Effect of immediate vs gradual reduction in nicotine content of cigarettes on biomarkers of smoke exposure a randomized clinical trial

Dorothy K. Hatsukami, Xianghua Luo, Joni A. Jensen, Mustafa Al'Absi, Sharon S. Allen, Steven G. Carmella, Menglan Chen, Paul M. Cinciripini, Rachel Denlinger-Apte, David J. Drobes, Joseph S. Koopmeiners, Tonya Lane, Chap T. Le, Scott Leischow, Kai Luo, F. Joseph McClernon, Sharon E. Murphy, Viviana Paiano, Jason D. Robinson, Herbert SeversonChristopher Sipe, Andrew A. Strasser, Lori G. Strayer, Mei Kuen Tang, Ryan Vandrey, Stephen S. Hecht, Neal L. Benowitz, Eric C. Donny

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)880-891
Number of pages12
JournalJAMA - Journal of the American Medical Association
Volume320
Issue number9
DOIs
StatePublished - Sep 4 2018

Bibliographical note

Funding Information:
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.

Funding Information:
Funding/Support: This study was funded by

Funding Information:
National Institute on Drug Abuse and Food and Drug Administration grant U54DA031659. All mass spectrometry was carried out in the Analytical Biochemistry Shared Resource of the Masonic Cancer Center, supported in part by National Cancer Institute Cancer Center Support grant P30CA077598. REDCap (Research Electronic Data Capture) services were provided by grant UL1TR000114 from the National Center for Advancing Translational Sciences of the National Institutes of Health.

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