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A Novel Compound for Alcoholism Treatment

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Collaborators:
University of Rhode Island
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute on Alcohol Abuse and Alcoholism (NIAAA) )
ClinicalTrials.gov Identifier:
NCT02039349
First received: January 15, 2014
Last updated: November 7, 2014
Last verified: October 2014
  Purpose

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.

Condition Intervention Phase
Alcoholism
Alcohol-Related Disorders
Alcohol Dependence
Alcohol Drinking Related Problems
Alcohol Drinking
Drug: PF-05190457
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Single Blind
Primary Purpose: Treatment
Official Title: A Novel Compound for Alcoholism Treatment: A Translational Strategy

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Side effects/adverse events and maximum tolerated dose of PF-05190457 alone and in combination with alcohol administration. [ Time Frame: 3 days ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 15
Study Start Date: January 2014
Estimated Study Completion Date: June 2017
Estimated Primary Completion Date: June 2017 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: PF-05190457
    N/A
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 =15). The study will be conducted in the Inpatient Unit at the NIAAA Intramural Clinical Program.

Study Design: 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.

  Eligibility

Ages Eligible for Study:   21 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Males or females 21-65 years old (inclusive);
  • Heavy drinking defined as on average at least 21 drinks per week for men or at least 14 drinks for women based on the timeline follow-back (TLFB) done at screening.
  • Be in good health as confirmed by medical history, physical examination, ECG, blood/urine lab tests;
  • Female subjects must be of non childbearing potential as defined by at least one of the following criteria:

    1. Females 45 65 years old, who are menopausal, defined as follows:

      • 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.
      • Females who are between 56 65 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

  • Females 21-65 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:
  • Abstinence.
  • A condom AND one of the following:

    • Vasectomy for more than 6 months.
    • Female partner who meets one of the following conditions:

      • Has had a tubal ligation, hysterectomy, or bilateral oophorectomy;
      • Is post menopausal;
      • 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:

  • Interest in receiving treatment for heavy drinking.
  • Current DSM-IV diagnosis (based on SCID) of substance dependence (other than nicotine); a negative urine drug screen will also be required.
  • DSM-IV Axis I criteria for a lifetime diagnosis of schizophrenia, bipolar disorder, or other psychoses;
  • Active illness within the past 6 months of the screening visit that meet the DSM-IV criteria for a diagnosis of major depressive disorder or anxiety disorder; subjects with a history of attempted suicide will be excluded;
  • Clinically significant medical abnormalities (e.g., unstable hypertension, clinically significant EKG abnormalities, Creatinine greater than or equal to 2 mg/dL, liver cirrhosis, AST or ALT > 3x the upper normal limit, hemoglobin < 10.5 g/dl);
  • Heart rate > 100 at screening on two separate measurements given potential of study medication to increase heart rate.

    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 65 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 21-65 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:

    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:

      Has had a tubal ligation, hysterectomy, or bilateral oophorectomy;

      Is post menopausal;

      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:

  • Interest in receiving treatment for heavy drinking.
  • Current DSM-IV diagnosis (based on SCID) of substance dependence (other than alcohol and/or nicotine); a negative urine drug screen will also be required.
  • DSM-IV Axis I criteria for a lifetime diagnosis of schizophrenia, bipolar disorder, or other psychoses;
  • Active illness within the past 6 months of the screening visit that meet the DSM-IV criteria for a diagnosis of major depressive disorder or anxiety disorder; subjects with a history of attempted suicide will be excluded;
  • Clinically significant medical abnormalities (e.g., unstable hypertension, clinically significant EKG abnormalities, Creatinine greater than or equal to 2 mg/dL, liver cirrhosis, AST or ALT > 3 times the upper normal limit, hemoglobin < 10.5 g/dl);
  • Heart rate > 100 at screening on two separate measurements given potential of study medication to increase heart rate.
  • BMI less than or equal to 18.5 or anorexia given potential of the study medication to reduce appetite.
  • BMI greater than or equal to 35 kg/m(2).
  • Not advisable to abstain from using psychotropic medications, i.e. naltrexone, acamprosate, alcohol dehydrogenase inhibitors, topiramate, gabapentin, ondansetron, benzodiazepines, beta-blockers, H2-blockers, and alpha-1 blockers, baclofen, and barbiturates, in addition to nonprescription drugs, dietary/herbal supplements, and hormone replacement therapy within 2 weeks of the study medication.
  • History of epilepsy or alcohol-related seizures;
  • patients 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);
  • History of alcohol-induced flushing reactions.
  • Clinically significant alcohol withdrawal symptoms, as assessed by a CIWA-Ar score > 8 at screening.
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02039349

Contacts
Contact: Lorenzo Leggio, M.D. (301) 435-9398 lorenzo.leggio@nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
Sponsors and Collaborators
University of Rhode Island
Investigators
Principal Investigator: Lorenzo Leggio, M.D. National Institute on Alcohol Abuse and Alcoholism (NIAAA)
  More Information

Additional Information:
Publications:

Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute on Alcohol Abuse and Alcoholism (NIAAA) )
ClinicalTrials.gov Identifier: NCT02039349     History of Changes
Other Study ID Numbers: 140042, 14-AA-0042
Study First Received: January 15, 2014
Last Updated: November 7, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Alcoholism
Ghrelin
Ghrelin Antagonism

Additional relevant MeSH terms:
Alcohol Drinking
Alcohol-Related Disorders
Alcoholism
Chemically-Induced Disorders
Drinking Behavior
Mental Disorders
Substance-Related Disorders

ClinicalTrials.gov processed this record on November 27, 2014