Clinical trial NCT02634333: Anti-VEGF Treatment for Prevention of PDR/DME
Official title: Intravitreous Anti-Vascular Endothelial Growth Factor Treatment for Prevention of Vision Threatening Diabetic Retinopathy in Eyes at High Risk
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetic Retinopathy
Diabetic Macular Edema
Keywords: anti-vascular endothelial growth factor
nonproliferative diabetic retinopathy
Lead sponsor: Jaeb Center for Health Research
Sponsor class: OTHER
Collaborators: name: Regeneron Pharmaceuticals
name: Juvenile Diabetes Research Foundation
name: National Eye Institute (NEI)
name: National Institutes of Health (NIH)
First posted: 2015-12-18
Enrollment: 399
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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). 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


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 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:

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 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.

Primary outcomes:
measure: Development of PDR and/or DME (Whichever Came First)
timeFrame: 2 years
measure: Change in Visual Acuity From Baseline
timeFrame: 2 years
Secondary outcomes:
measure: Change in Visual Acuity From Baseline
timeFrame: 4 years
measure: Development of PDR and/or DME (Whichever Came First)
timeFrame: 4 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: Huntington Beach
country: United States
facility: Atlantis Eye Care
state: California
city: Loma Linda
country: United States
facility: Loma Linda University Health Care, Department of Ophthalmology
state: California
city: Oakland
country: United States
facility: East Bay Retina Consultants, Inc.
state: California
city: Palm Desert
country: United States
facility: Southern California Desert Retina Consultants, MC
state: California
city: Porterville
country: United States
facility: Shashi D Ganti, MD PC
state: California
city: Redlands
country: United States
facility: Retina Consultants of Southern California
state: California
city: Sacramento
country: United States
facility: U.C. Davis Eye Center
state: California
city: Santa Barbara
country: United States
facility: California Retina Consultants
state: California
city: Westlake Village
country: United States
facility: Retinal Consultants of Southern California Medical Group, Inc.
state: California
city: Hamden
country: United States
facility: New England Retina Associates
state: Connecticut
city: Fort Lauderdale
country: United States
facility: Retina Group of Florida
state: Florida
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, Jacksonville Health Science Cent
state: Florida
city: Jacksonville
country: United States
facility: Florida Retina Institute-Jacksonville
state: Florida
city: Lakeland
country: United States
facility: Florida Retina Consultants
state: Florida
city: Miami
country: United States
facility: Bascom Palmer Eye Institute
state: Florida
city: Orlando
country: United States
facility: Magruder Eye Institute
state: Florida
city: Orlando
country: United States
facility: Florida Retina Institute
state: Florida
city: Pinellas Park
country: United States
facility: Southeast Eye Institute, P.A. dba Eye Associates of Pinellas
state: Florida
city: Plantation
country: United States
facility: Fort Lauderdale Eye Institute
state: Florida
city: Sarasota
country: United States
facility: 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: Bloomington
country: United States
facility: Gailey Eye Clinic
state: Illinois
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: Springfield
country: United States
facility: Springfield Clinic, LLP
state: Illinois
city: Indianapolis
country: United States
facility: Raj K. Maturi, M.D., P.C.
state: Indiana
city: 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: Shawnee Mission
country: United States
facility: Retina Associates, P.A.
state: Kansas
city: Paducah
country: United States
facility: Paducah Retinal Center
state: Kentucky
city: West Monroe
country: United States
facility: Eye Associates of Northeast Louisiana dba Haik Humble Eye Center
state: Louisiana
city: 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: Hagerstown
country: United States
facility: Mid Atlantic Retina Specialists
state: Maryland
city: Ayer
country: United States
facility: Valley Eye Physicians and Surgeons
state: Massachusetts
city: Boston
country: United States
facility: Joslin Diabetes Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health System, Dept of Ophthalmology and Eye Care Services
state: Michigan
city: Grand Rapids
country: United States
facility: Vitreo-Retinal Associates
state: Michigan
city: Minneapolis
country: United States
facility: Retina Center, PA
state: Minnesota
city: Kansas City
country: United States
facility: Mid-America Retina Consultants, P.A.
state: Missouri
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: 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: 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 Clinical Research, LLC
state: North Carolina
city: Chapel Hill
country: United States
facility: Kittner Eye Center
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: University Hospitals Cleveland Medical Center
state: Ohio
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: 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: 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: DeSoto
country: United States
facility: Robert E. Torti, MD, PA dba Retina Specialists
state: Texas
city: Grapevine
country: United States
facility: Retina Center of Texas
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: 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: Madison
country: United States
facility: University of Wisconsin-Madison, Dept of Ophthalmology/Retina Service
state: Wisconsin
city: Vancouver
country: Canada
facility: UBC/VCHA Eye Care Centre
state: British Columbia
city: Halifax
country: Canada
facility: Nova Scotia District Health Authority
state: Nova Scotia
city: North York
country: Canada
facility: Toronto Retina Institute (TRI)
state: Ontario
city: Toronto
country: Canada
facility: University Health Network - Toronto Western Hospital
state: Ontario
Study officials:
affiliation: Joslin Diabetes Center
name: Jennifer K. Sun, MD, MPH
role: STUDY_CHAIR
References:
citation: 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.