Assessment of High Dose Transdermal Nicotine for Fast Metabolizers of Nicotine (HDP)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Robert Schnoll, University of Pennsylvania
ClinicalTrials.gov Identifier:
NCT00956943
First received: July 23, 2009
Last updated: August 12, 2014
Last verified: August 2014

July 23, 2009
August 12, 2014
August 2009
August 2011   (final data collection date for primary outcome measure)
Biochemically Verified 7-day Point Prevalence Abstinence at the End of 8 Weeks of Treatment [ Time Frame: After 8 weeks of treatment with the patch, outcome will be measured. ] [ Designated as safety issue: No ]
quit rate verified with carbon monoxide breath sample (abstinence: less than or equal to 10ppm)
Biochemically verified 7-day point prevalence abstinence at the end of 8 weeks of treatment [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00956943 on ClinicalTrials.gov Archive Site
Side Effects [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
frequency of serious adverse events
Side effects [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
Not Provided
Not Provided
 
Assessment of High Dose Transdermal Nicotine for Fast Metabolizers of Nicotine
Assessment of High Dose Transdermal Nicotine for Fast Metabolizers of Nicotine

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.

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.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Nicotine Dependence
  • Drug: Nicoderm CQ transdermal nicotine
    Transdermal nicotine patch (21mg vs. 42mg), 8 weeks
  • Drug: placebo
    placebo patch
  • Active Comparator: 21mg transdermal nicotine + placebo patch
    21mg transdermal nicotine + placebo patch
    Interventions:
    • Drug: Nicoderm CQ transdermal nicotine
    • Drug: placebo
  • Experimental: 42mg transdermal nicotine
    42mg transdermal nicotine
    Intervention: Drug: Nicoderm CQ transdermal nicotine
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
87
August 2011
August 2011   (final data collection date for primary outcome measure)

Inclusion Criteria:

  1. Males and females age 18-45 who smoke > 10 cigarettes/ day;
  2. Able to communicate in English;
  3. Able to use NRT safely (e.g., no allergy to latex);
  4. Able to provide written informed consent for study procedures;
  5. Residing in the geographic area for at least 6 months; and
  6. A 3-HC/cotinine ratio in the top quartile of the distribution (Schnoll et al., 2008). Age 45 was selected as an upper limit to reduce the likelihood of adverse effects from high dose transdermal nicotine.

Exclusion Criteria:

  1. History of substance abuse or currently receiving treatment for substance abuse (e.g., alcohol, opioids, cocaine, marijuana);
  2. Current (last 6-months) alcohol consumption that exceeds 25 standard drinks/week.
  3. Current use or discontinuation within last 14 days of:

    • Smoking cessation medications (bupropion, Chantix, NRT);
    • Antipsychotics, atypicals, mood-stabilizers, anti-depressants (tricyclics, SSRIs, MAOIs), anti-panic agents, anti-obsessive agents, anti-anxiety agents, stimulants);
    • Medication for pain;
    • Anti-coagulants;
    • Heart medications;
    • Daily medication for asthma or diabetes.
  4. Women who are pregnant, planning a pregnancy, or lactating;
  5. History or current diagnosis of psychosis, major depression or bipolar disorder, psychotic disorder, or generalized anxiety disorder;
  6. Serious/unstable disease within the past 6 months (e.g., cancer [but melanoma], HIV/AIDS);
  7. History of epilepsy or seizure disorder;
  8. History or diagnosis within the last 6 months of abnormal rhythms and/or tachycardia (>100 beats/minute); history or current diagnosis of COPD, cardiovascular disease (stroke, angina), heart attack in the last 6 months, uncontrolled hypertension (SBP>150 or DBP>90);
  9. History of kidney or liver failure.
  10. Any medical condition or medication that could compromise safety as determined by a study physician;
  11. Inability to provide informed consent or complete the study tasks as determined by the Principal Investigator or study physician.
Both
18 Years to 45 Years
Yes
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00956943
809716, R21DA026889
No
Robert Schnoll, University of Pennsylvania
University of Pennsylvania
Not Provided
Principal Investigator: Robert A Schnoll, PhD University of Pennsylvania
University of Pennsylvania
August 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP