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

• 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
• 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

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.

项目摘要 本探索性建议的目的是评估拉莫三嗪（LTG）的可行性和潜在疗效， 一种能减弱多巴胺能传递的电压门控钠通道抑制剂，用于治疗青少年 酒精使用障碍（AUD）酒精使用通常在青春期开始，AUD的患病率 在21岁之前达到顶峰。然而，尽管有临床需求，但对青年的治疗依赖于心理社会干预， 只产生适度的好处;大多数人回到危险的饮酒。改善青少年酒精的一种潜在方法 治疗的方法是用药物疗法来加强现有的最佳心理社会干预。尽管FDA 批准了四种药物治疗成人AUD，没有药物适用于青少年，并控制 青少年的临床试验几乎不存在。优化青年治疗方案将需要关闭 药物开发研究中的空白。先前的研究表明，抗惊厥药可以减弱酒精 戒断，钝渴望，减少酒精和其他药物的使用。虽然这些药物产生中等 当与心理社会治疗配对时，对饮酒结果的叠加效应，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， 副作用最小，耐受性良好，并显示可减少成人的酒精和其他药物使用。其 然而，对青少年AUD的影响尚未得到验证。这项概念验证研究将利用一种创新的 针对青少年AUD的药物开发方法，将人类实验室和生态学相结合 瞬时评估（EMA）方法。酒精使用障碍青少年（N = 50，年龄16-19岁）将 随机分配至LTG或安慰剂组。6周的滴定期之后是3周的目标剂量（200 mg/天）和两周的逐渐减少期。在我们之前的工作中，所有的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。 这个行为平台提供了最有意义和道德的测试LTG在这个脆弱和高风险的 人口3个月随访将评估持续获益。我们的主要目标是评估 和LTG在青少年AUD中的耐受性，应用我们的人体实验室和EMA范式， 评估LTG对与酒精使用相关的中间表型和临床结局的影响， 试验，并评估LTG在目标剂量和3个月随访时对酒精使用的影响。这 该研究旨在填补青少年AUD药物开发的关键空白。我们的目标还 解决国家优先事项，收集治疗青少年AUD药物的安全性和有效性数据。结果 这一概念验证研究的结果将告知是否需要进行更大规模的（R 01）临床试验。