DRCR.Net Aflibercept vs. Bevacizumab + Deferred Aflibercept for the Treatment of CI-DME (DRCR AC)

Randomized Trial of Intravitreous Aflibercept Versus Intravitreous Bevacizumab + Deferred Aflibercept for Treatment of Central-Involved Diabetic Macular Edema

Both aflibercept and bevacizumab have been shown to improve vision in eyes with DME. In eyes with DME and at least moderate vision loss, both aflibercept and bevacizumab were also shown to be successful in many eyes. However, aflibercept was shown to be more effective at improving vision, on average, at 1 year and at 2 years. Due to the large cost difference between the two drugs, many clinicians and patients are choosing to initiate treatment with bevacizumab and then switch to aflibercept depending on the eye's response to bevacizumab treatment. However, there is no scientific evidence that this treatment strategy is as effective at improving vision as initiating treatment with aflibercept. Patients and clinicians do not know if this approach ultimately has deleterious effects on visual acuity. If starting with aflibercept is not better than starting with bevacizumab and switching to aflibercept if needed, the potential cost savings to future patients and the health care system would be substantial. However, if starting with aflibercept is better, then patients, clinicians, and health care providers can make informed decisions for how to best treat patients with DME and at least moderate vision loss.

Study Objectives To compare the efficacy of intravitreous aflibercept with intravitreous bevacizumab + deferred aflibercept if needed in eyes with CI DME and moderate vision loss

Study Overview

• Status: Completed
• Conditions: Diabetic Macular Edema
• Intervention / Treatment: Drug: intravitreous aflibercept; Drug: Bevacizumab + Deferred Aflibercept Group

• Study Type: Interventional
• Enrollment (Actual): 270
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Campbell, California, United States, 95008
      • Retinal Diagnostic Center
    • Glendale, California, United States, 91203
      • Macula & Retina Institute
    • Loma Linda, California, United States, 92354
      • Loma Linda University Health Care, Department of Ophthalmology
    • Oakland, California, United States, 94609-3028
      • East Bay Retina Consultants, Inc
  • Florida
    • Fort Myers, Florida, United States, 33912
      • National Ophthalmic Research Institute
    • Jacksonville, Florida, United States, 32216
      • Florida Retina Institute-Jacksonville
    • Lakeland, Florida, United States, 33805
      • Florida Retina Consultants
    • Miami, Florida, United States, 33126
      • Retina Macula Specialists of Miami
    • Orlando, Florida, United States, 32806
      • Florida Retina Institute
    • Orlando, Florida, United States, 32806
      • Central Florida Retina
    • 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
    • Sarasota, Florida, United States, 34233
      • Retina Associates of Sarasota
    • Tampa, Florida, United States, 33609
      • Retina Associates of Florida, LLC
    • Wesley Chapel, Florida, United States, 33544
      • Retina Specialists of Tampa
  • Georgia
    • Augusta, Georgia, United States, 30909
      • Southeast Retina Center, P.C.
    • Sandy Springs, Georgia, United States, 30328
      • Thomas Eye Group
  • Illinois
    • Oak Park, Illinois, United States, 60304
      • Illinois Retina Associates, S.C.
    • Springfield, Illinois, United States, 62703
      • Springfield Clinic, Llp
  • Indiana
    • Indianapolis, Indiana, United States, 46290
      • Raj K. Maturi, M.D., P.C.
    • New Albany, Indiana, United States, 47150
      • John-Kenyon American Eye Institute
  • Kansas
    • Overland Park, Kansas, United States, 66211
      • Mid-America Retina Consultants, P.A.
    • 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
    • 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
    • Grand Rapids, Michigan, United States, 49546
      • Vitreo-Retinal Associates
    • Grand Rapids, Michigan, United States, 49546
      • Retina Specialists of Michigan
  • Missouri
    • Saint Louis, Missouri, United States, 63128
      • The Retina Institute
  • New Mexico
    • Albuquerque, New Mexico, United States, 87109
      • Eye Associates of New Mexico
  • New York
    • New York, New York, United States, 10021
      • MaculaCare
    • Rochester, New York, United States, 14620
      • Retina Associates of Western New York
  • North Carolina
    • Asheville, North Carolina, United States, 28803
      • Western Carolina Clinical Research, LLC
    • Charlotte, North Carolina, United States, 28210
      • Charlotte Eye, Ear, Nose and Throat Assoc., PA
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Dean A. McGee Eye Institute
  • Oregon
    • Portland, Oregon, United States, 97221
      • Retina Northwest, PC
    • Springfield, Oregon, United States, 97477
      • Cascade Medical Research Institute, LLC
  • Pennsylvania
    • Monroeville, Pennsylvania, United States, 15146
      • Retina Vitreous Consultants
    • Philadelphia, Pennsylvania, United States, 19107-5109
      • Retinavitreous Associates, dba; Mid Atlantic Retina
  • Tennessee
    • Knoxville, Tennessee, United States, 37909
      • Southeastern Retina Associates, P.C.
  • Texas
    • Austin, Texas, United States, 78705
      • Austin Retina Associates
    • Austin, Texas, United States, 78705
      • Retina Research Center
    • Grapevine, Texas, United States, 76051
      • Retina Center of Texas
    • Houston, Texas, United States, 77030
      • Retina Consultants of Houston, PA
    • 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
  • 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: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Participant-level Criteria Inclusion

