Department of Neurology with Friedrich-Baur-Institute, Ludwig Maximilians University, University Hospital, Munich, Germany.
German Center for Vertigo and Balance Disorders (DSGZ), Ludwig Maximilians University, University Hospital, Campus Grosshadern, Munich, Germany.
JAMA Netw Open. 2021 Dec 1;4(12):e2135841. doi: 10.1001/jamanetworkopen.2021.35841.
Cerebellar ataxia is a neurodegenerative disease impairing motor function characterized by ataxia of stance, gait, speech, and fine motor disturbances.
To investigate the efficacy, safety, and tolerability of the modified essential amino acid acetyl-DL-leucine in treating patients who have cerebellar ataxia.
DESIGN, SETTING, AND PARTICIPANTS: The Acetyl-DL-leucine on Cerebellar Ataxia (ALCAT) trial was an investigator-initiated, multicenter, double-blind, randomized, placebo-controlled, clinical crossover trial. The study was conducted at 7 university hospitals in Germany and Austria between January 25, 2016, and February 17, 2017. Patients were aged at least 18 years and diagnosed with cerebellar ataxia of hereditary (suspected or genetically confirmed) or nonhereditary or unknown type presenting with a total score of at least 3 points on the Scale for the Assessment and Rating of Ataxia (SARA). Statistical analysis was performed from April 2018 to June 2018 and January 2020 to March 2020.
Patients were randomly assigned (1:1) to receive acetyl-DL-leucine orally (5 g per day after 2 weeks up-titration) followed by a matched placebo, each for 6 weeks, separated by a 4-week washout, or vice versa. The randomization was done via a web-based, permuted block-wise randomization list (block size, 2) that was stratified by disease subtype (hereditary vs nonhereditary or unknown) and site.
Primary efficacy outcome was the absolute change of SARA total score from (period-dependent) baseline to week 6.
Among 108 patients who were randomly assigned to sequence groups (54 patients each), 55 (50.9%) were female; the mean (SD) age was 54.8 (14.4) years; and the mean (SD) SARA total score was 13.33 (5.57) points. The full analysis set included 105 patients (80 patients with hereditary, 25 with nonhereditary or unknown cerebellar ataxia). There was no evidence of a difference in the mean absolute change from baseline to week 6 in SARA total scores between both treatments (mean treatment difference: 0.23 points [95% CI, -0.40 to 0.85 points]).
In this large multicenter, double-blind, randomized, placebo-controlled clinical crossover trial, acetyl-DL-leucine in the investigated dosage and treatment duration was not superior to placebo for the symptomatic treatment of certain types of ataxia. The drug was well tolerated; and ALCAT yielded valuable information about the duration of treatment periods and the role of placebo response in cerebellar ataxia. These findings suggest that further symptom-oriented trials are needed for evaluating the long-term effects of acetyl-DL-leucine for well-defined subgroups of cerebellar ataxia.
EudraCT 2015-000460-34.
小脑性共济失调是一种神经退行性疾病，会损害运动功能，其特征为姿势、步态、言语和精细运动障碍的共济失调。
研究改良必需氨基酸乙酰-DL-亮氨酸治疗小脑性共济失调患者的疗效、安全性和耐受性。
设计、地点和参与者：乙酰-DL-亮氨酸治疗小脑性共济失调（ALCAT）试验是一项由研究者发起的、多中心、双盲、随机、安慰剂对照、临床交叉试验。该研究于 2016 年 1 月 25 日至 2017 年 2 月 17 日在德国和奥地利的 7 所大学医院进行。患者年龄至少 18 岁，诊断为遗传性（疑似或基因证实）或非遗传性或未知类型的小脑性共济失调，其共济失调评定量表（SARA）总分为至少 3 分。统计分析于 2018 年 4 月至 6 月和 2020 年 1 月至 3 月进行。
患者被随机分配（1:1）接受乙酰-DL-亮氨酸（2 周滴定后每天 5 克）或匹配的安慰剂，每个疗程 6 周，间隔 4 周洗脱期，或反之。随机分配通过一个基于网络的、按区组大小为 2 的、区组随机化列表进行，该列表按疾病亚型（遗传性与非遗传性或未知）和地点分层。
主要疗效结局是 SARA 总评分从（与时间相关的）基线到第 6 周的绝对变化。
在 108 名被随机分配至序列组（每组 54 名）的患者中，有 55 名（50.9%）为女性；平均（SD）年龄为 54.8（14.4）岁；SARA 总评分平均（SD）为 13.33（5.57）分。全分析集包括 105 名患者（80 名遗传性小脑性共济失调，25 名非遗传性或未知小脑性共济失调）。两种治疗方法在 SARA 总评分从基线到第 6 周的平均绝对变化方面没有证据表明存在差异（平均治疗差异：0.23 分[95%CI，-0.40 至 0.85 分]）。
在这项大型多中心、双盲、随机、安慰剂对照的临床交叉试验中，研究剂量和治疗持续时间的乙酰-DL-亮氨酸在治疗某些类型的共济失调方面并不优于安慰剂。该药物耐受性良好；ALCAT 提供了关于治疗期持续时间和安慰剂反应在小脑性共济失调中的作用的有价值信息。这些发现表明，对于小脑性共济失调的明确亚组，需要进行进一步的以症状为导向的试验，以评估乙酰-DL-亮氨酸的长期效果。
EudraCT 2015-000460-34。
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