study to investigate the efficacy and safety of mexiletine in patients with myotonic dystrophy type 1 and type 2

Conditions: Myotonic Dystrophy Type 1 and Type 2

Summary: a randomized, double-blind, placebo-controlled, multi-center study to investigate the efficacy and safety of mexiletine during 26 weeks of treatment in patients with myotonic dystrophy type 1 and type 2 \[the mind study\]

this is a multicenter, randomized, double-blind, parallel-group, placebo-controlled study intended to evaluate the safety and efficacy of mexiletine in patients with myotonic dystrophy type 1 and type 2 (dm1 and dm2). the study will consist of a 4-week screening period and a 26-week treatment phase with patient visits as screening, baseline, weeks 1, 2, 6, 14, 18, and 26. eligible patients will be randomized to mexiletine or placebo in a 1:1 ratio. approximately 158 dm1 patients (79 active: 79 placebo) are planned to be enrolled across 10-15 experienced investigational centers in europe. in addition, up to 16 dm2 patients are planned to be enrolled (sub-group - 8 active: 8 placebo). study drug (mexiletine 167 mg or placebo) will be started as a once a day (qd) treatment regimen. the dose will be titrated up at the week 1 and week 2 visits to a maximum of 1 capsule three times a day. depending on tolerability, the dose can also be either maintained or - if required - reduced by one dose step at any time during the study to a minimum dose of 167 mg qd.

Eligibility criteria:
inclusion criteria: 1. dm1 or dm2 diagnosis confirmed genetically; 2. ability to provide informed consent; 3. ability to understand the study requirements including intention to stay in the study until the end-of-study visit at 26 weeks of treatment; 4. male or non-pregnant female ≥18 years of age; 5. 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, have a vasectomized partner, or are practicing abstinence; 6. no significant cardiac abnormalities as determined by a cardiologist's assessment of the electrocardiogram (ecg) and echocardiogram; 7. capable of swallowing capsules; 8. have sufficient finger flexor strength to grasp the handle of the dynamometer used to measure myotonia; 9. presence of clinical handgrip myotonia (delayed relaxation of grip of ≥ 3 seconds after maximum voluntary contraction) at screening; 10. have a day 1 (pre-dose) handgrip dynamometer mean relaxation time of ≥1.5 seconds for the force to decline from 90% of maximum voluntary contraction force to 5%; 11. be able to walk independently 10 meters (cane, walker, orthoses allowed); 12. dm1 patients only - muscular impairment rating scale (mirs) score of 2, 3, or 4. exclusion criteria: 1. are pregnant or lactating; 2. 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; 3. severe renal impairment (glomerular filtration rate (gfr) \< 30 ml/min); 4. medical conditions which could interfere with muscle function such as infections, trauma, fractures, or planned surgery; 5. medical conditions that could affect hand functioning including but not limited to rheumatoid arthritis, dupuytren's contracture, hand deformity, etc.; 6. severe arthritis or other medical condition (besides dm1/dm2) that would significantly impact ambulation; 7. high incidence of falls or fall-associated fractures (\>5 falls during the past 12 months); 8. 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 the investigator; 9. treatment with mexiletine within 4 weeks prior to baseline (day 1); 10. intake of any anti-myotonic treatment within 4 weeks prior to baseline (day 1) such as propafenone, flecainide, lamotrigine, carbamazepine or any other channel-blocker/ anticonvulsive drugs; 11. use of any concomitant medications that could increase the cardiac risk; 12. known allergy to mexiletine or any local anesthetics; 13. participation in another interventional clinical study during the last 3 months; 14. wheelchair-bound or bed-ridden; 15. any cardiac safety-associated condition including any of the following criteria detected by screening cardiac evaluations including 24-hour holter monitoring, ecg, 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 * 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% * 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 mexiletine and 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) * patients with implantable cardioverter defibrillators (icds) and pacemakers are excluded