Effect of LY686017 on Alcohol Craving
Condition: Alcohol Dependence; Alcoholism
MeSH terms: Alcoholism
Intervention: LY686017; Placebo
Intervention description: 50 mg administered orally on a daily basis; Administered on a daily basis
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 66.0
Sex: All
Minimum age: 21 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Anxiety; Alcohol Dependence; Alcoholism

Summary:

      This study will determine whether the experimental drug LY686017 can reduce a person's desire
      for alcohol. A brain chemical called Substance P acts at places in the brain called NK1
      receptors. Substance P is released in response to stress and gives rise to behaviors that are
      thought to represent anxiety. LY686017 blocks Substance P from acting at the NK1 receptors.

      People between 21 and 65 years of age who have been drinking on a regular basis for at least
      one month before entering the study, who meet the criteria for alcohol dependence and who
      have an elevated score on a general test of anxiety may be eligible for this study.

      Participants are admitted to the NIH Clinical Center for 35 days. They participate in an
      alcohol treatment program in addition to the research study. After having been withdrawn from
      alcohol for at least 2 days, participants receive either 50 mg of LY686017 or placebo (an
      inactive substance that looks like the study drug) every morning for 28 days. In addition to
      drug treatment, they undergo the following procedures:

        -  Functional magnetic resonance imaging (fMRI): In the last week of the study, subjects
           undergo MRI to study the amount of blood going to brain structures thought to be
           involved in anxiety and craving. During the procedure, they look at pictures of faces
           exhibiting various emotions and pictures related to alcohol.

        -  Cue reactivity: At the beginning and towards the end of the study, subjects are asked to
           rate their alcohol craving and their anxiety level while they sniff and handle their
           favorite alcoholic beverage or water.

        -  Metyrapone test: During weeks 1 and 4 of the study, subjects are given metyrapone - a
           drug that interferes with the body's ability to make the stress hormone cortisol - to
           determine how LY686017 affects the body's hormonal response. The drop in cortisol from
           metyrapone administration causes the brain to release ACTH, a hormone that causes the
           adrenal gland to make cortisol.

        -  Trier test: In the last week of the study, subjects give a 5-minute speech to three
           people and are then asked to subtract numbers in their head. Then they are asked to rate
           their feelings and desire for alcohol on two rating scales. Blood is drawn from a saline
           lock at the beginning and end of the test to measure hormone levels.

        -  Rating scales: Subjects complete an Obsessive Drinking Scale weekly and an Alcohol Urge
           Questionnaire and Comprehensive Psychiatric Rating Scale twice a week.

        -  Blood tests: Blood samples are collected periodically to check blood chemistries,
           clotting time, and the amount of LY686017 in the blood.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Age 21 - 65.

          -  DSM-IV diagnosis of alcohol dependence on SCID, alcohol problems as primary complaint
             among substance use disorder, and alcohol use within the last month.

          -  Spielberger trait anxiety score greater than 39.

          -  Females of childbearing potential must agree to use a reliable method of birth control
             during the study. Reliable methods of birth control include oral contraceptives or
             Norplant(Registered Trademark); barrier methods such as diaphragms with contraceptive
             jelly, cervical caps with contraceptive jelly, condoms with contraceptive foam, or
             intrauterine devices; a partner with a vasectomy; or abstinence from intercourse.

        EXCLUSION CRITERIA:

        Subjects will be excluded if they meet any of the criteria below. The criteria for
        enrollment will be followed explicitly. If a subject who does not meet enrollment criteria
        is inadvertently enrolled, that subject will be discontinued from the study and Eli Lilly
        will be contacted.

        General exclusion criteria for the NIAAA intramural treatment program:

          -  People who present with complicated medical problems requiring intensive medical or
             diagnostic management, such as hypertensive emergency, serious GI bleeding, major
             organ or body system dysfunction such as decompensated liver disease, renal failure,
             myocardial ischemia, congestive heart failure or cerebrovascular disease, major
             endocrine problems such as uncontrolled diabetes, pancreatic or thyroid disease.

          -  People who are infected with the Human Immunodeficiency Virus (HIV).

          -  Serious neuro-psychiatric conditions which impair judgment or cognitive function to an
             extent that precludes them from providing informed consent or complying with
             treatment, such as psychotic illness or severe dementia (incompetent individuals).

          -  People who are unlikely or unable to complete the treatment program because they
             become or are likely to be incarcerated while on the protocol.

          -  People who are required to receive treatment by a court of law or who are
             involuntarily committed to treatment.

          -  People with uncontrolled hypertension

        Study specific exclusion criteria:

          -  People who are investigator site personnel directly affiliated with this study and/or
             their immediate families. Immediate family is defined as a spouse, parent, child or
             sibling, whether biological or legally adopted.

          -  People who are employees of Eli Lilly & Co.

          -  Treatment within the last 30 days with a drug [not including study drug] that has not
             received regulatory approval for any indication at the time of study entry.

          -  A history of seizures, other than documented febrile seizures

          -  Patients with clinically significant hepatobiliary disease (as evaluated by a trained
             hepatologist) will be excluded from the protocol

          -  Pregnancy or lactation (negative pregnancy test required)

          -  Regular use of psychotropic medication (antidepressant, lithium, antipsychotic,
             anxiolytic, antiepileptic) within last 4 weeks, with the exception of benzodiazepines
             administered within the NIAAA program as part of alcohol withdrawal treatment.

          -  Inability or unwillingness to participate in an fMRI scan, including presence of
             metallic objects in the body, or pronounced claustrophobia

          -  Hypopituitarism or reduced adrenal secretory activity because of the risk of
             precipitating acute adrenal failure with metyrapone.

          -  Porphyria because metyrapone may be porphyrinogenic based on data from in-vitro
             systems.

          -  Thyroid dysfunction, which may alter the response to metyrapone.