Rivastigmine for gait stability in patients with Parkinson's disease (ReSPonD): a randomised, double-blind, placebo-controlled, phase 2 trial
Rivastigmine for gait stability in patients with Parkinson's disease (ReSPonD): a randomised, double-blind, placebo-controlled, phase 2 trial
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DOI：
10.1016/s1474-4422(15)00389-0
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发表时间：
2016-03-01
期刊：
影响因子：
48
通讯作者：
Ben-Shlomo, Y.
中科院分区：
文献类型：
--
作者：
Henderson, Emily J.;Lord, Stephen R.;Ben-Shlomo, Y.
背景跌倒是帕金森病常见且严重的并发症，部分与潜在的胆碱能缺陷有关，胆碱能缺陷导致这些患者的步态和认知功能障碍。步态功能障碍会导致步态从一步到另一步的变异性增加，从而增加跌倒的可能性。在 ReSPonD 试验中，我们旨在评估使用乙酰胆碱酯酶抑制剂卡巴拉汀改善这种胆碱能缺陷是否会减少步态变异性。 方法 我们在英国布里斯托尔的北布里斯托尔 NHS 信托医院进行了这项随机、双盲、安慰剂对照的 2 期试验，受试者是从英国社区和医院招募的帕金森病患者。我们纳入的患者在入组前一年至少跌倒过一次，能够在没有帮助的情况下行走 18 m，之前没有接触过乙酰胆碱酯酶抑制剂，并且没有痴呆症。我们的临床试验部门使用计算机生成的随机序列和基于网络的分配，将患者随机分配 (1:1) 口服卡巴拉汀或安慰剂胶囊（均每天服用两次）。在 12 周内，卡巴拉汀从每天 3 mg 上调至每天 12 mg 的目标剂量。试验团队和患者都对治疗分配情况不知情。通过匹配的安慰剂胶囊和虚拟的滴定时间表来实现掩蔽。主要终点是 32 周时两组之间的步数时间变异性差异，并根据基线年龄、认知、步数时间变异性和上一年跌倒次数进行调整。我们在 18 m 步行任务中在三种情况下使用三轴加速度计测量了步时变化：正常步行、具有音素语言流利性的简单双任务（步行时命名以单个字母开头的单词），以及具有音素语言流利性的复杂双任务切换（一边命名单词，一边交替使用字母表中的两个字母）。分析是根据修改后的治疗意向进行的；我们将退出、死亡或未参加 32 周评估的患者排除在主要分析之外。该试验已在 ISRCTN 注册，编号为 19880883。 结果 2012 年 10 月 4 日至 2013 年 3 月 28 日期间，我们招募了 130 名患者，并随机将 65 名患者分配至卡巴拉汀组，65 名患者分配至安慰剂组。第 32 周时，与分配至安慰剂组的患者（59 名接受评估的患者）相比，分配至卡巴拉汀组的患者（55 名接受评估的患者）正常步行（几何平均值之比为 0.72，95% CI 0.58-0.88；p=0.002）和简单双重任务（0.79；0.62-0.99；p=0.045）的步数变异性有所改善。复杂双重任务的步骤时间变异性的改善在各组之间没有差异（0.81、0.60-1.09；p=0.17）。卡巴拉汀组的胃肠道副作用比安慰剂组更常见（p
Background Falls are a frequent and serious complication of Parkinson's disease and are related partly to an underlying cholinergic deficit that contributes to gait and cognitive dysfunction in these patients. Gait dysfunction can lead to an increased variability of gait from one step to another, raising the likelihood of falls. In the ReSPonD trial we aimed to assess whether ameliorating this cholinergic deficit with the acetylcholinesterase inhibitor rivastigmine would reduce gait variability.Methods We did this randomised, double-blind, placebo-controlled, phase 2 trial at the North Bristol NHS Trust Hospital, Bristol, UK, in patients with Parkinson's disease recruited from community and hospital settings in the UK. We included patients who had fallen at least once in the year before enrolment, were able to walk 18 m without an aid, had no previous exposure to an acetylcholinesterase inhibitor, and did not have dementia. Our clinical trials unit randomly assigned (1:1) patients to oral rivastigmine or placebo capsules (both taken twice a day) using a computer generated randomisation sequence and web-based allocation. Rivastigmine was uptitrated from 3 mg per day to the target dose of 12 mg per day over 12 weeks. Both the trial team and patients were masked to treatment allocation. Masking was achieved with matched placebo capsules and a dummy uptitration schedule. The primary endpoint was difference in step time variability between the two groups at 32 weeks, adjusted for baseline age, cognition, step time variability, and number of falls in the previous year. We measured step time variability with a triaxial accelerometer during an 18 m walking task in three conditions: normal walking, simple dual task with phonemic verbal fluency (walking while naming words beginning with a single letter), and complex dual task switching with phonemic verbal fluency (walking while naming words, alternating between two letters of the alphabet). Analysis was by modified intention to treat; we excluded from the primary analysis patients who withdrew, died, or did not attend the 32 week assessment. This trial is registered with ISRCTN, number 19880883.Findings Between Oct 4, 2012 and March 28, 2013, we enrolled 130 patients and randomly assigned 65 to the rivastigmine group and 65 to the placebo group. At week 32, compared with patients assigned to placebo (59 assessed), those assigned to rivastigmine (55 assessed) had improved step time variability for normal walking (ratio of geometric means 0.72, 95% CI 0.58-0.88; p=0.002) and the simple dual task (0.79; 0.62-0.99; p=0.045). Improvements in step time variability for the complex dual task did not differ between groups (0.81, 0.60-1.09; p=0.17). Gastrointestinal side-effects were more common in the rivastigmine group than in the placebo group (p