Primary mitochondrial disorders (PMDs) are challenging due to overall poor outcomes, no proven treatments, and a history of failed clinical trials, leading to a critical need to design future trials that can prove efficacy of an intervention. Selection of outcome measures for PMDs is complicated by extreme clinical, biochemical and genetic heterogeneity; PMDs are effectively a collection of nearly 400 individually ultrarare diseases. In clinical trials, outcome measures aim to evaluate, and ideally quantitate, the efficacy of an intervention in ameliorating clinical phenotype(s). The heterogeneity and multisystemic nature of PMDs makes it unlikely that a universal outcome measure will be applicable to all PMDs. Instead, a composite score of the individual's most worrisome symptoms may be a preferable endpoint. A further challenge arises from the tension between finding outcomes suitable for use in clinical trials (able to produce a measurable change in a relatively short period of time, namely the duration of a clinical trial) vs measures that are clinically meaningful to individual patients. A number of clinical rating scales and proposed biomarkers have emerged to capture the features of PMDs for natural history and interventional trials. Here we review our collective experiences with clinical rating scales, patient‐reported outcome measures, and physiological, imaging, biochemical and muscle phenotypes as outcome measures in paediatric and adult PMDs in natural history studies and recent clinical trials. There is a pressing need to agree on a set of validated, robust, clinically meaningful outcome measures internationally, to facilitate the multicentre international clinical trials needed for optimal evaluation of novel therapies for these ultrarare diseases.

中文翻译：

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寻求影响：原发性线粒体疾病转化和临床研究结果测量选择的全球视角

由于总体结果不佳、没有经过验证的治疗方法以及临床试验失败的历史，原发性线粒体疾病 (PMD) 具有挑战性，因此迫切需要设计可以证明干预措施有效性的未来试验。由于极端的临床、生化和遗传异质性，PMD 结局指标的选择变得复杂；PMD 实际上是近 400 种单独的极罕见疾病的集合。在临床试验中，结果测量旨在评估并理想地量化干预在改善临床表型方面的功效。PMD 的异质性和多系统性质使得通用结果衡量指标不太可能适用于所有 PMD。相反，个人最令人担忧的症状的综合评分可能是一个更可取的终点。另一个挑战来自寻找适用于临床试验的结果（能够在相对较短的时间内产生可测量的变化，即临床试验的持续时间）与对个体患者具有临床意义的措施之间的紧张关系。已经出现了许多临床评分量表和提议的生物标志物，以捕捉自然病程和介入试验中 PMD 的特征。在这里，我们回顾了我们在自然史研究和最近的临床试验中使用临床评分量表、患者报告的结果测量以及生理、成像、生化和肌肉表型作为儿科和成人 PMD 的结果测量的集体经验。迫切需要在国际上就一套经过验证的、稳健的、具有临床意义的结果衡量标准达成一致，