Clinical trial NCT01573572
Conditions: Age-Related Macular Degeneration Retinal Vein Occlusion Diabetic Macular Edema
Sponsor: Bausch & Lomb Incorporated
Start date: 2010-04-22; Completion date: 2019-11-14
Enrollment: 131 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study was conducted because the FDA requested clinical information on potential effects of intravitreal injections of Macugen (pegaptanib sodium injection) on the corneal endothelium from a 1-year (minimum) post-approval clinical study to support that there are no adverse effects on the corneal endothelium following intravitreal injections of Macugen.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: pegaptanib sodium injection
Intervention descriptions: intervention 1: 0.3mg of Macugen in a single-use, prefilled glass syringe given every 6 weeks for 48 weeks

Protocol documents:
Prot_SAP_000.pdf: 
Valeant Pharmaceuticals  
Protocol  EOP 1024 - Confidential 
              Page 1 of 36   
Date: September 26, 2018  
                 
 
A PHASE IV, OPEN LABEL, MULTI-CENTER STUDY TO ASSESS THE EFFECT OF INTRAVITREAL 
INJECTIONS OF MACUGEN
 (PEGAPTANIB SODIUM INJECTION) ADMINISTERED EVERY 6 WEEKS 
FOR 48 WEEKS ON THE CORNEAL ENDOTHELIUM 
 
PROTOCOL NUMBER:  EOP 1024 AMENDMENT 3 
Dated: September 26, 2018 
SPONSOR:  
Valeant Pharmaceuticals North America LLC 
as engaged by and acting as a service provider to 
Valeant International (Barbados) SRL 
 
Address: 
400 Somerset Corporate Blvd  
Bridgewater, NJ  08807 
 
FOR MEDICAL EMERGENCIES, CALL 
 
 
 
 
 
 
Confidentiality Statement 
 
The information in this document is confidential and will not be disclosed to others without written authorization from 
Valeant Pharmaceuticals North America LLC except to the extent necessary to obtain informed consent from persons 
receiving the investigational procedure or their legal guardians, or for discussions with local regulatory authorities, 
institutional review boards (IRB), or persons participating in the conduct of the study. 


Valeant Pharmaceuticals  
Protocol  EOP 1024 - Confidential 
              Page 2 of 36   
Date: September 26, 2018  
                 
Protocol Amendment No. 3 
Amendment rationale and changes to the protocol: 
 Change of Medical Monitor 
 Change medical emergency phone numbers 
 Update revision to 100 evaluable subjects at recommendation of FDA  
  Subsections 4.3.1.1-4.3.1.4 have been added to separate clinical trial descriptions for Macugen treatment 
of wet AMD, diabetic macular edema, central retinal vein occlusion, and branched retinal vein occlusion, 
respectively 
 Update Introduction and Sections, 4.1, 4.3.1, and 4.3.1.1-4.3.1.4 to recognize and describe  additional 
clinical trials and indications that have been completed with Macugen 
 Update reference list and links to references for clarification in the Introduction 
 Reword Section 12 for clarity 
 
Protocol Amendment No. 2 
Amendment rationale and changes to the protocol: 
 Modification of study schedule / window period for visits extended to +/- 14 days 
 Valeant supplying study drug 
 
Protocol Amendment No. 1 
Amendment rationale and changes to the protocol 
The purpose of this amendment is to document the change in sponsorship of the protocol; the Sponsor has changed 
from Eyetech, Inc. to: 
Valeant Pharmaceuticals North America LLC 
as engaged by and acting as service provider to 
Valeant International (Barbados) SRL. 
Other changes to the protocol include: 
 
Modifications to Exclusion criteria: 
 Unilateral ocular blunt trauma within one year of enrollment and no greater than 5% difference in central 
endothelial cell density between the 2 eyes 
 intraocular surgery (cataract surgery and surgery for glaucoma without tube shunt or mini-shunt) within 
one year of enrollment, 
 Anterior segment laser surgery (laser trabeculoplasty) performed within one year of enrollment 
 Glaucoma tube-shunt surgery 
 Known serious allergies to the components of pegaptanib sodium formulation 
 Significant media opacities, including cataract, which might interfere with visual acuity, or assessment of 
toxicity.  Subjects should not be entered if there is likelihood that they will require cataract or glaucoma 
surgery in either eye during the study treatment and follow-up period. 
 Clarification for corneal specular microscopy results sent to CIARC within 3 days 
 Protocol Deviation/Waiver Request instruction 


Valeant Pharmaceuticals  
Protocol  EOP 1024 - Confidential 
              Page 3 of 36   
Date: September 26, 2018  
                 
TABLE OF CONTENTS 
1.0 
GLOSSARY OF ABBREVIATIONS ........................................................................................................... 5 
2.0 
SUMMARY OF PROTOCOL  EOP 1024 ................................................................................................... 6 
3.0 
STUDY FLOW CHART ................................................................................................................................ 9 
4.0 
INTRODUCTION ........................................................................................................................................ 
10 
4.1 
BACKGROUND............................................................................................................................................. 
10 
4.2 
MACUGEN (
PEGAPTANIB SODIUM INJECTION)
 (F
ORMERLY EYE001 AND NX1838) ................................. 
11 
4.2.1 Pre-Clinical Efficacy 
............................................................................................................................ 
11 
4.2.2 Intravitreous Pharmacokinetics of Pegaptanib 
................................................................................. 
11 
4.2.3 Toxicology 
............................................................................................................................................. 
11 
4.3 
CLINICAL DATA 
.......................................................................................................................................... 
11 
4.3.1 Clinical Summary of Phase 1 & 2 Safety, and Phase 2/3 Pivotal Studies........................................ 
11 
4.4 
CORNEAL ENDOTHELIUM AND CLINICAL SPECULAR MICROSCOPY 
............................................................ 
16 
5.0 
STUDY OBJECTIVE .................................................................................................................................. 
16 
5.1 
OBJECTIVE 
.................................................................................................................................................. 
16 
6.0 
INVESTIGATIONAL PLAN ...................................................................................................................... 
16 
6.1 
STUDY DESIGN ........................................................................................................................................... 
16 
6.2 
RATIONALE 
................................................................................................................................................. 
16 
6.3 
ELIGIBILITY CRITERIA ................................................................................................................................ 
17 
6.3.1 Inclusion Criteria ................................................................................................................................... 
17 
6.3.2 Exclusion Criteria .................................................................................................................................. 
17 
7.0 
STUDY MEDICATION ............................................................................................................................... 
18 
7.1 
I
NVESTIGATIONAL DRUG SUPPLY 
............................................................................................................... 
18 
7.2 
DOSE AND ADMINISTRATION 
...................................................................................................................... 
19 
7.2.1 Preparation ............................................................................................................................................. 
19 
7.2.2 Treatment Regimen and Duration .......................................................................................................... 
19 
7.2.3 Administration of Study Drug and Controls .......................................................................................... 
20 
7.2.4 Stability of Final Solution ...................................................................................................................... 
20 
7.2.5 Storage of Drug product ........................................................................................................................ 
20 
7.3 
PREVIOUS OR CONCOMITANT MEDICATIONS AND RESTRICTIONS 
............................................................... 
20 
8.0 
STUDY CONDUCT ..................................................................................................................................... 
20 
8.1 
STUDY EVALUATIONS 
................................................................................................................................. 
20 
8.1.1 Baseline Visit ......................................................................................................................................... 
20 
8.1.2 Day 0 ...................................................................................................................................................... 
21 
8.1.3 Week 6, Week 12, Week 18, Week 30, Week 36, Week 42, Week 48 .................................................. 
21 
8.1.4 Week 24 ................................................................................................................................................. 
21 
8.1.5 Week 54 ................................................................................................................................................. 
21 
8.1.6 Early Termination Visit ......................................................................................................................... 
21 
8.2 
PROTOCOL COMPLIANCE AND VIOLATIONS 
................................................................................................ 
21 
8.3 
SUBJECT DISCONTINUATION 
....................................................................................................................... 
22 
8.4 
STUDY DISCONTINUATION 
.......................................................................................................................... 
22 
9.0 
OUTCOME MEASURES ............................................................................................................................ 
22 
9.1 
SAFETY MEASUREMENTS AND ENDPOINTS 
................................................................................................. 
22 
9.1.1 Corneal Specular Microscopy ................................................................................................................ 
22 
9.2 
EFFICACY MEASUREMENT AND ENDPOINTS ............................................................................................... 
23 
10.0 STATISTICAL METHODS ........................................................................................................................ 
23 
10.1 DETERMINATION OF SAMPLE SIZE 
.............................................................................................................. 
23 
10.2 METHODS OF ANALYSIS.............................................................................................................................. 
23 
10.2.1 
General Statistical Methods ............................................................................................................... 
23 


Valeant Pharmaceuticals  
Protocol  EOP 1024 - Confidential 
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Date: September 26, 2018  
                 
