Once-daily mexiletine for muscle stiffness in myotonic dystrophy type 1 and 2

Who can take part

• DM1 or DM2 diagnosis confirmed genetically
• Be able to walk independently 10 meters (cane, walker, orthoses allowed)
• DM1 patients only - Muscular impairment rating scale (MIRS) score of 2, 3 or 4
• Ability to comprehend and willingness to sign an informed consent (ICF) or ICF of the parent(s)/legal guardian and written assent from the patient (if patient < 18 years of age)
• Ability to understand the study requirements including intention to stay in the study until the end-of-study visit at 26 weeks of treatment
• Male or non-pregnant female ≥16 years of age
• Body Mass Index (BMI) of 18.5 kg/m2 to 30 kg/m2, and weight ≥45 kg
• Female patients of childbearing potential must be using a highly effective form of birth control for the duration of the study and for at least 7 days after last dose of study drug
• No significant cardiac abnormalities as determined by a cardiologist’s assessment
• Have sufficient finger flexor strength to grasp the handle of the dynamometer used to measure myotonia
• Presence of clinical handgrip myotonia (delayed relaxation of grip of ≥ 3 seconds after maximum voluntary contraction) at screening using VHOT

Who cannot take part

• Treatment with mexiletine within 4 weeks prior to baseline (Day 1)
• Intake of any anti-myotonic treatment within 4 weeks prior to baseline (Day 1) or 5 half-lives, whichever is longer such as metformin, such as propafenone, flecainide, lamotrigine, carbamazepine or any other channel-blocker/ anticonvulsive drugs
• Use of any concomitant medications that could increase the cardiac risk
• Have any one of the following medical conditions: uncontrolled diabetes mellitus, cancer other than skin cancer less than five years previously (e.g., basal-cell carcinoma (BCC) and squamous-cell carcinoma (SCC) of skin allowed), multiple sclerosis, seizure disorders, or other serious medical illness
• Known allergy to mexiletine or any local anesthetics
• Medical conditions which could interfere with muscle function such as infections, trauma, fractures, or planned surgery
• Medical conditions that could affect hand functioning including but not limited to rheumatoid arthritis, Dupuytren’s contracture, hand deformity, etc
• Severe arthritis or medical condition (other thanDM1/DM2) that would significantly impact ambulation
• Any cardiac safety associated condition including any of the following criteria detected by screening cardiac evaluations including 24-hr Holter monitor, echocardiogram and clinical evaluations: • PR interval ≥240 ms or QRS duration ≥120 ms on resting ECG • Personal history of 3rd degree or 2nd degree type 2 atrioventricular block or sinus node dysfunction with pauses ≥3 seconds, complete bundle branch block, bifascicular and trifascicular block or any heart block susceptible to evolve to complete heart block • Personal history of sustained atrial fibrillation, flutter or tachycardia (duration >30 seconds) • Personal history of non-sustained (ventricular triplets or more) or sustained ventricular tachycardia • Myocardial infarction (acute or past) or coronary artery stenosis >50%, presence of abnormal Q waves • New York Heart Association (NYHA) Class II to IV heart failure • Left ventricular systolic dysfunction with ejection fraction <50% • Sinus node dysfunction (including ECG sinus rate <50 beats per minute (BPM)) • Co-administration of antiarrhythmics inducing torsades de pointes (class Ia: quinidine, procainamide, disopyramide, ajmaline; class Ic: encainide, flecainide, propafenone, moricizine; class III: amiodarone, sotalol, ibutilide, dofetilide, dronedarone, vernakalant) • Co-administration of other classes of antiarrhythmics (class Ib: lidocaine, phenytoin, tocainide; class II: propranolol, esmolol, timolol, metoprolol, atenolol, carvedilol, bisoprolol, nebivolol; class IV: verapamil, diltiazem) • Patients with implantable cardioverter defibrillators (ICDs) and pacemakers are excluded • Presence of symptomatic coronary artery disease
• Severe renal impairment (glomerular filtration rate (GFR) < 30 mL/min)
• Preexisting elevated liver function tests > 3 times the upper limit of normal (ULN) at screening (alanine transaminase (ALT)/aspartate transaminase (AST), gamma-glutamyl transferase (GGT)) and/or any abnormal chemistry, hematology or urine lab considered clinically significant by investigator
• Serum potassium values < 3.5 mmol/L or > 5.0 mmol/L or serum magnesium values < 1.7 mg/dL. Electrolytic imbalance such as hypokalaemia, hyperkalaemia or hypomagnesaemia may increase the proarrhythmic effects of mexiletine. Electrolyte imbalances need to be corrected before administering mexiletine and will be monitored throughout treatment
• Are pregnant or lactating
• Participation in another interventional clinical study during the last 3 months or 5 half-lives of the investigational medicinal product, whichever is longer
• Wheelchair-bound or bed-ridden
• High incidence of falls or fall-associated fractures (>5 falls during the past 12 months)