Objective
The main objective of this request to Breakthrough T1D is to seek additional funding to allow us to complete the FAME-1 Eye Trial. This is an investigator-led trial sponsored by the University of Sydney, Australia, with collaborators in Australia, New Zealand, Hong Kong and Northern Ireland, funded by the NHMRC Australia, JDRF Australia and Abbott Europe with donation of bulk drug (fenofibrate 145 mg) and placebo by Viatris / Abbvie. The trial includes 24 (all recruiting) sites in Australia, New Zealand, Hong Kong and N. Ireland.
This trial is related to the prevention of the progression of diabetic retinopathy (DR) in adults with Type 1 diabetes (T1D) and existent mild to moderate DR.
This trial is recruiting adults with T1D and existent non-proliferative DR to determine over a minimum of 1-year (average 4.5 years) follow-up the effects of a once daily tablet of fenofibrate vs. an inert (placebo) tablet on clinically significant eye health, including vision loss and need for laser treatment of injections into the eye or surgery for DR.
In addition, we are looking at the effects of fenofibrate on kidney function by blood and urine tests, and on nerve health (in the periphery and in the heart) based on questionnaires, physical examination a special non-invasive nerve testing device and EKG recordings of the heart.
We will use questionnaires to determine effects of diabetes and the test drugs on the study participant’s quality of life.
Blood and urine, including genetic material (DNA and RNA), will be collected to test levels of factors which may predict and medicate tissue damage or protection. These tests are separately funded and include factors related to implicated processes such as inflammation and changes in growth factors affecting blood vessel growth and in genes and cell communication factors. which are strongly implicated in the development and progression of the blood vessel and nerve related complications of T1D. Levels of individual factors, and combinations thereof, may be useful to predict early on who will or will not develop T1D complications and who will respond well to treatments. Such knowledge will also inform regarding potential treatment targets and guide other research to develop new and better treatments to prevent and reverse T1D damage.
Trial progress was substantially impacted by COVID-19 during which many sites were closed for almost 2-years and many trial site staff were diverted to clinical roles, which delayed recruitment. Many sites had to replace and retrain staff post-COVID shutdowns. Central costs at the Uni. of Sydney for trial management staff were reduced wherever possible and subsidized by other grants. This allowed the original 5-year projected trial to run for 8-years to date (including 2 years initial delay getting drug supplies due to company take over).
Our current remaining funds will be expended by the end of 2025. As of 21/10/24 of 291 participants in the randomized trial 279 are randomized and 12 are in the run-in stage; 100 adults with T1D and more or less severe DR than eligible for the FAME-1 trial are in observational follow-up and 31 of 50 planned non-diabetic subjects have been recruited to provide reference ranges for biomarkers.
This study is helping to build collaboration, experience and research capacity across Australia, train the current and next generation of T1D researchers, and build capacity for other national and international collaborations in T1D research. Achieving these objectives would promote better outcomes for people with T1D in Australia and overseas in the near future and beyond.
Background Rationale
Apart from the unacceptably high prevalence and personal and economic burden of diabetic retinopathy (DR) for people with Type 1 diabetes (T1D), major rationale for this proposal stems from the major benefit of fenofibrate for DR and other complications in people with T2D, as demonstrated in the FIELD Trial and the ACCORD Eye Study.
These two trials led to the Australian regulatory body approving use of fenofibrate tablets to treat DR in people with T2D and existent DR. This indication does not include T1D due to lack of evidence re clinical benefit, which this trial aims to provide. The FIELD Trial, which was designed and led by Co-PI Prof Keech included many of the FAME-1 Eye Team, hence an experienced team with relevant expertise and trial conduct resources is available.
In the FIELD Trial five years of a once daily fenofibrate tablet reduced sight-threatening DR by 37%, and also significantly protected against kidney and nerve damage, amputations and some heart disease events. There was even some reversal of existent kidney and nerve damage. Fenofibrate also had favorable effects on many clinical, biochemical and molecular tests of blood vessel damage, such as related to inflammation, blood vessel growth, oxidative stress, insulin resistance and fat cells, which may explain and predict clinical outcomes. Clinical factors, including detailed analysis of retinal photographs (which are already often taken for the clinical care of people with T1D), and other non-invasive tests of nerve and blood vessel health that may be used in future clinical practice may improve prediction of complications and treatment outcomes and be useful monitoring tests. The team is equipped for and experienced with these tests from their FIELD Trial work and their T1D studies and using these techniques and skills in the FAME-1 Eye Study.
