title: Combined N-of-1 trials to investigate mexiletine in non-dystrophic myotonia using a Bayesian approach; study rationale and protocol.
abstract: BACKGROUND
  To 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
  We 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.
  
  
  CONCLUSIONS
  The 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.
  
  
  BACKGROUND
  ClinicalTrials.gov Identifier: NCT02045667.
authors.affiliation: Department of Neurology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. Bas.Stunnenberg@Radboudumc.nl.
authors.forename: Bas C
authors.initials: BC
authors.lastname: Stunnenberg
authors.affiliation: Department of Health Evidence, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. Willem.Woertman@Radboudumc.nl.
authors.forename: Willem
authors.initials: W
authors.lastname: Woertman
authors.affiliation: Department of Neurology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. Joost.Raaphorst@Radboudumc.nl.
authors.forename: Joost
authors.initials: J
authors.lastname: Raaphorst
authors.affiliation: Department of Neurology, University of Kansas Medical Center, PO Box 2012, KS 66160, Kansas City, USA. JStatland@kumc.edu.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Statland
authors.affiliation: Department of Neurology, University of Rochester Medical Center, PO Box 420669, Rochester, NY, 14642, USA. Robert_Griggs@URMC.Rochester.edu.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Griggs
authors.affiliation: Department of Cardiology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. Janneke.Timmermans@Radboudumc.nl.
authors.forename: Janneke
authors.initials: J
authors.lastname: Timmermans
authors.affiliation: Department of Neurology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. Christiaan.Saris@Radboudumc.nl.
authors.forename: Christiaan G
authors.initials: CG
authors.lastname: Saris
authors.affiliation: Department of Pharmacology-Toxicology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. Bas.Schouwenberg@Radboudumc.nl.
authors.forename: Bas J
authors.initials: BJ
authors.lastname: Schouwenberg
authors.affiliation: Department of Health Evidence, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. Hans.Groenewoud@Radboudumc.nl.
authors.forename: Hans M
authors.initials: HM
authors.lastname: Groenewoud
authors.affiliation: Department of Neurology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. Dick.Stegeman@Radboudumc.nl.
authors.forename: Dick F
authors.initials: DF
authors.lastname: Stegeman
authors.affiliation: Department of Neurology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. Baziel.vanEngelen@Radboudumc.nl.
authors.forename: Baziel G M
authors.initials: BG
authors.lastname: van Engelen
authors.affiliation: Department of Neurology and Neurosurgery, University Medical Center Groningen, PO Box 30001, 9700 RB, Groningen, The Netherlands. Gea.Drost@umcg.nl.
authors.forename: Gea
authors.initials: G
authors.lastname: Drost
authors.affiliation: Department of Health Evidence, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. GertJan.vanderWilt@Radboudumc.nl.
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: van der Wilt
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000465:Algorithms; D001499:Bayes Theorem; D003362:Cost-Benefit Analysis; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004576:Electromyography; D005143:Eyelids / Q000187:drug effects; D005260:Female; D018737:Hand Strength; D006801:Humans; D008297:Male; D008801:Mexiletine / Q000191:economics / Q000627:therapeutic use*; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D009222:Myotonia / Q000188:drug therapy*; D009799:Ocular Physiological Phenomena; D011786:Quality Control; D035583:Rare Diseases / Q000188:drug therapy*; D012107:Research Design; D061567:Voltage-Gated Sodium Channel Blockers / Q000191:economics / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D061567:Voltage-Gated Sodium Channel Blockers; D008801:Mexiletine