Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab, and Ranibizumab for Diabetic Macular Edema (Protocol T)

July 22, 2020 updated by: Jaeb Center for Health Research

A Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab and Ranibizumab for Diabetic Macular Edema

Although multiple studies have suggested that treatment with ranibizumab is safe and efficacious and superior to focal/grid laser alone for patients with center-involved diabetic macular edema (DME), there may be barriers in place to widespread adoption of ranibizumab use given its high cost per dose and the need for multiple treatments over time. Prioritizing resources from a public health policy perspective could be easier if more precise estimates regarding the risks and benefits of other anti-vascular endothelial growth factor (anti-VEGF) therapies were available, especially when the difference in costs could be billions of dollars over just a few years. Thus, there is a clear rationale at this time to explore potential anti-VEGF alternatives to ranibizumab that might prove to be as or more efficacious, might deliver equally lasting or longer-lasting treatment effects, and cost substantially less. Of the potentially available alternative anti-VEGF agents for this trial, bevacizumab and aflibercept are the best candidates for a direct comparison study. Bevacizumab shares the most similar molecular structure, costs far less, and is widely available. Furthermore, there is already preliminary evidence to suggest that it may be efficacious in the treatment of DME and it is already being widely used for this indication. Although aflibercept has a similar cost per unit dose to ranibizumab, it has the potential to decrease treatment burden and associated cost. If results from a comparative trial demonstrate improved efficacy or suggest similar efficacy of bevacizumab or aflibercept over ranibizumab, this information might give clinicians scientific rationale to substitute either one of these drugs for ranibizumab in the treatment of DME, and might thereby have substantial implications for public policy in terms of future estimates of health care dollars and possibly number of treatments necessary for anti-VEGF treatment of diabetic macular disease.

Because of its availability and lower cost, bevacizumab is already currently in widespread clinical use for treatment of DME despite the lack of FDA approval for this indication. Thus, a clinical trial that suggested whether bevacizumab could be used as a safe and efficacious alternative to ranibizumab could substantially impact nationwide practice patterns for treatment of DME by either validating the current use of bevacizumab or by demonstrating improved outcomes with ranibizumab or aflibercept treatment for DME.

Study Objective The primary objective of the proposed research is to compare the efficacy and safety of (1) intravitreal aflibercept, (2) intravitreal bevacizumab, and (3) intravitreal ranibizumab when given to treat central-involved DME in eyes with visual acuity of 20/32 to 20/320.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

A five year follow-up visit is being conducted to gather information on long term outcomes

Study Type

Interventional

Enrollment (Actual)

