Protocol AF: Fenofibrate for Prevention of DR Worsening
This randomized trial will evaluate the effect of fenofibrate compared with placebo for prevention of diabetic retinopathy (DR) worsening through 4 years of follow-up in participants with mild to moderately severe non-proliferative DR (NPDR) and no CI-DME at baseline.
In addition to evaluating efficacy, this study aims to evaluate the feasibility of a model for ophthalmologists to prescribe or collaborate with a primary care provider such as an internist/endocrinologist to prescribe and monitor the drug safely. If this study demonstrates that fenofibrate is effective for reducing the onset of proliferative diabetic retinopathy (PDR) or and the results are adopted by the community of retina specialists, a new strategy to prevent vision threatening complications of diabetes could be widely adopted. Widespread use of an oral agent effective at reducing worsening of DR would decrease the numbers of patients who undergo more invasive and much more expensive treatment for DR and who are consequently at risk for side effects that adversely affect visual function. This study will also assess the relationship of glycemic variability as measured by continuous glucose monitoring with DR outcomes. Ancillary studies will characterize functional and structural outcomes in this cohort.
|Condition or Disease||Intervention/Treatment||Phase|
Arms and Interventions
|Experimental: Fenofibrate 160-mg|
Drug: Fenofibrate 160mg
Participants begin with a dose of 160mg fenofibrate taken once daily with food. The dose may be adjusted during follow-up based on protocol guidelines.
|Placebo Comparator: Placebo|
Participants begin with a dose of 160mg placebo taken once daily with food. The dose may be adjusted during follow-up based on protocol guidelines.
Primary Outcome Measures
- Worsening of diabetic retinopathy [4- years]
Defined as 3 or more step worsening in person-level Early Treatment Diabetic Retinopathy Study (ETDRS) diabetic retinopathy severity on fundus photographs. Development of neovascularization within the 7-modified ETDRS fields on fluorescein angiography in either eye. Intraocular procedure undertaken to treat diabetic retinopathy in either eye including panretinal photocoagulation, intraocular anti-vascular endothelial growth factor, corticosteroid, or vitrectomy.
Secondary Outcome Measures
- Intraocular procedure undertaken to treat diabetic retinopathy or diabetic macular edema in either eye including PRP, intraocular anti-VEGF, corticosteroid, focal/grid laser or vitrectomy [4 years]
- Development of CI-DME in either eye [4 years]
Defined as, either 1) at least a 10% increase in OCT central subfield thickness from baseline, OCT central subfield thickness greater than sex and machine-specific threshold values (Zeiss Cirrus: CST ≥290 µm in women or ≥ 305 µm in men; Heidelberg Spectralis: CST ≥305 µm in women or ≥320 µm in men), and Investigator determination that thickening cannot be attributed to any cause other than CI-DME, or 2)Non-topical DME treatment including focal/grid laser, intraocular anti-VEGF, intraocular corticosteroid, or vitrectomy
- Development of center-involved diabetic macular edema with vision loss in either eye [4 years]
Defined as either 1) an increase in OCT central subfield thickness of 10% or more from baseline, OCT central subfield thickness greater than sex and machine-specific threshold values (Zeiss Cirrus: CST ≥290 µm in women or ≥ 305 µm in men; Heidelberg Spectralis: CST ≥305 µm in women or ≥320 µm in men), investigator determination that thickening cannot be attributed to any cause other than DME, and a decrease in visual acuity from baseline of 10 or more letters at a single visit or 5 to 9 letters at 2 consecutive visits at least 21 days apart with vision loss presumed to be from DME, non-topical DME or 2) treatment including focal/grid laser, intraocular anti-VEGF, intraocular corticosteroid, or vitrectomy
- Visual acuity loss from any cause [4 years]
Defined as a decrease in visual acuity from baseline of 10 or more letters at a single visit or a 5 to 9-letter decrease at 2 consecutive visits at least 21 days apart in either eye regardless of whether vision loss is presumed to be from DME or any other cause in either eye
- Inclusion Criteria
- Age >= 18 and < 80 years
• Individuals <18 years old are not being included because DR is so rare in this age group that the diagnosis of NPDR may be questionable. Individuals ≥80 years old are excluded to limit co-morbidities and mortality over this long-term trial.
- 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, or documented diabetes by American Diabetes Association and/or the World Health Organization criteria.
Both eyes meet the study eye criteria listed below.
Able and willing to provide informed consent.
Able and willing to wear a continuous glucose monitoring (CGM) device (for United States participants only).
- Eye level inclusion criteria:
- Either (1) both eyes have mild to moderately severe NPDR (defined by ETDRS DR severity level 35 to 47) or (2) one eye has mild to moderately severe NPDR and the other eye has microaneurysms only (DR severity level 20).
- Confirmation of DR severity level is required by both the investigator and central Reading Center grading of fundus photographs.
- Both eyes must have best-corrected E-ETDRS visual acuity letter score ≥79 (approximate Snellen equivalent 20/25 or better) 8. Both eyes must have 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)
A condition that, in the opinion of the investigator, would preclude participation in the study (e.g., unstable medical status that may preclude successful completion of follow-up).
Initiation of intensive insulin treatment (a pump or multiple daily injections) within 3 months prior to screening or plans to do so in the next 3 months.
Participation in an investigational trial that involved treatment within 30 days of screening with any drug that has not received regulatory approval for the indication being studied.
Known allergy or hypersensitivity to any component of fenofibrate.
Known allergy to fluorescein dye.
