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

摘要 酒精使用障碍（AUD）是一种慢性和复发性疾病，目前的药物治疗 效果一般。开发有效的治疗AUD的药物仍然是一项高研究 优先考虑，最近重点是确定AUD治疗的新分子靶点，并有效筛选 针对这些目标的新化合物。异丁司特（IBUD）已被作为一种新的成瘾性药物提出 靶向神经营养因子信号传导和神经免疫功能的药物治疗。IBUD抑制 磷酸二酯酶-4（PDE 4）和-10（PDE 10）和巨噬细胞迁移抑制因子。推进 针对AUD的药物开发，我们的实验室最近完成了一项随机，双盲， 在当前AUD非寻求治疗个体中开展的IBUD安慰剂对照交叉实验室研究 (R21 AA022214; NCT02025998）。本研究测试了安全性、耐受性和初始人体实验室疗效。 IBUD（50 mg BID）。结果表明，IBUD耐受性良好，并与情绪改善相关 在压力和酒精线索暴露以及酒精渴望的紧张水平下降。基础上 IBUD的强有力的理论基础和临床前发现，沿着人体试验的安全性数据和早期疗效 在我们的实验室进行，这项建议旨在进行一项为期12周的，双盲，安慰剂对照 IBUD（50 mg BID）的随机临床试验。我们建议随机选择132名寻求治疗的男性， 现在的AUD。主要目的是（a）测试IBUD（50 mg BID）是否会降低 重度饮酒日（PHDD; HDD定义为男性饮酒5+，女性饮酒4+）与安慰剂相比， （B）测试IBUD（50 mg BID）对仲醇的功效 消费终点，即（a）每天的饮酒量，（B）每个饮酒日的饮酒量，（c）戒酒天数百分比，（d） 没有大量饮酒日的受试者百分比，和（e）戒酒的受试者百分比，以及 酒精渴望和消极情绪，在12周的试验过程中。圆满完成 拟议的研究将进一步开发IBUD，这是一种安全且有前途的新型化合物，具有很强的临床前和临床应用价值。 AUD的安全性数据。如果IBUD在本研究中被证明上级安慰剂，它将为验证性研究奠定基础。 多中心试验导致FDA批准一种新的AUD治疗。

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.