Conditions: Adverse Effect of Radiation Therapy
Keywords: Radiation Retinopathy aflibercept
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 40
Healthy volunteers: no

Brief summary:
The primary objective of the study is to assess the safety of intravitreal aflibercept injection in treating visually compromising radiation maculopathy secondary to treatment of uveal melanoma by iodione-125 brachytherapy. The study will consist of two arms of 25 patients each (totaling 50 patients). Subjects in arm 1 will undergo treatment every 6 weeks. Subjects in arm 2 will undergo treatment and if improvement is documented at the following evaluation the next treatment will be extended by two weeks. Secondary objectives of the study include evaluation and analysis of visual acuity, number of injections, macular edema, and vascular activity between both arms.

Detailed description:
This study will consist of 2 simultaneous treatment arms: A six week dosing regimen arm and a treat and extend (TAE) dosing regimen arm, total duration 54 weeks. In the TAE arm the patients will receive an intravitreal aflibercept injection first visit, again at the second visit at 6 weeks, and then begin treat and extend from second injection forward. Treatment will be given at each visit. Patients with improved radiation maculopathy (SD-OCT analysis) will extend re-evaluation by two weeks (e.g. first interval 6 weeks; second interval 10 weeks; third interval 12 weeks, etc). Patients with increased radiation maculopathy (SD-OCT analysis) will have re-evaluation decreased by one week. Both arms will consist of 25 subjects (eyes). Fluorescein angiography will be completed at baseline, after the 4th injection (or within three weeks of week 24 for the TAE arm), and at the end of the study in all patients. Spectral domain OCT, and clinical evaluation including visual acuity will be assessed every visit in all patients. Radiation maculopathy will be graded every visit in all patients in a blinded fashion using the following classification system: Grade 1 indicates extrafoveal, noncystoid edema; grade 2, extrafoveal cystoid edema; grade 3, foveal noncystoid edema; grade 4, mild-to-moderate foveal cystoid edema; grade 5, severe foveal cystoid edema and grade 6 subretinal fluid. All patients will undergo comprehensive evaluation including adverse event questioning at each study timepoint. Patients in the six-week dosing arm will receive a total of 9 intravitreal aflibercept injections during the study window while the TAE treatment group will receive a maximum of 9 with a minimum of 5.

Arms:
arm 1: Patients will receive an intravitreal aflibercept injection the first visit, and then again every six weeks. Treatment will be given at each visit. arm 2: Patients will receive an intravitreal aflibercept injection the first visit, again at the second visit at 6 weeks, and then begin treat and extend from second injection forward. Patients with decreased radiation maculopathy by one grade or more will extend re-evaluation by two weeks. Patients with increased radiation maculopathy by one grade or more will have re-evaluation decreased by one week. Patients that show no maculopathy grade change will remain at the same re-evaluation interval.

Interventions: intervention 1: aflibercept
Intervention descriptions: intervention 1: This study will consist of 2 simultaneous treatment arms of aflibercept: A six week dosing regimen arm and a treat and extend (TAE) dosing regimen arm, total duration 54 weeks. In the TAE arm the patients will receive an intravitreal aflibercept injection first visit, again at the second visit at 6 weeks, and then begin treat and extend from second injection forward.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
Clinical Study Protocol 
 
Role of intravitreal aflibercept injection for the treatment of radiation maculopathy 
 
 
 
Compound: 
Intravitreal aflibercept injection 
 
 
Study Name: 
Role of intravitreal aflibercept injection 
for the treatment of radiation 
maculopathy 
 
 
Clinical Phase: 
Phase II, randomized treatment 
comparing an every six week 
intravitreal injection arm to a treat and 
extend arm. 
 
 
 
 
Date of Issue: 
15 September 2015 
 
 
Primary Investigator: 
Timothy G. Murray, MD, MBA 
 
 
 
 


 
Version 1.1 (Sept 2015) 
CLINICAL STUDY PROTOCOL SYNOPSIS 
TITLE  
Role of intravitreal aflibercept injection for the 
treatment of radiation maculopathy 
SITE LOCATION(S) 
 
Principal 
Investigator 
Murray Ocular Oncology & Retina, Miami, FL 
Timothy G. Murray, MD, MBA 
OBJECTIVE(S) 
To evaluate the benefits of intravitreal aflibercept in 
patients with visually compromising radiation 
maculopathy following iodine-125 plaque 
brachytherapy for uveal melanoma. 
STUDY DESIGN 
Phase II, randomized treatment comparing an every six 
week intravitreal injection arm to a treat and extend arm. 
STUDY DURATION 
54 weeks 
ESTIMATED STUDY 
COMPLETION DATE 
September - December 2016 
POPULATION 
 
 
Sample Size: 
Two arms of 25 patients each (totaling 50 patients) 
 
Target Population: 
Patients with radiation maculopathy from uveal 
melanoma treatment (brachytherapy) who have received 
previous treatment 
TREATMENT #1  
 
Study Drug 
Dose/Route/Schedule: 
Intravitreal aflibercept injection 2 mg                                 
0.05ml/ 40 mg/mL/Intravitreal Injection every q6 weeks   
 
 
 
 
Treatment #2  
Study Drug 
Dose/Route/Schedule: 
 
Intravitreal aflibercept injection 2 mg                                 
0.05ml/ 40 mg/mL/Intravitreal Injection Treat and 
Extend                 


 
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ENDPOINT(S) 
 
 
Primary:  
 
The primary objective of the study is to assess the safety 
of intravitreal aflibercept injection in treating visually 
compromising radiation maculopathy secondary to 
treatment of uveal melanoma by iodione-125 
brachytherapy  
 
 
Secondary: 
 
 
 
 
 
 
 
 
 
 
 
 
 
           
Exploratory: 
The secondary objectives of the study that will be 
evaluated at the study endpoint include: 
 Number of injections in control arm compared to 
TAE arm through week 54 (mean, median, and 
mode) 
 BCVA and mean change in BCVA through week 
54 
 CRT on SD-OCT and mean change in CRT 
through week 54 
 Change in grade and score of radiation 
maculopathy through week 54 
 Change in Qualitative evaluation of FA/ICG at 
endpoints measured 
 We will assess tumor activity as part of standard 
of 
care 
at 
each 
visit. 
 