10.2.2 
Safety Data Analysis ......................................................................................................................... 
23 
11.0 DRUG SAFETY ........................................................................................................................................... 
24 
11.1 DEFINITION OF ADVERSE EVENT ................................................................................................................ 
24 
11.1.1 
Relationship of Adverse Events ........................................................................................................ 
24 
11.2 SEVERITY  OF ADVERSE EVENTS 
................................................................................................................. 
25 
11.3 SERIOUS ADVERSE EVENTS ........................................................................................................................ 
25 
11.4 REPORTING OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
........................................................... 
25 
11.5 EXPOSURE IN UTERO .................................................................................................................................. 
26 
12.0 INVESTIGATOR RESPONSIBILITIES 
................................................................................................... 
26 
12.1 ETHICS REVIEW 
.......................................................................................................................................... 
27 
12.2 SOURCE DOCUMENTS ................................................................................................................................. 
27 
12.3 TRAINING 
.................................................................................................................................................... 
27 
12.4 STUDY AGREEMENTS 
.................................................................................................................................. 
27 
12.5 CONFIDENTIALITY ...................................................................................................................................... 
28 
13.0 STUDY MANAGEMENT ........................................................................................................................... 
28 
13.1 STUDY I
NITIATION REQUIREMENTS 
............................................................................................................ 
28 
13.2 MONITORING,
 VERIFICATION OF DATA,
 AUDITING AND I
NSPECTION 
.......................................................... 
28 
13.3 DATA MANAGEMENT 
.................................................................................................................................. 
28 
13.4 STUDY DRUG ACCOUNTABILITY 
................................................................................................................. 
29 
13.5 PROTOCOL COMPLIANCE ............................................................................................................................ 
29 
13.6 ETHICAL ASPECTS ...................................................................................................................................... 
29 
13.7 I
NSTITUTIONAL REVIEW BOARD (IRB)
 APPROVAL AND I
NFORMED CONSENT............................................ 
29 
13.8 RECORD RETENTION 
................................................................................................................................... 
29 
13.9 CONFIDENTIALITY ...................................................................................................................................... 
30 
13.10 
USE OF DATA AND PUBLICATION ........................................................................................................... 
30 
14.0 REFERENCES ............................................................................................................................................. 
31 
15.0 SIGNATURE PAGE .................................................................................................................................... 
33 
APPENDIX 1 MACUGEN PRESCRIBING INFORMATION ............................................................................. 
34 
APPENDIX 2 NYHA FUNCTIONAL CLASSIFICATIONS 
................................................................................ 
36 
 
 
 
 


Valeant Pharmaceuticals  
Protocol  EOP 1024 - Confidential 
              Page 5 of 36   
Date: September 26, 2018  
                 
1.0 GLOSSARY OF ABBREVIATIONS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation                           
Term 
AE 
Adverse Event 
AMD 
Age-Related Macular Degeneration 
ANCOVA 
Analysis of Covariance 
CIARC 
Cornea Image  Analysis Reading Center 
CMH 
Cochran-Mantel-Haenszel 
CNV 
Choroidal neovascularization 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EW 
Early Withdrawal 
FA 
Fluorescein Angiography 
FDA 
Food & Drug Administration 
GLP 
Good Laboratory Practices 
GCP 
Good Clinical Practices 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonization 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
ITT 
Intent To Treat 
LOCF 
Last Observation Carried Forward 
NEI 
National Eye Institute 
NLP 
No Light Perception 
PDT 
Photodynamic Therapy 
PEG 
PolyEthylene Glycol 
SAE 
Serious Adverse Event 
VA 
Visual Acuity 
VEGF 
Vascular Endothelial Growth Factor 
WHO 
World Health Organization 




Valeant Pharmaceuticals  
Protocol  EOP 1024 - Confidential 
              Page 7 of 36   
Date: September 26, 2018  
                 
Inclusion Criteria 
 Subjects of either gender aged  50 years diagnosed with Subfoveal 
Neovascular Age-Related Macular Degeneration (AMD), Diabetic Macular 
Edema (DME) or Retinal Vein Occlusion (RVO). 
 Best corrected visual acuity in the study eye between 85 and 20 ETDRS 
letters or between 20/20 and 20/400 using a Snellen chart. 
 Ability to return for all study visits. 
 Women must be using two forms of effective contraception, be post-
menopausal for at least 12 months prior to study entry, or surgically sterile; if 
of child-bearing potential, a urine pregnancy test must be performed within 
7 days prior to the first injection with a negative result.  If the test is positive, 
a serum test must be done to confirm.  The two forms of effective 
contraception must be implemented during the study and for at least 60 days 
following the last dose of test medication. 
 Provide written informed consent. 
Exclusion Criteria 
 Unilateral ocular blunt trauma within one year of enrollment and no greater 
than 5% difference in central endothelial cell density between the 2 eyes. 
 Intraocular surgery (cataract surgery and surgery for glaucoma without tube 
shunt or mini-shunt) within one year of enrollment 
 Anterior segment laser surgery (laser traberculoplasty) performed within one 
year of enrollment 
 Glaucoma tube-shunt surgery  
 Previous history of corneal transplant in the study or non-study eye. 
 Presence of vitreous macular traction 
 Previous therapeutic radiation in the region of the study eye. 
 Any treatment with an investigational agent in the past 30 days for any 
condition. 
 Known serious allergies to the components of pegaptanib sodium  
(pegaptanib sodium injection)  formulation 
 Any of the following underlying diseases including: 
o History or evidence of severe cardiac disease (e.g., NYHA 
Functional Class III or IV - see  Appendix 2, clinical or medical 
history of unstable angina, acute coronary syndrome, myocardial 
infarction or revascularization within 6 months, ventricular 
tachyarrythmias requiring ongoing treatment. 
o History or evidence of clinically significant peripheral vascular 
disease, such as intermittent claudication or prior amputation. 
o History or evidence of clinically significant impaired renal or 
hepatic function 
o Stroke (within 12 months of study entry). 
o Any major surgical procedure within one month of study entry. 
 Significant media opacities, including cataract, which might interfere with 
visual acuity, or assessment of toxicity.  Subjects should not be entered if 
there is likelihood that they will require cataract or glaucoma surgery in 
either eye during the study treatment and follow-up period. 


Valeant Pharmaceuticals  
Protocol  EOP 1024 - Confidential 
              Page 8 of 36   
Date: September 26, 2018  
                 
Statistics 
Descriptive statistics will be provided to summarize baseline and on-study measures, 
including demographic information, treatment administration, study outcomes and 
protocol deviations. 
Safety 
All adverse events spontaneously reported, elicited or observed by the Investigators, 
will be recorded.   
Test Product, Dose, 
Formulation and Mode of 
Administration: 
Test Product:   Macugen
 (pegaptanib sodium injection) 
Administration:   intravitreous injection 
Dose: All subjects will receive intravitreous injections of 0.3 mg/eye pegaptanib 
sodium every 6 weeks for 48 weeks. 
 
Other available therapy of the Investigator’s choice may be employed at the 
Investigator’s discretion for circumstances judged to be clinical deterioration, such as 
but not restricted to:  ≥ 2 line vision loss; retinal thickness at center point ≥ 300µm; an 
increase of retinal thickness at center point ≥ 100µm from baseline visit. 
Corneal Specular 
Microscopy 
Specular microscopy assessments of the corneal endothelium will be completed and 
compared individually for central cell density and cell characteristics changes 
(polymegathism and polymorphism) occurring from baseline.  All 10 targeted clinical 
sites will perform corneal specular microscopy assessments on a total of 
approximately 125 enrolled subjects. Both contact and non-contact microscopes are 
permitted, but consistency throughout the entire study is required (same method must 
be used for each subject throughout the study).  Corneal specular microscopy 
examinations must be performed at Baseline and at Weeks 24 and 54 or early 
withdrawal.  All examinations that are collected for the study must be sent to Central 
Image Analysis Reading Center (CIARC, Cleveland, OH)   within 3 days of 
collection.  For complete procedures for specular microscopy of the corneal 
endothelium and data transfer, please refer to the Corneal Specular Microscopy 
Instruction Manual. 




Valeant Pharmaceuticals  
Protocol  EOP 1024 - Confidential 
                Page 10 of 36   
Date: September 26, 2018 
4.0 INTRODUCTION 
4.1 
Background 
The objective of this study will be to assess the effects of intravitreal injections of 
Macugen® (pegaptanib sodium injection) administered every 6 weeks for 48 weeks on the 
corneal endothelium.  Macugen (pegaptanib sodium injection) is the first anti-VEGF 
inhibitor approved by the FDA for the treatment of wet AMD. Extensive research has 
been conducted on Macugen (pegaptanib sodium injection) and it has been shown to be 
effective at slowing vision loss in patients with such condition.  Macugen
 (pegaptanib 
sodium injection) has been studied in phase 2 and phase 3 trials in several other retinal 
ophthalmic diseases in which VEGF plays a major role, including Age-related macular 
degeneration (AMD) Diabetic Macular Edema (DME), Branched Retinal Vein Occlusion 
(BRVO) and Central Retinal Vein Occlusion (CRVO).   
Age-related macular degeneration (AMD) is a disease characterized by progressive 
degenerative abnormalities in the macula of the eye, a small area in the central portion of 
the retina.  Age-related macular degeneration is classified into one of two general 
subgroups; the non-neovascular (non-exudative or wet) form of the disease and the 
neovascular (exudative) 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 [1, 2]. By contrast, neovascular 
AMD, although less prevalent, more 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, 4].  The neovascular form of the disease is responsible for the majority of cases 
of severe vision loss.  This type of AMD results when abnormal blood vessels proliferate 
under and/or within the retina.  These blood vessels leak blood and fluid into the retina, 
which results in vision loss.  The natural history of AMD is that of scarring with 
progressive destruction of the central retina.   
Diabetic Macular Edema (DME) can occur with either non-proliferative diabetic 
retinopathy (NPDR) or proliferative diabetic retinopathy (PDR) and is the most common 
cause of diabetic-related visual acuity impairment.  Laser photocoagulation or other 
surgical modalities can help reduce the risk of moderate (3 or more lines) or severe 
(<20/800) distance visual acuity loss.  Panretinal photocoagulation (or scatter laser 
therapy) is the standard treatment for patients with high risk PDR or patients approaching 
high risk PDR.  Clinically, DME is defined as retinal thickness within 2 disc diameters of 
the center of the macula, with or without lipid exudates, and with or without cystoids 
features.  Clinically significant macular edema (CSME) is defined as having one or more 
of the following features: retinal thickness within 500 µm from the center of the macula; 
hard exudates within 500 µm of the center of the macula with adjacent retinal thickness; 
retinal thickness of at least 1 disc area of which at least 1 part is within 1 disc diameter of 
the center of the macula.  Hence, patients with CSME have maculopathy that threatens or 
affects the center of the macula. 
Retinal Vein Occlusion (RVO), either BRVO or CRVO, is the second leading cause of 
blindness (among vascular disorders) after diabetic retinopathy [5].   The estimated 
annual incidence of RVO is 160,000 cases in the United States and RVO prevalence is 
much higher, especially in the population over 65 years of age [5, 6]. Blindness from 
RVO can develop over a long period or occur suddenly.  RVO occurs when a blood clot 
or other substances, such as fat or plaque, obstruct the normal blood flow in a retinal vein.  
Consequently, during the occlusive event different pathophysiologic mechanisms 
including over expression of VEGF lead to different degrees of macular edema and 


