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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
30
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.
Placebo tablets do not contain any active medicinal component.
Departments of Neurology, Radboud University Nijmegen Medical Centre, the Netherlands
Nijmegen, Gelderland, Netherlands
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.
Time frame: Weeks 3-4 of each period - up to 44 weeks.
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.
Time frame: Week 4 of each period - up to 44 weeks.
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.
Time frame: Week 4 of each period - up to 44 weeks.
Change in Clinical myotonia bedside-tests (Seconds)
1. 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. 2. 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. 3. Percussion myotonia.
Time frame: Week 4 of each period - up to 44 weeks.
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.
Time frame: Week 4 of each period - up to 44 weeks.
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.
Time frame: Week 4 of each period - up to 44 weeks.
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.
Time frame: Weeks 1 and 4 of each period - up to 44 weeks.
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.
Time frame: Weeks 3-4 of each period - up to 44 weeks.
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.
Time frame: Weeks 3-4 of each period - up to 44 weeks.
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.
Time frame: Weeks 3-4 of each period - up to 44 weeks.
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.
Time frame: Week 4 of each period - up to 44 weeks.
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