An Open-Label Extension Study to Evaluate the Long-Term Safety and Efficacy of Once Daily Mexiletine PR in Patients With Myotonic Dystrophy Type 1 and Type 2 Who Have Completed MEX-DM-302 Study.

Phase 3Enrolling By InvitationNCT06549400

Lupin Ltd.176 enrolled

Overview

This is an open-label extension study intended to evaluate the long-term safety and efficacy of mexiletine PR in patients with myotonic dystrophy type 1 and type 2 (DM1 and DM2) who have completed the parent study MEX-DM-302.

At the completion of the final visit in Study MEX-DM-302 patients who continued to meet the eligibility criteria will be invited to rollover into this open-label study for an additional 18 months. All patients who elect to continue into this open-label study will receive active mexiletine (no placebo). Mexiletine PR will be started as 167 mg once a day (QD) treatment regimen. The dose will be titrated up at Week 1 to 333 mg and at Week 2 to a maximum dose of 500 mg QD depending on tolerability. If unable to tolerate the escalated dose, the dose will be reduced by one dose step during the titration period of the study to a maximum tolerated dose. Study drug should be taken with food at approximately the same time of the day every day, preferably in the morning (See Section 7 for further details on reconstitution and dosing titration). Safety assessments include patient- and physician-reported adverse events, standard clinical laboratory evaluations, physical examinations, and vital signs. In addition, ECG, Holter monitors, and echocardiogram assessments will be collected to assess cardiac safety during the study.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

176

Conditions

Myotonic Dystrophy

Interventions

Mexiletine granules for prolonged-release oral suspensionDRUG

Mexiletine PR

Eligibility

Sex: ALLMin age: 16 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. DM1 or DM2 diagnosis confirmed genetically; 2. 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); 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 ≥16 years of age; 5. Body Mass Index (BMI) of 18.5 kg/m2 to 30 kg/m2, and weight ≥45 kg; 6. 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; 7. No significant cardiac abnormalities as determined by a cardiologist's assessment; 8. Have sufficient finger flexor strength to grasp the handle of the dynamometer used to measure myotonia; 9. 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 medical condition (other thanDM1/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) on Day 1 (alanine transaminase (ALT)/aspartate transaminase (AST), gamma-glutamyl transferase (GGT)) and/or any abnormal chemistry, hematology or urine lab considered clinically significant by investigator; 9. 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. 10. 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; 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 or 5 half-lives of the investigational medicinal product, whichever is longer (with the exception of participation in the previous MEX-DM-302 study); 14. Wheelchair-bound or bed-ridden; 15. Any cardiac safety associated condition including any of the following criteria detected by 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

Locations (6)

Laboratory for Muscle Diseases and Neuropathies

Leuven, Belgium

Aarhus University Hospital

Aarhus, Denmark

Ludug-Maximilians University

München, Germany

Azienda Ospedaliera Universitaria Policlinico Tor Vergata

Rome, Italy

Outcomes

Primary Outcomes

To assess the long-term 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) who have completed MEX-DM-302 study.

Handgrip relaxation time in DM1 patients by mean change in baseline of handgrip relaxation time (seconds) after maximal voluntary isometric contraction (MVIC)

Time frame: 78 weeks

Secondary Outcomes

To assess the long-term 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) who have completed the MEX-DM-302 study

Number and frequency of AEs/SAEs throughout the study while on treatment

Time frame: 78 weeks

Mean change in VAS

Score for muscle stiffness (myotonia severity) as self-reported by patients on a Visual Analog Scale (VAS)

Time frame: 78 weeks

Mean change in MBS scores

Mean change in Myotonia Behavior Scale (MBS) scores on a scale of 0 (no stiffness) to 5 (incapacitating stiffness)

Time frame: 78 weeks

Mean change in health-related quality of life

Mean change in health-related quality of life (measured by INQoL)

Time frame: 78 weeks

Mean change in DM1-Activ-c scale (DM1 patients only)

Mean change in measure of activity and social participation (measured by a Rasch-built scale with a 0-100 interval range)

Time frame: 78 weeks

Mean change in time to perform the 10-meter Walk Test

Data from ClinicalTrials.gov

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University Hospital of Madrid

Madrid, Spain

University College Hospital

London, United Kingdom

Mean change in time (seconds) to perform the 10-meter Walk Test (10mWT)

Time frame: 78 weeks

Mean change in handgrip relaxation time

Mean change in maximal voluntary isometric contraction (MVIC) and relaxation time by Video-recording of Hand Opening Time (VHOT) functional evaluation

Time frame: 78 weeks

Mean change in time to perform Timed-up and go (TUG) test

Mean change in time (seconds) to perform Timed-up and go (TUG) test

Time frame: 78 weeks

Mean change in health-related quality of life measured by EQ-5D

Mean change in health-related quality of life measured by EQ-5D (5-point scale)

Time frame: 78 weeks

Mean change in Myotonic Dystrophy Health Index (MDHI) score (DM1 patients)

Mean change in Myotonic Dystrophy Health Index (MDHI) score (DM1 patients) as measured by patient's perceived health

