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
Highlights
To obtain evidence for the clinical and cost-effectiveness of treatments for patients with rare diseases is a challenge
In Europe, 30 million patients (6 to 8% of the population) have a rare disease [1]. International regulatory authorities such as the Food and Drug Administration (FDA) and European Medical Agency (EMA) accept that it is unreasonable to demand the standard level of evidence of multiple Randomized Controlled Trials (RCTs) in building an evidence-base for treatment of rare diseases [2,3,4]
Bayesian hierarchical analysis This study aims to answer the following questions: What is the probability that mexiletine is clinically effective in patients with non-dystrophic myotonia (NDM) on the individual and group level? To combine the results of the multiple N-of-1 trials, a hierarchical Bayesian model will be used, with the Interactive voice response diary (IVR) measure for stiffness as the dependent variable, and with the patient and the subgroup as the structural grouping factors
Summary
To obtain evidence for the clinical and cost-effectiveness of treatments for patients with rare diseases is a challenge. 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 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. Relying on case reports or case series incurs a considerable risk of selection and ascertainment bias It is unclear which concessions can be accepted towards the level 1 evidence needed for coverage decisions in case of rare diseases [5,6,7]
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