Clinical trial NCT01909791: Treatment for CI-DME in Eyes With Very Good VA Study
Official title: Treatment for Central-Involved Diabetic Macular Edema in Eyes With Very Good Visual Acuity
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
Collaborators: name: Regeneron Pharmaceuticals
name: National Eye Institute (NEI)
name: National Institutes of Health (NIH)
First posted: 2013-07-29
Enrollment: 702
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: 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


Eligibility criteria: Inclusion Criteria:

1. Age \>= 18 years
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:
   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.
3. Able and willing to provide informed consent.

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

1. 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.
2. On clinical exam, definite retinal thickening due to DME involving the center of the macula.
3. 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.
4. 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.
5. Media clarity, pupillary dilation, and individual cooperation sufficient for adequate OCT and fundus photographs.

Exclusion Criteria:

1. 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).
3. 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.
4. 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.
5. Known allergy to any component of the study drug.
6. 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.
7. Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to randomization.

   These drugs should not be used during the study.
8. 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.
9. 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:

1. 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.
2. 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).
3. 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.).
4. Cataract is present that, in the opinion of the investigator, may alter visual acuity during the course of the study.
5. 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).
6. History of topical steroid or nonsteroidal anti-inflammatory drugs (NSAID) treatment within 30 days prior to randomization.
7. History of intravitreal or peribulbar corticosteroid within 4 months prior to randomization for an ocular condition other than DME.
8. 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).
9. History of PRP within 4 months prior to randomization or anticipated need for PRP in the 6 months following randomization.
10. Any history of vitrectomy.
11. 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.
12. History of YAG capsulotomy performed within 2 months prior to randomization.
13. Aphakia.
14. Exam evidence of external ocular infection, including conjunctivitis, chalazion, or significant blepharitis.

