Effect of Mexiletine on Cortical Hyperexcitability in Sporadic Amyotrophic Lateral Sclerosis (SALS)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 20
- 试验地点
- 10
- 主要终点
- Change in Resting Motor Threshold
研究概览
简要总结
The purpose of this research study is to find out whether the drug mexiletine will be effective in lowering motor neuron electrical activity in the brains and nerves in the arms of people with ALS. The investigators will also determine if there are any signs that the drug may slow down the progression of ALS and reduce muscle cramps and muscle twitching. This will be determined through transcranial magnetic stimulation (TMS) and threshold tracking nerve conduction studies (TTNCS). In this trial, the participants will be taking either 300mg/day of mexiletine, 600mg/day of mexiletine, or placebo (non-active study drug).
详细描述
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting primarily motor neurons, for which treatment designed to slow or arrest progression remains lacking. Mexiletine is a use-dependent sodium channel blocker that has been FDA-approved for decades for the treatment of cardiac arrhythmias and more recently to treat neuropathic pain in diabetic polyneuropathy. Mexiletine has been shown also to be protective of neurons following spinal cord, head injury, and cerebral ischemia, largely by blocking excitotoxicity. Based on previous studies, mexiletine appears to penetrate into the central nervous system at concentrations sufficient to confer significant protection. Recent unpublished studies in the laboratory of Dr. Robert Brown at the University of Massachusetts have also demonstrated that mexiletine ingestion in mice genetically engineered to express high levels of mutant cytosolic copper-zinc superoxide dismutase-1 (SOD1) transgene prolongs survival in these animals. As mexiletine already has FDA-approval as an anti-arrhythmic agent, much is known about the pharmacology and safety of this drug in non-ALS patients. We anticipate that by excluding subjects with a known history of cardiac disease and with the known neuroprotectant properties of this medication, mexiletine is a good choice for further study in an ALS clinical trial.
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
- 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
- •Sporadic ALS diagnosed as possible, laboratory-supported probable, probable, or definite ALS as defined by revised El Escorial criteria.
- •Age 18 years or older.
- •Symptom onset of weakness or spasticity due to ALS ≤ 60 months prior to Screening Visit.
- •Slow vital capacity (SVC) measure ≥50% of predicted for gender, height, and age at the screening visit.
- •Must be able to swallow capsules throughout the course of the study, according to Site Investigator judgment.
- •Capable of providing informed consent and following trial procedures.
- •For TMS: a resting motor threshold defined as 50% of pulses eliciting a motor evoked potential (MEP) of amplitude ≥ 50 µV.
- •For TTNCS: median Compound Muscle Action Potential (CMAP) ≥ 1.5 mV.
- •Subjects must not have taken riluzole for at least 30 days or be on a stable dose of riluzole for at least 30 days prior to the Screening Visit and continue on the stable dose throughout the course of the study (riluzole-naïve subjects are permitted in the study).
- •Subjects must not have taken medication for muscle cramping such as cyclobenzaprine, baclofen, carisoprodol, or methocarbamol, for at least 30 days prior to screening or be on a stable dose for at least 60 days prior to screening.
- •Geographic accessibility to the site.
- •Women must not become pregnant for the duration of the study and must be willing to use two contraceptive therapies and have a negative pregnancy test throughout the course of the study.
- •Use of medications known to affect the neurophysiology measures in the study must be scheduled, not as needed (pro re nata, PRN). A subject must have been on a fixed dose for 30 days prior to the Screening Visit, and there must be no reason to believe that a subsequent change would be necessary during the course of the study. These medications include: benzodiazepines, muscle relaxants, tricyclic antidepressants, selective serotonin reuptake inhibitors, non-selective serotonin reuptake inhibitors, hypnotics (including anti-histamines) and anti-cholinergics.
排除标准
- •Invasive ventilator dependence, such as tracheostomy.
- •Creatinine level greater than 1.5 mg/dL at screening.
- •Serum Glutamic-Oxaloacetic (SGOT/AST) / Serum Glutamic-Pyruvic (SGPT/ALT) greater than 3 times the upper limit of normal at screening.
- •History of known sensitivity or intolerability to mexiletine or lidocaine.
- •Any history of either substance abuse within the past year, unstable psychiatric disease, cognitive impairment, or dementia.
- •Clinically significant conduction abnormalities on electrocardiogram or a known history of cardiac arrhythmia.
- •Known history of epilepsy.
- •Known history of congestive heart failure (CHF) or history of myocardial infarction within the past 24 months.
- •Use of mexiletine for 30 days prior to Screening Visit.
- •Exposure to any other experimental agent (off-label use or investigational) including high dose creatine (>10 grams a day) within 30 days prior to Screening Visit.
- •Metal in the head and neck region, cardiac pacemaker or brain stimulator, cochlear implants, implanted infusion device or personal history of epilepsy.
- •Use of amiodarone, flecainide, duloxetine, tizanidine, or clozapine.
- •Pregnant women or women currently breastfeeding.
- •Placement of Diaphragm Pacing System (DPS) device < 60 days prior to Screening Visit.
- •Planned DPS device implantation during study participation
研究组 & 干预措施
Mexiletine, 300 milligrams
Mexiletine, 300 milligrams by mouth per day for 4 weeks.
干预措施: Mexiletine (Drug)
Mexiletine, 600 milligrams
Mexiletine, 600 milligrams by mouth per day for 4 weeks.
干预措施: Mexiletine (Drug)
Placebo
Placebo, by mouth per day for 4 weeks.
干预措施: Placebo (Drug)
结局指标
主要结局
Change in Resting Motor Threshold
时间窗: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 and from Week 4 to Week 8 reported
The resting motor threshold (RMT) assessed from single pulse transcranial magnetic stimulation (TMS) measurements made before treatment, after 4 weeks of treatment, and then again after a 4 week washout, was used as the primary pharmacodynamic marker of cortical hyperexcitability. RMT is the stimulus intensity required to produce and maintain a 0.2 mV peak-to-peak motor evoked potential of the abductor pollicis brevis muscle by TMS. A smaller RMT is thought to suggest greater neuronal excitability.
次要结局
- Effect on Subexcitability(Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported)
- Effect on Strength Duration Time Constant(Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported)
- Effect on Hyperpolarizing Threshold Electrotonus (90-100 ms)(Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported)
- Effect on Short-interval Intracortical Inhibition(Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported)
- Change in Motor Evoked Potential Amplitude(Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported)
- Effect on Cortical Silent Period(Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported)
- Effect on Depolarizing Threshold Electrotonus (90-100 ms)(Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported)
- Effect on Superexcitability(Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported)
- Effect on Frequency of Muscle Cramps(Accessed at Screening, Baseline, Week 4, and Week 8; comparisons of treatments at Weeks 3-4 reported)
- Effect on Frequency of Fasciculations (Muscle Twitching)(Accessed at Screening, Baseline, Week 4, and Week 8; comparisons of treatments at Weeks 3-4 reported)
研究者
Michael D Weiss
Professor, Department of Neurology
University of Washington