Department of Neurology, Hospital Ramón y Cajal, CIBERNED, Madrid, Spain.
Lancet Neurol. 2011 Dec;10(12):1049-57. doi: 10.1016/S1474-4422(11)70233-2. Epub 2011 Nov 7.
Huntington's disease is a progressive neurodegenerative disorder, characterised by motor, cognitive, and behavioural deficits. Pridopidine belongs to a new class of compounds known as dopaminergic stabilisers, and results from a small phase 2 study in patients with Huntington's disease suggested that this drug might improve voluntary motor function. We aimed to assess further the effects of pridopidine in patients with Huntington's disease.
We undertook a 6 month, randomised, double-blind, placebo-controlled trial to assess the efficacy of pridopidine in the treatment of motor deficits in patients with Huntington's disease. Our primary endpoint was change in the modified motor score (mMS; derived from the unified Huntington's disease rating scale) at 26 weeks. We recruited patients with Huntington's disease from 32 European centres; patients were aged 30 years or older and had an mMS of 10 points or greater at baseline. Patients were randomly assigned (1:1:1) to receive placebo, 45 mg per day pridopidine, or 90 mg per day pridopidine by use of centralised computer-generated codes. Patients and investigators were masked to treatment assignment. We also assessed the safety and tolerability profile of pridopidine. For our primary analysis, all patients were eligible for inclusion in our full analysis set, in which we used the last observation carried forward method for missing values. We used an analysis of covariance model and the Bonferroni method to adjust for multiple comparisons. We used a prespecified per-protocol population as our sensitivity analysis. The α level was 0·025 for our primary analysis and 0·05 overall. This trial is registered with ClinicalTrials.gov, number NCT00665223.
At 26 weeks, in our full analysis set the difference in mean mMS was -0·99 points (97·5% CI -2·08 to 0·10, p=0·042) in patients who received 90 mg per day pridopidine (n=145) versus those who received placebo (n=144), and -0·36 points (-1·44 to 0·72, p=0·456) in those who received 45 mg per day pridopidine (n=148) versus those who received placebo. At the 90 mg per day dose, in our per-protocol population (n=114), the reduction in the mMS was of -1·29 points (-2·47 to -0·12; p=0·014) compared with placebo (n=120). We did not identify any changes in non-motor endpoints at either dose. Pridopidine was well tolerated and had an adverse event profile similar to that of placebo.
This study did not provide evidence of efficacy as measured by the mMS, but a potential effect of pridopidine on the motor phenotype of Huntington's disease merits further investigation. Pridopidine up to 90 mg per day was well tolerated in patients with Huntington's disease.
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亨廷顿舞蹈病是一种进行性神经退行性疾病，其特征为运动、认知和行为缺陷。普里多吡啶属于一种新的化合物类别，称为多巴胺稳定剂，一项针对亨廷顿病患者的小型 2 期研究结果表明，该药物可能改善自愿运动功能。我们旨在进一步评估普里多吡啶在亨廷顿病患者中的疗效。
我们进行了一项为期 6 个月的随机、双盲、安慰剂对照试验，以评估普里多吡啶治疗亨廷顿病患者运动障碍的效果。我们的主要终点是在 26 周时改良运动评分（mMS；源自统一亨廷顿病评定量表）的变化。我们从 32 个欧洲中心招募了亨廷顿病患者；患者年龄 30 岁或以上，基线时 mMS 为 10 分或更高。患者以 1:1:1 的比例随机分配（使用中央计算机生成的代码）接受安慰剂、45mg 普里多吡啶/天或 90mg 普里多吡啶/天。患者和研究者对治疗分配均不知情。我们还评估了普里多吡啶的安全性和耐受性。对于我们的主要分析，所有患者均有资格纳入我们的全分析集，其中我们对缺失值采用最后一次观测值结转的方法。我们使用协方差分析模型和 Bonferroni 方法进行调整以进行多次比较。我们使用预先指定的符合方案人群作为我们的敏感性分析。我们的主要分析的α水平为 0.025，总体为 0.05。这项试验在 ClinicalTrials.gov 注册，编号为 NCT00665223。
在 26 周时，在我们的全分析集中，每天接受 90mg 普里多吡啶治疗的患者（n=145）与接受安慰剂治疗的患者（n=144）之间的平均 mMS 差异为-0.99 分（97.5%CI -2.08 至 0.10，p=0.042），每天接受 45mg 普里多吡啶治疗的患者（n=148）与接受安慰剂治疗的患者（n=144）之间的差异为-0.36 分（-1.44 至 0.72，p=0.456）。在每天 90mg 的剂量下，在我们的符合方案人群（n=114）中，mMS 的降低幅度为-1.29 分（-2.47 至-0.12；p=0.014），与安慰剂（n=120）相比。我们在任何剂量下都没有发现非运动终点的任何变化。普里多吡啶耐受性良好，其不良事件谱与安慰剂相似。
这项研究没有提供通过 mMS 测量的疗效证据，但普里多吡啶对亨廷顿病运动表型的潜在影响值得进一步研究。每天 90mg 剂量的普里多吡啶在亨廷顿病患者中耐受良好。
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