Primary outcomes:
measure: Number of Eyes With at Least 5-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline
timeFrame: 2 years
Secondary outcomes:
measure: 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
timeFrame: 1 year
measure: Change in E-ETDRS Visual Acuity Letter Score From Baseline
timeFrame: 1 year
measure: Change in E-ETDRS Visual Acuity Letter Score From Baseline Over 2 Years (Area Under the Curve)
timeFrame: 2 year
measure: Change in OCT Central Subfield Thickness From Baseline
timeFrame: 2 years
measure: Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening
timeFrame: 1 year
measure: Number of Eyes With no Center-involved Diabetic Macular Edema and at Least 10% Central Subfield Thickness Decrease
timeFrame: 1 year
measure: Cumulative Number of Intraocular Injections of 2.0-mg Aflibercept Received Per Participant
timeFrame: 1 year
measure: Number of Eyes With ≥ 2-step Worsening of Diabetic Retinopathy
timeFrame: 2 years
measure: For Eyes Randomized to Initial Laser Photocoagulation and Initial Observation Groups, the Percentage Receiving Aflibercept Treatment
timeFrame: 2 years
measure: Number of Eyes With at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline
timeFrame: 2 years
measure: Change in E-ETDRS Visual Acuity Letter Score From Baseline
timeFrame: 2 years
measure: Change in OCT Central Subfield Thickness From Baseline
timeFrame: 1 year
measure: Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening
timeFrame: 2 years
measure: Number of Eyes With no Center-involved Diabetic Macular Edema and at Least 10% Central Subfield Thickness Decrease
timeFrame: 2 years
measure: Cumulative Number of Focal/Grid Photocoagulation Sessions Performed Per Participant
timeFrame: 2 years
measure: Number of Eyes With ≥ 2-step Improvement of Diabetic Retinopathy
timeFrame: 2 years
measure: Cumulative Number of Intraocular Injections of 2.0-mg Aflibercept Received Per Participant
timeFrame: 2 years
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Arizona Retina and Vitreous Consultants
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Medical Center/Department of Ophthalmology
state: Arizona
city: Little Rock
country: United States
facility: Jones Eye Institute/University of Arkansas for Medical Sciences
state: Arkansas
city: Campbell
country: United States
facility: Retinal Diagnostic Center
state: California
city: Loma Linda
country: United States
facility: Loma Linda University Health Care, Dept. of Ophthalmology
state: California
city: Long Beach
country: United States
facility: South Coast Retina Center
state: California
city: Palm Desert
country: United States
facility: Southern California Desert Retina Consultants, MC
state: California
city: Redlands
country: United States
facility: Retina Consultants of Southern California
state: California
city: Sacramento
country: United States
facility: Retinal Consultants Medical Group, Inc.
state: California
city: Santa Barbara
country: United States
facility: California Retina Consultants
state: California
city: Walnut Creek
country: United States
facility: Bay Area Retina Associates
state: California
city: Westlake Village
country: United States
facility: Retinal Consultants of Southern California Medical Group, Inc.
state: California
city: New London
country: United States
facility: Retina Group of New England
state: Connecticut
city: Norwich
country: United States
facility: New England Retina Associates
state: Connecticut
city: Fort Myers
country: United States
facility: National Ophthalmic Research Institute
state: Florida
city: Jacksonville
country: United States
facility: University of Florida College of Med., Department of Ophthalmology
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: Miami
country: United States
facility: Bascom Palmer Eye Institute
state: Florida
city: Ocala
country: United States
facility: Ocala Eye Retina Consultants
state: Florida
city: Orlando
country: United States
facility: Magruder Eye Institute
state: Florida
city: Plantation
country: United States
facility: Fort Lauderdale Eye Institute
state: Florida
city: Sarasota
country: United States
facility: Center for Sight
state: Florida
city: Sarasota
country: United States
facility: Sarasota Retina Institute
state: Florida
city: Tampa
country: United States
facility: Retina Associates of Florida, P.A.
state: Florida
city: Atlanta
country: United States
facility: Emory Eye Center
state: Georgia
city: Augusta
country: United States
facility: Southeast Retina Center, P.C.
state: Georgia
city: Marietta
country: United States
facility: Marietta Eye Clinic
state: Georgia
city: Sandy Springs
country: United States
facility: Thomas Eye Group
state: Georgia
city: Chicago
country: United States
facility: Northwestern Medical Faculty Foundation
state: Illinois
city: Chicago
country: United States
facility: University of Illinois at Chicago Medical Center
state: Illinois
city: Glenview
country: United States
facility: NorthShore University HealthSystem
state: Illinois
city: Joliet
country: United States
facility: Illinois Retina Associates
state: Illinois
city: Oak Forest
country: United States
facility: University Retina and Macula Associates
state: Illinois
city: Urbana
country: United States
facility: Carle Foundation Hospital
state: Illinois
city: Indianapolis
country: United States
facility: Raj Maturi
state: Indiana
city: New Albany
country: United States
facility: John-Kenyon American Eye Institute
state: Indiana
city: Dubuque
country: United States
facility: Medical Associates Clinic, P.C.
state: Iowa
city: West Des Moines
country: United States
facility: Wolfe Eye Clinic
state: Iowa
city: Prairie Village
country: United States
facility: University of Kansas Medical Center, Dept. of Ophthalmology
state: Kansas
city: Shawnee Mission
country: United States
facility: Retina Associates, P.A.
state: Kansas
city: Lexington
country: United States
facility: Retina and Vitreous Associates of Kentucky
