resulting appendectomy should be recorded as treatment of th
The investigator will take all therapeutic measures necessary for resolution of the 
adverse event.  Any medication necessary for treatment of the adverse event must 
be recorded in the subject’s source documents and on the appropriate pages of the 
subject’s case report form. 


 
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, anesthetic drops, mydriatic drops, antibiotic drops, 
itreous 
termed “injection procedure-related”, or to study drug (Fovista™, Avastin® 
or Eylea®). 
The relationship to the intravitreous injection procedure or to study drug will be 
a
ng th
Not Related 
= There is not a reasonable possibility that the adverse 
dy 
drug. 
12.3 Definition of Serious Adverse Events 
: 
1. Results in death; 
eatenin
3. Results in inpati
ation or prolongation of existing hospitalization; 
lts in a 
5. Results in conge
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse events when, based upon 
appropriate medical judgment, they may jeopardize the patient/subject and may 
To assist with grading of adverse event severity, the following definitions are 
provided: 
Mild 
= Aware of sign or symptom, but easily tolerated;  
Moderate 
= Discomfort enough to cause interference with usual 
activity; 
Severe 
= Incapacitating with inability to work or do usual activity; 
Adverse events are assessed as either related to the intravitreous injection 
procedure (eyelid speculum
povidone-iodine drops or flush, subconjunctival injection of anesthetic, intrav
injection), 
ssessed usi
e following definitions: 
event is related to the injection procedure or to the stu
Related  
=  There is a reasonable possibility that the adverse event 
is related to the injection procedure or to the study drug. 
 
A serious adverse event is any event that
2. Is life-thr
g (immediate risk of death); 
ent hospitaliz
4. Resu
persistent or significant disability/incapacity; or 
nital anomaly/birth defect. 


 
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quire medical or surgical intervention to prevent one of the outcomes listed in this 
include allergic bronchospasm 
cy room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of 
abuse. 
t places the patient/subject at 
 
used death. 
bility to conduct normal life 
functions. 
 Outpatient/same-day/ambulatory procedures and observation/short-
custodial care facilities 
dition not associated with 
the development of a new adverse event or with a worsening of the 
istent pretreatment lab 
ission (e.g., subject has no place to sleep) 
ical adverse 
re
definition.  Examples of such medical events 
requiring intensive treatment in an emergen
drug dependency or drug 
A life-threatening adverse event is any event tha
immediate risk of death from the reaction as it occurred; i.e., it does not include a
reaction that, had it occurred in a more severe form, might have ca
Disability is a substantial disruption of a person’s a
Hospitalization is defined as any formal inpatient admission (even if less than 
24 hours).  For chronic or long-term inpatients, inpatient admission also includes 
transfer within the hospital to an acute/intensive care inpatient unit (e.g., from the 
psychiatric wing to a medical floor, from a medical floor to the coronary care unit).   
• Inpatient admission does not include the following: 
o Emergency Room/Casualty Department visits 
o
stay units 
o Hospice facilities and Respite care (e.g., caregiver relief) 
o Rehabilitation facilities, skilled nursing facilities, nursing homes, 
• Inpatient admission in the absence of a precipitating, treatment-emergent, 
clinical adverse event may meet criteria for “seriousness” but is not an 
adverse event and thus is not subject to immediate reporting to the Sponsor.  
For example: 
o Admission for treatment of a pre-existing con
pre-existing condition (e.g., for work-up of pers
abnormality) 
o Social adm
o Optional admission not associated with a precipitating clin
event (e.g., yearly physical, elective cosmetic surgery) 


 
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e protocol, whichever comes later.  Any serious adverse 
ev
report
If a se
awareness
investigator.  In particular, if the serious adverse 
ev
ust be made 
regardless
also applies to additional new informati
serious adv
All Serious Adverse Events must be reported by FAX 
An Independent Data Monitoring Committee will review patient safety data during 
ponsor.  This must be done irrespective of whether 
an adverse e
 pregnancy.  
The Sponsor will i
 
12.7 Abno
If a clinically significant laboratory value occurs, the investigator will repeat the 
laboratory determination as judged appropriate until the abnormality is resolved, is 
no longer considered clinically significant by the investigator, or an explanation for 
the change is obtained.  
 
