title: Ephedrine as add-on therapy for patients with myasthenia gravis: protocol for a series of randomised, placebo-controlled n-of-1 trials.
abstract: BACKGROUND
  Myasthenia gravis (MG), a rare neuromuscular disease, is often initially treated using acetylcholinesterase inhibitors. Patients who do not respond adequately depend on the use of corticosteroids or other immunosuppressive medication, but these may have serious side effects. Clinical observations suggest that ephedrine can diminish, postpone or even prevent the need for immunosuppressive therapy when added to acetylcholinesterase inhibitors or low-dose prednisone. In the Netherlands, ephedrine is not licensed for MG nor is reimbursement guaranteed. MG is a rare condition, and ephedrine might be indicated only in a subset of patients. Thus, randomised controlled trials comparing large groups are difficult to conduct. We, therefore, aim to aggregate data from a small series of n-of-1 trials (also known as single patient trials) to assess the effect of ephedrine as add-on treatment for MG.
  
  
  METHODS
  Single-centre, placebo-controlled, double-blind, randomised, multiple crossover n-of-1 studies in 4 adult patients with generalised MG who show inadequate improvement on pyridostigmine and/or immunosuppressive drugs. Each n-of-1 trial has 3 cycles of two 5-day intervention periods.
  
  
  METHODS
  25 mg ephedrine or placebo, twice daily.
  
  
  METHODS
  Quantitative Myasthenia Gravis (QMG) test.
  
  
  METHODS
  fixed effects linear model for QMG for all patients combined.
  
  
  METHODS
  Clinical: effects on MG-Composite and MG-Activities of Daily Living (MG-ADL) scales; QMG at individual level; adverse events. Acceptability of trial design: number of patients eligible and enrolled; number of treatment cycles completed; patients' and caregivers' experiences.
  
  
  BACKGROUND
  This study was approved by the Medical Ethics Committee of Leiden University Medical Center, No. P14.108. Results of the trial will be reported in a peer-reviewed publication. Regulatory stakeholders will comment on the suitability of the trial for market authorisation and reimbursement purposes.
  
  
  BACKGROUND
  This study is registered under EudraCT number 2014-001355-23, protocol no. 40960, V.1.0, registration date 27 March 2014.
authors.affiliation: Department of Epidemiology and Public Health, University College London, London, UK Department of Clinical Genetics, EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Charlotte
authors.identifier: http://orcid.org/0000-0002-6187-0638
authors.initials: C
authors.lastname: Vrinten
authors.affiliation: Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Lipka
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Erik W
authors.initials: EW
authors.lastname: van Zwet
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Kirsten J M
authors.initials: KJ
authors.lastname: Schimmel
authors.affiliation: Department of Clinical Genetics, EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Martina C
authors.initials: MC
authors.lastname: Cornel
authors.affiliation: Department of Care, Section Pharmaceutical Care, National Health Care Institute, Diemen, The Netherlands.
authors.forename: Marja R
authors.initials: MR
authors.lastname: Kuijpers
authors.affiliation: Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Yechiel A
authors.initials: YA
authors.lastname: Hekster
authors.affiliation: Department of Clinical Genetics, EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Weinreich
authors.affiliation: Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jan J G M
authors.initials: JJ
authors.lastname: Verschuuren
mesh_terms: D000203:Activities of Daily Living; D000328:Adult; D001291:Attitude of Health Personnel; D001294:Attitude to Health; D000697:Central Nervous System Stimulants / Q000627:therapeutic use*; D002985:Clinical Protocols; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004809:Ephedrine / Q000627:therapeutic use*; D006801:Humans; D009157:Myasthenia Gravis / Q000188:drug therapy*; D056687:Off-Label Use; D018579:Patient Selection; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D016896:Treatment Outcome
chemical_list: D000697:Central Nervous System Stimulants; D004809:Ephedrine
keywords: STATISTICS & RESEARCH METHODS; THERAPEUTICS