Tumor 
recurrence/reactivity will be documented. 
PROCEDURES AND 
ASSESSMENTS 
This study will consist of 2 simultaneous treatment 
arms:  A six week dosing regimen arm and a treat and 
extend dosing regimen arm.   
STATISTICAL PLAN 
Analysis of both sdOCT and visual acuity via t-tests will 
be performed 
 


 
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1. 
INTRODUCTION AND RATIONALE 
1.1 
Introduction 
Radiation treatments for uveal melanoma, which include plaque brachytherapy, proton 
beam radiation, and helium ion radiotherapy, may result in long-term damage to the 
retinal vascular endothelial cells, causing radiation maculopathy in over 90% of eyes.  
This damage can be detected and classified through clinical examination, fluorescein 
angiography, or optical coherence tomography (OCT).  OCT classification has gained 
popularity in the detection and monitoring of radiation-induced maculopathy, and can be 
graded on a 1–6 scale. This edema grading scale has also been shown to correlate with 
foveal thickness and visual acuity. Recent findings utilizing spectral domain OCT (SD-
OCT) to detect intraretinal cystic spaces and photoreceptor loss have demonstrated that 
these earliest signs of radiation maculopathy manifest as macular edema, with average 
onset of OCT-evident edema by 12 months or up to 5 months earlier than clinically 
detectable radiation maculopathy and as early as 4 months after radiation treatment. 
1.2 
Rationale 
Radiation associated macular edema is a therapeutic challenging. Previous reports 
suggest that VEGF inhibitors provide a positive anatomic and visual outcome. However, 
no study to date has evaluated the benefits of intravitreal aflibercept injection in patients 
with radiation maculopathy. 
1.2.1 
Rationale for Study Design 
The potential reversibility of damage from macular edema can serve as a critical time 
point for therapeutic intervention. Antivascular endothelial growth factor (anti-VEGF) 
agents have been proposed for the treatment of radiation-related complications.  
Furthermore, studies on eyes with uveal melanomas have demonstrated statistically 
significant increases in the levels of VEGF in both aqueous and vitreous samples 
compared to eyes without tumors (tumors previously treated with radiotherapy displayed 
the highest VEGF concentrations). Previous generation anti-VEGF agents, such as 


 
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intravitreal bevacizumab, have been effectively used in multiple retinal diseases, 
including age-related macular degeneration, retinal vein occlusions, diabetic macular 
edema, and neovascularization.  Compared to bevacizumab, newer anti-VEGF agents, 
such as aflibercept, have been shown to have superior VEGF binding properties, 
lengthening the time interval between treatments for other retinal conditions; however, 
there is a lack of data on the effectiveness of intravitreal aflibercept injection in treating 
radiation maculopathy. Patient follow up will be performed every 6 weeks at a minimum. 
1.2.2 
Rationale for Dose Selection 
Dosing of intravitreal aflibercept injection in the control arm of this study will be within 
the range of the doses approved by the FDA for other retinal conditions that is known to 
be safe (2 mg Q4 or Q8Weeks). We expect aflibercept to be at least as effective as other, 
old anti VEGF agents so the comparator arm will be 2 mg utilizing a treat and extend 
approach.  However, if macular edema increases between follow-up visits, we will 
shorten the follow-up interval.  This interval change will only affect patients in the TAE 
arm. 
 
2. 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of the study is to assess the safety of intravitreal aflibercept 
injection in treating visually compromising radiation maculopathy secondary to treatment 
of uveal melanoma by iodione-125 brachytherapy.  
2.2 
Secondary Objective(s) 
The secondary objectives of the study that will be evaluated at the study endpoint 
include: 
 Number of injections in control arm compared to TAE arm through week 54 
(mean, median, and mode) 
 BCVA and mean change in BCVA through week 54 


 
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 CRT on SD-OCT and mean change in CRT through week 54 
 Change in grade and score of radiation maculopathy through week 54 (see 
Appendix II – maculopathy grading scale) 
 Change in Qualitative evaluation of FA/ICG at endpoints measured 
2.3 
Exploratory Objective 
We will assess tumor activity as part of standard of care at each visit.  Tumor 
recurrence/reactivity will be documented. 
 