Time frame: 78 weeks

Mean change in Myotonic Dystrophy 2 Health Index (MD2HI) score (DM2 patients)

Mean change in Myotonic Dystrophy 2 Health Index (MDHI) score (DM2 patients) as measured by patient's perceived health

Time frame: 78 weeks

Assess the long-term safety of mexiletine PR by changes in ECG

Mean change in ECG (PR, QRS, and QTc intervals in units of milliseconds \[ms\]) from baseline

Time frame: 78 weeks

Assess the long-term safety of mexiletine PR by changes in ECG (HR)

Mean change in ECG (HR in units of beats per minute) from baseline

Time frame: 78 weeks

Assess the long-term safety of mexiletine PR by AEs

Incidence of treatment emergent adverse events (TEAEs), treatment-related TEAEs, serious AEs, and patient discontinuation rate

Time frame: 78 weeks

Assess the long-term safety of mexiletine PR by standard clinical laboratory evaluations (hematology measured in units of μL [microliters]) from change in baseline

Assess the long-term safety of mexiletine PR by standard clinical laboratory evaluations as measured by hematology parameters in units of μL: white blood cell (WBC) with differential (absolute count), red blood cells (RBC), platelet count, and red blood cell indicies.

Time frame: 78 weeks

Assess the long-term safety of mexiletine PR by standard clinical laboratory evaluations (hematology measured in units of % [percentage]) from change in baseline

Assess the long-term safety of mexiletine PR by standard clinical laboratory evaluations as measured by hematology parameters in units of %: white blood cell (WBC) and differential (percentage) and hematocrit.

Time frame: 78 weeks

Assess the long-term safety of mexiletine PR by standard clinical laboratory evaluations (hematology measured in g/dL [units of grams per deciliter]) from change in baseline

Assess the long-term safety of mexiletine PR by standard clinical laboratory evaluations as measured by hematology parameters in units of g/dL: hemoglobin.

Time frame: 78 weeks

Assess the long-term safety of mexiletine PR by standard clinical laboratory evaluations (chemistry measured in units of mmol/L) from change in baseline

Assess the long-term safety of mexiletine PR by standard clinical laboratory evaluations as measured by chemistry parameters in units of mmol/L: chloride, carbon dioxide, potassium, and sodium

Time frame: 78 weeks

Assess the long-term safety of mexiletine PR by standard clinical laboratory evaluations (chemistry measured in units of U/L) from change in baseline

Assess the long-term safety of mexiletine PR by standard clinical laboratory evaluations as measured by chemistry parameters in units of U/L: alkaline phosphatase, aspartate aminotransferase (AST), aspartate transaminase (ALT), gamma-glutamyl transferase (GGT), and creatine phosphokinase.

Time frame: 78 weeks

Assess the long-term safety of mexiletine PR by standard clinical laboratory evaluations (chemistry measured in units of g/dL) from change in baseline

Assess the long-term safety of mexiletine PR by standard clinical laboratory evaluations as measured by chemistry parameters in units of g/dL: albumin and total protein.

Time frame: 78 weeks

Assess the long-term safety of mexiletine PR by standard clinical laboratory evaluations (chemistry measured in units of mg/dL) from change in baseline

Assess the long-term safety of mexiletine PR by standard clinical laboratory evaluations as measured by chemistry parameters in units of mg/dL: blood urea nitrogen (BUN), calcium, creatinine (eGFR), glucose, total bilirubin, and magnesium.

Time frame: 78 weeks

Assess the long-term safety of mexiletine PR by standard clinical laboratory evaluations (urinalysis) from change in baseline

Assess the long-term safety of mexiletine PR by standard clinical laboratory evaluations as measured by urinalysis parameters (measured as normal or abnormal): appearance, specific gravity, pH, protein, glucose, ketones, blood, leukocyte esterase, nitrite, bilirubin, urobilinogen, and microscopic examination.

Time frame: 78 weeks

Assess the long-term safety of mexiletine PR by vital signs (pulse)

Assess the long-term safety of mexiletine PR by vital signs (pulse in units of bpm \[beats per minute\]) from change in baseline

Time frame: 78 weeks

Assess the long-term safety of mexiletine PR by vital signs (body temperature)

Assess the long-term safety of mexiletine PR by vital signs (body temperature in units of Fahrenheit or Celsius) from change in baseline

Time frame: 78 weeks

Assess the long-term safety of mexiletine PR by vital signs (blood pressure)

Assess the long-term safety of mexiletine PR by vital signs (blood pressure \[diastolic and systolic\] in units of mmHg \[millimeters of mercury\]) from change in baseline

Time frame: 78 weeks

Assess the long-term safety of mexiletine PR by vital signs (respiration)

Assess the long-term safety of mexiletine PR by vital signs (respiration in units of breaths per minute) from change in baseline

Time frame: 78 weeks

Assess the long-term safety of mexiletine PR by physical examinations

Assess the long-term safety of mexiletine PR by change in baseline from physical examinations (normal or abnormal) in the following regions and systems: general appearance, head and neck, heart, lung, abdomen, chest and back, upper extremities, lower extremities, neurological, and dermatological.

Time frame: 78 weeks