NK1 Receptor Antagonism for Treatment of Anxiety and Craving in Anxious Alcohol Dependent Subjects During Early Abstinence
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 66
- 试验地点
- 1
- 主要终点
- Craving for Alcohol (Spontaneous)
研究概览
简要总结
This study will determine whether the experimental drug LY686017 can reduce a person's desire for alcohol. A brain chemical called Substance P acts at places in the brain called NK1 receptors. Substance P is released in response to stress and gives rise to behaviors that are thought to represent anxiety. LY686017 blocks Substance P from acting at the NK1 receptors.
People between 21 and 65 years of age who have been drinking on a regular basis for at least one month before entering the study, who meet the criteria for alcohol dependence and who have an elevated score on a general test of anxiety may be eligible for this study.
Participants are admitted to the NIH Clinical Center for 35 days. They participate in an alcohol treatment program in addition to the research study. After having been withdrawn from alcohol for at least 2 days, participants receive either 50 mg of LY686017 or placebo (an inactive substance that looks like the study drug) every morning for 28 days. In addition to drug treatment, they undergo the following procedures:
- Functional magnetic resonance imaging (fMRI): In the last week of the study, subjects undergo MRI to study the amount of blood going to brain structures thought to be involved in anxiety and craving. During the procedure, they look at pictures of faces exhibiting various emotions and pictures related to alcohol.
- Cue reactivity: At the beginning and towards the end of the study, subjects are asked to rate their alcohol craving and their anxiety level while they sniff and handle their favorite alcoholic beverage or water.
- Metyrapone test: During weeks 1 and 4 of the study, subjects are given metyrapone - a drug that interferes with the body's ability to make the stress hormone cortisol - to determine how LY686017 affects the body's hormonal response. The drop in cortisol from metyrapone administration causes the brain to release ACTH, a hormone that causes the adrenal gland to make cortisol.
- Trier test: In the last week of the study, subjects give a 5-minute speech to three people and are then asked to subtract numbers in their head. Then they are asked to rate their feelings and desire for alcohol on two rating scales. Blood is drawn from a saline lock at the beginning and end of the test to measure hormone levels.
- Rating scales: Subjects complete an Obsessive Drinking Scale weekly and an Alcohol Urge Questionnaire and Comprehensive Psychiatric Rating Scale twice a week.
- Blood tests: Blood samples are collected periodically to check blood chemistries, clotting time, and the amount of LY686017 in the blood.
详细描述
Background:
Alcoholism is a chronic relapsing disorder characterized by cycles of intoxication interspersed with phases of withdrawal and abstinence. Co-morbidity with depression and anxiety disorders is high. Even in absence of independent psychiatric co-morbidity, anxiety symptoms are almost invariably present during early as well as protracted abstinence, sensitized over repeated cycles of intoxication and withdrawal, and are correlated with craving for alcohol upon exposure to alcohol associated cues. This psychopathology is likely to maintain the dependent state since it has been shown that stress and negative affective states are major relapse triggering factors. Substance P, released in the amygdala in response to stress, acts at NK1 receptors as an important mediator of behavioral stress effects in experimental animals. Blockade of this receptor subtype represents a novel principle for anxiolytic like actions, which is well documented in animal models and has some supportive data in humans. Furthermore, decreased opiate reward following NK1 receptor inaction is indicated by the reports that deletion of the NK1 receptor decreases both conditioned place preference and self-administration of opiates, while a similar reduction of alcohol reward is suggested by preliminary data showing decreased voluntary intake of alcohol in NK1 null-mutants.
Aims:
The present study is aimed at providing an initial, exploratory evaluation of whether the NK1 receptor is a candidate target for treatment of alcohol dependence that would merit further clinical development in conventional, full-scale clinical trial designs. To evaluate this, the aim of the present study is to determine whether NK1 antagonism can beneficially affect, in anxious alcohol dependent subjects during early abstinence, surrogate variables correlated with clinical outcomes, i.e.
- reduce craving for alcohol, measured as baseline self-reported urges, or in response to presentation of alcohol associated cues
- reduce negative affect
- influence corresponding objective measures (brain fMRI responses to alcohol-associated cues and to fear stimuli, respectively; and endocrine stress responses).
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
- 21 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
LY686017
Subjects received 50 mg of the NK1 antagonist LY686017 orally on a daily basis.
干预措施: LY686017 (Drug)
Placebo
Subjects received placebo orally on a daily basis
干预措施: Placebo (Drug)
结局指标
主要结局
Craving for Alcohol (Spontaneous)
时间窗: Baseline
Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). This is a self-report rating scale, with scores ranging from 8 (lowest craving value) to 56 (highest craving value).
Change From Baseline in Spontaneous Alcohol Craving at Week 1, During the First of Two Weekly Ratings.
时间窗: Week 1/Rating 1 minus baseline
Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). This is a self-report rating scale, with scores ranging from 8 (lowest craving value) to 56 (highest craving value).
Change From Baseline in Spontaneous Alcohol Craving at Week 1, During the Second of Two Weekly Ratings.
时间窗: Week 1 Rating 2 minus baseline
Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). This is a self-report rating scale, with scores ranging from 8 (lowest craving value) to 56 (highest craving value).
Change From Baseline in Spontaneous Alcohol Craving at Week 2, During the First of Two Weekly Ratings.
时间窗: Week 2 Rating 1 minus baseline
Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). This is a self-report rating scale, with scores ranging from 8 (lowest craving value) to 56 (highest craving value).
Change From Baseline in Spontaneous Alcohol Craving at Week 2, During the Second of Two Weekly Ratings.
时间窗: Week 2 Rating 2 minus baseline
Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). This is a self-report rating scale, with scores ranging from 8 (lowest craving value) to 56 (highest craving value).
Change From Baseline in Spontaneous Alcohol Craving at Week 3, During the First of Two Weekly Ratings.
时间窗: Week 3 Rating 1 minus baseline
Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). This is a self-report rating scale, with scores ranging from 8 (lowest craving value) to 56 (highest craving value).
Change From Baseline in Spontaneous Alcohol Craving at Week 3, During the Second of Two Weekly Ratings.
时间窗: Week 3 Rating 2 minus baseline
Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). This is a self-report rating scale, with scores ranging from 8 (lowest craving value) to 56 (highest craving value).
Craving for Alcohol Evoked by Alcohol-cue Challenge
时间窗: Week 4
Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). This is a self-report rating scale, with scores ranging from 8 (lowest craving value) to 56 (highest craving value).
次要结局
未报告次要终点