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

线粒体是一种微小的细胞结构，含有它们自己的遗传物质(DNA)，在细胞能量(ATP)的产生中发挥着关键作用。当这些“发动机”发生故障时，可能会导致被称为线粒体疾病的慢性疾病。线粒体疾病是一组罕见的复杂遗传性疾病，患者更容易出现发育、身体和认知障碍。肌肉症状包括肌肉无力、疲劳和疼痛是非常普遍的，经常使人虚弱。因此，许多成年患者在确诊后往往无法工作或需要昂贵的医疗护理。据估计，在英国，线粒体疾病影响多达15,000名成年人(以及类似数量的儿童)。到目前为止，还没有获得许可的治疗方法，也没有根治疗法。因此，迫切需要找到一种有效的药物疗法。我们计划测试一种最初用于治疗高胆固醇和改善糖尿病控制的药物(Acipimox)。该药物还被证明可以提高肌肉细胞内的ATP水平，我们希望在患有线粒体疾病和肌肉受累的患者中利用这一功能来缓解衰弱的肌肉症状。使用一种已经在其他情况下使用的药物的好处，意味着我们已经了解了药物在人体内的行为，我们了解了药物的副作用，除了了解有效剂量外，我们已经知道如何管理药物。这种方法潜在地提供了一种更快、更便宜的途径来解决线粒体疾病对药物治疗的迫切需求。这项研究的设计是在患者和他们的护理提供者的帮助和支持下制定的，历时两年。首先，他们被问及他们的疾病的哪些方面，他们希望通过任何新的治疗方法来解决。肌肉症状被患者视为任何新药治疗的最重要目标。然后，我们紧张地合作，设计出最好的方法来测量他们日常功能的各个方面，这些方面可能可以通过药物治疗来解决。在线粒体疾病方面，我们第一次使用了“适应性设计模型”，这将使我们能够随着收集到更多的信息而定期修改所需的患者数量。这种方法使我们能够更快地识别出具有有益治疗效果的药物。这种伙伴关系使我们能够从最初开始就共同设计这项研究提案，并将持续到研究结束。这项研究将在12周内进行，多达120名患者每天服用三次药片。一半的患者将接受药物治疗，另一半患者将接受相同的安慰剂治疗。医生和病人都不知道谁接受了哪种治疗(双盲)。这对于确保任何影响都是由于药物而不是任何其他潜在因素(例如，更多地与医务人员互动或访问医院)。除了在研究开始和结束时采集一小块肌肉(为了更好地了解药物和线粒体疾病对肌肉的影响)，我们还将监测纳入研究的患者的安全性。我们亦会评估日常功能，包括步行、心肺容量、肌肉力量和表现、心智敏捷度，以及疾病征状对精神健康和福祉的影响。首先，除了更好地了解线粒体疾病的潜在机制外，线粒体疾病患者可能还可以获得已被证明安全有效的药物。此外，这项研究中使用的方法可以用于其他罕见疾病，特别是在获得所需的患者招募和保留被证明是临床进步的主要障碍的情况下。

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.