Anti-VEGF Treatment for Prevention of PDR/DME

Intravitreous Anti-Vascular Endothelial Growth Factor Treatment for Prevention of Vision Threatening Diabetic Retinopathy in Eyes at High Risk

Multiple studies have implicated vascular endothelial growth factor VEGF as a major causative factor in human eye diseases characterized by neovascularization including proliferative diabetic retinopathy (PDR) and vascular permeability including diabetic macular edema (DME). While there is strong evidence that PDR outcomes are markedly reduced in eyes that are treated with monthly anti-VEGF therapy (A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema (ME) With Center Involvement Secondary to Diabetes Mellitus: RIDE/RISE) and moderately reduced in eyes that received fairly frequent dosing during the 1st year of treatment (Diabetic Retinopathy Clinical Research Network protocol I), it is unknown whether or not an earlier but less frequent dosing regimen would result in similar, favorable anatomic outcomes, and whether favorable anatomic outcomes subsequently would result in favorable visual acuity outcomes.

If this study demonstrates that intravitreous aflibercept treatment is effective and safe for reducing the onset of PDR or center involved- DME (CI-DME) in eyes that are at high risk for these complications, a new strategy to prevent vision threatening complications of diabetes will be available for patients. The application of intravitreous aflibercept earlier in the course of disease (i.e., at the time when an eye has baseline severe non-proliferative diabetic retinopathy) could help to reduce future potential treatment burden in patients, at the same time resulting in similar or better long-term visual outcomes, if PDR and DME are prevented.

The primary objectives of this protocol are to 1) determine the efficacy and safety of intravitreous aflibercept injections versus sham injections (observation) for prevention of PDR or CI-DME in eyes at high risk for development of these complications and 2) compare long-term visual outcomes in eyes that receive anti-VEGF therapy early in the course of disease with those that are observed initially, and treated only if high-risk PDR or CI-DME with vision loss develops.

Secondary objectives include:

• Comparing other visual acuity outcomes between treatment groups, such as proportion of eyes with at least 10 or at least 15 letter loss from baseline, or gain or loss of at least 5 letters at the consecutive study visit just before and at the 2- or 4-year visit
• Comparing optical coherence tomography (OCT) outcomes, such as mean change in OCT central subfield thickness and volume from baseline
• Comparing proportion of eyes with at least 2 and 3-step worsening or improvement of diabetic retinopathy severity level (scale for individual eyes) by central reading center from baseline
• Comparing associated treatment and follow-up exam costs between treatment groups
• Comparing safety outcomes between treatment groups

Study Overview

• Status: Completed
• Conditions: Diabetic Retinopathy; Diabetic Macular Edema
• Intervention / Treatment: Procedure: Prompt Sham; Procedure: Deferred laser; Drug: Deferred aflibercept; Drug: Prompt aflibercept

