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]
试验速览
- 阶段
- 3 期
- 状态
- 撤回
- 发起方
- Lupin Ltd.
- 主要终点
- Assess the efficacy and safety of mexiletine for the symptomatic treatment of myotonia
研究概览
简要总结
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]
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
Mexiletine
Mexiletine 167 mg (equivalent to mexiletine HCl 200 mg)
干预措施: Mexiletine 167 mg (Drug)
Placebo
The placebo capsules contain the same ingredients as the active formulation with the exception of mexiletine
干预措施: Placebo (Drug)
结局指标
主要结局
Assess the efficacy and safety of mexiletine for the symptomatic treatment of myotonia
时间窗: 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%.
次要结局
- 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))
- 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))
- 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))
- To assess the efficacy of mexiletine on patient-reported outcomes by Timed "Up & Go" (TUG)(6 months)
- 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))
- 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 Visual Analog Scale (VAS) for myotonia.(6 months)
- To assess the efficacy of mexiletine on functional capacity outcome measures by 10 meter Walk Test (10mWT).(6 months)