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.
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.
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Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment