Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials.
Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials.
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DOI：
10.1093/brain/awad105
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发表时间：
2023-08-01
期刊：
影响因子：
14.5
通讯作者：
Rowe, James B.
中科院分区：
文献类型：
--
作者：
Street, Duncan;Jabbari, Edwin;Costantini, Alyssa;Jones, P. Simon;Holland, Negin;Rittman, Timothy;Jensen, Marte T.;Chelban, Viorica;Goh, Yen Y.;Guo, Tong;Heslegrave, Amanda J.;Roncaroli, Federico;Klein, Johannes C.;Ansorge, Olaf;Allinson, Kieren S. J.;Jaunmuktane, Zane;Revesz, Tamas;Warner, Thomas T.;Lees, Andrew J.;Zetterberg, Henrik;Russell, Lucy L.;Bocchetta, Martina;Rohrer, Jonathan D.;Burn, David J.;Pavese, Nicola;Gerhard, Alexander;Kobylecki, Christopher;Leigh, P. Nigel;Church, Alistair;Hu, Michele T. M.;Houlden, Henry;Morris, Huw;Rowe, James B.
关键词：
神经退行性疾病疾病修饰剂临床试验的出现，突出了以证据为基础的终点选择的必要性。在此，我们报告了进行性核上性麻痹（PSP）、皮质基底综合征（CBS）、多系统萎缩（MSA）及相关疾病的纵向PROSPECT-M-UK研究，以比较候选临床试验终点。在这项多中心的英国研究中，参与者在基线、6个月和12个月时接受了一系列问卷调查、运动检查、神经精神和MRI评估。根据基线和研究结束时的诊断，将参与者分为理查德森综合征、psp -皮质下（psp -帕金森病和进行性步态冻结亚型）、psp -皮质（psp -额叶、psp -言语和语言以及PSP-CBS亚型）、msa -帕金森病、msa -小脑、CBS有无阿尔茨海默病病理证据和不确定综合征。我们根据分组和评估类型，使用线性混合模型和疾病调节剂临床试验的样本量计算年变化率。共招募了243人[117名PSP， 68名CBS， 42名MSA， 16名不确定；男性138例（56.8%）；入职年龄[68.7±8.61岁]。159例完成了6个月的评估（82例PSP， 27例CBS， 40例MSA和10例不确定），153例完成了12个月的评估（80例PSP， 29例CBS， 35例MSA和9例不确定）。问卷调查、运动检查、神经精神病学和神经影像学指标在所有组中均有所下降，但组间纵向变化存在差异。与认知和功能测量相比，神经影像学指标可以使更小的样本量在临床试验中达到同等的功效，通常在1年的双组试验中达到N < 100（80%的功效检测到50%的减缓）。然而，最佳的结果测量是疾病特异性的。总之，PSP、CBS和MSA的表型差异是临床试验设计的主要挑战。我们的研究结果为选择临床试验终点提供了证据基础，从疾病进展的潜在功能、认知、临床或神经影像学指标。Street等人比较了进行性核上性麻痹、多系统萎缩、皮质基底综合征及相关疾病的候选临床试验终点。神经影像学指标通常比认知和功能测量的样本量更小，尽管最佳结果测量因疾病和亚型而异。
The advent of clinical trials of disease-modifying agents for neurodegenerative disease highlights the need for evidence-based end point selection. Here we report the longitudinal PROSPECT-M-UK study of progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), multiple system atrophy (MSA) and related disorders, to compare candidate clinical trial end points. In this multicentre UK study, participants were assessed with serial questionnaires, motor examination, neuropsychiatric and MRI assessments at baseline, 6 and 12 months. Participants were classified by diagnosis at baseline and study end, into Richardson syndrome, PSP-subcortical (PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (PSP-frontal, PSP-speech and language and PSP-CBS subtypes), MSA-parkinsonism, MSA-cerebellar, CBS with and without evidence of Alzheimer’s disease pathology and indeterminate syndromes. We calculated annual rate of change, with linear mixed modelling and sample sizes for clinical trials of disease-modifying agents, according to group and assessment type. Two hundred forty-three people were recruited [117 PSP, 68 CBS, 42 MSA and 16 indeterminate; 138 (56.8%) male; age at recruitment 68.7 ± 8.61 years]. One hundred and fifty-nine completed the 6-month assessment (82 PSP, 27 CBS, 40 MSA and 10 indeterminate) and 153 completed the 12-month assessment (80 PSP, 29 CBS, 35 MSA and nine indeterminate). Questionnaire, motor examination, neuropsychiatric and neuroimaging measures declined in all groups, with differences in longitudinal change between groups. Neuroimaging metrics would enable lower sample sizes to achieve equivalent power for clinical trials than cognitive and functional measures, often achieving N < 100 required for 1-year two-arm trials (with 80% power to detect 50% slowing). However, optimal outcome measures were disease-specific. In conclusion, phenotypic variance within PSP, CBS and MSA is a major challenge to clinical trial design. Our findings provide an evidence base for selection of clinical trial end points, from potential functional, cognitive, clinical or neuroimaging measures of disease progression. Street et al. compare candidate clinical trial end points in progressive supranuclear palsy, multiple system atrophy, corticobasal syndrome and related disorders. Neuroimaging metrics generally enable lower sample sizes than cognitive and functional measures, although optimal outcome measures vary by disease and subtype.
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