Conditions: Radiation Retinopathy
Keywords: Radiation Retinopathy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 40
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the tolerability and efficacy of ranibizumab treatment administered in subjects with radiation retinopathy

Detailed description:
RRR is a phase II, randomized, multicenter, clinical study to assess the tolerability and efficacy of ranibizumab treatment administered in subjects with radiation retinopathy. Subjects will be randomized into one of 3 arms; intravitreal (IVT) monthly vs. ranibizumab treatment administered IVT monthly combined with peripheral targeted photocoagulation vs. ranibizumab treatment administered IVT for three months followed by as needed treatment of ranibizumab combined with peripheral targeted photocoagulation over 48 weeks. From week 52 to week 101, all 3 treatment arms will employ a treat and extend protocol for IVT ranibizumab treatment.

Arms:
arm 1: Subject's will receive monthly treatment of an intravitreal injection of 0.5 mg ranibizumab for 48 weeks.

Starting at week 52, subject's will enter a treat \& extend regime, if a subject achieves a "dry" macula. For a macula to be considered "dry" persistent or recurrent fluid must be resolved on spectral domain (SD)-optical coherence tomography (OCT). The interval between injections will not exceed 12 weeks. After a subject is extended beyond 4-weeks \& develops recurrent disease activity, the eye is treated \& the treatment interval for the next visit is reduced by 1 week, compared to the previous treatment interval. The interval between treatments will be reduced by 1-week intervals until a dry macula is again established. Once a dry macula is again achieved, the interval between visits will be extended by 1-week intervals again. arm 2: Subject's receive monthly treatment of IVT of 0.5 mg ranibizumab for 48 weeks. 1 week after the initial dose of IVT ranibizumab, the subject will have peripheral targeted-retinal photocoagulation (TRP) to areas of peripheral retinal ischemia based on 120° or greater wide field angiography. After the first session of TRP, subjects will have a repeat wide field angiogram at 12 weeks \& 24 weeks \& will receive additional TRP as needed (PRN) to areas of peripheral retinal ischemia.

Starting at week 52, subject's will enter a treat \& extend regime as described in cohort A. arm 3: Subject's will receive 3 consecutive monthly doses of IVT 0.5 mg ranibizumab followed by PRN treatment with 0.5 mg ranibizumab intravitreal injection. 1 week after the initial dose of IVT ranibizumab, the subject will have peripheral targeted-retinal photocoagulation (TRP) to areas of peripheral retinal ischemia. After the first session of TRP, subjects will have a repeat wide field angiogram at 12 weeks \& 24 weeks \& will receive additional TRP as needed (PRN) to areas of peripheral retinal ischemia.

Starting at week 52, subject's will enter a treat \& extend regime as described in cohort A.

Interventions: intervention 1: 0.5 mg ranibizumab intervention 2: Targeted Retinal Photocoagulation (TRP)
Intervention descriptions: intervention 1: None intervention 2: TRP to areas of retinal ischemia

Protocol document:
Prot_000.pdf: 





























































































































SAP_001.pdf: 
Statistical Analysis Plan (SAP) 
RRR 
 
Title: A Randomized, Active-Controlled, Phase II Study of the Efficacy and Tolerability of 
Intravitreal Injections of Ranibizumab Compared to Intravitreal Injections of Ranibizumab 
Combined with Targeted Retinal Photocoagulation in Subjects with Radiation Retinopathy (RRR 
Study) 
Principal Investigator: Amy C. Schefler, MD 
Protocol Number: ML29236 (RRR) 
NCT Number: NCT02222610 
Date: July 14, 2020 
 
 


Abbreviations 
AE 
 
 
Adverse Events 
ATE 
 
 
Arterial Thromboembolic Events 
CMT  
 
Central Macular Thickness 
CNV  
 
Choroidal Neovascularization  
COMS  
 
Collaborative Ocular Melanoma Study 
EGF 
 
 
Epithelial Growth Factor 
ETDRS BCVA 
Early Treatment Diabetic Retinopathy Study Best Corrected Visual Acuity 
FGF 
 
 
Fibroblast Growth Factor 
IOP 
 
 
Intraocular Pressure 
IVT 
 
 
Intravitreal 
NV 
 
 
Neovascularization  
SD-OCT 
 
Spectral-Domain Optical Coherence Tomography 
PDGF  
 
Platelet-Derived Growth Factor 
PRN 
 
 
Pro Re Nata, As Needed 
SAE 
 
 
Serious Adverse Events 
TRP 
 
 
Targeted Retinal Photocoagulation 
USA 
 
 
United States of America 
VA 
 
 
Visual Acuity 
VEGF  
 
Vascular Endothelial Growth Factor 
VH 
 
 
Vitreous Hemorrhage 
 
 


