Anti-VEGF vs. Prompt Vitrectomy for VH From PDR (AB)

Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage From Proliferative Diabetic Retinopathy

Although vitreous hemorrhage (VH) from proliferative diabetic retinopathy (PDR) can cause acute and dramatic vision loss for patients with diabetes, there is no current, evidence-based clinical guidance as to what treatment method is most likely to provide the best visual outcomes once intervention is desired. Intravitreous anti-vascular endothelial growth factor (anti-VEGF) therapy alone or vitrectomy combined with intraoperative PRP each provide the opportunity to stabilize or regress retinal neovascularization. However, clinical trials are lacking to elucidate the relative time frame of visual recovery or final visual outcome in prompt vitrectomy compared with initial anti-VEGF treatment. The Diabetic Retinopathy Clinical Research Network Protocol N demonstrated short-term trends consistent with a possible beneficial effect of anti-VEGF treatment in eyes with VH from PDR, including greater visual acuity improvement and reduced rates of recurrent VH as compared with saline injection. It is possible that a study with a longer duration of follow-up with structured anti-VEGF retreatment would demonstrate even greater effectiveness of anti-VEGF for VH to avoid vitrectomy and its attendant adverse events while also improving visual acuity. On the other hand, advances in surgical techniques leading to faster operative times, quicker patient recovery, and reduced complication rates may make prompt vitrectomy a more attractive alternative since it results in the immediate ability to clear hemorrhage and to perform PRP if desired, often as part of one procedure. This proposed study will evaluate the safety and efficacy of two treatment approaches for eyes with VH from PDR: prompt vitrectomy + PRP and intravitreous aflibercept injections.

Study Overview

• Status: Completed
• Conditions: Proliferative Diabetic Retinopathy; Vitreous Hemorrhage
• Intervention / Treatment: Drug: 2-mg Intravitreous Aflibercept Injection; Procedure: Prompt Vitrectomy Plus Panretinal Photocoagulation

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 205
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 3N9
      • UBC/VCHA Eye Care Centre
  • Ontario
    • Toronto, Ontario, Canada, M5T 2S8
      • University Health Network - Toronto Western Hospital
• United States
  • California
    • Campbell, California, United States, 95008
      • Retinal Diagnostic Center
    • Glendale, California, United States, 91203
      • Macula & Retina Institute
    • Huntington Beach, California, United States, 92647
      • Atlantis Eye Care
    • Loma Linda, California, United States, 92354
      • Loma Linda University Health Care, Department of Ophthalmology
    • Porterville, California, United States, 93257
      • Shashi D Ganti, MD PC
  • Florida
    • Lakeland, Florida, United States, 33805
      • Florida Retina Consultants
    • Pinellas Park, Florida, United States, 33782
      • Southeast Eye Institute, P.A. dba Eye Associates of Pinellas
    • Sarasota, Florida, United States, 34233
      • Retina Associates of Sarasota
    • Tampa, Florida, United States, 33609
      • Retina Associates of Florida, P.A.
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory Eye Center
    • Augusta, Georgia, United States, 30909
      • Southeast Retina Center, P.C.
    • Marietta, Georgia, United States, 30060
      • Marietta Eye Clinic
    • Sandy Springs, Georgia, United States, 30328
      • Thomas Eye Group
  • Illinois
    • Bloomington, Illinois, United States, 61704
      • Gailey Eye Clinic
    • Chicago, Illinois, United States, 60611
      • Northwestern Medical Faculty Foundation
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago Medical Center
    • Urbana, Illinois, United States, 61801
      • Carle Foundation Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 42690
      • Raj K. Maturi, MD, PC
    • New Albany, Indiana, United States, 47150
      • John-Kenyon American Eye Institute
  • Kansas
    • Shawnee Mission, Kansas, United States, 66204
      • Retina Associates, P.A.
  • Kentucky
    • Paducah, Kentucky, United States, 42001
      • Paducah Retinal Center
  • Louisiana
    • West Monroe, Louisiana, United States, 71291
      • Eye Associates of Northeast Louisiana dba Haik Humble Eye Center
  • Maryland
    • Baltimore, Maryland, United States, 21237
      • Elman Retina Group, P.A.
    • Baltimore, Maryland, United States, 21287
      • Wilmer Eye Institute at Johns Hopkins
  • Massachusetts
    • Ayer, Massachusetts, United States, 01432
      • Valley Eye Physicians and Surgeons
    • Boston, Massachusetts, United States, 02215
      • Joslin Diabetes Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • Kellogg Eye Center, University of Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System, Dept of Ophthalmology and Eye Care Services
    • Grand Rapids, Michigan, United States, 49546
      • Retina Specialists of Michigan
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Retina Center, PA
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Department of Ophthalmology
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Mid-America Retina Consultants, P.A.
    • Saint Louis, Missouri, United States, 63128
      • The Retina Institute
  • New York
    • New York, New York, United States, 10021
      • Weill Cornell Medical College
    • New York, New York, United States, 10003
      • The New York Eye and Ear Infirmary/Faculty Eye Practice
    • New York, New York, United States, 10021
      • MaculaCare
    • Syracuse, New York, United States, 13224
      • Retina-Vitreous Surgeons of Central New York, PC
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27517
      • Kittner Eye Center
    • Charlotte, North Carolina, United States, 28210
      • Charlotte Eye, Ear, Nose and Throat Assoc., PA
  • Ohio
    • Beachwood, Ohio, United States, 44122
      • Retina Associates of Cleveland, Inc.
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
  • Oklahoma
    • Edmond, Oklahoma, United States, 73013
      • Retina Vitreous Center
    • Oklahoma City, Oklahoma, United States, 73104
      • Dean A. McGee Eye Institute
  • Oregon
    • Eugene, Oregon, United States, 97401
      • Oregon Retina, LLP
    • Portland, Oregon, United States, 97239
      • Casey Eye Institute
    • Portland, Oregon, United States, 97221
      • Retina Northwest, PC
  • Pennsylvania
    • Monroeville, Pennsylvania, United States, 15146
      • Retina Vitreous Consultants
  • South Carolina
    • West Columbia, South Carolina, United States, 29169
      • Palmetto Retina Center
  • Tennessee
    • Chattanooga, Tennessee, United States, 37421
      • Southeastern Retina Associates
    • Knoxville, Tennessee, United States, 37909
      • Southeastern Retina Associates, P.C.
  • Texas
    • Amarillo, Texas, United States, 79106
      • Southwest Retina Specialists
    • Austin, Texas, United States, 78705
      • Retina Research Center
    • Houston, Texas, United States, 77025
      • Retina and Vitreous of Texas
    • Houston, Texas, United States, 77030
      • Baylor Eye Physicians and Surgeons
    • Lubbock, Texas, United States, 79424
      • Texas Retina Associates
    • McAllen, Texas, United States, 78503
      • Valley Retina Institute
    • San Antonio, Texas, United States, 78240
      • Medical Center Ophthalmology Associates
    • San Antonio, Texas, United States, 78240
      • Retinal Consultants of San Antonio
  • Washington
    • Spokane, Washington, United States, 99204
      • Spokane Eye Clinic
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Intravitreous 2 mg aflibercept injections; Initial injection must be given on the day of randomization. Follow-up injections will be performed as often as every 4 weeks unless criteria for deferral are met.	Drug: 2-mg Intravitreous Aflibercept Injection; Soluble decoy receptor fusion protein that has a high binding affinity to all isoforms of VEGF as well as to placental growth factor.; Other Names: Eylea; Vascular endothelial growth factor Trap-Eye
Active Comparator: Prompt vitrectomy plus panretinal photocoagulation; For the prompt vitrectomy + panretinal photocoagulation group, the vitrectomy must be scheduled to be performed within 2 weeks of randomization. Vitrectomy will be performed according to the investigator's usual routine, including pre-operative care, surgical procedure, and post-operative care, although anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage.	Procedure: Prompt Vitrectomy Plus Panretinal Photocoagulation; Surgical removal of the vitreous gel and associated hemorrhage, concurrent delivery of panretinal endolaser; Other Names: PRP

