Diabetic RetinopathyPhase 3NCT02634333
Anti-VEGF Treatment for Prevention of PDR/DME
A Phase 3 study testing Prompt aflibercept, Deferred laser and Deferred aflibercept in people with Diabetic Retinopathy and Diabetic Macular Edema, run by Jaeb Center for Health Research at 85 sites in 2 countries.
Trial summary
Multiple studies have implicated vascular endothelial growth factor VEGF as a major causative factor in human eye diseases characterized by neovascularization including proliferative diabetic retinopathy (PDR) and vascular permeability including diabetic macular edema (DME). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Diabetic Retinopathy, Diabetic Macular Edema
- What is being tested?
- Prompt aflibercept, Deferred laser and Deferred aflibercept
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 399 participants
- Where
- 85 sitesin 2 countries
- Study dates
- Jan 2016to 11 May 2022
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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:
- 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
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- Able and willing to provide informed consent.
- Meets all of the following ocular criteria in at least one eye:
- Best corrected Electronic-Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity letter score ≥79 (approximate Snellen equivalent 20/25 or better)
- 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:
- All 4 midperipheral quadrants show severe hemorrhages or microaneurysms (at least as great as Standard photograph 2A, approximately 20 dot and blot hemorrhages), or
- 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
- At least 1 field of moderate intraretinal microvascular abnormalities (IRMA) in the midperipheral quadrants, at least as severe as Standard photograph 8A
- 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).
- 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.
- 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:
- Zeiss Cirrus: 290 µm in women and 305 µm in men
- Heidelberg Spectralis: 305 µm in women and 320 µm in men
- 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).
- 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.
- 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)
Who cannot join
- 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 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.
- Known allergy to any component of the study drug or any drug used in the injection prep (including povidone iodine prep).
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- Known allergy to fluorescein dye.
- 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 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.
- 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:
- Exam or photographic evidence of vitreous hemorrhage or preretinal hemorrhage presumed to be from PDR.
- History of prior vitreous hemorrhage or preretinal hemorrhage presumed to be from PDR.
- History of prior PRP (defined as ≥100 burns outside of the posterior pole).
- 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.).
- 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.
- 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.
- Any history of vitrectomy.
- History of yttrium aluminum garnet capsulotomy performed within 2 months prior to randomization.
- Aphakia.
- Exam evidence of severe external ocular infection, including conjunctivitis, chalazion, or substantial blepharitis.
- 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.
Trial locations and contacts
85 sites in 2 countries.
85 sites in 2 countries
United States81 sites
Eye Associates of New Mexico
Albuquerque, New Mexico, 87109
Southwest Retina Specialists
Amarillo, Texas, 79106
Western Carolina Clinical Research, LLC
Asheville, North Carolina, 28803
Emory Eye Center
Atlanta, Georgia, 30322
Southeast Retina Center, P.C.
Augusta, Georgia, 30909
Austin Retina Associates
Austin, Texas, 78705
Retina Research Center
Austin, Texas, 78705
Valley Eye Physicians and Surgeons
Ayer, Massachusetts, 01432
Elman Retina Group, P.A.
Baltimore, Maryland, 21237
Wilmer Eye Institute at Johns Hopkins
Baltimore, Maryland, 21287
Retina Associates of Cleveland, Inc.
Beachwood, Ohio, 44122
Gailey Eye Clinic
Bloomington, Illinois, 61704
Joslin Diabetes Center
Boston, Massachusetts, 02215
Kittner Eye Center
Chapel Hill, North Carolina, 27517
Charlotte Eye, Ear, Nose and Throat Assoc., PA
Charlotte, North Carolina, 28210
Southeastern Retina Associates
Chattanooga, Tennessee, 37421
Northwestern Medical Faculty Foundation
Chicago, Illinois, 60611
University of Illinois at Chicago Medical Center
Chicago, Illinois, 60612
University Hospitals Cleveland Medical Center
Cleveland, Ohio, 44106
Carolina Retina Center
Columbia, South Carolina, 29223
Robert E. Torti, MD, PA dba Retina Specialists
DeSoto, Texas, 75115
Henry Ford Health System, Dept of Ophthalmology and Eye Care Services
Detroit, Michigan, 48202
Medical Associates Clinic, P.C.
Dubuque, Iowa, 52002
Oregon Retina, LLP
Eugene, Oregon, 97401
Retina Group of Florida
Fort Lauderdale, Florida, 33308
National Ophthalmic Research Institute
Fort Myers, Florida, 33912
Vitreo-Retinal Associates
Grand Rapids, Michigan, 49546
Retina Center of Texas
Grapevine, Texas, 76051
Mid Atlantic Retina Specialists
Hagerstown, Maryland, 21740
New England Retina Associates
Hamden, Connecticut, 06518
Retina and Vitreous of Texas
Houston, Texas, 77025
Baylor Eye Physicians and Surgeons
Houston, Texas, 77030
Retina Consultants of Houston, PA
Houston, Texas, 77030
Atlantis Eye Care
Huntington Beach, California, 92647
Raj K. Maturi, M.D., P.C.
