Study to Investigate the Efficacy and Safety of Mexiletine in Patients With Myotonic Dystrophy Type 1 and Type 2

Study Overview
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Brief Summary
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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]

Detailed Description
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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.

Official Title
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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]

Conditions
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Myotonic Dystrophy Type 1 and Type 2

Intervention / Treatment
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* Drug: Mexiletine 167 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: DM1 or DM2 diagnosis confirmed genetically; Ability to provide informed consent; 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 ≥18 years of age; 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; No significant cardiac abnormalities as determined by a cardiologist's assessment of the electrocardiogram (ECG) and echocardiogram; Capable of swallowing capsules; 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; 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%; 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. Exclusion Criteria: Are pregnant or lactating; 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; Severe renal impairment (glomerular filtration rate (GFR) < 30 mL/min); 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 other medical condition (besides DM1/DM2) that would significantly impact ambulation; High incidence of falls or fall-associated fractures (>5 falls during the past 12 months); 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; 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) such as propafenone, flecainide, lamotrigine, carbamazepine or any other channel-blocker/ anticonvulsive drugs; Use of any concomitant medications that could increase the cardiac risk; Known allergy to mexiletine or any local anesthetics; Participation in another interventional clinical study during the last 3 months; Wheelchair-bound or bed-ridden; 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Mexiletine<br>Mexiletine 167 mg (equivalent to mexiletine HCl 200 mg) | Drug: Mexiletine 167 mg<br>* Mexiletine 167 mg (equivalent to mexiletine HCl 200 mg) immediate release, oral capsules.<br>|
| Placebo Comparator: Placebo<br>The placebo capsules contain the same ingredients as the active formulation with the exception of mexiletine | Drug: Placebo<br>* The placebo capsules contain the same ingredients as the active formulation with the exception of mexiletine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the efficacy and safety of mexiletine for the symptomatic treatment of myotonia | To assess the efficacy and safety of mexiletine for the symptomatic treatment of myotonia in adult patients with myotonic dystrophy type 1 and type 2 (DM1 and DM2) by handgrip relaxation time in DM1 patients: Mean change from baseline (i.e., Day 1, pre-dose) in relaxation time of handgrip after 3 seconds of MVIC of the dominant hand using a handgrip dynamometer at Week 26. Mean relaxation time at each timepoint will be calculated from the first contraction in each of the 3 trials (each trial consists of 6 maximal voluntary contractions). Relaxation time for the assessment of myotonia will be calculated as the time required for the force to decline from 90% of maximum voluntary contraction force to 5%. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the efficacy of mexiletine on patient-reported outcomes by way of standardized instrument for measuring generic health status, EuroQol- 5 Dimension (EQ-5D). | The EQ-5D is a multi-attribute utility instrument for measuring health-related quality of life. EQ-5D: EuroQol - 5 dimensions (Health-related quality of life measure developed by EuroQol group). The index score is calculated by software hence minimum/maximum or better/worse not applicable. The EQ-5D assessments will be collected on Day 1 (pre-dose), Week 14, and Week 26 (or early discontinuation). | Day 1 (pre-dose), Week 14, and Week 26 (or early discontinuation) | 
| To assess the efficacy of mexiletine on patient-reported outcomes by Timed Up & Go (TUG) | The TUG Test (Podsiadlo, 1991; Trip 2009a) measures, in seconds, the time taken by an individual to stand up from a standard arm chair (approximate seat height of 46 cm, arm height 65 cm), walk a distance of 3 meters (approximately 10 feet), turn, walk back to the chair, and sit down. | 6 months | 
| To assess the efficacy of mexiletine on patient-reported outcomes by Individualized Neuromuscular Quality of Life Questionnaire (INQoL) overall | INQoL- Individualized neuromuscular quality of life questionnaire. Higher score represents worsening and lower score represents better. Minimum/maximum- not applicable. The INQoL overall questionnaire will be completed on Day 1 (pre-dose), Week 14, and Week 26 (or early discontinuation) | Day 1 (pre-dose), Week 14, and Week 26 (or early discontinuation) | 
| To assess the efficacy of mexiletine on functional capacity outcome measures by Individualized Neuromuscular Quality of Life Questionnaire (INQoL) locking domain. | To assess the efficacy of mexiletine on functional capacity outcome measures by Individualized Neuromuscular Quality of Life Questionnaire (INQoL) locking domain.INQoL- Individualized neuromuscular quality of life questionnaire. Higher score represents worsening and lower score represents better. Minimum/maximum- not applicable. | 6 months | 
| To assess the efficacy of mexiletine on functional capacity outcome measures by Myotonia Behavior Scale (MBS). | MBS was originally developed by Budzynski, Stoyva, Adler and Mullaney as a pain measurement instrument (Budzynski, 1973). The patient chooses one out of six framed sentences, which most closely describe the impact of the stiffness on everyday life. MBS: myotonia behavior scale, score ranges 0 - 5. Lower score is better and higher score is worsening. The MBS assessments will be completed on Day 1 (pre-dose), Week 2, Week 6, Week 14, Week 18, and Week 26 (or early discontinuation) | Day 1 (pre-dose), Week 2, Week 6, Week 14, Week 18, and Week 26 (or early discontinuation) | 
| To assess the efficacy of mexiletine on functional capacity outcome measures by Visual Analog Scale (VAS) for myotonia. | The construction of VAS in this study is an absolute measure, with a straight, horizontal, 10 cm line having the endpoints No stiffness at all and Stiffness as worst possible. The patient responds with a score on the line to the nearest millimeter on a 100-point scale. The VAS will be completed on Day 1 (pre-dose), Week 2, Week 6, Week 14, Week 18, and Week 26 (or early discontinuation) | 6 months | 
| To assess the efficacy of mexiletine on functional capacity outcome measures by 10 meter Walk Test (10mWT). | the 10mWT is a performance-based test assessing walking in two different conditions, own preferred speed and maximum speed, over a short distance. The time taken to walk 10 meters at usual comfortable and maximum speed is recorded with a stopwatch. | 6 months | 
| To assess the efficacy of mexiletine on functional capacity outcome measures by DM1-Active-c. | DM1-Activ-c scale is a disease-specific, Rasch-built scale, developed as a patient-reported outcome measure of capacity for activity and social participation with a 0-100 interval range (a higher score indicates higher capacity) (Hermans, 2015).VAS- Visual analogue scale. Score ranges 0-100. Lower is better and higher is worsening. The DM1-Activ-c scale score will be collected on Day 1 (pre-dose), Week 14, and Week 26 (or early discontinuation) | Day 1 (pre-dose), Week 14, and Week 26 (or early discontinuation) |