Pexacerfont for Stress-induced Food Craving

Objective: To evaluate pexacerfont, an orally available, brain-penetrant selective CRF1
antagonist, for its ability to modulate food craving and consumption in chronic unsuccessful
dieters.

Study population: We will collect evaluable data from up to 90 restrained eaters
(individuals who indicate a history of chronic yo-yo dieting by scoring 15 or higher on the
Dietary Restraint Scale). To ensure that all participants have some degree of preoccupation
with food, an additional inclusion criterion will be endorsement of the Restraint Scale item
Do you give too much time and thought to food? Apart from their preoccupation with food,
participants will be healthy. They can be either normal-weight or overweight (Body Mass
Index (BMI) > 22kg/m2); this will be stratified across dose groups.

Frank eating disorders will be exclusionary.

Design: This will be a randomized, double-blind, between-groups study with two groups.

Participants will be stabilized on either pexacerfont or placebo for 28 days (300 mg/day
loading dose for 7 days, followed by 100 mg/day maintenance dose for 21 days). On day 15,
they will undergo a math-test stressor and have stress-induced food consumption and craving
assessed in a bogus taste test and on visual-analog scales. During three subsequent visits
between days 16 and 28, they will be exposed to three personalized imagery-induction
scripts-one stress-related, one food-related, and one neutral/relaxing. Food craving and
food consumption will be assessed on those visits as well.

Outcome measures: The primary outcome measure is stress-induced eating after the math-test
stressor. Other outcome measures will include spontaneous food consumption after the other
stressors, subjective ratings of stress, mood, and food craving, autonomic responses
(galvanic skin response (GSR), heart rate, and blood pressure), and endocrine responses
(salivary cortisol, salivary alpha-amylase, and serum cortisol).

- INCLUSION CRITERIA:

1. Body Mass Index (BMI) > 22 kg/m(2)

2. Score of 15 or higher on the Dietary Restraint Scale, with endorsement of the
Restraint

Scale item Do you give too much time and thought to food?

3. Age 21 - 65 years.

(4a) For 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 for a period of 6 months beginning from first dose
of randomized treatment. 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 progesterone 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.

(4b) Men, unless surgically sterilized (vasectomy with documentation of azoospermia),
must agree to practice abstinence or use barrier contraception, and not donate sperm,
for a period of 6 months beginning from first dose of randomized treatment.

EXCLUSION CRITERIA:

1. Current employment at NIDA IRP or Bristol-Myers Squibb (BMS), or being in the
immediate family of an employee. Immediate family is defined as a spouse, parent,
child, or sibling, whether biological or legally adopted.

2. Current participation in another clinical study that includes exposure to an
investigational or non-investigational drug or device.

3. Participation in a clinical study for a condition related to weight or dieting within
the preceding month.

4. Any history of participation in a trial involving pexacerfont or closely related
compounds.

5. Any medical condition or laboratory finding that, in the judgment of the
investigators, could adversely affect safety or study integrity. Examples include but
are not limited to diabetes type 1 and type 2, ischemic heart disease, uncontrolled
hypertension, and history of cerebrovascular accident or transient ischemic attack.

6. For women: pregnancy, breastfeeding, or planning to become pregnant within 6 months
from the administration of first dose of study drug.

7. Past or present diagnosis of any eating disorder, including Anorexia Nervosa, Bulimia
Nervosa, and Eating Disorder NOS (e.g., Binge-Eating Disorder). (Eating-disordered
individuals probably represent a distinct population and should therefore be studied
separately.)

8. Past or present diagnosis of schizophrenia, bipolar disease, or any psychotic
disorder; past or present diagnosis of dementia or any other disorder that has led to
a clinically significant cognitive impairment; present diagnosis of any mood or
anxiety disorder; any other psychiatric condition that presently requires, or in the
past month has required, pharmacological intervention.

9. Past or present diagnosis of any substance-use disorder except nicotine dependence.

10. Urine tests positive for illegal drugs.

11. Evidence of thyroid disorder by medical history or screening physical exam, with TSH
< 0.36 or greater than 3.74 UIU/ml; or current or history of use of thyroid
medication.

12. Adrenal or pituitary pathology as evidenced by medical history or suggested by
abnormal screening labs.

13. 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 (including closed head trauma, penetrating head injury, skull
fracture, or intracranial hemorrhage), or CNS tumor.

14. Active liver disease or a history of hepatic intolerance to medications that, in the
investigators' judgment, is medically significant.

15. 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).

16. Difficulty swallowing tablets or capsules.

17. Exclusionary physical and laboratory test findings:

QTc > 475 msec

platelets less than or equal to 75,000/mm(3)

hemoglobin less than or equal to 9g/dL

neutrophils, absolute less than or equal to 1000/mm3

SGOT (AST) > 2.5 times upper limit of normal

SGPT (ALT) > 2.5 times upper limit of normal

bilirubin 2 times upper limit of normal

GFR < 60mL/min/1.73m2 or significant proteinuria

diastolic blood pressure > 105 mmHg

TSH < 0.36 or > 3.74 UIU/ml

18. 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.

19. Any change in a non-excluded medication in the past 3 months.

20. Systemic intake of corticosteroids acutely within 2 weeks or chronically (> 28 days)
within the last 6 months. (Topical hydrocortisone and inhaled corticosteroids are
allowed.)

21. Use of medications that are CYP3A4 inhibitors or inducers (see Appendix 3); study
applicants should not take these medications for at least 7 days prior to
randomization and during the remainder of the study.

22. Dietary restrictions or food aversions that would interfere with valid assessment of
eating in our laboratory sessions.