TCH346 as a neuroprotective drug in Parkinson"s disease: a double-blind, randomised, controlled trial
TCH346 as a neuroprotective drug in Parkinson"s disease: a double-blind, randomised, controlled trial
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DOI：
10.1016/s1474-4422(06)70602-0
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发表时间：
2006-12-01
期刊：
影响因子：
48
通讯作者：
Hubble, Jean
中科院分区：
文献类型：
--
作者：
Olanow, C. Warren;Schapira, Anthony H. V.;Hubble, Jean
背景帕金森病的神经保护治疗是一个重要的未满足的医疗需求，可以减缓或阻止疾病进展。TCH346是一种有效的抗凋亡药物，可在实验室模型中防止多巴胺能神经元的损失。我们的目的是评估TCH346作为一种神经保护药物在帕金森病patients with Parkinson's disease. Methods患者提出在45个国际运动障碍诊所与早期未经治疗的帕金森病进行了评估，作为这个平行组，双盲，随机对照试验的一部分。301名符合条件的患者被随机分配接受12 - 18个月的TCH 346治疗，每日剂量为0.5 mg（n = 78）、2.5 mg（n = 79）或10 mg（n = 73），或安慰剂（n = 71），随后是4周的洗脱期。主要结果指标是至发生需要多巴胺能治疗的残疾的时间。次要结局指标是统一帕金森病评定量表（PDRS）和PDQ-39（一种生活质量指标）的年变化率。本研究正在等待ClinicalTrials.gov注册。结果255例患者完成了研究。TCH346与安慰剂在任何研究结局方面均无差异。TCH346 0.5 mg组有26例（34%）患者需要治疗，TCH346 2.5 mg组有30例（38%）患者需要治疗，TCH346 10 mg组有24例（33%）患者需要治疗，安慰剂组有23例（32%）患者需要治疗。两组间无显著差异。两组之间在BPRS或PDQ-39的年度变化方面也没有差异。很少有患者因为不良事件而退出研究，没有一个被认为与研究干预有关。TCH 346的临床前承诺和临床结果之间的差异可能是由于使用的实验室模型不能准确反映帕金森病的发病机制、使用的研究药物剂量、不敏感的临床终点和选择用于研究的患者人群。
Background There is an important unmet medical need in Parkinson's disease for a neuroprotective treatment that slows or stops disease progression. TCH346 is a potent anti-apoptotic drug that protects against loss of dopaminergic neurons in laboratory models. Our aim was to assess TCH346 as a neuroprotective drug in patients with Parkinson's disease.Methods Patients presenting at 45 international movement disorder clinics with early untreated Parkinson's disease were assessed as part of this parallel-group, double-blind, randomised controlled trial. 301 eligible patients were randomly assigned 12-18 months' treatment with TCH346 at a daily dose of 0.5 mg (n = 78), 2.5 mg (n = 79), or 10 mg (n = 73), or placebo (n = 71), followed by a 4 week washout period. The primary outcome measure was time to development of a disability requiring dopaminergic treatment. Secondary outcome measures were the annual rate of change in the unified Parkinson's disease rating scale (UPDRS) and the PDQ-39, a measure of quality of life. Analyses were by intention-to-treat. This study is pending registration with ClinicalTrials.gov.Findings 255 patients completed the study. TCH346 did not differ from placebo for any of the study outcomes. Treatment was needed in 26 (34%) patients in the TCH346 0.5 mg group, 30 (38%) in the TCH346 2.5 mg group, 24 (33%) in the TCH346 10 mg group, and 23 (32%) in the placebo group. There were no significant differences between groups. There were no differences between groups in the annual change in the UPDRS or PDQ-39 either. Few patients withdrew because of adverse events and none was judged to be related to the study intervention.Interpretation TCH346 did not show evidence of a neuroprotective effect. The discrepancy between the preclinical promise of TCH346 and the clinical outcome could have arisen because of the use of laboratory models that do not accurately reflect the pathogenesis of Parkinson's disease, the doses of study drug used, insensitive clinical endpoints, and the patient population selected for study.