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Open Access 01-09-2019 | Smoking and Nicotine Detoxification | IM - ORIGINAL

Evaluating the effects of switching from cigarette smoking to using a heated tobacco product on health effect indicators in healthy subjects: study protocol for a randomized controlled trial

Authors: Nik Newland, Frazer John Lowe, Oscar Martin Camacho, Mike McEwan, Nathan Gale, James Ebajemito, George Hardie, James Murphy, Christopher Proctor

Published in: Internal and Emergency Medicine | Issue 6/2019

Abstract

Tobacco heating products (THPs) are a potentially safer alternative to combustible cigarette smoking. Through continued use, THPs may reduce smoking-related disease risk, whilst maintaining the sensorial experience and nicotine delivery sought by smokers. While literature evidence of the biological effects of THP aerosol exposure is increasing, there remains a knowledge gap with respect to substantiation of THP reduced risk potential in longer term real-life use. This randomized, multi-centre, controlled clinical study will test the hypotheses that following a switch from combustible cigarettes to a THP for 1 year, participants will experience a sustained reduction in exposure to tobacco-related toxicants that will lead to favourable changes in health effect indicators associated with smoking-related disease development. Changes in such indicators will be contextualized against smoking cessation and never-smoker cohorts. Up to 280 participants who do not intend to quit smoking will be randomized to continued combustible smoking (arm A, up to n = 80) or a commercially available THP (arm B n = 200). Furthermore, up to 190 participants with a high intent to quit smoking will undergo smoking cessation (arm D), and 40 never smokers will serve as a control group (arm E). Recruitment numbers were determined to be sufficient to achieve n = 50 in arms A, B and D, at study end. Enrolment started in March 2018 and the trial is scheduled to be completed in March 2020. Data from this study will be a valuable addition to the growing body of evidence in the field of understanding the individual and public health impact of THPs.

Clinical Trial Registration: https://www.isrctn.com/ISRCTN81075760

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US Department of Health and Human Services (2014) The health consequences of smoking: 50 years of progress: a report of the surgeon general. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, Atlanta. https://www.surgeongeneral.gov/library/reports/50-years-of-progress/. Accessed 11 Jan 2019

US Department of Health and Human Services (1990) The health benefits of smoking cessation. US Department of Health and Human Services. Public Health Service. Centers for Disease Control. Center for Chronic Disease Prevention and Health Promotion. Office on Smoking and Health. DHHS Publication No.(CDC) 90-8416. https://profiles.nlm.nih.gov/ps/access/NNBBCV.pdf. Accessed 11 Jan 2019

Doll R, Peto R, Wheatley K, Gray R, Sutherland I (1994) Mortality in relation to smoking: 40 years’ observations on male British doctors. BMJ 309(6959):901–911CrossRefPubMedPubMedCentral

World Health Organization (2011) WHO report on the global tobacco epidemic 2011: Warning about the dangers of tobacco in (World Health Organization, 2011). https://www.who.int/tobacco/global_report/2011/en/. Accessed 11 Jan 2019

Prevalence of Tobacco Smoking (2019) World health Organization. https://www.who.int/gho/tobacco/use/en/. Accessed 11 Jan 2019

World Health Organization. https://www.who.int/tobacco/en/atlas38.pdf. Accessed 11 Jan 2019

Polosa R, Rodu B, Caponnetto P, Maglia M, Raciti C (2013) A fresh look at tobacco harm reduction: the case for the electronic cigarette. Harm Reduct J 4(10):19. https://doi.org/10.1186/1477-7517-10-19 CrossRef

Rodu B (2011) The scientific foundation for tobacco harm reduction, 2006–2011. Harm Reduct J 8:19. https://doi.org/10.1186/1477-7517-8-19 CrossRefPubMedPubMedCentral

Greenland S, Satterfield M, Lanes S (1998) A meta-analysis to assess the incidence of adverse effects associated with the transdermal nicotine patch. Drug Saf 18(4):297–308CrossRefPubMed

10.

