The Experimental Treatment of Bulbar Dysfunction in Amyotrophic Lateral Sclerosis (ALS)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 90
- 试验地点
- 7
- 主要终点
- Bulbar Function Scale (CNS-BFS) Sialorrhea Score
研究概览
简要总结
The purpose of this study is to determine whether Nuedexta is effective in the treatment of symptoms (impaired speech, swallowing, and saliva control)associated with Amyotrophic Lateral Sclerosis (ALS).
详细描述
Muscle weakness, the cardinal feature of ALS, leads to progressive loss of motor function affecting the limbs, tongue, respiratory and pharyngeal muscles. Symptomatic treatments such as the placement of a feeding tube, can compensate for the inability to swallow. Riluzole, the only approved treatment for ALS, may slow disease progression but no treatment is curative and none have improved function.
Unexpectedly, Nuedexta®, approved for the treatment of labile emotionality that occurs in association with ALS and other neurological disorders, has been observed to improve bulbar function, primarily speech and swallowing, in a number of neurological disorders, including ALS. The basis for this is conjectural but likely due to a direct effect of the drug on motor neurons in the part of the brain that controls speech and swallowing. The same part of the brain appears to modulate the expression of emotions and interestingly the site of action of the drug is the same as a site that has been implicated in a juvenile form of ALS.
This is a multicenter, randomized double-blind, placebo controlled, cross over study evaluating the palliative effect of Nuedexta® on bulbar dysfunction. It is expected that approximately 60 ALS patients from 7 clinical centers in the US will be enrolled.
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
- Double (Participant, Investigator)
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
- •ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by revised El Escorial criteria
- •Age 18 years or older
- •Exhibits bulbar dysfunction manifested by dysarthria and/or dysphagia, according to PI judgment, exhibits a score of 55 or above on the CNS-Bulbar Function Scale
- •Capable of providing informed consent and following trial procedures
- •Geographic accessibility to the site
- •Women must not be able to become pregnant for the duration of the study and must be willing to be on two contraceptive therapies
- •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 PI judgment
- •Subjects must not have taken riluzole for at least 30 days or be on a 50mg BID dose of riluzole for at least 30 days prior to randomization (subjects how have never taken riluzole are permitted in the study)
- •Subjects taking anti-sialorrhea medication(s) must be on a stable dose for at least 30 days prior to randomization (anti-sialorrhea naïve subjects are permitted in the study)
- •Must be able to safely swallow at least 30 milliliters (mLs) of water for the water swallowing test
排除标准
- •Prior use of Nuedexta®
- •Current use of dextromethorphan, quinidine, quinine, mefloquine or opioids
- •History of quinidine, quinine, or mefloquine-induced thrombocytopenia, hepatitis, or other hypersensitivity reactions
- •History of known sensitivity or intolerability to dextromethorphan
- •Use of an mono amine oxidase inhibitor (MAOI) or within 14 days of stopping an MAOI
- •Prolonged QT interval, congenital long QT syndrome, history suggestive of torsades de pointes, or heart failure
- •Complete atrioventricular (AV) block without implanted pacemaker, or subjects at high risk of complete AV block
- •Concomitant use with drugs that both prolong QT interval and are metabolized by cytochrome P 2D6 (CYP2D6) (i.e., thioridazine or pimozide)
- •Exposure to any other experimental agent (off-label use or investigational) within 30 days prior to Baseline Visit
- •Invasive ventilator dependence, such as tracheostomy
- •Any history of either substance abuse within the past year, unstable psychiatric disease, cognitive impairment, or dementia, according to PI judgment
- •Placement and/or usage of feeding tube
- •Pregnant women or women currently breastfeeding
- •Unable to turn diaphragm pacing device off during swallowing tests
- •Salivatory Botox within 90 days (3 months) of screening
- •Salivatory radiation within 180 days (6 months) of screening
研究组 & 干预措施
Nuedexta then Matching Placebo
Subjects in this arm will receive treatment with Nuedexta first for 28 days (±3 days) and then crossed over to receive treatment with matching placebo for 28 days (±3 days).
干预措施: Nuedexta (Drug)
Nuedexta then Matching Placebo
Subjects in this arm will receive treatment with Nuedexta first for 28 days (±3 days) and then crossed over to receive treatment with matching placebo for 28 days (±3 days).
