Effect of Immediate vs Gradual Reduction in Nicotine Content of Cigarettes on Biomarkers of Smoke Exposure: A Randomized Clinical Trial

Abstract

Importance: The optimal temporal approach for reducing nicotine to minimally or nonaddictive levels in all cigarettes sold in the United States has not been determined.

Objectives: To determine the effects of immediate vs gradual reduction in nicotine content to very low levels and as compared with usual nicotine level cigarettes on biomarkers of toxicant exposure.

Design, setting, and participants: A double-blind, randomized, parallel-design study with 2 weeks of baseline smoking and 20 weeks of intervention was conducted at 10 US sites. A volunteer sample of daily smokers with no intention to quit within 30 days was recruited between July 2014 and September 2016, with the last follow-up completed in March 2017.

Interventions: (1) Immediate reduction to 0.4 mg of nicotine per gram of tobacco cigarettes; (2) gradual reduction from 15.5 mg to 0.4 mg of nicotine per gram of tobacco cigarettes with 5 monthly dose changes; or (3) maintenance on 15.5 mg of nicotine per gram of tobacco cigarettes.

Main outcomes and measures: Between-group differences in 3 co-primary biomarkers of smoke toxicant exposure: breath carbon monoxide (CO), urine 3-hydroxypropylmercapturic acid (3-HPMA, metabolite of acrolein), and urine phenanthrene tetraol (PheT, indicator of polycyclic aromatic hydrocarbons) calculated as area under the concentration-time curve over the 20 weeks of intervention.

Results: Among 1250 randomized participants (mean age, 45 years; 549 women [44%]; 958 [77%] completed the trial), significantly lower levels of exposure were observed in the immediate vs gradual reduction group for CO (mean difference, -4.06 parts per million [ppm] [95% CI, -4.89 to -3.23]; P < .0055), 3-HPMA (ratio of geometric means, 0.83 [95% CI, 0.77 to 0.88]; P < .0055), and PheT (ratio of geometric means, 0.88 [95% CI, 0.83 to 0.93]; P < .0055). Significantly lower levels of exposure were observed in the immediate reduction vs control group for CO (mean difference, -3.38 [95% CI, -4.40 to -2.36]; P < .0055), 3-HPMA (ratio of geometric means, 0.81 [95% CI, 0.75 to 0.88]; P < .0055), and PheT (ratio of geometric means, 0.86 [95% CI, 0.81 to 0.92]; P < .0055). No significant differences were observed between the gradual reduction vs control groups for CO (mean difference, 0.68 [95% CI, -0.31 to 1.67]; P = .18), 3-HPMA (ratio of geometric means, 0.98 [95% CI, 0.91 to 1.06]; P = .64), and PheT (ratio of geometric means, 0.98 [95% CI, 0.92 to 1.04]; P = .52).

Conclusions and relevance: Among smokers, immediate reduction of nicotine in cigarettes led to significantly greater decreases in biomarkers of smoke exposure across time compared with gradual reduction or a control group, with no significant differences between gradual reduction and control.

Trial registration: clinicaltrials.gov Identifier: NCT02139930.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Hatsukami, Koopmeiners, and Donny; Ms Jensen; and Ms Strayer reported receiving grants from the National Institute on Drug Abuse. Dr Cinciripini reported serving on the scientific advisory board of Pfizer Pharmaceuticals, conducting educational talks sponsored by Pfizer on smoking cessation (2006–2008), and receiving grant support from Pfizer. Dr Drobes reported serving as a paid expert witness in litigation against tobacco companies. Dr Leischow reported being the editor in chief of Tobacco Regulatory Science. Dr McClernon provides consulting and marketing research services to GlaxoSmithKline Consumer Healthcare on smoking cessation behavioral support programs. Dr Robinson reported receiving grants from the National Institutes of Health and the Duncan Family Institute for Cancer Prevention and Risk Assessment. Dr Strasser reported receiving grant support through the Pfizer GRAND grant funding program. Dr Benowitz reported being a consultant to Pfizer and Achieve Life Sciences, companies that market or are developing smoking cessation medications, and being a paid expert witness in litigation against tobacco companies. No other disclosures were reported.

Figures

Figure 1.. Recruitment, Randomization, and Retention of Participants

PI indicates principal investigator.a Withdrawal from the study for personal reasons included time commitment, lost interest, moved out of area, or unrelated health concerns. b Reasons for site PI withdrawal included unstable physical or mental health (eg, adverse events), nonadherence (eg, behavior issues, cigarette misuse, questionable data, consistently elevated breath alcohol level), ineligibility determined after randomization, and elevated carbon monoxide.c Self-withdrawal due to adverse event included reasons such as did not tolerate withdrawal symptoms and a new illness or injury that required individual’s time and/or focus.d Numbers of participants in the primary end point analyses were the same as the numbers of randomized participants.e Death by drug overdose, unrelated to study product.

Figure 2.. Exposure Biomarkers (Primary End Points) and Total Cigarettes per Day (CPD; Secondary End Point) During Intervention

Week 0 was based on usual brand cigarettes and subsequent weeks measured study cigarettes. The boxplot is of the observed data (ie, no imputation): the box shows the interquartile range (IQR) with the bottom and top indicating the 25th and 75th percentiles; the line inside the box indicating the median; the upper whisker extends from the top of the box to the largest value no further than 1.5 times the IQR and the bottom whisker extends from the bottom of the box to the smallest value no further than 1.5 times the IQR; the trajectory line connects the median at each visit; boxplots at each visit are staggered to avoid superimposition. The number of participants may differ from Figure 1 due to inclusion of partial data collected from the participant within a dosing period prior to drop out or missing values. Phenanthrene tetraol is an indicator for exposure to polycyclic aromatic hydrocarbons, expressed per milligram of creatinine). 3-HPMA indicates 3-hydroxypropylmercapturic acid, biomarker for acrolein, expressed per milligram of creatinine). Total cigarettes per day included study and nonstudy cigarettes.

Figure 3.. Exposure Biomarkers, Minnesota Nicotine Withdrawal Scale (MNWS), and Questionnaire on Smoking Urges-Brief (QSU) Factor 1 (Secondary End Points)

The MNWS score ranges from 0 to 32, with higher scores indicating more intense withdrawal symptoms. QSU Factor 1 scores measure anticipation of pleasurable effects from smoking (scale ranges from 5 to 35). Week 0 was based on usual brand cigarettes and subsequent weeks measured study cigarettes. The boxplot is of the observed data (ie, no imputation): the box shows the interquartile range [IQR] with the bottom and top indicating the 25th and 75th percentiles; the line inside the box indicating the median; the upper whisker extends from the top of the box to the largest value no further than 1.5 times IQR and the bottom whisker extends from the bottom of the box to the smallest value no further than 1.5 times IQR; the trajectory line connects the median at each visit; boxplots at each visit are staggered to avoid superimposition. Number of participants may differ from Figure 1 due to inclusion of partial data collected from the participant within a dosing period prior to drop out or missing values. Total nicotine equivalents are a biomarker for nicotine exposure. Total NNAL indicates 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides, a biomarker for exposure to NNK, a potent lung carcinogen specific to tobacco. Biomarkers are expressed per milligram of creatinine.