Guanfacine Target Engagement and Validation to Improve Substance Use Outcomes in Women

胍法辛目标参与和验证以改善女性药物使用结果

基本信息

批准号：
9899239
负责人：
Rajita Sinha
金额：
$ 81.11万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9899239
关键词：
Abstinence Address Adrenergic Agonists Alcohol or Other Drugs use Alcohols Ambulatory Care Anxiety Attention Basic Science Cannabis Chronic Clinical Clinical Research Clinical Trials Clinical assessments Cocaine Cocaine Abuse Cognitive Corpus striatum structure Cues Data Decision Making Development Disease Dose Drug Targeting Drug usage Exposure to FDA approved Gender Guanfacine Health Heterogeneity Inpatients Investigational Therapies Laboratories Laboratory Animals Lead Measures Mediating Medical Moods Morbidity - disease rate National Institute of Drug Abuse Neurocognitive Nicotine Outcome Outcome Study Outpatients Pathway interactions Pharmaceutical Preparations Pharmacology Phase Placebo Effect Placebos Post-Traumatic Stress Disorders Preparation Process Public Health Randomized Relapse Reporting Research Rewards Role Sex Differences Short-Term Memory Site Stress Substance Use Disorder Substance abuse problem Testing Treatment outcome Up-Regulation Urine Validation Woman Work base biobehavior clinical research site cocaine use comorbidity drug craving drug seeking behavior experimental study flexibility improved men noradrenergic novel personalized medicine psychiatric symptom relapse prediction relapse risk relating to nervous system response sex social stressor treatment duration week trial

项目摘要

Abstract Substance Use Disorders (SUDs) present a serious public health problem with significant health-related morbidity, and no FDA-approved treatments target cocaine use disorder (CUD) or co-occurring substance abuse. A major obstacle to SUD treatment are the high relapse rates, and high drug craving and reduced cognitive flexibility, particularly in stress, drug cue and challenge contexts, are target processes that contribute to such high relapse rates. Furthermore, CUD women show greater drug craving and poor cognitive flexibility during stress and drug cue challenge contexts, and preliminary data show that treatment with the alpha-2 adrenergic agonist, Guanfacine (GUA) at 3mg/s day versus placebo (PBO) reverses these effects in CUD women but not men. Preliminary data also show that GUA 3 mg/day vs. PBO led to higher drug-negative urines in an 8- week outpatient setting in CUD women than men. On the basis of this previous development work, we propose a 3- year R01 pilot clinical and laboratory outcome study to test the overall hypothesis that GUA (3mg/day) will reduce target drug craving and improve cognitive flexibility processes in CUD women, and that such targeted engagement will result in lower cocaine and other drug use outcomes in women with CUD. One hundred treatment seeking CUD women will be randomly assigned to GUA (3 mg/day) vs Placebo (PBO) over a 10-week clinical trial across 2 sites (N=50 per site), and will also be assessed in a pre-treatment and week 9 laboratory challenge test with exposure to stress and drug cue provocation. The primary target engagement outcome will be reduction in drug craving and improved cognitive flexibility and the primary target validation outcome will be reduced cocaine use as measured by percent negative drug urines and last three weeks of abstinence. The following aims will be addressed. Aim #1 - Target Engagement: To examine whether GUA will reduce drug craving and improve cognitive flexibility in laboratory challenge and in clinical assessments over the 10-week period. Aim #2: Target Validation: To evaluate whether GUA vs PBO effects on drug craving and cognitive flexibility significantly predicts CUD clinical outcomes in the 10-week trial. Aim #3: Data Replication and Scalability: To replicate target engagement and validation outcomes across two sites (Yale and SUNY-Stony Brook) and inform scalability for larger clinical trials. Exploratory Aim 1: To explore GUA’s role in mediating the relationship between target drug craving and cognitive flexibility processes and cocaine use and other drug use outcomes. Exploratory Aim 2: To explore the role of co-morbid psychiatric symptoms (mood, anxiety and PTSD) in moderating the proposed target engagement and validation processes. Acknowledging the heterogeneity in CUD and significant sex differences, this project utilizes an experimental therapeutics approach to further develop and test whether GUA’s targeted effects on drug craving and cognitive flexibility impacts substance use clinical outcomes, thereby providing critical data on whether such a personalized medicine approach to the development of GUA in the treatment of women with CUD is warranted.

抽象的物质使用障碍 (SUD) 是一个严重的公共卫生问题，与健康密切相关发病率，且 FDA 批准的治疗方法均未针对可卡因使用障碍 (CUD) 或共存物质 SUD 治疗的一个主要障碍是高复发率、高药物渴望和减少。认知灵活性，特别是在压力、药物提示和挑战环境中，是有助于提高认知灵活性的目标过程。此外，CUD 女性表现出更大的药物渴望和较差的认知灵活性。在压力和药物提示挑战环境中，初步数据表明使用 alpha-2 进行治疗每天 3 毫克/秒的肾上腺素激动剂胍法辛 (GUA) 与安慰剂 (PBO) 相比，可逆转 CUD 女性的这些影响但初步数据还显示，与 PBO 相比，每天 3 毫克的 GUA 会导致 8 岁以下患者的药物阴性尿液增多。女性 CUD 周门诊量高于男性根据之前的开发工作，我们提出了 3- R01 年试点临床和实验室结果研究，测试 GUA（3 毫克/天）将减少的总体假设针对 CUD 女性的药物渴望并改善认知灵活性过程，并且这种有针对性的参与将导致患有 CUD 的女性减少可卡因和其他药物的使用结果 100 寻求治疗。在为期 10 周的临床试验中，CUD 女性将被随机分配至 GUA（3 毫克/天）与安慰剂（PBO）组跨 2 个中心（每个中心 N=50），还将在治疗前和第 9 周实验室挑战中进行评估暴露于压力和药物提示刺激的测试主要目标参与结果将是。减少药物渴望并提高认知灵活性，主要目标验证结果将是通过药物尿液阴性百分比和最后三周的戒断来衡量可卡因使用量的减少。将解决以下目标：目标#1 - 目标参与：检查 GUA 是否会减少药物使用。渴望并在 10 周内提高实验室挑战和临床评估中的认知灵活性目标#2：目标验证：评估 GUA 与 PBO 是否对药物渴望和认知产生影响。灵活性可显着预测 10 周试验中的 CUD 临床结果：数据复制和。可扩展性：在两个站点（耶鲁大学和纽约州立大学斯托尼分校）复制目标参与和验证结果 Brook）并为更大规模的临床试验提供可扩展性，探索性目标 1：探索 GUA 在调解中的作用。目标药物渴望和认知灵活性过程与可卡因和其他药物使用之间的关系探索性目标 2：探讨共病精神症状（情绪、焦虑和抑郁）的作用。 PTSD）来调节拟议的目标参与和验证过程。由于 CUD 的异质性和显着的性别差异，该项目采用了实验疗法进一步开发和测试 GUA 是否对药物渴望和认知灵活性有针对性的影响的方法影响物质使用的临床结果，从而提供关于这种个性化治疗是否有效的关键数据开发 GUA 治疗女性 CUD 的医学方法是有必要的。