• Study Type: Interventional
• Enrollment (Actual): 399
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 3N9
      • UBC/VCHA Eye Care Centre
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • Nova Scotia District Health Authority
  • Ontario
    • North York, Ontario, Canada, M3C 0G9
      • Toronto Retina Institute (TRI)
    • Toronto, Ontario, Canada, M5T 2S8
      • University Health Network - Toronto Western Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85021
      • Arizona Retina and Vitreous Consultants
    • Tucson, Arizona, United States, 85711
      • University of Arizona Medical Center/Department of Ophthalmology
  • California
    • Huntington Beach, California, United States, 92647
      • Atlantis Eye Care
    • Loma Linda, California, United States, 92354
      • Loma Linda University Health Care, Department of Ophthalmology
    • Oakland, California, United States, 94609
      • East Bay Retina Consultants, Inc.
    • Palm Desert, California, United States, 92211
      • Southern California Desert Retina Consultants, MC
    • Porterville, California, United States, 93257
      • Shashi D Ganti, MD PC
    • Redlands, California, United States, 92374
      • Retina Consultants of Southern California
    • Sacramento, California, United States, 95817
      • U.C. Davis Eye Center
    • Santa Barbara, California, United States, 93103
      • California Retina Consultants
    • Westlake Village, California, United States, 91361
      • Retinal Consultants of Southern California Medical Group, Inc.
  • Connecticut
    • Hamden, Connecticut, United States, 06518
      • New England Retina Associates
  • Florida
    • Fort Lauderdale, Florida, United States, 33308
      • Retina Group of Florida
    • Fort Myers, Florida, United States, 33912
      • National Ophthalmic Research Institute
    • Jacksonville, Florida, United States, 32216
      • Florida Retina Institute-Jacksonville
    • Jacksonville, Florida, United States, 32209
      • University of Florida College of Med., Department of Ophthalmology, Jacksonville Health Science Cent
    • Lakeland, Florida, United States, 33805
      • Florida Retina Consultants
    • Miami, Florida, United States, 33136
      • Bascom Palmer Eye Institute
    • Orlando, Florida, United States, 32803
      • Magruder Eye Institute
    • Orlando, Florida, United States, 32806
      • Florida Retina Institute
    • Pinellas Park, Florida, United States, 33782
      • Southeast Eye Institute, P.A. dba Eye Associates of Pinellas
    • Plantation, Florida, United States, 33324
      • Fort Lauderdale Eye Institute
    • Sarasota, Florida, United States, 34239
      • Sarasota Retina Institute
    • 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
    • Springfield, Illinois, United States, 62703
      • Springfield Clinic, LLP
  • Indiana
    • Indianapolis, Indiana, United States, 46290
      • Raj K. Maturi, M.D., P.C.
  • Iowa
    • Dubuque, Iowa, United States, 52002
      • Medical Associates Clinic, P.C.
    • West Des Moines, Iowa, United States, 50266
      • Wolfe Eye Clinic
  • 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
    • Hagerstown, Maryland, United States, 21740
      • Mid Atlantic Retina Specialists
  • Massachusetts
    • Ayer, Massachusetts, United States, 01432
      • Valley Eye Physicians and Surgeons
    • Boston, Massachusetts, United States, 02215
      • Joslin Diabetes Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System, Dept of Ophthalmology and Eye Care Services
    • Grand Rapids, Michigan, United States, 49546
      • Vitreo-Retinal Associates
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Retina Center, PA
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Mid-America Retina Consultants, P.A.
  • New Jersey
    • Northfield, New Jersey, United States, 08225
      • Retinal and Ophthalmic Consultants, PC
  • New Mexico
    • Albuquerque, New Mexico, United States, 87109
      • Eye Associates of New Mexico
  • New York
    • 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
    • Rochester, New York, United States, 14642
      • University of Rochester
    • Syracuse, New York, United States, 13224
      • Retina-Vitreous Surgeons of Central New York, PC
  • North Carolina
    • Asheville, North Carolina, United States, 28803
      • Western Carolina Clinical Research, LLC
    • 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
  • Oregon
    • Eugene, Oregon, United States, 97401
      • Oregon Retina, LLP
    • Portland, Oregon, United States, 97239
      • Casey Eye Institute
    • Portland, Oregon, United States, 97210
      • Retina Northwest, PC
  • Pennsylvania
    • Monroeville, Pennsylvania, United States, 15146
      • Retina Vitreous Consultants
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Scheie Eye Institute
  • South Carolina
    • Columbia, South Carolina, United States, 29223
      • Carolina Retina Center
    • 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
      • Austin Retina Associates
    • Austin, Texas, United States, 78705
      • Retina Research Center
    • DeSoto, Texas, United States, 75115
      • Robert E. Torti, MD, PA dba Retina Specialists
    • Grapevine, Texas, United States, 76051
      • Retina Center of Texas
    • Houston, Texas, United States, 77030
      • Retina Consultants of Houston, PA
    • 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
      • Retinal Consultants of San Antonio
  • Virginia
    • Richmond, Virginia, United States, 23235
      • Retina Institute of Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University, Dept. of Ophthalmology
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • University of Wisconsin-Madison, Dept of Ophthalmology/Retina Service

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age >= 18 years

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:

   1. Current regular use of insulin for the treatment of diabetes
   2. Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes
   3. Documented diabetes by American Diabetes Association and/or World Health Organization criteria
3. Able and willing to provide informed consent.

Meets all of the following ocular criteria in at least one eye:

1. Best corrected Electronic-Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity letter score ≥79 (approximate Snellen equivalent 20/25 or better)

2. Severe non-proliferative diabetic retinopathy (NPDR) (based on the 4:2:1 rule) evident on clinical examination and on digital imaging as judged by the investigator. Reading center grading of less than ETDRS level 43 or greater than 53 is an exclusion.

   Severe NPDR is defined as:

   1. All 4 midperipheral quadrants show severe hemorrhages or microaneurysms (at least as great as Standard photograph 2A, approximately 20 dot and blot hemorrhages), or
   2. At least 2 fields of definite venous beading in the midperipheral quadrants or at least 1 field at least as severe as Standard photograph 6A, or
   3. At least 1 field of moderate intraretinal microvascular abnormalities (IRMA) in the midperipheral quadrants, at least as severe as Standard photograph 8A
3. No evidence of neovascularization on clinical exam including active neovascularization of the iris (small iris tufts are not an exclusion) or angle neovascularization (if the angle is assessed).