Valeant Pharmaceuticals  
Protocol  EOP 1024 - Confidential 
                Page 11 of 36   
Date: September 26, 2018 
ischemia.  Visual loss may result from chronic macular edema, macular ischemia or 
ocular neovascularization 
4.2 
Macugen (pegaptanib sodium injection) (Formerly EYE001 and NX1838) 
Macugen
 (pegaptanib sodium injection) is composed of 28 nucleotide bases, containing 
2’F-substituted pyrimidines and 2’O-methyl-substituted purines, with the exception of 
two 2’OH adenosines.  One molecule of ~40,000 dalton molecular weight polyethylene 
glycol (40kD PEG) is attached to the 5’ end of the oligonucleotide.  The 3’ end is capped 
with an inverted thymidine.  Pegylated pegaptanib has a molecular weight of 
approximately 50,000 daltons and is roughly one-third the size of an IgG molecule.  
Pegaptanib selectively binds VEGF165, which is the most abundant isoform of VEGF and 
is the isoform associated with pathological ocular neovascularization, with high 
specificity and affinity (K
d approximately 80 pM).  
4.2.1 
Pre-Clinical Efficacy 
The preclinical data demonstrating the anti-angiogenic properties of pegaptanib are 
described in detail in the Investigator Brochure (IB).   
4.2.2 
Intravitreous Pharmacokinetics of Pegaptanib 
Single and repeat dose pharmacokinetic studies in both the rabbit and monkey are 
described in full in the Investigator Brochure (IB) for pegaptanib.  While there are 
some differences in the pharmacokinetic parameters of pegaptanib among species, 
vitreous concentrations of pegaptanib after intravitreous injections are consistently and 
substantially higher than plasma concentrations by at least several hundred-fold.  Thus, 
after intravitreous injections, there is a low systemic exposure to pegaptanib compared 
to that seen in the vitreous.  Of note, vitreous concentrations appear to remain 
sufficiently high to allow a dosing interval of 6 weeks. 
4.2.3 
Toxicology 
Studies to evaluate the potential toxicity of pegaptanib include evaluations of 
genotoxicity, immunogenicity, acute toxicity, and sub-chronic toxicity.  Studies were 
conducted in accordance with GLP and ICH guidelines. 
4.3 
Clinical Data 
4.3.1 
Clinical Summary of Phase 1 & 2 Safety, and Phase 2/3 Pivotal Studies 
In a dose-finding Phase 1 study (NX109-01) described in the IB, pegaptanib sodium 
was given to 15 subjects as single doses ranging from 0.25 mg/eye (6.9 mM) to 3 
mg/eye (110 mM) [7].  Due to increasing viscosity with increasing dose, 3 mg is the 
maximal dose that can be given in an acceptable volume (0.1ml) for intravitreous 
injection with the current formulation. In addition, three repeat doses (4 weeks apart) 
of 3 mg/eye were given to a total of 21 subjects in two phase 2 studies,  EOP1000B and 
EOP1001 [7].There were no local dose-limiting toxicities observed and no systemic 
toxicity attributed to pegaptanib sodium in any of the three studies.  Approximately 
30% of the subjects exhibited a three, or more, line improvement 3 months after 
starting treatment. 
4.3.1.1 Macugen for Exudative (Wet) Age-Related Macular Degeneration (AMD) 
A phase 2 dose-ranging study (EOP1009), including a sham treatment cohort, was 
conducted with 137 subjects with AMD.  Pegaptanib intraviteous injections of 0.3 mg 


Valeant Pharmaceuticals  
Protocol  EOP 1024 - Confidential 
                Page 12 of 36   
Date: September 26, 2018 
or 1.0 mg were completed with subjects for a 12-week period (3 injections) and a 
subsequent 24-week periods (5 injections).  There was no evidence of specific 
systemic safety concerns, and one SAE (endophthalmitis) considered related to the 
injection procedure.  The most commonly reported adverse events in the study eye 
were eye pain and punctate keratitis.  Small increases in mean intraocular pressure 
(IOP) were transient after injections and returned to baseline levels within 1 week of 
injection.  There were no findings in relation to laboratory test results or ECG results 
suggestive of a relationship to pegaptanib sodium treatment. 
Two Phase 2/3 randomized, double-masked, controlled, multi-center, comparative 
studies (EOP1003 and EOP1004) were done to establish the safety and efficacy of 
intravitreous injections of pegaptanib sodium (0.3, 1 or 3 mg) as compared to sham 
injection given every 6 weeks for 54 weeks, in patients with exudative (wet) age-
related macular degeneration [8, 9].     
A total of 1,200 subjects with wet AMD were randomized for enrollment in studies 
EOP1003 and EOP1004 and a total of 1,190 of these subjects provided safety data.    
Data from the first year of these studies demonstrates that pegaptanib sodium was well 
tolerated. More than 10,000 intravitreous or sham injections have been administered 
with 25% of subjects receiving a sham injection.  A total of 7,545 intravitreous 
injections of pegaptanib sodium (0.3, 1 or 3 mg) have been administered during the 
first year of these two studies. The mean number of injections per subject during the 
studies ranged from 8.4 to 8.6 of a possible 9 total injections.  The median age of 
subjects participating in EOP1003 and EOP1004 was 77 years.   
In the combined analysis, all pegaptanib sodium doses tested demonstrated statistically 
significant efficacy compared with control for the clinically relevant primary efficacy 
endpoint of the proportion of subjects losing less than 15 letters of VA up to 54 weeks.  
Pegaptanib sodium activity was observed at the 6-week post-injection visit and was 
sustained throughout the year.  There was no evidence to suggest that the overall effect 
was derived from any one subject subgroup (e.g., baseline visual acuity, lesion subtype, 
lesion size, or prior treatment with PDT).  Mean visual acuity loss at 1 year was 
reduced in approximately 50% compared to usual care.  In the second year, subjects 
were re-randomized to either continue or discontinue masked therapy for 48 more 
weeks.  The data revealed that the treatment benefit continued throughout the second 
year of pegaptanib sodium therapy as compared to usual care controls.  During the 
second year, subjects receiving continued pegaptanib (pegaptanib sodium injection) 
0.3mg were less likely to experience a 15-letter loss compared with subjects 
discontinuing treatment after 1 year.  Fifty nine percent (59%) of the subjects receiving 
pegaptanib (pegaptanib sodium injection) 0.3mg for two years lost less than 15 letters 
of VA at week 102 compared to 45% of the subjects who continued in the usual care 
group for two years 
Overall, adverse events (AE) in the first year were reported in similar percentages of 
pegaptanib sodium and sham treated subjects (96% and 95% respectively). The most 
frequent adverse events were ocular in nature and mild to moderate in severity. The 
majority of ocular events were attributed by Investigators of the injection procedure, 
not to pegaptanib sodium. Overall, 92% of pegaptanib sodium and 87% of sham 
treated subjects experienced one or more ocular events.  
Ocular adverse events (i.e., eye pain, vitreous floaters, punctate keratitis, cataract, 
vitreous opacities, anterior chamber inflammation, visual disturbance and corneal 
edema) were reported in the study eye in 10% or more of pegaptanib sodium treated 
subjects.  This is comparable with ocular adverse events reported for sham treated 
subjects. When these most frequent ocular events were analyzed by study and fellow 


