Clinical trial NCT06549400: 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.
Official title: 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 the MEX-DM-302 Study (ATLAS Study)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Myotonic Dystrophy
Lead sponsor: Lupin Ltd.
Sponsor class: INDUSTRY
Collaborators: name: Lupin Atlantis Holdings S.A.
First posted: 2024-08-12
Enrollment: 176
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This is an open-label extension study intended to evaluate the continuous long-term (18 months) safety and efficacy of once daily mexiletine-prolonged release (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 parent study MEX-DM-302. The MEX-DM-302 is a multicenter, randomized, double-blind, parallel-group, placebocontrolled study intended to evaluate the safety and efficacy of mexiletine PR in patients with DM1 and DM2) for 6 months. At the completion of the final visit in Study MEX-DM-302 patients who continue 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 PR (no placebo).
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: 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.
timeFrame: 78 weeks
measure: 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
timeFrame: 78 weeks
Secondary outcomes:
measure: Mean change in VAS
timeFrame: 78 weeks
measure: Mean change in MBS scores
timeFrame: 78 weeks
measure: Mean change in health-related quality of life
timeFrame: 78 weeks
measure: Mean change in DM1-Activ-c scale (DM1 patients only)
timeFrame: 78 weeks
measure: Mean change in time to perform the 10-meter Walk Test
timeFrame: 78 weeks
measure: Mean change in handgrip relaxation time
timeFrame: 78 weeks
measure: Mean change in time to perform Timed-up and go (TUG) test
timeFrame: 78 weeks
measure: Mean change in health-related quality of life measured by EQ-5D
timeFrame: 78 weeks
measure: Mean change in Myotonic Dystrophy Health Index (MDHI) score (DM1 patients)
timeFrame: 78 weeks
measure: Mean change in Myotonic Dystrophy 2 Health Index (MD2HI) score (DM2 patients)
timeFrame: 78 weeks
measure: Assess the long-term safety of mexiletine PR by changes in ECG
timeFrame: 78 weeks
measure: Assess the long-term safety of mexiletine PR by changes in ECG (HR)
timeFrame: 78 weeks
measure: Assess the long-term safety of mexiletine PR by AEs
timeFrame: 78 weeks
measure: Assess the long-term safety of mexiletine PR by standard clinical laboratory evaluations (hematology measured in units of μL [microliters]) from change in baseline
timeFrame: 78 weeks
measure: Assess the long-term safety of mexiletine PR by standard clinical laboratory evaluations (hematology measured in units of % [percentage]) from change in baseline
timeFrame: 78 weeks
measure: 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
timeFrame: 78 weeks
measure: Assess the long-term safety of mexiletine PR by standard clinical laboratory evaluations (chemistry measured in units of mmol/L) from change in baseline
timeFrame: 78 weeks
measure: Assess the long-term safety of mexiletine PR by standard clinical laboratory evaluations (chemistry measured in units of U/L) from change in baseline
timeFrame: 78 weeks
measure: Assess the long-term safety of mexiletine PR by standard clinical laboratory evaluations (chemistry measured in units of g/dL) from change in baseline
timeFrame: 78 weeks
measure: Assess the long-term safety of mexiletine PR by standard clinical laboratory evaluations (chemistry measured in units of mg/dL) from change in baseline
timeFrame: 78 weeks
measure: Assess the long-term safety of mexiletine PR by standard clinical laboratory evaluations (urinalysis) from change in baseline
timeFrame: 78 weeks
measure: Assess the long-term safety of mexiletine PR by vital signs (pulse)
timeFrame: 78 weeks
measure: Assess the long-term safety of mexiletine PR by vital signs (body temperature)
timeFrame: 78 weeks
measure: Assess the long-term safety of mexiletine PR by vital signs (blood pressure)
timeFrame: 78 weeks
measure: Assess the long-term safety of mexiletine PR by vital signs (respiration)
timeFrame: 78 weeks
measure: Assess the long-term safety of mexiletine PR by physical examinations
timeFrame: 78 weeks
Other outcomes:
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