Pexacerfont to Reduce Stress-induced Tobacco Craving

Objective:

To evaluate pexacerfont, an orally available, brain-penetrant selective CRF1 antagonist, for
its ability to modulate emotional and motivational processes in daily smokers who are
seeking to quit smoking.

Study population:

We will collect evaluable data from up to 60 adult, greater than or equal to 10 cigarettes
per day smokers who smoke their first cigarette within one hour of waking as reported on the
Fagerstrom Test of Nicotine Dependence (FTND) and wish to quit smoking.

Design:

Participants will be randomly assigned to one of two groups to receive 30 days of oral
pexacerfont (300 mg/day loading dose for 7 days, followed by 100 mg/day maintenance dose for
23 days) or matching placebo under double-blind conditions. On Day 15 and 16, subjects will
have two days of testing to evaluate reactivity to stressful/neutral stimuli with and
without the presence of smoking cues. Reactivity will be tested in terms of physiological
parameters, subjective reports, nicotine reinforcemen, smoking resistance paradigms and
functional Magnetic Resonance Imaging (fMRI) Blood Oxygen Level Dependent (BOLD) signal at
rest and in response to stress/cue-related tasks. In addition, during the last 14 days of
study drug administration, subjects will attempt to stop smoking. Daily assessments of
smoking behavior will be obtained. Finally, on days 26 and 27, participants will again have
two days of testing to evaluate reactivity to stressful/neutral stimuli. Reactivity will be
tested in terms of physiological parameters, subjective reports, cue reactivity paradigms
and functional Magnetic Resonance Imaging (fMRI) Blood Oxygen Level Dependent (BOLD) signal
at rest and in response to stress/cue-related tasks.

Outcome measures:

Outcome measures in laboratory sessions will include nicotine reinforcement, latency to
lapse in a smoking resistance paradigm, subjective ratings of stress, mood, and tobacco
craving, autonomic responses (galvanic skin response, heart rate, and blood pressure),
endocrine responses (salivary cortisol and salivary (alpha) amylase, a measure of endogenous
adrenergic activity during stress), and fMRI BOLD signal at rest and in response to
stress/cue-related tasks. Outcome measures during the quit attempt will include, change in
consumption, number of lapses, and latency to lapse.

- INCLUSION CRITERIA:

Daily smokers for at least one year; smoke at least 10 cigarettes per day; smoke first
cigarette of day within one hour of waking as recorded on Fagerstrom Test of Nicotine
Dependence (FTND).

Currently wish to quit smoking. Stage of Change (Prochaska and DiClemente, 1983) will be
assessed for each participant and those who are in the contemplation and planning stages
will be included in the study.

Urinary continine level greater than or equal to 100 ng/ml (NicAlert(Registered Trademark)
reading greater than or equal to 3) at screening.

Men and women, ages 18 to 55 years. Justification: Many cognitive processes change with
age. In addition, the risk of difficult-to-detect medical abnormalities such as silent
cerebral infarcts increases with age. As this study includes fMRI scanning, older
individuals, defined as those over 55, will be excluded as these age-related abnormalities
may affect quality of imaging data.

Women of childbearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the
start of study drug, and agree to use an adequate method of contraception to avoid
pregnancy from study entry to 6 months following the last dose of study drug. Women of
childbearing potential 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 for
sexually active women are having a male sexual partner(s) who is surgically sterilized
prior to inclusion; having a sexual partner(s) who is/are exclusively female; using oral
contraceptives (either combined or progestrogen only) with a 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; or using an approved intrauterine device (IUD) with established efficacy.

Men, unless surgically sterilized (vasectomy with documentation of azoospermia), must
agree to practice abstinence or use barrier contraception with spermacide (unless their
partner has been surgically sterilized or is infertile), and not donate sperm, during drug
administration and for a period of 6 months after the last dose of randomized treatment.

EXCLUSION CRITERIA:

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.

Employees of BristolMyersSquibb (BMS) or immediate family of BMS employees.

People who are currently participating in another clinical study in which they are exposed
to an investigational or non-investigational drug or device; people who have ever
participated in a trial involving pexacerfont or closely related compounds.

People who are unable or unwilling to participate in an MR scan, including those who are
left-handed, have metallic objects in the body (pacemaker, plates, clips, pins, rods,
joints, pellets, cochlear implants, etc.), have pronounced claustrophobia, or who are
physically incompatible with the machine dimensions.

Women who are pregnant, breastfeeding, or planning to become pregnant within 6 months from
the administration of last dose of study drug.

People with: Present Major Depressive Disorder, a past or present diagnosis of
schizophrenia, bipolar disorder, or any psychotic disorder; past or present diagnosis of
dementia, or any other disorder which has led to a clinically significant cognitive
impairment as assessed on screening evaluation by computerized SCID and clinical interview
as well as the Wechsler Abbreviated Scale of Intelligence (WASI) vocabulary subtest with
exclusion of participants with estimated full IQ less than 85.

People who currently use any illicit drugs or whose urine tests positive for illegal drugs
at screening. People with a past history of dependence to drugs or alcohol, or who
currently meet DSM-IV criteria for alcohol abuse or dependence or who consume more than 15
alcoholic drinks per week during the past month.

People with evidence of thyroid disease by medical history, on screening physical exam or

laboratory tests with TSH greater than 1.6 times upper limit of normal.

People with a current seizure disorder or a significant history (as judged by the
investigators) of a seizure disorder, other significant neurological disorders (e.g.,
Parkinson's Disease, multiple sclerosis, stroke, neurodegenerative disease, cerebral
palsy) or severe head trauma, or CNS tumor.

People with current renal or liver disease including abnormal liver function tests
(LFT's): greater than or equal to 2.5 times upper limit of normal, Bilirubin 2 times upper
limit of normal, or abnormal renal function: serum creatinine greater than or equal to
2mg/dL.

People with a history of diabetes mellitus type I and II or gastric bypass or reduction
surgery. Justification: illnesses that change metabolism or the absorption from the GI
tract, would interfere with drug metabolism or absorption).

People with cardiovascular abnormalities including diastolic BP greater than 105; systolic
BP greater than 180; QTc greater than 475 msec.

People with hematologic abnormalities at screening: Platelets less than or equal
to75,000/mm(3), hemoglobin less than or equal to 9g/dL, neutrophils, absolute less than or
equal to 1000/mm(3).

People with HIV infection Justification: HIV can have CNS sequelae, thus introducing
unnecessary variability into the data. Assessment tool(s): HIV salivary test.

People with difficulty swallowing capsules.

Current use or history of use in the last 3 months of psychiatric medications including
but not limited to antidepressants, lithium, antipsychotics, anxiolytics, antiepileptics,
opiates, or hypnotics.

Any change in a non-excluded medication in the past 3 months. If systemic intake of
corticosteroids has occurred acutely within last 4 weeks or chronically within the last 6
months, one month should elapse since the last dose of systemic steroids before study drug
initiation. (Topical hydrocortisone and inhaled corticosteroids are allowed).

Use of medications that are CYP3A4 inhibitors or inducers.