660

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Arizona
      • Tucson, Arizona, United States, 85710
        • Retina Associates
    • California
      • Beverly Hills, California, United States, 90211
        • Retina-Vitreous Associates Medical Group
      • Loma Linda, California, United States, 92354
        • Loma Linda University Health Care, Dept. of Ophthalmology
      • Palm Desert, California, United States, 92211
        • Southern California Desert Retina Consultants, MC
      • Santa Barbara, California, United States, 93103
        • California Retina Consultants
      • Walnut Creek, California, United States, 94598
        • Bay Area Retina Associates
      • Westlake Village, California, United States, 91361
        • Retinal Consultants of Southern California Medical Group, Inc.
    • Connecticut
      • Norwich, Connecticut, United States, 06360
        • New England Retina Associates
    • Florida
      • Clearwater, Florida, United States, 33761
        • Gulf Coast Retina Center
      • Fort Lauderdale, Florida, United States, 33334
        • Retina Group of Florida
      • Fort Myers, Florida, United States, 33912
        • National Ophthalmic Research Institute
      • Lakeland, Florida, United States, 33805
        • Central Florida Retina Institute
      • Ocala, Florida, United States, 34474
        • Ocala Eye Retina Consultants
      • Orlando, Florida, United States, 32803
        • Magruder Eye Institute
      • 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
      • Atlanta, Georgia, United States, 30342
        • Georgia Retina, P.C.
      • Atlanta, Georgia, United States, 30342
        • Thomas Eye Group
      • Augusta, Georgia, United States, 30909
        • Southeast Retina Center, P.C.
    • Hawaii
      • Honolulu, Hawaii, United States, 96701
        • Retina Consultants of Hawaii, Inc.
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Northwestern Medical Faculty Foundation
      • Chicago, Illinois, United States, 60612
        • University of Illinois at Chicago Medical Center
      • Glenview, Illinois, United States, 60026
        • Northshore University Healthsystem
    • Indiana
      • Indianapolis, Indiana, United States, 46280
        • Raj K. Maturi, M.D., P.C.
      • New Albany, Indiana, United States, 47150
        • John-Kenyon American Eye Institute
    • 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
      • Lexington, Kentucky, United States, 40509-1802
        • Retina and Vitreous Associates of Kentucky
      • Paducah, Kentucky, United States, 42001
        • Paducah Retinal Center
    • Maryland
      • Baltimore, Maryland, United States, 21237
        • Elman Retina Group, P.A.
      • Baltimore, Maryland, United States, 21287-9277
        • Wilmer Eye Institute at Johns Hopkins
    • Massachusetts
      • Boston, Massachusetts, United States, 02215
        • Joslin Diabetes Center
      • Boston, Massachusetts, United States, 02114
        • Ophthalmic Consultants of Boston
      • Worcester, Massachusetts, United States, 01605
        • Vitreo-Retinal Associates, PC
    • Michigan
      • Detroit, Michigan, United States, 48202
        • Henry Ford Health System, Dept of Ophthalmology and Eye Care Services
      • Grand Blanc, Michigan, United States, 48439
        • Retina Vitrous Center
      • Grand Rapids, Michigan, United States, 49525
        • Retina Specialists Of Michigan
      • Grand Rapids, Michigan, United States, 49525
        • Vitreo-Retinal Associates
    • Minnesota
      • Minneapolis, Minnesota, United States, 55404
        • Retina Center, PA
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic Department of Ophthalmology
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Barnes Retina Institute
    • New Hampshire
      • Portsmouth, New Hampshire, United States, 03801
        • Eyesight Ophthalmic Services, PA
    • New Jersey
      • Newark, New Jersey, United States, 07103
        • The Institute of Ophthalmology and Visual Science (IOVS)
    • New Mexico
      • Albuquerque, New Mexico, United States, 87102
        • Eye Associates of New Mexico
      • Albuquerque, New Mexico, United States, 871310001
        • University of New Mexico Health Sciences Center
    • New York
      • Bronx, New York, United States, 10467-2401
        • Montefiore Medical Center
      • 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
      • New York, New York, United States, 10029
        • Mount Sinai School of Medicine, Dept. of Ophthalmology
      • Rochester, New York, United States, 14642
        • University of Rochester
      • Rochester, New York, United States, 14618
        • Retina Associates of Western New York
      • Syracuse, New York, United States, 13224
        • Retina-Vitreous Surgeons of Central New York, PC
    • North Carolina
      • Asheville, North Carolina, United States, 28803
        • Western Carolina Retinal Associates, PA
      • Chapel Hill, North Carolina, United States, 27599-7040
        • University of North Carolina
      • Charlotte, North Carolina, United States, 28210
        • Charlotte Eye, Ear, Nose and Throat Assoc., PA
      • Winston-Salem, North Carolina, United States, 27157
        • Wake Forest University Eye Center
    • Ohio
      • Beachwood, Ohio, United States, 44122
        • Retina Associates of Cleveland, Inc.
      • Cleveland, Ohio, United States, 44106
        • Case Western Reserve University
      • Columbus, Ohio, United States, 43212
        • OSU Eye Physicians and Surgeons, LLC.
    • Oklahoma
      • Edmond, Oklahoma, United States, 73013
        • Retina Vitreous Center
      • Oklahoma City, Oklahoma, United States, 73104
        • Dean A. McGee Eye Institute
    • Oregon
      • Portland, Oregon, United States, 97239
        • Casey Eye Institute
      • Portland, Oregon, United States, 97210
        • Retina Northwest, PC
    • Pennsylvania
      • Lancaster, Pennsylvania, United States, 17601-2644
        • Family Eye Group
      • Philadelphia, Pennsylvania, United States, 19104
        • University of Pennsylvania Scheie Eye Institute
      • Pittsburgh, Pennsylvania, United States, 15213
        • Retina Vitrous Consultants
    • South Carolina
      • Charleston, South Carolina, United States, 29425
        • Storm Eye Institute, Medical University of South Carolina
      • Columbia, South Carolina, United States, 29223
        • Carolina Retina Center
      • Columbia, South Carolina, United States, 29169
        • Palmetto Retina Center
    • Tennessee
      • Kingsport, Tennessee, United States, 37660
        • Southeastern Retina Associates, PC
      • 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
      • 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
    • Utah
      • Salt Lake City, Utah, United States, 84107
        • Retina Associates of Utah, P.C.
    • Virginia
      • Leesburg, Virginia, United States, 20176
        • Virginia Retina Center
      • Richmond, Virginia, United States, 23235
        • Retina Institute of Virginia
    • Washington
      • Seattle, Washington, United States, 98195
        • University of Washington Medical Center
      • Spokane, Washington, United States, 99204
        • Spokane Eye Clinic
    • Wisconsin
      • Madison, Wisconsin, United States, 53705
        • University of Wisconsin-Madison, Dept of Ophthalmology/Retina Service
      • Milwaukee, Wisconsin, United States, 53226
        • Medical College of Wiconsin

