A Safety and Tolerability Study of Mexiletine in Patients With Sporadic Amyotrophic Lateral Sclerosis (SALS)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 75
- 试验地点
- 10
- 主要终点
- Percentage of Participants That Discontinued Study Drug
研究概览
简要总结
The purpose of this research is to find out if mexiletine is safe and effective in people with Amyotrophic Lateral Sclerosis (ALS). In this trial, participants will be taking either 300 milligrams per day of mexiletine, 900 milligrams per day of mexiletine or placebo (non-active study drug). The safety and efficacy of these doses will be compared to see if one dose is better than the other.
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 Recent unpublished studies in the laboratory of Dr.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 Amyotrophic Lateral Sclerosis (SALS) diagnosed as possible, laboratory-supported probable, probable, or definite ALS as defined by revised El Escorial criteria.
- •Age 18 years or older.
- •Disease duration ≤ 36 months from ALS symptom onset.
- •Capable of providing informed consent and following trial procedures.
- •Subjects must not have taken riluzole for at least 30 days or be on a 50 milligrams twice daily dose of riluzole for at least 60 days prior to randomization (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 randomization or be on a stable dose for at least 60 days prior to randomization.
- •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.
- •Slow vital capacity (SVC) measure greater than or equal to 50% of predicted for gender, height, and age at the screening visit.
- •Subjects medically able to undergo lumbar puncture (LP) as determined by the investigator (for example, no bleeding disorder, allergy to local anesthetics, a skin infection at or near the LP site, or evidence of high intracranial pressure).
- •Must be able to swallow capsules throughout the course of the study, according to Principal Investigator (PI) judgment.
- •Must have a caregiver assist with dispensing the study drug.
排除标准
- •Invasive ventilator dependence, such as tracheostomy.
- •Creatinine level greater than 1.5 milligram/deciliter.
- •Serum glutamic oxaloacetic transaminase or (aspartate transaminase) / serum glutamic pyruvic transaminase (alanine aminotransferase) 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 60 days prior to Baseline Visit.
- •Exposure to any other experimental agent (off-label use or investigational) including high dose creatine (greater than 10 grams a day) within 30 days prior to Baseline Visit.
- •Use of amiodarone, flecainide, duloxetine, tizanidine, or clozapine.
- •Pregnant women or women currently breastfeeding.
- •Placement of Diaphragm Pacing System (DPS) device less than 60 days prior to Baseline Visit.
- •Planned DPS device implantation after Baseline Visit.
研究组 & 干预措施
Mexiletine, 300 milligrams
Mexiletine, 300 milligrams by mouth per day for 12 weeks.
干预措施: Mexiletine (Drug)
Mexiletine, 900 milligrams
Mexiletine, 900 milligrams by mouth per day for 12 weeks.
干预措施: Mexiletine (Drug)
Placebo
Placebo, by mouth per day for 12 weeks.
干预措施: Placebo (Drug)
结局指标
主要结局
Percentage of Participants That Discontinued Study Drug
时间窗: Screening, Baseline Visit Pre-Dose and Post-Dose, Weeks 2, 6, and 12, and at the Final Safety Visit, if a subject discontinues study drug early. Adverse Events will be assessed via telephone Weeks 1, 10, and 16.
Information on adverse effects of mexiletine will be determined at each visit by direct questioning of the subjects, clinical examination, review of concomitant medications, vital signs and laboratory test results.
次要结局
- Trough Plasma Concentration (Cmin) of Mexiletine(Week 6 Visit (pre-dose, hours 1, 2, 3, and 6 post-dose on Week 6))
- Area Under the Concentration Time Curve (AUC) of Mexiletine in Plasma.(Week 6 Visit (up to 6 hours post dose))
- Maximal Pain Severity(Weeks 3-12, post titration of study medication)
- Mean Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12(Week 3-12, post titration of study medication)
- Peak Plasma Concentration (Cmax) of Mexiletine(Week 6 Visit (pre-dose, hours 1, 2, 3, and 6 post-dose on Week 6))
- Mean Pain Severity(Weeks 3-12, post titration of study medication)
- Mean Cerebrospinal Fluid (CSF)/Plasma Ratio(Week 6 Visit (up to 6 hours post dose))
- Mean Weekly Cramp Frequency(Week 3-12, post titration of study medication)
- Maximal Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12(Week 3-12, post titration of study medication)
- Cramp Frequency - Ratios for Comparisons of Doses for Weeks 3-12(Week 3-12, post titration of study medication)
研究者
Michael D Weiss
Associate Professor, Department of Neurology
University of Washington