Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Donny EC, Denlinger RL, Tidey JW, et al. Randomized trial of reduced-nicotine standards for cigarettes. N Engl J Med 2015;373: DOI: /NEJMsa

2 SUPPLEMENTARY APPENDIX TO: Reduced Nicotine Standards for Cigarettes: A Randomized Trial Eric C. Donny 1, Rachel L. Denlinger 1, Jennifer W. Tidey 2, Joseph S. Koopmeiners 3, Neal L. Benowitz 4, Ryan G. Vandrey 5, Mustafa al Absi 6, Steven G. Carmella 7, Paul M. Cinciripini 8, Sarah S. Dermody 1, David J. Drobes 9, Stephen S. Hecht 7, Joni Jensen 7, Tonya Lane 1, Chap T. Le 3, F. Joseph McClernon 10, Ivan D. Montoya 11, Sharon E. Murphy 12, Jason D. Robinson 8, Maxine L. Stitzer 5, Andrew A. Strasser 13, Hilary Tindle 14, Dorothy K. Hatsukami 15 1 Department of Psychology, University of Pittsburgh, Pittsburgh PA, USA Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA Division of Biostatistics, School of Public Health and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA Departments of Medicine and Bioengineering & Therapeutic Sciences, University of California San Francisco, San Francisco, California Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA University of Minnesota Medical School, Duluth, MN, USA Masonic Cancer Center, University of Minnesota, Minneapolis, MN Department of Behavioral Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa FL, USA Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA, National Institute on Drug Abuse, Bethesda, MD, USA Department of Biochemistry Molecular Biology and Biophysics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN Department of Psychiatry, Perelman School of Medicine, and Abramson Cancer Center, University of Pennsylvania, Philadelphia PA P a g e

3 14 Department of Medicine, Vanderbilt University, Nashville, TN, USA At the time this study was conducted Dr. Tindle was faculty in the Department of Medicine, University of Pittsburgh, Pittsburgh, PA, Masonic Cancer Center and Department of Psychiatry, University of Minnesota, Minneapolis, MN P a g e

4 Table of Contents Reduced Nicotine Standards for Cigarettes: A Randomized Trial Supplementary Appendix I. CENIC Acknowledgements.. 5 II. Data Safety Monitoring Board and External Advisory Board.. 8 III. Supplementary Methods.. 9 IV. Supplementary Results.. 12 V. Figure S1: CONSORT diagram. 13 VI. Figure S2: Cigarettes per day (menthol status). 14 VII. Figure S3: Quit attempts and cigarettes per day at follow-up 15 VIII. Figure S4: Urinary cotinine.. 16 IX. Figure S5: Expired carbon monoxide 17 X. Figure S6: Smoke exposure from a single cigarette 18 XI. Figure S7: Estimated level of nicotine.. 19 XII. Figure S8: Estimated cigarettes per day at $6 per pack.. 20 XIII. Figure S9: Fagerström Test for Nicotine Dependence.. 21 XIV. Figure S10: Nicotine withdrawal. 22 XV. Figure S11: Craving across weeks 23 XVI. Figure S12: Craving during abstinence. 24 XVII. Table S1: SPECTRUM cigarettes as characterized by the National Institute on Drug Abuse..25 XVIII. Table S2: SPECTRUM cigarettes as characterized by the Center for Disease Control and Prevention. 26 XIX. Table S3: Demographics with non-completers.. 27 XX. Table S4: Mean difference in total cigarettes per day. 28 XXI. Table S5: Mean difference in study cigarettes per day XXII. Table S6: Menthol status interaction for total cigarettes per day XXIII. Table S7: Mean difference in total cigarettes per day (menthol smokers) XXIV. Table S8: Mean difference in total cigarettes per day (non-menthol smokers). 35 XXV. Table S9: Compliance with assigned study product 37 XXVI. Table S10: Association between current smoking status at 30 d and group 38 XXVII. Table S11: Mean difference in cigarettes per day at 30 d XXVIII. Table S12: Association between quit attempts at 30 d XXIX. Table S13: Ratio of geometric mean creatinine-corrected TNE XXX. Table S14: Ratio of geometric mean creatinine-corrected TNE (non-compliers).. 43 XXXI. Table S15: Ratio of geometric mean creatinine-corrected NNAL XXXII. Table S16: Ratio of geometric mean creatinine-corrected cotinine XXXIII. Table S17: Mean difference in expired carbon monoxide...48 XXXIV. Table S18: Differences in time since last cigarette and number of cigarettes prior to expired carbon monoxide..49 XXXV. Table S19: Mean difference in total puff volume P a g e

5 XXXVI. Table S20: Mean difference in expired carbon monoxide boost 52 XXXVII. Table S21: Mean difference in estimated nicotine levels.. 53 XXXVIII. Table S22: Mean difference in estimated cigarettes per day at $6 per pack XXXIX. Table S23: Mean difference in WISDM total score at Week XL. Table S24: Mean difference in WISDM primary motive subscales at Week XLI. Table S25: Mean difference in WISDM secondary motive subscales at Week XLII. Table S26: Mean difference in FTND.. 59 XLIII. Table S27: Mean difference in FTND excluding cigarettes per day XLIV. Table S28: Association between time-to-first-cigarette and nicotine content XLV. Table S29: Mean difference in MNWS score at Week XLVI. Table S30: Mean difference in maximum daily MNWS score during week XLVII. Table S31: Mean difference in QSU (factor 1) at Week XLVIII. Table S32: Mean difference in QSU (factor 2) at Week XLIX. Table S33: Mean difference in QSU (total) at Week L. Table S34: Mean difference in MNWS score during abstinence visit LI. Table S35: Mean difference in QSU (factor 1) during abstinence visit. 71 LII. Table S36: Mean difference in QSU (factor 2) during abstinence visit. 73 LIII. Table S37: Mean difference in QSU (total) during abstinence visit LIV. Table S38: Mean difference in CESD score LV. Table S39: Association between CESD 16 and nicotine content.. 77 LVI. Table S40: Mean difference in respiratory health question # 1 (cough) LVII. Table S41: Mean difference in respiratory health question # 2 (phlegm) LVIII. Table S42: Mean difference in respiratory health question # 3 (shortness of breath).. 80 LIX. Table S43: Mean difference in respiratory health question # 4 (irritation).. 81 LX. Table S44: Mean difference in respiratory health question (average). 82 LXI. Table S45: Mean difference in health changes question # 4 (overall health).. 83 LXII. Table S46: Number of events LXIII. Table S47: Number of participants with an event.. 87 LXIV. Table S48: Summary of adverse events. 90 LXV. Table S49: Serious events and withdrawals LXVI. References P a g e

