Background

Fatigue is one of the most disabling symptoms reported by people with multiple sclerosis. Although behavioural and pharmacological interventions might be partly beneficial, their combined effects have not been evaluated for multiple sclerosis fatigue, or examined with sufficient consideration of characteristics that might affect treatment response. In this comparative effectiveness research trial, we compared the effectiveness of cognitive behavioural therapy (CBT), modafinil, and their combination for treating multiple sclerosis fatigue.

Methods

This randomised, analyst-blinded, parallel-arm, comparative effectiveness trial was done at two universities in the USA. Adults (aged ≥18 years) with multiple sclerosis and problematic fatigue (Fatigue Severity Scale [FSS] score ≥4) were randomly assigned (1:1:1), using a web-based treatment assignment system with minimisation, to receive CBT, modafinil, or both for 12 weeks. Statisticians were masked to group assignment, but participants, study neurologists, CBT interventionalists, and coordinators were not masked to treatment assignment. The primary outcome was the change in Modified Fatigue Impact Scale (MFIS) from baseline to 12 weeks, assessed using multiple linear regression, adjusted for age, sex, study site, anxiety, pain, baselines MFIS score, and physical activity. Analyses were done by intent to treat. The trial was registered with clinicaltrials.gov, NCT03621761, and is completed.

Findings

Between Nov 15, 2018, and June 2, 2021, 336 participants were randomly assigned treatment (114 assigned to CBT, 114 assigned to modafinil, and 108 assigned to combination therapy). At 12 weeks, CBT (n=103), modafinil (n=107), and combination therapy (n=102) were associated with clinically meaningful within-group MFIS reductions of 15·20 (SD 11·90), 16·90 (15·90), and 17·30 (16·20) points, respectively. Change in MFIS scores from baseline to 12 weeks did not differ between groups: relative to combination therapy, the adjusted total mean difference in MFIS change score was 1·88 (95% CI –2·21 to 5·96) for CBT and 1·20 (–2·83 to 5·23) for modafinil. Most common adverse events for modafinil-containing treatment groups included insomnia (eight [7%] for modafinil and eight [7%] for combination therapy) and anxiety (three [3%] for modafinil and nine [8%] for combination therapy).

Interpretation

Modafinil, CBT, and combination therapy were associated with similar reductions in the effects of multiple sclerosis fatigue at 12 weeks. Combination therapy was not associated with augmented improvement compared with the individual interventions. Further research is needed to determine whether effects of these interventions on multiple sclerosis-related fatigue is influenced by sleep hygiene and sleepiness. No serious adverse events related to the study drug were encountered.

Funding

Patient-Centered Outcomes Research Institute and National Multiple Sclerosis Society.

中文翻译：

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认知行为疗法、莫达非尼及其联合治疗多发性硬化症疲劳 （COMBO-MS） 的比较效果：一项随机、统计学家设盲的平行臂试验

 背景

疲劳是多发性硬化症患者报告的最致残症状之一。尽管行为和药物干预可能部分有益，但尚未评估它们的综合效果对多发性硬化症疲劳的影响，也没有充分考虑可能影响治疗反应的特征进行检查。在这项比较有效性研究试验中，我们比较了认知行为疗法 （CBT）、莫达非尼及其联合治疗多发性硬化症疲劳的有效性。

 方法

这项随机、分析人员设盲、平行组、比较有效性试验在美国的两所大学进行。患有多发性硬化症和问题疲劳（疲劳严重程度量表 [FSS] 评分 ≥4）的成人 （≥18 岁） 被随机分配 （1：1：1），使用基于网络的治疗分配系统，最小化，接受 CBT、莫达非尼或两者，持续 12 周。统计学家对分组分配不设盲，但参与者、研究神经科医生、CBT 干预人员和协调员对治疗分配不设盲。主要结果是改良疲劳影响量表 （MFIS） 从基线到 12 周的变化，使用多元线性回归进行评估，并根据年龄、性别、研究地点、焦虑、疼痛、基线 MFIS 评分和身体活动进行调整。通过意向治疗进行分析。试验已在 clinicaltrials.gov NCT03621761 注册并已完成。

 发现

在 2018 年 11 月 15 日至 2021 年 6 月 2 日期间，336 名参与者被随机分配治疗（114 名分配给 CBT，114 名分配给莫达非尼，108 名分配给联合治疗）。12 周时，CBT （n=103） 、莫达非尼 （n=107） 和联合治疗 （n=102） 与具有临床意义的组内 MFIS 降低 15·20 （SD 11·90） 、 16·90 （15·90） 和 17·30 （16·20） 分相关。MFIS 评分从基线到 12 周的变化在组间没有差异：相对于联合治疗，CBT 的 MFIS 变化评分调整后的总均数差为 1·88 （95% CI -2·21 至 5·96），莫达非尼为 1·20 （-2·83 至 5·23）。含莫达非尼治疗组最常见的不良事件包括失眠（莫达非尼组 8 [7%] 和联合治疗组 8 [7%]）和焦虑（莫达非尼组 3 [3%] 和联合治疗组 9 [8%]）。

 解释

莫达非尼、 CBT 和联合治疗与 12 周时多发性硬化疲劳效果的类似降低相关。与个体干预相比，联合治疗与增强改善无关。需要进一步的研究来确定这些干预措施对多发性硬化症相关疲劳的影响是否受到睡眠卫生和嗜睡的影响。未遇到与研究药物相关的严重不良事件。

 资金

以患者为中心的结果研究所和国家多发性硬化症协会。