Treatment for CI-DME in Eyes With Very Good VA Study

Phase 3

Completed

Conditions: Diabetic Macular Edema

Interventions: Procedure: Prompt Laser
Drug: Prompt aflibercept
Procedure: Deferred laser
Drug: Deferred aflibercept

Registration Number: NCT01909791

Lead Sponsor: Jaeb Center for Health Research

Brief Summary: Although multiple studies have clearly demonstrated that ranibizumab therapy is more effective than laser alone for vision gain and avoiding vision loss in patients with central-involved Diabetic Macular Edema (DME), only eyes with poor visual acuity, such as a visual acuity letter score of 78 or worse (approximate Snellen equivalent of 20/32 or worse) were eligible. Eyes that have central-involved DME with "good" visual acuity (20/25 or better) have not been addressed systematically by recent studies for treatment of DME. Baseline cohort characteristics from the Early Treatment Diabetic Retinopathy Study (ETDRS) suggest that a substantial percentage of eyes with central-involved DME may retain good vision. The investigators do not know definitively whether eyes with central-involved DME and good vision do better with anti-VEGF (vascular endothelial growth factor) (e.g. aflibercept) therapy initially, or focal/grid laser treatment or observation initially followed by anti-VEGF only if vision worsens.

The primary objective of the protocol is to compare the % of eyes that have lost at least 5 letters of visual acuity at 2 years compared with baseline mean visual acuity in eyes with central-involved DME and good visual acuity defined as a Snellen equivalent of 20/25 or better (electronic-ETDRS letter score of 79 or better) that receive (1) prompt focal/grid photocoagulation + deferred anti-VEGF, (2) observation + deferred anti-VEGF, or (3) prompt anti-VEGF.

Secondary objectives include:

* Comparing other visual acuity outcomes between treatment groups, such as the percent of eyes with at least 5, 10 and 15 letter losses in visual acuity from baseline mean visual acuity, percent of eyes with at least 5 letter gain in visual acuity from baseline, mean visual acuity, mean change in visual acuity, adjusted for baseline mean visual acuity

* For eyes randomized to deferred anti-VEGF, the percentage of eyes needing anti-VEGF treatment

* Comparing optical coherence tomography (OCT) outcomes, such as the mean change in OCT central subfield (CSF) thickness, adjusted for baseline mean thickness

* Comparing the number of eyes with PDR at randomization, proportion of eyes avoiding vitreous hemorrhage or panretinal photocoagulation (PRP) or vitrectomy for PDR between treatment groups

* Comparing safety outcomes between treatment groups

* Comparing associated treatment and follow-up exam costs between treatment groups

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 702

Inclusion Criteria

Age >= 18 years
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:
1. Current regular use of insulin for the treatment of diabetes
2. Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes
3. Documented diabetes by American Diabetes Association (ADA) and/or World Health Organization (WHO) criteria.
Able and willing to provide informed consent.

Meets all of the following ocular criteria in at least the one eye:

Best corrected E-ETDRS visual acuity letter score ≥ 79 (approximate Snellen equivalent 20/25 or better) at two consecutive visits within 1 to 28 days.
On clinical exam, definite retinal thickening due to DME involving the center of the macula.
Diabetic macular edema confirmed on OCT (equivalent to CSF thickness on OCT ≥250 microns on Zeiss Stratus or gender-specific spectral domain OCT equivalent) at two consecutive visits within 1 to 28 days.

(a) Investigator must verify accuracy of OCT scan by ensuring it is centered and of adequate quality.
The investigator is comfortable with the eye being randomized to any of the three treatment groups (observation, laser, or anti-VEGF initially).

(a) If focal/grid photocoagulation is contraindicated because all leaking microaneurysms are too close to the fovea or the investigator believes the DME that is present will not benefit from focal/grid photocoagulation, the eye should not be enrolled.
Media clarity, pupillary dilation, and individual cooperation sufficient for adequate OCT and fundus photographs.

Exclusion Criteria

History of chronic renal failure requiring dialysis or kidney transplant.
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).
Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months prior to randomization or plans to do so in the next 4 months.
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.

(a) Note: study participants cannot receive another investigational drug while participating in the study.
Known allergy to any component of the study drug.
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.
Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to randomization.

These drugs should not be used during the study.
For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 24 months.

(a) 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.
Individual is expecting to move out of the area of the clinical center to an area not covered by another clinical center during the 24 months of the study.