 
 


 
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3. 
STUDY DESIGN 
3.1 
Study Description and Duration:   
This study will consist of 2 simultaneous treatment arms:  A six week dosing regimen 
arm and a TAE dosing regimen arm, total duration 54 weeks.  In the TAE arm the 
patients will receive an intravitreal aflibercept injection first visit, again at the second 
visit at 6 weeks, and then begin treat and extend from second injection forward.  
Treatment will be given at each visit.  We will utilize the radiation maculopathy 
classification system outlined below.  Patients with decreased radiation maculopathy by 
one grade or more (e.g. from grade 5 to grade 4) will extend re-evaluation by two weeks. 
Patients with increased radiation maculopathy by one grade or more (e.g. from grade 4 to 
grade 5) will have re-evaluation decreased by one week (however, we will not decrease 
follow-up intervals to under four weeks).  Patients that show no maculopathy grade 
change will remain at the same re-evaluation interval.  FA/ICG will be completed at 
baseline, after the 4th injection (or within three weeks of week 24 for the TAE arm), and 
at the end of the study in all patients. Spectral domain OCT, and clinical evaluation 
including visual acuity will be assessed every visit in all patients.  Radiation maculopathy 
will be graded every visit in all patients in a blinded fashion using the following 
classification system: Grade 1 indicates extrafoveal, noncystoid edema; grade 2, 
extrafoveal cystoid edema; grade 3, foveal noncystoid edema; grade 4, mild-to-moderate 
foveal cystoid edema; grade 5, severe foveal cystoid edema and grade 6 subretinal fluid. 
All patients will undergo comprehensive evaluation including adverse event questioning 
at each study timepoint.  
3.2 
Patients in the six week dosing arm will receive the last injection at the week 
48 visit for a total of 9 intravitreal aflibercept injections during the study. 
Patients in the TAE treatment group will have variable number of visits 
resulting in a variable number of injections. A minimum of a four-week 
follow-up will be required following the last injection for patients in this 
group. For example, if a patient in the TAE arm demonstrates increased 


 
Version 1.1 (Sept 2015) 
radiation maculopathy on every visit, their follow up visits will shorten from 
6 weeks, to 5 weeks, to 4 weeks, and continue at a q4week interval through 
the end of the study. Furthermore, if a TAE patient shows decreased radiation 
maculopathy on every visit, their follow up interval will increase from 6 
weeks to 8 week to 10 weeks to 12 weeks to 14 weeks.Planned Interim 
Analysis 
Visual acuity OCT outcomes and adverse events will be reviewed at, or around, 24 
weeks. Reports of adverse events from this study will be reviewed and summarized 
periodically while the study is ongoing to ensure the safety of patients.   
 
4. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS 
This study will consist of 2 simultaneous treatment arms:  Both arms will consist of 25 
subjects (eyes) for a total of 50, and will span 54 weeks.  Patients that withdraw from the 
study will not be replaced. 
4.1 
Study Population 
Patients over 21 years of age with radiation retinopathy who have received previous 
treatment will be candidates for the study. 
4.1.1 
Inclusion Criteria 
A Patient must meet the following criteria to be eligible for inclusion in the study: 
1. 21 years of age and over 
2. 20/800 or better visual acuity 
3. Must have received previous treatment for radiation maculopathy within the last 4-26 
weeks 
4. Any presence of macular edema (evaluated by SD-OCT) caused by radiation 
retinopathy 
5. Willing and able to comply with clinic visits and study-related procedures 
6. Provide signed informed consent 


 
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4.1.2 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. Patients less than 21 years of age. 
2. Patients with mental disability or any other condition that precludes the acquisition 
of an sdOCT image such as (nystagmus, neck disease, etc.) 
3. Patients who have previously been treated with intravitreal triamcinolone acetonide 
for macular edema (signs of recalcitrant disease) 
4. Patients who have received anti-VEGF treatments within the last 30 days 
5. Current ocular or periocular infection  
6. Active intraocular inflammation 
7. Any comorbid condition that may decrease visual acuity 
8. Any patients who have had intraocular surgery within the past 30 days for any 
condition 
9. Any other condition that the investigator believes would pose a significant hazard to 
the patient if the investigational therapy were initiated 
10. Participation in another simultaneous medical investigation or trial 
11. Advanced glaucoma (IOP > 25, even with medications, or cup/disc ratio > 0.8) 
12. Pregnant or breast-feeding women 
13. Sexually active men* or women of childbearing potential** who are unwilling to 
practice adequate contraception during the study (adequate contraceptive measures 
include stable use of oral contraceptives or other prescription pharmaceutical 
contraceptives for 2 or more menstrual cycles prior to screening; intrauterine device 
[IUD]; bilateral tubal ligation; vasectomy; condom plus contraceptive sponge, foam, 
or jelly, or diaphragm plus contraceptive sponge, foam, or jelly). For patients willing 
to practice adequate contraception during the study, we will recommend that 
contraception be continued for one month following the last visit 
14. Patients that develop anaphylaxis during ICG or FA will be discontinued from the 
study permanently 


 
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*Contraception is not required for men with documented vasectomy. 
**Postmenopausal women must be amenorrheic for at least 12 months in order not to be 
considered of child bearing potential.  Pregnancy testing and contraception are not 
required for women with documented hysterectomy or tubal ligation. 
4.2 
Premature Withdrawal from the Study 
A patient has the right to withdraw from the study at any time, for any reason, and 
without repercussion. 
The investigator has the right to withdraw a patient from the study in the event of an 
intercurrent illness, adverse event (“AE”), treatment failure, protocol violation, and for 
administrative or other reasons.  An excessive rate of withdrawals would render the study 
uninterpretable; therefore, unnecessary withdrawal of patients will be avoided. 
Should a patient decide to withdraw, all efforts will be made to complete and report 
observations as thoroughly as possible.  Early termination procedures will be followed. 
4.3 
Replacement of Patients 
Patients prematurely discontinued from the study will not be replaced. 
5. 
STUDY TREATMENTS 
This study will consist of 2 simultaneous treatment arms:  A six week dosing regimen 
arm and a treat and extend (TAE) dosing regimen arm.  Both arms will consist of 25 
subjects (eyes) and will span 54 weeks.  Spectral domain OCT, fluorescein angiography, 
and clinical evaluation including visual acuity will be assessed with sdOCT to determine 
the presence of intraretinal fluid leakage. All patients will receive intravitreal aflibercept 
injection 2 mg (0.05ml/ 40 mg/mL).  
5.1 
Investigational Treatment 
This study will investigate if the treat and extend dosing regimen arm has the same 
effectiveness as treatment every 6 weeks. 


