Background: The reduction of the nicotine content of cigarettes to non-addicting levels is a potential federal regulatory intervention to reduce the prevalence of cigarette smoking and related disease. Many clinical trials on the effects and safety of nicotine reduction are ongoing. An important methodological concern is non-compliance with reduced nicotine content cigarettes in the context of freely available conventional cigarettes. We propose two approaches using biomarkers to estimate non-compliance in smokers of very low nicotine content (VLNC) cigarettes in a clinical trial. Methods: Data from 50 subjects in a study of gradual nicotine reduction were analyzed. Using plasma cotinine concentrations measured at baseline and while smoking VLNC cigarettes, we compared within-subject ratios of plasma cotinine comparing usual brand to VLNC in relation to nicotine content of these cigarettes. In another approach we used nicotine pharmacokinetic data to estimate absolute plasma cotinine/cigarettes per day (CPD) threshold values for compliance based on the nicotine content of VLNC. Results: The two approaches showed concordance indicating at least 60% non-compliance with smoking VLNC. In a sensitivity analysis assuming extreme compensation and extreme values for nicotine metabolic parameters, non-compliance was still at least 40%, much higher than self-reported non-compliance. Conclusion: Biomarker analysis demonstrates a high degree of non-compliance with smoking VLNC cigarettes, indicating that smokers are supplementing these with conventional cigarettes. Impact: We propose a practical approach to assessing compliance with smoking VLNC in clinical trials of nicotine reduction.
- Received September 8, 2014.
- Revision received November 13, 2014.
- Accepted November 18, 2014.
- Copyright © 2014, American Association for Cancer Research.