干预措施: Matching Placebo (Drug)
Matching Placebo then Nuedexta
Subjects in this arm will receive treatment with matching placebo first for 28 days (±3 days) and then crossed over to receive treatment with Nuedexta for 28 days (±3 days).
干预措施: Nuedexta (Drug)
Matching Placebo then Nuedexta
Subjects in this arm will receive treatment with matching placebo first for 28 days (±3 days) and then crossed over to receive treatment with Nuedexta for 28 days (±3 days).
干预措施: Matching Placebo (Drug)
结局指标
主要结局
Bulbar Function Scale (CNS-BFS) Sialorrhea Score
时间窗: Average between Screening Visit to Visit 3
The Center for Neurologic Study-Bulbar Function Scale (CNS-BFS) is a 21-item self report scale that assesses three domains of bulbar function: speech, swallowing and salivation. Scores for each question range from 1 (does not apply) to 5 (applies most of the time). The higher the score, the worse the salivation (sialorrhea). There are 7 salivation (sialorrhea) questions, with a score range of 7 to 35.
Bulbar Function Scale (CNS-BFS) Total Score
时间窗: Average between Screening Visit to Visit 3
The Center for Neurologic Study-Bulbar Function Scale (CNS-BFS) is a 21-item self report scale that assesses three domains of bulbar function: speech, swallowing and salivation. Scores for each question range from 1 (does not apply) to 5 (applies most of the time). The higher the score, the worse the speech, swallowing and salivation (sialorrhea). \[Range of score: 21-105\] The scale was modeled on the Center for Neurologic Study Emotional Lability Scale (CNS-LS) that has been a robust endpoint in four clinical trials. The scale was validated in a large population of ALS patients (n=122) and detects impaired bulbar function at a sensitivity of 90% and a specificity of 0.97%. Test re-test correlation was 0.92% at six-months (n=53).
Bulbar Function Scale (CNS-BFS) Speech Score
时间窗: Average between Screening Visit to Visit 3
The Center for Neurologic Study-Bulbar Function Scale (CNS-BFS) is a 21-item self report scale that assesses three domains of bulbar function: speech, swallowing and salivation. Scores for each question range from 1 (does not apply) to 5 (applies most of the time). The higher the score, the worse the speech. There are 7 speech questions, with a score range of 7 to 35.
Bulbar Function Scale (CNS-BFS) Swallowing Score
时间窗: Average between Screening Visit to Visit 3
The Center for Neurologic Study-Bulbar Function Scale (CNS-BFS) is a 21-item self report scale that assesses three domains of bulbar function: speech, swallowing and salivation. Scores for each question range from 1 (does not apply) to 5 (applies most of the time). The higher the score, the worse the swallowing. There are 7 swallowing questions, with a score range of 7 to 35.
次要结局
- ALS Functional Rating Scale- Revised (ALSFRS-R) Total Score(Average between Screening Visit to Visit 3)
- Ashworth Spasticity Scale Score - Right Arm(Average between Baseline Visit to Visit 3)
- Visual Analog Scale - Speech Scores(Average between Baseline Visit to Visit 3)
- Average Water Swallowing Test (WST)(Average between Baseline Visit to Visit 3)
- Ashworth Spasticity Scale Score - Left Leg(Average between Baseline Visit to Visit 3)
- Center for Neurologic Study - Lability Scale (CNS-LS) Total Score(Average between Screening Visit to Visit 3)
- Timed Reading of Test Paragraph Result(Average between Baseline Visit to Visit 3)
- Average Solids Swallowing Test(Average between Baseline Visit to Visit 3)
- Ashworth Spasticity Scale Score - Right Leg(Average between Baseline Visit to Visit 3)
- Visual Analog Scale - Swallowing Score(Average between Baseline Visit to Visit 3)
- Visual Analog Scale - Salivation (Sialorrhea) Score(Average between Baseline Visit to Visit 3)
- Ashworth Spasticity Scale Score - Left Arm(Average between Baseline Visit to Visit 3)
研究者
Richard A. Smith, MD
Director
Center for Neurologic Study, La Jolla, California,