Efficacy & safety of baclofen to reduce alcohol use in veterans with HCV

描述（由申请人提供）： 巴氯芬减少HCV退伍军人饮酒的有效性和安全性背景：研究表明，在退伍军人事务医疗中心（VAMC）治疗的退伍军人中，慢性丙型肝炎（HCV）的患病率是普通人群患病率1.8%的3 - 4倍（Dominitz，2004; Cheung，2000）。相当一部分患有HCV的退伍军人有肝硬化和进展为终末期肝病的风险。患有HCV的退伍军人有很高的共病酒精使用障碍率，酒精大大加速了HCV引起的肝损伤。因此，一种安全有效的治疗酒精使用障碍的方法-一种不影响肝脏的方法-对患有HCV的退伍军人来说是必要的。巴氯芬是一种γ-氨基丁酸（GABA）β-受体激动剂药物，FDA批准用于控制痉挛，最近也已证明可有效治疗肝硬化患者的酒精使用障碍（Addolorato，Agabio，科隆博和Gasbarrini，2006）。此外，巴氯芬的肝脏代谢较低，主要通过肾脏未经修饰而消除（Daviberg，1985）。在神经系统疾病或酒精使用障碍患者的研究中，没有报告巴氯芬的肝脏副作用。尚未在慢性感染HCV的患者中研究酒精使用的有效治疗方法，目前FDA批准的酒精使用障碍药物可能会对肝脏产生不利影响。本研究的目的和主要目的是确定巴氯芬与安慰剂相比，在患有HCV和持续性酒精使用障碍的退伍军人中减少酒精使用行为的有效性和安全性。本研究的第二个目的是评估巴氯芬在减少酒精渴望方面的有效性。方法：这是一项多中心随机双盲安慰剂对照研究。位于明尼阿波利斯和波特兰VAMC的国家VA丙型肝炎资源中心的两个站点将招募120名男性，女性和少数民族退伍军人，他们是HCV阳性，目前正在饮酒。参与者将接受酒精使用障碍的评估，如果他们符合酒精滥用或酒精依赖的标准，他们目前的酒精使用将被量化。符合中度至重度饮酒标准的HCV退伍军人将被随机分配到两组之一：实验组（巴氯芬）或对照组（安慰剂）。参与者将接受12周的治疗。在此期间，受试者每周一次访视，持续4周，然后每2周一次，直至研究结束。在第12周，参与者将被给予继续巴氯芬的选择，如果他们在实验组（巴氯芬）或开始巴氯芬，如果他们在对照组（安慰剂）。我们研究的主要结果将是比较两组之间的比例与HCV的退伍军人谁实现和保持戒酒。主要结果指标将是完全戒酒的退伍军人人数，戒酒的总天数和每周饮酒的总次数。在入组时和研究结束时，将获得HCV病毒滴度，以确定戒酒或减少饮酒的影响。碳水化合物缺乏转铁蛋白百分比（%CDT）和乙基葡糖苷酸（EtG）将用于评估戒酒或减少饮酒对这些指标的影响，这些指标将在入组研究时、第4周、第8周和研究结束时（第12周）获得。最后将获得肝酶，以评估巴氯芬是否对肝功能产生不利影响。临床相关性：这项研究的重点之一VHA的最高优先事项：治疗退伍军人与HCV。大多数患有HCV的退伍军人没有接受抗病毒治疗，这在很大程度上是因为合并酒精使用障碍被认为是抗病毒治疗的禁忌症。目前还没有研究评估药物在减少HCV患者饮酒方面的安全性和有效性。这种药物既可以减缓酒精使用引起的肝脏疾病的加速，也可以增加接受抗病毒治疗的可能性。因此，这项研究的相关性不仅在于它有可能减少酒精使用和随之而来的加速肝损伤，而且还允许更多的HCV患者参与抗病毒治疗。 公共卫生相关性： 对兽医保健的潜在影响：有效地解决肝炎诊所的酒精使用障碍将有助于在VA内为HCV患者制定新的护理标准。这项研究有可能大大减少其肝损伤进展为肝硬化，肝细胞癌和终末期肝病的退伍军人的数量，这些疾病需要肝移植或甚至更可能导致死亡（因为许多需要肝移植的退伍军人被拒绝作为继发于共病酒精/物质使用障碍的候选人）。如果巴氯芬在患有HCV的退伍军人中是安全有效的，那么它有可能用于更广泛的患有酒精使用障碍的退伍军人群体。巴氯芬也有可能被非精神卫生保健提供者使用。最后，如果我们发现这项研究的结果是成功的，我们将使用现有的VA国家丙型肝炎资源中心基础设施和通信网络，将我们的研究结果传播到美国的所有VA设施。

DESCRIPTION (provided by applicant): Efficacy & Safety of Baclofen to Reduce Alcohol Use in Veterans with HCV BACKGROUND: Studies suggest the prevalence of chronic hepatitis C (HCV) among veterans treated within the Veterans Affairs Medical Centers (VAMCs) is 3 to 4 times greater than the general population prevalence of 1.8% (Dominitz, 2004; Cheung, 2000). A substantial proportion of veterans with HCV are at risk for cirrhosis and progression to end-stage liver disease. Veterans with HCV have high rates of co-morbid alcohol use disorders and alcohol accelerates greatly the liver damage caused by HCV. Therefore, a safe and efficacious treatment for alcohol use disorders-one that does not affect the liver- is needed for veterans with HCV. Baclofen, a gamma-aminobutyric acid (GABA) beta-receptor agonist medication that is FDA approved to control spasticity, more recently has also been shown to be effective in treating alcohol use disorders in patients with cirrhosis (Addolorato, Agabio, Colombo, & Gasbarrini, 2006). Furthermore, baclofen has a low liver metabolism and is mainly eliminated unmodified through the kidneys (Davidoff, 1985). There have been no hepatic side effects reported for baclofen in studies of patients with neurological disorders or alcohol use disorders. Effective treatments for alcohol use have not been studied in patients chronically infected with HCV and current FDA-approved medications for alcohol use disorders can adversely affect the liver. The purpose and primary aim of this study is to determine the efficacy and safety of Baclofen in reducing alcohol use behavior as compared with placebo in veterans who have HCV and persistent alcohol use disorders. A secondary aim of this study is to assess the effectiveness of Baclofen in reducing alcohol craving. PLAN/ METHODS: This is a multi-site randomized double-blind placebo