6 CENIC Acknowledgements A. University of Pittsburgh Cynthia Conklin, PhD Anna Marsland, PhD Matthew Muldoon, MD Danielle Joel Erin Goldstein Kristin Yahner Lee Bennett Cathy Scott Amanda Loeffert Ravi Choudhuri Patricia Schademan Bethany Koch Ann Jacob Isha Vasudeva B. University of Minnesota Research: Sharon Allen, MD Louise Hertsgaard Lor Moua Alexander Johnson Elizabeth Thompson Jane Shulz Laura Dick Jim Fingar Jamila Davis Astia Roper-Batker Margarita Omeonu Bioinformatics: Sandeep Kataria Donna Mosley Rowena Ochiagha Reed McEwan Namita Zakariasen Vidhyalakshmi Ramesh Khara Baumann Swapna Bapat Qing Cui Biostatistics: Chap Le, Ph.D. Qing Cao Xianghua Luo Biomarkers: Kwangsoo Choi Nicole Thompson Ben Ransom C. Brown University Suzanne Colby, PhD Rachel Cassidy, PhD Robert Swift, MD Patricia Coie, PhD RNP Phillip Russell, MD Netesha Reid Emily Xavier Ashley Marzullo Kimberly Duguay Christine Goodwin D. Johns Hopkins University Annie Umbricht, MD Lauren Pacek, PhD Cirielle Colino Joseph Harrison Chinedu Jon-Emefieh William Mitchell Timothy Williams 5 P a g e

7 E. University of Pennsylvania Frank Leone, MD Kathy Tang Valentina Souprountchouk Angela Halstead Rachel Dumont Dana Campetti David Yaron F. Duke University Scott Kollins, PhD Behrouz Namdari, MD Rachel Kozink Amy Brightwood Chelsea Hagmann Dana Van Wert G. MD Anderson Cancer Center Maher Karam-Hage, MD Rosario Wippold Sheila Kitaka David Hunt Jennifer Ferguson Christine Jeria Kristin Cortese Sarah Juarez Heather Bunch Alexandra Demo-Dananberg Niloufar Baktashi Janeene Frerking O Neak Henigan Tamera Davis Tarica Oliva Aleah Waxali Jocelyn Rausch Brittany Tolbert H. University of California San Francisco Natalie Nardone, PhD Delia Dempsey, MD Faith Allen, PhD Jennifer Ko Angela Chwa Shannon Lance Scott Rostler I. University of Minnesota Medical School Duluth Motohiro Nakajima, PhD Andrine Lemieux, PhD Jacob Prunuske, MD Ruth Westa, DO Caroline Woods Farynn Kimmes Lauren Schulberg Dayna Schleppenbach Souirya Thao Morgan Prochaska Jie Gooder J. Moffitt Cancer Center Thomas Brandon, PhD David Evans, PhD Richard Roetzheim, MD Vani Simmons, MD David McQueen Jason Oliver Melissa Conn Kade Jentink Emily Cutolo Dana Jordan Sally Stilwell Lori Kirchoff Yvonne Gorman 6 P a g e

8 National Institute on Drug Abuse Ivan Montoya, MD 7 P a g e

9 Data Safety Monitoring Board 1. Anne Joseph, M.D., M.P.H., Wexler Professor of Medicine, Applied Clinical Research Program Director, University of Minnesota 2. Linda Collins, Ph.D., Director, Methodology Center, Pennsylvania State University 3. Wallace Pickworth, Ph.D., Research Leader, Baltimore Operation, Centers for Public Health Research and Evaluation, Battelle 4. Peter Shields, M.D., College of Medicine, Deputy Director, The Ohio State University Comprehensive Cancer Center 5. Stephen Tiffany, Ph.D., Empire Innovation Professor and Chair of Psychology, University of Buffalo External Advisory Board 1. David Mendez, University of Michigan 2. Denis Choiniere, Healthy Environments and Consumer Safety Branch, Health Canada 3. Greg Connolly, Harvard School of Public Health 4. Jack Henningfield, Johns Hopkins School of Medicine 5. Kenneth Warner, University of Michigan 6. Marina Picciotto, Yale University 7. Mitch Zeller, Pinney Associates (currently at the Food and Drug Administration) 8. Vaughan Rees, Harvard School of Public Health 9. William Farone, Applied Power Concepts 8 P a g e

10 Supplementary Methods Contributions of authors Dr. Donny wrote the first draft of the paper and circulated to all authors for comments. Dr. Koopmeiners conducted all analyses in consultation with Dr. Donny and the other authors. All authors participated in designing the study and collecting the data. All authors share in the decision to publish the paper and in the responsibility for the manuscript as submitted. Study Protocol and Statistical Analysis Plan A complete study protocol, statistical analysis plan and summary of changes made after initiation of the study is provided at nejm.org. Cigarettes Additional information about the study product can be found in Tables S1 and S2. All products except the 0.4 mg/g cigarette used the same cigarette paper, tipping paper, and dual plug (paper: cellulose acetate) filters with a target pressure drop of 81 mmh2o. The filler in 0.4 mg/g cigarettes was comprised of a single very low nicotine tobacco variety. The filler in the 15.8 mg/g cigarettes contains 40% tobacco from the same variety, and 60% of a blend of a 60:40 mixture of bright tobacco and burley tobacco. The filler in the intermediate nicotine content products were mixtures of other ratios of these two tobacco sources. The products had similar tobacco weight and yielded similar levels of carbon monoxide both by ISO and Canadian Intensive methods. The 0.4 mg/g cigarette had a cellulose acetate filter with a target pressure drop of 56 mh2o and unperforated tipping. The products differed in constituents closely related to nicotine. For example, so-called minor alkaloids (e.g., anatabine) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were reduced along with nicotine. Additional information about the manufacturing process such as the use of additives and specific tobacco blends was acquired from the National Institute on Drug Abuse, Research Triangle Institute and/or 22 nd Century Group, Inc. The products differ in casings, including sugars. The 0.4, 1.3, 2.4 and 5.2 mg/g nicotine products had the same casing. More sugar is added to the higher nicotine (15.8 mg/g) tobacco to balance the nicotine to sugar ratio. The nicotine content of Quest 3, which was used as the reduced nicotine product in several previous studies 1-4, was approximately 0.86 mg/g (assuming 0.7 g tobacco in the rod) 5. A survey of 92 brands from the U.S., Canada and the U.K. found an average nicotine content of 14.6, 19.3 and 17.6 mg/g (assuming 0.7 g tobacco in the rod), respectively 6. Complete data on brands currently on the market have not been made publically available. However, we obtained data using the Freedom of Information Act for a number of popular brands. A survey of the data provided suggest that the nicotine content of current cigarettes on the market 9 P a g e

