A Novel Compound for Alcoholism Treatment: A Translational Strategy - Part II
Condition: Alcoholism
MeSH terms: Alcoholism
Intervention: PF-05190457; Placebo
Intervention description: Ghrelin Receptor Inverse Agonist; Placebo
Phase: Phase 2
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 42.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Alcohol Consumption; Alcohol Treatment; Alcoholism; Ghrelin; Ghrelin Antagonism

Summary:

      Background:

      Hormones are naturally occurring chemicals in the body. Ghrelin is a hormone that stimulates
      appetite. It may also stimulate alcohol cravings and use. Researchers want to learn more
      about alcohol cravings and test if a drug that blocks ghrelin lowers alcohol cravings.

      Objective:

      To test if the drug PF-05190457 decreases alcohol craving.

      Eligibility:

      People ages 18-70 who have:

      Alcohol use disorder

      No other serious medical problems

      Woman must be postmenopausal or have had surgery to prevent pregnancy.

      Design:

      Participants will stay on the inpatient unit here at the Clinical Center for two 2-week
      stages, which will be separated by at least 2 days. The inpatient phase include:

      Taking the study drug or placebo by mouth twice daily

      Blood tests

      Tasting several sweet solutions

      Physical exams

      Exposure to alcohol, water, and food cues in a bar-like room. Participants answer questions
      on a computer.

      Blood pressure and heart rate are monitored through an arm cuff and sensors on the chest.

      MRIs: Participants lie on a table that slides in and out of the cylinder, and a coil is
      placed over the head.

      They complete tasks on a computer screen while in the cylinder. This lasts up to 2 hours.

      Wearing a virtual reality headset, walking around a virtual room, and selecting virtual food
      and drink.

      Physical exams
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Male or female individuals 18-70 years old (inclusive)

          -  Current Alcohol Use Disorder (AUD) by DSM-5 criteria based on the SCID

          -  Most recent urine drug test for illegal drugs of abuse is negative

          -  Most recent Clinical Institute Withdrawal Assessment for Alcohol - revised (CIWA-Ar)
             score is less than or equal to 8

          -  Heart rate less than or equal to 100 on two separate measurements, both assessed after
             CIWA-Ar score is less than or equal to 8

          -  Female subjects must be of non childbearing potential as defined by at least one of
             the following criteria:

             a) Females 45-70 years old, who are menopausal, defined as follow:

             i) Females who are between 45-55 years old: they will be considered menopausal if they
             satisfy all the following three requirements during screening: 1) they are in
             amenorrhea, defined as absence of menstruation for the previous 12 months; 2) they
             have a negative urine pregnancy test; and 3) they have a serum FSH level within the
             laboratory s reference range for postmenopausal females.

        ii) Females who are between 56-70 years old: they will be considered menopausal if they are
        in amenorrhea, defined as absence of menstruation for the previous 12 months before
        screening.

        OR

        b) Females 21-70 years old, who have a documented hysterectomy and/or bilateral
        oophorectomy.

        All other female subjects (including females with tubal ligations and females that do NOT
        have a documented hysterectomy) will be considered to be of childbearing potential.

          -  Male subjects must use one of the following methods of contraception from the first
             dose of study medication and until 28 days after dosing (given that it is unknown
             whether the effects of this drug can cause birth defects):

               1. Abstinence.

               2. A condom AND one of the following:

                    -  Vasectomy for more than 6 months.

                    -  Female partner who meets one of the following conditions:

                         1. Has had a tubal ligation, hysterectomy, or bilateral oophorectomy;

                         2. Is post menopausal;

                         3. Uses one of the following forms of contraception:

                            Copper or hormonal containing IUD;

                            Spermicidal foam/gel/film/cream/suppository;

                            Diaphragm with spermicide;

                            Oral contraceptive;

                            Injectable progesterone;

                            Subdermal implant.

                            EXCLUSION CRITERIA:

          -  Lifetime clinical diagnosis of schizophrenia or bipolar disorder

          -  EKG with QTc > 450 msec as determined by the Fridericia formulas.

          -  BMI less than or equal to 18.5 kg/M(2) or anorexia

          -  BMI greater than or equal to 40 kg/m(2)

          -  History of epilepsy and/or seizures

        NOTE: individuals who have a history of alcohol withdrawal seizures may be in the study as
        long as they have been abstinent from alcohol for at least 2 weeks prior to consent and
        during that period of abstinence, there were no seizure episodes (otherwise, participant
        remains not eligible).

          -  Most recent blood tests show creatinine greater than or equal to 2 mg/dL, AST or ALT >
             3 times the upper normal limit, hemoglobin <10.5 g/dl

          -  Subjects who have diabetes and/or are treated with any drug with glucose lowering
             properties such as sulfonylurea, insulin, metformin, thiazolidinediones (TZD),
             Dipeptidyl peptidase-4 (DPP4) inhibitors, or Glucagon-like peptide-1(GLP-1)agonists
             (due to the glucose-lowering properties of PF-05190457 observed in healthy volunteers)

          -  Exclusionary Medications:

               -  A. Naltrexone, acamprosate, alcohol dehydrogenase inhibitors, topiramate,
                  gabapentin, ondansetron, benzodiazepines, baclofen, drugs that are known to
                  prolong the QTc interval and barbiturates as well as hormone replacement therapy;
                  medications and dietary/herbal supplements (like St. John's wort) that interact
                  with Cytochrome P450 3A4. Patients who take these medications may be enrolled in
                  the study only if the potentially interacting medication has been stopped for a
                  period of at least 5 half-lives of the interacting medication before PF-05190457
                  administration. Patients who take these medications on an as needed (PRN)
                  schedule or take

        the medication as a one-time dose as part of a medical procedure or a diagnostic test, for
        example, may not have to wait the 5 half-lives period of time before enrollment; this will
        be evaluated on a case by case basis by the MAI and/or PI, based on the specific
        pharmacological properties of the medication.

          -  Unable to pass a finger rub hearing test

          -  Vision is unable to be corrected to (Snellen) 20/100

          -  Clinically-significant history of motion or car sickness, or history of vestibular
             disorders

          -  Any other reason or clinical condition for which the PI or the MAI will consider
             unsafe for a possible participant to participate in this study

        EXCLUSION CRITERIA FOR fMRI ONLY:

          -  Have contraindications for brain fMRI, as determined by the NIAAA MRI Safety screening
             form (conducted under the 14-AA-0181 Screening Protocol)

          -  Colorblindness (this would prevent subject from completing the Stroop task) using the
             Ishihara Test for Color Deficiency, Concise Edition, 2014.