Proof-of-Concept Clinical Trial of Lamotrigine as a Candidate Pharmacotherapy for Adolescent Alcohol Use Disorder

拉莫三嗪作为青少年酒精使用障碍候选药物疗法的概念验证临床试验

基本信息

批准号：
10192619
负责人：
ROBERT MIRANDA
金额：
$ 19.61万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10192619
关键词：
21 year old Address Adolescence Adolescent Adolescent Development Adult Aftercare Age Alcohol abuse Alcohol consumption Alcohol withdrawal syndrome Alcohols Anticonvulsants Attenuated Behavioral Clinical Clinical Trials Cognitive Therapy Consumer Satisfaction Controlled Clinical Trials Data Development Dose Drug usage Ecological momentary assessment Enrollment Environment Ethics FDA approved Frequencies Future Glutamates Goals Heavy Drinking Human Intervention Laboratories Measures Method Acceptability Methods Moods Outcome Participant Pharmaceutical Preparations Pharmacotherapy Phase Phenotype Physiological Placebos Prevalence Randomized Research Rewards Safety Severities Sodium Channel Teenagers Testing Time Titrations Withdrawal Work Youth adolescent alcohol misuse adolescent alcohol treatment adolescents with alcohol use disorders alcohol and other drug alcohol cue alcohol effect alcohol use disorder base binge drinking cost effective craving cue reactivity drinking emerging adulthood follow-up hazardous drinking high risk population improved improved outcome in vivo inhibitor/antagonist innovation lamotrigine marijuana use motivational enhancement therapy outcome prediction psychosocial reduced alcohol use research and development response side effect tool topiramate transmission process treatment optimization underage drinker underage drinking voltage

项目摘要

PROJECT SUMMARY The goal of this exploratory proposal is to evaluate the feasibility and potential efficacy of lamotrigine (LTG), a voltage-gated sodium channel inhibitor that blunts glutamatergic transmission, for treating adolescents with alcohol use disorder (AUD). Alcohol use typically begins during adolescence and prevalence rates for AUD peak before age 21. Yet, despite clinical demand, treatments for youth rely on psychosocial interventions that yield only modest benefits; most return to hazardous drinking. One potential way to improve adolescent alcohol treatment is to augment the best available psychosocial interventions with pharmacotherapy. Although the FDA approved four medications to treat AUD in adults, no medication is indicated for adolescents, and controlled clinical trials with teenagers are almost nonexistent. Optimizing treatment options for youth will require closing this gap in medication development research. Prior work shows that anticonvulsants attenuate alcohol withdrawal, blunt craving, and reduce alcohol and other drug use. While these medications yield medium additive effects on drinking outcomes when paired with psychosocial treatments, they are poorly tolerated, especially by youth, which undermines their clinical utility. We propose to explore LTG, an anticonvulsant with a minimal side effect profile that is well-tolerated and shown to reduce alcohol and other drug use in adults. Its effects on adolescent AUD, however, are untested. This proof-of-concept study will leverage an innovative approach to medication development for youth with AUD that pairs human laboratory and ecological momentary assessment (EMA) methods. Adolescents with alcohol use disorder (N = 50, ages 16-19 years) will be randomized to LTG or placebo. A 6-week titration period will be followed by 3 weeks at the target dose (200 mg/day) and a two-week taper period. As in our prior work, all youth will receive a five session behavioral platform comprised of motivational enhancement therapy and alcohol-focused cognitive behavioral therapy. This behavioral platform affords the most meaningful and ethical test of LTG in this vulnerable and high-risk population. A 3-month follow-up will evaluate sustained benefit. Our major aims are to evaluate the feasibility and tolerability of LTG among adolescents with AUD, apply our human laboratory and EMA paradigms to evaluate the effects of LTG on intermediate phenotypes associated with alcohol use and outcomes in clinical trials, and evaluate the effects of LTG on alcohol use at the target dose and at the 3-month follow-up. This study is intended to fill a critical void in medication development for adolescents with AUD. Our aims also address national priorities to gather safety and efficacy data on medications for treating AUD in youth. Results from this proof-of-concept study will inform whether a larger (R01) clinical trial is warranted.

项目概要该探索性提案的目标是评估拉莫三嗪 (LTG) 的可行性和潜在功效，拉莫三嗪是一种电压门控钠通道抑制剂，可减弱谷氨酸能传输，用于治疗青少年酒精使用障碍（澳元）。饮酒通常从青春期开始，澳元的患病率 21 岁之前达到顶峰。然而，尽管有临床需求，青少年的治疗仍依赖于社会心理干预，只产生有限的效益；大多数人又重新开始危险饮酒。改善青少年酗酒的一种潜在方法治疗方法是通过药物治疗来加强现有的最佳心理社会干预措施。尽管FDA 批准了四种治疗成人 AUD 的药物，没有药物适用于青少年，并且受到控制针对青少年的临床试验几乎不存在。优化青少年的治疗方案需要关闭药物开发研究中的这一差距。先前的研究表明，抗惊厥药可以减弱酒精的作用戒断、直白的渴望，并减少酒精和其他药物的使用。虽然这些药物的效果中等当与心理社会治疗相结合时，会对饮酒结果产生附加影响，它们的耐受性很差，尤其是年轻人，这削弱了它们的临床效用。我们建议探索 LTG，一种抗惊厥药副作用极小，耐受性良好，并被证明可以减少成人酒精和其他药物的使用。它是然而，对青少年澳元的影响尚未经过测试。这项概念验证研究将利用创新的使用 AUD 为青少年开发药物的方法，将人类实验室和生态学相结合瞬时评估（EMA）方法。患有酒精使用障碍的青少年（N = 50，年龄 16-19 岁）将随机接受 LTG 或安慰剂治疗。 6 周的滴定期之后将是 3 周的目标剂量（200 毫克/天）和两周的减量期。与我们之前的工作一样，所有青少年都将接受五次行为训练该平台由动机增强疗法和以酒精为中心的认知行为疗法组成。这个行为平台为这个脆弱和高风险的 LTG 提供了最有意义和道德的测试人口。 3 个月的随访将评估持续效益。我们的主要目标是评估可行性和 AUD 青少年对 LTG 的耐受性，应用我们的人类实验室和 EMA 范式评估 LTG 对与饮酒相关的中间表型和临床结果的影响试验，并评估 LTG 对目标剂量和 3 个月随访时饮酒的影响。这该研究旨在填补 AUD 青少年药物开发的关键空白。我们的目标也是解决国家优先事项，收集治疗青少年 AUD 的药物的安全性和有效性数据。结果这项概念验证研究的结果将告知是否需要进行更大规模的 (R01) 临床试验。