Non Dystrophic Myotonia Clinical Trial
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.
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.
| Status | Completed |
| Enrollment | 30 |
| Est. completion date | June 2015 |
| Est. primary completion date | June 2015 |
| Accepts healthy volunteers | No |
| Gender | Both |
| Age group | 18 Years and older |
| Eligibility |
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. |
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
| Country | Name | City | State |
|---|---|---|---|
| Netherlands | Departments of Neurology, Radboud University Nijmegen Medical Centre, the Netherlands | Nijmegen | Gelderland |
| Lead Sponsor | Collaborator |
|---|---|
| Radboud University | ZonMw: The Netherlands Organisation for Health Research and Development |
Netherlands,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Other | Change in ECG conduction times: PR, QRS and QTc-time | PR, QRS and QTc-times are segments of the ECG that in case of a change (increase or decrease) could hold a risk for cardiac arrhythmia. | Week 4 of each period - up to 44 weeks. | Yes |
| Primary | 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. | No |
| Secondary | Change in Individualized Neuromuscular Quality of Life Scale - Summary Score | Quality of life scale for patinets with neuromuscular disorders. The INQoL summary score is a weighted average made up of 5 subdomains (activities, social relationships, independence, emotions, and body image) which document the impact of a disease on a patients' quality of life. Scores range from 0-100, and can be interpreted as the percent of maximal detrimental impact on quality of life. A higher score indicates more detrimental impact. | Week 4 of each period - up to 44 weeks. | No |
| Secondary | Change in Short Form 36 - Physical Composite Score | The SF-36 is a standard quality of life instrument. The physical composite score represents the the physical burden on quality of life and is a summary of questions related to physical impact of a disease or condition (physical function, role physical, bodily pain, and general health). The score is nomralized to the population and ranges from 0-100, with the US normal value of 50. A lower score represents a greater impact of quality of life. | Week 4 of each period - up to 44 weeks. | No |
| Secondary | Change in Clinical myotonia bedside-tests (Seconds) | Eye closure myotonia. The participant will be instructed to close the eyes tightly for three seconds and then to open the eyes. Eye closure myotonia is present if there is difficulty fully opening the eyelids. This will be repeated for a total of 5 times. Each attempt will be timed. Hand-grip myotonia. The participant will be instructed to forcefully close the fingers in a fist for three seconds and then rapidly open the fist and extend the fingers. Hand-grip myotonia is present if the fingers cannot be immediately extended. The time it takes (in seconds) for the fingers to be fully extended will be recorded. This will be repeated for a total of 5 times. Each attempt will be timed. Percussion myotonia. |
Week 4 of each period - up to 44 weeks. | No |
| Secondary | Change in Muscle relaxation times measured with quantitative grip myometry (Seconds) | Maximum Voluntary Isometric Contractions (MVIC's) of the long finger flexors and the subsequent relaxation time (myotonia) will be measured using a technique developed at the University of Rochester. To measure the extent of grip myotonia of resting forearm muscle, each participant will squeeze the grip handle with a maximum grip for 3 seconds then relax until the force returns to baseline. The time required for relaxation (the relaxation time (RT)) following this initial MVIC will be used to calculate the degree of myotonia. To determine if repeated muscle contractions shorten the time required for full muscle relaxation, eg., warm-up, a series of five MVICs will be made, each for three seconds duration followed by a ten second period of rest. The measurement of warm-up will be made by comparing relaxation time for the initial MVIC compared to the relaxation time following the final contraction in the series of five contractions used as warm-up exercise. | Week 4 of each period - up to 44 weeks. | No |
| Secondary | Change in Graded Myotonia by Needle Electromyography | Concentric needle EMG will be performed in the rectus femoris muscles. These muscle were chosen based on the data from the NDM natural history study as performed in Jeroen Trip his PhD-thesis, and will be consistent throughout this study. According to established criteria myotonic discharges will be defined and quantified: Myotonic discharges must be at least 500 msec and elicited in three areas of the muscle outside of the endplate zone. Grading of myotonic discharges: 1+: fulfills minimal requirements; 2+: myotonic discharges in more than ½ of needle locations; 3+: myotonic discharges with each needle movement in all examined areas. | Week 4 of each period - up to 44 weeks. | No |
| Secondary | Change in Mexiletine serum plasma concentration levels | Mexiletine serum plasma concentration levels will be measured using a High-performance liquid chromatography-technique to analyse if they are within therapeutic range and to exclude any carry-over effects. | Weeks 1 and 4 of each period - up to 44 weeks. | No |
| Secondary | Change in Patient-reported Pain on the IVR | Pain measured on a 1-9 scale, 1 being minimal, 9 the worst ever experienced. 0=no symptom reported. For analysis the average severity of pain 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. | No |
| Secondary | Change in Patient-reported Weakness on the IVR | Weakness measured on a 1-9 scale, 1 being minimal, 9 the worst ever experienced. 0=no symptom reported. For analysis the average severity of weakness 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. | No |
| Secondary | Change in Patient-reported Tiredness on the IVR | Tiredness measured on a 1-9 scale, 1 being minimal, 9 the worst ever experienced. 0=no symptom reported. For analysis the average severity of tiredness 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. | No |
| Secondary | Change in Short Form 36 - Mental Composite Score | The SF-36 is a standard quality of life instrument. The mental composite score represents the the mental burden on quality of life and is a summary of questions related to mental impact of a disease or condition (mental function, role emotional, vitality, and mental health). The score is nomralized to the population and ranges from 0-100, with the US normal value of 50. A lower score represents a greater impact of quality of life. | Week 4 of each period - up to 44 weeks. | No |