Mirtazapine for the treatment of methamphetamine dependence among MSM with high-r

描述（由申请人提供）：公众迫切需要开发有效的药物治疗甲基苯丙胺（冰毒）依赖。全世界有多达5700万安非他明使用者使用冰毒（迅速代谢成安非他明）在男男性行为者（MSM）中的流行程度是普通美国人口的20倍，也是艾滋病流行的主要原因。2-4甲基苯丙胺使用与高危性行为5-9和艾滋病毒血清转化独立相关。因此，有效的冰毒治疗不仅可以减少冰毒的使用，还可以通过减少冰毒导致的性风险，成为重要的艾滋病毒预防干预措施。目前还没有fda批准的针对冰毒依赖的药物治疗方法，这是该领域的一个主要空白，因为单独的行为干预效果有限，可能会从辅助药物治疗中获益在最近的一项中等规模（n=60）和有限持续时间（12周）的双盲随机对照试验中，我们发现口服米氮平（一种具有血清素和多巴胺能特性的抗抑郁药）与安慰剂相比，显著减少了冰毒的使用，这是通过降低治疗组尿液阳性来确定的（RR 0.57, 95% CI 0.35-0.93, p= 0.02）与安慰剂相比，治疗组的性危险行为也显著减少。米氮平减少了甲基苯丙胺的使用，尽管依从性较低：根据医疗事件监测系统（MEMS）上限，每日剂量仅为48.5%。所有参与者都接受了每周药物使用咨询和每月临床医生提供的简短依从性咨询的行为平台。我们建议在这些令人兴奋的结果的基础上，通过在上述试验的行为平台上添加每日依从提醒来确定米氮平在12周和24周的疗效，并确定停药后疗效是否持续至12周。120个样本量将确保结果比原始试验更精确。本研究的主要具体目的是：(1)确定每日米氮平与安慰剂在治疗0-12周内减少积极使用冰毒的男男性行为者使用冰毒和艾滋病毒性风险行为的疗效。两组参与者都将接受每周面对面的药物使用和每月简短的依从性咨询的行为平台，并通过每日短信提醒依从性。(2)确定米氮平与安慰剂的疗效是否持续12-24周，两组均接受行为平台。(3)确定米氮平与安慰剂的疗效是否持续24-36周，停药或安慰剂后24周的行为平台。

DESCRIPTION (provided by applicant): There is an urgent public need to develop effective pharmacotherapies for methamphetamine (meth) dependence. There are up to 57 million amphetamine users worldwide.1 Use of meth (rapidly metabolized to amphetamine) is up to 20 times more prevalent among men who have sex with men (MSM) than in the general U.S. population, and is a major contributor to the HIV epidemic.2-4 Meth use is independently associated with high-risk sexual behavior5-9 and HIV seroconversion.10-12 Effective meth treatments therefore will not only reduce meth use, they could also be important HIV prevention interventions by reducing meth-driven sexual risk. There are no FDA-approved pharmacologic treatments for meth dependence, a major gap in the field, because behavioral interventions alone have limited efficacy and would likely benefit from adjunctive pharmacologic treatments.13,14 In a recent double-blind, randomized controlled trial of modest size (n=60) and limited duration (12 weeks), we discovered that compared with placebo, oral mirtazapine, an antidepressant with serotonergic and dopaminergic properties, significantly reduced meth use as determined by reduction in urine positivity in the treatment arm (RR 0.57, 95% CI 0.35-0.93, p=.02).15 Sexual risk behaviors also declined significantly in the treatment arm compared to placebo. Mirtazapine decreased meth use despite low adherence: by medical event monitoring system (MEMS) caps, only 48.5% of daily doses were taken. All participants received a behavioral platform of weekly substance use counseling and monthly, brief clinician- delivered adherence counseling. We propose expanding upon these exciting results by determining mirtazapine's efficacy at both 12 and 24 weeks with daily adherence reminders added to the above trial's behavioral platform, and determining if efficacy is sustained up to 12 weeks after drug discontinuation. A sample size of 120 will ensure greater precision of results than the original trial. The primary specific aims of this study are: (1) To determine the efficacy of mirtazapine daily vs. placebo in reducing meth use and HIV sexual risk behaviors among actively- using meth-dependent MSM from 0-12 weeks of treatment. Participants in both arms will receive the behavioral platform of in-person weekly substance use and monthly brief adherence counseling, augmented by daily text messaging adherence reminders. (2) To determine if the efficacy of mirtazapine vs. placebo is sustained from 12-24 weeks on treatment, with both arms receiving the behavioral platform. (3) To determine if the efficacy of mirtazapine vs. placebo is sustained from 24-36 weeks, after discontinuation of medication or placebo and the behavioral platform at 24 weeks.