An Open-label, Non-Comparative Study to Evaluate the Steady-State Pharmacokinetics, Safety, and Efficacy of Mexiletine in Adolescents and Children With Myotonic Disorders
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- Lupin Ltd.
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Number and frequency of adverse events (AEs)/serious adverse events (SAEs)
研究概览
简要总结
This is an open-label, multi-centre, single arm, interventional study to describe the steady-state PK, safety, and efficacy of mexiletine in paediatric patients (6 to <18 years of age) with myotonic disorders.
详细描述
This is an open-label, multi-centre, single arm, interventional study to describe the steady-state PK, safety, and efficacy of mexiletine in paediatric patients (6 to <18 years of age) with myotonic disorders.
Patients who meet the eligibility criteria will be enrolled stepwise, sequentially in 2 cohorts by age groups.
Cohort 1 - Adolescents aged 12 to <18 years, will be enrolled first. If no safety concerns are observed (based on data evaluation by the Data Safety Monitoring Board [DSMB]), and the dose for the age group 6 to <12 years is confirmed by PK model, enrolment for Cohort 2 will begin.
Cohort 2 - Children aged 6 to <12 years, will be enrolled. The overall treatment duration for each cohort will be approximately 56 days (8 weeks): a dose titration phase of 4 weeks and the maintenance phase of 4 weeks. The overall study duration would be approximately 22 months.
Dose titration phase: In this phase, patients will receive mexiletine starting at an age appropriate dose (as evaluated by the investigator and based on body weight) at a frequency of once a day. Dose will be up-titrated every 14 days based on tolerability of mexiletine up to a maximum of three-times a day as assessed by investigator.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female patients aged ≥ 6 and < 18 years who are able to comply with the study requirements
- •A genetically confirmed diagnosis of NDM or DM (DM1or DM2)
- •Presence of clinical symptoms of myotonia (hand grip myotonia, myotonia in the leg muscles, any other myotonia symptoms)
- •No significant cardiac abnormalities as determined by a cardiologist's assessment of the ECG and echocardiogram performed within 3 months prior to enrolment in the study. (If not done within 3 months before trial, electrocardiogram (ECG) and echocardiogram assessments will be performed at screening)
- •No history of any significant liver disorder
- •Patients receiving mexiletine treatment agree to stop treatment at least 7 days prior to initiation of treatment with Namuscla
- •Patients receiving other antimyotonic treatment agree to stop treatment for at least 7 times the half-life of respective drug
- •Laboratory investigations for haematology, biochemistry, and urinalysis at screening are within the normal range, or showing no clinically relevant abnormal values, as judged by the Investigator.
- •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 or are practicing abstinence.
- •Patients able to provide assent to study participation and a parent or legal guardian to sign the written informed consent prior to study entry.
排除标准
- •Any contra-indication to mexiletine as listed in the Namuscla Summary of Product Characteristics (SmPC):
- •Hypersensitivity to the active substance, or to any of the excipients
- •Hypersensitivity to any local anaesthetic
- •Ventricular tachyarrhythmia
- •Complete heart block (i.e., third-degree atrioventricular block) or any heart block susceptible to evolve to complete heart block (first-degree atrioventricular block with markedly prolonged PR interval (≥ 200 ms) and/or wide QRS complex (≥ 120 ms), second-degree atrioventricular block, bundle branch block, bifascicular and trifascicular block),
- •QT interval > 450ms
- •Myocardial infarction (acute or past), or abnormal Q-waves
- •Symptomatic coronary artery disease
- •Heart failure with ejection fraction <50%
- •Atrial tachyarrhythmia, fibrillation or flutter
- •Sinus node dysfunction (including sinus rate < 50 bpm)
- •Co-administration with medicinal products inducing torsades de pointes (class Ia, Ic, III antiarrhythmics): Co-administration of mexiletine and antiarrhythmics inducing torsades de pointesclass Ia: quinidine, procainamide, disopyramide, ajmaline; class Ic: encainide, flecainide, propafenone, moricizine; class III: amiodarone, sotalol, ibutilide, dofetilide, dronedarone, vernakalant) increases the risk of potentially lethal torsades de pointes.