Indianapolis, Indiana, 46290
University of Florida College of Med., Department of Ophthalmology, Jacksonville Health Science Cent
Jacksonville, Florida, 32209
Florida Retina Institute-Jacksonville
Jacksonville, Florida, 32216
Mid-America Retina Consultants, P.A.
Kansas City, Missouri, 64111
Southeastern Retina Associates, P.C.
Knoxville, Tennessee, 37909
Florida Retina Consultants
Lakeland, Florida, 33805
Loma Linda University Health Care, Department of Ophthalmology
Loma Linda, California, 92354
Texas Retina Associates
Lubbock, Texas, 79424
University of Wisconsin-Madison, Dept of Ophthalmology/Retina Service
Madison, Wisconsin, 53705
Marietta Eye Clinic
Marietta, Georgia, 30060
Valley Retina Institute
McAllen, Texas, 78503
Bascom Palmer Eye Institute
Miami, Florida, 33136
Retina Center, PA
Minneapolis, Minnesota, 55404
Retina Vitreous Consultants
Monroeville, Pennsylvania, 15146
The New York Eye and Ear Infirmary/Faculty Eye Practice
New York, New York, 10003
MaculaCare
New York, New York, 10021
Retinal and Ophthalmic Consultants, PC
Northfield, New Jersey, 08225
East Bay Retina Consultants, Inc.
Oakland, California, 94609
Magruder Eye Institute
Orlando, Florida, 32803
Florida Retina Institute
Orlando, Florida, 32806
Paducah Retinal Center
Paducah, Kentucky, 42001
Southern California Desert Retina Consultants, MC
Palm Desert, California, 92211
University of Pennsylvania Scheie Eye Institute
Philadelphia, Pennsylvania, 19104
Arizona Retina and Vitreous Consultants
Phoenix, Arizona, 85021
Southeast Eye Institute, P.A. dba Eye Associates of Pinellas
Pinellas Park, Florida, 33782
Fort Lauderdale Eye Institute
Plantation, Florida, 33324
Shashi D Ganti, MD PC
Porterville, California, 93257
Retina Northwest, PC
Portland, Oregon, 97210
Casey Eye Institute
Portland, Oregon, 97239
Retina Consultants of Southern California
Redlands, California, 92374
Retina Institute of Virginia
Richmond, Virginia, 23235
Virginia Commonwealth University, Dept. of Ophthalmology
Richmond, Virginia, 23298
University of Rochester
Rochester, New York, 14642
U.C. Davis Eye Center
Sacramento, California, 95817
Retinal Consultants of San Antonio
San Antonio, Texas, 78240
Thomas Eye Group
Sandy Springs, Georgia, 30328
California Retina Consultants
Santa Barbara, California, 93103
Sarasota Retina Institute
Sarasota, Florida, 34239
Retina Associates, P.A.
Shawnee Mission, Kansas, 66204
Springfield Clinic, LLP
Springfield, Illinois, 62703
Retina-Vitreous Surgeons of Central New York, PC
Syracuse, New York, 13224
Retina Associates of Florida, P.A.
Tampa, Florida, 33609
University of Arizona Medical Center/Department of Ophthalmology
Tucson, Arizona, 85711
Palmetto Retina Center
West Columbia, South Carolina, 29169
Wolfe Eye Clinic
West Des Moines, Iowa, 50266
Eye Associates of Northeast Louisiana dba Haik Humble Eye Center
West Monroe, Louisiana, 71291
Retinal Consultants of Southern California Medical Group, Inc.
Westlake Village, California, 91361
Canada4 sites
Nova Scotia District Health Authority
Halifax, Nova Scotia, B3H 2Y9
Toronto Retina Institute (TRI)
North York, Ontario, M3C 0G9
University Health Network - Toronto Western Hospital
Toronto, Ontario, M5T 2S8
UBC/VCHA Eye Care Centre
Vancouver, British Columbia, V5Z 3N9
About this study
Official title: Intravitreous Anti-Vascular Endothelial Growth Factor Treatment for Prevention of Vision Threatening Diabetic Retinopathy in Eyes at High Risk
Multiple studies have implicated vascular endothelial growth factor VEGF as a major causative factor in human eye diseases characterized by neovascularization including proliferative diabetic retinopathy (PDR) and vascular permeability including diabetic macular edema (DME). While there is strong evidence that PDR outcomes are markedly reduced in eyes that are treated with monthly anti-VEGF therapy (A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema (ME) With Center Involvement Secondary to Diabetes Mellitus: RIDE/RISE) and moderately reduced in eyes that received fairly frequent dosing during the 1st year of treatment (Diabetic Retinopathy Clinical Research Network protocol I), it is unknown whether or not an earlier but less frequent dosing regimen would result in similar, favorable anatomic outcomes, and whether favorable anatomic outcomes subsequently would result in favorable visual acuity outcomes.