Individual has any of the following ocular characteristics:

Macular edema is considered to be due to a cause other than DME.

a) 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 contributing to the macular edema.
An ocular condition is present such that, in the opinion of the investigator, any visual acuity loss would not improve from resolution of macular edema (e.g., foveal atrophy, pigment abnormalities, dense subfoveal hard exudates, nonretinal condition).
An ocular condition is present (other than DME) 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.).
Cataract is present that, in the opinion of the investigator, may alter visual acuity during the course of the study.
Any history of prior laser or other surgical, intravitreal, or peribulbar treatment for DME (such as focal/grid macular photocoagulation, intravitreal or peribulbar corticosteroids, or anti-VEGF).
History of topical steroid or nonsteroidal anti-inflammatory drugs (NSAID) treatment within 30 days prior to randomization.
History of intravitreal or peribulbar corticosteroid within 4 months prior to randomization for an ocular condition other than DME.
Any history of or anticipated need for intravitreal anti-VEGF within the next 6 months for an ocular condition other than DME (e.g. choroidal neovascularization, central retinal vein occlusion, PDR).
History of PRP within 4 months prior to randomization or anticipated need for PRP in the 6 months following randomization.
Any history of vitrectomy.
History of major ocular surgery (cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior 4 months or anticipated within the next 6 months following randomization.
History of YAG capsulotomy performed within 2 months prior to randomization.
Aphakia.
Exam evidence of external ocular infection, including conjunctivitis, chalazion, or significant blepharitis.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Prompt Laser + Deferred Aflibercept	Prompt Laser	Focal/grid laser followed by intravitreal aflibercept if vision worsens
Prompt Aflibercept	Prompt aflibercept	Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)
Prompt Aflibercept	Deferred laser	Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)
Observation + Deferred Aflibercept	Deferred aflibercept	No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)
Observation + Deferred Aflibercept	Deferred laser	No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)
Prompt Laser + Deferred Aflibercept	Deferred aflibercept	Focal/grid laser followed by intravitreal aflibercept if vision worsens

Primary Outcome Measures

Name	Time	Method
Number of Eyes With at Least 5-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline	2 years	Best-corrected visual acuity following protocol-defined refraction. 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 of 20/12) to 0 letters (Snellen equivalent of 20/800).

Secondary Outcome Measures

Name	Time	Method
Change in E-ETDRS Visual Acuity Letter Score From Baseline	2 years	Best-corrected visual acuity following protocol-defined refraction. 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 of 20/12) to 0 letters (Snellen equivalent of 20/800).
Number of Eyes With at Least 5-letter Increase or at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline	1 year	Best-corrected visual acuity following protocol-defined refraction. 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 of 20/12) to 0 letters (Snellen equivalent of 20/800).
Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening	2 years	Logarithmic transformation of optical coherence tomography central subfield thickness is calculated by taking the log base 10 of the ratio of the central subfield thickness divided by 200 and rounding to the nearest hundredth. The change is the change in the log values.
For Eyes Randomized to Initial Laser Photocoagulation and Initial Observation Groups, the Percentage Receiving Aflibercept Treatment	2 years
Number of Eyes With at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline	2 years	Best-corrected visual acuity following protocol-defined refraction. 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 of 20/12) to 0 letters (Snellen equivalent of 20/800).
Number of Eyes With ≥ 2-step Improvement of Diabetic Retinopathy	2 years	Includes eyes with baseline severity level of 35 (mild non-proliferative diabetic retinopathy) or greater based on reading center grading of color fundus photographs using the Early Treatment Diabetic Retinopathy Study severity scale. Excludes eyes with severity level 60 at baseline since improvement is not possible in these eyes.
Change in E-ETDRS Visual Acuity Letter Score From Baseline Over 2 Years (Area Under the Curve)	2 year	Best-corrected visual acuity following protocol-defined refraction. 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 of 20/12) to 0 letters (Snellen equivalent of 20/800). The area under the curve (units = letters·years) was divided by 2 years (units = years) to obtain an average change in letter score (units = letters) over the 2-year follow-up.
Cumulative Number of Intraocular Injections of 2.0-mg Aflibercept Received Per Participant	2 years
Change in OCT Central Subfield Thickness From Baseline	1 year	Measured using spectral-domain optical coherence tomography (OCT).
Number of Eyes With no Center-involved Diabetic Macular Edema and at Least 10% Central Subfield Thickness Decrease	2 years	Center-involved diabetic macular edema defined as follows by central subfield thickness according to optical coherence tomography machine and sex: Heidelberg Spectralis ≥ 305 µm in women and ≥ 320 µm in men, and Zeiss Cirrus ≥ 290 µm in women and ≥ 305 µm in men.
Number of Eyes With ≥ 2-step Worsening of Diabetic Retinopathy	2 years	Includes eyes with baseline severity level of 75 (high-risk proliferative diabetic retinopathy) or less based on reading center grading of color fundus photographs using the Early Treatment Diabetic Retinopathy Study severity scale.
Cumulative Number of Focal/Grid Photocoagulation Sessions Performed Per Participant	2 years