11 today is generally similar, typically mg/g. Hence, the control investigational cigarettes appear to be similar to and possibly slightly lower in nicotine content. Questionnaire on Smoking Urges The Questionnaire on Smoking Urges was analyzed as total score and based on the established factor structure: Factor 1 (intention to smoke) and Factor 2 (relief from negative affect and urgent desire to smoke). Analytical chemistry Urinary total nicotine equivalents, the sum of nicotine and six metabolites, were quantified as a measure of nicotine exposure 7. Total nicotine, total cotinine, total trans 3'-hydroxycotinine ("total" refers to the sum of the analyte and its respective glucuronide conjugate) and nicotine- N-oxide were quantified in β-glucuronidase treated urine by liquid chromatography tandem mass spectrometry (LC/MS/MS) analysis as described previously 8. Cotinine and trans-3"- hydroxycotinine in saliva were quantified in saliva by LC/MS/MS method described previously 9. The ratio of 3-hydroxycotinine to cotinine, referred to as the nicotine metabolite ratio was determined as a phenotypic measure of CYP2A6 metabolic activity, which is highly correlated with the metabolic clearance of nicotine. Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (total NNAL; sum of NNAL and its glucuronide conjugates), a metabolite and biomarker of 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) exposure, was quantified by LC/MS/MS as described previously 10. Statistical Analyses The primary analysis compared the primary control condition (15.8 mg/g) to the reduced nicotine conditions: 5.2, 2.4, 1.3 and 0.4 mg/g. Participants were analyzed according to the group to which they were randomized regardless of compliance. The primary outcome was the average cigarettes per day during Week 6. The weekly average cigarettes per day for each visit was calculated using all days since the previous visit. If a participant missed a visit, then data from the 7 days following the previous visit was used. The primary analysis used linear regression adjusting for baseline cigarettes per day. A Bonferroni adjustment was used to account for the comparison of the four reduced nicotine content conditions to the control conditions to determine statistical significance (alpha=0.0125; two-tailed), resulting in an overall Type-I error rate of Analyses of secondary outcomes utilized the same approach (alpha=0.0125; two-tailed). Additional pairwise comparisons were completed among the reduced nicotine content conditions that differed significantly from the 15.8 mg/g cigarette control condition (alpha determined by the number of pairwise comparisons completed). Supplementary analyses included linear regression adjusting for baseline, age, sex, race (White, Black and other), and nicotine metabolite ratio (a measure of the CYP2A6 metabolism, a 10 P a g e

12 primary pathway of nicotine metabolism 11 ); repeated-measures analysis using a linear mixed model; and analyses utilizing the usual brand condition as the reference group. Non-completers were not included in the regression analyses, but were included in the mixed models. The number of adverse events was compared across groups using zero-inflated negative binomial regression. All statistical analyses used in this manuscript are provided in Tables S4-S45. P values larger than 0.01 are rounded to two decimal places. P values between 0.01 and are reported to 3 decimal places. P values smaller than are reported as P< P a g e

13 Supplementary Results All supplementary results include the exploratory arm (0.4 mg/g yield). A CONSORT diagram detailing retention through Week 6 (based on interactive voice response call completion; primary outcome measure) is provided in Figure S1. Additional figures presenting important outcomes are provided in Figures S2-12. Table S3 presents the demographic and baseline smoking characteristics for all participants including those that failed to complete. Pairwise comparisons indicated that none of the reduced nicotine groups significantly differed from 15.8 mg/g. Nicotine metabolite ratio was controlled for in all adjusted models. Adverse events, self-reported health status, and safety parameters None of the serious events were judged to be related or possibly related. For non-serious events, no significant differences between the groups were found in the total number of related or possibly related events (p=0.37). Likewise, participant ratings of overall health and symptoms specific to respiratory health (cough, phlegm production, shortness of breath, and irritation in throat and lungs) were not significantly related to condition. Total scores on the Center for Epidemiological Studies Depression Scale at Week 6 as well as the percentage of individuals exceeding the clinical criteria for depression (16+) did not vary significantly by cigarette condition. Finally, expired carbon monoxide exceeded 70 ppm in 4 participants (2 in 5.2 mg/g; 1 in both 2.4 mg/g and 1.3 mg/g conditions). One participant in the 1.3 mg/g condition was withdrawn at Week 2 for expired carbon monoxide>100 ppm (116 ppm; baseline expired carbon monoxide=37 ppm), although this individual also reported cannabis use prior to the expired carbon monoxide assessment. A summary of adverse events is provided in Tables S P a g e

14 Figure S1. CONSORT diagram 367 Ineligible 36 Eligible but declined 27 Eligible but withdrawn Consented (n=1270) Randomized (n=840) Ineligible (n=1) Figure S1. Enrollment, retention, and reasons for attrition as a function of study group. One randomized participant was found to be ineligible and excluded from all analyses per the local IRB (N=839 analyzed). Retention as defined by Week 6 IVR was not related significantly to group (p=0.64). 13 P a g e

15 Figure S2. Cigarettes smoked per day as a function of cigarette nicotine content and menthol status Figure S2. Mean number of cigarettes smoked per day as reported by participants using an Interactive Voice Response (IVR) system. The upper panel represents the mean total number of cigarettes smoked per day for participants smoking menthol cigarettes. The lower panel represents the mean total number of cigarettes smoked per day for participants smoking nonmenthol cigarettes. All analyses adjusted for baseline. * indicates significant difference relative to 15.8 mg/g group at Week 6 (p<0.002). 14 P a g e

16 Figure S3. Quit attempts and cigarettes smoked per day at follow-up as a function of cigarette nicotine content Figure S3. Percentage of participants reporting a quit attempt after completing the study (Upper panel) and mean number of cigarettes smoked per day (Lower panel) at the 30-day follow-up. All analyses adjusted for baseline. * indicates significant difference relative to 15.8 mg/g group at follow-up (p<0.01). 15 P a g e

17 Figure S4. Urinary cotinine as a function of cigarette nicotine content. Figure S4. Total cotinine presented as geometric means adjusted for creatinine. Urine samples were collected at baseline, week 2 and week 6. All analyses adjusted for baseline. * indicates significant difference compared to 15.8 mg/g condition at Week 6 (p<0.002). 16 P a g e

