Combined N-of-1 Trials Mexiletine vs Placebo in Patients With Non-Dystrophic Myotonia (NDM)

NCT02045667 | Completed Phase 2 DMC

• 2 other identifiers: Mexiletine201420152010-024026-38
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

The main objective of this study is to explore whether multiple trials with individual patients (N-of-1 trials) can produce a reliable evidence base for coverage decisions on clinical and cost-effectiveness of drug treatment for patients with rare diseases. As a case study, we will study the clinical and cost-effectiveness of Mexiletine in patients with Non-Dystrophic myotonia. The results of this analysis will be compared with the results obtained from a recently published international, multi-centre, randomized, placebo-controlled trial of Mexiletine in patients with Non-Dystrophic Myotonia (clinicaltrials.gov Identifier: NCT00832000). The secondary objective of this proposal is to assess whether mexiletine improves myotonia measured (both quantitatively and qualitative) in patients with non-dystrophic myotonia.

Conditions

Non Dystrophic Myotonia

Keywords

Becker's myotonia congenita (BMC); Thomson's myotonia congenita (TMC); Paramyotonia Congenita (PMC); Sodium Channel Myotonia (SCM)

Outcome Measures

Primary Outcomes (1)

• Change in patient-reported Stiffness on the IVR

  Stiffness measured on a 1-9 scale, 1 being minimal, 9 the worst ever experienced. 0=no symptom reported. For analysis the average severity of stiffness for each participant will be calculated form daily calls made in weeks 3-4 of each period.

  Weeks 3-4 of each period - up to 44 weeks.

Secondary Outcomes (10)

• Change in Individualized Neuromuscular Quality of Life Scale - Summary Score

  Week 4 of each period - up to 44 weeks.

• Change in Short Form 36 - Physical Composite Score

  Week 4 of each period - up to 44 weeks.

• Change in Clinical myotonia bedside-tests (Seconds)

  Week 4 of each period - up to 44 weeks.

• Change in Muscle relaxation times measured with quantitative grip myometry (Seconds)

  Week 4 of each period - up to 44 weeks.

• Change in Graded Myotonia by Needle Electromyography

  Week 4 of each period - up to 44 weeks.

Other Outcomes (1)

• Change in ECG conduction times: PR, QRS and QTc-time

  Week 4 of each period - up to 44 weeks.

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Placebo tablets three times daily orally

Drug: Mexiletine; Drug: Placebo

Mexiletine

ACTIVE COMPARATOR

Mexiletine 200mg three times daily orally

Drug: Mexiletine; Drug: Placebo

Interventions

Mexiletine DRUG

Mexiletine is a lidocaine-derivate and belongs to the class of 1B antiarrhythmic agents (Vaughan-Williams Classification of Antiarrhytmica). Class I antiarrhythmics have membrane-stabilizing properties. Drugs in this class work by interfering with the fast influx of sodium by inhibition of sodium ionchannels during the fast depolarization phase, thereby decreasing the maximal voltage and upshoot phase of the action potential. Mexiletine study-medication will be purchased from Stabilimento Chimico Farmaceutico Militare, Firenze, Italy.

Also known as: Mexitil, Ritalmex

Mexiletine; Placebo

Placebo DRUG

Placebo tablets do not contain any active medicinal component.

Also known as: Dummy, Control-arm medication

Mexiletine; Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• At least 18 years of age
• Genetically confirmed diagnosis of NDMs
• Participation in the "Genetical variability of the Non-dystrophic Myotonia" study of J. Trip or a new patient with genetically confirmed NDM.

