Background

Non-dystrophic myotonias are skeletal muscle channelopathies caused by ion channel dysfunction. Symptom onset is frequently in the first decade of life, causing disability in a young cohort. Although there is no cure, symptomatic treatments exist. Previous trials provide evidence of the efficacy of mexiletine. More recently, lamotrigine has been shown to be effective. Both treatments have different profiles, including pharmacokinetics and adverse events. This trial aimed to investigate whether lamotrigine is non-inferior to mexiletine to directly inform clinical practice.

Methods

We did a randomised, double-blind, crossover, non-inferiority, phase 3 trial at the National Hospital for Neurology and Neurosurgery (London, UK). Participants (aged ≥18 years) who had genetically confirmed symptomatic non-dystrophic myotonia were randomly assigned (1:1), by means of a block randomisation schedule created by a computer program, to receive either mexiletine for 8 weeks followed by lamotrigine for 8 weeks, or lamotrigine followed by mexiletine, with a 7-day washout period in between. Investigators and participants were masked to treatment allocation. The primary outcome measure was the mean interactive voice response (IVR) diary stiffness score (0–9 scale) over the participant's final 2 weeks of diary reporting in each treatment period. Non-inferiority was assessed using a mixed-effects model with a predefined margin of 0·5 and included all randomly assigned participants who contributed at least 7 days of IVR-diary data in either treatment period. The trial is registered at ClinicalTrials.gov, NCT05017155, and EudraCT, 2020-003375-17.

Findings

Between Aug 1, 2021, and Dec 12, 2022, of 60 participants were screened (24 females and 36 males) and randomly assigned between Aug 1, 2021 and Dec 12, 2022, to either the mexiletine–lamotrigine sequence (n=30) or the lamotrigine–mexiletine sequence (n=30). 53 participants contributed data to the primary analysis. The mean IVR stiffness score after treatment with mexiletine was 2·54 (95% CI 1·98 to 3·10) versus 2·77 (2·21 to 3·32) with lamotrigine (mean mexiletine–lamotrigine difference −0·23 [95% CI −0·63 to 0·17]). The most common adverse event with both treatments was indigestion–reflux (eight participants, 208 participant-days receiving mexiletine; seven participants, 130 participant-days receiving lamotrigine). No serious adverse events were reported.

Interpretation

We were unable to conclude that lamotrigine is non-inferior to mexiletine; however, improvements in all outcome measures from baseline were similar between lamotrigine and mexiletine. Lamotrigine is an important treatment consideration in non-dystrophic myotonias alongside mexiletine; we propose a treatment algorithm to guide clinical practice.

Funding

Neuromuscular Study Group, Jon Moulton Charity Trust, UCLH BRC Fast Track Grant.

中文翻译：

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美西律与拉莫三嗪治疗非肌营养不良性肌强直：一项随机、双盲、头对头、交叉、非劣效性、3 期试验

 背景

非营养不良性肌强直是由离子通道功能障碍引起的骨骼肌通道病。症状通常在生命的头十年出现，导致年轻群体残疾。虽然无法治愈，但存在对症治疗。以前的试验提供了美西律疗效的证据。最近，拉莫三嗪已被证明有效。两种治疗方法具有不同的特点，包括药代动力学和不良事件。该试验旨在调查拉莫三嗪是否不劣于美西律，以直接为临床实践提供信息。

 方法

我们在国家神经病学和神经外科医院（英国伦敦）进行了一项随机、双盲、交叉、非劣效性的 3 期试验。通过计算机程序创建的块随机化计划，将经基因证实为症状性非营养不良性肌强直的参与者（≥18 岁）随机分配 （1：1） 接受美西律 8 周，然后接受拉莫三嗪 8 周，或拉莫三嗪后接受美西律，中间有 7 天的清除期。研究人员和参与者对治疗分配不知情。主要结果指标是参与者在每个治疗期最后 2 周日记报告的平均交互式语音响应 （IVR） 日记僵硬评分（0-9 分）。使用预定义边际为 0·5 的混合效应模型评估非劣效性，并包括所有随机分配的参与者，这些参与者在任一治疗期间贡献了至少 7 天的 IVR 日记数据。该试验在 ClinicalTrials.gov、NCT05017155 和 EudraCT 注册，电话：2020-003375-17。

 发现

在 2021 年 8 月 1 日至 2022 年 12 月 12 日期间，筛选了 60 名参与者（24 名女性和 36 名男性），并在 2021 年 8 月 1 日至 2022 年 12 月 12 日期间随机分配到美西律-拉莫三嗪序列 （n=30） 或拉莫三嗪-美西律序列 （n=30）。53 名参与者为主要分析提供了数据。美西律治疗后的平均 IVR 僵硬评分为 2·54（95% CI 1·98 至 3·10）与拉莫三嗪治疗组 2·77（2·21 至 3·32）（平均美西律-拉莫三嗪差异 -0·23 [95% CI -0·63 至 0·17]）。两种治疗最常见的不良事件是消化不良-反流（8 名受试者，208 名受试者天接受美西律;7 名受试者，130 名受试者接受拉莫三嗪）。未报告严重不良事件。

 解释

我们无法得出拉莫三嗪不劣于美西律的结论;然而，拉莫三嗪和美西律之间所有结局指标相对于基线的改善相似。拉莫三嗪与美西律一起是非营养不良性肌强直的重要治疗考虑因素;我们提出了一种治疗算法来指导临床实践。

 资金

神经肌肉研究小组、Jon Moulton 慈善信托基金、UCLH BRC 快速通道补助金。