18 Figure S5. Exhaled carbon monoxide across weeks as a function of cigarette nicotine content. Figure S5. Carbon monoxide is a measure of smoke exposure. Time since last cigarette and the number of cigarettes smoked on the day of, and prior to, the carbon monoxide assessment failed to differ significantly by group. Expired carbon monoxide is presented as the arithmetic mean. All analyses adjusted for baseline. No significant differences at Week 6 were observed. 17 P a g e

19 Figure S6. Smoke exposure from a single cigarette as a function of cigarette nicotine content. Figure S6. Total puff volume (Upper panel) and boost in carbon monoxide (lower panel) from a single cigarette smoked in the laboratory. All analyses adjusted for baseline. No significant differences were observed. * indicates significant difference compared to 15.8 mg/g condition at Week 6 (p<0.01). 18 P a g e

20 Figure S7. Estimated level of nicotine as a function of actual cigarette nicotine content. Figure S7. Participant response to the question What level of nicotine do you think was in your study cigarette? at Week 6. Response options varied from very low (1) to very high (5). Participants randomized to usual brand were not administered this question. No adjustments for baseline were made as there was no baseline equivalent. * indicates significant difference compared to 15.8 mg/g condition (p<0.005). 19 P a g e

21 Figure S8. Estimated cigarettes per day at $6 per pack as a function of actual cigarette nicotine content. Figure S8. Participant estimated consumption (cigarettes smoked per day) at $6 per pack. All analyses adjusted for baseline. * indicates significant difference compared to 15.8 mg/g condition at Week 6 (p<0.001). 20 P a g e

22 Figure S9. Fagerström Test for Nicotine Dependence as a function of cigarette nicotine content. Figure S9. Total scores on the Fagerström Test for Nicotine Dependence including the cigarette per day item. All analyses adjusted for baseline. * indicates significant difference compared to 15.8 mg/g condition at Week 6 (p 0.001). 21 P a g e

23 Figure S10. Nicotine withdrawal as a function of cigarette nicotine content. Figure S10. Mean total scores during weekly assessments (upper panel) and mean maximum score during the baseline and first week of product use (lower panel) on the 8-item Minnesota Nicotine Withdrawal Scale during weekly assessments. All analyses adjusted for baseline. No significant differences were observed. 22 P a g e

24 Figure S11. Craving as a function of cigarette nicotine content. Figure S11. Scores on the Questionnaire of Smoking Urges reported as total score (Upper panel), Factor 1 (intention to smoke) (Middle panel) and Factor 2 (relief from negative affect and urgent desire to smoke) (Lower panel). Ratings were provided in reference to how the participant felt right now for the product currently being used (randomized condition). All analyses adjusted for baseline. * indicates significant difference (p<0.01 in all cases) compared to 15.8 mg/g condition at Week P a g e

25 Figure S12. Craving as a function of cigarette nicotine content after 18+ h of abstinence Figure S12. Factor scores on the Questionnaire of Smoking Urges during abstinence visit; Factor 1 (upper panel) indicates intention to smoke and Factor 2 (lower panel) indicates relief from negative affect and urgent desire to smoke. Ratings were provided in reference to how the participant felt right now for the product currently being used (randomized condition). All analyses adjusted for baseline. * indicates significant difference (p<0.01 in all cases) compared to 15.8 mg/g condition. 24 P a g e

26 Table S1. SPECTRUM cigarettes used on Donny et al. (2015), as characterized by the National Institute on Drug Abuse Unit 0.4 mg/g 1.3 mg/g 2.4 mg/g 5.2 mg/g 15.8 mg/g Nicotine Research Cigarette Code NRC102 NRC103 NRC104 NRC105 NRC200 NRC201 NRC300 NRC301 NRC400 NRC401 NRC600 NRC601 Flavor Regular Menthol Regular Menthol Regular Menthol Regular Menthol Regular Menthol Regular Menthol Tobacco Weight g Moisture % Nicotine mg/g Menthol mg/g LOQ 1.27 LOQ 1.05 LOQ 1.00 LOQ 0.83 LOQ 1.17 LOQ 1.10 Smoke (ISO) Nicotine mg/cigarette Tar mg/cigarette Total Particulate Matter mg/cigarette Carbon Monoxide mg/cigarette Menthol mg/cigarette LOQ 0.24 LOQ LOQ 0.21 LOQ 0.24 LOQ 0.31 Values represent the carton-weighted average of products based on data take from the data sheets provided by the National Institute on Drug Abuse. LOQ = value listed as limit of quantification and/or not detectable on the data sheets. ISO = International Standards Organization. 25 P a g e

27 Table S2. SPECTRUM cigarettes used in Donny et al. (2015), as characterized by the Center for Disease Control and Prevention Unit 0.4 mg/g 1.3 mg/g 2.4 mg/g 5.2 mg/g 15.8 mg/g Nicotine Research Cigarette Code NRC102 NRC103 NRC104 NRC105 NRC200 NRC201 NRC300 NRC301 NRC400 NRC401 NRC600 NRC601 Flavor Regular Menthol Regular Menthol Regular Menthol Regular Menthol Regular Menthol Regular Menthol Tobacco Nicotine mg/g Anabasine mcg/g Anatabine mcg/g Isonicoteine mcg/g Myosmine mcg/g Nornicotine mcg/g Menthol mg/cigarette NNK ng/g NNN ng/g Smoke (ISO) Nicotine mg/cigarette Tar mg/cigarette Carbon Monoxide mg/cigarette NNK ng/cigarette NNN ng/cigarette Smoke (Canadian Intensive) Nicotine mg/cigarette Tar mg/cigarette Carbon Monoxide mg/cigarette NNK ng/cigarette NNN ng/cigarette The higher menthol levels in tobacco relative to Table S1 are likely related to the measurement of menthol in the cigarette (including filter and paper) vs. only the tobacco. ISO = International Standards Organization 26 P a g e