4. No evidence of neovascularization (NV) on fluorescein angiography within the 7-modified ETDRS fields, confirmed by the central Reading Center prior to randomization.

   • The widest method of imaging available at the site must be used to document whether there is NV present in the periphery; however, presence of NV outside of the 7-modified ETDRS fields on ultrawide field imaging will not be an exclusion provided treatment is not planned.

5. No center-involved diabetic macular edema (CI-DME) on clinical exam and optical coherence tomography (OCT) central subfield thickness must be below the following gender and OCT-machine specific thresholds:

   1. Zeiss Cirrus: 290 µm in women and 305 µm in men
   2. Heidelberg Spectralis: 305 µm in women and 320 µm in men
   3. Investigator and potential participant are comfortable withholding treatment for DME until there is at least a 10% increase in OCT central subfield thickness with confirmed visual acuity loss (10 letter loss at a single visit or 5 to 9 at two consecutive visits).
6. Prompt panretinal photocoagulation (PRP) or anti-vascular endothelial growth factor (anti-VEGF) treatment not required AND investigator and potential participant are willing to wait for development of high-risk characteristics (defined in protocol) to treat PDR.

7. Media clarity, pupillary dilation, and study participant cooperation sufficient to obtain adequate fundus photographs, fluorescein angiogram, and OCT.

   • Investigator must verify accuracy of OCT scan by ensuring it is centered and of adequate quality (including segmentation line placement)

Exclusion Criteria:

1. History of chronic renal failure requiring 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. Participation in an investigational trial that involved treatment within 30 days of randomization with any drug that has not received regulatory approval for the indication being studied.

   • Note: study participants cannot participate in another investigational trial that involves treatment with an investigational drug while participating in the study.

5. Known allergy to any component of the study drug or any drug used in the injection prep (including povidone iodine prep).
6. Known allergy to fluorescein dye.
7. Blood pressure > 180/110 (systolic above 180 or diastolic above 110). • If blood pressure is brought below 180/110 by anti-hypertensive treatment, individual can become eligible.

8. Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to randomization.

   • These drugs should not be used during the study.

9. For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 2 years.

   • Women who are potential study participants should be questioned about the potential for pregnancy. Investigator judgment is used to determine when a pregnancy test is needed.

10. Individual is expecting to move out of the area of the clinical center to an area not covered by another Diabetic Retinopathy Clinical Research Network certified clinical center during the next 2 years.

Individual has any of the following ocular characteristics in the eye(s) being evaluated:

1. Exam or photographic evidence of vitreous hemorrhage or preretinal hemorrhage presumed to be from PDR.
2. History of prior vitreous hemorrhage or preretinal hemorrhage presumed to be from PDR.
3. History of prior PRP (defined as ≥100 burns outside of the posterior pole).
4. An ocular condition is present (other than diabetic retinopathy) that, in the opinion of the investigator, might alter visual acuity during the course of the study (e.g., retinal vein or artery occlusion, uveitis or other ocular inflammatory disease, vitreomacular traction, etc.).

5. History of DME or diabetic retinopathy treatment with laser or intraocular injections of medication within the prior 12 months and no more than 4 prior intraocular injections at any time in the past.

   • Enrollment will be limited to a maximum of 25% of the planned sample size with any history of treatment for DME and/or diabetic retinopathy. Once this number of eyes has been enrolled, any history of treatment for DME and/or diabetic retinopathy will be an exclusion criterion.

6. History of major ocular surgery (including cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior 4 months or anticipated within the next 6 months following randomization.
7. Any history of vitrectomy.
8. History of yttrium aluminum garnet capsulotomy performed within 2 months prior to randomization.
9. Aphakia.
10. Exam evidence of severe external ocular infection, including conjunctivitis, chalazion, or substantial blepharitis.

