Peripheral and Macular Retinal Vascular Perfusion and Leakage in DME and RVO

Diabetic macular edema (DME) and macular edema secondary to retinal venous occlusive diseases are the most common cause of vision loss from a retinal vascular disease. Recently, vascular endothelial growth factor (VEGF) inhibitors (bevacizumab, aflibercept, and ranibizumab) have been described as new first-line therapies for these conditions. Aflibercept is the most recently approved VEGF inhibitor for the management of these conditions. Clinical trials have shown that treatment with aflibercept improves visual acuity and reduces macular edema in a large percentage of patients.

This study will examine the changes that occur with intravitreal aflibercept to perfusion and leakage in treatment naive eyes over the course of 1 year.

• Aflibercept (Drug), also known as Eylea: Intravitreal aflibercept will be given q4 wks for 6 treatments and then q 8 weeks through month 12.

Primary outcomes

• Change in Panretinal Leakage Index at Month 12 From Baseline [12 months]: Change in panretinal leakage index (defined as the proportion of retinal area involved in angiographic leakage) at month 12 from baseline as measured by ultra-widefield angiography (UWFA).

Secondary outcomes

• Mean Change in Total Leakage Index [6 months]: Mean change in total leakage index from baseline to month 6
• Change in Panretinal Ischemic Index [12 months]: Change in panretinal ischemic index from baseline to postoperative month 12
• Change in Panretinal Ischemic Index From Baseline at 6 Months [6 months]: Change in panretinal ischemic index (defined as the proportion of retinal area with nonperfusion) from baseline at 6 months
• Mean Change From Baseline Central Subfield Thickness [6 months]: OCT central subfield thickness change from baseline to 6 months
• Mean Change From Baseline in Best-corrected Visual Acuity (BCVA) Score Based on ETDRS [12 months]: Mean change from baseline in best-corrected visual acuity (BCVA) score from baseline to month 12
• Number of Participants Who Gained 15 ETDRS Letters or More of Vision [12 months]
• Number of Patients Who Gained 15 ETDRS Letters or More of Vision [6 months]
• Number of Patients That Showed Visual Acuity 20/40 or Better [6 months]
• Number of Patients That Showed Visual Acuity 20/200 or Worse [6 months]
• Ocular Serious Adverse Events [12 months]
• Number of Participants Who Lost 15 ETDRS Letters or More of Vision [12 months]
• Number of Participants Who Lost 15 ETDRS Letters or More of Vision [6 months]
• Number of Patients That Showed Visual Acuity 20/40 or Better [12 months]
• Number of Patients That Showed Visual Acuity 20/200 or Worse [12 months]
• Mean Change From Baseline Central Subfield Thickness [12 months]
• Systemic Serious Adverse Events [12 Months]: Incidence of systemic SAEs

Sex: All, ages: 18 Years to any

Inclusion Criteria

A subject must meet the following criteria to be eligible for inclusion in the study:

1. Signed Informed Consent.
2. Men and women ≥ 18 years of age.
3. Foveal-involving retinal edema secondary to DME or RVO based on investigator review of SDOCT.
4. E-ETDRS best-corrected visual acuity of: 20/25 to 20/400 in the study eye or Hand Motion (HM) in the study eye.
5. Willing, committed, and able to return for all clinic visits and complete all study related procedures.
6. Able to read, (or, if unable to read due to visual impairment, be read to verbatim by the person administering the informed consent or a family member) understand and willing to sign the informed consent form.

Exclusion Criteria

A subject who meets any of the following criteria will be excluded from the study:

