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

Diabetic Macular Edema Clinical Trial

— DRCR AC  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03321513
• Other study ID #: DRCR.net Protocol AC
• Status: Completed
• Phase: Phase 3
• Start date: December 7, 2017
• Est. completion date: December 22, 2021

Study information

• Verified date: April 2024
• Source: Jaeb Center for Health Research
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 270
• Est. completion date: December 22, 2021
• Est. primary completion date: December 22, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Diabetic Macular Edema
• Edema
• Macular Edema

Intervention

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
• 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.

Locations

Country	Name	City	State
United States	Eye Associates of New Mexico	Albuquerque	New Mexico
United States	Western Carolina Clinical Research, LLC	Asheville	North Carolina
United States	Southeast Retina Center, P.C.	Augusta	Georgia
United States	Austin Retina Associates	Austin	Texas
United States	Retina Research Center	Austin	Texas
United States	Valley Eye Physicians and Surgeons	Ayer	Massachusetts
United States	Joslin Diabetes Center	Boston	Massachusetts
United States	Retinal Diagnostic Center	Campbell	California
United States	Charlotte Eye, Ear, Nose and Throat Assoc., PA	Charlotte	North Carolina
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	National Ophthalmic Research Institute	Fort Myers	Florida
United States	Macula & Retina Institute	Glendale	California
United States	Retina Specialists of Michigan	Grand Rapids	Michigan
United States	Vitreo-Retinal Associates	Grand Rapids	Michigan
United States	Retina Center of Texas	Grapevine	Texas
United States	Mid Atlantic Retina Specialists	Hagerstown	Maryland
United States	Baylor Eye Physicians and Surgeons	Houston	Texas
United States	Retina Consultants of Houston, PA	Houston	Texas
United States	Raj K. Maturi, M.D., P.C.	Indianapolis	Indiana
United States	Florida Retina Institute-Jacksonville	Jacksonville	Florida
United States	Southeastern Retina Associates, P.C.	Knoxville	Tennessee
United States	Florida Retina Consultants	Lakeland	Florida
United States	Loma Linda University Health Care, Department of Ophthalmology	Loma Linda	California
United States	Texas Retina Associates	Lubbock	Texas
United States	Valley Retina Institute	McAllen	Texas
United States	Retina Macula Specialists of Miami	Miami	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Retina Vitreous Consultants	Monroeville	Pennsylvania
United States	John-Kenyon American Eye Institute	New Albany	Indiana
United States	MaculaCare	New York	New York
United States	Illinois Retina Associates, S.C.	Oak Park	Illinois
United States	East Bay Retina Consultants, Inc	Oakland	California
United States	Dean A. McGee Eye Institute	Oklahoma City	Oklahoma
United States	Central Florida Retina	Orlando	Florida
United States	Florida Retina Institute	Orlando	Florida
United States	Mid-America Retina Consultants, P.A.	Overland Park	Kansas
United States	Paducah Retinal Center	Paducah	Kentucky
United States	Retinavitreous Associates, dba; Mid Atlantic Retina	Philadelphia	Pennsylvania
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 Northwest, PC	Portland	Oregon
United States	Retina Associates of Western New York	Rochester	New York
United States	The Retina Institute	Saint Louis	Missouri
United States	Retinal Consultants of San Antonio	San Antonio	Texas
United States	Thomas Eye Group	Sandy Springs	Georgia
United States	Retina Associates of Sarasota	Sarasota	Florida
United States	Sarasota Retina Institute	Sarasota	Florida
United States	Retina Associates, P.A.	Shawnee Mission	Kansas
United States	Spokane Eye Clinic	Spokane	Washington
United States	Cascade Medical Research Institute, LLC	Springfield	Oregon
United States	Springfield Clinic, LLP	Springfield	Illinois
United States	Retina Associates of Florida, LLC	Tampa	Florida
United States	Retina Specialists of Tampa	Wesley Chapel	Florida
United States	Eye Associates of Northeast Louisiana dba Haik Humble Eye Center	West Monroe	Louisiana

Sponsors (1)

Lead Sponsor	Collaborator
Jaeb Center for Health Research

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean Change in Visual Acuity	Area under the curve mean change in the electronic early treatment diabetic retinopathy study visual acuity. Visual acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study visual-acuity test on a scale from 100 letters (Snellen equivalent, 20/10) to 0 letters (Snellen equivalent, <20/800), with higher scores indicating better vision. The data presented are the best-corrected visual acuity in the study eye after protocol-defined refraction. The primary outcome was the time-averaged change in the visual-acuity letter score over a period of 104 weeks. The score was derived by calculating the area under the curve (AUC) over the 104-week period for the change in visual acuity from baseline and dividing by the length of follow-up.	2 years
Secondary	Change in Visual Acuity From Baseline	Visual acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study visual-acuity test on a scale from 100 letters (Snellen equivalent, 20/10) to 0 letters (Snellen equivalent, <20/800), with higher scores indicating better vision.	2 years
Secondary	Increase in E-ETDRS Visual Acuity Letter Score	Visual acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual-acuity test on a scale from 100 letters (Snellen equivalent, 20/10) to 0 letters (Snellen equivalent, <20/800), with higher scores indicating better vision.	2 years
Secondary	Decrease in E-ETDRS Visual Acuity Letter Score	Visual acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study visual-acuity test on a scale from 100 letters (Snellen equivalent, 20/10) to 0 letters (Snellen equivalent, <20/800), with higher scores indicating better vision.	2 years
Secondary	Visual Acuity	Visual acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study visual-acuity test on a scale from 100 letters (Snellen equivalent, 20/10) to 0 letters (Snellen equivalent, <20/800), with higher scores indicating better vision.	2 years
Secondary	Optical Coherence Tomography Central Subfield Thickness Change From Baseline	Measurements made on the Cirrus device were converted to equivalent scores as would be assessed on the Spectralis device with the use of the following formula: Spectralis score = 40.78 + 0.95 × Cirrus score.	2 years
Secondary	Optical Coherence Tomography Central Subfield Thickness Below the Sex-specific Threshold for Central-involved Diabetic Macular Edema	Optical coherence tomography (OCT) central subfield thickness equivalents for measurements obtained on Spectral domain OCT machines were 320 µm for men and 305 µm for women on the Spectralis device (Heidelberg) and were 305 µm and 290 µm, respectively on the Cirrus OCT measurement device (Zeiss).	2 years
Secondary	Number of Visits		2 years
Secondary	Number of Injections	All study injections were counted, including aflibercept injections received among eyes in the bevacizumab first group.	2 years
Secondary	Number of Eyes in the Bevacizumab-first Group Meeting the Switching Criteria		Baseline to 12 weeks
Secondary	Number of Eyes in the Bevacizumab-first Group Meeting the Switching Criteria		Baseline to 24 weeks
Secondary	Number of Eyes in the Bevacizumab-first Group Meeting the Switching Criteria		Baseline to 52 weeks
Secondary	Number of Eyes in the Bevacizumab-first Group Meeting the Switching Criteria		Baseline to 104 weeks