Open Label Study in Adolescents and Children With Myotonic Disorders

This is an open-label, multi-centre, single arm, interventional study to describe the steady-state PK, safety, and efficacy of mexiletine in paediatric patients (6 to <18 years of age) with myotonic disorders.

Patients who meet the eligibility criteria will be enrolled stepwise, sequentially in 2 cohorts by age groups.

Cohort 1 - Adolescents aged 12 to <18 years, will be enrolled first. If no safety concerns are observed (based on data evaluation by the Data Safety Monitoring Board [DSMB]), and the dose for the age group 6 to <12 years is confirmed by PK model, enrolment for Cohort 2 will begin.

Cohort 2 - Children aged 6 to <12 years, will be enrolled. The overall treatment duration for each cohort will be approximately 56 days (8 weeks): a dose titration phase of 4 weeks and the maintenance phase of 4 weeks. The overall study duration would be approximately 22 months.

Dose titration phase: In this phase, patients will receive mexiletine starting at an age appropriate dose (as evaluated by the investigator and based on body weight) at a frequency of once a day. Dose will be up-titrated every 14 days based on tolerability of mexiletine up to a maximum of three-times a day as assessed by investigator.

Maintenance phase: During the maintenance phase, patients will continue to receive mexiletine at the best-tolerated dose from the titration phase for further 4 weeks. Following completion, all participants will be offered follow-up in PIP Study 7 (MEX-NM-303) (EudraCT: 2019-003758-97).

Inclusion criteria

• Male or female patients aged ≥ 6 and < 18 years who are able to comply with the study requirements
• A genetically confirmed diagnosis of NDM or DM (DM1or DM2)
• Presence of clinical symptoms of myotonia (hand grip myotonia, myotonia in the leg muscles, any other myotonia symptoms)
• No significant cardiac abnormalities as determined by a cardiologist's assessment of the ECG and echocardiogram performed within 3 months prior to enrolment in the study. (If not done within 3 months before trial, electrocardiogram (ECG) and echocardiogram assessments will be performed at screening)
• No history of any significant liver disorder
• Patients receiving mexiletine treatment agree to stop treatment at least 7 days prior to initiation of treatment with Namuscla
• Patients receiving other antimyotonic treatment agree to stop treatment for at least 7 times the half-life of respective drug
• Laboratory investigations for haematology, biochemistry, and urinalysis at screening are within the normal range, or showing no clinically relevant abnormal values, as judged by the Investigator.
• Female patients of childbearing potential must be using an acceptable form of birth control as determined by the Investigator (e.g., oral contraception, implantable, injectable/transdermal hormonal contraception, intrauterine device (IUD), barrier methods), tubal ligation or are practicing abstinence.
• Patients able to provide assent to study participation and a parent or legal guardian to sign the written informed consent prior to study entry.

Exclusion criteria

• Any contra-indication to mexiletine as listed in the Namuscla Summary of Product Characteristics (SmPC):

• Hypersensitivity to the active substance, or to any of the excipients
• Hypersensitivity to any local anaesthetic
• Ventricular tachyarrhythmia
• Complete heart block (i.e., third-degree atrioventricular block) or any heart block susceptible to evolve to complete heart block (first-degree atrioventricular block with markedly prolonged PR interval (≥ 200 ms) and/or wide QRS complex (≥ 120 ms), second-degree atrioventricular block, bundle branch block, bifascicular and trifascicular block),
• QT interval > 450ms
• Myocardial infarction (acute or past), or abnormal Q-waves
• Symptomatic coronary artery disease
• Heart failure with ejection fraction <50%
• Atrial tachyarrhythmia, fibrillation or flutter
• Sinus node dysfunction (including sinus rate < 50 bpm)

• Co-administration with medicinal products inducing torsades de pointes (class Ia, Ic, III antiarrhythmics): Co-administration of mexiletine and antiarrhythmics inducing torsades de pointesclass Ia: quinidine, procainamide, disopyramide, ajmaline; class Ic: encainide, flecainide, propafenone, moricizine; class III: amiodarone, sotalol, ibutilide, dofetilide, dronedarone, vernakalant) increases the risk of potentially lethal torsades de pointes.
• Co-administration with medicinal products with narrow therapeutic index
• Any other neurological or psychiatric condition that might affect the study assessments
• Any clinically significant illness, laboratory findings, ECG, or other clinical symptoms, which in the opinion of the Investigator could affect the patient's optimal participation in the study
• Strong inducer or inhibitor of CYP2D6 or CYP1A2 within 7 days prior to study drug administration
• Any concurrent illness, or medications which could affect the muscle function
• Seizure disorder, diabetes mellitus requiring treatment by insulin
• Pregnant or breastfeeding
• Concurrent participation in any other clinical trial.