Lee PN (2013) The effect on health of switching from cigarettes to snus—a review. Regul Toxicol Pharmacol 66(1):1–5. https://doi.org/10.1016/j.yrtph.2013.02.010 CrossRefPubMed

11.

Polosa R, Benowitz NL (2011) Treatment of nicotine addiction: present therapeutic options and pipeline developments. Trends Pharmacol Sci 32(5):281–289. https://doi.org/10.1016/j.tips.2010.12.008 CrossRefPubMedPubMedCentral

12.

World Health Organization International Agency for Research on Cancer (2019) IARC monographs on the evaluation of carcinogenic risks to humans. Volume 83, tobacco smoke and involuntary smoking 2004. International Agency for Research on Cancer, Geneva. https://monographs.iarc.fr/ENG/Monographs/vol83/mono83.pdf. Accessed 11 Jan 2019

13.

Lunell E, Molander L, Ekberg K, Wahren J (2000) Site of nicotine absorption from a vapour inhaler—comparison with cigarette smoking. Eur J Clin Pharmacol 55:737–741CrossRefPubMed

14.

Digard H, Proctor C, Kulasekaran A, Malmqvist U, Richter A (2013) Determination of nicotine absorption from multiple tobacco products and nicotine gum. Nicotine Tob Res 15(1):255–261. https://doi.org/10.1093/ntr/nts123 CrossRefPubMed

15.

Schaller JP, Keller D, Poget L, Pratte P, Kaelin E, McHugh D, Cudazzo G, Smart D, Tricker AR, Gautier L, Yerly M, Reis Pires R, Le Bouhellec S, Ghosh D, Hofer I, Garcia E, Vanscheeuwijck P, Maeder S (2016) Evaluation of the tobacco heating system 2.2. Part 2: chemical composition, genotoxicity, cytotoxicity, and physical properties of the aerosol. Regul Toxicol Pharmacol 81(Suppl 2):S27–S47. https://doi.org/10.1016/j.yrtph.2016.10.001 CrossRefPubMed

16.

Forster M, Fiebelkorn S, Yurteri C, Mariner D, Liu C, Wright C et al (2018) Assessment of novel tobacco heating product THP1.0. Part 3: comprehensive chemical characterisation of harmful and potentially harmful aerosol emissions. Regul Toxicol Pharmacol 93:14–33. https://doi.org/10.1016/j.yrtph.2017.10.006 CrossRefPubMed

17.

Caponnetto P, Maglia M, Prosperini G, Busà B, Polosa R (2018) Carbon monoxide levels after inhalation from new generation heated tobacco products. Respir Res 19(1):164. https://doi.org/10.1186/s12931-018-0867-z CrossRefPubMedPubMedCentral

18.

Farsalinos KE, Yannovits N, Sarri T, Voudris V, Poulas K (2018) Nicotine delivery to the aerosol of a heat-not-burn tobacco product: comparison with a tobacco cigarette and e-cigarettes. Nicotine Tob Res 20(8):1004–1009. https://doi.org/10.1093/ntr/ntx138 CrossRefPubMed

19.

Jaccard G, Tafin Djoko D, Moennikes O, Jeannet C, Kondylis A, Belushkin M (2017) Comparative assessment of HPHC yields in the tobacco heating system THS2.2 and commercial cigarettes. Regul Toxicol Pharmacol 90:1–8. https://doi.org/10.1016/j.yrtph.2017.08.006 CrossRefPubMed

20.

Farsalinos KE, Yannovits N, Sarri T, Voudris V, Poulas K, Leischow SJ (2018) Carbonyl emissions from a novel heated tobacco product (IQOS): comparison with an e-cigarette and a tobacco cigarette. Addiction 113(11):2099–2106. https://doi.org/10.1111/add.14365 CrossRefPubMed

21.

Mallock N, Böss L, Burk R, Danziger M, Welsch T, Hahn H, Trieu HL, Hahn J, Pieper E, Henkler-Stephani F, Hutzler C, Luch A (2018) Levels of selected analytes in the emissions of "heat not burn" tobacco products that are relevant to assess human health risks. Arch Toxicol 92(6):2145–2149. https://doi.org/10.1007/s00204-018-2215-y CrossRefPubMedPubMedCentral

22.