28 Table S3. Demographics and smoking characteristics prior to randomization Variable Level/Unit Overall Usual brand 15.8 mg/g 5.2 mg/g 2.4 mg/g 1.3 mg/g 0.4 mg/g 0.4 mg/g Noncompleters Sample size Age Years 41.7 (13.2) 41.5 (13) 42.2 (13.7) 42 (13) 42.2 (12.1) 41.4 (14) 42.9 (13.6) 39.6 (13) 35.7 (12.6) Sex Male 481 (57.3%) 72 (61%) 71 (59.7%) 68 (55.7%) 77 (64.7%) 62 (52.1%) 63 (52.9%) 68 (55.3%) 40 (67.8%) Race White 428 (51.0%) 58 (49.2%) 58 (48.7%) 58 (47.5%) 59 (49.6%) 61 (51.3%) 66 (55.5%) 37 (62.7%) 37 (62.7%) Black 321 (38.3%) 51 (43.2%) 48 (40.3%) 51 (41.8%) 46 (38.7%) 44 (37%) 44 (37%) 18 (30.5%) 18 (30.5%) Ethnicity Hispanic 42 (5.0%) 2 (1.7%) 7 (5.9%) 8 (6.6%) 6 (5%) 7 (5.9%) 6 (5%) 2 (3.4%) 2 (3.8%) Education Some college 471 (56.1%) 59 (50%) 66 (55.5%) 67 (54.9%) 70 (58.8%) 63 (52.9%) 70 (58.8%) 28 (47.5%) 28 (47.5%) Cigarette type Menthol 481 (57.3%) 66 (55.9%) 74 (62.2%) 68 (55.7%) 72 (60.5%) 68 (57.1%) 61 (51.3%) 33 (55.9%) 33 (55.9%) Cigarettes per day 15.6 (7.6) 15.1 (7.5) 15.7 (8.3) 16.1 (7.7) 15.3 (7.2) 15.4 (7.5) 15.4 (7.6) 16 (8.3) 16.0 (8.3) Total nicotine nmol/mg equivalents (0.1,325.7) (2.0,184.6) (0.1,222.3) (3.2,229.8) (0.7,176.2) (1.2,196.5) (0.2,325.7) (0.95,325.71) (1.0,325.7) Carbon monoxide* ppm 15.1 (8.0) 13.1 (6.9) 14.9 (8.3) 14.9 (8.2) 16.7 (8.3) 16.9 (8.8) 14 (7.2) 16.5 (11.4) 16.5 (11.4) Other Tobacco Past 30 days 202 (24.1%) 34 (28.8%) 31 (26.1%) 32 (26.2%) 25 (21%) 26 (21.8%) 26 (21.8%) 39 (66.1%) 20 (33.9%) Fagerström Test for Nicotine Dependence Total score 5.1 (2.2) 5 (2.2) 5.1 (2.3) 5.3 (2.2) 5 (2.1) 5 (2.4) 5.2 (2.2) 5 (2.6) 5.0 (2.6) Nicotine content reported per g of tobacco filler. Cigarettes per day was determined by the weekly average during baseline using data collected by the interactive voice response system. Demographics, other tobacco use, and the Fagerström Test for Nicotine Dependence was assessed during the in-person screening by self-report. Fagerström Test for Nicotine Dependence ranges from 0 to 10; larger scores indicate greater dependence. Cigarette type, carbon monoxide and total nicotine equivalents per mg creatinine were assessed on the day of randomization. Values indicate count (%), arithmetic mean (standard deviation), or geometric mean (min, max). Non-completers defined as participants randomized to one of the seven conditions who failed to complete any IVR calls during the final week of the intervention. * indicates significant effect of group (p<.001). 27 P a g e

29 Table S4: Mean difference in total cigarettes per day relative to 15.8 mg/g or usual brand controls at the week 6 visit Treatment Group N Unadjusted Linear Adjusted Linear Regression 2 Unadjusted Linear Mixed Regression 1 Model mg group as reference group: 15.8 mg 111 Adjusted Linear Mixed Model mg (-3.67, 0.38) (-3.63, 0.46) (-3.56, -0.01) (-3.48, 0.09) mg (-6.58, ) 1.3 mg (-7.13, ) 0.4 mg (-8.12, ) 0.4 mg, high tar (-8.12, ) Usual brand group as reference group: Usual Brand 113 < (-6.67, ) < (-7.24, ) < (-8.24, ) < (-8.11, ) < (-6.23, -2.65) < (-6.31, -2.7) < < (-6.89, -3.31) < (-6.95, ) < < (-7.69, -4.11) < (-7.83, -4.2) < < (-7.94, -4.4) < (-7.89, ) 15.8 mg (-3.54, 0.53) (-3.77, 0.37) (-3.27, 0.31) (-3.52, 0.1) mg (-5.17, ) 2.4 mg (-8.08, ) 1.3 mg (-8.63, ) 0.4 mg (-9.62, ) 0.4 mg, high tar (-9.62, ) (-5.34, ) < (-5.04, -1.49) < (-5.21, -1.6) < < (-8.38, -4.2) < (-7.71, -4.13) < (-8.03, -4.4) < < (-8.95, -4.8) < (-8.37, -4.79) < (-8.67, ) < (-9.95, ) < (-9.81, ) 1 adjusted for baseline cigarettes per day 2 adjusted for baseline cigarettes per day, age, race, gender and salivary nicotine metabolite ratio < < (-9.17, -5.6) < (-9.55, -5.9) < < (-9.42, -5.89) < (-9.61, ) < P a g e

30 Table S4.a: P-values for pairwise comparisons of total cigarettes per day at the week 6 visit or nicotine conditions that were significant different from 15.8 mg/g control 2.4 mg 1.3 mg 0.4 mg 0.4 mg, 2.4 mg 1.3 mg mg mg, P a g e

31 Table S5: Mean difference in study cigarettes per day relative to 15.8 mg/g or usual brand controls at the week 6 visit Treatment Group N Unadjusted Linear Adjusted Linear Regression 2 Unadjusted Linear Mixed Regression 1 Model mg group as reference group: 15.8 mg 111 Adjusted Linear Mixed Model mg (-4.34, 0.16) (-4.33, 0.24) (-4.34, -0.32) (-4.29, ) 2.4 mg (-8.25, -3.68) < (-8.33, -3.68) < (-8.12, -4.07) < (-8.17, ) 1.3 mg (-8.62, -4.07) < (-8.71, -4.1) < (-8.56, -4.51) < (-8.6, -4.52) < mg (-9.34, -4.78) < (-9.45, -4.78) < (-9.18, -5.13) < (-9.32, ) 0.4 mg, high tar (-9.85, -5.37) < (-9.86, -5.31) < (-9.7, -5.69) < (-9.64, ) Usual brand group as reference group: Usual Brand mg (-3.84, 0.69) (-4.05, 0.57) (-3.51, 0.54) (-3.75, 0.36) mg (-5.91, -1.42) (-6.09, -1.48) (-5.82, -1.8) < (-6, -1.9) < mg (-9.82, -5.26) < (-10.08, -5.4) < (-9.6, -5.55) < (-9.89, ) 1.3 mg (-10.19, ) < (-10.46, ) 0.4 mg (-10.9, -6.37) < (-11.19, ) 0.4 mg, high tar (-11.42, ) < (-11.61, ) 1 adjusted for baseline cigarettes per day 2 adjusted for baseline cigarettes per day, age, race, gender and salivary nicotine metabolite ratio < (-10.04, -6) < (-10.31, - 6.2) < (-10.66, -6.62) < (-11.03, ) < (-11.18, -7.18) < (-11.35, ) 0.03 < < < < < < < P a g e

