Randomized Trial of Ibudilast for Methamphetamine Dependence

异丁司特治疗甲基苯丙胺依赖的随机试验

• 批准号: 9232095
• 负责人: Keith Gregory Heinzerling
• 金额: $ 58.88万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9232095
• 关键词: Abstinence; Address; Adverse event; Behavior Therapy; Bupropion; Cardiovascular Diseases; Cell Line; Chronic; Clinic Visits; Clinical Trials; Cocaine; Cocaine Dependence; Cognition; Cognitive Therapy; Collaborations; Combination Drug Therapy; Corpus striatum structure; Counseling; Development; Distress; Double-Blind Method; Event; Felis catus; Formulation; Frequencies; Functional disorder; Funding; GDNF gene; Genes; Genetic Polymorphism; HIV/HCV; Human; Impaired cognition; Impairment; Individual; Infection; Inflammation Mediators; Instruction; Intervention; Lead; Link; Marketing; Mediating; Methamphetamine; Methamphetamine dependence; Monitor; Naltrexone; Nerve Growth Factors; Neurocognitive; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurologic Effect; Outcome; Outcome Study; Paranoia; Participant; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase II Clinical Trials; Phosphodiesterase Inhibitors; Placebos; Preclinical Drug Evaluation; Principal Investigator; Process; Psychostimulant dependence; Public Health; Randomized; Rattus; Research; Safety; Seizures; Serum; Source; Stress; Stroke; Subgroup; Suicide; System; Testing; Time Study; Treatment outcome; Urine; Wood material; cognitive change; cognitive control; cognitive function; contingency management; dopaminergic neuron; effective therapy; glial activation; glial cell-line derived neurotrophic factor; improved; medication compliance; methamphetamine effect; methamphetamine use; neuroinflammation; neurotrophic factor; novel; novel strategies; preclinical study; randomized trial; response; reward processing; secondary analysis; success; volunteer; week trial

Despite numerous clinical trials, no medication has been approved to treat methamphetamine (MA) dependence. Dysfunction in dopaminergic systems and cognitive dysfunction are hallmarks of stimulant dependence and predict poor response to behavioral treatment for cocaine and MA dependence. As a result, novel approaches to restoring dopaminergic functioning is a promising approach to developing medications for MA dependence. Ibudiiast (IBUD) is a phosphodiesterase inhibitor and modulator of glial cell activation that may be effective for MA dependence via reductions in neuroinflammation and/or induction of neurotrophic factors such as GDNF. In preclinical studies, IBUD reduced MA-prime- and stress-induced reinstatement of MA seeking in rats, suggesting IBUD is a promising candidate medication with potential effects in restoring dopaminergic functioning. The proposed study is a phase II randomized, double-blind, clinical trial of IBUD (N=60) versus placebo. (N=60) with cognitive behavioral therapy for 12 weeks to determmine the safety and efficacy of IBUD for MA dependence. Primary aims will compare MA use and treatment retention for IBUD versus placebo. The study has >80% power to detect a benefit for IBUD over placebo on the FDA-preferred outcome in stimulant trials: urine drug screen confirmed MA abstinence during the final two weeks of treatment (weeks 11/12). Effects of potential confounders including medication safety/tolerability, medication non-adherence, and ability to achieve MA abstinence with a contingency management intervention during a two-week trial lead-in period, on outcomes will be assessed. Potential mechanisms of IBUD in MA dependence will be probed in exploratory analyses examining any effects of IBUD on cognitive function and changes in cognition during treatment, and associations between treatment outcomes and polymorphisms in dopaminergic genes, the gene for GDNF, and serum GDNF levels. A phase I human safety-interaction study of IBUD in MA dependence is currently underway at our Center and will be completed prior to funding of this proposed study. The proposed trial is the result of a long-standing , collaboration between our research Center and MediciNova, Inc. who are fully committed to seeing IBUD through the regulatory and marketing process for MA dependence. If unanticipated events preclude advancing IBUD into phase II testing in time for this study, the bupropion-naltrexone combination formulation undergoing phase 1 testing in Project 1 of this proposal will be advanced to phase II testing instead.

尽管进行了许多临床试验，但尚未批准治疗甲基苯丙胺（MA）的药物 依赖。多巴胺能系统和认知功能障碍的功能障碍是兴奋剂的标志 依赖性和预测对可卡因和MA依赖性行为治疗的反应不良。因此， 恢复多巴胺能功能的新方法是开发药物的一种有前途的方法 用于MA依赖。 ibudiiast（ibud）是一种磷酸二酯酶抑制剂和神经胶质细胞激活的调节剂 通过减少神经炎症和/或诱导的降低，这可能有效 神经营养因素，例如GDNF。在临床前研究中，辅助降低了MA-PRIME和应力诱导的 恢复在大鼠中寻求MA的人，这表明ibud是一种潜在的有前途的候选药物 恢复多巴胺能功能的影响。拟议的研究是II期随机，双盲， 同学（n = 60）与安慰剂的临床试验。 （n = 60）进行认知行为疗法12周 确定iBud对MA依赖的安全性和功效。主要目的将比较MA使用和 与安慰剂相对于安慰剂的治疗保留率。这项研究具有> 80％的能力来检测ibud的好处 刺激试验中FDA偏爱结果的安慰剂：尿液药物筛查证实了戒酒 最后两周的治疗（第11/12周）。包括药物在内的潜在混杂因素的影响 安全/耐受性，药物不遵守和通过意外事件实现MA禁欲的能力 在为期两周的试用期间，将评估管理干预措施。潜在的 在探索性分析中，将探测MA依赖性中ibud的机制，以检查的任何影响 关于认知功能和治疗过程中认知的变化以及治疗之间的关联 多巴胺能基因的结果和多态性，GDNF的基因和血清GDNF水平。一个阶段 我目前在我们中心正在进行的MA依赖性人类安全性研究研究，将是 在资助这项拟议的研究之前完成。拟议的试验是长期存在的结果 我们的研究中心与Medicinova，Inc。之间的合作，他们完全致力于看到ibud 通过MA依赖的监管和营销过程。如果意外事件排除 在这项研究的及时进入IBUD的IB次测试中 在本提案的项目1中进行1阶段测试将推进II期测试。