 
Version 1.1 (Sept 2015) 
5.2 
Reference Treatment 
Currently, we treat patients every 6-8 weeks with bevacizumab with success.  We want to 
compare the dosing strategy that we have found successful with intravitreal aflibercept 
injection. The reference treatment in this study will be treatment with intravitreal 
aflibercept injection every 6 weeks. 
5.3 
Dose Modification and Stopping Rules 
5.3.1 
Dose Modification 
Dose modification for an individual patient is not allowed. 
5.3.1.1 
Reasons for Permanent Discontinuation of Study Drug 
If a patient develops anaphylaxis or severe intraocular inflammation, the patient will be 
discontinued from the study permanently. Patients may be permanently discontinued 
from the study per investigator discretion. 
5.3.1.2 
Reasons for Temporary Discontinuation of Study Drug 
Although the study drug may be discontinued per investigator discretion, no patient will 
undergo a temporary discontinuation. 
5.4 
Management of Infusion Reactions 
Patients that develop anaphylaxis during ICG or FA will discontinued from the study 
permanently. 
5.4.1 
Interruption of the Infusion 
Patients having interruption of infusion during ICG or FA will remain in the study. 
5.4.2 
Termination of the Infusion 
Patients having termination of infusion during ICG or FA will remain in the study. 


 
Version 1.1 (Sept 2015) 
5.5 
Method of Treatment Assignment 
Patients will be randomly assigned a treatment arm by random number generator with 
prefixed, sealed envelopes. 
5.5.1 
Blinding 
Blinding will not be undertaken in the study. 
5.6 
Treatment Logistics and Accountability 
5.6.1 
Packaging, Labeling, and Storage 
2.0 mg intravitreal aflibercept injection is formulated as a sterile liquid to a final 
concentration of 40 mg/mL intravitreal aflibercept injection in 5% sucrose, 10 
mM sodium phosphate pH 6.3, 0.03% polysorbate 20, and 40 mM NaCl. 
Intravitreal aflibercept injection 2.0 mg study drug will be supplied by Regeneron 
Pharmaceuticals Inc. in sealed, sterile 3 mL vials with a “withdrawable” volume 
of approximately 0.5 mL. Vials must be used only once (defined as entered with a 
needle). The volume of injection will be 0.05 mL for the 2 mg dose. For study 
drug in vials, the study drug will be withdrawn using aseptic technique.  
 
Study drug will be shipped to the site via overnight shipping using cold packs to 
maintain a temperature of 2° to 8° C. The Investigator, or an approved 
representative (e.g. pharmacist), will ensure that all study drugs are stored in a 
secured area, under recommended storage conditions and in accordance with 
applicable regulatory requirements. The shipping box is to be opened and stored 
immediately at the site in a refrigerator intended for investigational products at a 
temperature of 2° to 8°C.  
 
When vials are removed from the refrigerator, the solution should be visually 
inspected and it should have no evidence of turbidity. If particulates, cloudiness, 
or discoloration are visible, the vial must not be used. Exposure of the material to 
temperatures outside these limits, except for warming prior to administration, is 
not recommended and may result in loss of activity. Records of actual storage 


 
Version 1.1 (Sept 2015) 
conditions (i.e. temperature log) at the study site must be maintained; and must 
include a record of the dates, when the refrigerator was checked, the initials of 
person checking, and the temperature. 
 
5.6.2 
Supply and Disposition of Treatments 
Study drug will be shipped at a temperature of 2° to 8°C to the investigator or designee at 
regular intervals or as needed during the study. At the end of the study, and following 
drug reconciliation and documentation, all opened and unopened vials of study drug will 
be destroyed or returned to Regeneron Pharmaceuticals, Inc. or designee. 
5.6.3 
Treatment Accountability 
All drug accountability records will be kept current. 
The investigator will account for all opened and unopened vials of study drug.  These 
records will contain the dates, quantity, and study medication 
 dispensed to each patient – or - 
 disposed of at the site or returned to Regeneron Pharmaceuticals, Inc. or designee. 
All accountability records will be made available for inspection by regulatory agency 
inspectors. 
5.6.4 
Treatment Compliance 
All drug compliance records will be kept current and will be made available for 
inspection by regulatory agency inspectors.


 
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5.7 
Concomitant Medications  
Patients will not receive any other treatment for macular edema to the study eye other 
than the study protocol.  If a patient needs Anti-VEGF treatment in the non-study eye, 
intravitreal aflibercept injection will be used as the Anti-VEGF agent throughout the 
study. 
5.7.1 
Permitted Medications and Procedure 
Patients may undergo cataract and/or vitrectomy during the span of the study. If surgery 
occurs, intravitreal treatment with triamcinolone acetonide may be used for post-cataract 
management. Additionally, they will be monitored on post-op day #1, post-op week #1, 
and post-op month #1. Patients will resume aflibercept treatment 4-6 weeks after surgery. 
5.7.2 
Prohibited Medications and Procedures 
Patients undergoing enucleation will be discontinued from the study.  
 
Concurrent use of systemic or intravenous anti-VEGF agents, intravitreal bevacizumab, 
ranibizumab or pegaptanib is prohibited. 
 
