A Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Assess the Safety and Efficacy and to Determine the Pharmacokinetics of Two Doses of AVP-923 (Dextromethorphan/Quinidine) in the Treatment of Pseudobulbar Affect (PBA) in Patients With Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 326
- 试验地点
- 62
- 主要终点
- PBA Episode Rate Ratio (Post/Pre), Regression Adjusted
研究概览
简要总结
Objectives of the study are to evaluate the safety, tolerability, and efficacy of two different doses of AVP-923 (capsules containing either 30 mg of dextromethorphan hydrobromide and 10 mg of quinidine sulfate [AVP-923-30] or 20 mg of dextromethorphan hydrobromide and 10 mg of quinidine sulfate [AVP-923-20]) when compared to placebo, for the treatment of PBA in a population of patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS) over a 12-week period. An additional objective is to determine the pharmacokinetic parameters of the two different doses of AVP-923 in a subset of the study population.
Pseudobulbar Affect (PBA) is a condition characterized by involuntary, sudden and frequent episodes of laughing and/or crying out of proportion or incongruous to the underlying emotion of happiness or sadness Other terms used to describe this condition include emotional lability, emotionalism, emotional incontinence, emotional discontrol, excessive emotionalism, and pathological laughing and crying. The outbursts can occur spontaneously or in response to provocative stimuli such as questions or events.
A body of evidence suggests that PBA can be modulated through pharmacologic intervention.
Dextromethorphan (DM) is a low-affinity uncompetitive antagonist of the N-Methyl-D-aspartate (NMDA) receptor, reducing the level of excitatory activity. DM also acts at the phencyclidine-binding site, which is part of the NMDA receptor complex. DM is a sigma receptor agonist, suppressing the release of excitatory neurotransmitters.
Quinidine (Q) is a known potent inhibitor of cytochrome P450 2D6 (CYP2D6), that decreases the metabolism of dextromethorphan and helps to achieve sustained and therapeutic levels of this drug.
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 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The patient has a diagnosis of Amyotrophic Lateral Sclerosis (according to El Escorial Criteria, WFN, 1998) and the time from diagnosis of ALS is not be longer than 30 months, or the patient has a diagnosis of multiple sclerosis or probable multiple sclerosis (according to McDonald criteria, 2001)
- •The patient has a clinical history and clinical relevant symptoms of Pseudobulbar Affect (PBA)
- •CNS-LS score at baseline is 13 or greater
排除标准
- •Patients with myasthenia gravis
- •Any personal history of complete heart block, QTc prolongation, or torsades de pointes
- •Any family history of congenital QT interval prolongation syndrome
- •Patients with known sensitivity to quinidine, dextromethorphan or opiate drugs (codeine, etc.)
研究组 & 干预措施
DM 30 mg/Q 10 mg
AVP-923-30/10 Capsules (30 mg dextromethorphan/10 mg quinidine)administered once daily for 1 week and then twice daily for 11 weeks
干预措施: dextromethorphan hydrobromide 30 mg and quinidine sulfate 10 mg (Drug)
DM 20 mg/ Q 10 mg
AVP-923-20/10 Capsules (20 mg dextromethorphan/10 mg quinidine)administered once daily for 1 week and then twice daily for 11 weeks
干预措施: dextromethorphan hydrobromide 20 mg and quinidine sulfate 10 mg (Drug)
Placebo
Placebo Capsules once daily for 1 week and then twice daily for an additional 11 weeks
干预措施: Placebo (Drug)
结局指标
主要结局
PBA Episode Rate Ratio (Post/Pre), Regression Adjusted
时间窗: Baseline to Day 84
Episodes were counted each day and recorded in a daily diary. The outcome measure is the ratio of the episode rate over the 84-day treatment period to the rate during the baseline period, adjusted for study site, and underlying disease using longitudinal negative binomial regression.
次要结局
- Mean Change From Baseline in CNS-LS Total Score by Visit(Baseline, Day 15, Day 29, Day 57, Day 84)
- Mean Change From Baseline to Day 84 in Neuropsychiatric Inventory (NPI-Q) Frequency and Severity Score (ITT Population)(Baseline to Day 84)
- Mean Change From Baseline at Day 84 in SF-36 (Short-Form) Health Survey Medical Outcome Score by Category(Baseline and Day 84)
- Mean Change From Baseline at Day 84 in Beck Depression Inventory (BDI-II) Total Score(Baseline and Day 84)
- Mean Change From Baseline to Day 84 in Neuropsychiatric Inventory (NPI-Q) Frequency and Severity Score (EE Population)(Baseline to Day 84)
- Mean Change From Baseline to Day 84 in Pain Rating Scale (PRS) of MS Subjects(Baseline, Day 15, Day 29, Day 57, Day 84)