Valeant Pharmaceuticals  
Protocol  EOP 1024 - Confidential 
                Page 13 of 36   
Date: September 26, 2018 
eye, it was noted that these events were reported in a higher proportion of subjects in 
the sham study eye than in the fellow eye for all treatment arms.  This suggests that 
some of these events were related to the pre-injection preparation procedure (i.e., 
eyelid speculum, anesthetic drops, mydriatic drops, antibiotic drops, povidone-iodine 
drops or flush, and subconjunctival injection of anesthetic), rather than the 
intravitreous injection alone. 
As would be anticipated with intravitreous injections, transient increases in intraocular 
pressure were noted immediately following intravitreous injection. However, in most 
of the subjects (90%), IOP values 30 minutes post-injection were less than 35 mmHg. 
Further, mean values for IOP returned to baseline or near baseline levels within one 
week of injection. There was no evidence of a persistent increase in IOP after one year 
of treatment. 
Most serious non-ocular adverse events were those that would be expected in this very 
elderly subject population. A relatively small percentage of subjects (2%) in both 
pegaptanib sodium and sham treatment groups discontinued treatment because of 
adverse events in the first year. The percentages of subjects who died during the course 
of treatment were the same (2%) in pegaptanib sodium and sham treated subjects. 
There were few injection-related serious adverse events (SAE).  These included 
endophthalmitis, occurring in 12 pegaptanib sodium subjects (0.16% per injection) in 
the first year.  Nine of these subjects continued in the study and only one developed 
severe visual acuity loss (≥ 6 line loss, ETDRS) at 54 weeks.  Iatrogenic traumatic 
cataract occurred in 5 pegaptanib sodium subjects (0.07% per injection), and retinal 
detachment occurred in 6 pegaptanib sodium subjects (0.08% per injection).  Four of 
the retinal detachments were rhegmatogenous; two were exudative and thought to be 
related to underlying AMD.   
No new systemic or ocular safety concerns were identified in the second or third year 
of treatment, third year subjects agreeing to participate in an extension cohort. There 
were 4 cases of endophthalmitis (0.1% per injection), one case of traumatic cataract 
(0.02% per injection), and 7 cases of retinal detachment (0.17% per injection; 6 
rhegmatogenous and 1 exudative in nature) by the end of the third year. 
A three year phase 2 dose-ranging study (EOP1006) of Macugen (pegaptanib sodium 
injection) given as 1 mg/eye or 3 mg/eye intravitreal injections given every 6 weeks for 
54 weeks to patients with wet AMD was conducted at 24 clinical sites in the US.  
These doses were chosen as the lowest efficacious doses from studies EOP1003 and 
EOP1004.  Safety was assessed by adverse event reporting, ophthalmic examination, 
tonometry, clinical laboratory tests, electrocardiograms (ECG), vital signs, and ≥ 20-
letter loss of visual acuity (VA) between 2 consecutive visits.  Safety endpoints 
included all adverse events and serious adverse events, all laboratory data, intraocular 
pressure (IOP) measurements, vital signs, ECGs, and vision loss of 20 letters or more 
between injections. 
Efficacy was not planned to be assessed in the first year of the study, but VA and 
fluorescein angiography assessments were performed and were reported as exploratory 
data.  VA endpoints were mean visual acuity over time and change in visual acuity 
prior to every injection from baseline to 156 weeks.  Pharmacodynamics endpoints 
were change in total lesion size in disc areas from baseline to 156 weeks, change in 
CNV size in disc areas from baseline to 156 weeks, and change in CNV leak size in 
disc areas from baseline to 156 weeks. 
Studies A5751010 and A5751015 were multicenter studies conducted in Japan for 
patients with AMD.  A total of 95 subjects were enrolled in this study and received 
intravitreal injections of pegaptanib sodium 0.3 mg or 1 mg/eye once every 6 weeks for 


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Date: September 26, 2018 
54 weeks. Protocol A5751015 was a multicenter, open label, extension study from 
protocol A5751010. A total of 61 subjects were continuously received intravitreal 
injections of pegaptanib sodium 0.3 mg/eye once every 6 weeks for a maximum of 144 
weeks.  The most common treatment-related adverse events were anterior chamber 
inflammation (0.3 mg 4.3%, 1 mg 6.3%), corneal oedema (0.3 mg 6.4%, 1 mg 4.2%) 
with protocol A5751010, and retinal haemorrhage (4.9%), anterior chamber 
inflammation (3.3%) with protocol A5751015.  There were no consistent trends 
considered to be treatment-related changes in laboratory values, and IOP increases 
were transient. 
Study EOP 1023[10] , was designed primarily to explore the safety and efficacy of 
intravitreous injections of Macugen
 (pegaptanib sodium injection) when given every 
6 weeks for 48 weeks in subjects with exudative maculopathy secondary to 
neovascular AMD who, after previous treatment regimen, have improved based upon 
clinical and anatomical (OCT) findings as determined by the Investigator.  A total of 
568 subjects were included in the study.  The mean visual acuity over time using last 
observation carried forward (LOCF) data showed a 3.7-letter loss from baseline to 
week 54.  After 54 weeks of maintenance therapy with Macugen® (pegaptanib sodium 
injection), 52% of subjects did not receive any additional treatment other than 
Macugen(pegaptanib sodium injection).  Of those who did receive additional 
treatment, 46% required only one additional treatment.    Safety profile is consistent 
with phase 2/3 pivotal studies.  The most frequently reported treatment emergent 
adverse events by system organ class are eye disorders (58%), infections and 
infestations (28%), gastrointestinal disorders (13%), investigations (13%), 
musculoskeletal and connective tissue disorders (12%), and nervous system disorders 
(11%).   The most frequently reported treatment emergent adverse events (high-level 
term) were punctate keratitis (13%), eye pain (11%), vitreous floaters (11%), macular 
degeneration (9%), intraocular pressure increased (9%), and hypertension (8%). 
4.3.1.2 Macugen for Treatment of Diabetic Macular Edema (DME) 
EOP1002 was an open label study of intravitreal injections of 3 mg pegaptanib 
sodium/eye every 6 weeks for up to 36 weeks in ten (10) patients with diabetic macular 
edema (DME).  No dose limiting toxicities were reported and there were no premature 
withdrawals from the EOP1002 study due to treatment-related AEs.   A total of 69 AEs 
were reported, 29 of which were considered treatment related.  Treatment-related AEs 
were mostly (28/29 reports) due to the injection procedure.  There were 5 SAEs 
experienced by two subjects, with one subject dying 26 days after the last injection of 
study treatment due to multisystem organ failure and pneumonia.  None of the SAEs 
was considered treatment-related.  
A phase 2 dose-ranging study, EOP1005 was conducted to evaluate safety and efficacy 
of Macugen (pegaptanib sodium injection) in the treatment of diabetic macular edema 
(DME) [11]. This was a randomized, double-masked, multicenter, dose-ranging, 
controlled trial.  Intravitreous pegaptanib sodium (0.3 mg, 1 mg, 3 mg) or sham 
injections were given at study entry, week 6, and week 12 with additional injections 
and/or focal photocoagulation as needed for another 18 weeks. Final assessments were 
conducted at week 36.  A total of 172 subjects were enrolled. Median VA was better at 
week 36 with pegaptanib sodium 0.3 mg (20/50), as compared with sham (20/63) (P = 
0.04).  A larger proportion of those receiving 0.3 mg gained VAs of ≥10 letters 
(approximately 2 lines) (34% vs. 10%, P = 0.003) and ≥15 letters (18% vs. 7%, P = 
0.12).  The results of this exploratory Phase 2 study did not identify any safety 
concerns for the treatment of patients with DME. Pegaptanib sodium was generally 
well tolerated. The safety profile in this study appears similar to that established in the 


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Date: September 26, 2018 
age-related macular degeneration (AMD) indication, with additional findings 
consistent with what would be anticipated in a diabetic population. 
A subsequent phase 2/3 study [EOP1013] was conducted to confirm the safety and 
compare the efficacy of intravitreal Macugen® (pegaptanib sodium injection) 0.3 mg 
versus sham injections in subjects with DME [12].  This was a 2 year study, with 260 
(pegaptanib, n = 133; sham, n = 127) and 207 (pegaptanib, n = 107; sham, n = 100) 
subjects included in years 1 and 2 intent-to-treat analyses, respectively.  Change in 
mean visual acuity from baseline for pegaptanib sodium was superior to sham injection 
(P < 0.05) at weeks 6, 24, 30, 36, 42, 54, 78, 84, 90, 96, and 102.  Additionally 
pegaptanib-treated subjects gained 6.1 letters on average at week 102 compared to 1.3 
letters for sham injection.  Pegaptanib was well tolerated, with frequencies of adverse 
events, treatment-related adverse events, and serious adverse events comparable in 
both treatment groups. 
The analysis of VA and fluorescein angiograms in the EOP1006 study showed a 
pettern of greater vision loss during the first year of the study followed by a degree of 
stabilization.  Macugen® was generally well tolerated, with AEs predominantly ocular 
in nature, mild, and predictable.  The most frequently o9ccurring ophthalmic adverse 
events during Yeats 2 and 3 were punctate keratitis, vitreous floaters, and eye pain.  
Four subjects experienced ophthalmic SAEs during Years 2 and 3, including 3 reports 
of endophthalmiitis (related to the injection procedure).   No generalized systemic 
safety concerns were observed, as most events other than eye disorders were infrequent 
and of the types often seen in an elderly population. 
4.3.1.3 Macugen for Treatment of Central Retinal Vein Occlusion (CRVO) 
The phase 2 study, EOP 1011 assessed the safety and efficacy of intravitreous 
pegaptanib sodium for the treatment of macular edema following central retinal vein 
occlusion (CRVO).  This was a dose-ranging, double-masked, multicenter trial 
including subjects with CRVO for 6 month or less duration randomly assigned (1:1:1) 
to receive pegaptanib sodium or sham injections every 6 weeks for 24 weeks (0.3 mg 
and 1 mg, n=33; sham, n=32).  In the primary analysis at week 30, 12 of 33 (36%) 
subjects treated with 0.3 mg of pegaptanib sodium and 13 of 33 (39%) treated with 1 
mg of pegaptanib sodium gained 15 or more letters from baseline vs. 9 of 32 (28%) 
sham treated subjects (P=.48 for 0.3 mg and P=.35 for 1 mg of pegaptanib sodium vs. 
sham). In secondary analyses, subjects treated with pegaptanib sodium were less likely 
to lose 15 or more letters (9% and 6%; 0.3-mg and 1-mg pegaptanib sodium groups, 
respectively) compared with sham-treated eyes (31%; P=.03 for 0.3 mg and P=.01 for 
1 mg of pegaptanib sodium vs. sham).  Pegaptanib sodium was generally well tolerated.  
AEs were predominantly ocular in nature, mild and predictable. No new safety 
concerns were detected [13].    
4.3.1.4 Macugen for Treatment of Branched Retinal Vein Occlusion (BRVO) 
Twenty subjects from three clinical practices in the US with BRVO of 1-6 months 
duration and central foveal thickness of 250 μm or more were included in this study.  
Subjects were randomized 3:1 to intravitreous injections of Macugen (pegaptanib 
sodium) 0.3 or 1.0 mg at baseline and at weeks 6 and 12 with subsequent injections at 
6-week intervals at investigator discretion until week 48.  Fifteen (15) subjects 
received 0.3 mg Macugen and Five (5) subjects received 1.0 mg Macugen.  The 
majority of subjects completed the 54-week follow-up visit, and results were similar 
for both Macugen doses.  VA response was rapid after the first dose, with mean BCVA 
improvement of 11 ± 7 letters at 1 week from baseline.  There was one retinal 
detachment and no cases of endophthalmitis [14]. 


