Efficacy and Safety of High-Dose Baclofen for Alcohol Dependence

高剂量巴氯芬治疗酒精依赖的功效和安全性

• 批准号: 8891309
• 负责人: James C. Garbutt
• 金额: $ 26.54万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891309
• 关键词: Abstinence; Accounting; Adverse event; Agonist; Alcohol dependence; Alcoholic beverage heavy drinker; Alcohols; Anti-Anxiety Agents; Anxiety; Area; Attention; Baclofen; Blood; Carbohydrates; Case Study; Cells; Clinical; Clinical Management; Clinical Trials; Counseling; Data; Data Analyses; Dependence; Development; Dose; Enrollment; Equilibrium; FDA approved; Gamma-glutamyl transferase; Goals; Health; Heavy Drinking; Individual; Intervention; Knowledge; Lead; Left; Liver Cirrhosis; Measures; Medical; Methods; Modality; Naltrexone; Participant; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Placebo Control; Placebos; Population; Predictive Value; Publishing; Randomized; Recording of previous events; Relapse; Reporting; Research; Safety; Severities; Sleep; Symptoms; Testing; Time; Uncertainty; Woman; acamprosate; addiction; alcohol craving; alcohol use disorder; anxiety management; anxiety states; base; carbohydrate-deficient transferrin; clinical care; clinically significant; double-blind placebo controlled trial; drinking; efficacy testing; high standard; improved; innovation; men; pilot trial; pre-clinical; randomized placebo controlled trial; receptor; response; screening

DESCRIPTION (provided by applicant): Alcohol dependence (AD) is a common problem with significant health consequences. Treatment of AD is evolving to include both counseling methods and medications. Several medications have been discovered, that show efficacy in AD, e.g. naltrexone, acamprosate. However, the overall effect of existing medications is modest leaving a clear need for the development of new pharmacotherapies. The GABAB receptor agonist baclofen has attracted attention as a potential new medication for AD based on preclinical data and early clinical trials. Baclofen is an FDA approved medication with an excellent safety profile even for patients with liver cirrhosis-a not uncommon consequence of AD. Questions have arisen with regards to the efficacy of baclofen and whether higher doses of baclofen are safe and more effective than the prior tested dose of 30 mg/ day. There is emerging evidence that severity of dependence is positively associated with baclofen response. The main goal of the present proposal is to test the efficacy and safety of 30 mg/d and 90 mg/d of baclofen compared to placebo controlling for severity of dependence as assessed by drinks/drinking day. A primary secondary goal will examine for an anxiolytic effect of baclofen. The study proposes to enroll 120 men and women with AD in a randomized, placebo-controlled trial to include at least 60 individuals with more severe AD (e14 drinks/drinking day for men; e10 drinks/drinking day for women) with randomization to baclofen or placebo balanced for this variable. Baclofen will be titrated to 10 mg t.i.d over 3 days and to 30 mg t.i.d over 12 days and maintained at that level for 12 weeks and then down- titrated for a total study time of 16 weeks. Medical Management will be provided to encourage progress towards drinking goals and to enhance retention and compliance. Drinking patterns, anxiety levels, sleep patterns, craving for alcohol, gamma-glutamyl transferase (GGT) and carbohydrate deficient transferring (CDT) will be assessed. Trough blood levels of R & S-baclofen will be assessed in all individuals at week 4. In summary, the present proposal is innovative and of clinical significance as it will test and compare standard and high-dose baclofen for efficacy and safety in individuals with AD. The proposal is adequately powered to test the primary hypothesis and provides good power to assess whether drinks/drinking day is predictive of baclofen response. Adequate power is also present to examine the anxiolytic effect of baclofen. Ascertaining the effects of standard and high-dose baclofen, the predictive value of heavy drinking on baclofen response and the anxiolytic effect of baclofen are important goals towards determining whether baclofen has true value for the clinical management of the patient with alcohol dependence. .

描述（由申请人提供）：酒精依赖（AD）是一个常见问题，会对健康造成严重后果。 AD 的治疗正在不断发展，包括咨询方法和药物治疗。已经发现了几种对 AD 有效的药物，例如纳曲酮、阿坎酸。然而，现有药物的总体效果有限，显然需要开发新的药物疗法。根据临床前数据和早期临床试验，GABAB 受体激动剂巴氯芬作为治疗 AD 的潜在新药而引起人们的关注。巴氯芬是 FDA 批准的药物，即使对于肝硬化患者（AD 的常见后果）也具有出色的安全性。人们对巴氯芬的功效以及更高剂量的巴氯芬是否比之前测试的 30 毫克/天剂量更安全、更有效产生了疑问。有新的证据表明依赖性的严重程度与巴氯芬反应呈正相关。本提案的主要目标是测试 30 毫克/天和 90 毫克/天的巴氯芬与安慰剂相比的功效和安全性，并控制通过饮酒/饮酒日评估的依赖严重程度。主要次要目标将检查巴氯芬的抗焦虑作用。该研究计划招募 120 名患有 AD 的男性和女性参加一项随机、安慰剂对照试验，其中至少包括 60 名患有更严重 AD 的个体（男性 e14 次饮酒/饮酒日；女性 e10 次饮酒/饮酒日），并随机分配至巴氯芬或安慰剂平衡该变量。巴氯芬将在 3 天内滴定至 10 mg t.i.d，在 12 天内滴定至 30 mg t.i.d，并维持在该水平 12 周，然后在 16 周的总研究时间内下调剂量。将提供医疗管理，以鼓励实现饮酒目标并提高保留率和依从性。将评估饮酒模式、焦虑水平、睡眠模式、对酒精的渴望、γ-谷氨酰转移酶 (GGT) 和碳水化合物缺乏转移 (CDT)。将在第 4 周对所有个体进行 R & S-巴氯芬的血谷浓度评估。总之，本提案具有创新性且具有临床意义，因为它将测试和比较标准剂量和高剂量巴氯芬对患有以下疾病的个体的有效性和安全性：广告。该提案有足够的能力来检验主要假设，并提供了良好的能力来评估饮酒/饮酒日是否可以预测巴氯芬反应。还存在足够的功效来检查巴氯芬的抗焦虑作用。确定标准剂量和高剂量巴氯芬的影响、大量饮酒对巴氯芬反应的预测价值以及巴氯芬的抗焦虑作用是确定巴氯芬对于酒精依赖患者的临床管理是否具有真正价值的重要目标。 。