Anti-VEGF vs. Prompt Vitrectomy for VH From PDR

A participant could have only one eye enrolled in the study.

• 2-mg Intravitreous Aflibercept Injection (Drug), also known as Eylea, Vascular endothelial growth factor Trap-Eye: Soluble decoy receptor fusion protein that has a high binding affinity to all isoforms of VEGF as well as to placental growth factor.
• Prompt Vitrectomy Plus Panretinal Photocoagulation (Procedure), also known as PRP: Surgical removal of the vitreous gel and associated hemorrhage, concurrent delivery of panretinal endolaser

Primary outcomes

• E-ETDRS Visual Acuity Letter Score (Area Under the Curve From Baseline) [24 weeks]: The area under the curve (units = letters·weeks) was divided by 24 weeks (units = weeks) to obtain an average change in letter score (units = letters) over the 24-weekr follow-up. Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent of <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.

Secondary outcomes

• E-ETDRS Visual Acuity Letter Score [4 Weeks]: Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.
• E-ETDRS Visual Acuity Letter Score [12 Weeks]: Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.
• E-ETDRS Visual Acuity Letter Score [24 Weeks]: Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.
• E-ETDRS Visual Acuity Letter Score [1-Year from participant randomization]: Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.
• E-ETDRS Visual Acuity Letter Score [2 Years]: Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.
• E-ETDRS Visual Acuity Letter Score (Area Under the Curve From Baseline) [2-Years]: Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity. The area under the curve (units = letters·years) was divided by 2 years (units = years) to obtain an average change in letter score (units = letters) over the 2-year follow-up. Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent of <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.
• Snellen Equivalent Range (Visual Acuity Score) [4 weeks]: Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.
• Snellen Equivalent Range (Visual Acuity Score) [12 weeks]: Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.
• Snellen Equivalent Range (Visual Acuity Score) [24 weeks]: Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.
• Snellen Equivalent Range (Visual Acuity Score) [1 year]: Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.
• Snellen Equivalent Range (Visual Acuity Score) [2 years]: Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity..
• Recurrent Vitreous Hemorrhage [At any time through 2 years]: Assessed by the investigator and defined as presence of vitreous hemorrhage after a period of absence. Excludes eyes in which vitreous hemorrhage could not be assessed during follow-up.
• Retinal Neovascularization on Clinical Exam [24 weeks]: Defined as neovascularization of the disc or elsewhere. Excludes eyes in which retinal neovascularization could not be determined.
• Retinal Neovascularization on Clinical Exam [1 year]: Defined as neovascularization of the disc or elsewhere. Excludes eyes in which retinal neovascularization could not be determined
• Retinal Neovascularization on Clinical Exam [2 years]: Defined as neovascularization of the disc or elsewhere. Excludes eyes in which retinal neovascularization could not be determined

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Age >= 18 years Participants <18 years old are not being included because proliferative diabetic retinopathy is so rare in this age group that the diagnosis may be questionable.
2. Diagnosis of diabetes mellitus (type 1 or type 2)

Any one of the following will be considered to be sufficient evidence that diabetes is present:

* Current regular use of insulin for the treatment of diabetes
* Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes
* Documented diabetes by American Diabetes Association and/or World Health Organization criteria 4. Able and willing to provide informed consent. 5. Patient is willing and able to undergo vitrectomy within next 2 weeks and the vitrectomy can be scheduled within that time frame.

  6\. Vitreous hemorrhage causing vision impairment, presumed to be from proliferative diabetic retinopathy, for which intervention is deemed necessary.
  * Note: Prior panretinal photocoagulation is neither a requirement nor an exclusion.
  * Subhyaloid hemorrhage alone does not make an eye eligible; however, presence of subhyaloid hemorrhage in addition to the criteria above will not preclude participation provided the investigator is comfortable with either treatment regimen.

    7\. Immediate vitrectomy not required (investigator and participant are willing to wait at least 4 months to see if hemorrhage clears sufficiently with anti-vascular endothelial growth factor without having to proceed to vitrectomy).

    8\. Visual acuity letter score ≤78 (approximate Snellen equivalent 20/32) and at least light perception.

    9\. Investigators should use particular caution when considering enrollment of an eye with visual acuity letter score 69 to 78 (approximate Snellen equivalent 20/32 to 20/40) to ensure that the need for vitrectomy and its potential benefits outweigh the potential risks.

