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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）造成了很高的社会经济负担，但没有食品和药物管理局