32 Table S5.a: P-values for pairwise comparisons of study cigarettes per day at the week 6 visit for nicotine conditions that were significant different from 15.8 mg/g control 2.4 mg 1.3 mg 0.4 mg 0.4 mg, 2.4 mg 1.3 mg mg mg, P a g e

33 Table S6: P-value for test of treatment group by menthol status interaction for total cigarettes per day at the week 6 visit Treatment Group Unadjusted Model Adjusted Model 15.8 mg/g as reference group: 5.2 mg/g by menthol interaction mg/g by menthol interaction mg/g by menthol interaction mg/g by menthol interaction by menthol interaction Usual brand as reference group: 15.8 mg/g by menthol interaction mg/g by menthol interaction mg/g by menthol interaction mg/g by menthol interaction mg/g by menthol interaction by menthol interaction P a g e

34 Table S7: Mean difference in total cigarettes per day relative to 15.8 mg/g or usual brand controls at the week 6 visit in menthol smokers Treatment Group N 15.8 mg/g as reference group: 15.8 mg/g 69 Unadjusted Linear Adjusted Linear Regression 2 Unadjusted Linear Mixed Model 1 Adjusted Linear Mixed Regression 1 Model mg/g (-7.04, -1.73) (-6.97, -1.6) (-7.22, -2.44) < (-7.12, -2.29) < mg/g (-7.19, -1.84) (-7.33, -1.91) (-7.01, -2.27) < (-7.13, -2.35) < mg/g (-8.35, -2.97) < (-8.5, -3.07) < (-8.15, -3.35) < (-8.28, -3.46) < mg/g (-9.41, -3.88) < (-9.56, -3.87) < (-9.24, -4.3) < (-9.36, -4.3) < Usual brand as reference group: Usual Brand (-9.46, -4.23) < (-9.58, -4.25) < (-9.4, -4.7) < (-9.49, -4.72) < mg/g (-4.3, 1.06) (-4.83, 0.69) (-3.79, 1.01) (-4.33, 0.6) mg/g (-8.72, -3.3) < (-9.15, -3.56) < (-8.66, -3.78) < (-9.07, -4.06) < mg/g (-8.86, -3.41) < (-9.5, -3.89) < (-8.45, -3.61) < (-9.08, -4.12) < mg/g (-10.02, ) 0.4 mg/g (-11.08, ) < (-10.67, -5.04) < (-9.59, -4.69) < (-10.24, ) < < (-11.73, -5.84) < (-10.67, -5.64) < (-11.31, -6.08) < (-11.14, -5.8) < (-11.75, -6.22) < (-10.84, -6.04) < (-11.45, ) 1 adjusted for baseline cigarettes per day 2 adjusted for baseline cigarettes per day, age, race, gender and salivary nicotine metabolite ratio < P a g e

35 Table S7.a: P-values for pairwise comparisons of total cigarettes per day at the week 6 visit or nicotine conditions that were significant different from 15.8 mg/g control in menthol smokers 5.2 mg/g 2.4 mg/g 1.3 mg/g 0.4 mg/g 5.2 mg/g mg/g mg/g mg/g P a g e

36 Table S8: Mean difference in total cigarettes per day relative to 15.8 mg/g or usual brand controls at the week 6 visit in nonmenthol smokers Treatment Group N 15.8 mg/g as reference group: 15.8 mg/g 42 Unadjusted Linear Adjusted Linear Regression 2 Unadjusted Linear Mixed Regression 1 Model 1 Adjusted Linear Mixed Model mg/g (-0.89, 5.29) (-0.79, 5.48) (-0.21, 5.07) (0.05, 5.33) mg/g (-7.62, ) 1.3 mg/g (-7.19, ) 0.4 mg/g (-8.18, ) Usual brand as reference group: Usual Brand (-7.78, ) (-6.75, -1.31) (-6.88, ) (-7.19, -0.9) (-6.63, -1.29) (-6.52, ) (-8.13, ) (-8.04, -1.8) (-7.89, ) (-7.12, -1.93) (-7.1, -1.91) (-7.44, -2.1) < (-7.18, ) 15.8 mg/g (-4.68, 1.5) (-4.92, 1.28) (-4.54, 0.79) (-4.79, 0.5) mg/g (-2.36, 3.58) (-2.51, 3.56) (-1.99, 3.1) (-2.02, 3.11) mg/g (-9.09, ) 1.3 mg/g (-8.66, ) 0.4 mg/g (-9.65, ) (-9.51, ) < (-9.51, ) < (-8.91, ) < (-9.84, ) < (-8.53, -3.28) < (-8.95, -3.65) < < (-8.41, -3.26) < (-8.58, -3.42) < < (-8.9, -3.9) < (-9.16, ) < (-9.6, -3.56) < (-9.22, -4.07) < (-9.23, ) 1 adjusted for baseline cigarettes per day 2 adjusted for baseline cigarettes per day, age, race, gender and salivary nicotine metabolite ratio < < P a g e

37 Table S8.a: P-values for pairwise comparisons of total cigarettes per day at the week 6 visit or nicotine conditions that were significant different from 15.8 mg/g control in non-menthol smokers 2.4 mg/g 1.3 mg/g 0.4 mg/g 2.4 mg/g mg/g mg/g P a g e