Nabavizadeh P, Liu J, Havel CM, Ibrahim S, Derakhshandeh R, Jacob Iii P, Springer ML (2018) Vascular endothelial function is impaired by aerosol from a single IQOS HeatStick to the same extent as by cigarette smoke. Tob Control 27(Suppl 1):s13–s19. https://doi.org/10.1136/tobaccocontrol-2018-054325 CrossRefPubMedPubMedCentral

23.

Zanetti F, Titz B, Sewer A, Lo Sasso G, Scotti E, Schlage WK, Mathis C, Leroy P, Majeed S, Torres LO, Keppler BR, Elamin A, Trivedi K, Guedj E, Martin F, Frentzel S, Ivanov NV, Peitsch MC, Hoeng J (2017) Comparative systems toxicology analysis of cigarette smoke and aerosol from a candidate modified risk tobacco product in organotypic human gingival epithelial cultures: a 3-day repeated exposure study. Food Chem Toxicol 101:15–35. https://doi.org/10.1016/j.fct.2016.12.027 CrossRefPubMed

24.

Breheny D, Adamson J, Azzopardi D, Baxter A, Bishop E, Carr T, Crooks I, Hewitt K, Jaunky T, Larard S, Lowe F, Oke O, Taylor M, Santopietro S, Thorne D, Zainuddin B, Gaça M, Liu C, Murphy J, Proctor C (2017) A novel hybrid tobacco product that delivers a tobacco flavour note with vapour aerosol (part 2): in vitro biological assessment and comparison with different tobacco-heating products. Food Chem Toxicol 106(Pt A):533–546. https://doi.org/10.1016/j.fct.2017.05.023 CrossRefPubMed

25.

Taylor M, Thorne D, Carr T, Breheny D, Walker P, Proctor C, Gaça M (2018) Assessment of novel tobacco heating product THP1.0. Part 6: a comparative in vitro study using contemporary screening approaches. Regul Toxicol Pharmacol 93:62–70. https://doi.org/10.1016/j.yrtph.2017.08.016 CrossRefPubMed

26.

Phillips BW, Schlage WK, Titz B, Kogel U, Sciuscio D, Martin F, Leroy P, Vuillaume G, Krishnan S, Lee T, Veljkovic E, Elamin A, Merg C, Ivanov NV, Peitsch MC, Hoeng J, Vanscheeuwijck P (2018) A 90-day OECD TG 413 rat inhalation study with systems toxicology endpoints demonstrates reduced exposure effects of the aerosol from the carbon heated tobacco product version 1.2 (CHTP1.2) compared with cigarette smoke. I. Inhalation exposure, clinical pathology and histopathology. Food Chem Toxicol 116(Pt B):388–413. https://doi.org/10.1016/j.fct.2018.04.015 CrossRefPubMed

27.

Tsuji H, Okubo C, Fujimoto H, Fukuda I, Nishino T, Lee KM, Yoshimura H (2014) Comparison of dermal tumor promotion activity of cigarette smoke condensate from prototype (heated) cigarette and reference (combusted) cigarette in SENCAR mice. Food Chem Toxicol 72:187–194. https://doi.org/10.1016/j.fct.2014.07.008 CrossRefPubMed

28.

Sewer A, Kogel U, Talikka M, Wong ET, Martin F, Xiang Y, Guedj E, Ivanov NV, Hoeng J, Peitsch MC (2016) Evaluation of the tobacco heating system 2.2 (THS2.2). Part 5: microRNA expression from a 90-day rat inhalation study indicates that exposure to THS2.2 aerosol causes reduced effects on lung tissue compared with cigarette smoke. Regul Toxicol Pharmacol 81(Suppl 2):S82–S92. https://doi.org/10.1016/j.yrtph.2016.11.018 CrossRefPubMed

29.