To be eligible, the following inclusion criteria must be met:

1. 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.

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

3. At least one eye meets the study eye criteria listed.

4. Able and willing to provide informed consent.

   Exclusion

   An individual is not eligible if any of the following exclusion criteria are present:

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

6. 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.

7. 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.

8. Known allergy to any component of the study drug or any drug used in the injection prep (including povidone iodine prep).

9. 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.

10. 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.

11. 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.

12. Individual is expecting to move out of the area of the clinical center to an area not covered by another clinical center during the next two years.

Study Eye Criteria The study participant must have at least one eye meeting all of the inclusion criteria and none of the exclusion criteria listed below.

Study participants can have two study eyes only if both eyes are eligible at the time of randomization. For study participants with two eligible eyes, the logistical complexities of the protocol must be considered for each individual prior to randomizing both eyes.

The eligibility criteria for a study eye are as follows:

Inclusion

1. Best corrected Electronic-Early Treatment Diabetic Retinopathy Study visual acuity letter score < 69 (i.e., 20/50 or worse) and ≥ 24 (i.e., 20/320 or better) within eight days of randomization.
2. On clinical exam, definite retinal thickening due to diabetic macular edema involving the center of the macula.

3. Diabetic macular edema present on optical coherence tomography (OCT) within eight days of randomization

   • Zeiss Cirrus central subfield: ≥ 290µm in women or ≥ 305µm in men
   • Heidelberg Spectralis central subfield: ≥ 305µm in women or ≥ 320µm in men
   • Investigator must verify accuracy of OCT scan by ensuring it is centered and of adequate quality

4. Media clarity, pupillary dilation, and individual cooperation sufficient for adequate fundus photographs.

   Exclusions

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

5. 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.

6. 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).
7. 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.).
8. 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).

9. History of an anti-vascular endothelial growth factor (anti-VEGF) treatment for diabetic macular edema (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, intravitreous 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.

10. History of pan-retinal photocoagulation within four months prior to randomization or anticipated need for pan-retinal photocoagulation in the six months following randomization.
11. History of anti-VEGF treatment for a disease other than DME in the past 12 months.
12. 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.
13. History of YAG capsulotomy performed within two months prior to randomization.
14. Aphakia.
15. Exam evidence of external ocular infection, including conjunctivitis, chalazion, or significant blepharitis.
16. 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