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.
Read more
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
- Conditions
- Diabetic Retinopathy, Diabetic Macular Edema
- Being tested
- Prompt Sham, Prompt aflibercept, Deferred laser, Deferred aflibercept
- Keywords
- anti-vascular endothelial growth factor, nonproliferative diabetic retinopathy
- Medical subject headings
- Diabetic Retinopathy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Prompt ShamProcedure or surgery
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 afliberceptDrug
Also called intravitreal anti-vascular endothelial growth factor, Eylea
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 laserProcedure or surgery
Also called focal/grid photocoagulation, panretinal photocoagulation
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 afliberceptDrug
Also called intravitreal anti-vascular endothelial growth factor, Eylea
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.
| Study group | Role | What they receive |
|---|---|---|
| Observation (Prompt Sham) | Sham comparator | 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. Receives: Procedure: Prompt Sham; Procedure: Deferred laser; Drug: Deferred aflibercept |
| Prompt aflibercept | Experimental | 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. Receives: Drug: Prompt aflibercept; Procedure: Deferred laser; Drug: Deferred aflibercept |
What is being measured
The primary outcome is the main question the study is designed to answer.
Development of PDR and/or DME (Whichever Came First)
CI-DME = center-involved diabetic macular edema, PDR = proliferative diabetic macular edema. First development of criteria meeting end point. Eyes that met any criteria are then censored from contributing to the next criteria. Eyes that did not meet the outcome were censored at the time of the last completed visit. Each outcome appears only once under "First PDR and/or DME criteria met." Outcomes appear under "Development of PDR" if PDR developed at any time in the study (regardless of if or when DME developed) and outcomes appear under "Development of DME" if DME developed at any time in the study (regardless of if or when PDR developed)
Measured: 2 years
Change in Visual Acuity From Baseline
Visual acuity is measured as a continuous integer letter score from 0 to 100, with higher numbers indicating better visual acuity. A letter score of 85 is approximately 20/20 and a letter score of 70 is approximately 20/40, the legal unrestricted driving limit in most states. A 5-letter change for an individual is approximately equal to a 1-line change on a vision chart.
Measured: 2 years
Secondary outcomes (2)
Change in Visual Acuity From Baseline
Visual acuity is measured as a continuous integer letter score from 0 to 100, with higher numbers indicating better visual acuity. A letter score of 85 is approximately 20/20 and a letter score of 70 is approximately 20/40, the legal unrestricted driving limit in most states. A 5-letter change for an individual is approximately equal to a 1-line change on a vision chart.
Measured: 4 years
Development of PDR and/or DME (Whichever Came First)
CI-DME = center-involved diabetic macular edema, PDR = proliferative diabetic macular edema. First development of criteria meeting end point. Eyes that met any criteria are then censored from contributing to the next criteria. Eyes that did not meet the outcome were censored at the time of the last completed visit. Each outcome appears only once under "First PDR and/or DME criteria met." Outcomes appear under "Development of PDR" if PDR developed at any time in the study (regardless of if or when DME developed) and outcomes appear under "Development of DME" if DME developed at any time in the study (regardless of if or when PDR developed)
Measured: 4 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Dec 2015 (estimated)
- Study startJan 2016
- Primary completionMay 2020
- Study completion11 May 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Diabetic RetinopathyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 399 participants (actual)
Sponsor and investigators
- Lead sponsor
- Jaeb Center for Health Research
- Sponsor type
- University, hospital or other
- Collaborators
- Regeneron Pharmaceuticals, Juvenile Diabetes Research Foundation, National Eye Institute (NEI), National Institutes of Health (NIH)
- Responsible party
- Sponsor
- Investigators
- Jennifer K. Sun, MD, MPH, Study chair, Joslin Diabetes Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02634333
- Sponsor's protocol ID
- DRCR.net Protocol W
- Other IDs
- EY14231, EY23207, EY18817
- Status last verified
- May 2023
- First submitted
- 11 Dec 2015
- Last updated
- 18 Jun 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 36749332Maturi 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.