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
E-ETDRS Visual Acuity Letter Score (Area Under the Curve From Baseline)	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.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
E-ETDRS Visual Acuity Letter Score	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.	4 Weeks
E-ETDRS Visual Acuity Letter Score	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.	12 Weeks
E-ETDRS Visual Acuity Letter Score	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.	24 Weeks
E-ETDRS Visual Acuity Letter Score	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.	1-Year from participant randomization
E-ETDRS Visual Acuity Letter Score	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.	2 Years
E-ETDRS Visual Acuity Letter Score (Area Under the Curve From Baseline)	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.	2-Years
Snellen Equivalent Range (Visual Acuity Score)	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.	4 weeks
Snellen Equivalent Range (Visual Acuity Score)	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.	12 weeks
Snellen Equivalent Range (Visual Acuity Score)	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.	24 weeks
Snellen Equivalent Range (Visual Acuity Score)	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.	1 year
Snellen Equivalent Range (Visual Acuity Score)	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..	2 years
Recurrent Vitreous Hemorrhage	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.	At any time through 2 years
Retinal Neovascularization on Clinical Exam	Defined as neovascularization of the disc or elsewhere. Excludes eyes in which retinal neovascularization could not be determined.	24 weeks
Retinal Neovascularization on Clinical Exam	Defined as neovascularization of the disc or elsewhere. Excludes eyes in which retinal neovascularization could not be determined	1 year
Retinal Neovascularization on Clinical Exam	Defined as neovascularization of the disc or elsewhere. Excludes eyes in which retinal neovascularization could not be determined	2 years

Collaborators and Investigators

• Sponsor: Jaeb Center for Health Research
• Collaborators: National Eye Institute (NEI); National Institutes of Health (NIH); Regeneron Pharmaceuticals
• Investigators: Study Chair: Andrew Antoszyk, MD, Charlotte Eye, Ear, Nose and Throat Assoc., PA

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2016
• Primary Completion (Actual): January 1, 2020
• Study Completion (Actual): January 1, 2020

Study Registration Dates

• First Submitted: August 3, 2016
• First Submitted That Met QC Criteria: August 3, 2016
• First Posted (Estimate): August 8, 2016

Study Record Updates

• Last Update Posted (Actual): April 20, 2021
• Last Update Submitted That Met QC Criteria: March 24, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Vitrectomy; Anti-VEGF
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Eye Diseases; Endocrine System Diseases; Diabetic Angiopathies; Diabetes Complications; Diabetes Mellitus; Eye Hemorrhage; Retinal Diseases; Diabetic Retinopathy; Hemorrhage; Vitreous Hemorrhage; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Aflibercept; Endothelial Growth Factors
• Other Study ID Numbers: DRCR.net Protocol AB; EY14231 (Other Grant/Funding Number: National Eye Institute); EY23207 (Other Grant/Funding Number: National Eye Institute); EY18817 (Other Grant/Funding Number: National Eye Institute)