Randomised, double-blinded, placebo-controlled, adaptive design trial of the efficacy of acipimox in patients with Mitochondrial Myopathy (AIMM)

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Mitochondria are tiny cellular structures that contain their own genetic material (DNA) and play a critical role in cellular energy (ATP) production. When these 'powerhouses' malfunction, it may result in chronic illnesses known as mitochondrial diseases. Mitochondrial diseases are a complex group of rare, inherited conditions in which patients are more susceptible to developmental, physical and cognitive disabilities. Muscle symptoms including muscle weakness, fatigue, and pain are extremely prevalent and often debilitating. As a result, many adult patients are often unable to work or require costly medical care after their diagnosis is made.It has been estimated that mitochondrial diseases affect up to 15,000 adults (and a similar numbers of children) in the UK. To date, there are no licensed treatments and no curative therapies. Hence, there is an urgent need to find an effective drug therapy. We plan to test a drug (acipimox) that has originally been used to treat high cholesterol and improve diabetic control. The drug has also been shown to boost ATP levels within muscles cells and it is this function that we wish to exploit in patients with mitochondrial disease and muscle involvement to relieve the debilitating muscle symptoms. The benefits of using a drug that has already been used in other conditions, means that we already understand the behaviour of the drug in humans, we understand the side effects of the drug, and we already know how to administer the drug in addition to understanding about effective doses. This method potentially provides a faster and less expensive pathway to address the urgent need for drug treatments in mitochondrial diseases. The design of this study was formulated over 2 years with the help and support of patients and their care providers. Firstly, they were asked about aspects of their disease that they hoped could be addressed with any new therapies. Muscle symptoms were considered by patients to be the most important target for any new drug treatments. We then intensely worked together to devise the best way to measure aspects of their everyday functioning that could potentially be addressed by a drug treatment. For the first time in mitochondrial disease, we have used an 'adaptive design model', that will allow us to regularly modify the number of patients needed, as more information is collected. This approach allows us to more quickly identify drugs to have a beneficial therapeutic effect. This partnership, has uniquely allowed us to co-design this study proposal from its initial inception and will continue until the end of the study. This study will take place over 12 weeks when up to 120 patients will take a tablet three times a day. Half of the patients will receive the drug and the other half will receive an identical 'placebo' treatment. Neither the doctor nor the patient will know who receives which treatment (double-blind). This is important to ensure that any effects are due to the drug and not to any other potential factors (eg. more interaction with medical staff or hospital visits). In addition to taking a small piece of muscle at study start and end (to better understand the effect of drug and mitochondrial disease on muscle), we will monitor the safety of patients enrolled. We will also perform assessments of everyday functioning including walking, heart and lung capacity, muscle strength and performance, mental agility and impact of disease symptoms on mental health and well-being.The potential impact of this work is considerable. Firstly, patients with mitochondrial disease may have access to a drug that has been proven to be safe and effective; in addition to a better understanding of the mechanisms underlying mitochondrial diseases. Furthermore, the methods used in this study could be used in other rare diseases, particularly where obtaining the desired patient recruitment and retention proves to be the primary barrier to clinical advancements.