Combined N-of-1 trials to investigate mexiletine in non-dystrophic myotonia using a Bayesian approach; study rationale and protocol

Abstract

BackgroundTo obtain evidence for the clinical and cost-effectiveness of treatments for patients with rare diseases is a challenge. Non-dystrophic myotonia (NDM) is a group of inherited, rare muscle diseases characterized by muscle stiffness. The reimbursement of mexiletine, the expert opinion drug for NDM, has been discontinued in some countries due to a lack of independent randomized controlled trials (RCTs). It remains unclear however, which concessions can be accepted towards the level 1 evidence needed for coverage decisions, in rare diseases. Considering the large number of rare diseases with a lack of treatment evidence, more experience with innovative trial designs is needed. Both NDM and mexiletine are well suited for an N-of-1 trial design. A Bayesian approach allows for the combination of N-of-1 trials, which enables the assessment of outcomes on the patient and group level simultaneously.Methods/DesignWe will combine 30 individual, double-blind, randomized, placebo-controlled N-of-1 trials of mexiletine (600 mg daily) vs. placebo in genetically confirmed NDM patients using hierarchical Bayesian modeling. Our results will be compared and combined with the main results of an international cross-over RCT (mexiletine vs. placebo in NDM) published in 2012 that will be used as an informative prior. Similar criteria of eligibility, treatment regimen, end-points and measurement instruments are employed as used in the international cross-over RCT.DiscussionThe treatment of patients with NDM with mexiletine offers a unique opportunity to compare outcomes and efficiency of novel N-of-1 trial-based designs and conventional approaches in producing evidence of clinical and cost-effectiveness of treatments for patients with rare diseases.Trial registrationClinicalTrials.gov Identifier: NCT02045667

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

“…The full trial protocol is available in Supplement 1 and also has been published. 8 The Radboud Clinical Trial Center was responsible for management of data quality and monitoring of the trial. We performed a series of double-blind, randomized, placebo-controlled N-of-1 trials in adult patients with a clinical phenotype and genetically confirmed diagnosis of NDM, without cardiac or psychiatric comorbidity or comedication (eTable 1 in Supplement 2 contains additional details of the inclusion and exclusion criteria), selected from the Dutch neuromuscular database.…”

N-of-1 Trials: Evidence-Based Clinical Care or Medical Research that Requires IRB Approval? A Practical Flowchart Based on an Ethical Framework

“…We refer to an N-of-1 trial (i.e. N = 1 trial, single patient trial) as a trial in which a single patient is attributed to multiple treatment sets of active treatment and placebo treatment ideally in a blinded and randomized fashion, while measuring key symptoms, signs or lab results as outcome measure, until treatment efficacy is demonstrated or excluded [1][2][3][4][5][6][7][8][9][10][11]. Data analysis only takes place at the level of a single patient.…”

“…An aggregated series of N-of-1 trials When, in a series of individual N-of-1 trials, statistical analysis is performed both at the individual and (sub)group level(s), with the goal to provide treatment estimates on these different levels, this is referred to as an aggregated series of N-of-1 trials [2][3][4][5][6][7][8][9][10][11]. Here, the goal is not only to provide high-class evidence for one or multiple patients at the individual level, but also to gain generalizable knowledge on the group-effectiveness, heterogeneity of treatment effect and factors that influence treatment response by aggregation of results.…”

“…Over the past decades, the N-of-1 trial design has received renewed interest due to improvements of the initial single patient design, such as an aggregated N-of-1 trials design with Bayesian approach [2] to provide evidence on the effectiveness of a drug at the single patient and group level simultaneously [3]. This is of particular interest in the context of building the evidence-base for treatments that can be considered for patients with rare diseases in which large randomized controlled trials are hampered by low patient numbers and large clinical and genetic heterogeneity [4].…”

Application of n-of-1 clinical trials in personalized nutrition research: a trial protocol for Westlake N-of-1 Trials for Macronutrient Intake (WE-MACNUTR)

“…In the present study, a total of 30 participants will be enrolled, and Bayesian hierarchical model meta-analysis will be applied to combine the results from each n-of-1 trial generating estimates of intervention effect at population level. However, no formulabased methodology exists for sample size or power calculations for such designs 28 .…”