Assessing novel alternative study designs and regulatory pathways

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.

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

Male or non-pregnant female ≥18 years of age