Transdermal Rotigotine as Adjunct to Behavioral Therapy for Cocaine Use Disorder

透皮罗替高汀作为可卡因使用障碍行为疗法的辅助疗法

基本信息

批准号：
10615366
负责人：
ALBERT JOSEPH ARIAS
金额：
$ 159.79万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2025-09-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615366
关键词：
Abstinence Affect Affinity Agonist Alzheimer&apos s Disease Attention Behavior Behavior Therapy Behavioral Blood Brain Clinical Trials Cocaine Cocaine Users Cocaine use disorder Cognitive Cognitive Therapy Cognitive deficits Cues Development Dopamine Dopamine Agonists Dopamine Receptor Dopaminergic Agents Dose Drug Controls Drug usage Equipment and supply inventories Executive Dysfunction Functional Magnetic Resonance Imaging Functional disorder Future Goals Impairment Impulsivity Individual Laboratories Link Names National Institute of Drug Abuse Neurocognition Neurocognitive Nootropic Agents Outcome Overdose Parkinson Disease Participant Patient Participation Patient Self-Report Patients Persons Pharmaceutical Preparations Pharmacotherapy Placebos Precision medicine trial Prefrontal Cortex Psyche structure Public Health Quality of life Randomized Regulation Relapse Rest Restless Legs Syndrome Rewards Risk Safety Sampling Self-control as a personality trait Short-Term Memory Stimulant Subgroup Substance Use Disorder System Testing Time Treatment outcome United States Food and Drug Administration Update Urine Visit Visuospatial abuse liability arm attentional bias brain behavior cocaine use cognitive ability cognitive function computerized effective therapy executive function flexibility follow-up frontal lobe improved indexing innovation insight mortality neural circuit neurobehavioral novel patient engagement phase III trial precision medicine prescription stimulants programs psychoeducation recruit response secondary endpoint sobriety socioeconomics stimulant user theories treatment arm

项目摘要

Cocaine Use Disorder (CocUD) incurs a high socioeconomic burden, yet no Food and Drug Administration (FDA)-approved pharmacotherapies are available for CocUD. We propose a proof of concept clinical trial of multiple dopamine (DA) receptor (D2/D3/D4/D5) agonist rotigotine (RTG) that could improve cocaine abstinence by increasing DA-dependent executive function (EF). EF is the set of cognitive abilities such as working memory, information updating and mental flexibility required for goal attainment. In patients with CocUD and poor EF, attention to and retention of psychoeducation information during cognitive behavioral therapy (CBT) could be impaired, and drug-predictive cues may capture attention away from sobriety goals more readily. Indeed, low EF has been linked to poor CocUD treatment outcomes. Such patients could benefit from DA-increasing medication to help maintain abstinence. In fact, prescription stimulants that release DA have been shown to reduce cocaine use, but are problematic because stimulants themselves have abuse potential. A multiple DA receptor agonist may be a safer alternative to improve DA function and EF. Although RTG is FDA-approved for Parkinson’s Disease treatment, RTG has been shown to improve cortical plasticity and EF in Alzheimer’s Disease. Moreover, the sustained-release RTG patches promote steady state drug levels. Therefore, we propose a clinical trial of six weeks of daily transdermal rotigotine (Neupro®) patches as an adjunct to CBT for cocaine use reduction in CocUD. Cocaine use outcomes will be compared between n = 30 (completed) participants randomized to six weeks of 4mg/d transdermal RTG, and n = 30 participants randomized to transdermal placebo. Per NIDA goals of identifying alternative quality of life-related endpoints beyond abstinence in clinical trials, we will also attain insights into RTG action by obtaining functional magnetic resonance imaging (fMRI) and neurocognition assessments pertinent to EF prior and following dosing as secondary endpoints. This will garner evidence as to whether RTG increases brain activation and overt behavioral signatures of EF. Such findings would provide critical mechanistic evidence that RTG induces its abstinence-promoting effect by way of improving EF and/or reducing impulsivity. Finally, in a step toward precision medicine for CocUD, we will determine how RTG benefits brain and behavior as a function of baseline EF. Several lines of evidence from previous trials of DA agents suggest that individuals with SUD and poor EF benefit most from DA enhancement, whereas participants with normal to supranormal EF at baseline derive lesser or no benefit from DA enhancement on substance abstinence. We will thus conduct a planned post-hoc analysis to detect differential change in EF and in EF- related brain connectivity and function following RTG as a function of whether the participant scored above vs below the median value of the RTG treatment arm in scores of a validated computerized cognitive battery that probes EF. A finding in this post-hoc analysis that RTG selectively benefited individuals with lower EF would augur a novel precision medicine approach in future clinical trials of other DA-promoting agents for CocUD.

可卡因使用障碍（COCUD）会引起高社会经济的伯恩伯恩（Burnen），但没有食物和药物管理局（FDA） - 批准的药物治疗可用于Cocud。我们提出了一项概念证明的临床试验证明多巴胺（DA）受体（D2/D3/D4/D5）激动剂Rotigotine（RTG），可以改善可卡因的禁欲通过增加DA依赖性执行功能（EF）。 EF是一组认知能力，例如工作记忆，目标属性所需的信息更新和心理灵活性。在Cocud和EF差的患者中，认知行为疗法（CBT）期间对心理教育信息的关注和保留可能是受损的，药物预测的提示可能会更容易引起人们的注意。确实，低EF 与官的治疗结果不良有关。这样的患者可以受益于药物帮助维持戒酒。实际上，已证明释放DA的处方兴奋剂可减少可卡因使用，但有问题，因为兴奋剂本身具有滥用潜力。多个DA接收器激动剂可能是改善DA功能和EF的更安全替代方案。虽然RTG已被FDA批准为帕金森氏症疾病治疗，RTG已被证明可以改善阿尔茨海默氏病的皮质可塑性和EF。而且，持续释放的RTG斑块促进了稳态药物水平。因此，我们提出了一项临床试验每天六周的透皮旋转二唑氨酸（NEUPRO®）贴片作为CBT的辅助可卡因的辅助 Cocud。可卡因的使用结果将在随机分配到六个参与者之间进行比较 4mg/d的透皮RTG的几周，n = 30个参与者随机分为透皮安慰剂。根据NIDA目标在临床试验中，确定与生活质量相关的端点的替代质量，我们还将达到通过获得功能磁共振成像（fMRI）和神经认知来洞悉RTG动作与EF有关的评估事先和剂量之后作为次要终点。这将获得有关的证据 RTG是否增加了EF的大脑激活和公开的行为特征。这样的发现将提供通过改善EF和/或降低冲动。最后，在迈向Cocud的精确医学的一步中，我们将确定RTG的好处大脑和行为是基线EF的函数。 DA代理先前试验的几条证据建议具有SUD和EF差的人受益于DA的增强，而参与者基线时的正常至EF的正常至EF较小或没有受益于底物的DA增强。节制。因此，我们将进行计划的事后分析，以检测EF和EF-中的差异变化 RTG之后的相关大脑连接性和功能是参与者是否得分低于RTG治疗臂的中值，该臂的数分经过验证的计算机认知电池问题EF。在此事后分析中，RTG有选择地使EF较低的人受益的发现将在其他DA促进药物的临床试验中，预示着一种新型的精确医学方法。