MExiletine Versus Lamotrigine in Non-Dystrophic Myotonias

Non-Dystrophic Myotonia Clinical Trial

— MEND  

Official title:

A Phase III, Randomised, Double Blinded, Head-to-head, Single-site, Cross-over Trial of Lamotrigine Versus Mexiletine for Non-dystrophic Myotonias

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05017155
• Other study ID #: 18/0582
• Status: Recruiting
• Phase: Phase 3
• Start date: August 12, 2021
• Est. completion date: April 2, 2024

Study information

• Verified date: November 2022
• Source: University College, London
• Contact: Vinojini Vivekanandam, Dr
• Phone: 02031087182
• Email: v.vivekanandam[@]ucl.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a clinical trial to determine if Lamotrigine is non-inferior to Mexiletine for the treatment of myotonia in patients with Non-Dystrophic Myotonia.

Non-dystrophic Myotonia is a genetic condition for which there is no cure. It affects patients for the duration of their life and impacts work, leisure and can lead to significant morbidity.

The study is a cross-over design - participants will be randomized to either lamotrigine or mexiletine first for 8 weeks and then swap over after a week wash-out to the other medication for a further 8 weeks. Participants and investigators will be blinded to the treatment schedule. 60 participants will recruited through the clinical service, national registry and national liaison.

Description:

The current first line treatment for Non-Dystrophic Myotonia (NDM) - Mexiletine - is ineffective in some patients, cannot be used in pregnancy, has side effects and is expensive with limited access in the UK, prompting the clear need for an alternative. A recent open label trial has demonstrated efficacy of Lamotrigine in treating NDMs, raising the possibility of Lamotrigine superseding Mexiletine as the first line agent. As the nationally commissioned highly specialised service for channelopathies, more patients are being seen than in other centres, have a track record of trials in NDMs published in high impact factor journals, and are best placed to conduct a trial of Mexiletine versus Lamotrigine.

Clinical morbidity: NDM impairs mobility, causes social embarrassment and impacts on quality of life. NDMs are a group of rare genetic neuromuscular disorders caused by dysfunction of ion channels that are critical for muscle membrane excitability. The hallmark of these disorders is that symptoms occur in an episodic or paroxysmal fashion causing acute disability. The NDMs include myotonia congenita (MC), sodium channel myotonia (SMC) and paramyotonia congenita (PMC). They have a point prevalence in England of 1.12/100,000. MC is due to mutations in the Chloride Channel gene (CLCN1), which codes for the muscle chloride channel clc-1. SMC and PMC are caused by mutations in the Sodium Channel Gene (SCN4A), which codes for the skeletal muscle voltage gated sodium channel Nav1.4. Both of these channels are essential for regulating normal muscle membrane excitability, muscle contraction and relaxation. NDMs are therefore unified by a common pathomechanism of altered muscle membrane excitability. The membrane becomes hyper-excitable resulting in spontaneous depolarisation and contraction after a motor nerve stimulus.

The primary clinical manifestation of NDM is myotonia - delayed relaxation of skeletal muscle after contraction. Myotonia is experienced by patients as muscles "locking", "sticking" or "cramping". Symptoms commonly affect the leg muscles and are precipitated by sudden or initial movement leading to falls and injury. They are also exacerbated by prolonged sitting, especially after preceding physical activity, and changes in environmental temperature. This can be particularly problematic on public transport which may stop abruptly, causing falls or inability to exit quickly enough, missing their destination. These difficulties can limit independence, social activity, choice of employment and are often socially embarrassing. The symptomatic relationship with activity often leads to sedentary behaviour which in turn is a risk factor for additional co-morbidities e.g. heart disease or stroke. The condition is frequently painful, with pain and impaired physical ability impacting significantly on quality of life. Symptoms commonly worsen during pregnancy which can be compounded by the need to discontinue current pharmacological therapies due to a lack of safety data during pregnancy.

Limitations of current pharmacological therapies: There is currently no cure or disease-modifying treatment for NDM. Sodium channel blockers are used for symptomatic relief. Previously it was shown that Mexiletine is effective in reducing myotonia and improving quality of life in an international randomised placebo controlled trial. Mexiletine has become first line treatment for NDM but not all patients respond to mexiletine and a significant proportion, up to a third develop side effects, the most common being gastro-intestinal. Mexiletine has also been shown to be less beneficial for patients with MC than those with Sodium Channel Myotonia (SCM) or PMC. Additionally, mexiletine cannot be prescribed in pregnancy, when myotonia often worsens. Mexiletine is expensive and can only be accessed by specialist centres. This can have practical difficulties and limit access to treatment for some patients. There is a clear clinical need for an alternative therapeutic option to Mexiletine for the treatment of NDM.

The study design has been chosen specifically to allow participants to be internal controls. The degree of myotonia varies with changes in temperature and degree of activity. A highly active participant cannot be directly compared to a sedentary participant, hence the use of internal controls in an 'n of one' trial accounts for this variability.

The participants and investigators will be blinded with the use of over-encapsulated mexiletine and lamotrigine dispensed via a predetermined randomisation scheduled. Blinding is important to eliminate bias and in ensuring unbiased completion of subjective questionnaires.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: April 2, 2024
• Est. primary completion date: August 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

Inclusion Criteria:

• adults (= 18years),

• genetically confirmed non-dystrophic myotonia (NDM),

• presence of symptomatic myotonia as reported by the participant.

Exclusion Criteria:

• concomitant medical conditions that would preclude the use of mexiletine or lamotrigine,

• evidence of severe kidney disease or severe liver impairment [estimated glomerular filtration rate (eGFR) as calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine Equation <60ml/min/1.73m2],

• pregnant or breastfeeding women,

• participation in other treatment studies <30days before enrolment.

Related Conditions & MeSH terms

• Myotonia
• Non-Dystrophic Myotonia

Intervention

Drug:
• Mexiletine
Mexiletine is a sodium channel blocker shown to be effective in reducing myotonia in a multi-centre randomised trial.
• Lamotrigine 25Mg Oral Tablet, Extended Release
Lamotrigine is an alternative sodium channel blocker that has been shown to be effective in one randomised controlled trial. It is currently used as a licensed medication for other neurological conditions.

Locations

Country	Name	City	State
United Kingdom	University College London Hospital	London

Sponsors (1)

Lead Sponsor	Collaborator
University College, London

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Interactive Voice Response (IVR) -diary score	Improvement seen on the 9 point Interactive Voice Response (IVR) -diary score	Time Frame: last two weeks of each treatment period - [Minimum value 0- no myotonia. Maximum value 9 - severe myotonia].
Secondary	Secondary Outcome - Timed up and go	Timed up and go	end of each treatment period (two months)
Secondary	Secondary Outcome - Timed sit to stand	Timed sit to stand	end of each treatment period (two months)
Secondary	Fatigue Scale	minimum 9 - minimal fatigue. maximum 63 - severe fatigue	end of each treatment period (two months)
Secondary	Secondary Outcome	Brain Pain inventory	end of each treatment period (two months)
Secondary	Short-Form Health Survey (SF-36)	minimum score 0 - more disability; maximum score 100 - less disability	end of each treatment period (two months)
Secondary	Myotonia Behaviour Score	minimum score 0 - minimum stiffness; maximum score 5 - incapacitating stiffness	end of each treatment period (two months)