The purpose of this study is to test the efficacy and safety of the NMDA glycine site antagonist, GW468816, versus placebo for smoking cessation. In addition, the study will include Zyban as an active comparator to measure the assay sensitivity of the clinical trial itself.

The investigators of this study hypothesize that both the GW468816 and Zyban treatment groups will have a higher rate of smoking abstinence, as measured by the primary outcome measure.

Condition	Intervention	Phase
Drugs, Investigational Nicotine Cessation Therapies Tobacco use cessation Tobacco Use Disorder	Drug: Nicotine Cessation Therapies	Phase III

Further Study Details: 

Primary Outcomes: Biochemically confirmed 7-day point prevalence of tobacco abstinence (e.g., self-report of smoking no cigarettes in the past 7 days) verified by saliva cotinine levels at Week 6
Secondary Outcomes: Biochemically-confirmed four-week continuous tobacco abstinence at week 6; Biochemically-confirmed sustained tobacco abstinence at the 12-month follow-up; Significant reduction in cigarette consumption, defined as a 50% or greater reduction in saliva cotinine levels, at week 6 compared with baseline; Change in measures of craving, nicotine withdrawal symptoms, depressive symptoms, anxiety, and negative affect with drug treatment

Smoking is the leading cause of preventable mortality in developed countries. Pharmacotherapy, including bupropion and nicotine replacement therapy (NRT), is universally recommended for smoking cessation treatment; however, even with treatment, the majority of smokers either fail to quit in the short term or relapse in the first year. The high failure rate reported for smoking cessation, then, presents a challenge to explore innovative approaches to treating nicotine dependence.

The purpose of this study is to test the efficacy and safety of the NMDA glycine site antagonist, GW468816, versus placebo for smoking cessation. In addition, the study will include Zyban as an active comparator to measure the assay sensitivity of the clinical trial itself.

270 adult outpatient smokers will be enrolled in this single-site, double-blind, placebo-controlled study. Participants will be randomized to GW468816, Zyban, or placebo, and will be treated weekly for six weeks.

Subjects who are are not abstinent at Week 6 will be eligible to participate in an exploratory crossover phase of the trial and will be re-randomized to GW468816, Zyban, or placebo for another six weeks.

Subjects who complete the six-week trial and are abstinent at Week 6 will enter the 12-Month Follow-Up to evaluate rates of long term abstinence from nicotine. They will have visits at one Week and at 1, 3 (by phone), 6, and 12 months from the date of discontinuation of study medications.

Participants who are abstinent at Week 6 will also be offered the opportunity to participate in a related neuroimaging study of mechanisms and surrogate markers of relapse that includes BOLD fMRI and MR spectroscopy at early abstinence and at 6-month follow up to be carried out at the McLean Brain Imaging Center.

Ages Eligible for Study:  18 Years   -   65 Years,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

1. Written informed consent
2. Men and women aged 18-65 years, inclusive
3. Self report of smoking 15 or more cigarettes per day and expired air CO >10 ppm at the time of enrollment
4. Self report of smoking an average of 15 or more cigarettes per day during the past year
5. Self report of tobacco abstinence not to exceed a period of greater than 1 of the past 12 months
6. DSM-IV criteria for Nicotine Dependence satisfied
7. Subjects must be willing to take the study medication and be motivated to quit smoking
8. Women of childbearing potential must have a negative urine pregnancy test (quantitative HCG) at baseline and females must agree to use an approved form of contraception during the study
9. Males must agree to use an approved form of contraception for up to 3 months after the last dose of study medication
10. Self report of smoking first cigarette of the day within 30 minutes of awakening

Exclusion Criteria:

1. Pregnant or able to become pregnant and not willing to use approved contraception (barrier, IUD, OCP)
2. Serious unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, neurological, or hematological disease such that hospitalization for treatment of that illness is likely within the next two months; life-threatening arrhythmia, cerebro-vascular or cardiovascular event within six months. Liver function tests elevated over twice normal
3. Severe respiratory compromise, as per medical history
4. Subjects using tobacco-containing products other than cigarettes (e.g., cigar, pipe) and unwilling to try to quit using these
5. Subjects with the following DSM-IV diagnoses in the past 6 months: Abuse or dependence of any substance other than nicotine or caffeine, bulimia or major depressive disorder
6. Subjects with the following DSM-IV diagnoses in their lifetime: Organic mental disorders, schizophrenia, schizoaffective disorder, bipolar disorder, delusional disorder or psychotic disorders not elsewhere classified, panic disorder or post-traumatic stress disorder
7. History of non-response in the past month to an adequate trial of nicotine replacement therapy or bupropion, defined as nicotine replacement > 21 mg per day patch (or equivalent dose of gum, inhaler, nasal spray, or lozenge) or bupropion > 150 mg/day for at least 4 weeks
8. Known CNS tumor
9. History of seizure disorder
10. History of multiple adverse drug reactions
11. Use of investigational drug or device within 4 weeks of screening

Please refer to this study by ClinicalTrials.gov identifier  NCT00218465

Dorothy Nelson-Plumb, M.A., B.S.      (617)726-2888    dnplumb@partners.org

Massachusetts
      Massachusetts General Hospital, Boston,  Massachusetts,  02114,  United States
      McLean Hospital, Dept. of Psychiatry, Belmont,  Massachusetts,  02478 9106,  United States

Study chairs or principal investigators

Maurizio Fava, M.D.,  Principal Investigator,  Massachusetts General Hospital   

Study ID Numbers:  NIDA-19378-2; U01-19378-2
Last Updated:  September 21, 2005
Record first received:  September 16, 2005
ClinicalTrials.gov Identifier:  NCT00218465
Health Authority: United States: Federal Government; United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2005-09-27