Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
399 participants
INTERVENTIONAL
2016-01-31
2022-05-11
Brief Summary
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If this study demonstrates that intravitreous aflibercept treatment is effective and safe for reducing the onset of PDR or center involved- DME (CI-DME) in eyes that are at high risk for these complications, a new strategy to prevent vision threatening complications of diabetes will be available for patients. The application of intravitreous aflibercept earlier in the course of disease (i.e., at the time when an eye has baseline severe non-proliferative diabetic retinopathy) could help to reduce future potential treatment burden in patients, at the same time resulting in similar or better long-term visual outcomes, if PDR and DME are prevented.
The primary objectives of this protocol are to 1) determine the efficacy and safety of intravitreous aflibercept injections versus sham injections (observation) for prevention of PDR or CI-DME in eyes at high risk for development of these complications and 2) compare long-term visual outcomes in eyes that receive anti-VEGF therapy early in the course of disease with those that are observed initially, and treated only if high-risk PDR or CI-DME with vision loss develops.
Secondary objectives include:
* Comparing other visual acuity outcomes between treatment groups, such as proportion of eyes with at least 10 or at least 15 letter loss from baseline, or gain or loss of at least 5 letters at the consecutive study visit just before and at the 2- or 4-year visit
* Comparing optical coherence tomography (OCT) outcomes, such as mean change in OCT central subfield thickness and volume from baseline
* Comparing proportion of eyes with at least 2 and 3-step worsening or improvement of diabetic retinopathy severity level (scale for individual eyes) by central reading center from baseline
* Comparing associated treatment and follow-up exam costs between treatment groups
* Comparing safety outcomes between treatment groups
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
PREVENTION
DOUBLE
Study Groups
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Observation (Prompt Sham)
Sham injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. Deferred aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met.
Prompt Sham
A sham injection (syringe without a needle pressed against the injection site) is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter.
Deferred laser
Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met
Deferred aflibercept
Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria.
Prompt aflibercept
Aflibercept injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. More frequent aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met.
Prompt aflibercept
Intravitreal injection of 2.0mg aflibercept is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter.
Deferred laser
Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met
Deferred aflibercept
Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria.
Interventions
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Prompt Sham
A sham injection (syringe without a needle pressed against the injection site) is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter.
Prompt aflibercept
Intravitreal injection of 2.0mg aflibercept is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter.
Deferred laser
Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met
Deferred aflibercept
Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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 and/or World Health Organization criteria
3. Able and willing to provide informed consent.
Meets all of the following ocular criteria in at least one eye:
1. Best corrected Electronic-Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity letter score ≥79 (approximate Snellen equivalent 20/25 or better)
2. Severe non-proliferative diabetic retinopathy (NPDR) (based on the 4:2:1 rule) evident on clinical examination and on digital imaging as judged by the investigator. Reading center grading of less than ETDRS level 43 or greater than 53 is an exclusion.
Severe NPDR is defined as:
1. All 4 midperipheral quadrants show severe hemorrhages or microaneurysms (at least as great as Standard photograph 2A, approximately 20 dot and blot hemorrhages), or
2. At least 2 fields of definite venous beading in the midperipheral quadrants or at least 1 field at least as severe as Standard photograph 6A, or
3. At least 1 field of moderate intraretinal microvascular abnormalities (IRMA) in the midperipheral quadrants, at least as severe as Standard photograph 8A
3. No evidence of neovascularization on clinical exam including active neovascularization of the iris (small iris tufts are not an exclusion) or angle neovascularization (if the angle is assessed).
4. No evidence of neovascularization (NV) on fluorescein angiography within the 7-modified ETDRS fields, confirmed by the central Reading Center prior to randomization.
• The widest method of imaging available at the site must be used to document whether there is NV present in the periphery; however, presence of NV outside of the 7-modified ETDRS fields on ultrawide field imaging will not be an exclusion provided treatment is not planned.
5. No center-involved diabetic macular edema (CI-DME) on clinical exam and optical coherence tomography (OCT) central subfield thickness must be below the following gender and OCT-machine specific thresholds:
1. Zeiss Cirrus: 290 µm in women and 305 µm in men
2. Heidelberg Spectralis: 305 µm in women and 320 µm in men
3. Investigator and potential participant are comfortable withholding treatment for DME until there is at least a 10% increase in OCT central subfield thickness with confirmed visual acuity loss (10 letter loss at a single visit or 5 to 9 at two consecutive visits).
6. Prompt panretinal photocoagulation (PRP) or anti-vascular endothelial growth factor (anti-VEGF) treatment not required AND investigator and potential participant are willing to wait for development of high-risk characteristics (defined in protocol) to treat PDR.
7. Media clarity, pupillary dilation, and study participant cooperation sufficient to obtain adequate fundus photographs, fluorescein angiogram, and OCT.
* Investigator must verify accuracy of OCT scan by ensuring it is centered and of adequate quality (including segmentation line placement)
Exclusion Criteria
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 that involved treatment within 30 days of randomization with any drug that has not received regulatory approval for the indication being studied.
