Olanow C Warren, Schapira Anthony H V, LeWitt Peter A, Kieburtz Karl, Sauer Dirk, Olivieri Gianfranco, Pohlmann Harald, Hubble Jean
Department of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA.
Lancet Neurol. 2006 Dec;5(12):1013-20. doi: 10.1016/S1474-4422(06)70602-0.
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.
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 .
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.
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.
帕金森病存在一项重要的未满足医疗需求，即需要一种能减缓或阻止疾病进展的神经保护治疗方法。TCH346是一种强效抗凋亡药物，在实验室模型中可保护多巴胺能神经元免于损失。我们的目的是评估TCH346作为帕金森病患者的神经保护药物的效果。
作为这项平行组、双盲、随机对照试验的一部分，对在45家国际运动障碍诊所就诊的早期未经治疗的帕金森病患者进行了评估。301名符合条件的患者被随机分配接受为期12 - 18个月的TCH346治疗，每日剂量分别为0.5毫克（n = 78）、2.5毫克（n = 79）或10毫克（n = 73），或安慰剂（n = 71），随后有4周的洗脱期。主要结局指标是出现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（UPDRS）的年变化率以及PDQ - 39（一种生活质量指标）。分析采用意向性分析。本研究正在等待在……注册。
255名患者完成了研究。在任何研究结局方面，TCH346与安慰剂均无差异。TCH346 0.5毫克组有26名（34%）患者需要治疗，TCH346 2.5毫克组有30名（38%），TCH346 10毫克组有24名（33%），安慰剂组有23名（32%）。各组之间无显著差异。在UPDRS或PDQ - 39的年变化方面，各组之间也无差异。很少有患者因不良事件退出，且无一例被判定与研究干预相关。
TCH346未显示出神经保护作用的证据。TCH346临床前的前景与临床结果之间的差异可能是由于使用了不能准确反映帕金森病发病机制的实验室模型、所使用的研究药物剂量、不敏感的临床终点以及所选择的研究患者群体。