Trial Locations

Locations (102): Case Western Reserve University
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Cleveland, Ohio, United States
Loma Linda University Health Care, Dept. of Ophthalmology
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Loma Linda, California, United States
California Retina Consultants
🇺🇸
Santa Barbara, California, United States
Retinal Consultants of Southern California Medical Group, Inc.
🇺🇸
Westlake Village, California, United States
Ocala Eye Retina Consultants
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Ocala, Florida, United States
Sarasota Retina Institute
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Sarasota, Florida, United States
Thomas Eye Group
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Sandy Springs, Georgia, United States
Northwestern Medical Faculty Foundation
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Chicago, Illinois, United States
Retina and Vitreous Associates of Kentucky
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Lexington, Kentucky, United States
Retina Associates of Cleveland, Inc.
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Beachwood, Ohio, United States
Texas Retina Associates
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Lubbock, Texas, United States
Valley Retina Institute
🇺🇸
McAllen, Texas, United States
University of Wisconsin-Madison, Dept of Ophthalmology/Retina Service
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Madison, Wisconsin, United States
Alberta Retina Consultants
🇨🇦
Edmonton, Alberta, Canada
Joslin Diabetes Center
🇺🇸
Boston, Massachusetts, United States
Retina Consultants of Houston, PA
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Houston, Texas, United States
Raj Maturi
🇺🇸
Indianapolis, Indiana, United States
University of Minnesota
🇺🇸
Minneapolis, Minnesota, United States
Retina Associates, P.A.
🇺🇸
Shawnee Mission, Kansas, United States
University of Kansas Medical Center, Dept. of Ophthalmology
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Prairie Village, Kansas, United States
University of Rochester
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Rochester, New York, United States
Arizona Retina and Vitreous Consultants
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Phoenix, Arizona, United States
Henry Ford Health System, Dept of Ophthalmology and Eye Care Services
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Detroit, Michigan, United States
Mayo Clinic Department of Ophthalmology
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Rochester, Minnesota, United States
Retina Northwest, PC
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Portland, Oregon, United States
Casey Eye Institute
🇺🇸
Portland, Oregon, United States
Retina Associates of Florida, P.A.
🇺🇸
Tampa, Florida, United States
Retinal Diagnostic Center
🇺🇸
Campbell, California, United States
Jones Eye Institute/University of Arkansas for Medical Sciences
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Little Rock, Arkansas, United States
Southern California Desert Retina Consultants, MC
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Palm Desert, California, United States
Retina Consultants of Southern California
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Redlands, California, United States
Bay Area Retina Associates
🇺🇸
Walnut Creek, California, United States
National Ophthalmic Research Institute
🇺🇸
Fort Myers, Florida, United States
University of Florida College of Med., Department of Ophthalmology
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Jacksonville, Florida, United States
Florida Retina Consultants
🇺🇸
Lakeland, Florida, United States
Bascom Palmer Eye Institute
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Miami, Florida, United States
Center for Sight
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Sarasota, Florida, United States
Fort Lauderdale Eye Institute
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Plantation, Florida, United States
Emory Eye Center
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Atlanta, Georgia, United States
University of Illinois at Chicago Medical Center
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Chicago, Illinois, United States
Illinois Retina Associates
🇺🇸
Joliet, Illinois, United States
Carle Foundation Hospital
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Urbana, Illinois, United States
University Retina and Macula Associates
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Oak Forest, Illinois, United States
Wilmer Eye Institute at Johns Hopkins