Table of Contents 
1. Description of study .................................................................................................................... 4 
2. Overview of Study Design .......................................................................................................... 4 
2.1 Sample Size Calculations .......................................................................................................... 5 
3. Aims and Objectives ................................................................................................................... 5 
3.1 Primary Objective .................................................................................................................... 5 
3.2 Secondary Objectives ............................................................................................................... 5 
4. Outcomes .................................................................................................................................... 5 
4.1 Primary Outcomes.................................................................................................................... 5 
4.2 Secondary Outcomes ................................................................................................................ 5 
4.3 Safety Outcomes ....................................................................................................................... 6 
5. Populations.................................................................................................................................. 6 
6. Analyses ...................................................................................................................................... 7 
6.1 Primary Outcome ..................................................................................................................... 8 
6.2 Secondary Outcomes ................................................................................................................ 8 


1. DESCRIPTION OF STUDY 
RRR is a phase II, randomized, multicenter, clinical study to assess the tolerability and efficacy of 
ranibizumab treatment administered in subjects with radiation retinopathy. Subjects will be randomized 
into one of 3 arms; ranibizumab treatment administered IVT monthly vs. ranibizumab treatment 
administered IVT monthly combined with peripheral targeted photocoagulation vs. ranibizumab treatment 
administered IVT for three months followed by as needed treatment of ranibizumab combined with 
peripheral targeted photocoagulation over 48 weeks. From week 52 to week 1010, all 3 treatment arms 
will employ a treat and extend protocol for IVT ranibizumab treatment. 
2. OVERVIEW OF STUDY DESIGN 
This trial will compare the results of 3 different combinations of therapy to assess the efficacy of 
peripheral targeted retinal photocoagulation (TRP) applied to areas of retinal nonperfusion and poor 
perfusion combined with ranibizumab injections for the treatment of macular edema secondary to 
radiation retinopathy. Specifically, this trial will evaluate the ability to reduce the monthly treatment 
burden by eliminating areas of peripheral ischemia as detected by wide field fluorescein angiography. 
This peripheral ischemic retina is likely a major VEGF production site. By selectively eliminating these 
ischemic areas with angiography-guided laser ablation while preserving more perfused areas of peripheral 
retinal, pathological levels of VEGF may be significantly reduced, translating into fewer necessary 
monthly intravitreal injections while preserving useful peripheral visual field. The study will include 3 
cohorts followed for a total of 104 weeks. 
Subjects will be randomized into one of three treatment cohorts in a 1:2:2 ratio.  
Day 1 through Week 48: 
 
Cohort A (n=8) will receive monthly treatment of 0.5 mg ranibizumab for 48 weeks. Monthly 
treatment is defined as every 28 days (+/- 7 days). 
 
Cohort B (n=16) will receive monthly treatment of 0.5mg ranibizumab for 48 weeks. 1 week (+/- 
3 days) after the initial dose of ranibizumab is delivered, the subject will have peripheral targeted-
retinal photocoagulation (TRP) to areas of peripheral retinal ischemia based on wide field 
angiography that was performed at the screen visit. After the first session of TRP, subjects will 
have a repeat wide field angiogram at week 24 and week 36 and will receive additional TRP as 
needed (PRN) to areas of peripheral retinal ischemia.   
 
Cohort C (n=16) will receive a loading dose (3 consecutive monthly doses) of 0.5mg ranibizumab 
followed by PRN treatment with 0.5mg ranibizumab. 1 week (+/- 3 days) after the initial dose of 
ranibizumab is delivered, the subject will have peripheral TRP to areas of peripheral retinal 
ischemia based on wide field angiography that was performed at the screen visit. After the first 
session of TRP, subjects will have a repeat wide field angiogram at week 24 and week 36 and 
will receive additional TRP as needed to areas of peripheral retinal ischemia.  
See RRR protocol for TRP and PRN treatment criteria. 
Week 52 through Week 101: 
All cohorts will enter a treat and extend protocol for IVT ranibizumab retreatment beginning at week 52. 
At any visit where a dry macula is achieved din the study eye, the visit interval between IVT ranibizumab 
treatments will be lengthened by 1 week. A dry macula is defined as the resolution of recurrent or 
persistent fluid based on SD-OCT, slit lamp examination, and/or indirect ophthalmoscopy.  


