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

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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.

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 Summary:

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 ou
Sponsor: Radboud University

Current Primary Outcome: Change in patient-reported Stiffness on the IVR [ Time Frame: Weeks 3-4 of each period - up to 44 weeks. ]

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.


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Change in Individualized Neuromuscular Quality of Life Scale - Summary Score [ Time Frame: Week 4 of each period - up to 44 weeks. ]
    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.
  • Change in Short Form 36 - Physical Composite Score [ Time Frame: Week 4 of each period - up to 44 weeks. ]
    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.
  • Change in Clinical myotonia bedside-tests (Seconds) [ Time Frame: Week 4 of each period - up to 44 weeks. ]
    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.
  • Change in Muscle relaxation times measured with quantitative grip myometry (Seconds) [ Time Frame: Week 4 of each period - up to 44 weeks. ]
    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.
  • Change in Graded Myotonia by Needle Electromyography [ Time Frame: Week 4 of each period - up to 44 weeks. ]
    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.
  • Change in Mexiletine serum plasma concentration levels [ Time Frame: Weeks 1 and 4 of each period - up to 44 weeks. ]
    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.
  • Change in Patient-reported Pain on the IVR [ Time Frame: Weeks 3-4 of each period - up to 44 weeks. ]
    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.
  • Change in Patient-reported Weakness on the IVR [ Time Frame: Weeks 3-4 of each period - up to 44 weeks. ]
    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.
  • Change in Patient-reported Tiredness on the IVR [ Time Frame: Weeks 3-4 of each period

    Original Secondary Outcome: Same as current

    Information By: Radboud University

    Dates:
    Date Received: November 18, 2013
    Date Started: January 2014
    Date Completion:
    Last Updated: January 25, 2016
    Last Verified: January 2016