There is scientific rationale for the use of fenofibrate to protect against blood vessel and nerve damage in diabetes. Fenofibrate acts mainly by activating a communication pathway in cells called PPAR alpha. PPAR alpha is expressed in tissues damaged by diabetes, including the retina at the back of the eye, kidneys, blood vessels and nerves. PPAR alpha activation, such as by fenofibrate drugs affects over 100 genes and cell communication pathways related to processes such as blood fat metabolism, inflammation, blood vessel growth and cell death, perturbations of which are implicated in diabetes complications, and which are improved by fenofibrate in T2D. The applicants, and others have shown in cells grown in the laboratory and in experimental animal models that PPAR alpha activation, including by fenofibrate, prevents retinal damage, including blood vessel leakage, inflammation and abnormal new blood vessel formation. We have demonstrated this in T1D models in the laboratory, and others are developing fenofibrate eye-drops for DR, which has been tested (including by us, successfully) in small animals. Study results would guide future laboratory research and accelerate development of fenofibrate eye drops for human testing.
Study funding is also providing a store of data and samples (a ‘biobank’) for future approved and independently funded analyses.
The study will provide many adults with T1D, people living with T1D and medical researchers with greater connections, resources and opportunities, all of which will contribute to improving the lives of people with T1D globally.
Description of Project
Globally diabetes is a common and feared cause of eye damage (diabetic retinopathy) and vision loss, with treatments for late-stage retinopathy including retinal laser therapy and injections of drugs into the eye or eye surgery (called vitrectomy). The major proven treatment to retard the development or progression or earlier stages of diabetic retinopathy is tight blood sugar (glucose) control, which is achieved by only about 20% of people with Type 1 diabetes. Two major Type 2 diabetes heart disease end-point trials, the FIELD and ACCORD Lipid Eye trials, showed that once daily oral fenofibrate can retard development of severe retinopathy by up to 40%. We are conducting the trial of once daily fenofibrate tablets in adults with Type 1 diabetes with retinopathy as the main end-point, the Fenofibrate and Microvascular End-Points in Type 1 diabetes – Eye (FAME-1 Eye trial). In 24 sites 347 participants with Type 1 diabetes and mild to moderate retinopathy have been recruited and to date 290 are randomized or just pre-randomization to fenofibrate or placebo, with a mean follow-up of 3.2 years (as of 10/24). Also, so far 31 non-diabetic adults to provide reference values for biomarkers have been recruited. Trial recruitment was delayed due to COVID-19, and is now regaining momentum.
We propose to complete the FAME-1 Eye trial, perform relevant studies of traditional and novel clinical, biochemical and molecular factors which will guide individualized health care (precision medicine) and development of novel therapies. Positive results would likely rapidly change clinical practice and guidelines globally and reduce the personal and socioeconomic burden of eye damage in people with Type 1 diabetes as fenofibrate is low cost, off patent and widely available.
Anticipated Outcome
We are seeking funding to allow us to complete this important study comparing outcomes in up to 320 adults with Type 1 diabetes (T1D) and existent eye damage (diabetic retinopathy (DR)) treated with up to 1 year (average 4.5 years) of a once daily fenofibrate tablet or an inert (placebo) tablet. We expect that fenofibrate will retard DR progression towards sight threating diabetic retinopathy that reduces vision or needs laser treatment to the eye, intraocular injections (of anti-VEGF or corticosteroids) or eye surgery (vitrectomy).
We also expect that fenofibrate will protect against diabetes related nerve and systemic blood vessel damage, will reduce progression and induce some regression of kidney. These complications are much more common in adults with T1D and DR and are common causes of kidney failure, amputations and heart disease and stroke. We expect that fenofibrate will be generally well-tolerated and safe and will be associated with favorable quality of life assessments in people with T1D. We anticipate that our health economics analysis will show that use of this low-cost drug, that can be prescribed by any doctor, will be highly cost-effective.