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age ≥ 18 years
  • Individuals <18 years old are not being included because DME is so rare in this age group that the diagnosis of DME may be questionable.
  • 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 (see Procedures Manual for definitions)

  • At least one eye meets the following study eye criteria:

    • Best corrected Electronic-Early Treatment Diabetic Retinopathy Study visual acuity letter score ≤ 78 (i.e., 20/32 or worse) and ≥ 24 (i.e., 20/320 or better) within eight days of randomization.
    • On clinical exam, definite retinal thickening due to diabetic macular edema involving the center of the macula.
    • Diabetic macular edema present on optical coherence tomography (OCT) (central subfield thickness on OCT >250 µm on Zeiss Stratus or the equivalent on spectral domain OCTs based on gender specific cutoffs), within eight days of randomization.
    • Investigator must verify accuracy of OCT scan by ensuring it is centered and of adequate quality (for Zeiss Stratus, standard deviation of center point thickness should be ≤ 10% of the center point thickness and signal strength should be ≥ 6)
    • Media clarity, pupillary dilation, and individual cooperation sufficient for adequate fundus photographs
  • Able and willing to provide informed consent.

Exclusion Criteria:

  • Significant renal disease, defined as a history of chronic renal failure requiring dialysis or kidney transplant.

  • 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).

    •Individuals in poor glycemic control who, within the last four months, initiated intensive insulin treatment (a pump or multiple daily injections) or plan to do so in the next four months should not be enrolled.

  • 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 at the time of study entry.

    • Note: study participants cannot receive another investigational drug while participating in the study.

  • Known allergy to any component of the study drug.

  • 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.

  • Myocardial infarction, other acute cardiac event requiring hospitalization, stroke, transient ischemic attack, or treatment for acute congestive heart failure within 4 months prior to randomization.

  • Systemic anti-VEGF or pro-VEGF treatment within four months prior to randomization or anticipated use during the study.

    • These drugs cannot be used during the study.

  • For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 24 months.
  • 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.
  • Individual is expecting to move out of the area of the clinical center to an area not covered by another clinical center during the first 12 months of the study.

