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 只是略微有效。开发治疗AUD的有效药物仍是一个很高的研究方向 优先事项，最近的重点是确定用于AUD治疗的新分子靶点和有效筛选 针对这些目标的新化合物。异丁司特(IBUD)是一种新型成瘾药物 针对神经营养因子信号和神经免疫功能的药物治疗。IBUD抑制 磷酸二酯酶-4(PDE4)和-10(PDE10)和巨噬细胞移动抑制因子。晋级 针对AUD的药物开发，我们实验室最近完成了随机、双盲、 未寻求治疗的当前AUD患者IBUD的安慰剂对照交叉实验室研究 (R21 AA022214；NCT02025998)。这项研究测试了该药物的安全性、耐受性和最初的人体实验室疗效。 IBUD 50 mg，2次/d。结果表明，IBUD耐受性良好，并与情绪改善有关 在压力和酒精暗示暴露期间，以及酒精渴望的紧张程度的减少。建立在 IBUD的强大理论基础和临床前发现，以及人体试验的安全性数据和早期疗效 在我们的实验室进行，这项建议试图进行为期12周的双盲安慰剂对照试验 IBUD随机临床试验(50 mg，2次/d)。我们建议将132名寻求治疗的男性随机分为 患有当前澳门氏症的女性。主要目的是(A)测试IBUD(50 Mg Bid)是否会下降百分比 重度饮酒日(PHDD；HDD定义为男性5+饮酒，女性4+饮酒)，与安慰剂相比， 在12周的试验过程中；和(B)测试IBUD(50 Mg Bid)对二次酒精的疗效 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) 没有大量饮酒的受试者百分比，和(E)戒酒受试者的百分比，以及 在为期12周的试验过程中，酒精渴望和负面情绪。成功地完成了 拟议的研究将进一步开发IBUD，一种安全而有前途的新化合物，具有强大的临床前和 澳元的安全数据。如果IBUD在这项研究中被证明优于安慰剂，它将为确认性研究奠定基础 多点试验导致FDA批准了一种新的AUD治疗方法。

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.