背景:酒精使用障碍(AUD)是全球发病率和死亡率的主要原因之一,全球超过9500万人生活在酒精依赖中。AUD的估计遗传力为50-60%,和多个基因被认为有助于疾病的各种内表型。先前的临床试验支持使用昂丹司琼(AD04,5-HT3拮抗剂)的精准医学方法,方法是通过特定血清素能基因型的生物遗传内表型和饮酒严重程度的生物心理社会内表型或两者将AUD人群分开。通过在AUD的生物心理社会背景下靶向生物基因信号的调节,低剂量AD04有望减少受影响个体的饮酒量,同时最大程度地减少不良反应。
方法:这是第三阶段,6个月,25-site,随机化,使用AD04治疗DSM-V分类的AUD个体的安慰剂对照临床试验,这些个体被预先分层为重度或非常重度饮酒个体的内表型,并且具有与5-羟色胺转运体和5-羟色胺-3AB受体相关的预定义遗传变异谱。参与者(N=303)表现为中度至重度AUD,>80%是男性,大多在五十多岁,>95%是欧洲人后裔。低剂量AD04(约033mg,每天两次)或匹配的安慰剂,每天两次,持续6个月。每两周进行一次简短的行为依从性增强治疗(BBCET[53]),以提高药物依从性和就诊率。
结果:重度饮酒天数的每月百分比显着减少,PHDD(-46·7%(2·7%),95CI:-52·1%至-41·2%与-38·1%(2·9%),95CI:-43·8%至-32·5%,分别;LS平均差=-8·5%;p=0.03)在AD04治疗的vs.在第6个月接受安慰剂的重度饮酒个体。大量饮酒的人也不太可能被诊断为AUD[第1个月:-32·0%(2·8%),95CI:-37·5%至-26·5%与-23·2%(2·9%),95CI:-28·9至-17·5%;LS平均差=-8·8%;p=0·026)],并且在WHO生活质量BREF量表上有所改善,至少有1级下移的显着影响(OR=3.4;95%CI:1·03-11·45,p=0·044)。重要的是,大量饮酒的人,与非常重度饮酒的人不同,生物心理社会内表型更能预测对AD04的治疗反应。AD04具有出色的安全性和耐受性,像安慰剂一样。
结论:在这项3期临床试验中,AD04被证明是目前饮用大量饮酒的AUD个体的有希望的治疗方法,这些个体在5-羟色胺转运蛋白和5-羟色胺-3AB受体复合物中也具有特定的基因型特征。使用AD04减少AUD对目前正在饮酒的重度饮酒个体的危害,不需要戒酒或戒酒,是精准医学领域的重要进展。AD04的不良事件简介,就像安慰剂一样,应通过降低不正确但普遍感知的个人失败的污名来提高AUD现代医学治疗的可及性和接受度。
BACKGROUND: Alcohol use disorder (AUD) is among the leading causes of morbidity and mortality worldwide, and over 95 million people live with alcohol dependence globally. The estimated heritability of AUD is 50-60 %, and multiple genes are thought to contribute to various endophenotypes of the disease. Previous clinical trials support a precision medicine approach using ondansetron (AD04, a 5-HT3 antagonist) by segregating AUD populations by the bio-genetic
endophenotype of specific serotonergic genotypes and the bio-psychosocial
endophenotype of the severity of drinking or both. By targeting the modulation of biogenetic signaling within the biopsychosocial context of AUD, low-dose AD04 holds promise in reducing alcohol consumption among affected individuals while minimizing adverse effects.
METHODS: This was a phase III, 6-month, 25-site, randomized, placebo-controlled clinical trial using AD04 to treat DSM-V-categorized AUD individuals who were pre-stratified into the endophenotypes of heavy or very heavy drinking individuals and possessed a pre-defined profile of genetic variants related to the serotonin transporter and serotonin-3AB receptor. Participants (N = 303) presented moderate to severe AUD, >80 % were men, mostly in their fifties, and >95 % were of European descent. Low-dose AD04 (approx. 033 mg twice daily) or a matching placebo was administered twice daily for 6 months. Brief Behavioral Compliance Enhancement Treatment (BBCET [53]) was administered every two weeks to enhance medication compliance and clinic attendance.
RESULTS: There was a significant reduction in the monthly percentage of heavy drinking days, PHDD (-46·7 % (2·7 %), 95 %CI: -52·1 % to -41·2 % vs. -38·1 % (2·9 %), 95 %CI: -43·8 % to -32·5 %, respectively; LS mean difference=-8·5 %; p = 0.03) among AD04-treated vs. placebo-receiving heavy drinking individuals at month 6. Heavy drinking individuals were also less likely to be diagnosed with AUD [Month 1: -32·0 % (2·8 %), 95 %CI: -37·5 % to -26·5 % vs. -23·2 % (2·9 %), 95 %CI: -28·9 to -17·5 %; LS mean difference= -8·8 %; p = 0·026)], and improved on the WHO quality of life BREF scale with a significant effect for at least a 1-level downward shift (OR = 3.4; 95 % CI: 1·03-11·45, p = 0·044). Importantly, heavy drinking individuals, as distinct from very heavy drinking individuals, were the bio-psychosocial
endophenotype more predictive of therapeutic response to AD04. AD04 had an exceptional safety and tolerability profile, like the placebo\'s.
CONCLUSIONS: In this Phase 3 clinical trial, AD04 was shown to be a promising treatment for currently drinking heavy drinking individuals with AUD who also possess a specific genotypic profile in the serotonin transporter and serotonin-3AB receptor complex. Using AD04 to reduce the harm of AUD in heavy drinking individuals who are currently drinking, without the necessity of abstinence or detoxification from alcohol use, is an important advance in the field of precision medicine. AD04\'s adverse events profile, which was like placebo, should enhance accessibility and acceptance of modern medical treatment for AUD by lowering the incorrect but commonly perceived stigma of personal failure.