Corticotropin-Releasing Hormone Receptor 1 (CRH1) Antagonism in Anxious Alcoholics^
Condition: Alcohol-Related Disorders; Alcohol Dependence; Alcoholism; Anxiety Disorder
MeSH terms: Alcoholism; Alcohol-Related Disorders; Anxiety Disorders
Intervention: Pexacerfont; Placebo
Intervention description: 300 mg, orally, once/day during week 1, 100 mg, orally, once/day during weeks 2 and 3.; 300 mg, orally, once/day during week 1, 100 mg, orally, once/day during weeks 2 and 3.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 70.0
Sex: All
Minimum age: 21 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Addiction; Alcohol; Alcohol Treatment; Alcoholics; Alcohol Dependence; Anxiety Disorder; Alcoholism

Summary:

      Background:

      - Individuals who are dependent on alcohol often have feelings of anxiety, irritability,
      anger, and depression. These feelings, as well as stress, may contribute to the risk of
      relapse and continued drinking. Studies have shown that alcohol consumption increases the
      activity of certain molecules in the brain known as CRH1 receptors, which are key to
      producing the body s response to stress, and whose activation generates feelings of anxiety.
      Researchers are interested in learning whether the experimental drug pexacerfont, which
      blocks CRH1 receptors and has been studied in individuals with anxiety disorders and
      depression, can lessen anxiety and craving for alcohol as part of alcohol-dependence
      treatment.

      Objectives:

      - To determine the safety and effectiveness of pexacerfont as a treatment for anxiety-related
      alcohol craving.

      Eligibility:

      - Individuals between 21 and 65 years of age who are alcohol-dependent and have problems with
      anxiety.

      Design:

        -  This study requires an inpatient admission to the NIH Clinical Center for approximately
           1 month, with two additional study visits 1 week and 1 month after discharge from the
           hospital.

        -  Participants will be screened with a medical history, physical examination, and blood
           and urine tests.

        -  During the inpatient period, participants will have standard treatment for alcohol
           dependence, including support and interventions from institute staff to address
           cravings, anxiety, or other psychological problems. Participants will not receive formal
           psychological treatment or psychiatric medications for anxiety, but will receive
           training in relaxation techniques.

        -  Participants will be assigned to take either pexacerfont or placebo for 3 weeks. During
           this time, participants will have the following procedures:

        -  Frequent blood tests.

        -  Rating scales and questionnaires about alcohol cravings and anxiety.

        -  Dexamethasone suppression test with frequent blood draws to study hormone response to
           stress.

        -  Social stress test involving public speaking, followed by blood samples and
           questionnaires on alcohol craving.

        -  Cue Reactivity (CR) session to study cravings and responses to alcohol-based cues.

        -  Functional magnetic resonance imaging scan to evaluate brain activity while taking the
           medication or placebo.

        -  Participants will have two follow-up visits for additional blood tests and
           questionnaires about the effects of the treatment ^.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

               1. Signed written informed consent:

                  a. Patients must be competent to understand the nature of the study, sign the
                  informed consent prior to any study-related procedures, agree to comply with the
                  prescribed dosage regimens, agree to remain hospitalized at the NIH Clinical
                  Center throughout the duration of the study and to return for follow-up visits as
                  specified, and agree to communicate to study personnel about adverse events and
                  concomitant medication use.

               2. Target population:

                    1. DSM-IV diagnosis of alcohol dependence on SCID interview,

                    2. alcohol problems as primary complaint among substance use disorders,

                    3. alcohol use within the last month.

                    4. Spielberger trait anxiety inventory score > 39.

                    5. Right-handedness

               3. Age and sex:

                    1. Men and women, ages 21 65 years.

                    2. Women of childbearing potential (WOCBP) must have a negative serum or urine
                       pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG)
                       prior to enrollment, and agree to using an adequate method of contraception
                       to avoid pregnancy for a period of 6 months beginning from first dose of
                       randomized treatment. WOCBP include any female who has experienced menarche
                       and who has not undergone successful surgical sterilization (hysterectomy,
                       bilateral tubal ligation, or bilateral oophorectomy) or is not
                       postmenopausal. Adequate methods of contraception are practicing complete
                       abstinence from intercourse for two weeks prior to administration of study
                       drug; having a male sexual partner(s) who is surgically sterilized
                       (vasectomy with documentation of azoospermia) prior to inclusion; having a
                       sexual partner(s) who is/are exclusively female; using oral contraceptives
                       (either combined or progestogen only) with single-barrier method of
                       contraception consisting of spermicide and condom or diaphragm; using
                       double-barrier contraception, specifically, a condom plus spermicide and a
                       female diaphragm or cervical cap; using an approved intrauterine device
                       (IUD) with established efficacy.

                    3. Men, unless surgically sterilized (vasectomy with documentation of
                       azoospermia), must agree to practicing abstinence or using barrier
                       contraception, and not donate sperm, for a period of 6 months beginning from
                       first dose of randomized treatment.