The following exclusions apply to the study eye only (i.e., they may be present for the nonstudy eye):

  • Macular edema is considered to be due to a cause other than diabetic macular edema.
  • An eye should not be considered eligible if: (1) the macular edema is considered to be related to ocular surgery such as cataract extraction or (2) clinical exam and/or OCT suggest that vitreoretinal interface abnormalities (e.g., a taut posterior hyaloid or epiretinal membrane) are the primary cause of the macular edema.
  • An ocular condition is present such that, in the opinion of the investigator, visual acuity loss would not improve from resolution of macular edema (e.g., foveal atrophy, pigment abnormalities, dense subfoveal hard exudates, nonretinal condition).
  • An ocular condition is present (other than diabetes) that, in the opinion of the investigator, might affect macular edema or alter visual acuity during the course of the study (e.g., vein occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, etc.).
  • Substantial cataract that, in the opinion of the investigator, is likely to be decreasing visual acuity by three lines or more (i.e., cataract would be reducing acuity to 20/40 or worse if eye was otherwise normal).
  • History of an anti-VEGF treatment for DME in the past 12 months or history of any other treatment for DME at any time in the past four months (such as focal/grid macular photocoagulation, intravitreal or peribulbar corticosteroids).
  • Enrollment will be limited to a maximum of 25% of the planned sample size with any history of anti-VEGF treatment for DME. Once this number of eyes has been enrolled, any history of anti-VEGF treatment for DME will be an exclusion criterion.
  • History of pan-retinal photocoagulation within four months prior to randomization or anticipated need for pan-retinal photocoagulation in the six months following randomization.
  • History of anti-VEGF treatment for a disease other than DME in the past 12 months.
  • History of major ocular surgery (including vitrectomy, cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior four months or anticipated within the next six months following randomization.
  • History of YAG capsulotomy performed within two months prior to randomization.
  • Aphakia.
  • Exam evidence of external ocular infection, including conjunctivitis, chalazion, or significant blepharitis.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Bevacizumab
Drug: 1.25 mg intravitreal bevacizumab
Intravitreal injection of 1.25 mg bevacizumab at baseline and up to every 4 weeks using defined retreatment criteria.
Active Comparator: Ranibizumab
Drug: 0.3 mg intravitreal ranibizumab
Intravitreal injection of 0.3 mg ranibizumab (Lucentis™) at baseline and up to every 4 weeks using defined retreatment criteria.
Experimental: Aflibercept
Drug: 2.0 mg intravitreal aflibercept
Intravitreal injection of 2.0 mg aflibercept at baseline and up to every 4 weeks using defined retreatment criteria.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 1-year
Time Frame: Baseline to 1-year
Visual Acuity was measured with the Electronic Early Treatment Study (E-ETDRS) visual acuity test. Unit of measure is based on the E-ETDRS letter score scale, 0-97, where 0 = worst and 97 = best.
Baseline to 1-year
Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 1-year: Baseline Visual Acuity Letter Score <69
Time Frame: Baseline to 1-year
Visual Acuity was measured with the Electronic Early Treatment Study (E-ETDRS) visual acuity test. Unit of measure is based on the E-ETDRS letter score scale, 0-97, where 0 = worst and 97 = best.
Baseline to 1-year
Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 1-year: Baseline Visual Acuity Letter Score 78-69
Time Frame: Baseline to 1-year
Visual Acuity was measured with the Electronic Early Treatment Study (E-ETDRS) visual acuity test. Unit of measure is based on the E-ETDRS letter score scale, 0-97, where 0 = worst and 97 = best.
Baseline to 1-year

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Change in Optical Coherence Tomography Central Subfield Thickness
Time Frame: baseline to 1-year

All baseline and 1-year optical coherence tomography (OCT) scans were graded by Duke Reading Center. In addition, a random sample of OCT images from other visits and images for which the investigator believed central grading was needed also were graded by Duke Reading Center.

Baseline CSF values were converted from the thickness value measured on a Spectralis or Cirrus OCT machine to a Stratus equivalent value for 583 scans. One-year CSF values were converted from a thickness value measured on a Spectralis or Cirrus OCT machine to a Stratus equivalent value for 604 scans. When calculating change in CSF thickness, measurements taken on the same machine at both visits were not converted, since the conversion equation slope is nearly 1 and the constant difference does not affect the change calculation. Therefore, change in CSF thickness was calculated after converting either the baseline and/or follow-up thickness value from Spectralis or Cirrus to a Stratus equivalent value in 26 eyes.
baseline to 1-year
Change in Optical Coherence Tomography Central Subfield Thickness: Baseline Visual Acuity Letter Score <69
Time Frame: baseline to 1-year

All baseline and 1-year optical coherence tomography (OCT) scans were graded by Duke Reading Center. In addition, a random sample of OCT images from other visits and images for which the investigator believed central grading was needed also were graded by Duke Reading Center.

