Combining N-of-1 Trials to Estimate Population Clinical and Cost-effectiveness of Drugs Using Bayesian Hierarchical Modeling. The Case of Mexiletine for Patients With Non- Dystrophic Myotonia.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Change in patient-reported Stiffness on the IVR
研究概览
简要总结
The main objective of this study is to explore whether multiple trials with individual patients (N-of-1 trials) can produce a reliable evidence base for coverage decisions on clinical and cost-effectiveness of drug treatment for patients with rare diseases. As a case study, we will study the clinical and cost-effectiveness of Mexiletine in patients with Non-Dystrophic myotonia. The results of this analysis will be compared with the results obtained from a recently published international, multi-centre, randomized, placebo-controlled trial of Mexiletine in patients with Non-Dystrophic Myotonia (clinicaltrials.gov Identifier: NCT00832000).
The secondary objective of this proposal is to assess whether mexiletine improves myotonia measured (both quantitatively and qualitative) in patients with non-dystrophic myotonia.
详细描述
Rationale: A current problem in the context of a coverage decision for the use of mexiletine for NDM patients is the lack of a sufficient evidence base. An innovative trial design could facilitate in establishing such an evidence base in a small group of rather heterogeneous patients. As more than 7000 rare diseases in Europe and the USA suffer from a similar lack of treatment evidence, more experience with this innovative trial design would be very helpful.
Study design: A double-blind, randomized and placebo-controlled combined N-of-1- trial using a Bayesian statistical approach.
Study population: Non-dystrophic myotonia (NDM) patients, at least 18 years old, with a genetically confirmed diagnosis.
Intervention: Each N-of-1 trial consists out of a minimum of one, and a maximum of 4 treatment sets, each comprising a 4-week period of active treatment (Mexiletine) and a 4-week period of treatment with placebo, in random order, with one week for wash-out in between. Within each mexiletine period, treatment dosage of mexiletine will be built up from 200 mg 1 time a day PO on the first day of the first week, to 200 mg 2 times a day on the second day of the first week, to the desired dosage of 200 mg 3 times a day PO on the third day of the first week and throughout the remaining days of the 4-week treatment period. A similar build-up scheme will be used within each placebo period.
Main study parameters/endpoints: The primary outcome measure for this study is a decrease in the most prominent clinical symptom: stiffness. Stiffness will be quantified by an Interactive Voice Response System (IVR) in which the patient will rate their mean daily IVR participant-assessed severity of stiffness on an ordinal scale (1-9). The secondary outcome measures will include changes in pain, weakness, and fatigue on IVR, Individual Neuromuscular Quality of Life (INQoL), the Short Form (36) Health Survey (SF-36) a patient-reported survey of patient health, blood plasma levels of mexiletine, clinical myotonia assessments, quantitative handgrip myotonia, biceps force test and needle-electromyography (EMG).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, 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
- •At least 18 years of age
- •Genetically confirmed diagnosis of NDMs
- •Participation in the "Genetical variability of the Non-dystrophic Myotonia" study of J. Trip or a new patient with genetically confirmed NDM.
排除标准
- •Inability or unwillingness to provide informed consent.
- •Other neurological conditions that might affect the assessment of the study measurements.
- •Genetic confirmed Myotonic Dystrophy type 1 (DM1) (CTG > 50 repeats), or Myotonic Dystrophy type 2 (DM2).
- •Patients with existing cardiac conduction defects, evidenced on ECG including but not limited to the following conditions: malignant arrhythmia or cardiac conduction disturbances (such as second degree AV block, third degree atrio-ventricular (AV) block, or prolonged QT interval >500 ms or QRS duration > 150 msec).
- •Current use of the following antiarrhythmic medication for a cardiac disorder:flecainide acetate, encainide, disopyramide, procainamide, quinidine, propafenone or mexiletine.
- •Women who are pregnant or lactating.
- •Patients currently on medications for myotonia such as phenytoin and flecainide acetate within 5 days of enrollment, carbamazepine and mexiletine within 3 days of enrollment, or propafenone, procainamide, disopyramide, quinidine and encainide within 2 days of enrollment.
- •Patients with renal or hepatic disease, heart failure, history of myocardial infarction, or seizure disorders.
研究组 & 干预措施
Placebo
Placebo tablets three times daily orally
干预措施: Mexiletine (Drug)
Placebo
Placebo tablets three times daily orally
干预措施: Placebo (Drug)
Mexiletine
Mexiletine 200mg three times daily orally
干预措施: Mexiletine (Drug)
Mexiletine
Mexiletine 200mg three times daily orally
干预措施: Placebo (Drug)
结局指标
主要结局
Change in patient-reported Stiffness on the IVR
时间窗: Weeks 3-4 of each period - up to 44 weeks.
Stiffness measured on a 1-9 scale, 1 being minimal, 9 the worst ever experienced. 0=no symptom reported. For analysis the average severity of stiffness for each participant will be calculated form daily calls made in weeks 3-4 of each period.
次要结局
- Change in Muscle relaxation times measured with quantitative grip myometry (Seconds)(Week 4 of each period - up to 44 weeks.)
- Change in Individualized Neuromuscular Quality of Life Scale - Summary Score(Week 4 of each period - up to 44 weeks.)
- Change in Short Form 36 - Physical Composite Score(Week 4 of each period - up to 44 weeks.)
- Change in Clinical myotonia bedside-tests (Seconds)(Week 4 of each period - up to 44 weeks.)
- Change in Graded Myotonia by Needle Electromyography(Week 4 of each period - up to 44 weeks.)
- Change in Mexiletine serum plasma concentration levels(Weeks 1 and 4 of each period - up to 44 weeks.)
- Change in Patient-reported Pain on the IVR(Weeks 3-4 of each period - up to 44 weeks.)
- Change in Patient-reported Tiredness on the IVR(Weeks 3-4 of each period - up to 44 weeks.)
- Change in Patient-reported Weakness on the IVR(Weeks 3-4 of each period - up to 44 weeks.)
- Change in Short Form 36 - Mental Composite Score(Week 4 of each period - up to 44 weeks.)