Clinical trial NCT02045667: Combined N-of-1 Trials Mexiletine vs Placebo in Patients With Non-Dystrophic Myotonia (NDM)
Official title: Combining N-of-1 Trials to Estimate Population Clinical and Cost-effectiveness of Drugs Using Bayesian Hierarchical Modeling. The Case of Mexiletine for Patients With Non- Dystrophic Myotonia.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non Dystrophic Myotonia
Keywords: Becker's myotonia congenita (BMC)
Thomson's myotonia congenita (TMC)
Paramyotonia Congenita (PMC)
Sodium Channel Myotonia (SCM)
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
First posted: 2014-01-27
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Detailed description: Rationale: A current problem in the context of a coverage decision for the use of mexiletine for NDM patients is the lack of a sufficient evidence base. An innovative trial design could facilitate in establishing such an evidence base in a small group of rather heterogeneous patients. As more than 7000 rare diseases in Europe and the USA suffer from a similar lack of treatment evidence, more experience with this innovative trial design would be very helpful.

Study design: A double-blind, randomized and placebo-controlled combined N-of-1- trial using a Bayesian statistical approach.

Study population: Non-dystrophic myotonia (NDM) patients, at least 18 years old, with a genetically confirmed diagnosis.

Intervention: Each N-of-1 trial consists out of a minimum of one, and a maximum of 4 treatment sets, each comprising a 4-week period of active treatment (Mexiletine) and a 4-week period of treatment with placebo, in random order, with one week for wash-out in between. Within each mexiletine period, treatment dosage of mexiletine will be built up from 200 mg 1 time a day PO on the first day of the first week, to 200 mg 2 times a day on the second day of the first week, to the desired dosage of 200 mg 3 times a day PO on the third day of the first week and throughout the remaining days of the 4-week treatment period. A similar build-up scheme will be used within each placebo period.

Main study parameters/endpoints: The primary outcome measure for this study is a decrease in the most prominent clinical symptom: stiffness. Stiffness will be quantified by an Interactive Voice Response System (IVR) in which the patient will rate their mean daily IVR participant-assessed severity of stiffness on an ordinal scale (1-9). The secondary outcome measures will include changes in pain, weakness, and fatigue on IVR, Individual Neuromuscular Quality of Life (INQoL), the Short Form (36) Health Survey (SF-36) a patient-reported survey of patient health, blood plasma levels of mexiletine, clinical myotonia assessments, quantitative handgrip myotonia, biceps force test and needle-electromyography (EMG).

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: In the screening phase, electrocardiography (ECG) and EMG recordings, laboratory values and baseline blood plasma levels of mexiletine will be tested. Medical history and written consent will also be obtained in this phase. Patients will be asked to visit the department of Neurology between 4-16 visits (depending on number of treatment sets necessary to obtain enough evidence) during the study enrolment. Each visit will approximately cost 2 hours; within each visit two questionnaires (INQoL, SF-36) need to be filled, blood plasma levels of mexiletine will be measured and clinical and electrophysiological myotonia tests need to be performed. Furthermore, an ECG and EMG will be recorded at the end of each treatment or placebo period. In addition, patients will have to call in to an interactive voice response system to report their mean daily IVR participant-assessed severity of stiffness once a week in every first and second week and daily in every third and fourth week of each treatment or placebo period.

Eligibility criteria: Inclusion Criteria:

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

Exclusion Criteria:

1. Inability or unwillingness to provide informed consent.
2. Other neurological conditions that might affect the assessment of the study measurements.
3. Genetic confirmed Myotonic Dystrophy type 1 (DM1) (CTG \> 50 repeats), or Myotonic Dystrophy type 2 (DM2).
4. 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).
5. Current use of the following antiarrhythmic medication for a cardiac disorder:flecainide acetate, encainide, disopyramide, procainamide, quinidine, propafenone or mexiletine.
6. Women who are pregnant or lactating.
7. 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.
8. Patients with renal or hepatic disease, heart failure, history of myocardial infarction, or seizure disorders.

Primary outcomes:
measure: Change in patient-reported Stiffness on the IVR
timeFrame: Weeks 3-4 of each period - up to 44 weeks.
Secondary outcomes:
measure: Change in Individualized Neuromuscular Quality of Life Scale - Summary Score
timeFrame: Week 4 of each period - up to 44 weeks.
measure: Change in Short Form 36 - Physical Composite Score
timeFrame: Week 4 of each period - up to 44 weeks.
measure: Change in Clinical myotonia bedside-tests (Seconds)
timeFrame: Week 4 of each period - up to 44 weeks.
measure: Change in Muscle relaxation times measured with quantitative grip myometry (Seconds)
timeFrame: Week 4 of each period - up to 44 weeks.
measure: Change in Graded Myotonia by Needle Electromyography
timeFrame: Week 4 of each period - up to 44 weeks.
measure: Change in Mexiletine serum plasma concentration levels
timeFrame: Weeks 1 and 4 of each period - up to 44 weeks.
measure: Change in Patient-reported Pain on the IVR
timeFrame: Weeks 3-4 of each period - up to 44 weeks.
measure: Change in Patient-reported Weakness on the IVR
timeFrame: Weeks 3-4 of each period - up to 44 weeks.
measure: Change in Patient-reported Tiredness on the IVR
timeFrame: Weeks 3-4 of each period - up to 44 weeks.
measure: Change in Short Form 36 - Mental Composite Score
timeFrame: Week 4 of each period - up to 44 weeks.
Other outcomes:
measure: Change in ECG conduction times: PR, QRS and QTc-time
timeFrame: Week 4 of each period - up to 44 weeks.
Locations:
city: Nijmegen
country: Netherlands
facility: Departments of Neurology, Radboud University Nijmegen Medical Centre, the Netherlands
state: Gelderland
Study officials:
affiliation: Department of Neurology, Radboud University Nijmegen Medical Centre, the Netherlands
name: Prof. dr. BGM van Engelen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Epidemiology, HTA and biostatistics, Radboud University Nijmegen Medical Centre, the Netherlands
name: Prof. dr. GJ van der Wilt, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Neurology, Radboud University Nijmegen Medical Centre, the Netherlands
name: Drs. BC Stunnenberg, MD
role: STUDY_CHAIR
affiliation: Department of Epidemiologie, HTA and biostatistics, Radboud University Nijmegen Medical Centre, the Netherlands
name: Drs. W Woertman, PhD
role: STUDY_CHAIR
affiliation: Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, the Netherlands
name: Drs. B Schouwenberg, MD
role: STUDY_CHAIR
affiliation: Department of Neurology, University Medical Centre Groningen, the Netherlands
name: Dr. G Drost, MD, PhD
role: STUDY_CHAIR
affiliation: Department of Neurology, Radboud University Nijmegen Medical Centre, the Netherlands
name: Drs. J Raaphorst, MD
role: STUDY_CHAIR
affiliation: Department of Neurology, Radboud University Nijmegen Medical Centre, the Netherlands
name: Drs. N van Alfen, MD, PhD
role: STUDY_CHAIR
affiliation: Department of Cardiology, Radboud University Nijmegen Medical Centre, the Netherlands
name: Drs. J Timmermans, MD
role: STUDY_CHAIR
affiliation: Department of Epidemiologie, HTA and biostatistics, Radboud University Nijmegen Medical Centre, the Netherlands
name: Drs. H Groenewoud, MSc
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.