Oviedo A, Lebrun S, Kogel U, Ho J, Tan WT, Titz B, Leroy P, Vuillaume G, Bera M, Martin F, Rodrigo G, Esposito M, Dempsey R, Ivanov NV, Hoeng J, Peitsch MC, Vanscheeuwijck P (2016) Evaluation of the tobacco heating system 2.2. Part 6: 90-day OECD 413 rat inhalation study with systems toxicology endpoints demonstrates reduced exposure effects of a mentholated version compared with mentholated and non-mentholated cigarette smoke. Regul Toxicol Pharmacol 81(Suppl 2):S93–S122. https://doi.org/10.1016/j.yrtph.2016.11.004 CrossRefPubMed

30.

Gale N, McEwan M, Eldridge AC, Fearon IM, Sherwood N, Bowen E, McDermott S, Holmes E, Hedge A, Hossack S, Wakenshaw L, Glew J, Camacho OM, Errington G, McAughey J, Murphy J, Liu C, Proctor CJ (2018) Changes in biomarkers of exposure on switching from a conventional cigarette to tobacco heating products: a randomized, controlled study in healthy Japanese subjects. Nicotine Tob Res. https://doi.org/10.1093/ntr/nty104 (Epub ahead of print (https://www.ncbi.nlm.nih.gov/pubmed/29912406))

31.

Martin Leroy C, Jarus-Dziedzic K, Ancerewicz J, Lindner D, Kulesza A, Magnette J (2012) Reduced exposure evaluation of an electrically heated cigarette smoking system. Part 7: a 1-month, randomized, ambulatory, controlled clinical study in Poland. Regul Toxicol Pharmacol 64(2 Suppl):S74–S84. https://doi.org/10.1016/j.yrtph.2012.08.006 CrossRefPubMed

32.

Murphy J, Liu C, McAdam K, Gaҫa M, Prasad K, Camacho O, McAughey J, Proctor C (2018) Assessment of tobacco heating product THP1.0. Part 9: the placement of a range of next-generation products on an emissions continuum relative to cigarettes via pre-clinical assessment studies. Regul Toxicol Pharmacol 93:92–104. https://doi.org/10.1016/j.yrtph.2017.10.001 CrossRefPubMed

33.

Evidence review of e-cigarettes and heated tobacco products 2018: executive summary. Public Health England. https://www.gov.uk/government/publications/e-cigarettes-and-heated-tobacco-products-evidence-review/evidence-review-of-e-cigarettes-and-heated-tobacco-products-2018-executive-summary. Accessed 11 Jan 2019

34.

Murphy J, Gaca M, Lowe F, Minet E, Breheny D, Prasad K, Camacho O, Fearon IM, Liu C, Wright C, McAdam K, Proctor C (2017) Assessing modified risk tobacco and nicotine products: description of the scientific framework and assessment of a closed modular electronic cigarette. Regul Toxicol Pharmacol 90:342–357. https://doi.org/10.1016/j.yrtph.2017.09.008 CrossRefPubMed

35.

Proctor C et al (2018) Assessment of tobacco heating product THP1.0. Parts 1–9. Regul Toxicol Pharmacol 93:1–104CrossRefPubMed

36.

Deveci SE, Deveci F, Acik Y, Ozan AT (2004) The measurement of exhaled carbon monoxide in healthy smokers and non-smokers. Respir Med 98(6):551–556CrossRefPubMed

37.

Scherer G, Newland K, Papadopoulou E, Minet E (2014) A correlation study applied to biomarkers of internal and effective dose for acrylonitrile and 4-aminobiphenyl in smokers. Biomarkers 19(4):291–301. https://doi.org/10.3109/1354750X.2014.910271 CrossRefPubMedPubMedCentral

38.

Eaton D, Jakaj B, Forster M, Nicol J, Mavropoulou E, Scott K, Liu C, McAdam K, Murphy J, Proctor CJ (2018) Assessment of tobacco heating product THP1.0. Part 2: product design, operation and thermophysical characterisation. Regul Toxicol Pharmacol 93:4–13. https://doi.org/10.1016/j.yrtph.2017.09.009 CrossRefPubMed

39.

Fagerström K, Russ C, Yu CR, Yunis C, Foulds J (2012) The Fagerström test for nicotine dependence as a predictor of smoking abstinence: a pooled analysis of varenicline clinical trial data. Nicotine Tob Res 14(12):1467–1473. https://doi.org/10.1093/ntr/nts018 Epub 2012 Mar 30 CrossRefPubMed

40.