6. 
STUDY SCHEDULE OF EVENTS AND VISIT DESCRIPTIONS 
6.1 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1. 


 
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Table 1 
Schedule of Events 
 
Screening Period 
Treatment Period 
Study Procedure 
Screening 
And 
Baseline 
Visit 1 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
End of 
Study 
Visit 10 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
Administer Study Drug 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
IOP assessed 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Slit Lamp Evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SD-OCT Assessment  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FA/ICG 
X 
 
 
X 
 
 
 
 
 
X 
Fundus Photography 
X 
 
 
X 
 
 
 
 
 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


 
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6.2 
Study Visit Descriptions 
6.2.1 
Screening / Day 1 
After the patient has provided informed consent, the following information will be 
collected: 
 Inclusion/exclusion 
 Demographics 
 Medical history and concurrent illnesses 
 Concomitant medications 
The following procedures and assessments will be conducted: 
 Vitals (blood pressure) 
 Pregnancy test, if applicable 
 ETDRS refraction and best-corrected visual acuity 
 IOP assessed 
 Slit lamp examination 
 Fundus photography 
 Fluorescein angiography 
 ICG angiography for choroidal tumor vasculature and ischemia 
 SD-OCT 
 Radiation maculopathy grade/score based on SD-OCT 
 Intravitreal aflibercept injection 
 Record adverse events 
6.2.2 
Treatment Period 
6.2.2.1 
Follow up visits (+/- 3 days) 
The following information will be collected: 
 Concomitant medications 
 Medical and ocular history update 
 AEs 
The following procedures and assessments will be conducted: 


 
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 ETDRS refraction and best-corrected visual acuity 
 SD-OCT 
 Fundus photography  
 Fluorescein angiography (after 4th injection or within three weeks of week 24 for 
the TAE arm) 
 ICG angiography (after 4th injection or within three weeks of week 24 for the TAE 
arm) 
 Radiation Maculopathy Grade/Score 
6.2.3 
Last Visit or Termination Visit 
All patients will have a mandatory final visit at the end of the study or upon early 
termination. No study treatment will be administered after the study termination visit. 
The following information will be collected at this last visit:  
 Concomitant medications 
 Medical and ocular history update 
 AEs 
The following procedures and assessments will be conducted at this last visit: 
 Vitals 
 ETDRS refraction and best-corrected visual acuity 
 Fundus photography 
 Fluorescein angiography 
 ICG angiography 
 SD-OCT 
 Radiation maculopathy grade/scale 
6.2.4 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule.  Unscheduled visits 
may be necessary to repeat testing following abnormal laboratory results, for follow-up 
of AEs, or for any other reason, as warranted. 
 


 
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7. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
7.1 
Definitions 
7.1.1 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which 
may or may not have a causal relationship with the study drug.  Therefore, an AE is any 
unfavorable and unintended sign (including abnormal laboratory finding), symptom, or 
disease which is temporally associated with the use of a study drug, whether or not 
considered related to the study drug.   
An AE also includes any worsening (i.e. any clinically significant change in frequency 
and/or intensity) of a pre-existing condition that is temporally associated with the use of 
the study drug. 
7.1.2 
Serious Adverse Event 
A SAE is any untoward medical occurrence that at any dose: 
 Results in death – includes all deaths, even those that appear to be completely 
unrelated to study drug (e.g. a car accident in which a patient is a passenger). 
 Is life-threatening – in the view of the investigator, the patient is at immediate 
risk of death at the time of the event.  This does not include an AE that had it 
occurred in a more severe form, might have caused death. 
 Requires in-patient hospitalization or prolongation of existing hospitalization.  
In-patient hospitalization is defined as admission to a hospital or an emergency 
room for longer than 24 hours.  Prolongation of existing hospitalization is defined 
as a hospital stay that is longer than was originally anticipated for the event, or is 
prolonged due to the development of a new AE as determined by the investigator 
or treating physician. 
 Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions). 
 Is a congenital anomaly/birth defect 


 
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 Is an important medical event – Important medical events may not be 
immediately life-threatening or result in death or hospitalization, but may 
jeopardize the patient or may require intervention to prevent 1 of the other serious 
outcomes listed above (e.g., intensive treatment in an emergency room or at home 
for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse).  Any 
malignancy (other than basal cell skin cancers) would be considered a medically 
important event. 
7.2 
Recording and Reporting Adverse Events 
All AEs and SAEs will be recorded on the CRF and in the patient’s source documents.  
Laboratory values, vital signs or ECG abnormalities will be recorded as AEs only if they 
are medically relevant. 
 
All SAEs, regardless of assessment of causal relationship to study drug will be reported 
to Regeneron Pharmaceuticals, Inc. 
 
The investigator will promptly report to the IRB all unanticipated problems involving 
risks to patients.  This includes death from any cause and all SAEs related to the use of 
the study drug.  All SAEs will be reported to the IRB, regardless of assessed causality. 
7.2.1 
Deaths 
Any AE that results in death is considered an SAE.  Deaths that occur from the time the 
patient signs the informed consent form (“ICF”) until 30 days after dosing will be 
reported to the appropriate IRB and to Regeneron Pharmacovigilance and Risk 
Management (or designee) within 24 hours of learning of the death.   
 
Any available autopsy reports and relevant medical reports will be sent to Regeneron 
Pharmaceuticals, Inc. as soon as possible. 
 
To report an SAE, Regeneron will be contacted at the following: 


 
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CONFIDENTIAL 
Medical.safety@regeneron.com 
Fax 914-345-7476 
SAE hotline: 914-593-1504 
7.2.2 
Pregnancy and Other Events that Require Accelerated Reporting 
The following events will be reported to Regeneron Pharmaceuticals, Inc. within 24 
hours of learning of the event: 
 
Overdose:  Accidental or intentional overdose of the study drug or concomitant 
medication, whether or not it is considered an AE. 
 
