Efficacy and Safety of the Melanocortin Activator Bupropion in Treating Binge Drinking

黑皮质素激活剂安非他酮治疗酗酒的功效和安全性

基本信息

批准号：
9167020
负责人：
James C. Garbutt
金额：
$ 18.05万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-15 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9167020
关键词：
Adult Adverse event Affect Age Age-Years Agonist Alcohol abuse Alcohol consumption Alcohol dependence Alcohols Animals Antidepressive Agents Appetitive Behavior Attention Biological Markers Blood alcohol level measurement Body Weight decreased Brain Bupropion Cessation of life Clinical Clinical Management Clinical Trials Consumption Controlled Clinical Trials Development Disease Dose Double-blind trial Employment FDA approved Family Foundations Frequencies Gamma-glutamyl transferase Gender Goals Health Heavy Drinking Hour Human Individual Intervention Intoxication Length Linear Models Medical Naltrexone Narcotic Antagonists Neurobiology Neurons Obesity Opioid Outcome Pharmaceutical Preparations Pharmacotherapy Phase Physical Dependence Placebo Control Placebos Population Pro-Opiomelanocortin Randomized Recruitment Activity Recurrence Reporting Risk Risk Behaviors Risk Factors Safety Sample Size Severities Signal Transduction System Testing Time Traffic accidents Translational trial United States Violence Woman Work arm beta-Endorphin binge drinking carbohydrate-deficient transferrin clinical care common treatment drinking economic cost endogenous opioids follow-up innovation man melanocortin receptor men mouse model novel strategies pre-clinical primary outcome problem drinker psychosocial translational clinical trial young adult

项目摘要

Abstract Binge drinking, the consumption of five or more standard drinks for a man or four or more drinks for a woman in about a two hour period leading to intoxication, is a risky behavior practiced by17% of the U.S. population including nearly 30% of adults 18-34 years of age. Binge drinking is associated with multiple consequences and risk of progression to physical dependence on alcohol. Treatment of binge drinking includes psychosocial interventions but, overall, individuals that regularly binge drink are less likely to seek and to receive treatment. There is no FDA approved medication for binge drinking. Preclinical evidence is laying out a neurobiology of binge drinking with relevance for medication development. Recent work has shown that activating the brain melanocortin system potently reduces binge drinking in a mouse model. Furthermore, because the endogenous opioid β-endorphin inhibits melanocortin actions, a combination of a melanocortin activator and an opioid antagonist has a synergistic effect to reduce binge drinking. This latter finding is intriguing given the recent successful clinical trial and FDA approval of Contrave™ for obesity. Contrave™ is a combination of bupropion (a melanocortin activator) and naltrexone (an opioid antagonist) with a target dose of 360 mg and 32 mg respectively. Therefore we hypothesize that activation of melanocortin systems +/- opioid antagonism will significantly reduce binge drinking in humans. The primary objective of the present proposal is to conduct a proof-of-concept, Phase IIa translational trial to assess for efficacy and tolerability of activating melanocortin systems +/- opioid blockade to reduce binge drinking. 60 men and women with recurrent binge drinking (at least 5 episodes a month for men and 3 for women in the prior 3 months) will be recruited and randomized to either placebo + placebo, bupropion XL 300 mg/d + placebo or bupropion XL 300 mg/d + naltrexone 50 mg/d. The trial will last 12 weeks with a 3 month follow-up to assess stability of change. Primary outcomes include frequency and intensity of binge drinking and changes in biomarkers of heavy drinking (gamma-glutamyl transferase and carbohydrate deficient transferrin) as well as adverse events. Medical Management will be provided to encourage progress towards drinking goals and to enhance retention and compliance. In summary, the present proposal is an innovative and translational clinical trial derived from exciting preclinical findings to test the hypothesis that treatment with a melanocortin activator can reduce binge drinking in humans and to test whether this action is augmented by an opioid antagonist. Evidence for an efficacy signal with good tolerability would form the foundation to conduct a well-powered Phase II/III trial. The development of an effective pharmacotherapy for binge drinking would be a significant clinical advance and one that would be expected to expand the identification and treatment of this common and highly destructive problem.

抽象的暴饮暴食，一个男人的五种或多种标准饮料的消费或四个或更多的饮料在大约两个小时的时间内导致醉酒，是17％的美国人口的危险行为包括近30％的成年人18-34岁。暴饮暴食与多重后果有关和进展到身体依赖酒精的风险。暴饮暴食的治疗包括社会心理干预措施，但总体而言，经常狂饮的人不太可能寻求和接受治疗。没有FDA批准的暴饮暴食药。临床前证据正在阐明饮酒的神经生物学，与药物开发相关。最近的工作表明，激活大脑黑素皮质系统可能会减少在鼠标模型。此外，由于内源性阿片类β-内啡肽抑制黑色素皮质素的作用，所以黑色素质激活剂和阿片类拮抗剂的组合具有协同作用，可减少暴饮暴食喝。鉴于最近成功的临床试验和FDA的批准，这一发现令人着迷 contrave™用于对象。 Contrave™是安非他酮（黑色素质激活剂）和纳曲酮的组合（一个阿片类拮抗剂）靶剂量分别为360 mg和32 mg。因此，我们假设黑色皮质素系统的激活+/-阿片类拮抗作用将显着减少人类的暴饮暴食。本提案的主要目的是进行概念验证，IA期翻译试验评估激活黑色皮质素系统的效率和耐受性+/- OOID阻滞以减少暴饮暴食喝。有60种经常性bbinge饮酒的男人和女人（男性至少有5集，3集，3集妇女在前3个月中）将被招募并随机分配给安慰剂 +安慰剂，安慰剂XL 300 mg/d +安慰剂或安非他酮XL 300 mg/d + naltrexone 50 mg/d。试验将持续12周，3个月评估变化稳定性的后续措施。主要结果包括暴饮暴食的频率和强度以及大量饮用的生物标志物的变化（γ-谷氨酰胺转移酶和碳氢化酸盐不足转铁蛋白）以及不良事件。将提供医疗管理以鼓励进步饮酒目标并增强保留和合规性。总而言之，本提案是一项创新且翻译的临床试验，源自令人兴奋的临床前试验测试假设的发现，即用黑色素皮质素激活剂治疗可以减少暴饮暴食人类并测试阿片类药物拮抗剂是否会增强此作用。有效信号的证据具有良好的耐受性将构成基础，以进行强大的II/III期试验。发展有效的饮酒药物疗法将是一个重大的临床进展，这将是期望扩大对这个常见和高度破坏性问题的识别和治疗。