11. Evidence of uncontrolled glaucoma.

    • Intraocular pressure must be <30, with no more than one topical glaucoma medication, and no documented glaucomatous field loss for the eye to be eligible.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Sham Comparator: Observation (Prompt Sham); Sham injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. Deferred aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met.	Procedure: Prompt Sham; A sham injection (syringe without a needle pressed against the injection site) is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter.; Procedure: Deferred laser; Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met; Other Names: focal/grid photocoagulation; panretinal photocoagulation; Drug: Deferred aflibercept; Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria.; Other Names: Eylea; intravitreal anti-vascular endothelial growth factor
Experimental: Prompt aflibercept; Aflibercept injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. More frequent aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met.	Procedure: Deferred laser; Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met; Other Names: focal/grid photocoagulation; panretinal photocoagulation; Drug: Deferred aflibercept; Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria.; Other Names: Eylea; intravitreal anti-vascular endothelial growth factor; Drug: Prompt aflibercept; Intravitreal injection of 2.0mg aflibercept is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter.; Other Names: Eylea; intravitreal anti-vascular endothelial growth factor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Development of PDR and/or DME (Whichever Came First)	CI-DME = center-involved diabetic macular edema, PDR = proliferative diabetic macular edema. First development of criteria meeting end point. Eyes that met any criteria are then censored from contributing to the next criteria. Eyes that did not meet the outcome were censored at the time of the last completed visit. Each outcome appears only once under "First PDR and/or DME criteria met." Outcomes appear under "Development of PDR" if PDR developed at any time in the study (regardless of if or when DME developed) and outcomes appear under "Development of DME" if DME developed at any time in the study (regardless of if or when PDR developed)	2 years
Change in Visual Acuity From Baseline	Visual acuity is measured as a continuous integer letter score from 0 to 100, with higher numbers indicating better visual acuity. A letter score of 85 is approximately 20/20 and a letter score of 70 is approximately 20/40, the legal unrestricted driving limit in most states. A 5-letter change for an individual is approximately equal to a 1-line change on a vision chart.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Visual Acuity From Baseline	Visual acuity is measured as a continuous integer letter score from 0 to 100, with higher numbers indicating better visual acuity. A letter score of 85 is approximately 20/20 and a letter score of 70 is approximately 20/40, the legal unrestricted driving limit in most states. A 5-letter change for an individual is approximately equal to a 1-line change on a vision chart.	4 years
Development of PDR and/or DME (Whichever Came First)	CI-DME = center-involved diabetic macular edema, PDR = proliferative diabetic macular edema. First development of criteria meeting end point. Eyes that met any criteria are then censored from contributing to the next criteria. Eyes that did not meet the outcome were censored at the time of the last completed visit. Each outcome appears only once under "First PDR and/or DME criteria met." Outcomes appear under "Development of PDR" if PDR developed at any time in the study (regardless of if or when DME developed) and outcomes appear under "Development of DME" if DME developed at any time in the study (regardless of if or when PDR developed)	4 years

Collaborators and Investigators

• Sponsor: Jaeb Center for Health Research
• Collaborators: Juvenile Diabetes Research Foundation; National Eye Institute (NEI); National Institutes of Health (NIH); Regeneron Pharmaceuticals
• Investigators: Study Chair: Jennifer K. Sun, MD, MPH, Joslin Diabetes Center

Publications and helpful links

General Publications

• Maturi RK, Glassman AR, Josic K, Antoszyk AN, Blodi BA, Jampol LM, Marcus DM, Martin DF, Melia M, Salehi-Had H, Stockdale CR, Punjabi OS, Sun JK; DRCR Retina Network. Effect of Intravitreous Anti-Vascular Endothelial Growth Factor vs Sham Treatment for Prevention of Vision-Threatening Complications of Diabetic Retinopathy: The Protocol W Randomized Clinical Trial. JAMA Ophthalmol. 2021 Jul 1;139(7):701-712. doi: 10.1001/jamaophthalmol.2021.0606.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2016
• Primary Completion (Actual): May 1, 2020
• Study Completion (Actual): May 11, 2022

Study Registration Dates

• First Submitted: December 11, 2015
• First Submitted That Met QC Criteria: December 15, 2015
• First Posted (Estimated): December 18, 2015

Study Record Updates

• Last Update Posted (Estimated): June 19, 2023
• Last Update Submitted That Met QC Criteria: May 22, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: anti-vascular endothelial growth factor; nonproliferative diabetic retinopathy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Eye Diseases; Endocrine System Diseases; Diabetic Angiopathies; Diabetes Complications; Diabetes Mellitus; Retinal Degeneration; Macular Degeneration; Retinal Diseases; Diabetic Retinopathy; Macular Edema; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Mitosis Modulators; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Aflibercept; Endothelial Growth Factors; Mitogens
• Other Study ID Numbers: DRCR.net Protocol W; EY14231 (Other Grant/Funding Number: National Eye Institute); EY23207 (Other Grant/Funding Number: National Eye Institute); EY18817 (Other Grant/Funding Number: National Eye Institute)