After a subject has been extended beyond a monthly visit interval between IVT ranibizumab treatments, 
the visit interval will be reduced by 1 week, if the study eye develops recurrent disease activity. Recurrent 
disease activity is defined as recurrent or persistent fluid based on SD-OCT, slit lamp examination, and/or 
indirect ophthalmoscopy.  
IVT ranibizumab treatment will be administered in the study eye at every visit, no earlier than 7 days 
before the target date and no longer than 7 days after the target date. The visit interval between IVT 
ranibizumab treatments is individualized based on each patient’s response to treatment. The visit interval 
between IVT ranibizumab treatments will not exceed 12 weeks.  
2.1 Sample Size Calculations 
A priori power calculation was performed and revealed that a sample size of n=41 was needed to achieve 
80% power using single factor ANOVA with a significance level (alpha) of 0.05. Based on this result, the 
final study size was 40. Patients randomized in a 1:2:2 ratio. Sample size estimation was performed using 
RStudio (Version 1.1.463, RStudio Inc., Boston, Massachusetts). Statistical analyses were performed 
using Prism (GraftPad Software, San Diego, CA) and the data analysis function in Microsoft Excel 
(Microsoft Inc., Redmond, WA).  
The reason for the 1:2:2 randomization ratio was that the monthly group would have less variability in 
terms of treatment course because each patient would receive an injection each month without alterations 
or additional factors to their treatment regimen, allowing for detection of the group’s trend with a smaller 
cohort size. On the other hand, the other two cohorts could have different treatment schedules and 
therefore would require more patients to capture the trend. The exception to this randomization was that 
patients whose central vision of 20/50 or better at screening exam were randomized into the three cohorts 
in a 1:1:1 ratio in order to minimize a disproportionate population of subjects with good vision in any one 
group and to minimize the chance of significant difference in baseline vision between groups. 
Randomization occurred on Day 0 in which a randomly selected envelope containing a cohort assignment 
was chosen for each patient.  
3. AIMS AND OBJECTIVES 
3.1 Primary Objective 
To evaluate the mean change in ETDRS visual acuity at 48 weeks and 104 weeks from Day 0. 
3.2 Secondary Objectives 
To evaluate the total number of intravitreal injections required during a 104 week study period (laser 
versus non laser). To evaluate the percentage of patients with persistent macular edema based on SD-
OCT at 48 weeks and 104 weeks. 
4. OUTCOMES 
4.1 Primary Outcomes 
 
Mean change in ETDRS visual acuity at week 48 and week 104 from day 0. 
 
4.2 Secondary Outcomes 
 
The mean number of intravitreal injections required per subject per cohort. 


 
Percentage of subjects with persistent macular edema, based on SD-OCT, at week 48 and week 
104 compared to day 0. 
 
Percentage of subjects avoiding the development of neovascular glaucoma and/or vitreous 
hemorrhage. 
4.3 Safety Outcomes 
The safety and tolerability of intravitreal ranibizumab have been investigated in previous Phase I, I/II and 
III studies in AMD, RVO, and DME trials. Potential safety issues associated with the route of 
administration or the pharmacology of aflibercept in the study population include decreased BCVA, 
intraocular inflammation, intraocular infection, transient and/or sustained elevation of intraocular pressure 
(IOP), cataract development or progression, retinal or intraretinal hemorrhage, macular edema, retinal 
break or detachment, and arterial thromboembolic events (ATEs). Safety will be assessed by visual 
acuity, ophthalmic examinations, fluorescein angiograms, SD-OCT, intraocular pressure, vital signs, and 
adverse event documentation. 
To minimize the risks of intraocular infections, all injections will be performed employing sterile 
techniques. Study drug administration will be held for subjects who experience certain ocular events or 
infections. In the event any subject develops an adverse event in the study eye that is considered by the 
evaluating physician to be severe in intensity, serious consideration should be given to withdrawing the 
subject from the study. 
The PI or designated Sub-Investigators will review all adverse events on an ongoing basis to determine 
causality and relationship to study drug and/or study procedures. 
5. POPULATIONS  
Subjects were eligible to participate if the following criteria were met: 
A subject must meet the following criteria to be eligible for inclusion in the study: 
1. Ability to provide written informed consent and comply with study assessments for the full 
duration of the study 
2. Age ≥18 years 
3. Active radiation retinopathy resulting from any form of radiation treatment. Radiation retinopathy 
is defined as any of the following: retinal hemorrhages, exudates, edema, and/or 
neovascularization, not attributable to other causes 
4. BCVA of 20/25 to 20/400 in the study eye 
 
