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Study to Investigate the Efficacy and Safety of Mexiletine in Patients With Myotonic Dystrophy Type 1 and Type 2 (MIND)

Primary Purpose

Myotonic Dystrophy Type 1 and Type 2

Status
Withdrawn
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Mexiletine 167 mg
Placebo
Sponsored by
Lupin Ltd.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myotonic Dystrophy Type 1 and Type 2

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    Placebo Comparator

    Arm Label

    Mexiletine

    Placebo

    Arm Description

    Mexiletine 167 mg (equivalent to mexiletine HCl 200 mg)

    The placebo capsules contain the same ingredients as the active formulation with the exception of mexiletine

    Outcomes

    Primary Outcome Measures

    Assess the efficacy and safety of mexiletine for the symptomatic treatment of myotonia
    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).
    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)
    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
    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.
    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).
    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.
    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).
    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.
    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)

    Full Information

    First Posted
    January 5, 2021
    Last Updated
    October 4, 2023
    Sponsor
    Lupin Ltd.
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    1. Study Identification

    Unique Protocol Identification Number
    NCT04700046
    Brief Title
    Study to Investigate the Efficacy and Safety of Mexiletine in Patients With Myotonic Dystrophy Type 1 and Type 2
    Acronym
    MIND
    Official Title
    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]
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    October 2023
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    Assessing novel alternative study designs and regulatory pathways
    Study Start Date
    August 6, 2023 (Anticipated)
    Primary Completion Date
    May 31, 2024 (Anticipated)
    Study Completion Date
    July 12, 2024 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Lupin Ltd.

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. 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]
    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Myotonic Dystrophy Type 1 and Type 2

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantInvestigatorOutcomes Assessor
    Allocation
    Randomized
    Enrollment
    0 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Mexiletine
    Arm Type
    Active Comparator
    Arm Description
    Mexiletine 167 mg (equivalent to mexiletine HCl 200 mg)
    Arm Title
    Placebo
    Arm Type
    Placebo Comparator
    Arm Description
    The placebo capsules contain the same ingredients as the active formulation with the exception of mexiletine
    Intervention Type
    Drug
    Intervention Name(s)
    Mexiletine 167 mg
    Intervention Description
    Mexiletine 167 mg (equivalent to mexiletine HCl 200 mg) immediate release, oral capsules.
    Intervention Type
    Drug
    Intervention Name(s)
    Placebo
    Intervention Description
    The placebo capsules contain the same ingredients as the active formulation with the exception of mexiletine
    Primary Outcome Measure Information:
    Title
    Assess the efficacy and safety of mexiletine for the symptomatic treatment of myotonia
    Description
    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%.
    Time Frame
    6 months
    Secondary Outcome Measure Information:
    Title
    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).
    Description
    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).
    Time Frame
    Day 1 (pre-dose), Week 14, and Week 26 (or early discontinuation)
    Title
    To assess the efficacy of mexiletine on patient-reported outcomes by Timed "Up & Go" (TUG)
    Description
    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.
    Time Frame
    6 months
    Title
    To assess the efficacy of mexiletine on patient-reported outcomes by Individualized Neuromuscular Quality of Life Questionnaire (INQoL) overall
    Description
    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)
    Time Frame
    Day 1 (pre-dose), Week 14, and Week 26 (or early discontinuation)
    Title
    To assess the efficacy of mexiletine on functional capacity outcome measures by Individualized Neuromuscular Quality of Life Questionnaire (INQoL) locking domain.
    Description
    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.
    Time Frame
    6 months
    Title
    To assess the efficacy of mexiletine on functional capacity outcome measures by Myotonia Behavior Scale (MBS).
    Description
    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)
    Time Frame
    Day 1 (pre-dose), Week 2, Week 6, Week 14, Week 18, and Week 26 (or early discontinuation)
    Title
    To assess the efficacy of mexiletine on functional capacity outcome measures by Visual Analog Scale (VAS) for myotonia.
    Description
    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)
    Time Frame
    6 months
    Title
    To assess the efficacy of mexiletine on functional capacity outcome measures by 10 meter Walk Test (10mWT).
    Description
    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.
    Time Frame
    6 months
    Title
    To assess the efficacy of mexiletine on functional capacity outcome measures by DM1-Active-c.
    Description
    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)
    Time Frame
    Day 1 (pre-dose), Week 14, and Week 26 (or early discontinuation)

    10. Eligibility

    Sex
    All
    Gender Based
    Yes
    Gender Eligibility Description
    Male or non-pregnant female ≥18 years of age
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: DM1 or DM2 diagnosis confirmed genetically; Ability to provide informed consent; 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 ≥18 years of age; 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; No significant cardiac abnormalities as determined by a cardiologist's assessment of the electrocardiogram (ECG) and echocardiogram; Capable of swallowing capsules; 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; 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%; 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 other medical condition (besides DM1/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 the investigator; 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) 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; Wheelchair-bound or bed-ridden; 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

    12. IPD Sharing Statement

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    Study to Investigate the Efficacy and Safety of Mexiletine in Patients With Myotonic Dystrophy Type 1 and Type 2

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