History of treatment with a prescription fibrate medication (e.g. bezafibrate, fenofibrate, gemfibrozil, fenofibric acid) within 12 months prior to screening or anticipated need for fibrate medication for another indication (e.g. lipid management).
Any prior systemic treatment for DME or DR.
Decreased renal dysfunction, defined as requiring dialysis or central laboratory eGFR value < 60
Active liver disease, defined as any liver function test >3x upper limit of normal based on central laboratory value.
Pre-existing symptomatic gallbladder disease including gallstones; however, prior gallbladder removal is not an exclusion.
Triglycerides >400mg/dL on treatment or >700mg/dL on no treatment based on central laboratory value.
Current use of any of the following medications:
Coumarin anticoagulants (Coumadin/Warfarin).
Immunosuppressants that affect kidney function, such as cyclosporine and tacrolimus
History of severe myalgia requiring discontinuation of lipid lowering treatment.
Blood pressure > 160/100 (systolic above 160 or diastolic above 100).
HbA1c > 11.0% based on central laboratory value or if lab sample cannot be analyzed, recent result within 3 months
Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to screening or anticipated use during the study.
For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 4 years.
Participant is expecting to move out of the area of the clinical center to an area not covered by another clinical center during the next four years.
The following exclusions apply to both eyes:
- Evidence of definite neovascularization according to the investigator or central Reading Center grading of fluorescein angiography.
• Includes presence of neovascularization (NV) outside of the 7-modified ETDRS fields on ultra-widefield imaging, which is an exclusion.
- Current CI-DME based on clinical exam or OCT central subfield thickness (CST), defined as:
Zeiss Cirrus: CST ≥290 µm in women or ≥ 305 µm in men.
Heidelberg Spectralis: CST ≥ 305 µm in women or ≥320 µm in men.
Major non-diabetic intraocular pathology that in the opinion of the investigator would substantially and adversely affect visual acuity or lead to ocular neovascularization during the study.
Any prior treatment for DME or DR.
History of major ocular surgery within prior 4 months or anticipated within the next 6 months following randomization.
Anticipated need for intraocular anti-VEGF or PRP in the next 6 months following randomization.
History of intraocular anti-VEGF or corticosteroid treatment within the prior year for any indication.
Any history of vitrectomy.
History of YAG capsulotomy performed within 2 months prior to screening.
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)
Contacts and Locations
|1||Kent W. Small, MD, AMC||Glendale||California||United States||91203-1971|
|2||Loma Linda University||Loma Linda||California||United States||92354|
|3||National Ophthalmic Research Institute||Fort Myers||Florida||United States||33912|
|4||Florida Retina Institute, James A. Staman, MD, PA- Jacksonville||Jacksonville||Florida||United States||32216|
|5||Florida Retina Consultants||Lakeland||Florida||United States||33805|
|6||Retina Vitreous Consultants, LLP||Sarasota||Florida||United States||34233-1261|
|7||Sarasota Retina Institute||Sarasota||Florida||United States||34239|
|8||Marietta Eye Clinic||Marietta||Georgia||United States||30060|
|9||Thomas Eye Group||Sandy Springs||Georgia||United States||30328|
|10||Illinois Retina Associates SC - Oak Park Site||Oak Park||Illinois||United States||60304|
|11||John Kenyon American Eye Institute, LLC||New Albany||Indiana||United States||47150|
|12||Wolfe Eye Clinic-Cedar Rapids||Hiawatha||Iowa||United States||52233|
|13||Elman Retina Group, P.A.||Baltimore||Maryland||United States||21237|
|14||Joslin Diabetes Center||Boston||Massachusetts||United States||02215|
|15||Henry Ford Health System||Detroit||Michigan||United States||48202-2689|
|16||Retina Center, PA DBA Retina Center of Minnesota||Minneapolis||Minnesota||United States||55404|
|17||Retina Research Institute, LLC||Saint Louis||Missouri||United States||63128-1729|
|18||Retina-Vitreous Surgeons of Central NY, PC||Liverpool||New York||United States||13088|
|19||Retina Associates of Western NY, P.C.||Rochester||New York||United States||14620-4655|
|20||Pamela Weber, MD/Island Retina||Shirley||New York||United States||11967|
|21||Dean A. McGee Eye Institute||Oklahoma City||Oklahoma||United States||73104|
|22||Verum Research LLC||Eugene||Oregon||United States||97401|
|23||Retina Consultants, LLC||Salem||Oregon||United States||97302|
|24||Retina-Vitreous Consultants, Inc.||Monroeville||Pennsylvania||United States||15146|
|25||Southeastern Retina Associates, P.C.||Knoxville||Tennessee||United States||37922|
|26||Retina Consultants of Texas, PA||Bellaire||Texas||United States||77401|
|27||Baylor College of Medicine, Baylor Eye Physicians and Surgeons||Houston||Texas||United States||77030-4101|
|28||Texas Retina Associates||Lubbock||Texas||United States||79424|
|29||Retinal Consultants of San Antonio||San Antonio||Texas||United States||78240|
Sponsors and Collaborators
- Jaeb Center for Health Research
- National Institutes of Health (NIH)
- National Eye Institute (NEI)
- Juvenile Diabetes Research Foundation
- Roche Pharma AG
- The Leona M. and Harry B. Helmsley Charitable Trust
- Study Chair: Emily Y Chew, MD, National Institutes of Health (NIH)
Study Documents (Full-Text)None provided.
- DRCR.net Protocol AF