TC Online First, published on October 27, 2015 as 10.1136/tobaccocontrol-2014-052080 Research paper Tob Control: first published as 10.1136/tobaccocontrol-2014-052080 on 19 May 2015. Downloaded from Randomised clinical trial of snus versus medicinal nicotine among smokers interested in product switching Dorothy K Hatsukami,1,2 Herbert Severson,3 Amanda Anderson,2 Rachael Isaksson Vogel,1 Joni Jensen,2 Berry Broadbent,3 Sharon E Murphy,1 Steven Carmella,1 Stephen S Hecht1 ▸ Additional material is ABSTRACT to substitution of cigarettes with snus. Smokers published online only. To view Background An essential component of evaluating who switch to snus appear to have similar risks for please visit the journal online potential modified risk tobacco products is to determine cancer and cardiovascular disease as those who quit (http://dx.doi.org/10.1136/ 7 tobaccocontrol-2014-052080). how consumers use the product and resulting effects on tobacco. 1 biomarkers of toxicant exposure. Furthermore, several cross-sectional survey Masonic Cancer Center, 289–11 University of Minnesota, Study design Cigarette smokers (n=391) recruited in studies conducted in Scandinavia and 12 Minneapolis, Minnesota, USA Minnesota and Oregon were randomised to either snus the USA show that smokers who have ever 2Department of Psychiatry, or 4 mg nicotine gum for 12 weeks. Participants were used or used snus or snuff daily have a higher University of Minnesota, instructed to completely switch from cigarettes to these probability of quitting smoking than non-snus or Minneapolis, Minnesota, USA 3 products. Urine samples were collected to analyse for non-snuff users. Survey studies conducted in Oregon Research Institute, 91013 14 Eugene, Oregon, USA carcinogenic tobacco-specific nitrosamine metabolites Scandinavia and USA also show that snus (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and or snuff, compared to medicinal nicotine, is more Correspondence to N0-nitrosonornicotine and their glucuronides) and frequently used and/or leads to greater smoking Dr Dorothy K Hatsukami, nicotine metabolites (total cotinine and nicotine cessation success, particularly among men. Masonic Cancer Center, University of Minnesota, 717 equivalents) levels. Cross-sectional studies, however, do not distin- Delaware St SE, Minneapolis, Results Of the 391 participants randomised, 52.9% guish whether or not the findings reflect differences MN 55414, USA; were male, the mean±SD age was 43.9±12.5 years, in the characteristics of the population who use [email protected] baseline number of cigarettes/day was 18.0±6.5 and snus to quit smoking or the effects of the products copyright. Received 3 October 2014 Fagerstrom Test for Nicotine Dependence score was 5.1 themselves. A randomised clinical trial would help Accepted 24 April 2015 ±2.0. The mean±SD number of snus pouches used/week determine if snus compared to medicinal nicotine at week 6 prior to tapering was 39.1±24.0 and nicotine leads to higher rates of stopping smoking as a result gum pieces used was 37.6±26.3. Dual use of cigarettes of complete switching or a greater reduction in and these products were observed in 52.9% and 58.2% smoking and consequent reduction in exposure to of those assigned to snus and nicotine gum, respectively, harmful constituents. Besides a small pilot study at week 12. The end of treatment biochemically verified that we conducted,15 no such clinical trial has been http://tobaccocontrol.bmj.com/ (carbon monoxide, CO <6 ppm) 7-day avoidance of reported in the literature. cigarettes was 21.9% in the snus group and 24.6% in The primary goal of this study was to compare the nicotine gum group. Toxicant exposure in the snus versus nicotine gum on the extent to which nicotine gum group was significantly less when smokers can completely switch to these products, compared to snus. the pattern of product use and effects on biomar- Conclusions Snus performed similarly to nicotine gum kers of exposure. The secondary goals were to in cigarette smokers who were interested in completely compare the effects of both products on with- switching to these products, but was associated with drawal symptom relief, product evaluation and less satisfaction and greater toxicant exposure than adverse events. nicotine gum. Trial registration number NCT: 00710034. on September 25, 2021 by guest. Protected METHODS Participant recruitment Cigarette smokers interested in completely switch- INTRODUCTION ing to snus or nicotine gum were recruited from In the USA and elsewhere, a low-nitrosamine Minneapolis/St Paul, Minnesota, and Eugene, smokeless tobacco known as snus is promoted as a Oregon, between May 2010 and May 2013, using complete or partial substitute for smoking. internet and local media advertisements. Differences in disease risk between cigarettes and Participants were followed through June 2014. snus have led some public health scientists to Interested smokers who telephoned the research believe that if smokers completely switched to snus, clinics were briefly informed about the study and To