Exclusion Criteria:

* A potential participant is not eligible if any of the following exclusion criteria are present:

  1. History of chronic renal failure requiring dialysis (including placement of fistula if performed in preparation for dialysis) or kidney transplant.
  2. A condition that, in the opinion of the investigator, would preclude participation in the study (e.g., unstable medical status including blood pressure, cardiovascular disease, and glycemic control).
  3. Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months prior to randomization or plans to do so in the next 4 months.
  4. A condition that, in the opinion of the investigator, would preclude participant undergoing elective vitrectomy surgery if indicated during the study.
  5. Participation in an investigational trial within 30 days of randomization that involved treatment with any drug that has not received regulatory approval for the indication being studied.

     • Note: participants cannot receive another investigational drug while participating in the study.
  6. Known allergy to any component of the study drug or any drug used in the injection prep (including povidone iodine).
  7. Blood pressure > 180/110 (systolic above 180 or diastolic above 110).
  8. If blood pressure is brought below 180/110 by anti-hypertensive treatment, potential participant can become eligible.
  9. Systemic anti-vascular endothelial growth factor or pro-vascular endothelial growth factor treatment within 4 months prior to randomization.

     • These drugs cannot be used during the study.
  10. For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next two years.

      • Women who are potential participants should be questioned about the potential for pregnancy. Investigator judgment is used to determine when a pregnancy test is needed.
  11. Potential participant is expecting to move out of the area of the clinical center to an area not covered by another clinical center during the two years.
  12. Evidence of traction detachment involving or threatening the macula.

      • If the density of the hemorrhage precludes a visual assessment on clinical exam to confirm eligibility, then it is recommended that assessment be performed with ultrasound as standard care.
  13. Evidence of rhegmatogenous retinal detachment.

      • If the density of the hemorrhage precludes a visual assessment on clinical exam to confirm eligibility, then it is recommended that assessment be performed with ultrasound as standard care.
  14. Evidence of neovascular glaucoma (iris or angle neovascularization is not an exclusion).
  15. Known diabetic macular edema (DME), defined as either
  16. Optical coherence tomography central subfield thickness (microns):
  17. Zeiss Cirrus: ≥290 in women; ≥305 in men
  18. Heidelberg Spectralis: ≥305 in women; ≥320 in men OR
  19. Diabetic macular edema on clinical exam that the investigator believes currently requires treatment.
  20. History of intravitreous anti-vascular endothelial growth factor treatment within 2 months prior to current vitreous hemorrhage onset or after onset.
  21. History of intraocular corticosteroid treatment within 4 months prior to current vitreous hemorrhage onset or after onset.
  22. History of major ocular surgery (including cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior 4 months or major ocular surgery other than vitrectomy anticipated within the next 6 months following randomization.
  23. History of vitrectomy.
  24. History of YAG capsulotomy performed within 2 months prior to randomization.
  25. Aphakia.
  26. Uncontrolled glaucoma (in investigator's judgment).
  27. Exam evidence of severe external ocular infection, including conjunctivitis, chalazion, or substantial blepharitis.