Pregnancy:  Although it is not considered an AE, the investigator will report to 
Regeneron Pharmaceuticals, Inc., any pregnancy occurring in a female patient or female 
partner of a male patient, during the study or within 30 days following the last dose of 
study drug.  The investigator will follow the pregnancy until delivery, or longer.  If the 
pregnancy continues to term (delivery), the health of the infant will also be reported to 
Regeneron Pharmaceuticals, Inc. 
 
To report an SAE, Regeneron will be contacted at the following: 
Medical.safety@regeneron.com 
Fax 914-345-7476 
SAE hotline: 914-593-1504 
7.2.3 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study will be reported to Regeneron 
Pharmaceuticals Inc. within 30 days. All SAEs leading to a patient’s withdrawal from the 
study will be reported. To report an SAE, Regeneron will be contacted at the following: 
Medical.safety@regeneron.com 
Fax 914-345-7476 
SAE hotline: 914-593-1504 
 


 
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7.2.4 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
The criteria for determining whether an abnormal objective test finding will be reported 
as an AE are as follows: 
 the test result is associated with accompanying symptoms, and/or 
 the test result requires additional diagnostic testing or medical/surgical 
intervention, and/or 
 the test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy. 
 
Repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not 
require reporting as an AE. 
7.2.5 
Follow-up 
Adverse event information will be collected until the end of study visit, or the early 
termination visit, if the patient withdraws consent. 
 
The investigator must make every effort to obtain follow-up information on the outcome 
of any SAE until the event is considered chronic and/or stable. 
7.3 
Evaluation of Severity and Causality 
7.3.1 
Evaluation of Severity 
The severity of an AE will be graded by the investigator using a 3–point scale (mild, 
moderate, or severe) and reported in detail as indicated on the CRF and/or SAE form, as 
appropriate. 
 Mild:  Does not interfere in a significant manner with the patient’s normal 
functioning level.  It may be an annoyance.  Prescription drugs are not ordinarily 
needed for relief of symptoms, but may be given because of personality of the 
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 Moderate:  Produces some impairment of functioning but is not hazardous to 
health.  It is uncomfortable or an embarrassment.  Treatment for symptom may be 
needed. 
 Severe:  Produces significant impairment of functioning or incapacitation and is a 
definite hazard to the patient’s health.  Treatment for symptom may be given 
and/or patient hospitalized. 
7.3.2 
Evaluation of Causality 
The relationship to treatment will be determined by the investigator and reported on the 
CRF and/or SAE form, as appropriate.  The following terms will be used: 
Not Related:  likely or clearly due to causes other than the study drug. 
Related:  possibly, probably, or definitely related to the study drug. 
 
8. 
STUDY VARIABLES 
8.1 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (e.g. age, race, etc.), disease 
characteristics including medical history, and medication history for each patient. 
8.2 
Primary and Secondary Endpoints 
The primary objective of this study is to assess the safety of intravitreal aflibercept 
injection in treating visually compromising radiation maculopathy secondary to treatment 
of uveal melanoma by iodine-125 brachytherapy 
The secondary objectives of this study are: 
 Number of injections in control arm compared to TAE arm through week 54 
(mean, median, and mode) 
 BCVA and mean change in BCVA through week 54 
 CRT on SD-OCT and mean change in CRT through week 54 


 
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 Change in grade and score of radiation maculopathy through week 54 (Appendix 
II) 
 Change in Qualitative evaluation of FA/ICG at endpoints measured 
The exploratory objective of this study will be to assess tumor activity as part of standard 
of care at each visit.  Tumor recurrence/reactivity will be documented. 
 
9. 
STATISTICAL PLAN. 
9.1 
Analysis Sets 
We will analyze the total number of patients enrolled and in each arm.  Adverse events 
will be reported for all arms.  Visual acuity and SD-OCT analysis will be performed for 
each group. 
9.2 
Statistical Methods  
9.2.1 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment 
group.  Continuous variables will be summarized with mean, median, standard deviation, 
minimum, and maximum.  Categorical variables will be summarized with frequency and 
percentage. Descriptive statistics will be used and, when needed, will be acknowledged. 
9.2.2 
Efficacy Analyses 
At each time point mean letter change will be analyzed for all eyes 
Number of injections administered will be recorded for each patient 
At each time point SD-OCT will be compared to baseline 
Analysis of both SD-OCT and visual acuity via t-tests will be performed.  
At each time point radiation maculopathy grade/scale will be compared to baseline 
FA/ICG/Fundus Photography assessments will be compared to baseline 
Tumor progression / reactivation will be assessed and reported as deemed necessary 


 
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9.2.3 
Safety Analysis 
Safety analyses will include all randomized subjects who received any study drug. All 
AEs will be listed and summarized by treatment group. 
 
Safety and tolerability will be determined by incidence and severity of ocular and 
systemic adverse events (AEs). Prespecified ocular AEs of interest, identified by 
ophthalmic examination, are: 6-line loss of VA within the first 3 months of therapy; 
major subretinal hemorrhage involving ≥ 75% of the clinical macula; disease-related 
vitreous hemorrhage; injection-related endophthalmitis; retinal detachment or vitreous 
hemorrhage; and drug-related uveitis. Systemic AEs such as vital sign changes, 
uncontrolled 
hypertension, 
thromboembolic 
events, 
hospitalizations, 
surgeries, 
emergency department visits, and deaths, will be identified by physical examination, 
patient reporting, vital sign changes, uncontrolled hypertension, thromboembolic events, 
hospitalizations, surgeries, emergency department visits, and deaths. 
 