Olufade AO, Shaw JW, Foster SA, Leischow SJ, Hays RD, Coons SJ (1999) Development of the smoking cessation quality of life questionnaire. Clin Ther 21(12):2113–2130CrossRefPubMed

41.

Roux A et al (2010) Early improvement in peripheral vascular tone following smoking cessation using nicotine replacement therapy: aortic wave reflection analysis. Cardiology 117(1):37–43. https://doi.org/10.1159/000319596 CrossRefPubMed

42.

O’Brien PC, Fleming TR (1979) A multiple testing procedure for clinical trials. Biometrics 35:549–556CrossRefPubMed

43.

Shepperd CJ, Newland N, Eldridge A, Haswell L, Lowe F, Papadopoulou E, Camacho O, Proctor CJ, Graff D, Meyer I (2015) Changes in levels of biomarkers of exposure and biological effect in a controlled study of smokers switched from conventional cigarettes to reduced-toxicant-prototype cigarettes. Regul Toxicol Pharmacol 72(2):273–291. https://doi.org/10.1016/j.yrtph.2015.04.016 CrossRefPubMed

44.

Scheuermann TS, Richter KP, Rigotti NA, Cummins SE, Harrington KF, Sherman SE, Zhu SH, Tindle HA, Preacher KJ, Consortium of Hospitals Advancing Research on Tobacco (CHART) (2017) Accuracy of self-reported smoking abstinence in clinical trials of hospital-initiated smoking interventions. Addiction 112(12):2227–2236. https://doi.org/10.1111/add.13913 CrossRefPubMedPubMedCentral

45.

Houghton D, Jones TW, Cassidy S, Siervo M, MacGowan GA, Trenell MI, Jakovljevic DG (2016) The effect of age on the relationship between cardiac and vascular function. Mech Ageing Dev 153:1–6. https://doi.org/10.1016/j.mad.2015.11.001 CrossRefPubMedPubMedCentral

46.

Scherer G (2018) Suitability of biomarkers of biological effects (BOBEs) for assessing the likelihood of reducing the tobacco related disease risk by new and innovative tobacco products: a literature review. Regul Toxicol Pharmacol 94:203–233. https://doi.org/10.1016/j.yrtph.2018.02.002 CrossRefPubMed

47.

Chobanian AV, Bakris GL, Black HR et al (2003) Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 42(6):1206–1252CrossRefPubMed

48.

Higashi Y, Maruhashi T, Noma K et al (2014) Oxidative stress and endothelial dysfunction: clinical evidence and therapeutic implications. Trends Cardiovasc Med 24(4):165–169. https://doi.org/10.1016/j.tcm.2013.12.001 CrossRefPubMed

49.

Lowe FJ, Luettich K, Talikka M, Hoang V, Haswell LE, Hoeng J, Gaca MD (2017) Development of an adverse outcome pathway for the onset of hypertension by oxidative stress-mediated perturbation of endothelial nitric oxide bioavailability. Appl In Vitro Toxicol 3(1):131–148CrossRef

50.

Safar ME (2018) Arterial stiffness as a risk factor for clinical hypertension. Nat Rev Cardiol 15(2):97–105. https://doi.org/10.1038/nrcardio.2017.155 CrossRefPubMed

Title: Evaluating the effects of switching from cigarette smoking to using a heated tobacco product on health effect indicators in healthy subjects: study protocol for a randomized controlled trial
Authors: Nik Newland
Frazer John Lowe
Oscar Martin Camacho
Mike McEwan
Nathan Gale
James Ebajemito
George Hardie
James Murphy
Christopher Proctor
Publication date: 01-09-2019
Publisher: Springer International Publishing
Keywords: Smoking and Nicotine Detoxification
Biomarkers
Published in: Internal and Emergency Medicine / Issue 6/2019
Print ISSN: 1828-0447
Electronic ISSN: 1970-9366
DOI: https://doi.org/10.1007/s11739-019-02090-8

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