        EXCLUSION CRITERIA:

          1. General:

               1. 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.

               2. Employees of Bristol-Meyers Squibb (BMS) or immediate family of BMS employees.

               3. Subjects with current participation in another clinical study in which the
                  subject is or will be exposed to an investigational or non investigational drug
                  or device; participation in a clinical study for an illness unrelated to alcohol
                  use within the preceding month; or any previous participation in a trial
                  involving pexacerfont or closely related compounds.

               4. Inability or unwillingness to participate in an MR scan, including presence of
                  ferromagnetic metallic objects in the body, or pronounced claustrophobia

               5. Any medical or psychiatric condition or laboratory finding that, in the judgment
                  of the investigator could adversely affect subject safety or study integrity.

               6. Subjects who are unlikely or unable to complete this study because of impending
                  or likely incarceration while on the protocol.

               7. Subjects who are required to receive treatment by a court of law or involuntarily
                  committed to treatment.

          2. Sex and reproductive status:

               1. Inability or unwillingness to practice contraception as described above

               2. Women who are pregnant, breastfeeding, or planning to become pregnant within 6
                  months from the administration of first study drug dose.

               3. Men who are planning to father a child within 6 months from the

             administration of the first study drug dose

          3. Exclusionary psychiatric conditions:

               1. Past or present diagnosis of schizophrenia, bipolar disease, or any psychotic
                  disorder other than one determined to be substance induced; past or present
                  diagnosis of dementia, or any other disorder which has led to a clinically
                  significant cognitive impairment; any other psychiatric condition which at the
                  present time requires, or in the past month has required pharmacological
                  intervention other than standard withdrawal treatment as described in the NIAAA
                  Assessment and Treatment Protocol (#05-AA-0121).

               2. A personality disorder which, in the investigator s judgment could lead to
                  non-compliance with study procedures.

               3. Subjects, who in the investigator's judgment, pose a significant suicide risk.
                  Evidence of serious suicide risk may include any history of suicidal behavior in
                  the last 6 months and/or any suicidal ideation of type 4 or 5 on the Columbia
                  Suicide Severity Rating Scale (C-SSRS) in the last 2 months.

               4. Positive urine test for illegal drug use.

          4. Exclusionary medical history and concurrent medical conditions:

               1. Subjects with clinically significant thyroid pathology that would interfere with
                  efficacy or safety evaluations, or who are undergoing treatment for their thyroid
                  pathology (e.g., thyroid supplementation).

               2. Subjects with adrenal or pituitary pathology as evidenced by medical history or
                  suggested from abnormal screening laboratory tests.

               3. Subjects with a significant history (as judged by the Investigator) of seizure
                  disorder (e.g., epilepsy or withdrawal seizures), other significant neurological
                  disorders (e.g., Parkinson s Disease, multiple sclerosis, stroke,
                  neurodegenerative disease, cerebral palsy) or severe head trauma.

               4. Subjects with active liver disease or a history of hepatic intolerance to
                  medications that in the Investigator s judgment, is medically significant.

               5. Subjects with a history of Diabetes Mellitus Type I and II or gastric bypass or
                  reduction surgery.

               6. Subjects with Human Immunodeficiency Virus (HIV) infection.

               7. Subjects with difficulty swallowing tablets or capsules.

          5. Exclusionary physical and laboratory test findings

               1. QTc > 475 msec

               2. Platelets less than or equal to 75,000/mm(3)

               3. Hemoglobin less than or equal to 9g/dL

               4. Neutrophils, Absolute less than or equal to 1000/mm(3)

               5. SGOT (AST) > 3.0 times Upper Limit of Normal

               6. SGPT (ALT) > 3.0 times Upper Limit of Normal

               7. Bilirubin 2 times Upper Limit of Normal

               8. Creatinine greater than or equal to 2mg/dL

               9. Diastolic blood pressure > 105 mmHg

              10. TSH > 1.6 times Upper Limit of Normal

              11. Creatine kinase > 5 times Upper Limit of Normal

          6. Prohibited treatments

               1. Regular use of psychotropic medication (antidepressant, lithium,

                  antipsychotic, anxiolytic, antiepileptic, opiates, or hypnotics), within one week
                  prior to inclusion, with the exception of benzodiazepines

                  administered within the NIAAA program as part of alcohol withdrawal

                  treatment. Fluoxetine may not have been taken within 5 weeks, and depot
                  antipsychotics may not have been taken within 12 weeks.

               2. Any change in a non-excluded medication in the past 3 months.

               3. Systemic intake of corticosteroids acutely within two weeks or chronically within
                  the last 6 months (Topical hydrocortisone and inhaled corticosteroids are
                  allowed).

               4. Patients taking medications that are CYP3A4 inhibitors or inducers, should not be
                  taking these medications for at least seven days prior to randomization and
                  during the remainder of the study.