controlled study. Two sites of the national VA Hepatitis C Resource Center located at the Minneapolis and Portland VAMCs will recruit 120 men, women, and minority veterans who are HCV positive and currently drinking alcohol. Participants will be assessed for alcohol use disorders and, if they meet criteria for alcohol abuse or alcohol dependence, their current alcohol use will be quantified. Veterans with HCV who meet criteria for moderate to heavy alcohol use will be randomly assigned to one of two groups: Experimental group (baclofen) or control (placebo). Participants will be treated for 12 weeks. During this period subjects will be seen weekly for 4 weeks then every 2 weeks until the end of the study. At week 12,participants will be given the option of continuing baclofen if they were in the experimental (baclofen) group or starting baclofen if they were in the control (placebo) group. The primary outcome of our study will be a comparison between the two groups of the proportion of veterans with HCV who achieve and maintain alcohol abstinence. Primary outcome measures will be the number of veterans with total abstinence, the total number of days abstinent, and the total number of drinks per week. Upon enrollment and at the end of the study HCV viral titers will be obtained to determine the effect of abstinence or drinking reduction. A Percent Carbohydrate Deficient Transferrin (%CDT) and Ethyl Glucuronide (EtG) will be used to assess the effect of abstinence or drinking reduction on these measures, which will be obtained upon enrollment to the study, at week 4, at week 8 and at the end of the study (week 12). Finally liver enzymes will be obtained in order to access whether Baclofen adversely affects liver function. CLINICAL RELEVANCE: This study focuses on one of VHA's highest priorities: treatment of veterans with HCV. A majority of veterans with HCV have not been treated with antiviral therapy, in large part because co- morbid alcohol use disorders are considered a contra-indication to antiviral therapy. Currently no studies evaluate the safety and efficacy of medications in reducing alcohol use in patients with HCV. Such medication could both slow the acceleration of liver disease caused by alcohol use and increase the likelihood of receiving antiviral therapy. Therefore this study's relevance lies not only in its potential to reduce alcohol use and the consequent accelerated liver damage but also in allowing more HCV patients to participate in antiviral therapy. PUBLIC HEALTH RELEVANCE: POTENTIAL IMPACT ON VETERANS HEALTH CARE: Effectively addressing alcohol use disorders in a hepatitis clinic will contribute to a new standard of care for HCV patients within the VA. This study has the potential to greatly reduce the number of veterans whose liver damage progresses to cirrhosis, hepatocellular carcinoma, and end stage liver disease that requires liver transplant or even more likely results in death (as many veterans who require liver transplant are rejected as candidates secondary to co-morbid alcohol/ substance use disorders). If baclofen is safe and efficacious in veterans with HCV, it has the potential to be used in the broader group of veterans with alcohol use disorders who do not have HCV. Also baclofen has the potential to be used by non-mental health care providers. Finally if we find that the results of this study are successful, we will use the already existing VA National Hepatitis C Resource Center infrastructure and communication network to disseminate our findings to all VA facilities in the US.