Anti-VEGF Treatment for Prevention of PDR/DME

Diabetic Retinopathy Clinical Trial

Official title:

Intravitreous Anti-Vascular Endothelial Growth Factor Treatment for Prevention of Vision Threatening Diabetic Retinopathy in Eyes at High Risk

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02634333
• Other study ID #: DRCR.net Protocol W
• Secondary ID: EY14231EY23207EY
• Status: Completed
• Phase: Phase 3
• Start date: January 2016
• Est. completion date: May 11, 2022

Study information

• Verified date: May 2023
• Source: Jaeb Center for Health Research
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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). 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 399
• Est. completion date: May 11, 2022
• Est. primary completion date: May 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Diabetic Macular Edema
• Diabetic Retinopathy
• Macular Edema
• Retinal Diseases

Intervention

Procedure:
• 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.

Drug:
• 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.

Procedure:
• 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

Drug:
• 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.

Locations

Country	Name	City	State
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	UBC/VCHA Eye Care Centre	Vancouver	British Columbia
United States	Eye Associates of New Mexico	Albuquerque	New Mexico
United States	Southwest Retina Specialists	Amarillo	Texas
United States	Western Carolina Clinical Research, LLC	Asheville	North Carolina
United States	Emory Eye Center	Atlanta	Georgia
United States	Southeast Retina Center, P.C.	Augusta	Georgia
United States	Austin Retina Associates	Austin	Texas
United States	Retina Research Center	Austin	Texas
United States	Valley Eye Physicians and Surgeons	Ayer	Massachusetts
United States	Elman Retina Group, P.A.	Baltimore	Maryland
United States	Wilmer Eye Institute at Johns Hopkins	Baltimore	Maryland
United States	Retina Associates of Cleveland, Inc.	Beachwood	Ohio
United States	Gailey Eye Clinic	Bloomington	Illinois
United States	Joslin Diabetes Center	Boston	Massachusetts
United States	Kittner Eye Center	Chapel Hill	North Carolina
United States	Charlotte Eye, Ear, Nose and Throat Assoc., PA	Charlotte	North Carolina
United States	Southeastern Retina Associates	Chattanooga	Tennessee
United States	Northwestern Medical Faculty Foundation	Chicago	Illinois
United States	University of Illinois at Chicago Medical Center	Chicago	Illinois
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	Carolina Retina Center	Columbia	South Carolina
United States	Robert E. Torti, MD, PA dba Retina Specialists	DeSoto	Texas
United States	Henry Ford Health System, Dept of Ophthalmology and Eye Care Services	Detroit	Michigan
United States	Medical Associates Clinic, P.C.	Dubuque	Iowa
United States	Oregon Retina, LLP	Eugene	Oregon
United States	Retina Group of Florida	Fort Lauderdale	Florida
United States	National Ophthalmic Research Institute	Fort Myers	Florida
United States	Vitreo-Retinal Associates	Grand Rapids	Michigan
United States	Retina Center of Texas	Grapevine	Texas
United States	Mid Atlantic Retina Specialists	Hagerstown	Maryland
United States	New England Retina Associates	Hamden	Connecticut
United States	Baylor Eye Physicians and Surgeons	Houston	Texas
United States	Retina and Vitreous of Texas	Houston	Texas
United States	Retina Consultants of Houston, PA	Houston	Texas
United States	Atlantis Eye Care	Huntington Beach	California
United States	Raj K. Maturi, M.D., P.C.	Indianapolis	Indiana
United States	Florida Retina Institute-Jacksonville	Jacksonville	Florida
United States	University of Florida College of Med., Department of Ophthalmology, Jacksonville Health Science Cent	Jacksonville	Florida
United States	Mid-America Retina Consultants, P.A.	Kansas City	Missouri
United States	Southeastern Retina Associates, P.C.	Knoxville	Tennessee
United States	Florida Retina Consultants	Lakeland	Florida
United States	Loma Linda University Health Care, Department of Ophthalmology	Loma Linda	California
United States	Texas Retina Associates	Lubbock	Texas
United States	University of Wisconsin-Madison, Dept of Ophthalmology/Retina Service	Madison	Wisconsin
United States	Marietta Eye Clinic	Marietta	Georgia
United States	Valley Retina Institute	McAllen	Texas
United States	Bascom Palmer Eye Institute	Miami	Florida
United States	Retina Center, PA	Minneapolis	Minnesota
United States	Retina Vitreous Consultants	Monroeville	Pennsylvania
United States	MaculaCare	New York	New York
United States	The New York Eye and Ear Infirmary/Faculty Eye Practice	New York	New York
United States	Retinal and Ophthalmic Consultants, PC	Northfield	New Jersey
United States	East Bay Retina Consultants, Inc.	Oakland	California
United States	Florida Retina Institute	Orlando	Florida
United States	Magruder Eye Institute	Orlando	Florida
United States	Paducah Retinal Center	Paducah	Kentucky
United States	Southern California Desert Retina Consultants, MC	Palm Desert	California
United States	University of Pennsylvania Scheie Eye Institute	Philadelphia	Pennsylvania
United States	Arizona Retina and Vitreous Consultants	Phoenix	Arizona
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	Shashi D Ganti, MD PC	Porterville	California
United States	Casey Eye Institute	Portland	Oregon
United States	Retina Northwest, PC	Portland	Oregon
United States	Retina Consultants of Southern California	Redlands	California
United States	Retina Institute of Virginia	Richmond	Virginia
United States	Virginia Commonwealth University, Dept. of Ophthalmology	Richmond	Virginia
United States	University of Rochester	Rochester	New York
United States	U.C. Davis Eye Center	Sacramento	California
United States	Retinal Consultants of San Antonio	San Antonio	Texas
United States	Thomas Eye Group	Sandy Springs	Georgia
United States	California Retina Consultants	Santa Barbara	California
United States	Sarasota Retina Institute	Sarasota	Florida
United States	Retina Associates, P.A.	Shawnee Mission	Kansas
United States	Springfield Clinic, LLP	Springfield	Illinois
United States	Retina-Vitreous Surgeons of Central New York, PC	Syracuse	New York
United States	Retina Associates of Florida, P.A.	Tampa	Florida
United States	University of Arizona Medical Center/Department of Ophthalmology	Tucson	Arizona
United States	Palmetto Retina Center	West Columbia	South Carolina
United States	Wolfe Eye Clinic	West Des Moines	Iowa
United States	Eye Associates of Northeast Louisiana dba Haik Humble Eye Center	West Monroe	Louisiana
United States	Retinal Consultants of Southern California Medical Group, Inc.	Westlake Village	California

Sponsors (5)

Lead Sponsor	Collaborator
Jaeb Center for Health Research	Juvenile Diabetes Research Foundation, National Eye Institute (NEI), National Institutes of Health (NIH), Regeneron Pharmaceuticals

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	2 years
Primary	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.	2 years
Secondary	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.	4 years
Secondary	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)	4 years