Goetz Christopher G, Damier Philippe, Hicking Christine, Laska Eugene, Müller Thomas, Olanow C Warren, Rascol Olivier, Russ Hermann
Rush University Medical Center, Chicago, Illinois 60612, USA.
Mov Disord. 2007 Jan 15;22(2):179-86. doi: 10.1002/mds.21226.
The objective of this study is to conduct a dose-finding study of sarizotan in Parkinson's disease (PD) patients with dyskinesia to identify a safe dose and to identify a sensitive dyskinesia rating measure. Sarizotan is a novel compound with full 5-HT(1A) agonist properties and additional high affinity for D(3) and D(4) receptors. An open label study documented improvements in PD patients with levodopa-induced dyskinesia. There is no precedent for study designs or outcome measures in pivotal trials of antidyskinesia therapies. The approach used here was a multicenter, randomized, placebo-controlled, double-blind, parallel study. Included were PD patients optimized to levodopa and dopaminergic drugs with moderately disabling dyskinesias present greater than or equal to 25% of the waking day. Interventions included sarizotan 2, 4, or 10 mg/day or matching placebo, given in two doses. There were two outcome measures: the primary measure was change from baseline in diary-based on time without dyskinesia; the secondary measures were change from baseline in scores on the Abnormal Involuntary Movement Scale (AIMS), the composite score of Unified Parkinson's Disease Rating Scale (UPDRS) Items 32+33 (dyskinesia duration and disability) and total UPDRS. A total of 398 subjects were randomized, with 381 included in the intention-to-treat population. No significant changes occurred on sarizotan compared to placebo on any diary-based measure of dyskinesia or the AIMS score. The composite score of UPDRS Items 32+33 was significantly improved with 2 mg/day sarizotan, with a trend at 10 mg/day. Adverse events were not significantly different in sarizotan- and placebo-treated patients, but off time significantly increased with sarizotan 10 mg/day. Sarizotan 2 mg/day is a safe agent in PD patients with dyskinesia. To test its role in abating dyskinesia, future studies should focus on this dose and will use the composite score of UPDRS Items 32+33 as the primary outcome.
本研究的目的是对患有运动障碍的帕金森病（PD）患者进行沙立佐坦的剂量探索研究，以确定安全剂量并确定一种敏感的运动障碍评分方法。沙立佐坦是一种新型化合物，具有完全的5-HT(1A)激动剂特性，并且对D(3)和D(4)受体具有额外的高亲和力。一项开放标签研究记录了左旋多巴诱导的运动障碍的PD患者的病情改善情况。在抗运动障碍疗法的关键试验中，尚无研究设计或结局指标的先例。此处采用的方法是一项多中心、随机、安慰剂对照、双盲、平行研究。纳入的患者为接受左旋多巴和多巴胺能药物优化治疗且存在中度致残性运动障碍（清醒日大于或等于25%时间）的PD患者。干预措施包括每天服用2、4或10毫克沙立佐坦或匹配的安慰剂，分两次给药。有两个结局指标：主要指标是基于日记的无运动障碍时间相对于基线的变化；次要指标是异常不自主运动量表（AIMS）评分相对于基线的变化、统一帕金森病评定量表（UPDRS）项目32 + 33的综合评分（运动障碍持续时间和残疾程度）以及UPDRS总分。共有398名受试者被随机分组，381名纳入意向性治疗人群。与安慰剂相比，在任何基于日记的运动障碍测量或AIMS评分方面，沙立佐坦均未出现显著变化。UPDRS项目32 + 33的综合评分在每天服用2毫克沙立佐坦时显著改善，在每天服用10毫克时呈趋势性改善。沙立佐坦治疗组和安慰剂治疗组的不良事件无显著差异，但每天服用10毫克沙立佐坦时“关”期时间显著增加。每天服用2毫克沙立佐坦对患有运动障碍的PD患者是一种安全的药物。为了检验其在减轻运动障碍方面所起的作用，未来的研究应聚焦于该剂量，并将使用UPDRS项目32 + 33的综合评分作为主要结局指标。
