■随着时间的推移客观地测量帕金森病（PD）的体征和症状对于成功开发旨在阻止PD患者疾病进展的治疗方法至关重要。
■创建一种临床试验模拟工具，该工具可以表征PD进展的自然史，并支持数据驱动的随机对照研究设计，测试早期PD的潜在疾病改善治疗（DMT）。
■使用非线性混合效应建模技术分析了帕金森进展标志物计划（PPMI）的数据，以表征MDS-UPDRS第一部分（日常生活经验的非运动方面）的进展，第二部分(日常生活经验的运动方面)，和第三部分（运动标志）。根据这些疾病模型构建临床试验模拟工具，并将其用于根据试验设计预测成功概率。
■MDS-UPDRS第三部分的进展速度比MDS-UPDRS第二部分和第一部分快大约3倍，每年增加3分比1分。较高量的对症治疗与MDS-UPDRS部分II和III的较慢进展相关。建模框架预测，DMT对MDS-UPDRS第三部分的影响可能先于对第二部分的影响大约2至3年。
■我们的临床试验模拟工具预测，在一项为期两年的随机对照试验中，MDS-UPDRS第三部分可用于评估潜在的新型DMT，而第II部分则需要更长的试验,最短持续时间为3~5年,强调需要创新的试验设计方法,包括新的以患者为中心的措施.
开发能够减缓或阻止帕金森病（PD）进展的有效药物，准确了解疾病如何随着时间的推移而恶化是很重要的。我们使用了一项观察性研究的数据，由迈克尔·J·福克斯基金会领导，称为帕金森进展标志物倡议（PPMI），以了解PD的自然进展。我们使用不同的尺度在计算机上模拟临床试验以测量PD的进展。我们特别研究了医生报告的MDS-UPDRS第三部分，以及在患者报告的MDS-UPDRS第二部分中，PD症状如何随着时间的推移而恶化。使用患者报告的MDS-UPDRS第二部分测量一种新药减缓PD进展的效果，我们估计我们可能需要进行至少3~5年的临床试验.另一方面,使用医生报告的MDS-UPDRS第三部分测量效果，试验持续时间可能短于2年.我们还能够证明，医生报告的MDS-UPDRS第三部分记录的恶化可以预测患者报告的MDS-UPDRS第二部分记录的后期恶化。我们得出的结论是，MDS-UPDRS第III部分可能是合理持续时间的临床试验的良好终点，并且MDS-UPDRS第II部分可以在更长的研究中进行测量，例如,开放标签扩展。
UNASSIGNED: Objectively measuring Parkinson\'s disease (PD) signs and symptoms over time is critical for the successful development of treatments aimed at halting the disease progression of people with PD.
UNASSIGNED: To create a clinical trial simulation tool that characterizes the natural history of PD progression and enables a data-driven design of randomized controlled studies testing potential disease-modifying treatments (DMT) in early-stage PD.
UNASSIGNED: Data from the Parkinson\'s Progression Markers Initiative (PPMI) were analyzed with nonlinear mixed-effect modeling techniques to characterize the progression of MDS-UPDRS part I (non-motor aspects of experiences of daily living), part II (motor aspects of experiences of daily living), and part III (motor signs). A clinical trial simulation tool was built from these disease models and used to predict probability of success as a function of trial design.
UNASSIGNED: MDS-UPDRS part III progresses approximately 3 times faster than MDS-UPDRS part II and I, with an increase of 3 versus 1 points/year. Higher amounts of symptomatic therapy is associated with slower progression of MDS-UPDRS part II and III. The modeling framework predicts that a DMT effect on MDS-UPDRS part III could precede effect on part II by approximately 2 to 3 years.
UNASSIGNED: Our clinical trial simulation tool predicted that in a two-year randomized controlled trial, MDS-UPDRS part III could be used to evaluate a potential novel DMT, while part II would require longer trials of a minimum duration of 3 to 5 years underscoring the need for innovative trial design approaches including novel patient-centric measures.
To develop effective medicines that can slow down or stop the progression of Parkinson’s disease (PD), it is important to accurately understand how the disease worsens over time. We used data from an observational study, led by the Michael J. Fox Foundation, called the Parkinson’s Progression Markers Initiative (PPMI) to understand the natural progression of PD. We simulated clinical trials on a computer using different scales to measure the progression of PD. We specifically looked at a physician-reported measure MDS-UPDRS part III, and at a patient-reported measure MDS-UPDRS part II of how PD symptoms worsen over time. To measure the effect of a new medicine slowing down the progression of PD using patient-reported measure MDS-UPDRS part II, we estimate that we may need to conduct a clinical trial of at least 3 to 5 years. On the other hand, to measure an effect using physician-reported measure MDS-UPDRS part III, the duration of the trial could be shorter than 2 years. We were also able to show that worsening recorded by the physician-reported measure MDS-UPDRS part III could be predictive of a later worsening recorded by the patient-reported measure MDS-UPDRS part II. We concluded that MDS-UPDRS part III may be a good endpoint for a clinical trial of a reasonable duration and that MDS-UPDRS part II could be measured in longer studies, for example, open-label extensions.
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