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

基本信息

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
项目类别：
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

项目摘要

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.

尽管进行了大量临床试验，但尚未批准治疗甲基苯丙胺 (MA) 的药物依赖性。多巴胺能系统功能障碍和认知功能障碍是兴奋剂的标志依赖性并预测可卡因和 MA 依赖性对行为治疗的不良反应。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对于 MA 依赖。 Ibudiiast (IBUD) 是一种磷酸二酯酶抑制剂和神经胶质细胞活化调节剂可能通过减少神经炎症和/或诱导 MA 依赖性而有效神经营养因子，如 GDNF。在临床前研究中，IBUD 减少了 MA 引发和应激诱导的在大鼠中恢复 MA 寻求，表明 IBUD 是一种有前途的候选药物，具有潜在的潜力恢复多巴胺能功能的作用。拟议的研究是一项随机、双盲的 II 期研究， IBUD (N=60) 与安慰剂的临床试验。 (N=60) 认知行为治疗 12 周确定 IBUD 对 MA 依赖的安全性和有效性。主要目标将比较 MA 的使用和 IBUD 与安慰剂的治疗保留。该研究有 >80% 的功效检测到 IBUD 的益处安慰剂在兴奋剂试验中获得 FDA 首选结果：尿液药物筛查证实 MA 戒断治疗的最后两周（第 11/12 周）。潜在混杂因素（包括药物）的影响安全性/耐受性、药物不依从性以及在紧急情况下实现 MA 戒断的能力将评估在两周试验导入期内管理干预对结果的影响。潜在的 IBUD 在 MA 依赖中的机制将在探索性分析中进行探讨，以检查以下因素的影响： IBUD 对认知功能和治疗期间认知变化以及治疗之间关联的影响多巴胺能基因、GDNF 基因和血清 GDNF 水平的结果和多态性。 A相 IBUD 对 MA 依赖的人类安全相互作用研究目前正在我们中心进行，并将于在资助这项拟议研究之前完成。拟议的试验是长期的结果，我们的研究中心与 MediciNova, Inc. 之间的合作，后者完全致力于研究 IBUD 通过 MA 依赖的监管和营销流程。如果意外事件阻止为这项研究及时推进 IBUD 进入 II 期测试，安非他酮-纳曲酮组合制剂在本提案的项目 1 中进行第一阶段测试的将被推进到第二阶段测试。