BACKGROUND Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis; however, the evidence supporting their efficacy is sparse and conflicting. Our goal was to compare the efficacy of these three medications with each other and placebo in patients with multiple sclerosis fatigue. METHODS In this randomised, placebo-controlled, four-sequence, four-period, crossover, double-blind trial, patients with multiple sclerosis who reported fatigue and had a Modified Fatigue Impact Scale (MFIS) score of more than 33 were recruited at two academic multiple sclerosis centres in the USA. Participants received oral amantadine (up to 100 mg twice daily), modafinil (up to 100 mg twice daily), methylphenidate (up to 10 mg twice daily), or placebo, each given for up to 6 weeks. All patients were intended to receive all four study medications, in turn, in one of four different sequences with 2-week washout periods between medications. A biostatistician prepared a concealed allocation schedule, stratified by site, randomly assigning a sequence of medications in approximately a 1:1:1:1 ratio, in blocks of eight, to a consecutive series of numbers. The statistician and pharmacists had no role in assessing the participants or collecting data, and the participants, caregivers, and assessors were masked to allocation. The primary outcome measure was the MFIS measured while taking the highest tolerated dose at week 5 of each medication period, analysed by use of a linear mixed-effect regression model. This trial is registered with ClinicalTrials.gov, NCT03185065 and is closed. FINDINGS Between Oct 4, 2017, and Feb 27, 2019, of 169 patients screened, 141 patients were enrolled and randomly assigned to one of four medication administration sequences: 35 (25%) patients to the amantadine, placebo, modafinil, and methylphenidate sequence; 34 (24%) patients to the placebo, methylphenidate, amantadine, and modafinil sequence; 35 (25%) patients to the modafinil, amantadine, methylphenidate, and placebo sequence; and 37 (26%) patients to the methylphenidate, modafinil, placebo, and amantadine sequence. Data from 136 participants were available for the intention-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores at baseline and the maximal tolerated dose were as follows: 51·3 (95% CI 49·0-53·6) at baseline, 40·6 (38·2-43·1) with placebo, 41·3 (38·8-43·7) with amantadine, 39·0 (36·6-41·4) with modafinil, and 38·6 (36·2-41·0) with methylphenidate (p=0·20 for the overall medication effect in the linear mixed-effect regression model). As compared with placebo (38 [31%] of 124 patients), higher proportions of participants reported adverse events while taking amantadine (49 [39%] of 127 patients), modafinil (50 [40%] of 125 patients), and methylphenidate (51 [40%] of 129 patients). Three serious adverse events occurred during the study (pulmonary embolism and myocarditis while taking amantadine, and a multiple sclerosis exacerbation requiring hospital admission while taking modafinil). INTERPRETATION Amantadine, modafinil, and methylphenidate were not superior to placebo in improving multiple sclerosis fatigue and caused more frequent adverse events. The results of this study do not support an indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in multiple sclerosis. FUNDING Patient-Centered Outcomes Research Institute.

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金刚烷胺、莫达非尼和哌甲酯治疗多发性硬化症疲劳的安全性和有效性：一项随机、安慰剂对照、交叉、双盲试验

背景技术哌醋甲酯、莫达非尼和金刚烷胺是缓解多发性硬化症疲劳的常用处方药；然而，支持其功效的证据很少且相互矛盾。我们的目标是比较这三种药物与安慰剂对多发性硬化症疲劳患者的疗效。方美国多发性硬化症学术中心。参与者接受口服金刚烷胺（每天两次，最多 100 毫克）、莫达非尼（每天两次，最多 100 毫克）、哌醋甲酯（每天两次，最多 10 毫克）或安慰剂，每次服用最多 6 周。所有患者都打算接受所有四种研究药物，依次采用四种不同顺序之一，药物之间有 2 周的清除期。一位生物统计学家准备了一个隐蔽的分配时间表，按地点分层，以大约 1:1:1:1 的比例随机分配一系列药物，以八个为一组，分配给一系列连续的数字。统计学家和药剂师在评估参与者或收集数据方面没有任何作用，并且参与者、护理人员和评估员对分配不知情。主要结果指标是在每个用药期第 5 周服用最高耐受剂量时测量的 MFIS，使用线性混合效应回归模型进行分析。该试验已在 ClinicalTrials.gov 注册，NCT03185065，现已结束。2017 年 10 月 4 日至 2019 年 2 月 27 日期间的调查结果，在筛选的 169 名患者中，141 名患者被纳入并随机分配到四种药物给药顺序之一：35 名 (25%) 患者接受金刚烷胺、安慰剂、莫达非尼和哌醋甲酯顺序；34 名 (24%) 患者接受安慰剂、哌醋甲酯、金刚烷胺和莫达非尼序列；35 名 (25%) 患者接受莫达非尼、金刚烷胺、哌醋甲酯和安慰剂序列；37 名 (26%) 患者服用哌醋甲酯、莫达非尼、安慰剂和金刚烷胺。来自 136 名参与者的数据可用于主要结局的意向治疗分析。基线时 MFIS 总分和最大耐受剂量的估计平均值如下：基线时 51·3 (95% CI 49·0-53·6)，40·6 (38·2-43·1)安慰剂，41·3 (38·8-43·7) 金刚烷胺，39·0 (36·6-41·4) 莫达非尼，38·6 (36·2-41·0) 与哌醋甲酯（线性混合效应回归模型中的总体药物效应 p=0·20）。与安慰剂（124 名患者中的 38 名 [31%]）相比，更高比例的参与者在服用金刚烷胺（127 名患者中的 49 名 [39%]）、莫达非尼（125 名患者中的 50 名 [40%]）和哌醋甲酯时报告了不良事件（129 名患者中的 51 [40%]）。研究期间发生了三起严重的不良事件（服用金刚烷胺时发生肺栓塞和心肌炎，服用莫达非尼时多发性硬化症恶化需要住院）。解读 金刚烷胺、莫达非尼和哌醋甲酯在改善多发性硬化症疲劳方面并不优于安慰剂，但会引起更频繁的不良事件。本研究结果不支持滥用金刚烷胺、莫达非尼、或哌甲酯用于治疗多发性硬化症的疲劳。资助以患者为中心的结果研究所。