- •Co-administration with medicinal products with narrow therapeutic index
- •Any other neurological or psychiatric condition that might affect the study assessments
- •Any clinically significant illness, laboratory findings, ECG, or other clinical symptoms, which in the opinion of the Investigator could affect the patient's optimal participation in the study
- •Strong inducer or inhibitor of CYP2D6 or CYP1A2 within 7 days prior to study drug administration
- •Any concurrent illness, or medications which could affect the muscle function
- •Seizure disorder, diabetes mellitus requiring treatment by insulin
- •Pregnant or breastfeeding
- •Concurrent participation in any other clinical trial.
研究组 & 干预措施
Cohort 1 and 2
7 patients aged 12 to < 18 years , inclusive in cohort-1 7 patients aged 6 to < 12 years, inclusive in cohort-2
干预措施: Mexiletine (Drug)
结局指标
主要结局
Number and frequency of adverse events (AEs)/serious adverse events (SAEs)
时间窗: Baseline to Day 56
Number and frequency of adverse events (AEs)/serious adverse events (SAEs), throughout the study while on treatment with Namuscla
Efficacy of Namuscla treatment on the clinical outcomes(change from baseline to Days 14, 28, 42 and 56, respectively) based on the following functional evaluation
时间窗: Baseline to Day 56
The score of handgrip myotonia as quantitatively measured using a commercially available grip dynamometer and computerised capture system. In standardised conditions (i.e. in a room at controlled temperature, after a definite period of rest), maximum voluntary contractions following forced right hand grip will be recorded and the time to relax from 90% to 5% of maximal force will be determined using automated analysis software
Incidence of adverse events of special interest (AESI)
时间窗: Baseline to Day 56
Incidence of adverse events of special interest (AESI)
Changes in ECG assessments from baseline
时间窗: Baseline to Day 56
On resting ECG any alteration will be noted: * Mild ECG abnormalities: PR interval ≥200 ms and QRS duration ≥100 ms * Severe ECG abnormalities: PR interval ≥240 ms, QRS duration ≥120 ms, second or third degree AV block and a rhythm other than sinus
Efficacy of Namuscla treatment on the clinical outcomes based on the following functional evaluation mean change in Visual Analogue Scale (VAS) for muscle stiffness.
时间窗: Baseline to Day 56
Mean change in Visual Analogue Scale (VAS) for muscle stiffness. The VAS is constructed as an absolute measure, with a 10 cm straight horizontal line having the endpoints "no stiffness at all" and "stiffness as worst possible". The patient's responses will be scored on the line to the nearest millimetre (a 100-point scale). (myotonia severity).
次要结局
- Mean change in health-related quality-of-life as measured by the Paediatric Quality of Life (PedsQL) score(Baseline - Day 56)
- Clinical Global Impression (CGI) scores (efficacy and tolerability) evaluated by the patient(Baseline - Day 56)
- Acceptability of the capsule formulation with respect to the swallowability.(Baseline - Day 56)
- Palatability of alternative administration(Baseline - Day 56)
- Changes in clinical laboratory values from baseline to Day 56 for laboratory safety assessments - Changes in Magnesium values(Baseline - Day 56)
- Clinical myotonia assessment for mean change in time to open the eyes(Baseline - Day 56)
- Clinical myotonia assessment of clinical change in flexor myotonia(Baseline - Day 56)
- Mean change in VAS score for muscle pain, weakness and fatigue(Baseline - Day 56)
- Clinical myotonia assessment of mean change in time to perform Timed-up and go (TUG) test(Baseline - Day 56)
- Changes in clinical laboratory values for laboratory safety assessments - Potassium(Baseline - Day 56)
- Changes in clinical laboratory values from baseline to Day 56 for laboratory safety assessments - Changes in Sodium values(Baseline - Day 56)
- Mean change in Myotonia Behaviour Scale (MBS) scores(Baseline - Day 56)
- Changes in clinical laboratory values from baseline to Day 56 for laboratory safety assessments - Changes in Calcium values(Baseline - Day 56)
- Changes in clinical laboratory values from baseline to Day 56 for laboratory safety assessments - Changes in Chloride values(Baseline - Day 56)
- Mean change in Faces scale for muscle pain, weakness and fatigue(Baseline - Day 56)