Effectiveness of GW468816, an NMDA Glycine Site Antagonist, for Prevention of Relapse to Smoking

Inclusion Criteria:

1. Written informed consent
2. WOMEN aged 18-65 years, inclusive
3. Self-report of smoking 10 or more cigarettes per day in the past 6 months and expired air CO >10 ppm at the time of enrollment
4. DSM-IV criteria for current Nicotine Dependence satisfied
5. Subjects must be willing to take the study medication and be motivated to quit smoking (willing to set a quit date within 2 weeks of entry into the protocol)

6. Women of childbearing potential must have a negative urine pregnancy test (quantitative HCG) at baseline and at week 8, prior to receiving the first dose of study medication and females must agree to use an approved form of contraception from the day of the first dose of study medication for 90 days after the last dose of study medication. Approved forms of contraception include any of the following:

   • Complete abstinence from intercourse from 2 weeks prior to administration of the study drug, through the treatment phase and for 90 days after discontinuation of study medication.
   • Sterilization of male partner
   • Implant of levonorgestrel
   • Injectable progesterone
   • Intrauterine device (IUD) with <1 percent rate of failure per year
   • Any other method with published rate of failure of <1 percent per year Due to induction of cytochrome p450 3A4, oral contraceptives may be continued during the study but cannot be relied upon as a sole means of contraception, and a second method of contraception such as a barrier method will be required and reimbursed by the study.

Exclusion Criteria:

1. Pregnant or able to become pregnant and not willing to use approved contraception
2. Severe unstable medical illness including cardiovascular, hepatic, renal, respiratory, metabolic, neurological, or hematological disease by history, physical examination or clinical laboratory test results such that hospitalization for treatment of that illness is likely within the next two months
3. Life-threatening arrhythmia, cerebro-vascular or cardiovascular event within six months of enrollment
4. Elevation over 1.5 times upper limit of normal value (ULN) of any of the following laboratory results: Total, conjugated, or unconjugated bilirubin; alkaline phosphatase, alanine transferase (ALT), aspartate aminotransferase (AST), creatine phosphokinase (CPK), or lactate dehydrogenase (LDH).
5. Use of tobacco-containing products other than cigarettes (e.g., cigar, pipe)
6. Abuse or dependence of any substance other than nicotine or caffeine in the past 6 months. Abuse of alcohol is here defined as an average weekly intake of greater than 21 units or an average daily intake of greater than three units (males) or defined as an average weekly intake of greater than 14 units or an average daily intake of greater than two units (females). One unit is equivalent to a half-pint (220mL) of beer or one (25mL) measure of spirits or one glass (125mL) of wine.
7. Diagnosis of major depressive disorder in the past 6 months
8. Lifetime DSM-IV diagnosis of organic mental disorder, schizophrenia, schizoaffective disorder, bipolar disorder, delusional disorder or psychotic disorders not elsewhere classified
9. History of non-response in the past month to an adequate trial of nicotine re placement therapy, defined as nicotine replacement > 21 mg per day patch (or equivalent dose of gum, inhaler, nasal spray, or lozenge) for at least 4 weeks.
10. History of multiple adverse drug reactions
11. Use of an investigational drug or device within 4 weeks of enrollment
12. Concurrently enrolled in a study that involves exposure to a drug or device.
13. Urine positive for drugs of abuse at screening visit.
14. Use of statins during the period of the investigation.