cite: Hatsukami DK, then reduced tobacco-related mortality and morbid- screened for eligibility. Eligibility criteria included: – Severson H, Anderson A, ity would likely ensue.1 5 For example, the signifi- (1) 18–70 years old; (2) smoking at least 10 cigar- et al. Tob Control Published Online First: [please include cant reduction in smoking among Swedish men ettes daily for the past year, (3) in good physical Day Month Year] leading to reductions in lung cancer, cardiovascular and mental health (no unstable or untreated doi:10.1136/tobaccocontrol- and all causes mortality, compared to other medical or psychiatric condition); (4) no contrain- 2014-052080 European Union countries,26has been attributed dications for medicinal nicotine; (5) no regular use Hatsukami DK, et al. Tob Control 2015;0:1–8. doi:10.1136/tobaccocontrol-2014-052080 1 Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd under licence. Research paper Tob Control: first published as 10.1136/tobaccocontrol-2014-052080 on 19 May 2015. Downloaded from of other nicotine or tobacco products; and (6) if female, not 19 and 39 (not included in the analysis). Participants were reim- pregnant or nursing. Eligible participants attended the research bursed a total of $360 for visit attendance and blood draws. clinic for an orientation visit, provided informed consent and engaged in more thorough screening, including assessment of Measures their medical and tobacco use history, and nicotine dependence, Throughout treatment, participants reported product use and using the Fagerstrom Test for Nicotine Dependence,16 and preg- any cigarettes smoked on a daily basis using the IVR system. nancy testing. This study was approved by each site’s Other measures collected at the baseline and treatment clinic Institutional Review Board, and a Data and Safety Monitoring visits included the past week’s MNWS, adverse events, vitals Board (DSMB) met annually to monitor study progress and and alveolar carbon monoxide (CO). Responses to products adverse events. were measured using Product Evaluation Scale (Weeks 1, 4 and 12),21 a 7-point Likert-type scale modified from the Products Cigarette Evaluation Scale.22 Scale scores addressed four The oral tobacco product chosen was Camel snus (Winterchill factors: reflecting product satisfaction, psychological reward, and Robust, 2.5 and 2.6 mg nicotine/pouch, respectively, distrib- sensation in mouth and aversion.23 uted by Reynolds American Inc). These snus products were Biomarkers were collected at baseline and week 4 (to maxi- chosen because of the higher levels of unprotonated nicotine in mise the number of data points, prior to relapse or drop-outs). them compared to other US manufactured snus products and Biomarkers included measures of nicotine exposure: total coti- prior research showing that suppression of smoking is greater nine24 and total nicotine equivalents (the sum of total nicotine, with oral non-combusted products with higher nicotine levels.17 total cotinine and total 30hydroxycotinine, TNE)25 In addition, Participants who experienced adverse effects from these doses biomarkers included measures of tobacco-specific carcinogens: were provided Frost or Mellow (1.5 and 1.3 mg nicotine/pouch, (1) urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and respectively). A Swedish snus product with even higher levels of its glucuronides (total NNAL),26 which are metabolites of nicotine may have been preferable to compare with the Swedish 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and (2) experience. However, our prior preference study showed that no N0-nitrosonornicotine (NNN) and its glucuronides (total smoker chose the Swedish snus (General Snus).17 Nicotine gum NNN),27 which reflect the uptake of NNN. (4 mg Nicorette distributed by GlaxoSmithKline) was chosen as At follow-up, 26 weeks after start of treatment, smoking the medicinal nicotine product, and participants who experi- abstinence and use of any other tobacco or medicinal nicotine enced adverse effects were down-titrated to 2 mg nicotine gum. products were assessed using time line follow-back,28 and bio- chemical verification was obtained. Study design copyright. Participants were informed that the study examined the effects Sample size calculation of snus versus nicotine gum on smoking behaviour and potential The planned sample size for this study was 400 participants, health effects. During an initial 1-week baseline data collection, powered to detect differences between treatment groups in the participants reported the number of cigarettes and symptoms point prevalence (7-day cigarette avoidance) at the completion associated with withdrawal (Minnesota Nicotine Withdrawal of treatment (week 12). Group sample sizes of 200 in each Scale, MNWS18 19) using an Interactive Voice Response (IVR) group would achieve at least 80% power to detect an absolute system at the end of each day. Other baseline measures were col- difference between 7-day cigarette avoidance rates of 10%, if http://tobaccocontrol.bmj.com/ lected at the clinic visit (see below).