Assessment of High Dose Transdermal Nicotine for Fast Metabolizers of Nicotine
Condition: Nicotine Dependence
MeSH terms: Tobacco Use Disorder
Study type: Interventional
Phase: Phase 2

Summary: 
      Unfortunately, the investigators still need to assess and identify novel ways to help people
      quit smoking. Differences between people in terms of how fast they metabolize nicotine
      influences response to transdermal nicotine patches, the most popular nicotine dependence
      treatment, and it affects plasma levels of nicotine from treatment. These studies suggest
      that fast metabolizers of nicotine may show better quit rates if they receive higher doses of
      transdermal nicotine. This preliminary study is designed to assess, for the first time,
      whether fast nicotine metabolizers show higher quit rates if given high dose transdermal
      nicotine, versus standard dose. The study findings may help to support a subsequent large
      trial to assess standard versus high dose transdermal nicotine for slow versus fast
      metabolizers of nicotine, which may lead to a more personalized approach to treating nicotine
      dependence using the nicotine patch to improve therapeutic benefits of transdermal nicotine.
    

Detailed description: 
      Novel approaches to treating nicotine dependence remain a priority. The transdermal nicotine
      patch is the most widely used form of tobacco dependence treatment, but only ~1 in 5 smokers
      who use this treatment achieve cessation. One factor that may contribute to a poor response
      to transdermal nicotine is inter-individual variability in the rate of nicotine metabolism,
      which can be measured in saliva by the ratio of 3'hydroxycotinine (3-HC) to its precursor
      cotinine.

      Two clinical trials with transdermal nicotine have shown that the 3-HC/cotinine ratio
      predicts response to transdermal nicotine such that faster metabolizers of nicotine (higher
      3-HC/cotinine ratios) have lower quit rates, vs. slower nicotine metabolizers. Among
      abstainers in these trials, the 3-HC/cotinine ratio also predicts therapeutic levels of
      nicotine on transdermal nicotine, with faster metabolizers of nicotine exhibiting lower
      nicotine. Thus, faster metabolizers of nicotine may require higher nicotine doses to achieve
      the same therapeutic benefit from transdermal nicotine as do slow nicotine metabolizers.

      To date, clinical trials have shown that, compared to the standard dose of transdermal
      nicotine (21mg), higher doses (42mg) have no significant effect on quit rates. However, no
      trial of high dose transdermal nicotine considered inter-individual variability in the rate
      of nicotine metabolism. Thus, as a preliminary step toward conducting a fully-powered,
      randomized clinical trial to assess standard vs. high dose transdermal nicotine for slow vs.
      fast metabolizers of nicotine, we propose to evaluate, for the first time, the efficacy of
      high-dose transdermal nicotine (vs. standard dose) among fast metabolizers of nicotine (i.e.,
      upper quartile of the 3-HC/cotinine ratio distribution).

      We chose only fast metabolizers of nicotine for this trial since: 1) slow metabolizers of
      nicotine exhibit high quit rates on standard transdermal nicotine and may experience adverse
      effects from higher doses; and 2) as a "proof of concept" R21 application, our primary
      objective is to test whether high doses of nicotine increase quit rates among fast
      metabolizers of nicotine. Specifically, smokers who are fast metabolizers of nicotine will
      receive counseling and will be randomized to: 1) standard (1 X 21mg patch and 1 X placebo
      patch), or 2) high dose (2 x 21mg patches) transdermal nicotine.

      The primary outcome is biochemically-verified 7-day point prevalence cessation after 8 weeks
      of treatment. Differences in patch-related side effects and mediators of transdermal nicotine
      effects (e.g., nicotine levels, withdrawal) across the study conditions will also be
      assessed.

      Ultimately, this line of research hopes to provide the evidence necessary to translate
      research on the 3-HC/cotinine ratio to clinical practice for the treatment of tobacco
      dependence. Specifically, this research may show that a measure of nicotine metabolism rate
      could be used to maximize the therapeutic benefits of transdermal nicotine by providing slow
      metabolizers of nicotine with a standard patch dose and fast metabolizers of nicotine with
      high dose transdermal nicotine. Identifying an effective treatment for faster metabolizers of
      nicotine is also critical since these individuals are at increased risk for lung cancer.
    

Intervention name(s): Nicoderm CQ transdermal nicotine; placebo
Intervention type(s): Drug; Drug
Intervention description(s): Transdermal nicotine patch (21mg vs. 42mg), 8 weeks; placebo patch
Intervention MeSH terms: Nicotine
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: nicotine dependence; nicotine replacement therapy; transdermal nicotine; nicotine metabolism; high dose