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Date: September 26, 2018 
 
4.4 
Corneal Endothelium and Clinical Specular Microscopy 
A specular microscope will be used to assess adverse effects of the corneal endothelium.  
Results will be compared individually for central cell density and cell characteristics 
changes (polymegathism and polymorphism) occurring from baseline.   
The corneal endothelium is the posterior layer of the cornea consisting of a single layer of 
cells, about 5 μm thick, bound together and predominantly hexagonal in shape. The 
posterior border is in direct contact with the aqueous humour while the anterior border is 
in contact with Descemet
's membrane. The endothelium is the structure responsible for 
the relative dehydration of the corneal stroma. The endothelium receives most of its 
energy from the oxidative breakdown of carbohydrates via the Krebs cycle. In the normal 
adult eye the cell density varies from around 3000 cells/mm
2 in the centre of the cornea to 
about 2000 cells/mm
2 in the periphery. With age, disease or trauma the density of cells 
decreases but with disease or trauma this reduction may affect corneal transparency, as 
some fluid then leaks into the cornea. 
The corneal endothelial cells do not replicate in general. When destroyed by disease or 
surgery, the remaining cells enlarge and spread out to cover the posterior corneal surface, 
thus decreasing the cell density (cell count). Corneas with extremely low endothelial cell 
densities can no longer maintain a dehydrated state. The corneas may decompensate, 
swell, and become cloudy over time, with an associated loss of visual acuity. The 
specular microscope provides a magnified view of a small area of corneal endothelial 
cells to measure and record endothelial cell counts of the cornea. 
5.0 STUDY OBJECTIVE 
5.1 
Objective 
The objective of this study will be to assess the effect of intravitreal injections of 
Macugen® (pegaptanib sodium injection) administered every 6 weeks for 48 weeks on the 
corneal endothelium. 
 
6.0 INVESTIGATIONAL PLAN 
6.1 
Study Design  
This will be a Phase IV, open label, multi-center study.   Subjects will receive intravitreal 
injections of Macugen
® (pegaptanib sodium) every 6 weeks for 48 weeks.  Additional 
therapy may be employed at the Investigator’s discretion for circumstances judged to be 
deterioration.   The Investigator will decide which treatment to provide as additional 
therapy.   Macugen
 (pegaptanib sodium injection) injections should remain on the 6-
week schedule defined by the protocol even if an additional therapy is given.     
6.2 
Rationale 
Due to the lack of information generated in the pivotal phase III trials assessing potential 
effects of intravitreal injections of Macugen
® on the corneal endothelium, the FDA 
requested clinical information from a 1-year (minimum) clinical study to support that 
there are no adverse effects on the corneal endothelium following intravitreal injections 
of Macugen®.   


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Date: September 26, 2018 
6.3 
Eligibility Criteria 
6.3.1 
Inclusion Criteria 
6.3.1.1 Ophthalmic Criteria 
6.3.1.1.1 
Subjects of either gender aged ≥ 50 years diagnosed with subfoveal neovascular 
Age-Related Macular Degeneration (AMD), Diabetic Macular Edema (DME) or 
Retinal Vein Occlusion (RVO)  
6.3.1.1.2 
Best corrected visual acuity in the study eye between 85 and 20 ETDRS letters or 
between 20/20 and 20/400 using a Snellen chart 
6.3.1.2 General Criteria 
6.3.1.2.1 
Women must be using two forms of effective contraception, be post-menopausal 
for at least 12 months prior to study entry, or surgically sterile; if of child-bearing 
potential, a urine pregnancy test must be performed within 7 days prior to the first 
injection with a negative result.  If the test is positive, a serum test must be done to 
confirm.  The two forms of effective contraception must be implemented during 
the study and for at least 60 days following the last dose of test medication. 
6.3.1.2.2 
Provide written informed consent. 
6.3.1.2.3 
Ability to return for all study visits. 
6.3.2 
Exclusion Criteria 
Subjects will not be eligible for the study if subjects cannot attend all study-required 
visits, or if any of the following criteria are present 


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Date: September 26, 2018 
6.3.2.1 
Unilateral ocular blunt trauma within one year of enrollment and no greater than 5% 
difference in central endothelial cell density between the 2 eyes 
6.3.2.2 
intraocular surgery (cataract surgery and surgery for glaucoma without tube shunt or 
mini-shunt) within one year of enrollment 
6.3.2.3 
Anterior segment laser surgery (laser trabeculoplasty) performed within one year of 
enrollment 
6.3.2.4 
Glaucoma tube-shunt surgery 
6.3.2.5 
Previous history of corneal transplant in the study or non-study eye. 
6.3.2.6 
Presence of vitreous macular traction 
6.3.2.7 
Previous therapeutic radiation in the region of the study eye. 
6.3.2.8 
Any treatment with an investigational agent in the past 30 days for any  condition. 
6.3.2.9 
Known serious allergies to the components of pegaptanib sodium formulation 
6.3.2.10 Any of the following underlying diseases including: 
6.3.2.10.1  
History or evidence of severe cardiac disease (e.g., NYHA Functional 
Class III or IV - see Appendix 2), clinical or medical history of unstable angina, 
acute coronary syndrome, myocardial infarction or revascularization within 6 
months, ventricular tachyarrythmias requiring ongoing treatment. 
6.3.2.10.2  
History or evidence of clinically significant peripheral vascular disease, 
such as intermittent claudication or prior amputation. 
6.3.2.10.3  
History or evidence of clinically significant impaired renal or hepatic 
function 
6.3.2.10.4  
Stroke (within 12 months of study entry). 
6.3.2.10.5  
Any major surgical procedure within one month of study entry. 
6.3.2.11 Significant media opacities, including cataract, which might interfere with visual 
acuity, or assessment of toxicity.  Subjects should not be entered if there is likelihood 
that they will require cataract or glaucoma surgery in either eye during the study 
treatment and follow-up period. 
7.0 STUDY MEDICATION 
7.1 
Investigational Drug Supply 
Bausch Health will provide study drug to the sites. The drug provided will be specifically 
labeled as clinical trial materials for this study, utilizing a label on both the primary foil 
pouch and the carton. The carton will be closed and secured with tamper evident tape. 
 
Pegaptanib sodium drug substance is a pegylated (40 kDa branched PEG molecule 
consisting of two 20 kDa PEG arms) anti-VEGF aptamer.  It is formulated in phosphate 


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Date: September 26, 2018 
buffered saline at pH 6-7.  Sodium hydroxide or hydrochloric acid may be added for pH 
adjustment. 
 
The drug product is supplied in a sterile foil pouch as a single-use glass pre-filled syringe.  
After proper preparation, the syringe will contain 0.3mg of Macugen® in a nominal 90µL 
deliverable volume pack.  A sterile packaged BD
® single use 30G X ½” Precision Glide
® 
Luer Lok
® needle is supplied in a separate pouch.  The foil pouch and needle are 
packaged together in a carton. For a full description of the drug product, please review 
the package insert located in Appendix 1. 
 