38 Table S9: Summaries of compliance with assigned study product by treatment group Summary Usual brand 15.8 mg 5.2 mg 2.4 mg 1.3 mg 0.4 mg 0.4 mg, high tar N N(%) compliant 74 (62.7) 51 (43.2) 33 (27) 24 (20.3) 30 (25.2) 23 (19.5) 28 (22.8) N(%) non-compliant 44 (37.3) 67 (56.8) 89 (73) 94 (79.7) 89 (74.8) 95 (80.5) 95 (77.2) < < < N with no follow-up Median # of non-study cigarettes 2 75 th percentile of non-study cigarettes 1 95 th percentile of non-study cigarettes % of days non-compliant Median # of non-study cigarettes when non-compliant : for significance test comparing rate of non-compliance to the 15.8 mg/g control group 2 : Summary considers all post-randomization days for subjects in the given treatment group Table S9.a: N(%) of subjects self-reporting full compliance (i.e., no non-study cigarette use) by treatment group and week Week Usual brand 15.8 mg 5.2 mg 2.4 mg 1.3 mg 0.4 mg 0.4 mg, Randomized Week (88.1) 66 (56.4) 54 (44.3) 37 (31.4) 44 (37.6) 34 (28.8) 44 (35.8) Week (84.7) 71 (61.7) 55 (46.2) 42 (36.2) 49 (41.9) 55 (47.4) 47 (39.5) Week (88.9) 79 (69.3) 67 (56.8) 48 (41.4) 50 (44.2) 59 (50.9) 61 (50.8) Week (93) 80 (70.8) 65 (57) 55 (50) 56 (50.5) 66 (57.4) 67 (56.3) Week (87.7) 85 (76.6) 70 (61.9) 61 (56.5) 63 (58.3) 68 (60.2) 68 (58.1) Week (90.3) 80 (72.1) 76 (66.7) 57 (53.3) 64 (58.2) 70 (64.2) 67 (57.8) 37 P a g e

39 Table S10: Association between Do you currently smoke cigarettes? at the 30-day follow-up visit and group Treatment Group 15.8 group as reference group: N Yes No Unadjusted Logistic Regression Adjusted Logistic Regression mg/g (98) 2 (2) Odds Ratio Odds Ratio (95% CI) 5.2 mg/g (92.6) 7 (7.4) 3.9 (0.79, 19.26) (0.85, 21.01) mg/g (95.7) 4 (4.3) 2.23 (0.4, 12.46) (0.38, 12.21) mg/g (90.3) 9 (9.7) 5.25 (1.1, 24.97) (1.13, 25.92) mg/g (89.1) 11 (10.9) 5.99 (1.29, 27.75) (1.25, 27.9) 0.02 high tar Usual brand as reference group: (90.8) 9 (9.2) 4.96 (1.04, 23.55) (1.01, 23.15) 0.05 Usual Brand (92.8) 7 (7.2) 15.8 mg/g (98) 2 (2) 0.26 (0.05, 1.3) (0.05, 1.31) mg/g (92.6) 7 (7.4) 1.02 (0.34, 3.04) (0.37, 3.35) mg/g (95.7) 4 (4.3) 0.58 (0.17, 2.07) (0.16, 2.04) mg/g (90.3) 9 (9.7) 1.38 (0.49, 3.86) (0.5, 4.06) mg/g (89.1) 11 (10.9) 1.57 (0.58, 4.24) (0.56, 4.33) 0.4 high tar (90.8) 9 (9.2) 1.3 (0.46, 3.64) (0.45, 3.61) adjusted for age, race, gender and salivary nicotine metabolite ratio 38 P a g e

40 Table S11: Mean difference in cigarettes per day relative to 15.8 mg/g or usual brand controls at the 30-day follow-up visit Treatment Group N 15.8 mg/g as reference group: 15.8 mg/g 100 Unadjusted Linear Regression 1 Adjusted Linear Regression mg/g (-3.96, -0.13) (-4.05, -0.17) mg/g (-3.5, 0.36) (-3.52, 0.38) mg/g (-4.59, -0.73) (-4.78, -0.9) mg/g (-5.53, -1.75) < (-5.57, -1.74) < Usual brand as reference group: Usual Brand (-5.07, -1.27) (-5.16, -1.32) mg/g (-2.96, 0.85) (-2.94, 0.93) mg/g (-5.02, -1.18) (-5.09, -1.15) mg/g (-4.56, -0.69) (-4.54, -0.6) mg/g (-5.65, -1.78) < (-5.81, -1.88) < mg/g (-6.58, -2.8) < (-6.6, -2.72) < (-6.13, -2.32) < (-6.18, -2.31) < adjusted for baseline cigarettes per day 2 adjusted for baseline cigarettes per day, age, race, gender and salivary nicotine metabolite ratio Table S11.a: P-values for pairwise comparisons of cigarettes per day at the 30-day follow-up visit for nicotine conditions that were significant different from 15.8 mg/g control 1.3 mg/g 0.4 mg/g 1.3 mg/g mg/g P a g e

41 Table S12: Association between Did you attempt to quit smoking after completing the study? and group Treatment Group 15.8 group as reference group: N No Yes Unadjusted Logistic Regression Adjusted Logistic Regression mg/g (83) 17 (17) Odds Ratio Odds Ratio (95% CI) 5.2 mg/g (75.8) 23 (24.2) 1.56 (0.77, 3.15) (0.8, 3.39) mg/g (75) 23 (25) 1.63 (0.81, 3.29) (0.81, 3.44) mg/g (68.8) 29 (31.2) 2.21 (1.12, 4.37) (1.19, 4.79) 0.01 ns 0.4 mg/g (65.3) 35 (34.7) 2.59 (1.33, 5.03) (1.46, 5.74) high tar Usual brand as reference group: (62.2) 37 (37.8) 2.96 (1.53, 5.74) (1.6, 6.26) Usual Brand (76.3) 23 (23.7) 15.8 mg/g (83) 17 (17) 0.66 (0.33, 1.33) (0.29, 1.21) mg/g (75.8) 23 (24.2) 1.03 (0.53, 1.99) (0.49, 1.92) mg/g (75) 23 (25) 1.07 (0.55, 2.08) (0.5, 1.94) mg/g (68.8) 29 (31.2) 1.46 (0.77, 2.77) (0.74, 2.71) mg/g (65.3) 35 (34.7) 1.71 (0.92, 3.18) (0.91, 3.23) 0.1 high tar (62.2) 37 (37.8) 1.95 (1.05, 3.63) (1, 3.52) adjusted for age, race, gender and salivary nicotine metabolite ratio ns indicates the comparison was not significant after Bonferroni correction (alpha=0.0125) Table S12.a: P-values for pairwise comparisons Did you attempt to quit smoking after completing the study? at the 30-day follow-up visit for nicotine conditions that were significantly different from 15.8 mg/g control 0.4 mg/g mg/g P a g e

