Moderna, Inc., Cambridge, MA, USA.
ICON plc, Raleigh, NC, USA.
Mol Genet Metab. 2024 Sep-Oct;143(1-2):108577. doi: 10.1016/j.ymgme.2024.108577. Epub 2024 Sep 13.
Methylmalonic acidemia (MMA) and propionic acidemia (PA) are rare inborn errors of metabolism with shared signs and symptoms that are associated with significant morbidity and mortality. No disease-specific clinical outcomes assessment instruments for MMA and/or PA currently exist to capture the patient perspective in clinical trials. Because patients with these conditions are generally young and have cognitive impairments, an observer-reported outcome (ObsRO) instrument is crucial. We report results from qualitative research supporting development of the Methylmalonic Acidemia and Propionic Acidemia Questionnaire (MMAPAQ), a signs and symptoms ObsRO measure for caregivers of patients with MMA and/or PA.
Concept elicitation (CE) interviews were conducted with 35 participants across 2 studies who were aged ≥18 years and caregivers of patients with a confirmed diagnosis of MMA or PA, and an additional 5 patients aged ≥6 years with MMA or PA in Study 1, to identify core signs/symptoms for inclusion in the MMAPAQ. All interviews were conducted in English. Study 2 included cognitive interviews (CI) with caregivers and clinical experts to further assess content validity. CE and a conceptual framework review were also conducted with clinical experts to further support findings.
A consistent set of signs/symptoms of MMA and PA were reported by eligible caregivers interviewed in study 1 (n = 21) and study 2 (n = 14), representing 11 patients with MMA and 20 with PA. Based on concepts reported in study 1, a draft instrument was constructed and compared with the Pediatric Quality of Life Inventory™ (PedsQL™) and Family Impact module, demonstrating face validity for measuring key signs/symptoms important to patients and caregivers. The PedsQL™ and Family Impact modules were preferred to assess patient and caregiver impacts. Two waves of CE and CIs were conducted in study 2, with wave 1 resulting in removal of 7 items and other revisions to improve clarity, and wave 2 resulting in modification of examples used for 2 items. The final instrument consisted of the following 7 items assessed over the past 7 days using a Likert-type response scale ranging from "never" to "very often": uncontrollable or involuntary movements, dehydration, rapid breathing at rest, appearing lethargic, appearing disinterested in eating, refusing to eat, and vomiting.
This study establishes the content validity of the MMAPAQ as the first ObsRO questionnaire for measuring core signs and symptoms of MMA and PA in clinical trials and community research. Scoring and psychometric measurement properties of the MMAPAQ will be established in future studies. The PedsQL™ was found to have face validity in measuring concepts that affect the MMA and PA patient populations and should also be considered for use in clinical trials in MMA and PA.
甲基丙二酸血症（MMA）和丙酸血症（PA）是罕见的代谢性遗传疾病，具有共同的体征和症状，这些症状与显著的发病率和死亡率有关。目前尚无针对 MMA 和/或 PA 的特定疾病临床结局评估工具，无法从患者角度评估临床试验结果。由于这些病症的患者通常年龄较小且认知受损，因此需要使用观察者报告的结局（ObsRO）工具。我们报告了支持开发甲基丙二酸血症和丙酸血症问卷（MMAPAQ）的定性研究结果，这是一种针对 MMA 和/或 PA 患者照顾者的体征和症状的观察报告结局（ObsRO）测量工具。
我们在两项研究中对 35 名年龄≥18 岁的参与者进行了概念提取（CE）访谈，这些参与者是 MMA 或 PA 确诊患者的照顾者，另外在研究 1 中还包括 5 名年龄≥6 岁的 MMA 或 PA 患者。进行 CE 访谈的目的是确定纳入 MMAPAQ 的核心体征/症状。所有访谈均以英语进行。研究 2 包括对照顾者和临床专家进行认知访谈（CI），以进一步评估内容的有效性。还与临床专家进行了 CE 和概念框架审查，以进一步支持研究结果。
在研究 1（n=21）和研究 2（n=14）中，符合条件的照顾者报告了一致的 MMA 和 PA 体征/症状，代表了 11 名 MMA 患者和 20 名 PA 患者。基于研究 1 中报告的概念，构建了一份仪器草案，并与儿科生存质量量表（PedsQL）和家庭影响模块进行了比较，证明了该仪器在衡量对患者和照顾者重要的关键体征/症状方面具有表面有效性。PedsQL 和家庭影响模块更适合评估患者和照顾者的影响。在研究 2 中进行了两轮 CE 和 CI，第一轮结果删除了 7 个项目并对其他项目进行了修订以提高清晰度，第二轮修改了用于 2 个项目的示例。最终的仪器由以下 7 个项目组成，采用李克特量表进行评估，范围为“从不”到“非常频繁”，评估时间为过去 7 天：无法控制或不由自主的运动、脱水、休息时呼吸急促、看起来昏昏欲睡、对进食不感兴趣、拒绝进食和呕吐。
这项研究确立了 MMAPAQ 的内容有效性，这是第一个用于在临床试验和社区研究中测量 MMA 和 PA 核心体征和症状的观察报告结局（ObsRO）问卷。未来的研究将建立 MMAPAQ 的评分和心理测量学测量特性。发现 PedsQL 在测量影响 MMA 和 PA 患者人群的概念方面具有表面有效性，也应考虑在 MMA 和 PA 的临床试验中使用。