Participant flow

Outcome results

• E-ETDRS Visual Acuity Letter Score (Area Under the Curve From Baseline) (Primary), Mean, units on a scale: Intravitreous 2 mg Aflibercept Injections 59.3 +/- 21.9; Prompt Vitrectomy Plus Panretinal Photocoagulation 63.0 +/- 21.7
• E-ETDRS Visual Acuity Letter Score (Secondary), Mean, units on a scale: Intravitreous 2 mg Aflibercept Injections 52.6 +/- 29.4; Vitrectomy With Panretinal Photocoagulation 62.3 +/- 26.8
• E-ETDRS Visual Acuity Letter Score (Secondary), Mean, units on a scale: Intravitreous 2 mg Aflibercept Injections 63.7 +/- 25.0; Prompt Vitrectomy Plus Panretinal Photocoagulation 67.3 +/- 24.7
• E-ETDRS Visual Acuity Letter Score (Secondary), Mean, units on a scale: Intravitreous 2 mg Aflibercept Injections 69.4 +/- 23.8; Prompt Vitrectomy Plus Panretinal Photocoagulation 69.0 +/- 23.1
• E-ETDRS Visual Acuity Letter Score (Secondary), Mean, units on a scale: Intravitreous 2 mg Aflibercept Injections 70.5 +/- 20.3; Prompt Vitrectomy Plus Panretinal Photocoagulation 72.7 +/- 20.3
• E-ETDRS Visual Acuity Letter Score (Secondary), Mean, units on a scale: Intravitreous 2 mg Aflibercept Injections 73.7 +/- 16.4; Prompt Vitrectomy Plus Panretinal Photocoagulation 71.0 +/- 24.0
• E-ETDRS Visual Acuity Letter Score (Area Under the Curve From Baseline) (Secondary), Mean, units on a scale: Intravitreous 2 mg Aflibercept Injections 68.7 +/- 15.0; Prompt Vitrectomy Plus Panretinal Photocoagulation 70.0 +/- 18.8
• Snellen Equivalent Range (Visual Acuity Score) (Secondary), Count of participants, Participants: Intravitreous 2 mg Aflibercept Injections 24; Prompt Vitrectomy Plus Panretinal Photocoagulation 49
• Snellen Equivalent Range (Visual Acuity Score) (Secondary), Count of participants, Participants: Intravitreous 2 mg Aflibercept Injections 45; Prompt Vitrectomy Plus Panretinal Photocoagulation 58
• Snellen Equivalent Range (Visual Acuity Score) (Secondary), Count of participants, Participants: Intravitreous 2 mg Aflibercept Injections 61; Prompt Vitrectomy Plus Panretinal Photocoagulation 59
• Snellen Equivalent Range (Visual Acuity Score) (Secondary), Count of participants, Participants: Intravitreous 2 mg Aflibercept Injections 55; Prompt Vitrectomy Plus Panretinal Photocoagulation 65
• Snellen Equivalent Range (Visual Acuity Score) (Secondary), Count of participants, Participants: Intravitreous 2 mg Aflibercept Injections 56; Prompt Vitrectomy Plus Panretinal Photocoagulation 59
• Recurrent Vitreous Hemorrhage (Secondary), Count of participants, Participants: Intravitreous 2 mg Aflibercept Injections 48; Prompt Vitrectomy Plus Panretinal Photocoagulation 16
• Retinal Neovascularization on Clinical Exam (Secondary), Count of participants, Participants: Intravitreous 2 mg Aflibercept Injections 25; Prompt Vitrectomy Plus Panretinal Photocoagulation 3
• Retinal Neovascularization on Clinical Exam (Secondary), Count of participants, Participants: Intravitreous 2 mg Aflibercept Injections 15; Prompt Vitrectomy Plus Panretinal Photocoagulation 2
• Retinal Neovascularization on Clinical Exam (Secondary), Count of participants, Participants: Intravitreous 2 mg Aflibercept Injections 20; Prompt Vitrectomy Plus Panretinal Photocoagulation 2

Adverse events

Time frame: 2 Years

Serious adverse events by term

67 more terms not shown.

Other adverse events by term

364 more terms not shown.

• Results publication: Beaulieu WT, Maguire MG, Antoszyk AN; DRCR Retina Network. Changes in activity impairment and work productivity after treatment for vitreous hemorrhage due to proliferative diabetic retinopathy: Secondary outcomes from a randomized controlled trial (DRCR Retina Network Protocol AB). PLoS One. 2023 Nov 16;18(11):e0293543. doi: 10.1371/journal.pone.0293543. eCollection 2023. PMID 37972038
• Results publication: Glassman AR, Beaulieu WT, Maguire MG, Antoszyk AN, Chow CC, Elman MJ, Jampol LM, Salehi-Had H, Sun JK; DRCR Retina Network. Visual Acuity, Vitreous Hemorrhage, and Other Ocular Outcomes After Vitrectomy vs Aflibercept for Vitreous Hemorrhage Due to Diabetic Retinopathy: A Secondary Analysis of a Randomized Clinical Trial. JAMA Ophthalmol. 2021 Jul 1;139(7):725-733. doi: 10.1001/jamaophthalmol.2021.1110. PMID 33956075
• Results publication: Antoszyk AN, Glassman AR, Beaulieu WT, Jampol LM, Jhaveri CD, Punjabi OS, Salehi-Had H, Wells JA 3rd, Maguire MG, Stockdale CR, Martin DF, Sun JK; DRCR Retina Network. Effect of Intravitreous Aflibercept vs Vitrectomy With Panretinal Photocoagulation on Visual Acuity in Patients With Vitreous Hemorrhage From Proliferative Diabetic Retinopathy: A Randomized Clinical Trial. JAMA. 2020 Dec 15;324(23):2383-2395. doi: 10.1001/jama.2020.23027. PMID 33320223

• Study Protocol (PDF, 2016-07-28)
• Statistical Analysis Plan (PDF, 2020-04-27)
• Informed Consent Form (PDF, 2016-06-24)

• Andrew Antoszyk, MD, Study chair, Charlotte Eye, Ear, Nose and Throat Assoc., PA