Effect of Mexiletine on Muscle Stiffness in Patients With Nondystrophic Myotonia Evaluated Using Aggregated N-of-1 Trials

Abstract

Importance: In rare diseases it is difficult to achieve high-quality evidence of treatment efficacy because of small cohorts and clinical heterogeneity. With emerging treatments for rare diseases, innovative trial designs are needed.

Objective: To investigate the effectiveness of mexiletine in nondystrophic myotonia using an aggregated N-of-1 trials design and compare results between this innovative design and a previously conducted RCT.

Design, setting, and participants: A series of aggregated, double-blind, randomized, placebo-controlled N-of-1-trials, performed in a single academic referral center. Thirty Dutch adult patients with genetically confirmed nondystrophic myotonia (38 patients screened) were enrolled between February 2014 and June 2015. Follow-up was completed in September 2016.

Interventions: Mexiletine (600 mg daily) vs placebo during multiple treatment periods of 4 weeks.

Main outcomes and measures: Reduction in daily-reported muscle stiffness on a scale of 1 to 9, with higher scores indicating more impairment. A Bayesian hierarchical model aggregated individual N-of-1 trial data to determine the posterior probability of reaching a clinically meaningful effect of a greater than 0.75-point difference.

Results: Among 30 enrolled patients (mean age, 43.4 [SD, 15.24] years; 22% men; 19 CLCN1 and 11 SCN4A genotype), 27 completed the study and 3 dropped out (1 because of a serious adverse event). In 24 of the 27 completers, a clinically meaningful treatment effect was found. In the Bayesian hierarchical model, mexiletine resulted in a 100% posterior probability of reaching a clinically meaningful reduction in self-reported muscle stiffness for the nondystrophic myotonia group overall and the CLCN1 genotype subgroup and 93% posterior probability for the SCN4A genotype subgroup. In the total nondystrophic myotonia group, the median muscle stiffness score was 6.08 (interquartile range, 4.71-6.80) at baseline and was 2.50 (95% credible interval [CrI], 1.77-3.24) during the mexiletine period and 5.56 (95% CrI, 4.73-6.39) during the placebo period; difference in symptom score reduction, 3.06 (95% CrI, 1.96-4.15; n = 27) favoring mexiletine. The most common adverse event was gastrointestinal discomfort (21 mexiletine [70%], 1 placebo [3%]). One serious adverse event occurred (1 mexiletine [3%]; allergic skin reaction). Using frequentist reanalysis, mexiletine compared with placebo resulted in a mean reduction in daily-reported muscle stiffness of 3.12 (95% CI, 2.46-3.78), consistent with the previous RCT treatment effect of 2.69 (95% CI, 2.12-3.26).

Conclusions and relevance: In a series of N-of-1 trials of mexiletine vs placebo in patients with nondystrophic myotonia, there was a reduction in mean daily-reported muscle stiffness that was consistent with the treatment effect in a previous randomized clinical trial. These findings support the efficacy of mexiletine for treatment of nondystrophic myotonia as well as the feasibility of N-of-1 trials for assessing interventions in some chronic rare diseases.

Trial registration: ClinicalTrials.gov Identifier: NCT02045667.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Statland reported receiving grants from the National Institute of Neurological Disorders and Stroke and the FSH Society and receiving personal fees from Acceleron, Sarepta, Fulcrum, and PTC. Dr Griggs reported receiving grants (during the conduct of the study) from the National Institutes of Health, Muscular Dystrophy Association, and Parent Project for Muscular Dystrophy and receiving personal fees from Strongbridge Pharmaceuticals, Sarepta Pharmaceuticals, Marathon Pharmaceuticals, and Stealth Pharmaceuticals. Dr Matthews reported receiving compensation, after the research and manuscript were completed and submitted, for attending a scientific advisory meeting at the request of LUPIN pharmaceuticals, which is seeking European Medicines Agency approval for mexiletine. Dr van Engelen reported receiving grants from European Union’s Horizon 2020 research and innovation programme (Murab), European FP7 programme (OPTIMISTIC), Association Francaise contre les Myopathies, Global FSH, The Netherlands Organisation for Health Research and Development (ZonMw), Prinses Beatrix Spierfonds, Stiching Spieren voor Spieren, Dutch FSHD Foundation, and The Netherlands Organisation for Scientific Research and receiving personal fees from Fulcrum. No other disclosures were reported.

Figures

Figure 1.. Recruitment and Patient Flow

Figure 2.. Results From Bayesian Analysis at the Individual and Group Level

Primary outcome (interactive voice response [IVR]–reported stiffness) mean treatment effect and 95% credible interval (CrI) for each patient. The estimates for each genotype subgroup (CLCN1 [skeletal muscle chloride channel gene]; SCN4A [skeletal muscle sodium channel gene]) are informed by information from all patients, in light of their genotype. Individual treatment effects (circles) are ordered from smallest to largest effect on the x-axis, with patient numbers beneath data markers for cross-referencing with demographic and baseline information in eTables 2 and 3 in Supplement 2. Patients 3, 6, and 7 dropped out. Open circles indicate patients who had 2 treatment sets instead of 1 as part of their individual N-of-1 trial (patients 1, 2, 4, and 5). Blue dotted line at y = 0.75 represents the threshold for a clinically meaningful treatment effect.

Figure 3.. Results From Bayesian Analysis at the Group Level

A, Probability density functions of primary outcome (interactive voice response [IVR]–reported stiffness) treatment effects for the total nondystrophic myotonia (NDM) disease group (n = 27) and genotype subgroups (skeletal muscle chloride channel gene [CLCN1], n = 16; skeletal muscle sodium channel gene [SCN4A], n = 11). Blue dotted line at x = 0.75 represents the threshold for a clinically meaningful treatment effect. Posterior probabilities of a clinically meaningful treatment effect represent the area under the curve to the right of the dotted line. The estimates for each genotype subgroup are informed by information from all patients, in light of their genotype. B, Cumulative representation of panel A into a probability effect function provides readout for the posterior probability belonging to the treatment effect of interest. As examples, the blue dotted lines provide readouts for posterior probabilities of reaching a clinically meaningful treatment effect of 0.75-point difference (corresponding to a 20% change on the mean baseline IVR stiffness score; effect size, 0.43), and a 2.0-point difference (corresponding to a 52% change on the mean baseline IVR stiffness score; effect size, 1.14) on the IVR scale. C, Posterior probability of reaching a clinically meaningful mexiletine treatment effect as function of the number of consecutive patients used in the Bayesian analysis. Note that a probability of 95% or greater is reached after the first 11 consecutive patients (patients 1-11, as labeled in Figure 2 and in eTables 2 and 3 in Supplement 2) for the total NDM. Numbers on the x-axis do not match those in Figure 2.