12.4 Assessment and Reporting of Serious Adverse Events 
Serious adverse events will be recorded starting after the first dose of trial 
drug and continuing until 30 days after the last dose or until the last follow-up 
visit required by th
ent occurring at any other time after completion of the trial must be promptly 
ed if a causal relationship to trial drug is suspected.  
rious adverse event occurs, the Sponsor is to be notified within 24 hours of 
 of the event by the 
ent is fatal or life-threatening, notification to the Sponsor m
 of the extent of available adverse event information.  This timeframe 
on (follow-up) on previously forwarded 
erse event reports. 
to the Sponsor or Designee within 24 hours. 
FAX NUMBER:  
Refer to the “Safety Contact List” provided separately 
 
12.5 Independent Data Monitoring Committee (IDMC) 
the course of the trial.   
 
12.6 Exposure in Utero 
If any trial subject becomes or is found to be pregnant while receiving trial drug, the 
investigator must contact the S
vent has occurred and within 24 hours of awareness of the
nform the site of the information to be provided. 
rmal Laboratory Results 


 
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ipment 
ll participating sites should have emergency resuscitation equipment available, 
mbu bag, IV tubing, D5W IV fluid, oxygen, and 
 
The investigator will complete the appropriate case report form pages within 3   
 with prior written agreement by the trial sponsor and 
monitor, the case report form may be used to record source data. 
 made available to Ophthotech Corp. clinical monitors 
ts, to auditors during any audits requested by 
y agencies during inspections. 
d 
iginal source documents including ocular images should 
e stored for a minimum of two years after a marketing application has been 
f development of the 
investigational drug, or five years after completion of the trial, whichever is longer.  
 the Principal 
 
13 RESPONSIBILITIES 
13.1 Emergency Equ
A
including at a minimum, an A
epinephrine 1:1000, and Diphenhydramine Hydrochloride (Benadryl).  It is each 
center’s responsibility to ensure that all equipment is within specifications for the 
duration of the trial.  Each center should have written policies regarding 
resuscitation procedures.   
13.2 Case Report Forms and Trial Documentation 
business days following completion of each procedure or evaluation. 
All data recorded on case report forms will be supported by source documents.  For 
certain trial parameters,
All source documents will be
during scheduled monitoring visi
Ophthotech Corp., and to regulator
The investigator will maintain a Trial File containing all trial related documentation 
required by Good Clinical Practice (GCP). This Trial File will be reviewe
periodically for completeness by Ophthotech Corp.’s clinical monitors and must be 
made available to auditors and regulatory agencies. 
All case report forms and or
b
approved, or two years after formal discontinuation o
Documents should not be destroyed without the permission of Ophthotech Corp.  In 
the event of the Principal Investigator leaving the clinical site, it is
Investigator’s responsibility to notify Ophthotech Corp. in writing and to designate 
which trial material will be transferred at the clinical site. 
 


 
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e temperature at 
phthotech Corp. will not compensate the Investigator for evaluation of cases in 
 in a manner other than that 
13.5 Ethical Aspects 
chever affords the greater protection to the 
dividual.  The trial must fully adhere to the principles outlined in “Guideline for 
Good Clinical Practice” ICH Tripartite Guideline (May 9th 1997) and with local law if 
it affords greater protection to the subject. For studies conducted in the USA or 
under US IND, the investigator will additionally ensure adherence to the basic 
principles of “Good Clinical Practice” as outlined in the current version of 21 CFR, 
13.3 Drug Accountability/Storage Conditions 
The investigator is responsible for the accountability of all used and unused trial 
medication and for recording and documenting the drug storag
arrival and throughout the trial.  Drug accountability records will be reviewed during 
monitoring visits.  Adequate drug accountability records include documentation of 
all trial drug supplies received, dispensed to trial subjects, and returned to 
Ophthotech Corp. 
At the end of the trial, all drug supplies and documentation will be reviewed and 
verified by the trial monitors.  The sites will be instructed to destroy unused trial 
drug supplies when the trial is completed, or the site may choose to return the drug 
to an Ophthotech Corp. contracted drug management facility for destruction.  If the 
drug is destroyed at the site, the drug accountability form must be completed and 
sent to Ophthotech Corp. for archiving. 
 
