Corticotropin-Releasing Hormone Receptor 1 (CRH1) Antagonism in Anxious Alcoholics^

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.

- 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.