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

NCT ID: NCT03321513

Last Updated: 2024-04-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 270 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-12-07
• Study Completion Date: 2021-12-22

Brief Summary

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

Conditions

Diabetic Macular Edema

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Aflibercept Group

2.0 mg intravitreous aflibercept

Group Type: ACTIVE_COMPARATOR

intravitreous aflibercept

Intervention Type: DRUG

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

Bevacizumab + Deferred Aflibercept Group

1.25 mg intravitreous bevacizumab + deferred intravitreous 2.0 mg aflibercept if eye meets switch criteria

Group Type: EXPERIMENTAL

intravitreous aflibercept

Intervention Type: DRUG

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

Bevacizumab + Deferred Aflibercept Group

Intervention Type: DRUG

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.

Interventions

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

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Eylea; Avastin

Eligibility Criteria

Inclusion Criteria

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

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

Exclusion Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Jaeb Center for Health Research

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Retinal Diagnostic Center

Campbell, California, United States

Macula & Retina Institute

Glendale, California, United States

Loma Linda University Health Care, Department of Ophthalmology

Loma Linda, California, United States

East Bay Retina Consultants, Inc

Oakland, California, United States

National Ophthalmic Research Institute

Fort Myers, Florida, United States

Florida Retina Institute-Jacksonville

Jacksonville, Florida, United States

Florida Retina Consultants

Lakeland, Florida, United States

Retina Macula Specialists of Miami

Miami, Florida, United States

Central Florida Retina

Orlando, Florida, United States

Florida Retina Institute

Orlando, Florida, United States

Southeast Eye Institute, P.A. dba Eye Associates of Pinellas

Pinellas Park, Florida, United States

Fort Lauderdale Eye Institute

Plantation, Florida, United States

Retina Associates of Sarasota

Sarasota, Florida, United States

Sarasota Retina Institute

Sarasota, Florida, United States

Retina Associates of Florida, LLC

Tampa, Florida, United States

Retina Specialists of Tampa

Wesley Chapel, Florida, United States

Southeast Retina Center, P.C.

Augusta, Georgia, United States

Thomas Eye Group

Sandy Springs, Georgia, United States

Illinois Retina Associates, S.C.

Oak Park, Illinois, United States

Springfield Clinic, LLP

Springfield, Illinois, United States

Raj K. Maturi, M.D., P.C.

Indianapolis, Indiana, United States

John-Kenyon American Eye Institute

New Albany, Indiana, United States

Mid-America Retina Consultants, P.A.

Overland Park, Kansas, United States

Retina Associates, P.A.

Shawnee Mission, Kansas, United States

Paducah Retinal Center

Paducah, Kentucky, United States

Eye Associates of Northeast Louisiana dba Haik Humble Eye Center

West Monroe, Louisiana, United States

Mid Atlantic Retina Specialists

Hagerstown, Maryland, United States

Valley Eye Physicians and Surgeons

Ayer, Massachusetts, United States

Joslin Diabetes Center

Boston, Massachusetts, United States

Retina Specialists of Michigan

Grand Rapids, Michigan, United States

Vitreo-Retinal Associates

Grand Rapids, Michigan, United States

The Retina Institute

St Louis, Missouri, United States

Eye Associates of New Mexico

Albuquerque, New Mexico, United States

MaculaCare

New York, New York, United States

Retina Associates of Western New York

Rochester, New York, United States

Western Carolina Clinical Research, LLC

Asheville, North Carolina, United States

Charlotte Eye, Ear, Nose and Throat Assoc., PA

Charlotte, North Carolina, United States

University Hospitals Cleveland Medical Center

Cleveland, Ohio, United States

Dean A. McGee Eye Institute

Oklahoma City, Oklahoma, United States

Retina Northwest, PC

Portland, Oregon, United States

Cascade Medical Research Institute, LLC

Springfield, Oregon, United States

Retina Vitreous Consultants

Monroeville, Pennsylvania, United States

Retinavitreous Associates, dba; Mid Atlantic Retina

Philadelphia, Pennsylvania, United States

Southeastern Retina Associates, P.C.

Knoxville, Tennessee, United States

Austin Retina Associates

Austin, Texas, United States

Retina Research Center

Austin, Texas, United States

Retina Center of Texas

Grapevine, Texas, United States

Baylor Eye Physicians and Surgeons

Houston, Texas, United States

Retina Consultants of Houston, PA

Houston, Texas, United States

Texas Retina Associates

Lubbock, Texas, United States

Valley Retina Institute

McAllen, Texas, United States

Retinal Consultants of San Antonio

San Antonio, Texas, United States

Spokane Eye Clinic

Spokane, Washington, United States

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 35833805 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

DRCR.net Protocol AC

Identifier Type: -

Identifier Source: org_study_id