If fenofibrate has favorable effects on eye health there will be an increase in prescription of oral fenofibrate in adults with T1D and DR. Positive study results will influence clinical practice recommendations for adults with T1D in Australia (such as the NHMRC T1D guidelines and those by the Australian Diabetes Society Council, National Heart and National Kidney Foundations and similar overseas agencies). Data will guide regulatory body decisions (e.g. FDA and TGA and European bodies) re indications and subsidies for fenofibrate use by adults with T1D.
The trial conduct will provide opportunity for many people with T1D to participate in a clinical trial, which we believe is the largest T1D clinical trial for retinopathy to date. Awareness of and/or participation in this trial may encourage participation in other clinical research.
The FAME-1 Eye Study will upskill clinics and personnel in T1D clinical research, including use of devices that may be used in T1D clinical care in the future. This trial will also facilitate the mentoring, training and career advancement of T1D researchers and the involvement of many people and advocates living with T1D
The trial will build and maintain a data and sample bank (a ‘Biorepository’), a valuable resource for biological material and data to explore (additional, separately funded) biomarkers. Results will provide impetus for basic science studies exploring mechanisms of T1D tissue damage, and protection by fenofibrate.
In summary, we anticipate that conduct of the FAME-1 Eye study will inform as to whether and how fenofibrate protects against sight threatening eye damage and related complications in adults with T1D and will contribute in many other ways to improving the lives of people with T1D around the world.
Relevance to T1D
Type 1 diabetes (T1D) currently affects over 9M people globally, 90% of whom are adults, and prevalence is increasing at about 3% pa. T1D generates substantial health burden, premature death and health-care costs, particularly when associated with diabetes complications such as those affecting the small and large blood vessels of the body, including the eye. Damage to the eye, predominantly in the film (retina) at the back of the eye, ‘diabetic retinopathy’ is present in almost all people after 20 years of T1D. Diabetic retinopathy (DR) is a feared and major cause of vision loss, often occuring in young to middle-age adulthood, substantially reducing quality of life and negatively impacting their work capacity, their family, friends and community interactions.
Clinical trials such as the DCCT/EDIC study (1441 people with T1D followed for 30y), show that tight blood glucose control for 6-–7 years can substantially reduce the onset and progression of DR, and also of kidney, nerve and heart disease damage for many years, even decades later. Unfortunately, even with modern insulins and insulin delivery modes, such as insulin pumps, tight glucose control can be very difficult to achieve. Blood pressure and blood fat (lipid) control have also reduced diabetes complication rates, but unfortunately the commonly used lipid controlling drugs (statins) do not protect against DR. Hence, despite modest benefits with established treatments, DR risk in people with T1D remains high, and costs dearly. We are also unable to predict early on the course of T1D whether a person will develop DR and other complications and how well they will respond to various treatments.
This is the first study to explore fenofibrate use in T1D alone, after striking protective effects of feneofibrate have been shown in major Type 2 diabetes (T2D) studies, the FIELD and ACCORD Lipid Trials. Based on these studies regulatory agencies in Australia and 18 low and middle income countries have approved fenofibrate for the treatment of DR in T2D, irrespective of blood fat levels, but as yet there is little data to inform fenofibrate use in T1D.
The recently completed LENS trial of fenofibrate for DR included 305 T1D and over 700 T2D, and was positive overall and for T2D, but showed a not statistically significant trend in T1D. With the indication s for the use of fenofibrate to treat established DR in T2D there is a risk of gradual use of the medicine in T1D without gaining the necessary level evidence of benefit in T1D (benefits outweighing any harms) from proper randomised evaluation. As treatment may be life-long, obtaining robust evidence of net benefit is critical to evidence-based practice, and will accelerate its implementation if proving beneficial. This study will provide such knowledge. People with T1D should not be assumed to behave the same way in response to risk factors and treatments as people with T2.
Unlike laser treatment and injections into the eye of expensive drugs, which require regular visits to an eye specialist (ophthalmologist) for late-stage DR, fenofibrate tablets, if effective, can be implemented by all doctors and is relatively inexpensive. Fenofibrate may also protect other tissues, such as the kidneys, nerves and heart, as has been shown in adults with T2D. Results will also facilitate risk prediction and risk stratification for earlier and better targeted therapy of people with T1D at high risk of DR and its related complications. Positive study results would also guide and promote further research to determine mechanisms of vision loss and protection in people with T1D. Findings will add new globally relevant knowledge and will ultimately contribute to improved outcomes for people with T1D.