MIND: Study to Investigate the Efficacy and Safety of Mexiletine in Patients With Myotonic Dystrophy Type 1 and Type 2
Study Details
Study Description
Brief Summary
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]
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Mexiletine Mexiletine 167 mg (equivalent to mexiletine HCl 200 mg) |
Drug: Mexiletine 167 mg
Mexiletine 167 mg (equivalent to mexiletine HCl 200 mg) immediate release, oral capsules.
|
| Placebo Comparator: Placebo The placebo capsules contain the same ingredients as the active formulation with the exception of mexiletine |
Drug: Placebo
The placebo capsules contain the same ingredients as the active formulation with the exception of mexiletine
|
Outcome Measures
Primary Outcome Measures
- Assess the efficacy and safety of mexiletine for the symptomatic treatment of myotonia [6 months]
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%.
Secondary Outcome Measures
- 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). [Day 1 (pre-dose), Week 14, and Week 26 (or early discontinuation)]
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).
- To assess the efficacy of mexiletine on patient-reported outcomes by Timed "Up & Go" (TUG) [6 months]
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.
- To assess the efficacy of mexiletine on patient-reported outcomes by Individualized Neuromuscular Quality of Life Questionnaire (INQoL) overall [Day 1 (pre-dose), Week 14, and Week 26 (or early discontinuation)]
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)
- To assess the efficacy of mexiletine on functional capacity outcome measures by Individualized Neuromuscular Quality of Life Questionnaire (INQoL) locking domain. [6 months]
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.
- To assess the efficacy of mexiletine on functional capacity outcome measures by Myotonia Behavior Scale (MBS). [Day 1 (pre-dose), Week 2, Week 6, Week 14, Week 18, and Week 26 (or early discontinuation)]
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)
- To assess the efficacy of mexiletine on functional capacity outcome measures by Visual Analog Scale (VAS) for myotonia. [6 months]
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)
- To assess the efficacy of mexiletine on functional capacity outcome measures by 10 meter Walk Test (10mWT). [6 months]
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.
- To assess the efficacy of mexiletine on functional capacity outcome measures by DM1-Active-c. [Day 1 (pre-dose), Week 14, and Week 26 (or early discontinuation)]
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)
Eligibility Criteria
Criteria
Inclusion Criteria:
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DM1 or DM2 diagnosis confirmed genetically;
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Ability to provide informed consent;
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Ability to understand the study requirements including intention to stay in the study until the end-of-study visit at 26 weeks of treatment;
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Male or non-pregnant female ≥18 years of age;
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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;
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No significant cardiac abnormalities as determined by a cardiologist's assessment of the electrocardiogram (ECG) and echocardiogram;
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Capable of swallowing capsules;
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Have sufficient finger flexor strength to grasp the handle of the dynamometer used to measure myotonia;
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Presence of clinical handgrip myotonia (delayed relaxation of grip of ≥ 3 seconds after maximum voluntary contraction) at screening;
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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%;
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Be able to walk independently 10 meters (cane, walker, orthoses allowed);
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DM1 patients only - Muscular impairment rating scale (MIRS) score of 2, 3, or 4.
Exclusion Criteria:
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Are pregnant or lactating;
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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;
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Severe renal impairment (glomerular filtration rate (GFR) < 30 mL/min);
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Medical conditions which could interfere with muscle function such as infections, trauma, fractures, or planned surgery;
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Medical conditions that could affect hand functioning including but not limited to rheumatoid arthritis, Dupuytren's contracture, hand deformity, etc.;
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Severe arthritis or other medical condition (besides DM1/DM2) that would significantly impact ambulation;
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High incidence of falls or fall-associated fractures (>5 falls during the past 12 months);
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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;
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Treatment with mexiletine within 4 weeks prior to baseline (Day 1);
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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;
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Use of any concomitant medications that could increase the cardiac risk;
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Known allergy to mexiletine or any local anesthetics;
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Participation in another interventional clinical study during the last 3 months;
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Wheelchair-bound or bed-ridden;
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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:
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PR interval ≥240 ms or QRS duration ≥120 ms on resting ECG
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Personal history of 3rd degree or 2nd degree type 2 atrioventricular block or sinus node dysfunction with pauses ≥3 seconds
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Personal history of sustained atrial fibrillation, flutter or tachycardia (duration >30 seconds)
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Personal history of non-sustained (ventricular triplets or more) or sustained ventricular tachycardia
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Myocardial infarction (acute or past) or coronary artery stenosis >50%
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New York Heart Association (NYHA) Class II to IV heart failure
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Left ventricular systolic dysfunction with ejection fraction <50%
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Sinus node dysfunction (including ECG sinus rate <50 beats per minute (BPM))
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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)
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Patients with implantable cardioverter defibrillators (ICDs) and pacemakers are excluded
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Lupin Ltd.
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- MEX-DM-301