Intravitreal Aflibercept for Retinal Non-Perfusion in Proliferative Diabetic Retinopathy

Study Overview
=================
Brief Summary
-----------------
The RECOVERY trial will assess the safety and tolerability of 2 mg intravitreal aflibercept injections (IAI) given monthly (Q4WK) or every 12 weeks (Q12WK) for the treatment of retinal capillary non-perfusion (RNP) associated with proliferative diabetic retinopathy (PDR). Assess the safety and tolerability of IAI for the treatment of proliferative diabetic retinopathy by evaluating the incidence and severity of ocular and systemic adverse events through week 52 Change in area of retinal capillary non-perfusion, as assessed by central reading center, from baseline through week 52

Detailed Description
-----------------
The investigational product is intravitreal aflibercept injection, which will be supplied by Regeneron Pharmaceuticals, Inc. in sterile vials for intravitreal (IVT) injection. Vials must be used (defined as entered with needle) only once. All drug supplies are to be kept under recommended storage conditions. The injection volume will be 50μL (0.05 mL) and will be administered to the subjects by IVT injection. Study eyes will be assigned randomly (1:1 ratio) to one of the following 2 treatment arms: Group 1- aflibercept 2 mg every 4 weeks (defined as every 28 days (+ 7 days) and at least 21 days between injections) through week 48. Subjects will have a mandatory Year 1 visit at week 48. Subjects have a mandatory visit at week 52 & will not receive treatment. During the second year of follow-up, subjects will be monitored and treated every 12 weeks (Week 60, 72, 84 and 96) with an end of study visit at week 100. If NV or PDR are worse per the pre-specified criteria at week 60, or at any study visit thereafter, the subject will be treated monthly through the end of the study. Group 2 - aflibercept 2 mg every 12-weeks for 48 weeks. Subjects will be followed every 4 weeks through week 12, and can be treated if the pre-specified criteria are met. Starting at week 12 if NV or PDR are stable or improved (as assessed by investigator) the subject will be monitored and treated at a 12-week interval through week 48. If NV or PDR are worse per the pre-specified criteria at week 12, or at any study visit thereafter, the subject will be treated monthly through week 48. At week 52 - For subjects without any retinal non-perfusion, monitoring and treatment will continue at every 12 weeks (Week 60, 72, 84, 96) with an end of study visit at week 100. For subjects with visible retinal non-perfusion, monitoring and treatment will be at a 4-week interval (defined as every 28 days + 7 days and at least 21 days between injections). If retinal non-perfusion has completely resolved at week 72, the subject will be switched back to monitoring and treatment every 12 weeks (Week 72, 84, 96). Pre-specified criteria (subject must meet at least one criterion, which must be documented with imaging): Increased neovascularization Decrease in BCVA by 5 or more letters due to progressive DME or PDR Worsening central subfield diabetic macular edema causing vision loss, with principal investigator or other delegated investigator confirmation Total area of retinal ischemia increases by 10% as determined by the central reading center Rescue Treatment At any point throughout the study, for either treatment arm, if PDR progresses despite 3 monthly IAI, a fluorescein angiogram will be performed to evaluate PDR progression. PRP will only be permitted after confirmation of PDR progression with the primary

Official Title
-----------------
Intravitreal Aflibercept for Retinal Non-Perfusion in Proliferative Diabetic Retinopathy