A subject who meets any of the following criteria will be excluded from the study: 
1. Pregnancy (verified by positive pregnancy test) or lactation 
2. Premenopausal women not using adequate methods of contraception 
3. Any other condition that the investigator believes would pos a significant hazard to the 
subject if the investigational therapy were initiated 
4. Participation in any other simultaneous medical investigation or trial 
5. Previous participation in any studies involving investigational drugs within 30 days before 
Day 0 (excluding vitamins and minerals) 
6. History of allergy fluorescein, not amenable to treatment 
7. Previous intravitreal treatment with any anti-VEGF drug within 60 days of Day 0 
8. Previous intravitreal or subconjunctival treatment with cortical steroids within 90 days of 
Day 0 


9. History of vitrectomy 
10. History of treatment with more than one form of radiation to the eye 
11. Subjects who have more than 7DD of ischemia in the central macula that would hinder 
visual acuity improvement 
12. History of panretinal photocoagulation treatment in the study eye 
13. Inability to obtain fundus photographs or fluorescein angiograms of sufficient quality to be 
analyzed 
14. Any concurrent intraocular condition in the study eye that, in the opinion of the 
investigator, could:  
a. Require medical or surgical intervention during the 104 week study period to 
prevent or treat visual loss that might result from that condition 
b. Contribute to loss of at least 2 Snellen equivalent lines of BCVA over the 104 week 
study period, if allowed to progress untreated 
15. Active intraocular inflammation (grade 2+ or above) in the study eye 
16. Current vitreous hemorrhage in the study eye 
17. History of rhegmatogenous retinal detachment or macular hole (stage 3 or 4) in the study 
eye 
18. Active infectious or conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye 
19. Aphakia or absence of the posterior capsule in the study eye 
20. Intraocular surgery (including cataract surgery) in the study eye within 2 months preceding 
Day 0 
21. Uncontrolled glaucoma in the study eye (defined as IOP ≥ 30 mmHg despite treatment with 
anti-glaucoma medication) 
22. History of glaucoma-filtering surgery in the study eye 
23. History of corneal transplant in the study eye 
24. Uncontrolled blood pressure (defined as systolic and/or diastolic >180/110 mmHg while 
subject is seated). A second reading may be taken at least 30 minutes later. If the subject 
requires antihypertensive medication, the subject can become eligible if medication is 
taken continuously for at least 14 days prior to Day 0 and blood pressure is less than 
180/110 mmHg 
25. New diagnosis of atrial fibrillation not managed by subject’s primary care physician or 
cardiologist within 3 months of Day 0 
26. History of stroke within the last 3 months of Day 0 
27. History of myocardial infarction within 3 months of Day 0 
28. History of other disease, metabolic dysfunction, or physical examination finding giving 
reasonable suspicion of a disease or condition that contraindicates the use of an 
investigational drug or that might affect interpretation of the results of the study or renders 
the subject at high risk for treatment complications 
29. Active malignancy other than uveal melanoma 
30. Presence of metastases 
 
6. ANALYSES 
All outcomes will be presented using descriptive statistics. For comparison of groups for primary and 
secondary outcomes, variables of interest will be statistically analyzed using analysis of variance 
(ANOVA), Student’s t-tests, Chi square and Fisher’s exact test. ETDRS data will be obtained for all visits 


for all 40 of the participants. Bonferroni correction was applied to all pairwise comparison analyses for 
this study.  
 
6.1 Primary Outcome 
The primary analysis will compare cohorts (A vs. B vs. C) on their mean change in ETDRS BCVA from 
baseline to week 48 and week 104 with the above described statistical tests. Adverse events will be 
reported using counts and percentages for each cohort. 
 
6.2 Secondary Outcomes 
The secondary analysis will compare cohorts (A vs. B vs. C) on their mean CMT measurements at 
baseline, week 48 and week 104. The secondary analysis will also compare percentage of eyes with 
intraretinal exudates, retinal hemorrhage, and neovascularization at baseline, week 48 and week 104. The 
frequency of injection will be compared between cohorts and the correlation between injection frequency 
and CMT and/or ETDRS BCVA will be assessed.