• Note: study participants cannot participate in another investigational trial that involves treatment with an investigational drug while participating in the study.
5. Known allergy to any component of the study drug or any drug used in the injection prep (including povidone iodine prep).
6. Known allergy to fluorescein dye.
7. 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.
8. Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to randomization.
• These drugs should not be used during the study.
9. For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 2 years.
• 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.
10. Individual is expecting to move out of the area of the clinical center to an area not covered by another Diabetic Retinopathy Clinical Research Network certified clinical center during the next 2 years.
Individual has any of the following ocular characteristics in the eye(s) being evaluated:
1. Exam or photographic evidence of vitreous hemorrhage or preretinal hemorrhage presumed to be from PDR.
2. History of prior vitreous hemorrhage or preretinal hemorrhage presumed to be from PDR.
3. History of prior PRP (defined as ≥100 burns outside of the posterior pole).
4. An ocular condition is present (other than diabetic retinopathy) that, in the opinion of the investigator, might alter visual acuity during the course of the study (e.g., retinal vein or artery occlusion, uveitis or other ocular inflammatory disease, vitreomacular traction, etc.).
5. History of DME or diabetic retinopathy treatment with laser or intraocular injections of medication within the prior 12 months and no more than 4 prior intraocular injections at any time in the past.
• Enrollment will be limited to a maximum of 25% of the planned sample size with any history of treatment for DME and/or diabetic retinopathy. Once this number of eyes has been enrolled, any history of treatment for DME and/or diabetic retinopathy will be an exclusion criterion.
6. History of major ocular surgery (including cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior 4 months or anticipated within the next 6 months following randomization.
7. Any history of vitrectomy.
8. History of yttrium aluminum garnet capsulotomy performed within 2 months prior to randomization.
9. Aphakia.
10. Exam evidence of severe external ocular infection, including conjunctivitis, chalazion, or substantial blepharitis.
11. 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.
18 Years
ALL
No
Sponsors
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Regeneron Pharmaceuticals
INDUSTRY
Juvenile Diabetes Research Foundation
OTHER
National Eye Institute (NEI)
NIH
National Institutes of Health (NIH)
NIH
Jaeb Center for Health Research
OTHER
Responsible Party
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Principal Investigators
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Jennifer K. Sun, MD, MPH
Role: STUDY_CHAIR
Joslin Diabetes Center
Locations
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Arizona Retina and Vitreous Consultants
Phoenix, Arizona, United States
University of Arizona Medical Center/Department of Ophthalmology
Tucson, Arizona, United States
Atlantis Eye Care
Huntington Beach, California, United States
Loma Linda University Health Care, Department of Ophthalmology
Loma Linda, California, United States
East Bay Retina Consultants, Inc.
Oakland, California, United States
Southern California Desert Retina Consultants, MC
Palm Desert, California, United States
Shashi D Ganti, MD PC
Porterville, California, United States
Retina Consultants of Southern California
Redlands, California, United States
U.C. Davis Eye Center
Sacramento, California, United States
California Retina Consultants
Santa Barbara, California, United States
Retinal Consultants of Southern California Medical Group, Inc.
Westlake Village, California, United States
New England Retina Associates
Hamden, Connecticut, United States
Retina Group of Florida
Fort Lauderdale, Florida, United States
National Ophthalmic Research Institute
Fort Myers, Florida, United States
University of Florida College of Med., Department of Ophthalmology, Jacksonville Health Science Cent
Jacksonville, Florida, United States
Florida Retina Institute-Jacksonville
Jacksonville, Florida, United States
Florida Retina Consultants
Lakeland, Florida, United States
Bascom Palmer Eye Institute
Miami, Florida, United States
Magruder Eye Institute
Orlando, Florida, United States
Florida Retina Institute
Orlando, Florida, 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
Sarasota Retina Institute
Sarasota, Florida, United States
Retina Associates of Florida, P.A.
Tampa, Florida, United States
Emory Eye Center
Atlanta, Georgia, United States
Southeast Retina Center, P.C.
Augusta, Georgia, United States
Marietta Eye Clinic
Marietta, Georgia, United States
Thomas Eye Group
Sandy Springs, Georgia, United States
Gailey Eye Clinic
Bloomington, Illinois, United States
Northwestern Medical Faculty Foundation
Chicago, Illinois, United States
University of Illinois at Chicago Medical Center
Chicago, Illinois, United States
Springfield Clinic, LLP
Springfield, Illinois, United States
Raj K. Maturi, M.D., P.C.
Indianapolis, Indiana, United States
Medical Associates Clinic, P.C.
Dubuque, Iowa, United States
Wolfe Eye Clinic
West Des Moines, Iowa, United States
Retina Associates, P.A.
Shawnee Mission, Kansas, United States
Paducah Retinal Center
Paducah, Kentucky, United States
Eye Associates of Northeast Louisiana dba Haik Humble Eye Center
West Monroe, Louisiana, United States
Elman Retina Group, P.A.