Conditions
-----------------
Proliferative Diabetic Retinopathy

Intervention / Treatment
-----------------
* Drug: Aflibercept


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Type 1 or type 2 diabetes mellitus BCVA ETDRS > 20/400 in the study eye Willing and able to comply with clinic visits and study-related procedures Provide signed informed consent Substantial non perfusion (defined as greater than 20 disc areas), as assessed by the investigator Early PDR, as assessed by the investigator, with no vitreous hemorrhage* Early PDR is defined in which PRP can safely be deferred and vitreous hemorrhage that does not obscure the application of PRP Exclusion Criteria: Any prior systemic anti-VEGF (anti vascular endothelial growth factor) or IVT anti-VEGF treatment in the study eye, SD-OCT (Spectral Domain Optical Coherence Tomography) central subfield thickness measurement of > 320 µm, in the study eye Evidence of infectious ocular infection, in the study eye, at time of screening History of vitreoretinal surgery in the study eye Any prior Panretinal laser photocoagulation (PRP) in the study eye Current vitreous hemorrhage obscuring retinal imaging in the study eye Cataract surgery in the study eye within 4 weeks of Day 0 Uncontrolled blood pressure (defined as > 180/110 mm Hg systolic/diastolic, while seated) Significant renal disease defined as a history of chronic renal failure requiring dialysis or renal transplant Tractional Retinal Detachment threatening the macula in the study eye Corticosteroid treatment (intravitreal or peribulbar) in the study eye within 12 weeks of screening Pregnant or breast-feeding women 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. Contraception is not required for men with documented vasectomy.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Q4WKS<br>Aflibercept 2 mg every 4 weeks (defined as every 28 days (+ 7 days) and at least 21 days between injections) through week 48. Following week 48, aflibercept 2 mg every 12 weeks through week 96. If NV or PDR are worse per pre-specified criteria at week 60, or at any study visit thereafter, the subject will be treated every 4 weeks through the end of the study. | Drug: Aflibercept<br>* Intravitreal injection<br>* Other names: Eylea;|
| Experimental: Q12WKS<br>Aflibercept 2 mg every 12-weeks. Subjects will be followed every 4 weeks through week 12, and can be treated if the pre-specified criteria are met. Starting at week 12 if NV or PDR are stable or improved (as assessed by investigator) the subject will be monitored and treated at a 12-week interval through week 48. If NV or PDR are worse per the pre-specified criteria at week 12, or at any study visit thereafter, the subject will be treated monthly through the end of the study. At week 52, aflibercept 2 mg every 4 weeks (defined as 28 days (+ 7 days) and at least 21 days between injections) for subjects with visible retinal non-perfusion. If retinal non-perfusion has completely resolved at week 72, aflibercept every 12 weeks through end of study. For subjects without retinal non-perfusion at week 52, aflibercept 2 mg every 12 weeks through the end of study. | Drug: Aflibercept<br>* Intravitreal injection<br>* Other names: Eylea;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | • Assess the safety and tolerability of IAI for the treatment of proliferative diabetic retinopathy by evaluating the incidence and severity of ocular and systemic adverse events through week 52 and week 100. | 52 and 100 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Early Treatment of Diabetic Retinopathy Severity Best Corrected Visual Acuity | Mean change in Early Treatment of Diabetic Retinopathy Study Best Corrected Visual Acuity (ETDRS-BCVA) from baseline to week 52 and week 100. | 52 weeks and 100 weeks | 
| Change in Area of Retinal Capillary Non-perfusion Within the Macula | Change in area of retinal capillary non-perfusion within the macula compared to baseline, as assessed by ultrawide-field fluorescein angiogram from baseline to week 52 and week 100. | 52 weeks and 100 weeks | 
| Change in Area of Retinal Capillary Non-perfusion Outside of the Macula | Change in area of retinal capillary non-perfusion outside of the macula from baseline to week 52 and week 100. | 52 weeks and 100 weeks | 
| Percentage of Subjects With Neovascularization Regression | Percentage of subjects with neovascularization regression (reduced area of neovascularization) as measured by the central image reading center from baseline to week 52 and week 100. | 52 Weeks and 100 Weeks | 
| Percentage of Subjects With Increased Neovascularization | Percentage of subjects with increased neovascularization from baseline to week 52 and week 100. | 52 Weeks and 100 Weeks | 
| Percentage of Subjects Who Develop Vitreous Hemorrhage | Percentage of subjects who develop vitreous hemorrhage from baseline to week 52 and week 100. | 52 Weeks and 100 Weeks | 
| Percentage of Subjects Treated With Pan-retinal Photocoagulation or Vitrectomy | Percentage of subjects treated with PRP or vitrectomy for progression of PDR from baseline to week 52 and week 100. | 52 Weeks and 100 Weeks | 
| Percentage of Subjects Who Develop Center-involving Diabetic Macular Edema | Percentage of subjects, at week 52 and week 100, who develop center-involving diabetic macular edema who did not have center-involving diabetic macular edema at baseline | 52 Weeks and 100 Weeks | 
| Changes in Visual Function Outcomes (Self Reported Visual Function) | Changes in self reported visual function utilizing the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) from baseline to week 52 and week 100. The NEI VFQ is a validated measure of patient-reported visual function measured on a scale from 0 (worst function) to 100 (best function). | 52 weeks and 100 weeks | 
| Mean Change in Central Subfield Thickness | Mean change in central subfield thickness (CST) from baseline to week 52 and week 100 | 52 weeks and 100 weeks | 
| Change in Area of Total Retinal Capillary Non-perfusion, as Assessed by the Central Reading Center | Change in area of total retinal capillary non-perfusion, as assessed by the central reading center, at week 52 and week 100 compared to baseline. | 52 weeks and 100 weeks |