Note, combination therapies are considered more than one medication

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Aflibercept Group; 2.0 mg intravitreous aflibercept	Drug: intravitreous aflibercept; Intravitreous aflibercept injection is made by Regeneron Pharmaceuticals, Inc. and is approved by the FDA for the treatment of neovascular age-related macular degeneration, macular edema due to central retinal vein occlusion, macular edema due to branch retinal vein occlusion, diabetic macular edema, and diabetic retinopathy in eyes with diabetic macular edema. Study eyes assigned to receive aflibercept will receive a dose of 2.0 mg in 0.05 cc. Aflibercept will be obtained commercially by the clinical site. The physical, chemical, and pharmaceutical properties and formulation of aflibercept are provided in the Package Insert. Intravitreous Injection Technique The injection is preceded by a povidone iodine prep of the conjunctiva. In general, topical antibiotics in the pre-, peri-, or post-injection period should not be used. The injection will be performed using sterile technique; Other Names: Eylea
Experimental: Bevacizumab + Deferred Aflibercept Group; 1.25 mg intravitreous bevacizumab + deferred intravitreous 2.0 mg aflibercept if eye meets switch criteria	Drug: intravitreous aflibercept; Intravitreous aflibercept injection is made by Regeneron Pharmaceuticals, Inc. and is approved by the FDA for the treatment of neovascular age-related macular degeneration, macular edema due to central retinal vein occlusion, macular edema due to branch retinal vein occlusion, diabetic macular edema, and diabetic retinopathy in eyes with diabetic macular edema. Study eyes assigned to receive aflibercept will receive a dose of 2.0 mg in 0.05 cc. Aflibercept will be obtained commercially by the clinical site. The physical, chemical, and pharmaceutical properties and formulation of aflibercept are provided in the Package Insert. Intravitreous Injection Technique The injection is preceded by a povidone iodine prep of the conjunctiva. In general, topical antibiotics in the pre-, peri-, or post-injection period should not be used. The injection will be performed using sterile technique; Other Names: Eylea; Drug: Bevacizumab + Deferred Aflibercept Group; Bevacizumab is made by Genentech, Inc. and is approved by the FDA for the treatment of metastatic colorectal cancer as well as the treatment of non-squamous non-small cell lung cancer, glioblastoma, and metastatic renal cell carcinoma. Study eyes assigned to receive bevacizumab will receive a dose of 1.25 mg provided by a single compounding pharmacy identified by the Network and distributed by the Network. The volume of the injections will be 0.05 cc. Intravitreous injection technique: The injection is preceded by a povidone iodine prep of the conjunctiva. In general, topical antibiotics in the pre-, peri-, or post-injection period should not be used. The injection will be performed using a sterile technique.; Other Names: Avastin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in Visual Acuity	Area under the curve mean change in the electronic early treatment diabetic retinopathy study visual acuity	2 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Mean change in visual acuity from baseline	24 weeks, 1 year, 2 years
Percentages of eyes with a gain (increase) or loss (decrease) of at least 10 or at least 15 letters of visual acuity from baseline	1 year, 2 years
Percentages of eyes with visual acuity 20/20 or greater, 20/40 or greater, and 20/200 or worse	1 year, 2 years
Mean change in optical coherence tomography central subfield thickness from baseline	24 weeks, 1 year, 2 years
Percentage of eyes with optical coherence tomography central subfield thickness below the gender-specific spectral domain optical coherence tomography equivalent of 250 µm on Zeiss Stratus OCT	1 year, 2 years
Percentages of eyes with worsening or improvement of diabetic retinopathy on fundus photographs	1 year, 2 years
Percentage of eyes receiving panretinal photocoagulation, vitrectomy, or having vitreous hemorrhage from proliferative diabetic retinopathy	1 year, 2 years
Number of visits	2 years
Number of injections	1 year, 2 years
Percentage of eyes that met switch criteria (bevacizumab + deferred aflibercept group only)	12, 24, 52, and 104-week visits

Collaborators and Investigators

• Sponsor: Jaeb Center for Health Research

Publications and helpful links

General Publications

• Jhaveri CD, Glassman AR, Ferris FL 3rd, Liu D, Maguire MG, Allen JB, Baker CW, Browning D, Cunningham MA, Friedman SM, Jampol LM, Marcus DM, Martin DF, Preston CM, Stockdale CR, Sun JK; DRCR Retina Network. Aflibercept Monotherapy or Bevacizumab First for Diabetic Macular Edema. N Engl J Med. 2022 Aug 25;387(8):692-703. doi: 10.1056/NEJMoa2204225. Epub 2022 Jul 14.

Study record dates

Study Major Dates

• Study Start (Actual): December 7, 2017
• Primary Completion (Actual): December 22, 2021
• Study Completion (Actual): December 22, 2021

Study Registration Dates

• First Submitted: October 23, 2017
• First Submitted That Met QC Criteria: October 23, 2017
• First Posted (Actual): October 25, 2017

Study Record Updates

• Last Update Posted (Actual): December 1, 2022
• Last Update Submitted That Met QC Criteria: November 28, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Diabetic Macular Edema; anti-vascular endothelial growth factor
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Degeneration; Retinal Diseases; Macular Degeneration; Macular Edema; Edema; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab; Aflibercept
• Other Study ID Numbers: DRCR.net Protocol AC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No