Baseline CSF values were converted from the thickness value measured on a Spectralis or Cirrus OCT machine to a Stratus equivalent value for 583 scans. One-year CSF values were converted from a thickness value measured on a Spectralis or Cirrus OCT machine to a Stratus equivalent value for 604 scans. When calculating change in CSF thickness, measurements taken on the same machine at both visits were not converted, since the conversion equation slope is nearly 1 and the constant difference does not affect the change calculation. Therefore, change in CSF thickness was calculated after converting either the baseline and/or follow-up thickness value from Spectralis or Cirrus to a Stratus equivalent value in 26 eyes.
baseline to 1-year
Change in Optical Coherence Tomography Central Subfield Thickness: Baseline Visual Acuity Letter Score 78-69
Time Frame: baseline to 1-year

All baseline and 1-year optical coherence tomography (OCT) scans were graded by Duke Reading Center. In addition, a random sample of OCT images from other visits and images for which the investigator believed central grading was needed also were graded by Duke Reading Center.

Baseline CSF values were converted from the thickness value measured on a Spectralis or Cirrus OCT machine to a Stratus equivalent value for 583 scans. One-year CSF values were converted from a thickness value measured on a Spectralis or Cirrus OCT machine to a Stratus equivalent value for 604 scans. When calculating change in CSF thickness, measurements taken on the same machine at both visits were not converted, since the conversion equation slope is nearly 1 and the constant difference does not affect the change calculation. Therefore, change in CSF thickness was calculated after converting either the baseline and/or follow-up thickness value from Spectralis or Cirrus to a Stratus equivalent value in 26 eyes.
baseline to 1-year
Overall Change in Retinal Volume
Time Frame: Baseline to 1-year
Baseline volume values were converted from the thickness value measured on a Spectralis or Cirrus OCT machine to a Stratus equivalent value for 459 scans. One-year volume values were converted from a thickness value measured on a Spectralis or Cirrus OCT machine to a Stratus equivalent value for 472 scans. When calculating change in volume, measurements taken on the same machine at both visits were not converted, because the conversion equation slope is nearly 1 and the constant difference does not affect the change calculation. Therefore, change in volume was calculated after converting either the baseline and/or follow-up value from Spectralis or Cirrus to a Stratus equivalent value in 17 eyes.
Baseline to 1-year
Total Number of Injections Prior to 1 Year
Time Frame: Baseline to 1-year
Only includes participants that completed the 1 year visit
Baseline to 1-year
Total Number of Laser Treatments
Time Frame: between 24 weeks and 1 year
Only includes participants that completed the 1 year visit.
between 24 weeks and 1 year
Eyes Receiving 1 or More Alternative Treatments for DME Other Than Laser
Time Frame: Baseline to 1-year
Baseline to 1-year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Jaeb Center for Health Research

Collaborators

National Eye Institute (NEI)
Genentech, Inc.
Regeneron Pharmaceuticals

Investigators

  • Study Chair: John A Wells, MD, Palmetto Retina Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2012

Primary Completion (Actual)

October 1, 2014

Study Completion (Actual)

April 18, 2019

Study Registration Dates

First Submitted

June 21, 2012

First Submitted That Met QC Criteria

June 22, 2012

First Posted (Estimate)

June 25, 2012

Study Record Updates

Last Update Posted (Actual)

August 10, 2020

Last Update Submitted That Met QC Criteria

July 22, 2020

Last Verified

July 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DRCR.net Protocol T
  • EY14231 (Other Grant/Funding Number: National Eye Institute)
  • EY23207 (Other Grant/Funding Number: National Eye Institute)
  • EY18817 (Other Grant/Funding Number: National Eye Institute)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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