13.4 Protocol Compliance 
O
which the procedures and evaluations are conducted
specified by the protocol. 
Under certain circumstances, individual protocol criteria may be waived by 
Ophthotech Corp. and in agreement with the investigator.  Any such waiver will be 
documented in writing and provided to the investigator by Ophthotech Corp. 
 
Local Regulations/Declaration of Helsinki 
The investigator will ensure that this trial is conducted in full conformance with the 
principles of the “Declaration of Helsinki” (as amended in Tokyo, Venice, Hong 
Kong, South Africa, and Scotland) and with the laws and regulations of the country 
in which the research is conducted, whi
in


 
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nsibilities of Sponsors and Investigators”, part 50, 
ew Board (IRB) or Ethics Committee (EC) 
opriate 
B/EC prior to initiating the trial.  The investigator will forward the following 
ncement of subject enrollment:  
abilities incurred during clinical trials with its compounds. 
13.8 Trial Report and Publications 
ulti-center publication of 
the 
unction with various participating 
investigator
nts. Subsequently, 
indiv
sent results from the trial; 
how
 Should the 
subchapter D, part 312, “Respo
“Protection of Human Subjects”, and part 56, “Institutional Review Boards”. 
 
13.6 Institutional Revi
Approval and Informed Consent 
The investigator is responsible for obtaining approval of the trial protocol, informed 
consent, and any advertising used for subject recruitment from the appr
IR
documents prior to comme
• 
IRB/EC approval documentation 
• 
Approved trial subject informed consent 
• 
A list of IRB/EC members, or statement of compliance 
Prior to enrollment, written informed consent must be obtained from each subject or 
his/her legally authorized representative.  The informed consent must contain all of 
the elements prescribed by the relevant regulatory authorities and must be 
appropriately signed, dated and witnessed. Any changes by the Investigator or 
local IRB/EC to the sample consent provided by the Sponsor must be 
approved by the Sponsor before initiating enrollment. 
 
13.7 Clinical Trial Insurance 
Ophthotech Corp. has insurance coverage for medicine-induced injury and other 
li
 
The trial will be documented in a final report, which will contain appropriate 
statistical analysis and medical overview. No individual site or investigator may 
publish or present any results from the trial until a joint, m
trial results is made by Sponsor in conj
s and appropriate sites contributing data and comme
idual investigators may request to publish or pre
ever, approval will be at the sole discretion of the Sponsor.
foregoing language be in conflict with the language addressing publication in the 
clinical trial agreement, the language in the clinical trial agreement will prevail. 


 
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roughout the trial.  These monitoring visits are for the purpose of verifying protocol 
 adequacy of data collected. 
 
14 MONITORING 
The investigator will permit representatives of Ophthotech Corp. to review all case 
report forms, trial documentation, and subject medical records at regular intervals
th
compliance, subject safety, and the


