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

• 7-day, point-prevalence tobacco abstinence at the end of the first week of exposure to GSK598809/placebo [ Time Frame: Week 3 of the study ] [ Designated as safety issue: No ]
  Those assigned to GSK598809 will demonstrate a higher rate of biochemically-verified, 7-day, point-prevalence tobacco abstinence than those assigned to identical placebo at the end of the first week of exposure to GSK598809/placebo.
• 7-day, point-prevalence tobacco abstinence at the end of 6 weeks exposure to GSK598809/placebo [ Time Frame: Week 8 of the study ] [ Designated as safety issue: No ]
  Those assigned to GSK598809 will demonstrate a higher rate of biochemically-verified, 7-day, point-prevalence tobacco abstinence than those assigned to identical placebo at the end of 6 weeks exposure to GSK598809/placebo.
• 7-day, point-prevalence tobacco abstinence 2-weeks after discontinuation of double blind study medications [ Time Frame: Week 10 of the study ] [ Designated as safety issue: No ]
  Those assigned to GSK598809 will demonstrate a higher rate of biochemically-verified, 7-day, point-prevalence tobacco abstinence than those assigned to identical placebo two weeks after discontinuation of double blind study medications.

The purpose of this research study is to find out if an investigational drug, GSK598809 can help people who have very recently quit smoking; the investigators want to find out if continuing to take GSK598809 over six weeks can help prevent smokers from relapsing. To relapse means you "fall back" into smoking again after quitting. The investigators also want to find out if GSK598809 is safe to take without causing too many side effects.

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.

• Drug: GSK598809
  Oral dose of 60 mg/day for a treatment period six weeks
• Drug: Placebo
  Placebo

• Experimental: GSK598809
  Intervention: Drug: GSK598809
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

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.

• National Institute on Drug Abuse (NIDA)
• Mclean Hospital
• GlaxoSmithKline