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

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

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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.

项目摘要具有稳健效果大小的新型药物的开发以及良好的安全性和耐受性是一种INIA RFA 研究优先。这个翻译项目将通过提供概念证明来应对这一研究挑战人类实验室测试对已确定为治疗的前三名神经免疫性药物候选者 Mayfield/Farris/Ponomarev博士的“吸毒网络”计算的潜力基因组分析和DRS。贝尔，布莱德诺夫/梅辛，克拉贝/奥兹本和拉斯克的动物模型。毒品确定人类研究的确定要么FDA批准其他适应症，要么在IND下进行研究并将由梅森博士根据科学优先级选择，由Inia-Neurommune主管委员会和安全考虑。药物将在高度标准化，可靠和有效的人类中进行测试实验室模型通知成瘾周期的三个阶段：撤回/负面影响，人类实验室的结果和狂欢/中毒，人类实验室的结果可作为类似双盲，安慰剂控制的临床试验的饮酒结果。每项研究的受试者将为50个非 - 符合DSM-5酒精使用障碍标准的男性和女性寻求治疗的男性和女性有偿志愿者中度严重程度（AUD-MS）。研究是随机，双盲和安慰剂对照的。治疗持续时间至少为1周，并在药物药代动力学的指导下。主要终点是渴望分数对实验室中提出的体内酒精提示的反应，确认生理结果，饮酒，情绪和渴望的自然主义测量。特定目的1：评估inia-neurommune药物使用人类实验室模型的当前AUD-MS的付费非治疗寻求志愿者的候选人告知目标成瘾周期的三个阶段的目标。特定目的2：确定潜在的生物标志物压力和注射的外围标记中的临床结果（例如，高敏C反应蛋白，与DRS合作，选择的趋化因子，促和抗炎细胞因子和皮质醇）。 Roberto/Roberts/Bajo。安全目标：评估INIA- NEUROMMUNE药物的安全性和耐受性由EKG，常规血液中基线的重大变化评估，在患有AUD-MS的受试者的候选人中以及相对于安慰剂的尿液生物化学，生命体征，身体检查和主题投诉。假设：正在检验的总体假设，因为与安慰剂相对于安慰神经免疫性将显着减弱人类实验室模型中对酒精提示的反应性，并减少在治疗期间和治疗后1个月的饮酒，渴望和负面影响。解释结果：积极的发现将提供鉴定的神经免疫目标和机制的临床验证通过inia-neurommune，为候选药物的后期测试提供了合理的基础 AUD-MS的治疗。