42 Table S13: Ratio of geometric mean creatinine-corrected total nicotine equivalent relative to 15.8 mg/g or usual brand controls at the week 6 visit Treatment Group N 15.8 mg/g as reference group: 15.8 mg/g 107 Unadjusted Linear Adjusted Linear Regression 2 Unadjusted Linear Mixed Regression 1 Model 1 Ratio of Geometric Means Ratio of Geometric Means Ratio of Geometric Means Adjusted Linear Mixed Model 2 Ratio of Geometric Means 5.2 mg/g (0.5, 0.91) (0.5, 0.92) 0.01 ns 0.68 (0.51, 0.9) (0.51, 0.91) mg/g (0.43, 0.79) < (0.43, 0.79) (0.44, 0.77) < (0.43, 0.77) < mg/g (0.39, 0.72) < (0.38, 0.71) < (0.42, 0.74) < (0.41, 0.73) < mg/g (0.3, 0.54) < (0.29, 0.54) < (0.31, 0.55) < (0.3, 0.55) < Usual brand as reference group: Usual Brand (0.29, 0.53) < (0.3, 0.54) < (0.3, 0.52) < (0.29, 0.52) < mg/g (0.78, 1.42) (0.79, 1.46) (0.78, 1.38) (0.79, 1.41) mg/g (0.52, 0.96) (0.54, 0.99) (0.53, 0.94) (0.54, 0.96) mg/g (0.46, 0.83) (0.46, 0.85) (0.46, 0.8) < (0.46, 0.82) mg/g (0.41, 0.75) < (0.41, 0.76) < (0.44, 0.77) < (0.43, 0.77) < mg/g (0.31, 0.57) < (0.31, 0.58) < (0.33, 0.58) < (0.32, 0.58) < adjusted for baseline log(tne) (0.31, 0.56) < (0.32, 0.58) < (0.31, 0.54) < (0.31, 0.55) < adjusted for baseline log(tne), age, race, gender and salivary nicotine metabolite ratio ns indicates the comparison was not significant after Bonferroni correction (alpha=0.0125) 41 P a g e

43 Table S13.a: P-values for pairwise comparisons of creatinine-corrected total nicotine equivalents at the week 6 visit for nicotine conditions that were significant different from 15.8 mg/g control 5.2 mg/g 2.4 mg/g 1.3 mg/g 0.4 mg/g 5.2 mg/g mg/g mg/g mg/g ns < ns indicates the comparison was not significant after Bonferroni correction (alpha=0.0125) 42 P a g e

44 Table S14: Ratio of geometric mean creatinine-corrected total nicotine equivalents relative to 15.8 mg/g or usual brand controls at the week 6 visit for non-compliers only Treatment Group N 15.8 mg/g as reference group: 15.8 mg/g 61 Unadjusted Linear Adjusted Linear Regression 2 Unadjusted Linear Mixed Regression 1 Model 1 Ratio of Geometric Means Ratio of Geometric Means Ratio of Geometric Means Adjusted Linear Mixed Model 2 Ratio of Geometric Means 5.2 mg/g (0.52, 1.02) (0.51, 1.02) (0.52, 1.01) (0.51, 1) mg/g (0.43, 0.84) (0.43, 0.84) (0.43, 0.82) (0.42, 0.81) mg/g (0.39, 0.77) < (0.38, 0.75) < (0.41, 0.78) (0.39, 0.76) < mg/g (0.3, 0.58) < (0.3, 0.59) < (0.31, 0.59) < (0.31, 0.6) < Usual brand as reference group: Usual Brand (0.3, 0.58) < (0.29, 0.57) < (0.29, 0.56) < (0.28, 0.54) < mg/g (0.63, 1.45) (0.64, 1.49) (0.66, 1.46) (0.66, 1.49) mg/g (0.47, 1.04) (0.47, 1.07) (0.48, 1.04) (0.48, 1.05) mg/g (0.39, 0.85) (0.39, 0.87) (0.4, 0.84) (0.39, 0.85) mg/g (0.35, 0.78) (0.35, 0.78) (0.38, 0.81) (0.37, 0.81) mg/g (0.27, 0.59) < (0.27, 0.62) < (0.29, 0.61) < (0.29, 0.63) < adjusted for baseline log(tne) (0.27, 0.59) < (0.26, 0.59) < (0.27, 0.58) < (0.27, 0.57) < adjusted for baseline log(tne), age, race, gender and salivary nicotine metabolite ratio 43 P a g e

45 Table S14.a: P-values for pairwise comparisons of creatinine-corrected TNE at the week 6 visit for nicotine conditions that were significant different from 15.8 mg/g control for non-compliers only 2.4 mg/g 1.3 mg/g 0.4 mg/g 2.4 mg/g mg/g mg/g P a g e

46 Table S15: Ratio of geometric mean creatinine-corrected NNAL relative to 15.8 mg/g or usual brand controls at the week 6 Treatment Group N 15.8 mg/g as reference group: 15.8 mg/g 100 Unadjusted Linear Adjusted Linear Regression 2 Unadjusted Linear Mixed Regression 1 Model 1 Ratio of Geometric Means Ratio of Geometric Means Ratio of Geometric Means Adjusted Linear Mixed Model 2 Ratio of Geometric Means 5.2 mg/g (0.8, 1.2) (0.81, 1.21) (0.81, 1.18) (0.81, 1.19) mg/g (0.72, 1.08) (0.72, 1.07) (0.71, 1.04) (0.71, 1.04) mg/g (0.69, 1.03) (0.68, 1.01) (0.7, 1.03) (0.69, 1.02) mg/g (0.64, 0.96) (0.62, 0.93) (0.66, 0.96) (0.64, 0.94) 0.01 Usual brand as reference group: Usual Brand (0.69, 1.02) (0.7, 1.04) (0.71, 1.03) (0.72, 1.05) mg/g (0.7, 1.04) (0.71, 1.06) (0.71, 1.04) (0.72, 1.05) mg/g (0.69, 1.02) (0.7, 1.05) (0.69, 1.01) (0.7, 1.03) mg/g (0.62, 0.92) (0.62, 0.93) (0.61, 0.9) (0.61, 0.9) mg/g (0.59, 0.88) (0.59, 0.88) (0.6, 0.88) (0.6, 0.88) mg/g (0.55, 0.82) < (0.54, 0.81) < (0.56, 0.83) < (0.55, 0.82) < adjusted for baseline log(nnal) (0.59, 0.87) (0.6, 0.9) (0.61, 0.88) (0.62, 0.91) adjusted for baseline log(nnal), age, race, gender and salivary nicotine metabolite ratio 45 P a g e