9.2.3.1 
Other Safety 
Vital Signs 
Vital signs (pulse, and blood pressure) will be summarized by baseline and change from 
baseline to each scheduled assessment time with descriptive statistics. 
9.3 
Statistical Considerations Surrounding the Premature Termination of a 
Study 
If the study is terminated prematurely, only safety parameters will be summarized.   
 
10. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
A data management plan specifying all relevant aspects of data processing for the study 
(including data validation, cleaning, correcting, releasing) will be maintained and stored 
at the study site. 


 
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11. 
STUDY MONITORING 
11.1 
Source Document Requirements 
Investigator will prepare and maintain adequate and accurate patient records (source 
documents). 
The investigator will keep all source documents on file with the CRF.  Case report forms 
and source documents will be available at all times for inspection by authorized 
representatives of the regulatory authorities. 
11.2 
Case Report Form Requirements 
A CRF for each patient enrolled in the study will be completed and signed by the study 
investigator or authorized designee. The CRF will be typed or filled out using indelible 
ink.  The writing will be legible. Errors will be crossed out but not obliterated, the 
correction inserted, and the change initialed and dated by the investigator or authorized 
designee. The investigator will ensure the accuracy, completeness, legibility, and 
timeliness of the data reported in the CRFs.  Case report forms will be available at all 
times for inspection by authorized representatives of the regulatory authorities. 
 
12. 
AUDITS AND INSPECTIONS 
This study may be subject to a quality assurance audit or inspection by the regulatory 
authorities.  Should this occur, the investigator will be responsible for: 
 Informing Regeneron of a planned inspection by the authorities as soon as 
notification is received 
 Providing access to all necessary facilities, study data, and documents for the 
inspection or audit 
 Communicating any information arising from inspection by the regulatory 
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 Taking all appropriate measures requested by the regulatory authorities to resolve 
the problems found during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source 
documents, CRFs, medical records, correspondence, ICFs, IRB files, documentation of 
certification and quality control of supporting laboratories, and records relevant to the 
study maintained in any supporting pharmacy facilities.  Conditions of study material 
storage are also subject to inspection.   
In all instances, the confidentiality of the data will be respected. 
 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1 
Good Clinical Practice Statement 
It is the responsibility of the investigator(s) to ensure that this clinical study will be 
conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, and that are consistent with the ICH guidelines for Good Clinical 
Practice (GCP) and applicable regulatory requirements. 
13.2 
Informed Consent 
The principles of informed consent are described in ICH Guidelines for GCP. 
Regeneron will have the right to review and comment on the informed consent form. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) 
to obtain written informed consent from each patient prior to his/her participation in the 
study and after the aims, methods, objectives, and potential hazards of the study have 
been explained to the patient in a language that he/she can understand.  The ICF will be 
signed and dated by the patient and by the investigator or authorized designee who 
reviewed the ICF with the patient.   
Patients who can write but cannot read will have the ICF read to them before signing and 
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Patients who can understand but who can neither write nor read will have the ICF read to 
them in presence of an impartial witness, who will sign and date the ICF to confirm that 
informed consent was given. 
The original ICF will be retained by the investigator as part of the patient's study record, 
and a copy of the signed ICF will be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, the 
ICF will be reviewed and updated appropriately.  All study patients will be informed of 
the new information and provide their written consent if they wish to continue in the 
study.  The original signed revised ICF will be maintained in the patient’s study record 
and a copy will be given to the patient. 
13.3 
Patient Confidentiality and Data Protection 
The investigator will take all appropriate measures to ensure that the anonymity of each 
study patient will be maintained.   
The patient's and investigator's personal data will be treated in compliance with all 
applicable laws and regulations.   
13.4 
Institutional Review Board  
An appropriately constituted IRB, as described in ICH Guidelines for GCP, will review 
and approve:  
 The protocol, ICF, and any other materials to be provided to the patients 
(e.g. advertising) before any patient may be enrolled in the study  
 Any amendment or modification to the study protocol or ICF before 
implementation, unless the change is necessary to eliminate an immediate hazard 
to the patients, in which case the IRB will be informed as soon as possible  
Ongoing studies will be reviewed by the IRB on an annual basis or at intervals 
appropriate to the degree of risk.  
In addition, the IRB will be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 


 
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A copy of the IRB approval letter will be sent to Regeneron prior to shipment of drug 
supplies to the investigator.  The approval letter will include the study number and title, 
the documents reviewed, and the date of the review. 
Records of the IRB review and approval of all study documents (including approval of 
ongoing studies) will be kept on file by the investigator. 
14. 
PROTOCOL AMENDMENTS 
The investigator will not implement a change in the design or operation of the protocol or 
ICF without an IRB-approved amendment. 
 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A SITE 
15.1 
Premature Termination of the Study 
The investigator will notify Regeneron of a desire to close-out a site in writing, providing 
approximately 30 days’ notice.  The final decision will be made through mutual 
agreement with Regeneron.  Both parties will arrange the close-out procedures after 
review and consultation. 
In all cases, the appropriate IRB and Health Authorities will be informed according to 
applicable regulatory requirements, and adequate consideration will be given to the 
protection of the patients’ interests. 
 
16. 
STUDY DOCUMENTATION 
16.1 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRFs will be 
signed by the investigator.  This certification form accompanies each set of CRFs.  


 
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16.2 
Retention of Records 
The investigator will retain all essential study documents, including ICFs, source 
documents, CRFs, and drug accountability records for at least 3 years following the 
completion or discontinuation of the study, or longer if a longer period is required by 
relevant regulatory authorities.  Records will be destroyed in a manner that ensures 
confidentiality. 
17. 
APPENDIX I – INJECTION PROCEDURE 
Intravitreal aflibercept injection is formulated as a sterile liquid to a final concentration of 
40 mg/mL. The volume of injection will be 50 l (0.05 mL) for the 2 mg dose of 
intravitreal aflibercept injection.  
 
