Effectiveness of GSK598809, a Selective D3 Antagonist, Added to Cognitive Behavioral Therapy and Nicotine Replacement Therapy for Smoking Cessation and Prevention of Very Early Relapse to Smoking

We propose to conduct a first test of the effect of the dopamine D3 receptor antagonist,
GSK598809, on smoking behavior when treatment is started immediately following the quit
date. To do this, we propose to conduct a 10-week, double-blind, placebo-controlled, proof
of mechanism study in 90 adult smokers. Participants will complete baseline evaluations.
They will receive manualized cognitive behavioral therapy, beginning prior to the quit date,
and will set a quit date for the day before their week 2 study visit. They will be given
short acting NRT (gum or lozenge) to use on their quit date. They will be asked to arrive
for the week 2 visit with 18-24 hours abstinence and an expired air CO ≤ 10ppm. Those who do
so will be randomly assigned to receive double blind GSK598809 or identical placebo for six
weeks. Participants will begin double blind GSK598809 or placebo, both in conjunction with
prn NRT up to 8 mg per day for two weeks. Participants will then continue double blind
GSK598809 or placebo in the absence of NRT for 4 more weeks. At the end of this period (week
8 of the study), participants will then be followed 2 weeks after discontinuation of double
blind treatment to complete the 10 weeks of the study.

Exclusion criteria:

1. Pregnant or able to become pregnant and not willing to use approved contraception.

2. Breastfeeding or planning to breastfeed during the study or lactating within the
month prior to enrollment.

3. Has any of the following medical conditions/situations:

Severe or unstable COPD or Asthma Bundle branch block Evidence of active neurological
disease, including current migraine headaches requiring chronic treatment.

Clinically significant renal dysfunction eGFR <60 History of any tissue/organ
transplant Total fasting cholesterol or triglycerides greater than 2 times the upper
limit of normal Previous or current history of cancer, including skin cancer Serum
Prolactin > 25 ng/mL at the time of screening or randomization Evidence of chronic
liver disease or ALT, AST, or alkaline phosphatase values >1.5 times the upper limit
of normal, total bilirubin values > the upper limit of normal, or history of severe
hepatobiliary disease (e.g. hepatitis B or C, or cirrhosis, Child-Pugh Class B/C)
Positive screening Hepatitis B surface antigen or Hepatitis C antibody, or positive
result within 3 months of screening A positive test for HIV antibody Any other
unstable cardiovascular or pulmonary disease, or medication for said diseases has
been changed in the past 3 months, or the medication is listed on the excluded
medications list.

4. Is unlikely to cooperate or unable to follow all of the procedures outlined in the
protocol

5. Use of tobacco-containing products other than cigarettes (e.g., cigar, pipe) and
unwilling to discontinue use of these on the quit date.

6. Abuse or dependence of any substance other than nicotine or caffeine in the past 6
months.

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 as determined by SCID.

9. History of multiple adverse drug reactions.

10. Has participated in a clinical trial and has received an investigational product
within the following time period prior to the first dosing day in the current study:
30 days, 5 half-lives or twice the duration of the biological effect of the
investigational product (whichever is longer).

11. Urine positive for drugs of abuse at screening and any pre-randomization visit.

12. Alcohol abuse, defined as self-report of an average weekly intake of > 21 standard
drinks or an average daily intake of >3 standard drinks (males) or an average weekly
intake of >14 standard drinks or an average daily intake of >2 standard drinks
(females) in the past 6 months. One unit is equivalent to a half-pint (220mL) of beer
or one (25mL) measure of spirits or one glass (125mL) of wine. Participants will be
advised to minimize alcohol consumption during the study, as there may be the
potential for additive effects of study medication and alcohol, potentially causing
greater sedation and feeling of intoxication than alcohol alone.

13. Has been exposed to more than four new chemical entities within 12 months prior to
the first day of the double-blind treatment phase.

14. Has used non-prescription drugs or herbal medicines that are centrally active within
14 days prior to the first dosing day, with the exception of non-daily PRN use of
acetaminophen or ibuprofen and daily use of vitamins.

15. Has ever used chronic antipsychotic, anti-epileptic, or mood stabilizing medication;
has used anti-anxiety medication, antidepressant medication, or prescription
sedatives or hypnotics within 5 half lives or two weeks of randomization, whichever
is greater.

16. Has a history of sensitivity to any of the study medications, or components thereof
or a history of drug or other allergy that, in the opinion of the investigator makes
participation contraindicated.

17. Has donated blood such that participation in the study would result in donation of
blood or blood products in excess of 500 ml within a 56-day period.

18. Has a failed smoking cessation attempt using adequate smoking cessation
pharmacotherapy within the last month.

19. Current Axis II DSM-IV diagnosis that may interfere with the conduct of the study.

20. Personal or family history of long QT syndrome, personal or family history of
unexplained syncope, or family history of unexplained sudden death.

21. Currently using, or have used within the month prior to study start, any drug that
can cause prolongation of the QT interval.

22. Currently using any HMG CoA Reductase Inhibitor.