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

基本信息

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
项目类别：
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

项目摘要

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) 是一种慢性复发性疾病，目前的药物治疗方法只能起到一定的作用。开发治疗 AUD 的有效药物仍然是一项高度研究最近的重点是确定 AUD 治疗的新分子靶标并有效筛选针对这些目标的新化合物。异丁司特 (IBUD) 已被提升为一种新型成瘾药物针对神经营养素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) 以及巨噬细胞迁移抑制因子。前进 AUD 药物开发，我们的实验室最近完成了一项随机、双盲、在当前 AUD 未接受治疗的个体中进行 IBUD 安慰剂对照交叉实验室研究（R21 AA022214；NCT02025998）。该研究测试了安全性、耐受性和初始人体实验室功效 IBUD（50mg BID）。结果表明 IBUD 具有良好的耐受性并且与情绪改善相关在压力和酒精提示暴露期间以及减少对酒精的渴望的滋补水平。建立在 IBUD 的强有力的理论依据和临床前研究结果，以及人体测试的安全性数据和早期疗效在我们的实验室进行，该提案旨在进行为期 12 周、双盲、安慰剂对照的研究 IBUD（50mg BID）的随机临床试验。我们建议对 132 名寻求治疗的男性进行随机分组，女性当前澳元。主要目的是 (a) 测试 IBUD（50mg BID）是否会降低百分比酗酒日（PHDD；HDD 定义为男性饮酒 5 次以上，女性饮酒 4 次以上），与安慰剂相比，在 12 周的试验过程中； (b) 测试 IBUD（50mg BID）对仲醇的功效消费终点，即 (a) 每天饮酒量，(b) 每天饮酒量，(c) 戒酒天数百分比，(d) 没有酗酒日的受试者百分比，以及 (e) 戒酒受试者百分比，以及在 12 周的试验过程中，人们对酒精的渴望和消极情绪。此次活动的顺利完成拟议的研究将进一步开发 IBUD，一种安全且有前途的新型化合物，具有强大的临床前和澳元的安全数据。如果在本研究中 IBUD 被证明优于安慰剂，它将为验证性研究奠定基础多中心试验导致 FDA 批准一种新型 AUD 治疗方法。