A Novel Compound for Alcoholism Treatment
Condition: Alcoholism; Alcohol-Related Disorders; Alcohol Dependence; Alcohol Drinking Related Problems; Alcohol Drinking
MeSH terms: Alcoholism; Alcohol-Related Disorders; Alcohol Drinking
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      - Hormones are naturally occurring chemicals in your body. Ghrelin is a hormone that is
      mainly produced by the stomach and stimulates appetite. Some studies suggest it may stimulate
      alcohol craving and use. Drugs have been developed that block ghrelin. Researchers want to
      know if people can tolerate a particular drug that blocks ghrelin. It will be given at two
      dose levels, combined with alcohol.

      Objective:

      - To determine if a drug that may decrease alcohol consumption when given along with alcohol
      is safe and tolerable.

      Eligibility:

        -  Healthy adults 21-65 years old who have 14 (women) to 21 (men) drinks a week.

        -  No one of childbearing potential can participate.

      Design:

        -  Participants will have 3 inpatient clinic visits; each will last 4 days.

        -  They will have physical exam and blood and urine tests.

        -  They will have breath tests for alcohol and smoking.

        -  They will answer health and mood questions.

        -  Researchers will measure their reaction to smelling alcohol and tasting a sweet drink.

        -  They will eat only the food provided by the clinic. They will keep a food diary 1 day
           before each stay.

        -  They will be randomly assigned to take the study drug or placebo 5 times each stay.

        -  On Day 3, they will drink alcohol after taking the drug. They will give many blood
           samples that day through a tube inserted in their skin.

        -  Smokers can take smoke breaks. Once, they will smoke a cigarette through a device.

        -  One week after the last stay, participants will have a follow-up visit to answer
           questions.
    

Detailed description: 
      Objective: Ghrelin is a 28-aminoacid peptide that stimulates appetite and food intake. It is
      an endogenous ligand for the growth hormone secretagogue receptor (GHSR1a). Preclinical
      studies suggest that ghrelin modulates alcohol reward processing. Furthermore, findings from
      a translational human lab study at Brown University (PI: Leggio) indicate that intravenous
      (IV) ghrelin administration, compared to placebo, results in an acute increase in craving for
      alcohol during a cue-reactivity experiment in alcoholic individuals. Therefore, an orally
      bioavailable, ghrelin receptor antagonist, that can pass through the blood brain barrier
      holds particular promise as an AD treatment. This project has been recently funded by NCATS.
      The goals of this protocol are to generate preliminary evidence on the safety and efficacy of
      a ghrelin receptor antagonist (GHSR1a antagonist), PF-05190457, an existing molecule
      available under the NIH-Industry Pilot Program at NCATS.

      Study population: Non-treatment seeking heavy drinkers (n =20). The study will be conducted
      in the Inpatient Unit at the NIAAA Intramural Clinical Program.

      Study Design: Single-blind dose-escalating placebo-controlled inpatient study using
      PF-05190457, in non-treatment seeking heavy drinking subjects. This Phase 1b study will be a
      within-subject design.

      Outcome measures: Primary objectives will be to determine: 1) the number of adverse events
      (AEs) experienced, compared between all three PF-05190457 dose categories (0mg or placebo,
      50mg, and 100mg b.i.d.); and 2) the total concentration of the drug, compared between the two
      non-placebo drug doses (50mg and 100mg b.i.d.), when co-administered with alcohol. We
      hypothesize that both doses of PF-05190457, as compared to placebo, will not result in an
      increased number of AEs. As a secondary objective, we will determine whether PF-05190457
      dose-dependently affects the subjective effects of alcohol and craving. We will include
      pharmacokinetics (PK) and pharmacodynamic (PD) investigations conducted at University of
      Rhode Island (URI; Associate Investigator: Akhlaghi). The PK/PD component will include (i)
      measuring total, unbound or tissue concentrations of the drug using liquid chromatography
      tandem mass spectrometry (LC-MS/MS) and evaluation of biomarkers of effect and (ii)
      estimation of PK and PD parameters by the use of conventional and semi-mechanistic modeling
      approaches to assist in identifying an optimal dosing regimen of the drug in AD.
    

Intervention name(s): PF-05190457
Intervention type(s): Drug
Allocation: Randomized
Intervention model: Crossover Assignment
Primary purpose: Treatment
Keywords: Alcoholism; Ghrelin; Ghrelin Antagonism