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

• Sponsor: Jaeb Center for Health Research (Other)
• Overall Status: Completed
• CT.gov ID: NCT03321513
• Collaborator: (none)
• Enrollment: 270
• Locations: 54
• Arms: 2
• Actual Duration (Months): 48.5
• Patients Per Site: 5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Diabetic Macular Edema	Drug: intravitreous aflibercept; Drug: Bevacizumab + Deferred Aflibercept Group	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 270 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized Trial of Intravitreous Aflibercept Versus Intravitreous Bevacizumab + Deferred Aflibercept for Treatment of Central-Involved Diabetic Macular Edema
• Actual Study Start Date: Dec 7, 2017
• Actual Primary Completion Date: Dec 22, 2021
• Actual Study Completion Date: Dec 22, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Mean Change in Visual Acuity [2 years]

   Area under the curve mean change in the electronic early treatment diabetic retinopathy study visual acuity

Secondary Outcome Measures

1. Mean change in visual acuity from baseline [24 weeks, 1 year, 2 years]

2. 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]

3. Percentages of eyes with visual acuity 20/20 or greater, 20/40 or greater, and 20/200 or worse [1 year, 2 years]

4. Mean change in optical coherence tomography central subfield thickness from baseline [24 weeks, 1 year, 2 years]

5. 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]

6. Percentages of eyes with worsening or improvement of diabetic retinopathy on fundus photographs [1 year, 2 years]

7. Percentage of eyes receiving panretinal photocoagulation, vitrectomy, or having vitreous hemorrhage from proliferative diabetic retinopathy [1 year, 2 years]

8. Number of visits [2 years]

9. Number of injections [1 year, 2 years]

10. Percentage of eyes that met switch criteria (bevacizumab + deferred aflibercept group only) [12, 24, 52, and 104-week visits]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

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

2. Able and willing to provide informed consent.

Exclusion

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

1. Significant renal disease, defined as a 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).

• 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.

1. 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.

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

2. 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.

1. 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.

1. 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.

1. 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

1. 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):

1. 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.

1. 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).

2. 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.).

3. 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).

4. 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.

1. History of pan-retinal photocoagulation within four months prior to randomization or anticipated need for pan-retinal photocoagulation in the six months following randomization.

2. History of anti-VEGF treatment for a disease other than DME in the past 12 months.

3. 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.

4. History of YAG capsulotomy performed within two months prior to randomization.

5. Aphakia.

6. Exam evidence of external ocular infection, including conjunctivitis, chalazion, or significant blepharitis.

7. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Retinal Diagnostic Center	Campbell	California	United States	95008
2	Macula & Retina Institute	Glendale	California	United States	91203
3	Loma Linda University Health Care, Department of Ophthalmology	Loma Linda	California	United States	92354
4	East Bay Retina Consultants, Inc	Oakland	California	United States	94609-3028
5	National Ophthalmic Research Institute	Fort Myers	Florida	United States	33912
6	Florida Retina Institute-Jacksonville	Jacksonville	Florida	United States	32216
7	Florida Retina Consultants	Lakeland	Florida	United States	33805
8	Retina Macula Specialists of Miami	Miami	Florida	United States	33126
9	Central Florida Retina	Orlando	Florida	United States	32806
10	Florida Retina Institute	Orlando	Florida	United States	32806
11	Southeast Eye Institute, P.A. dba Eye Associates of Pinellas	Pinellas Park	Florida	United States	33782
12	Fort Lauderdale Eye Institute	Plantation	Florida	United States	33324
13	Retina Associates of Sarasota	Sarasota	Florida	United States	34233
14	Sarasota Retina Institute	Sarasota	Florida	United States	34239
15	Retina Associates of Florida, LLC	Tampa	Florida	United States	33609
16	Retina Specialists of Tampa	Wesley Chapel	Florida	United States	33544
17	Southeast Retina Center, P.C.	Augusta	Georgia	United States	30909
18	Thomas Eye Group	Sandy Springs	Georgia	United States	30328
19	Illinois Retina Associates, S.C.	Oak Park	Illinois	United States	60304
20	Springfield Clinic, LLP	Springfield	Illinois	United States	62703
21	Raj K. Maturi, M.D., P.C.	Indianapolis	Indiana	United States	46290
22	John-Kenyon American Eye Institute	New Albany	Indiana	United States	47150
23	Mid-America Retina Consultants, P.A.	Overland Park	Kansas	United States	66211
24	Retina Associates, P.A.	Shawnee Mission	Kansas	United States	66204
25	Paducah Retinal Center	Paducah	Kentucky	United States	42001
26	Eye Associates of Northeast Louisiana dba Haik Humble Eye Center	West Monroe	Louisiana	United States	71291
27	Mid Atlantic Retina Specialists	Hagerstown	Maryland	United States	21740
28	Valley Eye Physicians and Surgeons	Ayer	Massachusetts	United States	01432
29	Joslin Diabetes Center	Boston	Massachusetts	United States	02215
30	Retina Specialists of Michigan	Grand Rapids	Michigan	United States	49546
31	Vitreo-Retinal Associates	Grand Rapids	Michigan	United States	49546
32	The Retina Institute	Saint Louis	Missouri	United States	63128
33	Eye Associates of New Mexico	Albuquerque	New Mexico	United States	87109
34	MaculaCare	New York	New York	United States	10021
35	Retina Associates of Western New York	Rochester	New York	United States	14620
36	Western Carolina Clinical Research, LLC	Asheville	North Carolina	United States	28803
37	Charlotte Eye, Ear, Nose and Throat Assoc., PA	Charlotte	North Carolina	United States	28210
38	University Hospitals Cleveland Medical Center	Cleveland	Ohio	United States	44106
39	Dean A. McGee Eye Institute	Oklahoma City	Oklahoma	United States	73104
40	Retina Northwest, PC	Portland	Oregon	United States	97221
41	Cascade Medical Research Institute, LLC	Springfield	Oregon	United States	97477
42	Retina Vitreous Consultants	Monroeville	Pennsylvania	United States	15146
43	Retinavitreous Associates, dba; Mid Atlantic Retina	Philadelphia	Pennsylvania	United States	19107-5109
44	Southeastern Retina Associates, P.C.	Knoxville	Tennessee	United States	37909
45	Austin Retina Associates	Austin	Texas	United States	78705
46	Retina Research Center	Austin	Texas	United States	78705
47	Retina Center of Texas	Grapevine	Texas	United States	76051
48	Baylor Eye Physicians and Surgeons	Houston	Texas	United States	77030
49	Retina Consultants of Houston, PA	Houston	Texas	United States	77030
50	Texas Retina Associates	Lubbock	Texas	United States	79424
51	Valley Retina Institute	McAllen	Texas	United States	78503
52	Retinal Consultants of San Antonio	San Antonio	Texas	United States	78240
53	Spokane Eye Clinic	Spokane	Washington	United States	99204
54	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Jaeb Center for Health Research

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jaeb Center for Health Research
• ClinicalTrials.gov Identifier: NCT03321513
• Other Study ID Numbers: DRCR.net Protocol AC
• First Posted: Oct 25, 2017
• Last Update Posted: Jun 28, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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
• Keywords provided by Jaeb Center for Health Research: Diabetic Macular Edema; anti-vascular endothelial growth factor
• Additional relevant MeSH terms: Macular Edema; Edema; Bevacizumab; Aflibercept

Study Results

No Results Posted as of Jun 28, 2022