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 该探索性建议的目的是评估Lamotrigine（LTG）的可行性和潜在功效，A 电压门控钠通道抑制剂钝性谷氨酸能传播，用于治疗青少年 酒精使用障碍（AUD）。饮酒通常在青春期开始，并且AUD的患病率 21岁之前的峰 仅产生适中的好处；大多数返回危险饮酒。改善青少年酒精的一种潜在方法 治疗方法是通过药物疗法来增强最佳的心理社会心理干预措施。虽然是FDA 批准的四种用于治疗成人AUD的药物，没有针对青少年的药物，并受控 与青少年的临床试验几乎不存在。优化青年的治疗选择将需要关闭 药物开发研究的这一差距。先前的工作表明抗惊厥药减弱了酒精 戒断，渴望并减少酒精和其他吸毒。这些药物产生培养基 与心理社会疗法配对时，对饮酒结果的添加剂影响不佳，它们的耐受性不佳， 尤其是青年，这破坏了他们的临床实用性。我们建议探索LTG，这是一种抗惊厥药 最小的副作用曲线，其耐受性良好，并证明可减少成人的酒精和其他药物使用。它是 但是，对青春期AUD的影响未经测试。这项概念验证研究将利用创新的 配对人类实验室和生态学的AUD的青年开发药物开发方法 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 随机分为LTG或安慰剂。目标剂量将在6周内进行3周的滴定期（200个星期 mg/day）和为期两周的锥度。与我们先前的工作一样，所有年轻人都将获得五个会议的行为 平台包括动机增强疗法和以酒精为中心的认知行为疗法。 这个行为平台为LTG提供了这种脆弱和高风险的LTG的最有意义和道德的考验 人口。 3个月的随访将评估持续的收益。我们的主要目的是评估可行性 LTG在具有AUD的青少年中的耐受性，将我们的人类实验室和EMA范式应用于 评估LTG对与酒精使用和临床结果相关的中间表型的影响 试验，并评估LTG对目标剂量和3个月随访的饮酒的影响。这 研究旨在填补AUD青少年的药物开发中的关键空隙。我们的目标也是如此 解决国家优先事项，以收集有关在青年中治疗AUD的药物的安全和功效数据。结果 从这项概念证明的研究中，是否有必要进行较大的（R01）临床试验。