Damage to the back of the eye is a common complication of type 1 diabetes, and can lead to blindness. The Fenofibrate and Microvascular Events (FAME) 1 Eye Study is investigating whether fenofibrate, a drug that is used to lower cholesterol and blood fats, can slow or reverse eye damage, or retinopathy, in adults with type 1 diabetes. 

Fenofibrate is already approved for use to treat retinopathy in people with type 2 diabetes, but not for type 1 diabetes, as until now there has been no direct evidence that it will work the same way. The FAME 1 Eye Study is funded by the NHMRC and aims to show that fenofibrate can be successfully used to slow or reverse eye damage caused by type 1 diabetes.  

The T1DCRN is funding additional studies that will test whether fenofibrate can protect against other complications of type 1 diabetes, such as kidney, blood vessel and nerve damage. This is because fenofibrate targets a receptor that is found not only in the retina but also in these other tissues damaged by diabetes. T1DCRN funding will also allow researchers to conduct more sophisticated, non-invasive photography of the back of the eye to better see the effects of fenofibrate on the retina. 

Professor Alicia Jenkins from the NHMRC Clinical Trials Centre and collaborators in NSW and Victoria will treat 450 adults with type 1 diabetes and early-stage retinopathy with a daily tablet of fenofibrate or placebo for three years. During this period the researchers will measure changes in the eye as well as blood vessel damage and kidney function to see if fenofibrate can slow or reverse the development of type 1 diabetes complications.

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Full Detail About This Clinical Trial

Technical Summary

Diabetic Retinopathy (DR) is a common and early complication of Type 1 diabetes (T1D), and is the major cause of vision loss in people with T1D. DR is difficult to prevent even with intensive glycaemic, blood pressure and statin-induced LDL control.

Daily oral administration of fenofibrate, a triglyceride lowering lipid PPARα agonist drug, has been shown to prevent progression of DR in type 2 diabetes, and has been approved for use in Australia for this indication. However, the use of fenofibrate for T1D DR has not been approved due to a lack of equivalent evidence of benefit.

The FAME 1 Eye Study aims to determine over 3 years of follow-up in 450 adults with T1D and existing nonproliferative diabetic retinopathy randomly allocated to either once daily oral fenofibrate or placebo treatment if fenofibrate:

Aim 1. Reduces the rates of clinically significant diabetic retinopathy progression assessed by visual acuity, serial non-invasive retinal photography, Optical Computerised Tomography (OCT), and need for ocular medical or surgical intervention for sight-threatening retinopathy

Aim 2. Reduces other diabetic vascular complications, including renal dysfunction, peripheral nerve and cardiac autonomic dysfunction and arterial dysfunction

Aim 3. Improves blood and urine profiles of traditional and novel vascular risk biomarkers including biochemical and molecular (telomere and microRNA) markers. Markers relating to lipoproteins, oxidative stress, advanced glycation end-products (AGEs), inflammation, angiogenesis, adipokines and insulin resistance, telomeres and microRNAs will be analysed over 3 years.

Quality of life and health economics analyses will also be conducted.

The main FAME 1 Eye Study is funded by the NHMRC. In parallel, T1DCRN funding will be used to examine additional endpoints of major clinical importance, including development and progression of renal disease, neuropathy and more sophisticated assessments of early ocular changes by Optical Coherence Tomography, and Corneal Confocal Microscopy.

Trial Design

A randomised, double-blind, placebo controlled phase III clinical trial in 450 adults with T1D and established DR (ETDRS Score 35-53) evaluating the effects of 145mg fenofibrate once-daily over at least 3 years of treatment.

Principal Investigator

Professor Alicia Jenkins

Funder

The National Health and Medical Research Council (NHMRC)

The Australian Type 1 Diabetes Clinical Research Network

Locations

New South Wales

  • Royal North Shore Hospital
  • Concord Repatriation General Hospital
  • Garvan Institute of Medical Research

Victoria

  • St Vincent’s Hospital Melbourne

South Australia

  • Repatriation General Hospital

Western Australia

  • Fremantle Hospital

New Zealand

  • Auckland Diabetes Centre
  • Christchurch Hospital
Primary Endpoint

The occurrence of clinically significant DR progression, comprising 2-step progression of ETDRS score (to at least moderately severe grade), clinically significant macular oedema, need for laser surgery, intraocular anti-VEGF or corticosteroid therapy or vitrectomy, adjudicated to be for DR.

Secondary Endpoints
    1. The individual components of the primary endpoint
    2. Retinal vessel calibre and geometry
    3. Urine albumin:creatinine ratio [ACR]
    4. eGFR (measured 8 weeks after treatment withdrawal)
    5. Peripheral neuropathy (symptoms, monofilament testing, vibration and temperature sensation [Neuropen]);
    6. Autonomic neuropathy: QTc and RR intervals on yearly ECGs
    7. Congnition (questionnaire)
    8. Corneal nerve damage by Corneal Confocal Microscopy CCM
    9. Central macular volume and thickness by OCT;
    10. Corneal nerve indices by CCM
    11. Total CVD events, including myocardial infarction, stroke, sudden cardiac death, hospitalisation for acute coronary syndrome or any revascularization requirements
    12. Small artery elasticity (by pulse wave analysis PWA);
    13. Peripheral and autonomic nerve function by Sudoscan
    14. ECG based: QTc and RR interval
Inclusion/Exclusion

Inclusion Criteria

    1. Men or non-pregnant women (on acceptable contraception) with T1D
    2. Age 18 years or over;
    3. eGFR must exceed 30 ml/min/1.73m2;
    4. Must have non-proliferative DR (ETDRS score 35-53 inclusive) confirmed by retinal photography within the last 3 months (or proven prior to ocular treatment);
    5. All types of insulin and delivery modes, with no restriction by HbA1c level;
    6. Willing and able to comply with all study requirements, including treatment, assessment and clinic visit attendances;

Exclusion Criteria

    1. Definite indication for or contraindications to fibrate treatment. (Other lipid drugs [e.g. statins, ezetimibe, fish oils] are allowed.);
    2. Need for intra-ocular treatment or photocoagulation therapy within the next 3 months;
    3. History of photosensitive skin rash or myositis;
    4. Abnormal thyroid function or liver function tests exceeding 3xULN;
    5. Persistent elevated unexplained blood CK levels;
    6. Documented fasting TG levels >6.5 mmol/L;
    7. History of pancreatitis, DVT or pulmonary embolism;
    8. Use of investigational drugs in the prior 8 weeks;
    9. Any unstable condition in last 3 months including active sepsis, DKA;
    10. MI, unstable angina, stroke or heart failure within last 6 months;
    11. Diagnosed cancer with ongoing treatment or prognosis anticipated at <5 years;
    12. Any obstacle to regular follow-up; and
    13. 13) Prior or planned within trial timeframe organ transplant
Anticipated Outcomes

The anticipated outcomes for this project are:

    1. Development of clinical standards for islet transplantation and development of better guidelines for the management of severe hypoglycaemia.
    2. Reduce requirements for immunosuppression for beta cell replacement therapy and the development of islet cell transplantation tolerance. Novel therapeutic reagents will be developed into a clinical therapy to reduce or eliminate the requirement of chronic immunosuppression.
Start/End Date

2016- 2019