Intravitreal Aflibercept for Retinal Non-Perfusion in Proliferative Diabetic Retinopathy (RECOVERY)

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

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

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.

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.

• 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.

Mean change in Early Treatment of Diabetic Retinopathy Study Best Corrected Visual Acuity (ETDRS-BCVA) from baseline to week 52 and week 100.

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.

Change in area of retinal capillary non-perfusion outside of the macula from baseline to week 52 and week 100.

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.

Percentage of subjects treated with PRP or vitrectomy for progression of PDR from baseline to week 52 and week 100.

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

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).

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.

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.

Kempen JH, O'Colmain BJ, Leske MC, Haffner SM, Klein R, Moss SE, Taylor HR, Hamman RF; Eye Diseases Prevalence Research Group. The prevalence of diabetic retinopathy among adults in the United States. Arch Ophthalmol. 2004 Apr;122(4):552-63. doi: 10.1001/archopht.122.4.552.

Klein R, Klein BE, Moss SE. A population-based study of diabetic retinopathy in insulin-using patients diagnosed before 30 years of age. Diabetes Care. 1985 Sep-Oct;8 Suppl 1:71-6. doi: 10.2337/diacare.8.1.s71.

Preliminary report on effects of photocoagulation therapy. The Diabetic Retinopathy Study Research Group. Am J Ophthalmol. 1976 Apr;81(4):383-96. doi: 10.1016/0002-9394(76)90292-0.

Writing Committee for the Diabetic Retinopathy Clinical Research Network; Gross JG, Glassman AR, Jampol LM, Inusah S, Aiello LP, Antoszyk AN, Baker CW, Berger BB, Bressler NM, Browning D, Elman MJ, Ferris FL 3rd, Friedman SM, Marcus DM, Melia M, Stockdale CR, Sun JK, Beck RW. Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial. JAMA. 2015 Nov 24;314(20):2137-2146. doi: 10.1001/jama.2015.15217. Erratum In: JAMA. 2016 Mar 1;315(9):944. JAMA. 2019 Mar 12;321(10):1008.

Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8. The Diabetic Retinopathy Study Research Group. Ophthalmology. 1981 Jul;88(7):583-600.

Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1991 May;98(5 Suppl):766-85.

Ferris F. Early photocoagulation in patients with either type I or type II diabetes. Trans Am Ophthalmol Soc. 1996;94:505-37.

Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994 Dec 1;331(22):1480-7. doi: 10.1056/NEJM199412013312203.

Ip MS, Domalpally A, Hopkins JJ, Wong P, Ehrlich JS. Long-term effects of ranibizumab on diabetic retinopathy severity and progression. Arch Ophthalmol. 2012 Sep;130(9):1145-52. doi: 10.1001/archophthalmol.2012.1043.

Ip MS, Domalpally A, Sun JK, Ehrlich JS. Long-term effects of therapy with ranibizumab on diabetic retinopathy severity and baseline risk factors for worsening retinopathy. Ophthalmology. 2015 Feb;122(2):367-74. doi: 10.1016/j.ophtha.2014.08.048. Epub 2014 Nov 18.

Brown DM, Schmidt-Erfurth U, Do DV, Holz FG, Boyer DS, Midena E, Heier JS, Terasaki H, Kaiser PK, Marcus DM, Nguyen QD, Jaffe GJ, Slakter JS, Simader C, Soo Y, Schmelter T, Yancopoulos GD, Stahl N, Vitti R, Berliner AJ, Zeitz O, Metzig C, Korobelnik JF. Intravitreal Aflibercept for Diabetic Macular Edema: 100-Week Results From the VISTA and VIVID Studies. Ophthalmology. 2015 Oct;122(10):2044-52. doi: 10.1016/j.ophtha.2015.06.017. Epub 2015 Jul 18.

Campochiaro PA, Wykoff CC, Singer M, Johnson R, Marcus D, Yau L, Sternberg G. Monthly versus as-needed ranibizumab injections in patients with retinal vein occlusion: the SHORE study. Ophthalmology. 2014 Dec;121(12):2432-42. doi: 10.1016/j.ophtha.2014.06.011. Epub 2014 Jul 21.

Heier J. The Effect of Intravitreal Aflibercept on Capillary Non-perfusion in Patients with Proliferative Retinopathy and/or Macular Edema Secondary to Proliferative Diabetic Retinopathy and Central Retinal Venous Occlusive Disease (ANDROID Study). Retina Society, Paris, France. 2015.

Babiuch A, Wykoff CC, Hach J, Srivastava S, Talcott KE, Yu HJ, Nittala M, Sadda S, Ip MS, Le T, Hu M, Reese J, Ehlers JP. Longitudinal panretinal microaneurysm dynamics on ultra-widefield fluorescein angiography in eyes treated with intravitreal aflibercept for proliferative diabetic retinopathy in the recovery study. Br J Ophthalmol. 2021 Aug;105(8):1111-1115. doi: 10.1136/bjophthalmol-2020-316952. Epub 2020 Aug 22.

Alagorie AR, Nittala MG, Velaga S, Zhou B, Rusakevich AM, Wykoff CC, Sadda SR. Association of Intravitreal Aflibercept With Optical Coherence Tomography Angiography Vessel Density in Patients With Proliferative Diabetic Retinopathy: A Secondary Analysis of a Randomized Clinical Trial. JAMA Ophthalmol. 2020 Aug 1;138(8):851-857. doi: 10.1001/jamaophthalmol.2020.2130.

Babiuch AS, Wykoff CC, Srivastava SK, Talcott K, Zhou B, Hach J, Hu M, Reese JL, Ehlers JP. RETINAL LEAKAGE INDEX DYNAMICS ON ULTRA-WIDEFIELD FLUORESCEIN ANGIOGRAPHY IN EYES TREATED WITH INTRAVITREAL AFLIBERCEPT FOR PROLIFERATIVE DIABETIC RETINOPATHY IN THE RECOVERY STUDY. Retina. 2020 Nov;40(11):2175-2183. doi: 10.1097/IAE.0000000000002727.