Combining N-of-1 trials to estimate population clinical effectiveness of drugs using Bayesian hierarchical modeling. The case of Mexilitin for patients with Non-Dystrophic Myotonia.

(voor meer details zie CMO-protocol paragraaf 1: Introduction and rationale)

Non-dystrophic myotonic syndromes are a heterogeneous group of rare diseases
caused by mutations in genes encoding skeletal muscle ion channels. The key
symptom is myotonia, a delayed relaxation after voluntary contraction. Despite
the general notion that NDMs are benign diseases, symptoms do cause lifetime
morbidity and a recent study demonstrated that the symptoms of these patients
do greatly impact their self-reported health status. In our recent Cochrane
review, we concluded that there is insufficient evidence of effectiveness and
safety of drug treatment in myotonic syndromes.
Based on this review, the Healthcare Insurance Board (CVZ) decided to
discontinue coverage of drugs for NDM patients. However, absence of evidence of
effectiveness should not be confused with evidence of absence of effectiveness,
and this decision might deprive NDM patients of substantial benefits. Indeed,
CVZ has acknowledged that in the case of rare diseases, it is unreasonable to
demand level 1 evidence (CVZ report 2007). As more than 7000 rare diseases in
Europe and the USA suffer from this lack of treatment evidence, an innovative
trial design is urgently needed.

The objective of our project is to further refine N-of-1 trial methodology, and
explore whether Bayesian analysis of multiple N-of-1 trials can serve as a
sufficient basis for coverage decisions on drugs for rare diseases. As reported
in our Cochrane review, there is no level 1 evidence of classic RCTs available
for treatment of myotonia in NDMs.3 However, evidence from single case reports
and expert opinion point towards the class I antiarrhythmic agents with
mexiletine as the (off-label) drug of choice in patients with NDMs. Drug
efficacy of mexiletine will be tested in our study on NDM patients.

(voor meer details zie CMO-protocol paragraaf 2: Objectives)

Primary Objective: The objective of this project is to further refine N-of-1
trial methodology, and explore whether Bayesian analysis of multiple N-of-1
trials can serve as a sufficient basis for coverage decisions on drugs for rare
diseases.

The previously mentioned will be tested in combined N-of-1 trials using
mexiletine vs. placebo in NDM patients. The secondary objective of this
proposal is to assess whether mexiletine improves myotonia measured (both
quantitatively and qualitative) in patients with non-dystrophic myotonia.

(voor meer details zie CMO-protocol paragraaf 3: study design)

Study design: Bayesian hierarchical approach of N of 1 trials
N-of-1 trials have initially been developed to optimize individual patient
management. More recently, results of multiple N-of-1 trials have been used to
produce an evidence base for drug effectiveness at group level, using Bayesian
hierarchical modeling. , Bayesian methodology is highly appropriate for this,
since it allows for an estimate of the probability that wrong inferences are
made on the basis of available data (e.g., concluding that a drug is effective,
whereas in reality it is not, or vice versa). For this, we will test robustness
of the method, by comparing results when using noninformative or informative
priors. Furthermore we will compare the results of our study with the results
of the worldwide multi-center trial *Phase II therapeutic trial of mexiletine
in Non-Dystrophic myotonia* of the consortium of Clinical Investigation of
Neurological Channelopathies (CINCH) with dr. Robert Griggs (University of
Rochester) and dr. Richard Barohn (University of Kansas Medical Center) as the
principal investigators. NDM provides an excellent model, since prior
probability estimates can be based on the detailed knowledge of the
pathophysiology of the disease and mechanism of action of the various drugs

Each N-of-1 trial consists 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 (see Figure 1). Total study enrolment will be maximally 44
weeks per patient and minimally 11 weeks. Patients will be enrolled in two
cohorts, each consisting of ten patients. Patients in one cohort will be
treated and followed up in parallel. Thus, all N-of-1 trials can be conducted
within 88 weeks.

Mexiletine intervention:
Three times a day 200 mg tablet.

Placebo intervention:
Three times a day a placebo tablet.

(voor meer details zie CMO-protocol 10.4: Benefits and risks assessment, group
relatedness)

Benefits and risks assessment, group relatedness
Testing Related Risk:
EMG testing may be painful. It may be uncomfortable for some participants. The
patient may feel some pain or discomfort when the needles are inserted, but
most people are able to complete the test without significant difficulty.
Afterward, the muscle may feel tender or bruised for a few days. The risks
associated with blood drawing include discomfort from the needle stick,
bruising, and rarely, an infection from the needle stick.
Other measurements are non-invasive and are not associated with any risks.

Pregnancy Related Risk:
It is not known how Mexiletine will affect an unborn or nursing child. There
may be risks to an unborn or nursing child that have not yet been identified.
There are no adequate and well-controlled studies in pregnant women. Because
the drug(s) in this research study may affect an unborn child, pregnant
patients will be excluded from this study. If a patient becomes pregnant during
the study the patient must immediately inform the primary investigator and
visit a doctor. If female patients have not been surgically sterilized, or have
not undergone menopause at least 1 year ago, they must practice a method of
birth control during the trial. Examples of birth control include: birth
control pills, implant, intrauterine device, (IUD), or a barrier method such as
a diaphragm with intravaginal spermicide, cervical cap, male or female condom

Possibility of Unknown Risks
There may be other risks that have not yet been identified and unexpected side
effects that have not been previously observed may occur

New findings statement:
You will be informed if any significant new findings develop during the course
of the study that may affect your willingness to participate in this study.

Benefits
Because of the proposed design of combined N-of-1 trials, each patient is
treated with several treatment periods with mexiletine and placebo. Thereby,
patients could directly benefit from participation in this study. Information
on adverse events from therapy can already be registered and if therapy
significantly decreases complaints of myotonia, the trial could be preliminary
ended and treatment with mexiletine could be started.