Active Ingredient: 
Pegaptanib Sodium Injection formulated as: 
 
3.47mg/mL solution to deliver a dose of 0.3mg pegaptanib sodium 
injection 
 
 
Excipients: 
Sodium Chloride, USP 
 
Sodium Phosphate Monobasic, Monohydrate, USP 
 
Sodium Phosphate Dibasic, Heptahydrate, USP 
 
Sodium Hydroxide, USP (as needed) 
 
Hydrochloric acid, USP (as needed) 
Water for injection, USP 
7.2 
Dose and Administration 
7.2.1 
Preparation 
The drug product, pegaptanib sodium, is a ready-to-use sterile solution provided in a 
single-use glass syringe. Ensure that the drug to be administered is labeled specifically 
for this study. Preparation of the syringe for drug administration includes the following 
steps (see Appendix 1 for more details): 
1. Remove the syringe from the plastic clip. 
2. Twist off cap.  
3. Attach the sterile administration needle (included) to the syringe by screwing it 
into the syringe tip. Another sterile administration needle may be used in lieu 
of the one included.  Remove the plastic needle shield from the needle.  
4. Holding the syringe with the needle pointing up, check the syringe for bubbles. 
If there are bubbles, gently tap the syringe with your finger until the bubbles 
rise to the top of the syringe. SLOWLY depress the plunger rod to eliminate all 
the bubbles and to expel the excess drug so that the top edge of the 3rd rib on 
the plunger aligns with the pre-printed black dosing line. 
5. Inject the entire contents of the syringe. 
7.2.2 
Treatment Regimen and Duration 
Pegaptanib sodium will be administered as 90l (nominal delivered volume) 
intravitreous injections every 6 weeks from Day 0 to Week 48 as described in Section 
3, Study Flow Chart.  


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7.2.3 
Administration of Study Drug and Controls 
The method for intravitreous administration of pegaptanib sodium is described in  
Appendix 1.  
7.2.4 
Stability of Final Solution 
The drug product should be used without further dilution.  Expiration dating will be 
based on available stability information and will not exceed what is approved for the 
commercial product. 
7.2.5 
Storage of Drug product 
The Investigator, or an approved representative (e.g. pharmacist), will be using the 
drug supplied by Valeant Pharmaceuticals NA.  The Investigator or representative will 
be asked to document treatments given to each patient during each visit.  The drug will 
be stored in a secured area, under recommended storage conditions and in accordance 
with applicable regulatory requirements. The pegaptanib sodium is to be stored under 
standard refrigeration conditions (2-8C; 36-46F) and not frozen.   
7.3 
Previous or Concomitant Medications and Restrictions 
Any treatment with any investigational agent for any condition in the past 30 days is not 
permitted.  Additional therapy during the study, with a therapy of the Investigator’s 
choosing (except Macugen
), may be employed at the Investigator’s discretion for 
circumstances judged to be clinical deterioration, such as but not restricted to: ≥2 line 
vision loss; retinal thickness at center point > 300 µm; an increase in retinal thickness of 
100µm from baseline visit.   Additional treatment of a non-VEGF agent may be given on 
any day the Investigator prefers.  It is recommended that additional treatment with 
another VEGF agent should be given at least 3-weeks after a Macugen
  (pegaptanib 
sodium injection)
 injection unless the Investigator does not feel this is in the best interest 
of the subject.    
8.0 STUDY CONDUCT 
8.1 
Study Evaluations 
Written informed consent must be obtained before any of the Baseline procedures listed 
below are performed.  An explanation of the study 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 study.  
The following assessments will be performed at Baseline and during the treatment and 
follow-up periods.  All visits for injections must occur within +/- 14 days of the schedule. 
8.1.1 
Baseline Visit 
The following Baseline evaluations, as outlined in the Study Flow Chart (see Section 
3), will be performed within 7 days prior to receiving Macugen (Pegaptanib Sodium 
injection).  Baseline assessments can be broken into 2 days if necessary.   If all 
screening is completed during the baseline visit, DAY 0 assessments may be done on 
the same day. 


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Date: September 26, 2018 
 Informed consent 
 Medical history 
 Ophthalmologic/AMD history 
 Urine pregnancy test within 7 days of first injection (if applicable) 
 Concomitant Medication Assessment and Serious Adverse Events 
8.1.2 
Day 0 
The following assessments will be performed at the Day 0 Visit.  
 Macugen (Pegaptanib Sodium injection) administration 
 Corneal Specular Microscopy (Both eyes).  Send results to CIARC  
 Concomitant Medication Assessment and Adverse Events 
 
8.1.3 
Week 6, Week 12, Week 18, Week 30, Week 36, Week 42, Week 48 
The following assessments will be performed at the Visit: 
 Macugen (Pegaptanib Sodium injection) administration 
 Concomitant Medication Assessment and Adverse Events 
 
8.1.4 
Week 24 
The following assessments will be performed at the Visit: 
 Macugen (Pegaptanib Sodium injection) administration 
 Corneal Specular Microscopy (Both eyes).  Send results to CIARC   
 Concomitant Medication Assessment and Adverse Events 
8.1.5 
Week 54 
The following assessments will be performed at the Visit: 
 Corneal Specular Microscopy (Both Eyes).  Send results to CIARC  
 Concomitant Medication Assessment and Adverse Events 
 
8.1.6 
Early Termination Visit 
Due to the critical nature of the corneal specular microscopy data set, any patient who 
discontinues from the study early outside of a scheduled clinic visit, the study doctor 
will need to notify the Sponsor for further instruction. The Sponsor should also be 
notified if a patient is not expected to complete the study.   
 
8.2 
Protocol Compliance and Violations 
The protocol must be read thoroughly and the instructions should be followed exactly. 
Either the Sponsor or the Investigator without agreement by both parties will not 
implement modifications to the study protocol. However, the Investigator may implement 
a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to the 
study subjects without prior IRB/Sponsor approval/favorable opinion. As soon as 


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possible, the implemented deviation or change, the reasons for it and, if appropriate, the 
proposed protocol amendment should be submitted to the IRB/Sponsor.  Significant 
protocol deviations or violations may require that the subject be withdrawn from the 
study. The Investigator is responsible for notifying the IRB of all protocol deviations or 
violations. 
8.3 
Subject Discontinuation 
Subjects have the right to withdraw from the study at any time for any reason.  The 
Investigator (after consultation with the Sponsor) or Sponsor also have the right to 
withdraw subjects from the study in the event of concurrent illness, adverse events, 
treatment-failure after a prescribed procedure, protocol violations, cure, administrative or 
other reasons.  Every reasonable attempt should be made to encourage the subject to 
return at Week 54 for evaluation. 
Final study assessments as outlined in the Study Flow 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.   
8.4 
Study Discontinuation 
The reason for a subject discontinuing from the study will be recorded in the case report 
form.  A discontinuation occurs when an enrolled subject ceases participation in the study, 
regardless of the circumstances, prior to completion of the protocol.  The Investigator 
must determine the primary reason for discontinuation.  A discontinuation must be 
reported immediately to the Sponsor or his/her designated representative if it is due to a 
serious adverse event (SAE) (see Section 11).  The final evaluation required by the 
protocol will be performed at the time of study discontinuation.  The Investigator will 
record the reason for study 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 study may occur because of a regulatory authority 
decision, change in opinion of the IRB/EC, product or procedure safety problems, or at 
the discretion of the Sponsor. 
9.0 OUTCOME MEASURES 
9.1 
Safety Measurements and Endpoints 
9.1.1 
Corneal Specular Microscopy 
A post marketing study commitment was made to the FDA stating that the sponsor 
would, “provide clinical information from a 1-year (minimum) clinical study to 
support that there are no adverse effects on the corneal endothelium following the 
intravitreal administration of Macugen
®.” Corneal specular microscopy data will be 
collected on an enrollment of approximately 125 subjects in order to fulfill the 
commitment made to the FDA. Assessments of specular microscopy of the corneal 
endothelium will be completed and compared individually for central cell density and 
cell characteristics changes (polymegathism and polymorphism) occurring from 
baseline. All 10 targeted clinical sites will perform Corneal Specular Microscopy 
assessments on approximately 125 enrolled subjects. Both contact and non-contact 
microscopes are permitted, but consistency throughout the entire study is required 


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Date: September 26, 2018 
(same method must be used for each subject at any given site). Corneal Specular 
Microscopy examinations must be performed at Baseline and at Weeks 24 and 54 or 
early withdrawal.     
The study sites will perform the corneal specular microscopy assessment in accordance 
with the protocol and the Corneal Specular Microscopy Instruction Manual. At 
baseline, Week 24, Week 54 or early withdrawal, the site will send all the data to 
CIARC within 3 days of collection. At the completion of the study, CIARC will 
perform a final analysis of the corneal specular microspy data. CIARC will calibrate 
and certify study site Specular Microscopes. For complete procedures for specular 
microscopy of the corneal endothelium, please refer to the Corneal Specular 
Microscopy Instruction Manual. 
9.2 
Efficacy Measurement and Endpoints 
This is a safety study and no primary efficacy endpoint is defined.  The effect on the 
corneal endothelium will be assessed by specular microscopy: Mean cell density loss 
from baseline over time and frequency distribution.   
 
10.0 STATISTICAL METHODS 
10.1 Determination of Sample Size 
In order to fulfill a commitment to FDA, at least 100 subjects will need to complete the 
study.  To achieve this number of completed subjects, approximately 125 subjects will be 
enrolled to account for possible early withdrawals.  
10.2 Methods of Analysis 
The objective of this study will be to assess the effect of intravitreal injections of 
Macugen® (pegaptanib sodium injection) administered every 6 weeks for 48 weeks on the 
corneal endothelium.  The primary analysis will be carried out when all subjects have 
reached their Week 54 assessment. 
10.2.1 General Statistical Methods 
Categorical data will be summarized using frequency tables, presenting the patient 
counts and the percentage of patients falling into the category.  McNemar’s chi-square 
may be used to assess within-subject change in a bivariate response variable. 
Confidence intervals will be constructed using traditional large-sample methodology. 
The SAS system will be used to perform all analyses. 
A final data analysis plan will be developed prior to locking the CRF database at the 
conclusion of the study.  The statistical plan will include mock-ups of all tables, 
listings, and figures to be included in a summary report, as well as documentation of 
all data derivations and statistical methods utilized, including any deviations from 
those described here. 
All statistical analyses will be performed by a statistical office independent of the study 
Sponsor.   
10.2.2 Safety Data Analysis 
The safety analysis will be conducted on all subjects who had at least one 
administration of the study drug.  Adverse events will be summarized using MedDRA 


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terms. The incidence and severity of adverse events will be listed and grouped by body 
system. 
Summary statistics will be given on the number of subjects for whom the study 
medication had to be reduced or permanently stopped. 
Safety endpoints are: 
 All adverse events reported, whether deemed related to treatment or not 
 All serious adverse events (SAE) reported, whether deemed related to treatment 
or not 
11.0 DRUG SAFETY 
11.1 Definition of Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a subject 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with the treatment. Therefore, any unfavorable, unintended and 
emergent medical sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study medication must be reported whether or not 
considered related. Furthermore, in addition to events not present prior to exposure, any 
event already present that worsens in intensity or frequency following exposure to study 
medication must also be reported. All AEs, whether or not they are considered related to 
the product or device are to be recorded in the subject’s medical record and the CRF.  
The definitions and terminology to be used during the study are those that reflect the 
International Conference on Harmonization (ICH E6 (R2)) of Technical Requirements 
for Registration of Pharmaceuticals for Human Use Guidelines for Good Clinical Practice 
(GCP). 
Each subject eye treated must be examined for the presence/absence of adverse events at 
all visits, whether scheduled or not.  If an adverse event occurs, the first concern will be 
the safety and welfare of the subject; treatment should be provided as appropriate for the 
event.  Depending on the severity and attribution of the event to the investigational 
device, FDA regulations and GCPs determine how incidences of safety events are to be 
recorded and/or reported during the study. 
11.1.1 Relationship of Adverse Events 
The assessment of the relationship of an AE to the administration of study procedure is 
a clinical decision based on all available information at the time of the completion of 
the CRF. In this study, adverse events will be assessed for their relationship to the 
study drug. 
 
The relationship to study treatment (administrative procedure or (drug)) will be 
assessed using the following definitions.  
Related 
= There is at least a reasonable possibility that the AE/SAE is 
related to the study drug. Reasonable possibility means that 
there is evidence to suggest a causal relationship between the 
drug and the AE. 


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Not 
Related  
=  There is little or no reasonable possibility that the AE/SAE is 
related to the study drug. This assessment implies that the 
AE/SAE has little or no temporal relationship to the study 
drug and/or a more likely or certain alternative etiology 
exists. 
Events may be attributed to either the administrative procedure of the protocol or the 
drug (and not both), or to neither. 
11.2 Severity  of Adverse Events 
The severity of all adverse events will be categorized as follows (see Appendix 2 for 
reference): 
 Mild: mild events are those that are easily tolerated with no disruption of normal 
daily activity. 
 Moderate: moderate events are those that cause sufficient discomfort to interfere 
with daily activity and/or require a simple dose medication. 
 Severe: severe events are those that incapacitate and prevent usual activity or 
require complex medication 
11.3 Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that results in any of 
the following outcomes and at any dose: 
 Death  
 Life-threatening situation (the subject was at risk of death at the time of the event. 
It does not refer to the hypothetical risk of death if the AE were more severe or 
were to progress) 
 Subject Hospitalization or prolongation of existing hospitalization 
 Persistent or significant disability or incapacity 
 Congenital anomaly or birth defect (any structural abnormality in subject 
offspring that occurs after intrauterine exposure to treatment) 
 Other medically important events (important medical events that may not result 
in death, be life threatening, or require hospitalization may be considered a 
serious adverse event when, based upon medical judgment, they may jeopardize 
the subject or may require intervention to prevent one of the outcomes listed 
above. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in subject hospitalization; or the development of 
drug dependency or drug abuse) 
11.4 Reporting of Adverse Events and Serious Adverse Events 
The Investigator will follow up on all AEs and SAEs observed or reported by the subject 
until resolution, stabilization, and loss to follow-up or until an adequate medical 
explanation is available, whether or not considered related to the study medication.   All 
serious adverse events must be reported with-in 24 hours of being aware of the event by 
faxing the Serious Adverse Event form to the number below.  Any SAE resulting in death 


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or was life threatening should be immediately telephoned to the Sponsor’s  medical 
monitor. The numbers below can be used for both phone and fax reporting. 
 
The contacts for reporting SAEs are: 
 
 
AND 
 
 
The vigilance team will notify the regulatory authorities within the required time frames 
for all serious adverse events subject to expedited reporting, either due to their nature 
(e.g., “serious”) or due to the significant, unexpected information they provide. 
It is the Investigator’s responsibility to notify the Institutional Review Board (IRB) of all 
serious adverse events occurring during the study that are likely to affect the safety of 
study subjects or conduct of the study. 
11.5 Exposure in Utero 
If any study subject becomes or is found to be pregnant while receiving study drug, the 
Investigator must inform the Sponsor/designee via a pregnancy report form.  This must 
be done irrespective of whether an adverse event has occurred and within 24 hours of 
awareness of the pregnancy.  If a pregnancy is associated with an SAE, a pregnancy 
report form along with a SAE from should be submitted to the Sponsor/designee. 
12.0 INVESTIGATOR RESPONSIBILITIES 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigator 
abide by all ethical principles originating from the Declaration of Helsinki, ICH 
guidelines, GCP guidelines, and in compliance with local and federal regulatory 
requirements.Informed Consent. 
Prior to participation in this study, the Investigator must fully explain to the subjects all 
aspects of the study that are relevant to the decision of participating in the study. The 
Informed Consent Form (ICF) is documented by means of a written, signed and dated 
consent form prior to the start of the study. The ICF must be written in a language and in 
a form understandable to the subject. The Investigator and/or site delegate will sign the 
ICF in conjunction with the subject. An ICF template will be provided to all study sites 
and any modifications to template must be submitted to the Sponsor or Sponsor 


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representative for approval prior to the implementation of the ICF, and prior to 
submission to the IRB/IEC or any changes requested by the IRB/IEC. 
A copy of the signed and dated ICF will be given to the subject and the Investigator in the 
study will file and retain the original signed and dated copy. The Investigator should 
clearly indicate the subject’s enrollment in a clinical study in the study medical chart. 
Institutions, Investigators, Contract Research Organizations, etc., under this Protocol 
shall abide by all requirements applicable to the use and disclosure of subjects’ protected 
health information (such as the requirements provided for under the Health Insurance 
Portability and Accountability Act (HIPAA), Hospital Trust and Regulatory authorities.) 
12.1 Ethics Review 
Documented approval from an appropriate IRB/IEC must be obtained for all participating 
sites prior to study start, according to GCP, local laws, regulations and organizations. 
When necessary, an extension, amendment or renewal of the IRB/IEC approval must be 
obtained and also forwarded to the Sponsor.  
Either the Investigator(s) or representatives of the Sponsor must submit progress reports 
to the IRB/IEC according to local regulations and guidelines. The Principal Investigator(s) 
must also provide the IRB/IEC with any reports of SAEs from the study site.  
12.2 Source Documents 
The Investigator must keep a written or electronic subject file for every subject 
participating in the study. This subject file should contain the available demographic and 
medical information of the subject, in particular the following: name, date of birth, sex, 
height, weight, subject history, concomitant diseases and concomitant medications 
(including changes during the study), statement of entry into the study, study 
identification, the date of informed consent, all study visit dates, predefined performed 
examinations and clinical findings, observed AEs (if applicable), and reason for 
withdrawal from the study if applicable. It should be possible to verify the inclusion and 
exclusion criteria for the study from the available data in this file.  
Any other documents with source data, especially original documents of data that were 
generated by technical equipment, have to be filed. All these documents have to bear at 
least the subject identification number and the printing date printed by the recording 
device, to indicate to which subject and to which study procedure the document belongs. 
All data are to be recorded directly onto the CRF.  
12.3 Training 
The record of all individuals involved in the study is to be maintained in the regulatory 
binder. The Principal Investigator will ensure that appropriate training relevant to the 
study is given to all the staff included in the study, and that they will receive any new 
information of relevance to the performance of this study.  
12.4 Study Agreements 
The Principal Investigator at each center must comply with all the terms, conditions and 
obligations of the agreements for this study. In the event of any inconsistency between 
this protocol and the study agreement, the study agreement will prevail.  


