Intravitreal Aflibercept for Retinal Non-Perfusion in Proliferative Diabetic Retinopathy

Intravitreal Aflibercept for Retinal Non-Perfusion in Proliferative Diabetic Retinopathy

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):

1. Increased neovascularization
2. Decrease in BCVA by 5 or more letters due to progressive DME or PDR
3. Worsening central subfield diabetic macular edema causing vision loss, with principal investigator or other delegated investigator confirmation
4. 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

Inclusion Criteria:

1. Type 1 or type 2 diabetes mellitus

2. BCVA ETDRS > 20/400 in the study eye

3. Willing and able to comply with clinic visits and study-related procedures

4. Provide signed informed consent

5. Substantial non perfusion (defined as greater than 20 disc areas), as assessed by the investigator

6. 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:

1. Any prior systemic anti-VEGF (anti vascular endothelial growth factor) or IVT anti-VEGF treatment in the study eye,

2. SD-OCT (Spectral Domain Optical Coherence Tomography) central subfield thickness measurement of > 320 µm, in the study eye

3. Evidence of infectious ocular infection, in the study eye, at time of screening

4. History of vitreoretinal surgery in the study eye

5. Any prior Panretinal laser photocoagulation (PRP) in the study eye

6. Current vitreous hemorrhage obscuring retinal imaging in the study eye

7. Cataract surgery in the study eye within 4 weeks of Day 0

8. Uncontrolled blood pressure (defined as > 180/110 mm Hg systolic/diastolic, while seated)

9. Significant renal disease defined as a history of chronic renal failure requiring dialysis or renal transplant

10. Tractional Retinal Detachment threatening the macula in the study eye

11. Corticosteroid treatment (intravitreal or peribulbar) in the study eye within 12 weeks of screening

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.

    • Contraception is not required for men with documented vasectomy.