You may not qualify if:

• Inability or unwillingness to provide informed consent.
• Other neurological conditions that might affect the assessment of the study measurements.
• Genetic confirmed Myotonic Dystrophy type 1 (DM1) (CTG \> 50 repeats), or Myotonic Dystrophy type 2 (DM2).
• Patients with existing cardiac conduction defects, evidenced on ECG including but not limited to the following conditions: malignant arrhythmia or cardiac conduction disturbances (such as second degree AV block, third degree atrio-ventricular (AV) block, or prolonged QT interval \>500 ms or QRS duration \> 150 msec).
• Current use of the following antiarrhythmic medication for a cardiac disorder:flecainide acetate, encainide, disopyramide, procainamide, quinidine, propafenone or mexiletine.
• Women who are pregnant or lactating.
• Patients currently on medications for myotonia such as phenytoin and flecainide acetate within 5 days of enrollment, carbamazepine and mexiletine within 3 days of enrollment, or propafenone, procainamide, disopyramide, quinidine and encainide within 2 days of enrollment.
• Patients with renal or hepatic disease, heart failure, history of myocardial infarction, or seizure disorders.

Sponsors & Collaborators

• Radboud University Medical Center: lead
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator

Study Sites (1)

Departments of Neurology, Radboud University Nijmegen Medical Centre, the Netherlands

Nijmegen, Gelderland, 6500HB, Netherlands

Location

Related Publications (2)

• Stunnenberg BC, Raaphorst J, Groenewoud HM, Statland JM, Griggs RC, Woertman W, Stegeman DF, Timmermans J, Trivedi J, Matthews E, Saris CGJ, Schouwenberg BJ, Drost G, van Engelen BGM, van der Wilt GJ. Effect of Mexiletine on Muscle Stiffness in Patients With Nondystrophic Myotonia Evaluated Using Aggregated N-of-1 Trials. JAMA. 2018 Dec 11;320(22):2344-2353. doi: 10.1001/jama.2018.18020.

  PMID: 30535218 DERIVED

• Stunnenberg BC, Woertman W, Raaphorst J, Statland JM, Griggs RC, Timmermans J, Saris CG, Schouwenberg BJ, Groenewoud HM, Stegeman DF, van Engelen BG, Drost G, van der Wilt GJ. Combined N-of-1 trials to investigate mexiletine in non-dystrophic myotonia using a Bayesian approach; study rationale and protocol. BMC Neurol. 2015 Mar 25;15:43. doi: 10.1186/s12883-015-0294-4.

  PMID: 25880166 DERIVED

MeSH Terms

Conditions

Myotonic Disorders; Potassium aggravated myotonia

Interventions

Mexiletine

Condition Hierarchy (Ancestors)

Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals; Phenyl Ethers; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons

Study Officials

• Prof. dr. BGM van Engelen, MD, PhD

  Department of Neurology, Radboud University Nijmegen Medical Centre, the Netherlands

  PRINCIPAL INVESTIGATOR

• Prof. dr. GJ van der Wilt, PhD

  Department of Epidemiology, HTA and biostatistics, Radboud University Nijmegen Medical Centre, the Netherlands

  PRINCIPAL INVESTIGATOR

• Drs. BC Stunnenberg, MD

  Department of Neurology, Radboud University Nijmegen Medical Centre, the Netherlands

  STUDY CHAIR

• Drs. W Woertman, PhD

  Department of Epidemiologie, HTA and biostatistics, Radboud University Nijmegen Medical Centre, the Netherlands

  STUDY CHAIR

• Drs. B Schouwenberg, MD

  Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, the Netherlands

  STUDY CHAIR

• Dr. G Drost, MD, PhD

  Department of Neurology, University Medical Centre Groningen, the Netherlands

  STUDY CHAIR

• Drs. J Raaphorst, MD

  Department of Neurology, Radboud University Nijmegen Medical Centre, the Netherlands

  STUDY CHAIR

• Drs. N van Alfen, MD, PhD

  Department of Neurology, Radboud University Nijmegen Medical Centre, the Netherlands

  STUDY CHAIR

• Drs. J Timmermans, MD

  Department of Cardiology, Radboud University Nijmegen Medical Centre, the Netherlands

  STUDY CHAIR

• Drs. H Groenewoud, MSc

  Department of Epidemiologie, HTA and biostatistics, Radboud University Nijmegen Medical Centre, the Netherlands

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 18, 2013
• First Posted: January 27, 2014
• Study Start: January 1, 2014
• Primary Completion: June 1, 2015
• Study Completion: June 1, 2015
• Last Updated: January 26, 2016

Record last verified: 2016-01

Locations

NL (1)