The Efficacy and Safety of Once Daily Mexiletine PR in Patients With Myotonic Dystrophy Type 1 and Type 2

Official title

A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Investigate the Efficacy and Safety of Once Daily Mexiletine PR During 26 Weeks of Treatment in Patients With Myotonic Dystrophy Type 1 and Type 2 (Phase 3)

Overview

A Randomized, Double-blind, Placebo-Controlled, Multi-Center Study to Investigate the Efficacy and Safety of Once Daily Mexiletine PR During 26 Weeks of Treatment in Patients with Myotonic Dystrophy Type 1 and Type 2 (HERCULES study)

Detailed description

This is a multicenter, randomized, double-blind, parallel-group, placebo-controlled study intended to evaluate the efficacy and the safety of mexiletine PR 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 at screening, baseline, Weeks 1, 2, 14, and 26. Eligible patients will be randomized to mexiletine or placebo in a 1:1 ratio. Approximately 80 DM1 patients (40 active: 40 placebo) are planned to be enrolled. For the purpose of sample size re-estimation, an interim analysis will be conducted when a total of 40 patients in total complete/early terminate the study.

In addition, 16 DM2 patients are planned to be enrolled (sub-group - 8 active: 8 placebo).

Interventions

• Drug Mexiletine granules for prolonged-release oral suspension
  Mexiletine PR
• Drug Placebo
  Matching Placebo

Primary outcome measures

• To assess the efficacy of once daily mexiletine PR for the symptomatic treatment of myotonia in patients with myotonic dystrophy type 1 and type 2 (DM1 and DM2). [Time frame: 26 weeks]

Secondary outcome measures (12)

• To assess the safety of once daily mexiletine PR for the symptomatic treatment of myotonia in patients with myotonic dystrophy type 1 and type 2 (DM1 and DM2). [Time frame: 26 weeks]
• Mean change in VAS [Time frame: 26 weeks]
• Mean change in MBS scores [Time frame: 26 weeks]
• Mean change in health-related quality of life [Time frame: 26 weeks]
• Mean change in DM1-Activ-c scale (DM1 patients only) [Time frame: 26 weeks]
• Mean change in time to perform the 10-meter Walk Test [Time frame: 26 weeks]
• Mean change in handgrip relaxation time [Time frame: 26 weeks]
• Mean change in time to perform Timed-up and go (TUG) test [Time frame: 26 Weeks]
• Mean change in health-related quality of life measured by EQ-5D [Time frame: 26 weeks]
• Mean change in Myotonic Dystrophy Health Index (MDHI) score (DM1 patients) [Time frame: 26 weeks]
• Mean change in Myotonic Dystrophy 2 Health Index (MD2HI) score (DM2 patients) [Time frame: 26 weeks]
• Assess the safety of mexiletine PR by changes in ECG [Time frame: 26 weeks]

Eligibility criteria

Inclusion criteria

• DM1 or DM2 diagnosis confirmed genetically;
• 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;
• 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 medical condition (other thanDM1/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 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.
• 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;
• Known allergy to mexiletine or any local anesthetics;
• 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;
• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United Kingdom · 2 centers

• Saint George's University Hospitals NHS Foundation Trust — London
• University College Hospital — London

Belgium · 1 center

• Laboratory for Muscle Diseases and Neuropathies — Leuven

Denmark · 1 center

• Aarhus University Hospital — Aarhus

Germany · 1 center

• Ludug-Maximilians University — München

Italy · 1 center

• Azienda Ospedaliera Universitaria Policlinico Tor Vergata — Rome

Spain · 1 center

• University Hospital of Madrid — Madrid

Identifiers

NCT: NCT06523400 · MEX-DM-302

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