Clinical trial NCT03321513: DRCR.Net Aflibercept vs. Bevacizumab + Deferred Aflibercept for the Treatment of CI-DME
Official title: Randomized Trial of Intravitreous Aflibercept Versus Intravitreous Bevacizumab + Deferred Aflibercept for Treatment of Central-Involved Diabetic Macular Edema
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetic Macular Edema
Keywords: Diabetic Macular Edema
anti-vascular endothelial growth factor
Lead sponsor: Jaeb Center for Health Research
Sponsor class: OTHER
First posted: 2017-10-25
Enrollment: 270
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


Eligibility criteria: 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

Primary outcomes:
measure: Mean Change in Visual Acuity
timeFrame: 2 years
Secondary outcomes:
measure: Change in Visual Acuity From Baseline
timeFrame: 2 years
measure: Increase in E-ETDRS Visual Acuity Letter Score
timeFrame: 2 years
measure: Decrease in E-ETDRS Visual Acuity Letter Score
timeFrame: 2 years
measure: Visual Acuity
timeFrame: 2 years
measure: Optical Coherence Tomography Central Subfield Thickness Change From Baseline
timeFrame: 2 years
measure: Optical Coherence Tomography Central Subfield Thickness Below the Sex-specific Threshold for Central-involved Diabetic Macular Edema
timeFrame: 2 years
measure: Number of Visits
timeFrame: 2 years
measure: Number of Injections
timeFrame: 2 years
measure: Number of Eyes in the Bevacizumab-first Group Meeting the Switching Criteria
timeFrame: Baseline to 12 weeks
measure: Number of Eyes in the Bevacizumab-first Group Meeting the Switching Criteria
timeFrame: Baseline to 24 weeks
measure: Number of Eyes in the Bevacizumab-first Group Meeting the Switching Criteria
timeFrame: Baseline to 52 weeks
measure: Number of Eyes in the Bevacizumab-first Group Meeting the Switching Criteria
timeFrame: Baseline to 104 weeks
Other outcomes:
Locations:
city: Campbell
country: United States
facility: Retinal Diagnostic Center
state: California
city: Glendale
country: United States
facility: Macula & Retina Institute
state: California
city: Loma Linda
country: United States
facility: Loma Linda University Health Care, Department of Ophthalmology
state: California
city: Oakland
country: United States
facility: East Bay Retina Consultants, Inc
state: California
city: Fort Myers
country: United States
facility: National Ophthalmic Research Institute
state: Florida
city: Jacksonville
country: United States
facility: Florida Retina Institute-Jacksonville
state: Florida
city: Lakeland
country: United States
facility: Florida Retina Consultants
state: Florida
city: Miami
country: United States
facility: Retina Macula Specialists of Miami
state: Florida
city: Orlando
country: United States
facility: Central Florida Retina
state: Florida
city: Orlando
country: United States
facility: Florida Retina Institute
state: Florida
city: Pinellas Park
country: United States
facility: Southeast Eye Institute, P.A. dba Eye Associates of Pinellas
state: Florida
city: Plantation
country: United States
facility: Fort Lauderdale Eye Institute
state: Florida
city: Sarasota
country: United States
facility: Retina Associates of Sarasota
state: Florida
city: Sarasota
country: United States
facility: Sarasota Retina Institute
state: Florida
city: Tampa
country: United States
facility: Retina Associates of Florida, LLC
state: Florida
city: Wesley Chapel
country: United States
facility: Retina Specialists of Tampa
state: Florida
city: Augusta
country: United States
facility: Southeast Retina Center, P.C.
state: Georgia
city: Sandy Springs
country: United States
facility: Thomas Eye Group
state: Georgia
city: Oak Park
country: United States
facility: Illinois Retina Associates, S.C.
state: Illinois
city: Springfield
country: United States
facility: Springfield Clinic, LLP
state: Illinois
city: Indianapolis
country: United States
facility: Raj K. Maturi, M.D., P.C.
state: Indiana
city: New Albany
country: United States
facility: John-Kenyon American Eye Institute
state: Indiana
city: Overland Park
country: United States
facility: Mid-America Retina Consultants, P.A.
state: Kansas
city: Shawnee Mission
country: United States
facility: Retina Associates, P.A.
state: Kansas
city: Paducah
country: United States
facility: Paducah Retinal Center
state: Kentucky
city: West Monroe
country: United States
facility: Eye Associates of Northeast Louisiana dba Haik Humble Eye Center
state: Louisiana
city: Hagerstown
country: United States
facility: Mid Atlantic Retina Specialists
state: Maryland
city: Ayer
country: United States
facility: Valley Eye Physicians and Surgeons
state: Massachusetts
city: Boston
country: United States
facility: Joslin Diabetes Center
state: Massachusetts
city: Grand Rapids
country: United States
facility: Retina Specialists of Michigan
state: Michigan
city: Grand Rapids
country: United States
facility: Vitreo-Retinal Associates
state: Michigan
city: Saint Louis
country: United States
facility: The Retina Institute
state: Missouri
city: Albuquerque
country: United States
facility: Eye Associates of New Mexico
state: New Mexico
city: New York
country: United States
facility: MaculaCare
state: New York
city: Rochester
country: United States
facility: Retina Associates of Western New York
state: New York
city: Asheville
country: United States
facility: Western Carolina Clinical Research, LLC
state: North Carolina
city: Charlotte
country: United States
facility: Charlotte Eye, Ear, Nose and Throat Assoc., PA
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: Dean A. McGee Eye Institute
state: Oklahoma
city: Portland
country: United States
facility: Retina Northwest, PC
state: Oregon
city: Springfield
country: United States
facility: Cascade Medical Research Institute, LLC
state: Oregon
city: Monroeville
country: United States
facility: Retina Vitreous Consultants
state: Pennsylvania
city: Philadelphia
country: United States
facility: Retinavitreous Associates, dba; Mid Atlantic Retina
state: Pennsylvania
city: Knoxville
country: United States
facility: Southeastern Retina Associates, P.C.
state: Tennessee
city: Austin
country: United States
facility: Austin Retina Associates
state: Texas
city: Austin
country: United States
facility: Retina Research Center
state: Texas
city: Grapevine
country: United States
facility: Retina Center of Texas
state: Texas
city: Houston
country: United States
facility: Baylor Eye Physicians and Surgeons
state: Texas
city: Houston
country: United States
facility: Retina Consultants of Houston, PA
state: Texas
city: Lubbock
country: United States
facility: Texas Retina Associates
state: Texas
city: McAllen
country: United States
facility: Valley Retina Institute
state: Texas
city: San Antonio
country: United States
facility: Retinal Consultants of San Antonio
state: Texas
city: Spokane
country: United States
facility: Spokane Eye Clinic
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
References:
citation: 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.