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Clinical Component

The identification of novel medications with larger effect sizes is a NIAAA research priority. The Clinical Research Project is designed to focus on the hypothesis that one can translate the discoveries of preclinical TSRI-ARC investigators for potential therapeutic use using proof-of-concept human laboratory testing. This Research Project has 2-way interactions with all the individual Research Projects of the ARC and the Animal Models Core. The animal work will validate the choices of a glucocorticoid receptor (GR) antagonist drug and a drug that is hypothesized to restore microtubule homeostasis (key parts of the Contet and Roberto Research Projects and Animal Models Core), and the Clinical Research Project will validate these targets as potential therapeutics for the prevention of relapse and ultimately treatment of AUD.

Should either target ultimately prove to be untenable to pursue human studies, other systems under study by the TSRI-ARC may be viable, such as specific glutamate, serotonin, or hypocretin targets. Drugs selected for human study will either be FDA-approved for other indications or available for study under an IND. Mifepristone, a mixed GR/progesterone antagonist, showed efficacy in TSRI-ARC animal and human laboratory models of protracted abstinence, but mifepristone’s progesterone antagonism causes abortion and does not contribute to AUD efficacy. CORT122928, a “next generation” selective GR antagonist, has been proposed as the first drug for human study based on its performance in TSRI-ARC animal models and its superior side effect profile relative to the parent compound (i.e., no risk of abortion). MAP4343 is our lead compound to test microtubule assembly as a novel therapeutic strategy for AUD and has shown efficacy in TSRI-ARC models of AUD, as well as in animal models of depression and anxiety.(1) 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—will serve as a screen of novel drugs for treating AUD.(2, 3) The predictive validity of our human lab model has been supported in studies of approved drugs (acamprosate, naltrexone) and novel drugs (gabapentin, mifepristone, pregabalin, and duloxetine), with human laboratory results converging with drinking outcomes of double-blind, placebo-controlled clinical trials ranging from 2 weeks to 1 year in duration.(4-9) Of particular relevance to this proposal, gabapentin was identified by TSRI-ARC electrophysiological studies and animal models(10) as having therapeutic potential for AUD, which was also found in our human lab model(5) and randomized controlled trial,(9) lending support to the translational methods proposed across TSRI-ARC components.

Subjects for each study will be 50 non-treatment-seeking male and female paid volunteers meeting DSM-5 criteria for AUD of ≥ moderate severity (AUD-MS). Studies are randomized, double-blind, and placebocontrolled. The dosing duration is subchronic, at least 1 week, and based on drug pharmacokinetics, with 1 month of post-treatment follow-up. The primary endpoint is craving severity in response to in vivo alcohol cues presented in the laboratory, with secondary naturalistic measures of drinking, negative affect, craving, sleep, and executive function at baseline, during treatment, and 1-month post-treatment follow-up.

SPECIFIC AIM ONE

To evaluate the efficacy of TSRI-ARC’s top two drug candidates compared with placebo in non treatment-seeking volunteers with current AUD-MS for reducing responsivity to in vivo alcohol cues in a validated human laboratory model and on naturalistic measures of drinking, negative affect, insomnia, craving, and executive function.

SPECIFIC AIM TWO

To collaborate with TSRI-ARC investigators (Roberto, Contet, Martin-Fardon, George/Zorrilla) and INIA-Neuroimmune to identify potential biomarkers of clinical outcomes (e.g., peripheral markers of stress, including hypothalamic-pituitary-adrenal axis, serotonin, hypocretin, and/or measures of microtubule homeostasis) and drug plasma concentration.

SPECIFIC AIM THREE

To evaluate the safety and tolerability of TSRI-ARC 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 subjects treated with placebo.

BARBARA MASON

Clinical Component Project Lead