Critical Path Institute, Tucson, AZ, USA.
University College London, UK.
J Parkinsons Dis. 2019;9(3):553-563. doi: 10.3233/JPD-191648.
As therapeutic trials target early stages of Parkinson's disease (PD), appropriate patient selection based purely on clinical criteria poses significant challenges. Members of the Critical Path for Parkinson's Consortium formally submitted documentation to the European Medicines Agency (EMA) supporting the use of Dopamine Transporter (DAT) neuroimaging in early PD. Regulatory documents included a comprehensive literature review, a proposed analysis plan of both observational and clinical trial data, and an assessment of biomarker reproducibility and reliability. The research plan included longitudinal analysis of the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) and the Parkinson's Progression Markers Initiative (PPMI) study to estimate the degree of enrichment achieved and impact on future trials in subjects with early motor PD. The presence of reduced striatal DAT binding based on visual reads of single photon emission tomography (SPECT) scans in early motor PD subjects was an independent predictor of faster decline in UPDRS Parts II and III as compared to subjects with scans without evidence of dopaminergic deficit (SWEDD) over 24 months. The EMA issued in 2018 a full Qualification Opinion for the use of DAT as an enrichment biomarker in PD trials targeting subjects with early motor symptoms. Exclusion of SWEDD subjects in future clinical trials targeting early motor PD subjects aims to enrich clinical trial populations with idiopathic PD patients, improve statistical power, and exclude subjects who are unlikely to progress clinically from being exposed to novel test therapeutics.
随着治疗试验针对帕金森病（PD）的早期阶段，仅基于临床标准进行适当的患者选择带来了重大挑战。帕金森关键路径联盟的成员正式向欧洲药品管理局（EMA）提交了支持在早期 PD 中使用多巴胺转运蛋白（DAT）神经影像学的文件。监管文件包括对文献的全面审查、对观察性和临床试验数据的拟议分析计划，以及对生物标志物可重复性和可靠性的评估。研究计划包括对帕金森研究中 CEP-1347 试验（PRECEPT）和帕金森进展标志物倡议（PPMI）研究的纵向分析，以估计在早期运动 PD 受试者中实现的富集程度及其对未来试验的影响。基于单光子发射断层扫描（SPECT）扫描的早期运动 PD 受试者纹状体 DAT 结合减少的存在是 UPDRS 第二和第三部分更快下降的独立预测因素，与扫描没有多巴胺能缺陷（SWEDD）的受试者相比，在 24 个月内。EMA 于 2018 年发布了 DAT 作为针对早期运动症状患者的 PD 试验的富集生物标志物的全面资格意见。在针对早期运动 PD 受试者的未来临床试验中排除 SWEDD 受试者的目的是在临床试验人群中富集特发性 PD 患者，提高统计能力，并排除不太可能因接触新型试验治疗而出现临床进展的受试者。