Baltimore, Maryland, United States
Wilmer Eye Institute at Johns Hopkins
Baltimore, Maryland, United States
Mid Atlantic Retina Specialists
Hagerstown, Maryland, United States
Valley Eye Physicians and Surgeons
Ayer, Massachusetts, United States
Joslin Diabetes Center
Boston, Massachusetts, United States
Henry Ford Health System, Dept of Ophthalmology and Eye Care Services
Detroit, Michigan, United States
Vitreo-Retinal Associates
Grand Rapids, Michigan, United States
Retina Center, PA
Minneapolis, Minnesota, United States
Mid-America Retina Consultants, P.A.
Kansas City, Missouri, United States
Retinal and Ophthalmic Consultants, PC
Northfield, New Jersey, United States
Eye Associates of New Mexico
Albuquerque, New Mexico, United States
The New York Eye and Ear Infirmary/Faculty Eye Practice
New York, New York, United States
MaculaCare
New York, New York, United States
University of Rochester
Rochester, New York, United States
Retina-Vitreous Surgeons of Central New York, PC
Syracuse, New York, United States
Western Carolina Clinical Research, LLC
Asheville, North Carolina, United States
Kittner Eye Center
Chapel Hill, North Carolina, United States
Charlotte Eye, Ear, Nose and Throat Assoc., PA
Charlotte, North Carolina, United States
Retina Associates of Cleveland, Inc.
Beachwood, Ohio, United States
University Hospitals Cleveland Medical Center
Cleveland, Ohio, United States
Oregon Retina, LLP
Eugene, Oregon, United States
Retina Northwest, PC
Portland, Oregon, United States
Casey Eye Institute
Portland, Oregon, United States
Retina Vitreous Consultants
Monroeville, Pennsylvania, United States
University of Pennsylvania Scheie Eye Institute
Philadelphia, Pennsylvania, United States
Carolina Retina Center
Columbia, South Carolina, United States
Palmetto Retina Center
West Columbia, South Carolina, United States
Southeastern Retina Associates
Chattanooga, Tennessee, United States
Southeastern Retina Associates, P.C.
Knoxville, Tennessee, United States
Southwest Retina Specialists
Amarillo, Texas, United States
Austin Retina Associates
Austin, Texas, United States
Retina Research Center
Austin, Texas, United States
Robert E. Torti, MD, PA dba Retina Specialists
DeSoto, Texas, United States
Retina Center of Texas
Grapevine, Texas, United States
Retina and Vitreous of Texas
Houston, Texas, United States
Baylor Eye Physicians and Surgeons
Houston, Texas, United States
Retina Consultants of Houston, PA
Houston, Texas, United States
Texas Retina Associates
Lubbock, Texas, United States
Valley Retina Institute
McAllen, Texas, United States
Retinal Consultants of San Antonio
San Antonio, Texas, United States
Retina Institute of Virginia
Richmond, Virginia, United States
Virginia Commonwealth University, Dept. of Ophthalmology
Richmond, Virginia, United States
University of Wisconsin-Madison, Dept of Ophthalmology/Retina Service
Madison, Wisconsin, United States
UBC/VCHA Eye Care Centre
Vancouver, British Columbia, Canada
Nova Scotia District Health Authority
Halifax, Nova Scotia, Canada
Toronto Retina Institute (TRI)
North York, Ontario, Canada
University Health Network - Toronto Western Hospital
Toronto, Ontario, Canada
Countries
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References
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Maturi RK, Glassman AR, Josic K, Baker CW, Gerstenblith AT, Jampol LM, Meleth A, Martin DF, Melia M, Punjabi OS, Rofagha S, Salehi-Had H, Stockdale CR, Sun JK; DRCR Retina Network. Four-Year Visual Outcomes in the Protocol W Randomized Trial of Intravitreous Aflibercept for Prevention of Vision-Threatening Complications of Diabetic Retinopathy. JAMA. 2023 Feb 7;329(5):376-385. doi: 10.1001/jama.2022.25029.
Maturi RK, Glassman AR, Josic K, Antoszyk AN, Blodi BA, Jampol LM, Marcus DM, Martin DF, Melia M, Salehi-Had H, Stockdale CR, Punjabi OS, Sun JK; DRCR Retina Network. Effect of Intravitreous Anti-Vascular Endothelial Growth Factor vs Sham Treatment for Prevention of Vision-Threatening Complications of Diabetic Retinopathy: The Protocol W Randomized Clinical Trial. JAMA Ophthalmol. 2021 Jul 1;139(7):701-712. doi: 10.1001/jamaophthalmol.2021.0606.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Other Identifiers
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EY14231
Identifier Type: OTHER_GRANT
Identifier Source: secondary_id
EY23207
Identifier Type: OTHER_GRANT
Identifier Source: secondary_id
EY18817
Identifier Type: OTHER_GRANT
Identifier Source: secondary_id
DRCR.net Protocol W
Identifier Type: -
Identifier Source: org_study_id
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