The required sequence of steps must be adhered to for administration of the dose in 
this clinical trial.  
 Preparation (please see below regarding the optional use of topical antibiotic agents 
pre and post dose): 
a. Apply topical anesthetic.  
b. Apply povidone iodine to eyelid margins, eyelashes, and conjunctival surface.  
For patients who have a known sensitivity to povidone iodine, another equally 
effective agent may be used. 
c. Place 1 or 2 drops of 5% povidone-iodine on the ocular surface at the intended 
injection site. 
d. Optional:  inject 0.5 mL of 2% xylocaine without epinephrine 
subjconjunctivally at the intended injection site; (the entry site of the needle 
for the intravitreous injection should be 3.0-3.5 mm from the limbus in 
aphakic/pseudophakic patients, and 3.5-4.0 mm in the phakic patients).   
e. Single use Proparacaine bottles should be used for all patients. “Fluoracaine” 
or other combination Fluorescein Sodium and Proparacaine HCl mixtures 
should NOT be used. 
f. Apply additional drop of povidone-iodine to site of injection. 
 


 
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 Study Drug Administration: 
a. Insert needle at marked injection point.  
b. Gently inject study drug.  
c. As the needle is withdrawn, a sterile cotton tip applicator should be rolled 
over the entry site to minimize the risk of drug reflux. This should be held in 
place for a full 10 seconds. 
 
 Post-Injection Procedures 
Measure patient’s IOP before the end of the observation period for each injection.  
See guidelines below for additional post-injection management procedures.   
 
Guidelines for Pre and Post-injection Management 
 Use of Topical Antibiotic Agents 
At the time of this study, the use of topical antibiotics as prophylaxis in IVT 
injections, both in the preparation and post injection varies considerably between the 
different practices. There is no consensus on the use of topical antibiotics, the agent to 
be used and the dose to be administered. In this protocol, it is recommended that a 
broad-spectrum topical antibiotic be used as part of the preparation for the intravitreal 
injection procedure, and as prophylaxis in the days immediately following the 
injection.   
 
Suggested use: 
o Instruct the patient to self-administer 1-2 drops of the antibiotic to the study 
eye, 3 times a day, for 3 days before the injection day. 
o On the injection day, as part of the preparation for injection, instill 1 drop to 
the eye 1 hour before the injection, and another drop 15 minutes before the 
injection.  
o After the injection, instruct the patient to self-administer 1-2 drops of the 
topical antibiotic to the injected eye, 3 times a day, for additional 3 days. 
 
 Post-injection reperfusion of the optic nerve 


 
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Visualize the optic nerve to verify reperfusion of the central retinal artery in the 
immediate post-injection period.  Verify intravitreal location of therapeutic agent 
when possible.  Verify that the retina is attached and that there is no new intraocular 
hemorrhage.  
 
 Intraocular pressure 
Monitor intraocular pressure (IOP) before the end of the approximate 30-minute 
observation period post each injection.  Check the IOP while maintaining a clean 
field.  Monitor the IOP closely until it is below 30 mm Hg. If a Tono-pen™ is used to 
check pressure, a clean Tono-pen™ condom should be placed on the tip before taking 
each measurement. If Goldmann applanation tonometry is used, the applanator tip 
should be swabbed with alcohol and let to dry before using it to measure IOP.  IOP 
may be lowered by pharmaceutical or surgical intervention, if required.  Treatment 
should be initiated whenever IOP is increased to the extent that the central retinal 
artery remains closed and the patient has no light perception for more than 1 to 2 
minutes.  Transient graying or obscuration of vision following injection, however, is 
expected and should not be treated. 
 
Paracentesis should be used only in extreme circumstances when the degree of 
pressure elevation poses an imminent and irreversible threat to vision. In the rare 
situation when a paracentesis is warranted, the IOP should be recorded both before 
and after the procedure. A 0.1 to 0.2 mL paracentesis may be performed at the 
temporal limbus using a 27-gauge or 30-gauge needle or surgical knife if judged to be 
necessary by the investigator. Record all IOP measurements in the source document 
and on the appropriate eCRF page, and related treatments in the concomitant 
medications section of the source documents and the eCRF. 
 
 Discharge 
No special precautions are required before discharge of a patient who has had an 
uneventful recovery from intravitreal injection, but patients and/or caregivers should 
be educated to avoid rubbing the eye and to recognize the signs and symptoms of 


 
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endophthalmitis, retinal detachment, or intraocular hemorrhage; these are eye pain or 
increased discomfort, increased redness of the eye (compared to immediately after 
injection), blurred or decreased vision, and increased ocular sensitivity to light.  
Patients should be informed that some blurring of vision is common post-injection, 
which is often described as seeing spots floating in the eye.  The floaters usually 
resolve after a few days or weeks.  Patients who experience post-injection adverse 
events that require additional monitoring should remain in the clinic for longer than 
30 minutes, and treated according to the investigator’s medical judgment. 
 
18. 
APPENDIX II – MACULOPATHY GRADING BY SD-OCT 
 
Spectral domain OCT, and clinical evaluation will be graded every visit in all patients 
in a blinded fashion using the following classification system:  
Grade 1 - indicates extrafoveal, noncystoid edema 
Grade 2 - extrafoveal cystoid edema 
Grade 3 - foveal noncystoid edema 
Grade 4 - mild-to-moderate foveal cystoid edema 
Grade 5 - severe foveal cystoid edema and grade 6 subretinal fluid.