 
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15   REFERENCES
1. Leibowitz HM et al.  The Framingham Eye Trial monograph:  an ophthalmological and 
epidemiological 
trial 
of 
cataract, 
glaucoma, 
diabetic 
retinopathy, 
macular 
degeneration, and visual acuity in a general population of 2,631 adults, 1973-1975.  
Surv Ophthalmol 24 (suppl):335-610, 1980. 
2. Cheeseman-Day J.  Population projection of the United States, by age, sex, race, and 
Hispanic origin: 1993 to 2050.  U.S. Bureau of the Census - Current Population 
Reports:  25-1104, U.S. Government Printing Office, 1993. 
3. Vingerling JR et al.  Prevalence of age-related maculopathy in the Rotterdam trial.  
Ophthalmology 102:205-210, 1995. 
4. Brown DM, 
Kaiser PK, 
Michels M, 
et al. Ranibizumab 
versus 
verteporfin 
for 
neovascular age-related macular degeneration. N Engl J Med. 2006;355:1432-1444. 
5. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related 
macular degeneration. N Engl J Med. 2006;355:1419-1431.  
6. Heier JS, Brown DM, Chong V et al. Intravitreal aflibercept (VEGF trap-eye) in wet 
age-related macular degeneration. Ophthalmology. 2012 Dec;119(12):2537-48. 
7. Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR. VEGF 
Inhibition Study in Ocular Neovascularization. N Engl J Med. 2004 Dec 
30;351(27):2805-16. 
8. Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) 
Research Group, Martin DF, Maguire MG.  Ranibizumab and bevacizumab for 
treatment of neovascular age-related macular degeneration: Two-year results. 
Ophthalmology. 2012 Jul;119(7):1388-98.  
9. Jo N, Mailhos C, Ju M, Cheung E, Bradley J, Nishijima K, Robinson GS, Adamis AP, 
Shima DT; Inhibition of Platelet-Derived Growth Factor B Signaling Enhances the 
Efficacy of Anti-Vascular Endothelial Growth Factor Therapy in Multiple Models of 
Ocular Neovascularization. American Journal of Pathology 2006; 168 (6): 2036-2053.  
10. Folkman J. and Shing Y.  Angiogenesis.  J Biol Chem 267:10931-10934, 1992.   


 
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11.  Keck PJ et al.  Vascular endothelial growth factor (VEGF) is a secreted angiogenic 
mitogen.   
Science 246:1309-1312, 1989. 
12. Heldin, CH., Eriksson, U. and Ostman, A (2002) New members of the platelet-derived 
growth factor family of mitogens. Arch Biochem Biophys. 398(2):284-90. 
13. Heldin CH.  Development and possible clinical use of antagonists for PDGF and TGF-
beta. Ups J Med Sci 109(3):  165-178, 2004. 
14. Klenkler BJ and Sheardown H.  Growth factors in the anterior segment: role in tissue 
maintenance, wound healing and ocular pathology. Exp Eye Res 79: 677-688 2004. 
15. Floege J, Ostendorf T, Janssen U, Burg M, Radeke HH, Vargeese C, Gill SC, Green 
LS, Janjic N.   Novel approach to specific growth factor inhibition in vivo: antagonism 
of platelet-derived growth factor in glomerulonephritis by aptamers. Am J 
Pathol.;154(1):169-79, 1999. 
16. Ng E, Mastyugin V,  De Erkenez A, Xing H, Robinson G, Shima D, The Interaction of 
the Anti-PDGF-B Aptamer (E10001) with Human, Canine, and Rabbit PDGF-BB, 
(OSI) Eyetech Study Report RD-RPT-0011, 2006. 
17. Risau W, Drexler H, et al.  Platelet-derived growth factor is angiogenic in vivo. Growth 
factors 7(4): 261-266, 1992.   
18. Cao R, Brakenhielm E, et al.  Angiogenesis stimulated by PDGF-CC, a novel member 
in the PDGF family, involves activation of PDGFR-alphaalpha and -alphabeta 
receptors. FASEB J. 16(12):  1575-1583, 2002. 
19. McCarty MF, Liu W, et al.  Promises and pitfalls of anti-angiogenic therapy in clinical 
trials. Trends Mol Med. 9(2): 53-58, 2003. 
20. Hellstrõm M, Kalen M, et al.  Role of PDGF-B and PDGFR-beta in recruitment of 
vascular smooth muscle cells and pericytes during embryonic blood vessel formation 
in the mouse. Development 126(14): 3047-3055, 1999. 
21. Östman A and Heldin CH. Involvement of platelet-derived growth factor in 
disease: development of specific antagonists. Adv Cancer Res; 80: 1-38, 
2001. 