PubMed 33784735
Study at a glance
From the registry record, last updated by the sponsor on 18 Jun 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Intravitreous Anti-Vascular Endothelial Growth Factor Treatment for Prevention of Vision Threatening Diabetic Retinopathy in Eyes at High Risk
- ClinicalTrials.gov ID
- NCT02634333
- Acronym / sponsor ID
- DRCR.net Protocol W
- Conditions
- Diabetic Retinopathy, Diabetic Macular Edema
- Keywords
- anti-vascular endothelial growth factor, nonproliferative diabetic retinopathy
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 399 participants (actual)
- Lead sponsor
- Jaeb Center for Health ResearchUniversity, hospital or other
- Collaborators
- Regeneron Pharmaceuticals, Juvenile Diabetes Research Foundation, National Eye Institute (NEI), National Institutes of Health (NIH)
- Study start
- Jan 2016 (actual)
- Primary completion
- May 2020 (actual)
- Study completion
- 11 May 2022 (actual)
- First posted
- 18 Dec 2015 (estimated)
- Results
- Posted 24 Nov 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Multiple studies have implicated vascular endothelial growth factor VEGF as a major causative factor in human eye diseases characterized by neovascularization including proliferative diabetic retinopathy (PDR) and vascular permeability including diabetic macular edema (DME). While there is strong evidence that PDR outcomes are markedly reduced in eyes that are treated with monthly anti-VEGF therapy (A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema (ME) With Center Involvement Secondary to Diabetes Mellitus: RIDE/RISE) and moderately reduced in eyes that received fairly frequent dosing during the 1st year of treatment (Diabetic Retinopathy Clinical Research Network protocol I), it is unknown whether or not an earlier but less frequent dosing regimen would result in similar, favorable anatomic outcomes, and whether favorable anatomic outcomes subsequently would result in favorable visual acuity outcomes.
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
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Observation (Prompt Sham) | Sham comparator | Procedure: Prompt Sham, Procedure: Deferred laser, Drug: Deferred afliberceptSham 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 aflibercept | Experimental | Drug: Prompt aflibercept, Procedure: Deferred laser, Drug: Deferred afliberceptAflibercept 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (24 listed)
- Age >= 18 years
- Diagnosis of diabetes mellitus (type 1 or type 2)
- Able and willing to provide informed consent.
- Best corrected Electronic-Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity letter score ≥79 (approximate Snellen equivalent 20/25 or better)
- 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.
Key exclusion criteria (27 listed)
- 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 that involved treatment within 30 days of randomization with any drug that has not received regulatory approval for the indication being studied.
- Known allergy to any component of the study drug or any drug used in the injection prep (including povidone iodine prep).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Prompt ShamA 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. | Procedure or surgery | Observation (Prompt Sham) |
| Prompt afliberceptAlso: intravitreal anti-vascular endothelial growth factor, EyleaIntravitreal 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. | Drug | Prompt aflibercept |
| Deferred laserAlso: focal/grid photocoagulation, panretinal photocoagulationLaser (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 | Procedure or surgery | Observation (Prompt Sham), Prompt aflibercept |
| Deferred afliberceptAlso: intravitreal anti-vascular endothelial growth factor, EyleaIntravitreal 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. | Drug | Observation (Prompt Sham), Prompt aflibercept |
Primary outcome
Development of PDR and/or DME (Whichever Came First)
Time frame: 2 years
CI-DME = center-involved diabetic macular edema, PDR = proliferative diabetic macular edema. First development of criteria meeting end point. Eyes that met any criteria are then censored from contributing to the next criteria. Eyes that did not meet the outcome were censored at the time of the last completed visit. Each outcome appears only once under "First PDR and/or DME criteria met." Outcomes appear under "Development of PDR" if PDR developed at any time in the study (regardless of if or when DME developed) and outcomes appear under "Development of DME" if DME developed at any time in the study (regardless of if or when PDR developed)
Change in Visual Acuity From Baseline
Time frame: 2 years
Visual acuity is measured as a continuous integer letter score from 0 to 100, with higher numbers indicating better visual acuity. A letter score of 85 is approximately 20/20 and a letter score of 70 is approximately 20/40, the legal unrestricted driving limit in most states. A 5-letter change for an individual is approximately equal to a 1-line change on a vision chart.
2 secondary outcomes
Change in Visual Acuity From Baseline
Time frame: 4 years
Development of PDR and/or DME (Whichever Came First)
Time frame: 4 years
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jun 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 36749332Maturi 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.
- Derived from this study: PubMed 33784735Maturi 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jennifer K. Sun, MD, MPH study chair
Joslin Diabetes Center
85 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Prompt aflibercept, Deferred laser and Deferred aflibercept in people with Diabetic Retinopathy and Diabetic Macular Edema, run by Jaeb Center for Health Research at 85 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 24 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Jun 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 85 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 24 Nov 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Development of PDR and/or DME (Whichever Came First) (time frame: 2 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02634333, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jun 2023.