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

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.

Muscle involvement manifesting as fatigue, exercise intolerance, myalgia and muscle weakness is a major problem in adult patients with mitochondrial disease. The management of these patients remains challenging, not least because there are currently no interventions that provide a realistic prospect of cure. This represents a compelling unmet need and suggests that key aspects of mitochondrial dysfunction remain untargeted. Novel approaches to management have recently included pharmacological stimulation of Sirtuin 1 (SIRT1)-mediated mitochondrial biogenesis, by boosting levels of NAD+. This has been demonstrated to be a highly effective therapeutic strategy to correct the underlying biochemical defect and alleviate the clinical phenotype in animal models of mitochondrial disease, and studies in patients with diabetes has shown that this approach should also be effective in patients with mitochondrial disease. Acipimox, a nicotinic acid derivative and natural nicotinamide adenine dinucleotide (NAD+) donor, is a generically available drug currently licensed for the management of hypertriglyceridemia. Supplementation with acipimox, has been shown to have a direct effect on muscle and mitochondrial function by improving mitochondrial oxidative phosphorylation and metabolic capacity. This trial aims to repurpose acipimox as a potent stimulator of mitochondrial biogenesis and disease-modifying agent for patients with mitochondrial disease and muscle involvement. The primary outcome will assess change in muscle adenosine triphosphate (ATP) content of placebo and acipimox-treated patients, as well as improving function and quality of life.

New applications of therapy: Success of this study will potentially impact most on patients with mitochondrial disease, as it holds considerable promise to provide a novel therapeutic strategy, in a condition with no currently licensed treatments. Moreover, we would suggest that, if acipimox demonstrates significant efficacy in the two genetic forms of mitochondrial disease included in this study design, that the compound will likely be beneficial for all forms of mitochondrial disease with significant muscle involvement. Hence, this would serve as a significant advancement in this field internationally, in which there are currently no licensed treatments.

New trial approaches: Randomized clinical trials and evidence-based studies on the efficacy of treatments in patients with mitochondrial disease is still lacking. In the clinical field of mitochondrial disease, the work will advance future trial design by linking several functional outcome measures with optimized clinical assessments. Beneficiaries will be patients, clinicians, allied health professionals and pharma with an interest in study design, clinical phenotypes and improved clinical trial endpoints. Indeed, we would propose extrapolating the adaptive design methodology into other rare diseases where obtaining the desired patient recruitment and retention proves to be the primary barrier to clinical advancements. This could then be used across multiple therapeutic areas and impact on many clinicians/basic scientists and patient groups globally.

New laboratory applications: We propose to apply muscle proteomics (including a mitochondrial profiling approach) to the comprehensive biochemical profiling of muscle of patients with mitochondrial disease in addition to the analysis of drug-related muscle adaptations. Biomedical investigations into proteome-wide alterations in skeletal muscle will be implemented to potentially establish novel biomarker signatures of mitochondrial disease and mass spectrometric studies will be employed to further interrogate the complexity of posttranslational modifications in skeletal muscle proteins.

Outcome measures refinement: This study will allow for further refinement of functional outcome measures, which will be applicable not only to mitochondrial disease but maybe useful in other forms of neuromuscular diseases, in which exercise intolerance and fatigue are prominent.

Skill development and training: The skills and experience gained by all those academics participating in this proposal will be enhanced, by the training of highly skilled researchers including the PI (Gorman), Co-I's and named researchers across clinical, laboratory, statistical and project management platforms, all of which are transferable to future projects targeted at the interrogation of therapeutic strategies and underlying disease mechanisms in mitochondrial disorders.

Economic and Societal Impact: Randomised clinical trials and evidence-based studies on the efficacy of treatments in patients with mitochondrial disease is still lacking. This research proposal has the potential to impact significantly on the health-related quality of life and well-being of patients with mitochondrial disease and muscle involvement, and indeed change our clinical and therapeutic approach to muscle disorders. Currently there are only 23 studies registered worldwide, interrogating the therapeutic efficacy of 15 pharmacological agents in patients with mitochondrial disease. Indeed, only one-proof-of concept study is specifically targeting patients with mitochondrial disease and muscle involvement. We recently calculated the cost of illness associated with having mitochondrial disease that indicates that the average person with mitochondrial disease consumes £300,000 more over their lifetime than they ultimately produce. Hence, the potential impact of this therapeutic strategy on the NHS and the wider health care system and policies, may prove considerable.