A randomized controlled clinical trial of the neuroimmune modulator ibudilast for the treatment of alcohol use disorder

神经免疫调节剂异丁司特治疗酒精使用障碍的随机对照临床试验

• 批准号: 9883692
• 负责人: LARA A. RAY
• 金额: $ 66.22万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9883692
• 关键词: Alcohol consumption; Alcohols; Attenuated; Behavioral; Blood; Brain; Chronic; Cues; Data; Development; Dose; Double-Blind Method; Genes; Heavy Drinking; Human; Individual; Inflammatory; Knock-out; Laboratories; Laboratory Study; Lipopolysaccharides; Maintenance; Measures; Migration Inhibitory Factor; Molecular Target; Moods; National Institute on Alcohol Abuse and Alcoholism; Neuroimmune; Online Systems; Outpatients; Participant; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Placebos; Protocols documentation; Randomized; Randomized Controlled Clinical Trials; Relapse; Research Priority; Rodent; Safety; Self Administration; Signal Transduction; Standardization; Stress; Testing; Visit; Woman; addiction; alcohol abuse therapy; alcohol craving; alcohol cue; alcohol effect; alcohol measurement; alcohol response; alcohol seeking behavior; alcohol use disorder; base; chronic alcohol ingestion; craving; cytokine; depressive symptoms; drinking; efficacy testing; improved; indexing; medication administration; men; multi-site trial; negative mood; neuroinflammation; neuron loss; neurotoxic; neurotrophic factor; novel; phosphodiesterase IV; positive mood; pre-clinical; preclinical safety; preference; primary endpoint; programs; randomized placebo-controlled clinical trial; safety testing; secondary endpoint; symptomatology; week trial

ABSTRACT Alcohol use disorder (AUD) is a chronic and relapsing condition for which current pharmacological treatments are only modestly effective. The development of efficacious medications for AUD remains a high research priority with recent emphasis on identifying novel molecular targets for AUD treatment and to efficiently screen new compounds aimed at those targets. Ibudilast (IBUD) has been advanced as a novel addiction pharmacotherapy that targets neurotrophin signaling and neuroimmune function. IBUD inhibits phosphodiesterases -4 (PDE4) and -10 (PDE10) and macrophage migration inhibitory factor. To advance medications development for AUD, our laboratory has recently completed a randomized, double-blind, placebo-controlled crossover laboratory study of IBUD in non-treatment seeking individuals with current AUD (R21 AA022214; NCT02025998). This study tested the safety, tolerability, and initial human laboratory efficacy of IBUD (50mg BID). Results indicated that IBUD was well tolerated and associated with mood improvements during stress- and alcohol-cue exposures as well as reductions in tonic levels of alcohol craving. Building upon the strong rationale and preclinical findings for IBUD, along with safety data and early efficacy in human testing conducted in our laboratory, this proposal seeks to conduct a 12-week, double-blind, placebo controlled randomized clinical trial of IBUD (50mg BID). We propose to randomize 132 treatment-seeking men and women with current AUD. The primary aims are (a) to test whether IBUD (50mg BID) will decrease percent heavy drinking days (PHDD; HDD defined as 5+ drinks for men and 4+ for women), as compared to placebo, over the course of the 12-week trial; and (b) to test the efficacy of IBUD (50mg BID) on secondary alcohol consumption endpoints, namely (a) drinks per day, (b) drinks per drinking day, (c) percent days abstinent, (d) percent subjects with no heavy drinking days, and (e) percent subjects abstinent, as well as measures of alcohol craving and negative mood, over the course of the 12-week trial. The successful completion of the proposed study will further develop IBUD, a safe and promising novel compound with strong preclinical and safety data for AUD. If IBUD proves superior to placebo in this study, it will set the stage for a confirmatory multi-site trial leading to FDA approval of a novel AUD treatment.

抽象的 酒精使用障碍（AUD）是一种慢性且复发的疾病，目前的药理治疗 只有适度的有效。开发有效的AUD药物仍然是一项高度研究 优先级，最近重点是识别新的分子靶标，以进行AUD处理和有效筛选 针对这些目标的新化合物。 ibudilast（ibud）已成为一种新颖的成瘾 靶向神经营养蛋白信号传导和神经免疫功能的药物疗法。 ibud抑制 磷酸二酯酶-4（PDE4）和-10（PDE10）和巨噬细胞迁移抑制因子。前进 AUD的药物开发，我们的实验室最近完成了一个随机的双盲， 安慰剂对照的跨界实验室在非治疗中，寻求当前AUD的人 （R21 AA022214; NCT02025998）。这项研究测试了安全性，耐受性和最初的人类实验室功效 ibud（50毫克竞标）。结果表明，舒适的耐受性良好，并且与情绪改善有关 在压力和酒精中间的暴露期间以及渴望酒精含量的降低。建立 ibud的强烈理由和临床前的发现，以及安全数据和人类测试的早期疗效 该提案在我们的实验室中进行，试图进行12周的双盲，安慰剂控制 ibud的随机临床试验（50mg bid）。我们建议将132名寻求治疗的男性和 当前有声音的妇女。主要目的是（a）测试ibud（50mg竞标）是否会降低百分比 与安慰剂相比 在为期12周的审判过程中； （b）测试ib饮酒的效力（50毫克竞标） 消费终点，即（a）每天饮料，（b）每天喝酒，（c）戒酒的百分比，（d） 没有大量饮酒日的受试者，（e）戒酒的百分比，以及措施 在为期12周的试验过程中，酒精渴望和负面情绪。成功完成 拟议的研究将进一步发展ibud，这是一种安全且有希望的新颖化合物，具有强大的临床前和 AUD的安全数据。如果iBud在这项研究中证明优于安慰剂，它将为确认性奠定基础 多站点试验导致FDA批准了新的AUD治疗。