Mitochondrial Medicine Frontier Program, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
J Inherit Metab Dis. 2021 Mar;44(2):343-357. doi: 10.1002/jimd.12320. Epub 2020 Oct 29.
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.
原发性线粒体疾病（PMD）的治疗效果不佳、缺乏已证实的治疗方法且临床试验屡屡失败，这些问题都使得疾病的诊治极具挑战性，因此迫切需要设计出能够验证干预措施疗效的未来临床试验。PMD 的临床表现、生化及遗传学异质性极大，导致其疗效评估指标的选择十分复杂；PMD 实际上是近 400 种超罕见疾病的集合。临床试验中的疗效评估指标旨在评价并在理想情况下量化干预措施改善临床表型的效果。PMD 的异质性和多系统受累特点使其不太可能存在适用于所有 PMD 的通用疗效评估指标。因此，采用患者最关注的症状的综合评分作为终点指标可能更为合适。此外，寻找适合临床试验使用的疗效评估指标（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）与寻找对个体患者具有临床意义的指标之间存在一定的矛盾。目前已经出现了许多临床评分量表和拟议的生物标志物，以用于 PMD 的自然史和干预试验来捕捉疾病特征。本文将回顾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、患者报告的结局测量指标以及生理、影像学、生物化学和肌肉表型作为儿童和成人 PMD 的疗效评估指标的经验。目前迫切需要在国际范围内达成共识，选择一套经过验证、可靠且具有临床意义的疗效评估指标，以促进多中心国际临床试验，从而优化对这些超罕见疾病新型治疗方法的评估。