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12.5 Confidentiality 
The Investigators must agree to maintain the confidentiality of the study at all times and 
must not reveal information relating to the Investigator’s Brochure, protocol, CRF or 
associated documents to unauthorized third parties.  
13.0 STUDY MANAGEMENT 
13.1 Study Initiation Requirements 
The following documents must be available prior to the recruitment of the first subject 
into the study: 
 Signed protocol signature page 
 Completed and signed Confidentiality Agreement and Clinical Study Agreement, 
Including an agreed-upon study budget 
 Completed and signed FDA 1572 Form and Financial Certification/Disclosure 
 Forms for all personnel listed on the FDA 1572 Form signed and dated within 
two years of the site initiation, a curriculum vitae for all persons listed FDA 
Form 1572 as an Investigator or sub-Investigators, and their Medical Licenses 
 Copy of the IEC/IRB approval of the protocol and the Informed Consent Form 
approved by the IEC/IRB and appropriate local regulatory agencies 
 List of members of the IEC/IRB or an IRB Assurance Number, IEC members 
and Constitution 
 Laboratory licenses/certification/accreditation 
 Copy of the most recent Package Insert 
 Copy of national regulatory authority approval (e.g. FDA) 
 Copy of hospital NHS Trust R&D approval, where applicable. 
 
13.2 Monitoring, Verification of Data, Auditing and Inspection 
An appointed representative of the Sponsor will visit each site periodically to discuss the 
progress of the clinical study and review CRFs against original source documents with 
the study personnel, for accuracy of data recording, study product or device 
accountability and correspondence. The Principal Investigator is to ensure that subjects 
are aware of and consent that personal information may be reviewed during the data 
verification process as part of monitoring or auditing by properly authorized agents of the 
sponsor or subject to inspection by regulatory authorities. In addition, participation and 
personal information must be treated as strictly confidential to the extent the applicable 
law permits and not publicly available. Audits or inspections may include, for example, a 
review of all source documents, product or device records, and original clinic medical 
notes, at some or all of the facilities used in the study. 
13.3 Data Management 
Once the CRFs have been retrieved from the site, each individual CRF page will be data 
entered and pre-validated. The data will then be further validated to ensure that the forms 
were completed properly and that all responses met the standards set forth by the 
validation specifications. Any suspect data identified during the validation process will be 
sent to the site as a data query to be compared against source documentation for 
resolution. The query response will then be returned for resolution in the database. An 
electronic audit trail will document any changes to all the CRFs. Medical coding will be 
performed throughout the data cleaning process for required fields. 


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13.4 Study Drug Accountability 
The Investigator will be using the drug supplied by Valeant.  They will have a specific 
amount of study drug.  The Investigator or representative will be asked to record the 
amount given to each patient during each visit.  The Investigator will be responsible for 
the accountability of all used and unused study medication.   
13.5 Protocol Compliance 
The Sponsor will not compensate the Investigator for evaluation of cases in which the 
procedures and evaluations are conducted in a manner other than that specified by the 
protocol. 
Under certain circumstances, individual protocol criteria may be waived by the Sponsor 
and in agreement with the Investigator.  Any such waiver will be documented in writing 
and provided to the Investigator by the Sponsor. 
13.6 Ethical Aspects 
Local Regulations/Declaration of Helsinki 
The Investigator will ensure that this study 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, whichever affords the greater protection to the individual.  The 
study 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 a 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, subchapter D, part 312, 
“Responsibilities of Sponsors and Investigators”, part 50, “Protection of Human 
Subjects”, and part 56, “Institutional Review Boards”. 
13.7 Institutional Review Board (IRB) Approval and Informed Consent 
The Investigator is responsible for obtaining approval of the study protocol, informed 
consent, and any advertising used for subject recruitment from the appropriate IRB/EC 
prior to initiating the study.  The Investigator will forward the following documents prior 
to commencement of subject enrollment: 
 IRB/EC approval documentation 
 Approved study 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 Sponsors must be approved by the Sponsors before 
initiating enrollment. 
13.8 Record Retention 
All data derived from the study and all correspondence should be organized in the 
appropriate file folders. In compliance with the ICH guidelines, GCP, and federal, state 


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and local laws, regulations and guidelines, the Investigator will retain all essential records 
related to the study for at least two years after the last approval of a marketing application 
in an ICH region or until there are no pending or contemplated marketing applications, 
and for a longer period if required by federal, state and local laws, regulations and 
guidelines. To avoid any possible errors, the Investigator must contact the Sponsor prior 
to the destruction of any study records. If the Investigator moves or withdraws from an 
investigation, the responsibility for maintaining the records may be transferred to another 
person who will accept responsibility. Notice of transfer must be made and agreed by the 
Sponsor. 
13.9 Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted 
by the applicable laws and/or regulations, will not be made publicly available. Subject 
names will not be supplied to the sponsor.  Only the subject number and subject initials 
will be recorded in the CRF, and if the subject name appears on any other document (e.g. 
pathology report), it must be obliterated before a copy of the document is supplied to the 
sponsor. Study findings stored on a computer will be stored in accordance with local data 
protection laws. The subjects will be informed in writing that representatives of the 
sponsor ., IRB, or Regulatory Authorities may inspect their medical records to verify the 
information collected, and that all personal information made available for inspection will 
be handled in strictest confidence and in accordance with local data protection laws. 
If the results of the study are published, the subject’s identity will remain confidential. 
The Investigator will maintain a list to enable subjects’ records to be identified. 
13.10 Use of Data and Publication 
All data and results, and all intellectual property rights in the data and results, derived 
from the study will be the property of the Sponsor, who may utilize the data in various 
ways, including but not limited to submission to government regulatory authorities or 
disclosure to other Investigators. 
 
The results of this study shall not be published or communicated in any manner without 
the expressed written agreement of the Sponsor. Valeant Pharmaceuticals North America 
LLC  (Valeant) will require advance review of any publication, disclosure, presentation 
or any other communication of the data, results or any other aspect of the study including 
but not limited to the content and conclusions of any abstract, presentation or paper 
before consent for publication will be provided. This provision also applies to any 
amendments that are subsequently requested by the referees or journal editors. The 
Sponsor will undertake to comment on the draft documents within thirty days of receipt, 
but additional time for Sponsor review is recommended. If Valeant does not comment 
within the allocated time, disclosure is still prohibited unless Valeant consents to such 
disclosure in writing. In case of a difference of opinion between the Sponsor and the 
Investigator(s), the contents of the publication will be discussed in order to find a solution, 
which satisfies both parties. 
 


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14.0 REFERENCES 
1. Vingerling JR et al. Prevalence of age-related maculopathy in the Rotterdam trial.  
Ophthalmology 102:205-210, 1995.  
2. 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.  
3. Bressler NM.  Early detection and Treatment of neovascular age-related macular 
degeneration.  J Am Board Fam Pract 2002; 15:142-152. 
4. Rosenfeld PJ, Brown DM, Heier JS, et al.  Ranibizumab for neovascular age-related 
macular degeneration.  N Engl J Med 2006; 355:1419-1431. 
5. Laouri M, Chen E, Looman M, et al.  The burden of disease of retinal vein occlusion: 
review of the literature.  Eye 2011; 25:981-988. 
6. Klein R, Moss SE, Meuer SM, et al.  The 15-year cumulative incidence of retinal vein 
occlusion.  The Beaver Dam Eye Study.  Arch Ophthalmol 2008; 126:513-518. 
7. Macugen® Investigator Brochure.  2015. 
8. EOP1003 Final study report: pegaptanib sodium (Macugen™).  A Phase II/III 
randomized, double-masked, controlled, dose-ranging, multi-center comparative trial, in 
parallel groups, to establish the safety and efficacy of intravitreous injections of 
pegaptanib sodium (anti-vascular endothelial growth factor [VEGF] pegylated aptamer) 
given every 6 weeks for 54 weeks, in patients with exudative age-realted macular 
degeneration (AMD). 
9. EOP1004 Final study report: pegaptanib sodium (Macugen™).  A Phase II/III 
randomized, double-masked, controlled, dose-ranging, multi-center comparative trial, in 
parallel groups, to establish the safety and efficacy of intravitreous injections of 
pegaptanib sodium (anti-vascular endothelial growth factor [VEGF] pegylated aptamer) 
given every 6 weeks for 54 weeks, in patients with exudative age-realted macular 
degeneration (AMD). 
10. 
EOP1023 Final study report: A Phase IV, open label, multi-center trial of maintenance 
intravitreous injections of Macugen™ (pegaptanib sodium) given every 6 weeks for 48 
weeks in subjects with subfoveal neovascular age-related macular degeneration (AMD) 
initially treated with a modality resulting in maculopathy improvement. 
11. 
EOP1005 Final study report: A Phase 2, randomized, controlled, double-masked, dose-
finding, multi-center, comparative trial, in parallel groups, to establish the safety and 
preliminary efficacy of intravitreous injections of EYE001 (anti-VEGF pegylated 


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aptamer), given every 6 weeks for 12 to 30 weeks to patients with clinically significant 
diabetic macular edema (DME) involving the center of the macula. 
12. 
Sultan MB, Zhou D, Loftus J, et al.  A phase 2/3, multicenter, randomized, double-
masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema.  
Ophthalmology 2011; 118:1107-1118. 
13. 
Wroblewski JJ, Wells JA, Adamis AP, et al.  Pegaptanib sodium for macular edema 
secondary to central retinal vein occlusion.  Arch Ophthalmol 2009; 127:374-380. 
14. 
Wroblewski JJ, Wells JA 3rd, Gonzales CR.  Pegaptanib sodium for macular edema 
secondary to branch retinal vein occlusion.  Am J Ophthalmol 2010; 149:147-154. 
 
 




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APPENDIX 1 MACUGEN PRESCRIBING INFORMATION 
 


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