 
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22. Capdeville R, Silberman S and Dimitrijevic S. Imatinib: the first 3 years. Eur J 
Cancer. Sep;38 Suppl 5:S77-82, 2002. 
23. Dugel, PU.  Phase 2b clinical trial of Fovista™ anti-PDGF therapy (1.5 mg) in patients 
with neovascular age-related macular degeneration (wet AMD). Retina Subspecialty 
Day at the American Academy of Ophthalmology Annual Meeting (AAO) Nov. 10, 
2012. 
24. Dvorak et al; AJP May 1995, Vol.146, No. 5:1029-1035 
25. Busbee BG, Ho AC, Brown DM, Heier JS, Suñer IJ, Li Z, Rubio RG, Lai P; HARBOR 
Study Group.   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 
Jan 
23. 
pii: 
S0161-6420(12)00986-4. 
doi: 
10.1016/j.ophtha.2012.10.014. [Epub ahead of print] 
26. Reinmuth N, Liu W, Jung YD, Ahmad SA, Shaheen RM, Fan F, Bucana CD, 
McMahon G, Gallick GE, Ellis LM. Induction of VEGF in perivascular cells defines a 
potential paracrine mechanism for endothelial cell survival. FASEB J. 2001 
May;15(7):1239-41. 
27. Armulik A, Abramsson A, Betsholtz C; Endothelial/Pericyte Interactions. Circ. Res. 
2005; 97: 512-523. 
28. Benjamin LM, Hemo I, Keshet E; A plasticity window for blood vessel remodelling is 
defined by pericyte coverage of the preformed endothelial network and is regulated by 
PDGF-B and VEGF.  Development 1998; 125: 1591-1598.  
29. Mitchell TS, Bradley J, Robinson GS, Shima DT, Ng Y-S; RGS5 expression is a 
quantitative measure of pericyte coverage of blood vessels. Angiogenesis 2008; 
11:141–151. 
30. Lindahl P, Johansson BR, Leveen P, Betsholtz C.  Pericyte Loss and Microaneurysm 
Formation in PDGF-B-Deficient Mice.  Science 1977; 277:242-245.  
31. Hall AP; Review of the Pericyte during Angiogenesis and its Role in Cancer and 
Diabetic Retinopathy. Toxicologic Pathology 2006; 34:763–775. 


 
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32. Gaengel K, Genove G, Armulik A, Betsholtz C, Endothelial-Mural Cell Signaling in 
Vascular Development and Angiogenesis. Arterioscler Thromb Vasc Biol. 2009; 29: 
630-638. 
33. Morikawa S, Baluk P, Kaidoh T, Haskell A, Jain RK, McDonald DM; Abnormalities in 
Pericytes on Blood Vessels and Endothelial Sprouts in Tumors. American Journal of 
Pathology 2002; 160(3): 985-1000. 


 
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16 SIGNATURE  PAGE 
Signatures confirm that this protocol OPH1004B has been carefully read and fully 
understood, and that there is agreement to comply with the conduct and terms of the trial 
specified herein in compliance with Good Clinical Practice and all other regulatory 
requirements.  
PROTOCOL OPH1004B:  “A phase 3 randomized, double-masked, controlled trial to 
establish the safety and efficacy of intravitreous administration of FovistaTM (Anti PDGF-B 
pegylated aptamer) administered in combination with either Avastin® or Eylea® compared to 
Avastin® or Eylea® monotherapy in subjects with subfoveal neovascular age-related macular 
degeneration.” 
Trial Sponsor:  
Ophthotech Corporation 
 
 


 
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17 APPENDICES 
 
17.1 Method for Evaluating Anterior Chamber Inflammatory Activity 
17.1.1 Examination 
1. The pupils will be maximally dilated. 
2. A slit-lamp biomicroscope will be used with a one by two mm2 beam at an angle of 30-
45°.  The number of cells within this wedge will be counted. 
3. The grade of anterior chamber inflammatory activity is determined. 
 
