Protocol: A Randomized Trial Evaluating Fenofibrate for Prevention of Diabetic Retinopathy Worsening
Status: Recruiting
Start Date: 03/01/2021
End Date:  
Clinical Trial ID: NCT04661358
Public Dataset:  

Full Protocol

Summary Slides

Protocol Summary

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description

Title

A Randomized Clinical Trial Evaluating Fenofibrate for Prevention of Diabetic Retinopathy Worsening

Précis

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) 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.

Investigational Drug

Fenofibrate (new indication)

Objectives

The primary objective is to determine if fenofibrate is effective at preventing DR worsening in participants with mild to moderately severe non-proliferative DR and no CI-DME at baseline.

 

Additional goals of the study are to 1) provide a model for ophthalmologists to prescribe or collaborate with a primary care provider to prescribe and monitor the drug safely, 2) disseminate standardized prescribing guidelines with the aim to encourage broader use, and 3) collect information on potential predictive biomarkers via blood sampling, functional, and structural testing as well as glucose levels from CGM over the course of DR progression.

Study Design

Randomized, double-masked, placebo-controlled clinical trial

Number of Sites

Approximately 80

Endpoint

Primary Efficacy Outcome:

Worsening of DR through 4 years (time-to-event composite outcome) defined as any of the following (see details in Section 10.4.1):

  • 3 or more step worsening in person-level ETDRS DR severity on fundus photographs.
  • Development of NV within the 7-modified ETDRS fields on fluorescein angiography in either eye.
  • Intraocular procedure undertaken to treat DR in either eye including PRP, intraocular anti-VEGF, corticosteroid, or vitrectomy.

Key Safety Outcomes:

Myopathy, rhabdomyolysis, renal disease (eGFR decreased below 30, dialysis, or renal transplant), cholelithiasis, increased liver function tests (ALT or AST), low HDL, muscle pain or weakness, easy bruising or bleeding, death, APTC events

 

Population

 

 

 

 

 

 

 

Key Inclusion Criteria

  • Age =18 years and < 80 years.
  • Type 1 or type 2 diabetes.
  • 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 have best-corrected E-ETDRS visual acuity letter score of =79 (approx. Snellen equivalent 20/25 or better).

Key Exclusion Criteria

  • Current CI-DME based on clinical exam or OCT central subfield thickness (CST) in either eye.

o   Zeiss Cirrus: CST =290 µm in women or = 305 µm in men

o   Heidelberg Spectralis: CST =305 µm in women or =320 µm in men

  • Any prior treatment for DME or DR in either eye.
  • History of intraocular anti-VEGF or corticosteroid treatment within the prior year for any indication in either eye.
  • Decreased renal function, defined as requiring dialysis or central laboratory eGFR value < 60

Sample Size

910

Treatment Groups

Random assignment (1:1) to 160 mg Fenofibrate or Placebo

Participant Duration

4 years of follow-up for each randomized participant. 

Protocol Overview/Synopsis

  1. Informed consent will be obtained.
  2. Study eligibility will be assessed by the site.
  3. Potentially eligible participants will complete a Screening visit after which:
    1. Eligibility will be confirmed via lab results and RC grading of DR severity level.
    2. Approval to participate in the study will be obtained from the participant’s health care provider responsible for primary systemic management (e.g., endocrinologist or primary care provider).
  4. Eligible participants will be randomly assigned 1:1 to fenofibrate or placebo.
  5. Participants will return for a follow-up visit at 3 months, 6 months, and every 6 months thereafter.
  6. Phone calls to the participant will be made at 3-month intervals in-between 6-month interval visits, starting after the 6-month visit.
  7. Participation in the study will be considered completed upon completion of the 4-year (48 month) visit. 





Schedule of Study Visits and Procedures

In addition to the visits listed below, phone calls will be made from the site at 3-month intervals in between annual visits, starting after the 6-month visit (months 9,15, 21, 27, 33, 39, 45).

Visit

Screening Visit

0

 

3-Month Safety Visit

6-Month Visit

Annual Visits (12, 24, 36, 48 Month) *

18, 30, 42-Month Visits

Visit Window

 

<35 days from Screening

±2 weeks

±4 weeks

±8 weeks

±4 weeks

Randomization

 

X

 

 

 

 

Visual acuitya

X

X

 

X

X

X

OCT

X

 

 

X

X

X

Eye Exam b

X

X

 

X

X

X

Fundus Photographyc

X

 

 

 

X

 

Fluorescein Angiographyc

X

 

 

 

X

 

Blood Pressure

X

X

X

X

X

 

Urine sample for  creatinine, albumin, and pregnancy test (if female of child-bearing potential)

X

 

X

X

X

Pregnancy test only

Whole blood sample for CBC and HbA1cd

X

 

CBC only

X

X

 

Serum sample for LFTs, serum creatinine, eGFR, CK, and lipid panelse

X

 

X

X

X

 

Safety assessmentf

 

 

X

X

X

X

Assess Compliance with Study Drug Regimen

 

 

X

X

X

X

CGM Insertiong

 

X

 

X

X

X

Ancillary Components – the following tests will only be performed at select sites and/or on select participants

OCT Angiography

 

X

 

X

 

X

Humphrey Visual Fieldh

 

X

 

X

X

X

Contrast sensitivity

 

X

 

 

X

 

Biomarker serum sample

X

 

X

X

X

 

RNA sample

X

 

X

X

X

 

 

*= In addition, if treatment with intraocular medication, PRP or vitrectomy is initiated at anon-annual or non-study visit, annual visit ocular testing will be completed. For testing that is to be performed pre-dilation, post-dilation testing will be accepted if the decision to treat is made after dilation. Systemic testing only required at a treatment initiation visit if fenofibrate will be discontinued (both eyes treated with intraocular medication, PRP orvitrectomy).

a= Usual care vision acceptable at Screening Visit; otherwise, visual acuity testing includes protocol refraction at each visit followed by electronic-ETDRS testing using the Electronic Visual Acuity Tester that has been validated against 4-meterchart ETDRS testing.

b=Includes slit lamp exam (including assessment of lens), measurement of intraocular pressure and dilated ophthalmoscopy.

c= Using the widest approach available (e.g. ultrawide field imaging device)

d= CBC =complete blood count; for HbA1c, central laboratory value preferred but value available from within the prior 3 months may be used if central lab sample cannot be analyzed. CBC only at 3-month visit.

e=LFTs = liver function tests; eGFR = estimated glomerular filtration rate; CK = creatine kinase; fasting required for lipid panels at screening and 4-year visit only. 

f=safety assessments include questions related to symptoms of myopathy/rhabdomyolysis or cholelithiasis

g= a “masked” CGM sensor will be placed and worn for approximately10 days.  The CGM will then be mailed back to the Coordinating Center for processing of the data.

h= 30-2 and 60-4 at baseline, then alternating tests every 6months (30-2 at 6-month visits and 60-4 at annual visits)

 



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