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Baltimore, Maryland, United States
John-Kenyon American Eye Institute
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New Albany, Indiana, United States
Wolfe Eye Clinic
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West Des Moines, Iowa, United States
Elman Retina Group, P.A.
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Baltimore, Maryland, United States
Vitreo-Retinal Associates, PC
🇺🇸
Worcester, Massachusetts, United States
Retina Vitreous Center
🇺🇸
Edmond, Oklahoma, United States
Retina Center, PA
🇺🇸
Minneapolis, Minnesota, United States
The Retina Institute
🇺🇸
Saint Louis, Missouri, United States
Eye Associates of New Mexico
🇺🇸
Albuquerque, New Mexico, United States
Ross Eye Institute, SUNY Buffalo
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Buffalo, New York, United States
Retina Associates of Western New York
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Rochester, New York, United States
MaculaCare
🇺🇸
New York, New York, United States
Charlotte Eye, Ear, Nose and Throat Assoc., PA
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Charlotte, North Carolina, United States
Oregon Retina, LLP
🇺🇸
Eugene, Oregon, United States
The New York Eye and Ear Infirmary/Faculty Eye Practice
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New York, New York, United States
Retina-Vitreous Surgeons of Central New York, PC
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Syracuse, New York, United States
Palmetto Retina Center
🇺🇸
West Columbia, South Carolina, United States
Southeastern Retina Associates
🇺🇸
Chattanooga, Tennessee, United States
Retina Vitreous Consultants
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Monroeville, Pennsylvania, United States
Carolina Retina Center
🇺🇸
Columbia, South Carolina, United States
Retina and Vitreous of Texas
🇺🇸
Houston, Texas, United States
Southeastern Retina Associates, P.C.
🇺🇸
Knoxville, Tennessee, United States
Southwest Retina Specialists
🇺🇸
Amarillo, Texas, United States
Retinal Consultants of San Antonio
🇺🇸
San Antonio, Texas, United States
Baylor Eye Physicians and Surgeons
🇺🇸
Houston, Texas, United States
UBC/VCHA Eye Care Centre
🇨🇦
Vancouver, Canada
University of Washington Medical Center
🇺🇸
Seattle, Washington, United States
Retina Associates of Utah, P.C.
🇺🇸
Salt Lake City, Utah, United States
Medical Associates Clinic, P.C.
🇺🇸
Dubuque, Iowa, United States
University of Arizona Medical Center/Department of Ophthalmology
🇺🇸
Tucson, Arizona, United States
South Coast Retina Center
🇺🇸
Long Beach, California, United States
Retina Macula Specialists of Miami
🇺🇸
Miami, Florida, United States
Southeast Retina Center, P.C.
🇺🇸
Augusta, Georgia, United States
NorthShore University HealthSystem
🇺🇸
Glenview, Illinois, United States
Paducah Retinal Center
🇺🇸
Paducah, Kentucky, United States
Family Eye Group
🇺🇸
Lancaster, Pennsylvania, United States
Spokane Eye Clinic
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Spokane, Washington, United States
Western Carolina Retinal Associates, PA
🇺🇸
Asheville, North Carolina, United States
Retina Specialists of Michigan
🇺🇸
Grand Rapids, Michigan, United States
Andersen Eye Associates
🇺🇸
Saginaw, Michigan, United States
Marietta Eye Clinic
🇺🇸
Marietta, Georgia, United States
University Health Network - Toronto Western Hospital
🇨🇦
Toronto, Ontario, Canada
Vitreo-Retinal Associates
🇺🇸
Grand Rapids, Michigan, United States
University of Pennsylvania Scheie Eye Institute
🇺🇸
Philadelphia, Pennsylvania, United States
Retinal Consultants Medical Group, Inc.
🇺🇸
Sacramento, California, United States
Magruder Eye Institute
🇺🇸
Orlando, Florida, United States
Kellogg Eye Center, University of Michigan
🇺🇸
Ann Arbor, Michigan, United States
Eyesight Ophthalmic Services, PA
🇺🇸
Portsmouth, New Hampshire, United States
Retina Group of New England
🇺🇸
New London, Connecticut, United States
Retinal and Ophthalmic Consultants, PC
🇺🇸
Northfield, New Jersey, United States
The Institute of Ophthalmology and Visual Science (IOVS)
🇺🇸
Newark, New Jersey, United States
New England Retina Associates
🇺🇸
Norwich, Connecticut, United States
Southeastern Retina Associates, PC
🇺🇸
Kingsport, Tennessee, United States
Austin Retina Associates
🇺🇸
Austin, Texas, United States
Retina Research Center
🇺🇸
Austin, Texas, United States
Retina Institute of Virginia
🇺🇸
Richmond, Virginia, United States
Virginia Commonwealth University, Dept. of Ophthalmology
🇺🇸
Richmond, Virginia, United States
Mid-America Retina Consultants, P.A.
🇺🇸
Kansas City, Missouri, United States
University of North Carolina
🇺🇸
Chapel Hill, North Carolina, United States