A series of aggregated randomized-controlled N-of-1 trials with mexiletine in non-dystrophic myotonia : clinical trial results and validation of rare disease design

Objective: We aimed to validate the aggregated N-of-1 trials design using the case of mexiletine treatment in non-dystrophic myotonia. Background: In rare diseases it is difficult to achieve level 1 evidence of treatment efficacy due to small cohorts and clinical heterogeneity. With emerging treatments for rare diseases, validation of innovative trial designs is urgently needed. Design/Methods: We performed a series of aggregated, double-blind, randomized-controlled N-of-1-trials (mexiletine versus placebo) in 30 patients with non-dystrophic myotonia. The primary outcome measure was daily-reported muscle stiffness on a 1–9 scale, with higher scores indicating more impairment. Secondary outcomes included quality of life, myotonia and safety measures. A Bayesian hierarchical model combined individual N-of-1 trial results into the probability of reaching a clinically meaningful effect ( ≥ 0.75 difference on the primary outcome measure). To assess our trial design validity, we compared our results head-to-head with a previously conducted RCT. Eligibility criteria, treatment regimen, end-points and assessments were fully compatible between trials. Results: In 24 of the 27 patients who completed their N-of-1 trial, a clinically meaningful treatment effect was found. Mexiletine resulted in a mean muscle stiffness reduction of 3.06 (n=27, 95% credible interval 1.96–4.15). Adverse reactions included gastro-intestinal complaints (70%). The evidence that mexiletine reduces myotonia with a meaningful difference, with 95% probability, was reached after the first 11 consecutive patients. Meta-analysis of aggregated N-of-1 trials and RCT results showed absence of statistical heterogeneity (I2 = 0%) on the primary outcome measure. Secondary outcomes and adverse reactions profiles were comparable between trials. Conclusions: Our data show that aggregated N-of-1 trials produce a valid estimate of treatment effect at the group level. Compared to conventional designs, this trial approach seems promising with regard to efficiency and when dealing with patient heterogeneity. Furthermore, our data strengthen the evidence of mexiletine as a safe and effective treatment in non-dystrophic myotonia. Study Supported by: ZonMw, The Netherlands Organisation for Health Research and Development (Project number: 152002029) Disclosure: Dr. Stunnenberg has nothing to disclose. Dr. Raaphorst has nothing to disclose. Dr. Groenewoud has nothing to disclose. Dr. Statland has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Strongbridge, Acceleron, Regeneron, and Sanofi. Dr. Griggs has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Serve on DSMB for PTC Therapeutics, Idera Pharma; consultant for Saretpta, Marathon, Strongbridge and Taro Pharma. Dr. Griggs has received personal compensation in an editorial capacity for Correspondence editor for Neurology. Dr. Griggs has received royalty, license fees, or contractual rights payments from Royalties from Marathon and PTC Pharmaceuticals. Dr. Griggs has received research support from Research support from Marathon, PTC. Dr. Woertman has nothing to disclose. Dr. Stegeman has nothing to disclose. Dr. Timmermans has nothing to disclose. Dr. Trivedi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sanofi. Dr. Trivedi has received research support from Sanofi, CSL Behring. Dr. Matthews has nothing to disclose. Dr. Saris has nothing to disclose. Dr. Schouwenberg has nothing to disclose. Dr. Drost has nothing to disclose. Dr. van Engelen has nothing to disclose. Dr. van der Wilt has nothing to disclose.