NCT06523400招募中3 期
A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Investigate the Efficacy and Safety of Once Daily Mexiletine PR During 26 Weeks of Treatment in Patients With Myotonic Dystrophy Type 1 and Type 2 (Phase 3)
适应症
干预措施
相关药物
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- Lupin Ltd.
- 入组人数
- 176
- 试验地点
- 7
- 主要终点
- To assess the 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).
研究概览
简要总结
A Randomized, Double-blind, Placebo-Controlled, Multi-Center Study to Investigate the Efficacy and Safety of Once Daily Mexiletine PR During 26 Weeks of Treatment in Patients with Myotonic Dystrophy Type 1 and Type 2 (HERCULES study)
详细描述
This is a multicenter, randomized, double-blind, parallel-group, placebo-controlled study intended to evaluate the efficacy and the safety of mexiletine PR 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 at screening, baseline, Weeks 1, 2, 14, and 26. Eligible patients will be randomized to mexiletine or placebo in a 1:1 ratio. Approximately 80 DM1 patients (40 active: 40 placebo) are planned to be enrolled. For the purpose of sample size re-estimation, an interim analysis will be conducted when a total of 40 patients in total complete/early terminate the study.
In addition, 16 DM2 patients are planned to be enrolled (sub-group - 8 active: 8 placebo).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 16 Years 至 —（Child, 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 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);
- •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 ≥16 years of age;
- •Body Mass Index (BMI) of 18.5 kg/m2 to 30 kg/m2, and weight ≥45 kg;
- •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;
- •No significant cardiac abnormalities as determined by a cardiologist's assessment;
- •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 using VHOT;
- •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 medical condition (other thanDM1/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 investigator;
- •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.
- •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) or 5 half-lives, whichever is longer such as metformin, 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 or 5 half-lives of the investigational medicinal product, whichever is longer;
- •Wheelchair-bound or bed-ridden;
- •Any cardiac safety associated condition including any of the following criteria detected by screening 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
研究组 & 干预措施
Placebo
Placebo Comparator
0 mg (matching sachet volumes to low, medium and high dose active drug)
干预措施: Placebo (Drug)
Mexiletine prolonged-release (PR)
Active Comparator
Mexiletine PR 167 mg (mexiletine HCl 200 mg) Mexiletine PR 333 mg (mexiletine HCl 400 mg) OR Mexiletine PR 500 mg (mexiletine HCl 600 mg)
干预措施: Mexiletine granules for prolonged-release oral suspension (Drug)
结局指标
主要结局
To assess the 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).
时间窗: 26 weeks
Handgrip relaxation time in DM1 patients by mean change in baseline of handgrip relaxation time (seconds) after maximal voluntary isometric contraction (MVIC)
次要结局
- Mean change in DM1-Activ-c scale (DM1 patients only)(26 weeks)
- Mean change in time to perform the 10-meter Walk Test(26 weeks)
- Mean change in handgrip relaxation time(26 weeks)
- Mean change in time to perform Timed-up and go (TUG) test(26 Weeks)
- Mean change in health-related quality of life measured by EQ-5D(26 weeks)
- Mean change in Myotonic Dystrophy Health Index (MDHI) score (DM1 patients)(26 weeks)
- Assess the safety of mexiletine PR by vital signs(26 weeks)
- Assess the safety of mexiletine PR by physical examinations(26 weeks)
- Mean change in health-related quality of life(26 weeks)
- Mean change in Myotonic Dystrophy 2 Health Index (MD2HI) score (DM2 patients)(26 weeks)
- Assess the safety of mexiletine PR by changes in ECG(26 weeks)
- Mean change in MBS scores(26 weeks)
- Mean change in VAS(26 weeks)
- Assess the safety of mexiletine PR by standard clinical laboratory evaluations(26 weeks)
- Assess the safety of mexiletine PR by AEs(26 weeks)
- To assess the pharmacokinetics of mexiletine PR(26 weeks)
- To assess the pharmacokinetics of mexiletine PR by AUC0-t(26 weeks)
- To assess the pharmacokinetics of mexiletine PR by Cmax(26 weeks)
- To assess the 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).(26 weeks)
研究者
研究点 (7)
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