1. Any prior or concomitant therapy with another investigational agent to treat DME or RVO in the study eye.
2. Prior panretinal photocoagulation in the study eye.
3. Prior intravitreal anti-VEGF therapy in the study eye.
4. Prior focal/grid laser photocoagulation in the study eye.
5. Prior history of intravitreal steroid therapy in the study eye.
6. Any history of allergy to fluorescein sodium or other reason that the patient is unable to undergo fluorescein angiography (e.g., inability to get vascular access, unable to tolerate procedure)
7. Prior systemic anti-VEGF therapy, investigational or FDA-approved, is only allowed up to 3 months prior to first dose, and will not be allowed during the study.
8. Significant vitreous hemorrhage obscuring view to the macula or the retinal periphery as determined by the investigator on clinical exam and ultra-widefield angiography.
9. Presence of other causes of macular edema, including myopic degeneration, ocular histoplasmosis syndrome, angioid streaks, choroidal rupture, choroidal neovascularization, neovascular age-related macular degeneration or multifocal choroiditis in the study eye. Epiretinal membranes are allowed.
10. Presence of macula-threatening traction retinal detachment.
11. Prior vitrectomy in the study eye.
12. History of retinal detachment or treatment or surgery for retinal detachment in the study eye.
13. Any history of macular hole of stage 2 and above in the study eye.
14. Any intraocular or periocular surgery within 3 months of Day 1 on the study eye, except lid surgery, which may not have taken place within 1 month of day 1, as long as it's unlikely to interfere with the injection.
15. Prior trabeculectomy or other filtration surgery in the study eye.
16. Uncontrolled glaucoma at baseline evaluation (defined as intraocular pressure ≥25 mmHg despite treatment with anti-glaucoma medication) in the study eye.
17. Active intraocular inflammation in either eye.
18. Active ocular or periocular infection in either eye.
19. Any ocular or periocular infection within the last 2 weeks prior to Screening in either eye.
20. Any history of uveitis in either eye.
21. Active scleritis or episcleritis in either eye.
22. Presence or history of scleromalacia in either eye.
23. Aphakia in the study eye.
24. Previous therapeutic radiation in the region of the study eye.
25. History of full-thickness penetrating keratoplasty in the study eye. Partial thickness corneal transplants including Descemet stripping automated endothelial keratoplasty and Descemet membrane endothelial keratoplasty are allowed.
26. Significant media opacities, including cataract, in the study eye which might interfere with visual acuity, assessment of safety, or fundus photography.
27. Any concurrent intraocular condition in the study eye (e.g. cataract) that, in the opinion of the investigator, could require either medical or surgical intervention during the 52 week study period.
28. Any concurrent ocular condition in the study eye which, in the opinion of the investigator, could either increase the risk to the subject beyond what is to be expected from standard procedures of intraocular injection, or which otherwise may interfere with the injection procedure or with evaluation of efficacy or safety.
29. Participation as a subject in any clinical study within the 12 weeks prior to Day 1.
30. Any systemic therapy with an investigational agent in the past 3 months prior to Day 1.
31. Any history of allergy to povidone iodine.
32. Pregnant or breast-feeding women
33. 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)

    * 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.

Participant flow

Outcome results

• Change in Panretinal Leakage Index at Month 12 From Baseline (Primary), Mean, percentage of region of interest in UWFA: Aflibercept -3.14 +/- 0.03
• Mean Change in Total Leakage Index (Secondary), Mean, percentage of region of interest in UWFA: Aflibercept 0.47 +/- 2.0
• Change in Panretinal Ischemic Index (Secondary), Mean, percentage of region of interest in UWFA: Aflibercept 3.2 +/- 0.12
• Change in Panretinal Ischemic Index From Baseline at 6 Months (Secondary), Mean, percentage of region of interest in UWFA: Aflibercept 0.67 +/- 0.03
• Mean Change From Baseline Central Subfield Thickness (Secondary), Mean, μm: Aflibercept 278.0 +/- 251.3
• Mean Change From Baseline in Best-corrected Visual Acuity (BCVA) Score Based on ETDRS (Secondary), Mean, ETDRS letters: Aflibercept 18.4 +/- 21.4
• Number of Participants Who Gained 15 ETDRS Letters or More of Vision (Secondary), Count of participants, Participants: Aflibercept 13
• Number of Patients Who Gained 15 ETDRS Letters or More of Vision (Secondary), Count of participants, Participants: Aflibercept 12
• Number of Patients That Showed Visual Acuity 20/40 or Better (Secondary), Count of participants, Participants: Aflibercept 20
• Number of Patients That Showed Visual Acuity 20/200 or Worse (Secondary), Count of participants, Participants: Aflibercept 2
• Ocular Serious Adverse Events (Secondary), Count of participants, Participants: Aflibercept 0
• Number of Participants Who Lost 15 ETDRS Letters or More of Vision (Secondary), Count of participants, Participants: Aflibercept 1
• Number of Participants Who Lost 15 ETDRS Letters or More of Vision (Secondary), Count of participants, Participants: Aflibercept 0
• Number of Patients That Showed Visual Acuity 20/40 or Better (Secondary), Count of participants, Participants: Aflibercept 19
• Number of Patients That Showed Visual Acuity 20/200 or Worse (Secondary), Count of participants, Participants: Aflibercept 0
• Mean Change From Baseline Central Subfield Thickness (Secondary), Mean, μm: Aflibercept 301.3 +/- 250.3
• Systemic Serious Adverse Events (Secondary), Count of participants, Participants: Aflibercept 3

Adverse events

Time frame: 1 year

Serious adverse events by term

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• Results publication: Figueiredo N, Srivastava SK, Singh RP, Babiuch A, Sharma S, Rachitskaya A, Talcott K, Reese J, Hu M, Ehlers JP. Longitudinal Panretinal Leakage and Ischemic Indices in Retinal Vascular Disease after Aflibercept Therapy: The PERMEATE Study. Ophthalmol Retina. 2020 Feb;4(2):154-163. doi: 10.1016/j.oret.2019.09.001. Epub 2019 Sep 10. PMID 31757691

• Study Protocol and Statistical Analysis Plan (PDF, 2017-01-20)

• Justis P Ehlers, MD, Principal investigator, Cole Eye Institute, Cleveland Clinic, OH 44195