Effects of Corticotropin-Releasing Hormone Receptor 1 (CRH1) Antagonism on Stress-Induced Craving in Alcoholic Women With High Anxiety

Objective:

To evaluate GSK561679, an orally available, brain penetrant selective CRH1 antagonist for
its ability to reduce alcohol craving in recently detoxified alcohol dependent women in
response to stress or alcohol-associated stimuli.

Study population:

Up to 60 anxious, alcohol dependent women, 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. One week of single blind placebo will be followed by randomized double
blind treatment with active medication or placebo for approximately 3 weeks. Spontaneous
craving for alcohol and ratings of psychopathology will be obtained twice weekly throughout
the study. During the placebo lead-in week, a diurnal cortisol curve will be obtained, and a
baseline dexamethasone-CRH test may be carried out. These measures will be repeated after
10-14 days of randomized treatment. Around this time, craving responses will also 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. An fMRI session will be carried
out last. Subjects will remain hospitalized throughout the study, and will remain on the
unit for a 3 day post-medication monitoring period.

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:

DSM-IV diagnosis of alcohol dependence on SCID interview (23), alcohol problems as primary
complaint among substance use disorders, and alcohol use within the last month.

Female sex

Spielberger trait anxiety inventory (24) score > 39.

Age 21 65 years.

Able to comprehend the consent form, and provide informed consent.

Either:

1. of non-childbearing potential defined as pre-menopausal (for definition, see appendix
females with a documented tubal ligation or hysterectomy; or postmenopausal defined
as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with
simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml
(< 140 pmol/L) is confirmatory]; or,

2. of child-bearing potential, has a negative serum pregnancy test both on screening and
during placebo lead-in, and agrees to one of the following methods of contraception:

i. Practices complete abstinence from intercourse two weeks prior to administration of
study drug, throughout participating in the clinical trial and for two weeks following
discontinuation of the study medication or,

ii. Has a male sexual partner(s) who is surgically sterilized (vasectomy with
documentation of azoospermia) prior to inclusion or,

iii. Has a sexual partner(s) who is/are exclusively female or,

iv. Uses oral contraceptives (either combined or progestogen only) with single-barrier
method of contraception consisting of spermicide and condom or diaphragm. Women of
child-bearing potential using an oral contraceptive in combination with a single-barrier
method of contraception are required to continue to use this form of contraception for 6
weeks following discontinuation of study medication.

v. Uses double-barrier contraception, specifically, a condom plus spermicide and a female
diaphragm or cervical cap. The subject must be using this method for at least 2 weeks
prior to the administration of the study drug, throughout the study, and 6 weeks following
discontinuation of study medication or,

vi. Uses any intrauterine device (IUD) with published data showing that the highest
expected failure rate is less than 1% per year. The subject must have the device inserted
at least 2 weeks prior to the first Screen Visit, throughout the study, and 6 weeks
following discontinuation of study medication.

EXCLUSION CRITERIA:

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 GlaxoSmithKline (GSK) or immediate family of GSK employees.

3. 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;
participation in a clinical study related to alcohol use within the preceding six
months; or any previous participation in a trial involving GSK561679 or closely
related compounds.

4. Inability or unwillingness to participate in an MR scan, including presence of
ferromagnetic objects in the body that constitute a contraindication for MRI of the
head, or pronounced claustrophobia

5. Any medical or psychiatric condition or laboratory finding other than those
explicitly listed below that, in the judgment of the investigator could adversely
affect subject safety or study integrity.

6. Schizophrenia, bipolar disease, or any past or present psychotic disorder other than
one determined to be substance induced; past or present dementia, or any other
disorder which has led to a cognitive impairment that in the opinion of the
investigator interferes with the subject s ability to provide informed consent, or
comply with study procedures. 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.

7. A personality disorder which, in the investigator s judgment could lead to
non-compliance with study procedures.

8. 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) (25) in the last 2 months.

9. Unlikely or unable to complete the treatment program because of impending or likely
incarceration while on the protocol.

10. Required to receive treatment by a court of law or involuntarily committed to
treatment.

11. Positive urine test for illegal drug use.

12. Human Immunodeficiency Virus (HIV) infection.

13. Peptic ulcer disease within the last 10 years, a history of an upper
gastro-intestinal (GI) bleeding, or a current stool positive for occult blood (if
such stool was obtained without the subject abstaining from red meat for three or
more days prior, testing may be repeated once following such abstinence. If that
stool is negative for occult blood by the Randomization Day the subject is considered
eligible).

14. Any clinically significant liver disease; specifically, cirrhosis as determined by
ultrasound; positive test for Hepatitis B surface antigen; positive test for
Hepatitis C antibody (hepatitis C antibody positivity confirmed by testing the same
sample using a highly specific immunoblot assay, or with hepatitis C RNA test on a
separate frozen sample); any of the following liver function test abnormalities:

1. On screening: gamma glutamyl transpeptidase (GGT) > 5 times the upper limit of
normal (ULN), aspartate aminotransferase (AST) > 3 times ULN, alanine
transaminase (ALT) > 3 times the ULN or Alkaline Phosphatase > 1.5 ULN; total
bilirubin > 1.5 times the ULN or direct bilirubin > 35%; Albumin below 3 g/dL;
INR > 1.5;

2. On the day preceding active medication: Alkaline Phosphatase > ULN, AST > 2
times ULN, ALT > 2 times the ULN or GGT > 4 times the ULN, total bilirubin > 1.5
times the ULN or direct bilirubin > 35%; Albumin below3 g/dL; INR > 1.5; if, on
the day preceding active medication,

3. On the day preceding active medication, any of the liver function tests above
have increased more than 1 time the ULN over the value at the screening.

15. Any cardiovascular condition, including uncontrolled hypertension, or ECG abnormality
that, in the investigator s judgment, may pose a safety concern; specifically, ECG
finding of a QTc time > 450 msec unless normalized on repeat ECG.

16. Subjects with known or suspected iron deficiency of unknown etiology.

17. Positive pregnancy test, lactating, or planning to become pregnant within 8 weeks
from the start of this 4-week study.

18. Regular use of psychotropic medication (antidepressant, lithium, antipsychotic,
anxiolytic, antiepileptic, opiates, or hypnotics), within one week, 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.

19. Current use, or likely requirement during the study, or use of within preceding 4
weeks, of contraindicated medications as listed in Appendix III and 2 weeks for
incidental use of non-steroid anti-inflammatory drugs (NSAIDs).

20. Subjects maintained on thyroid medication must have been euthyroid for at least six
months.

21. Systemic intake of corticosteroids acutely within two weeks or chronically within the
last 6 months (Topical hydrocortisone and inhaled corticosteroids are allowed).

22. A history of allergic reaction to, or significant adverse effects from excipients in
the GSK561679 tablet (see GSK561679 Investigator Brochure).