Proof-of-Concept Human Laboratory Testing of Novel Drug Candidates Identified by INIA-NeuroImmune

INIA-NeuroImmune 确定的新候选药物的概念验证人体实验室测试

基本信息

批准号：
9241910
负责人：
BARBARA J MASON
金额：
$ 52.61万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9241910
关键词：
Aftercare Agonist Alcohol consumption Alcohols American Animal Model Animals Anti-Inflammatory Agents Attenuated Biochemistry Biological Markers Blood C-reactive protein Clinical Collaborations Controlled Clinical Trials DSM-V Development Dose Double-Blind Method Drug Kinetics Electrocardiogram FDA approved Female Future Genomics Human Hydrocortisone Immune Inflammation Intoxication Laboratories Measures Methods Mifepristone Modeling Moods Naltrexone Neuroimmune Outcome Performance Peripheral Peroxisome Proliferators Pharmaceutical Preparations Phase Physiological Placebo Control Placebos Randomized Randomized Controlled Trials Research Research Personnel Research Priority Role Safety Scientist Severities Signal Pathway Standardization Stress TNF gene Testing Therapeutic Translating Urine Validation Withdrawal acamprosate addiction alcohol abuse therapy alcohol cue alcohol use disorder analog anaplastic lymphoma kinase base chemokine craving cytokine drinking drug candidate duloxetine factor A follow-up gabapentin human data human study in vivo inhibitor/antagonist interdisciplinary approach kinase inhibitor male meetings negative affect novel novel therapeutics phosphodiesterase IV potential biomarker pregabalin receptor response response biomarker small molecule treatment duration volunteer

项目摘要

Project Summary The development of novel medications with robust effect sizes and good safety and tolerability is an INIA RFA research priority. This translational project will respond to this research challenge by providing proof-of-concept human laboratory testing of the top three neuroimmune drug candidates identified as having therapeutic potential for alcohol use disorder by Dr. Mayfield/Farris/Ponomarev's “drugging the network” computational genomic analyses and by Drs. Bell's, Blednov/Messing's, Crabbe/Ozburn's and Lasek's animal models. Drugs identified for human study will either be FDA-approved for other indications or available for study under an IND and will be selected by Dr. Mason based on scientific prioritization by the INIA-Neuroimmune Executive Committee and safety considerations. Drugs will be tested in a highly standardized, reliable, and valid human laboratory model informing the three stages of the addiction cycle: withdrawal/negative affect, preoccupation/anticipation, and binge/intoxication, with human laboratory results serving as an analogue for drinking outcomes of double-blind, placebo-controlled clinical trials. Subjects for each study will be 50 non- treatment-seeking male and female paid volunteers who meet DSM-5 criteria for alcohol use disorder of ≥ moderate severity (AUD-MS). Studies are randomized, double-blind, and placebo-controlled. The treatment duration is at least 1-week and guided by drug pharmacokinetics. The primary endpoint is craving scores in response to in vivo alcohol cues presented in the laboratory, with confirmatory physiological outcomes, and naturalistic measures of drinking, mood, and craving. Specific Aim 1: To evaluate INIA-Neuroimmune drug candidates in paid non-treatment-seeking volunteers with current AUD-MS using the human lab model informing targets for the 3 stages of the addiction cycle. Specific Aim 2: To identify potential biomarkers of clinical outcomes in peripheral markers of stress and inflammation (e.g., high-sensitivity C-reactive protein, selected chemokines, pro- and antiinflammatory cytokines, and cortisol) in collaboration with Drs. Roberto/Roberts/Bajo. Safety Aim: To evaluate the safety and tolerability of INIA-Neuroimmune drug candidates in subjects with AUD-MS, as assessed by significant changes from baseline in EKG, routine blood and urine biochemistry, vital signs, physical exam, and subjective complaints relative to placebo. Hypothesis: The overall hypothesis under test in that, relative to placebo, novel drug candidates identified by INIA- Neuroimmune will significantly attenuate responsivity to alcohol cues in the human lab model and reduce drinking, craving, and negative affect during treatment and 1-month of post-treatment follow-up. Interpretation of Results: Positive findings will provide clinical validation of neuroimmune targets and mechanisms identified by INIA-Neuroimmune and provide a rational basis for later phase testing of candidate drugs as potential therapeutics for AUD-MS.

项目概要开发具有强大疗效、良好安全性和耐受性的新型药物是 INIA RFA 的一项任务该转化项目将通过提供概念验证来应对这一研究挑战。对被确定具有治疗作用的前三种神经免疫药物候选药物进行人体实验室测试 Mayfield/Farris/Ponomarev 博士的“网络药物”计算揭示了酒精使用障碍的可能性基因组分析以及 Bell 博士、Blednov/Messing 博士、Crabbe/Ozburn 博士和 Lasek 博士的动物模型。确定用于人体研究的药物将获得 FDA 批准用于其他适应症，或者可用于 IND 下的研究并将由梅森博士根据 INIA-神经免疫执行官的科学优先顺序进行选择委员会和安全考虑。药物将在高度标准化、可靠且有效的人体中进行测试。实验室模型告知成瘾周期的三个阶段：戒断/负面影响，全神贯注/期待，以及暴饮暴食/中毒，人类实验室结果可以作为类似物每项研究的双盲、安慰剂对照临床试验的饮酒结果将是 50 名非受试者。符合 DSM-5 酒精使用障碍标准 ≥ 的寻求治疗的男性和女性付费志愿者中等严重程度（AUD-MS）研究是随机、双盲和安慰剂对照的。持续时间至少为 1 周，并以药物药代动力学为指导，主要终点是渴望评分。对实验室中呈现的体内酒精线索的反应，具有确认的生理结果，以及具体目标 1：评估 INIA-神经免疫药物。使用人体实验室模型使用当前 AUD-MS 的付费非寻求治疗志愿者中的候选人为成瘾周期的三个阶段提供目标信息具体目标 2：确定成瘾周期的潜在生物标志物。应激和炎症外周标志物的临床结果（例如高敏 C 反应蛋白、与 Drs 合作选择的趋化因子、促炎细胞因子和抗炎细胞因子以及皮质醇）。 Roberto/Roberts/Bajo 安全目标：评估 INIA-神经免疫药物的安全性和耐受性。患有 AUD-MS 受试者的候选者，通过心电图、血常规较基线的显着变化进行评估和与安慰剂相关的尿液生化、生命体征、体格检查和主观主诉：正在测试的总体假设是，相对于安慰剂，INIA 确定的新候选药物- 神经免疫将显着减弱人类实验室模型中对酒精线索的反应，并减少治疗期间和治疗后 1 个月的随访中饮酒、渴望和负面情绪。结果：积极的发现将为已确定的神经免疫靶点和机制提供临床验证通过 INIA-Neuroimmune 并为候选药物的后期测试提供合理的基础 AUD-MS 的治疗方法。