17.1.2 Standardized Description of Anterior Chamber Activity 
Anterior chamber activity will be graded on a scale of 0, trace, 1+, 2+, 3+, and 4+. 
The grading is as follows: 
0 
None 
Trace  
<5 cells in wedge 
1+ 
5 - 10 cells in wedge 
2+  
11 - 20 cells in wedge 
3+  
21 - 50 cells in wedge 
4+  
>50 cells in wedge 
 
Hogan MJ, Kimura SJ, Thygeson P.  Signs and symptoms of Uveitis.  I.  Anterior uveitis.  Am 
J Ophthalmol 1959; 47:155-170. 
 


 
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17.2 Method for Evaluating Vitreous Inflammatory Activity 
All subjects will have the standard fundus examination followed by evaluation for 
inflammatory activity in the vitreous. 
 
17.2.1 Marking 
The clarity of the optic nerve head, retinal vessels, and the nerve fiber layer are used as 
landmarks for the marking criteria. 
 
17.2.2 Examination 
1. The pupils will be maximally dilated. 
2. An indirect ophthalmoscope and a 20+ diopter aspheric lens will be used as the standard. 
3. Standard fundus examination is performed with the last view being over the disc and 
surrounding retina. 
4. Inflammatory activity is evaluated by the examiner by determining which standardized 
description most closely resembles the vitreal haze seen through the indirect 
ophthalmoscope. 
 
17.2.3 Standardized Description of Vitreous Inflammation 
Vitreous activity will be graded on a scale of 0, 1+, 2+, 3+, and 4+. 
The grading is as follows1: 
0 
No evident vitreal haze at all. 
1+  
Minimal haze.  Optic nerve head and retinal vessels are both clearly 
defined. 
2+  
Retinal vessels are visible, but not clearly defined. 
3+  
Optic nerve head is visible but the borders are blurry, and cannot see 
vessels. 
4+  
Optic nerve head is obscured. 
 
17.2.4 References 
1. Nussenblatt RB et al.  Standardization of Vitreal Inflammatory Activity in Intermediate 
and posterior Uveitis.  Ophthalmology 92:467-471, 1985. 


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SAP_001.pdf: 








































                         
Confidential 
OPHTHOTECH – OPH1004 – SAP – V1.0 – FINAL – 21MAR2017                      Page 20 of 34 
 
Descriptive tables will be used for the supportive endpoints based on observed data (i.e. missing 
data will not be imputed for the supportive endpoints).  
7.5 
QUALITY OF LIFE ANALYSES 
The VFQ-25 will be administered at Baseline (Day 1), Month 3, 6, 9, 12, 18, and 24. Based on the 
VFQ-25 and the scoring rules, the 12 VFQ-25 sub-scales and the composite score will be 
generated, computed and used in the QOL analyses (See Appendix 2). 
Of the 12 VFQ-25 sub-scales, 4 are considered of interest in this trial: 
x Near vision activities 
x Distance vision activities 
x Dependency 
x Role difficulties 
The composite score will be used as an overall measure of vision-targeted health related quality of 
life. 
7.5.1 
Descriptive Summaries by Visit 
The change in score from baseline will be analyzed as continuous variables. The composite score 
and the scores of each sub-scale at Baseline and the changes from Baseline will be summarized 
descriptively by visit and by treatment group using the observed cases (missing values will not be 
imputed).   
The proportions (%) of subjects gaining/losing ≥ 10 points in score for the 4 pre-specified sub-
scales, as well as the Composite score, will be tabulated by visit and by treatment group using the 
observed cases (missing values will not be imputed).  
Change in mean score from Baseline over time will be plotted by visit and by treatment group.  
No inferential treatment comparisons will be performed for QOL data. 
7.6 
 
 
 
                                                         Version: 1.0