state: Kentucky
city: Paducah
country: United States
facility: Paducah Retinal Center
state: Kentucky
city: Baltimore
country: United States
facility: Elman Retina Group, P.A.
state: Maryland
city: Baltimore
country: United States
facility: Wilmer Eye Institute at Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Joslin Diabetes Center
state: Massachusetts
city: Worcester
country: United States
facility: Vitreo-Retinal Associates, PC
state: Massachusetts
city: Ann Arbor
country: United States
facility: Kellogg Eye Center, University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System, Dept of Ophthalmology and Eye Care Services
state: Michigan
city: Grand Blanc
country: United States
facility: Retina Vitreous Center
state: Michigan
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: Saginaw
country: United States
facility: Andersen Eye Associates
state: Michigan
city: Minneapolis
country: United States
facility: Retina Center, PA
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic Department of Ophthalmology
state: Minnesota
city: Kansas City
country: United States
facility: Mid-America Retina Consultants, P.A.
state: Missouri
city: Saint Louis
country: United States
facility: The Retina Institute
state: Missouri
city: Portsmouth
country: United States
facility: Eyesight Ophthalmic Services, PA
state: New Hampshire
city: Newark
country: United States
facility: The Institute of Ophthalmology and Visual Science (IOVS)
state: New Jersey
city: Northfield
country: United States
facility: Retinal and Ophthalmic Consultants, PC
state: New Jersey
city: Albuquerque
country: United States
facility: Eye Associates of New Mexico
state: New Mexico
city: Buffalo
country: United States
facility: Ross Eye Institute, SUNY Buffalo
state: New York
city: New York
country: United States
facility: The New York Eye and Ear Infirmary/Faculty Eye Practice
state: New York
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: Rochester
country: United States
facility: University of Rochester
state: New York
city: Syracuse
country: United States
facility: Retina-Vitreous Surgeons of Central New York, PC
state: New York
city: Asheville
country: United States
facility: Western Carolina Retinal Associates, PA
state: North Carolina
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Charlotte
country: United States
facility: Charlotte Eye, Ear, Nose and Throat Assoc., PA
state: North Carolina
city: Beachwood
country: United States
facility: Retina Associates of Cleveland, Inc.
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Edmond
country: United States
facility: Retina Vitreous Center
state: Oklahoma
city: Eugene
country: United States
facility: Oregon Retina, LLP
state: Oregon
city: Portland
country: United States
facility: Retina Northwest, PC
state: Oregon
city: Portland
country: United States
facility: Casey Eye Institute
state: Oregon
city: Lancaster
country: United States
facility: Family Eye Group
state: Pennsylvania
city: Monroeville
country: United States
facility: Retina Vitreous Consultants
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania Scheie Eye Institute
state: Pennsylvania
city: Columbia
country: United States
facility: Carolina Retina Center
state: South Carolina
city: West Columbia
country: United States
facility: Palmetto Retina Center
state: South Carolina
city: Chattanooga
country: United States
facility: Southeastern Retina Associates
state: Tennessee
city: Kingsport
country: United States
facility: Southeastern Retina Associates, PC
state: Tennessee
city: Knoxville
country: United States
facility: Southeastern Retina Associates, P.C.
state: Tennessee
city: Amarillo
country: United States
facility: Southwest Retina Specialists
state: Texas
city: Austin
country: United States
facility: Austin Retina Associates
state: Texas
city: Austin
country: United States
facility: Retina Research Center
state: Texas
city: Houston
country: United States
facility: Retina and Vitreous 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: Salt Lake City
country: United States
facility: Retina Associates of Utah, P.C.
state: Utah
city: Richmond
country: United States
facility: Retina Institute of Virginia
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University, Dept. of Ophthalmology
state: Virginia
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Spokane
country: United States
facility: Spokane Eye Clinic
state: Washington
city: Madison
country: United States
facility: University of Wisconsin-Madison, Dept of Ophthalmology/Retina Service
state: Wisconsin
city: Edmonton
country: Canada
facility: Alberta Retina Consultants
state: Alberta
city: Toronto
country: Canada
facility: University Health Network - Toronto Western Hospital
state: Ontario
city: Vancouver
country: Canada
facility: UBC/VCHA Eye Care Centre
Study officials:
affiliation: Paducah Retina Center
name: Carl Baker, MD
role: STUDY_CHAIR
affiliation: Jaeb Center for Health Research
name: Adam Glassman, MS
role: PRINCIPAL_INVESTIGATOR
References:
citation: Glassman AR, Baker CW, Beaulieu WT, Bressler NM, Punjabi OS, Stockdale CR, Wykoff CC, Jampol LM, Sun JK; DRCR Retina Network. Assessment of the DRCR Retina Network Approach to Management With Initial Observation for Eyes With Center-Involved Diabetic Macular Edema and Good Visual Acuity: A Secondary Analysis of a Randomized Clinical Trial. JAMA Ophthalmol. 2020 Apr 1;138(4):341-349. doi: 10.1001/jamaophthalmol.2019.6035.
citation: Baker CW, Glassman AR, Beaulieu WT, Antoszyk AN, Browning DJ, Chalam KV, Grover S, Jampol LM, Jhaveri CD, Melia M, Stockdale CR, Martin DF, Sun JK; DRCR Retina Network. Effect of Initial Management With Aflibercept vs Laser Photocoagulation vs Observation on Vision Loss Among Patients With Diabetic Macular Edema Involving the Center of the Macula and Good Visual Acuity: A Randomized Clinical Trial. JAMA. 2019 May 21;321(19):1880-1894. doi: 10.1001/jama.2019.5790.