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
Study type: Interventional
Phase: Phase 2

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 ^.
    

Detailed description: 
      OBJECTIVE :

      To evaluate pexacerfont, an orally available, brain penetrant selective CRH1 antagonist for
      its ability to modulate emotional and motivational processes in anxious, recently detoxified
      alcohol dependent patients.

      STUDY POPULATION:

      Up to 70 anxious, alcohol dependent subjects, aged 21-65 years will be enrolled to complete
      the study in 50 patients.

      DESIGN

      Subjects will be inpatients and enter the present protocol once withdrawal treatment, if
      needed, is completed. They will undergo interviews for construction of guided imagery scripts
      during a 3 day pre-treatment phase, after which they will receive randomized double blind
      treatment with active medication or placebo for 23 days, followed by a 3 day post-treatment
      inpatient monitoring phase, and two follow-up outpatient visits. While hospitalized, repeated
      measures of spontaneous craving for alcohol, ratings of psychopathology, and blood chemistry
      including cortisol will be obtained over this time. During the second week of treatment,
      craving responses will be assessed in a challenge session that combines a social stressor and
      exposure to physical alcohol cues. During the final week, three sessions of guided imagery
      will be carried out, on separate days and in a counter-balanced order, exposing the subject
      to personalized stress-, alcohol- or neutral condition associated stimuli. The final week
      will also include an fMRI session with emotional and motivational tasks, on a day separate
      from any guided imagery session. Subjects will remain hospitalized throughout the study, will
      remain on the unit for a 3 day post-medication monitoring period, and will return for follow
      up app. 1 and 4 weeks following completion of randomized treatment.

      OUTCOME MEASURES

      The primary outcome will be craving for alcohol on guided imagery challenge sessions.
      Secondary outcomes will include craving as measured in the combined social stress alcohol cue
      challenge session, spontaneous craving and psychopathology ratings repeatedly measured on the
      inpatient unit over time. Exploratory blood biomarkers and brain responses to positive and
      negative affective stimuli on the fMRI session will also be obtained.
    

Intervention name(s): Pexacerfont; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Addiction; Alcohol; Alcohol Treatment; Alcoholics; Alcohol Dependence; Anxiety Disorder; Alcoholism