Trial Outcomes & Findings for A Study to Evaluate Changes in Smokers Using Oral Tobacco-derived Nicotine Products. (NCT NCT03692078)

Subjects were required to complete a test product tolerability trial and baseline assessment over the course of 3 days prior to randomization on Day 1 of the study. A total of 213 subjects were randomized to one of the six groups in this study.

A Study to Evaluate Changes in Smokers Using Oral Tobacco-derived Nicotine Products.

Summary of urine total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) amount excreted (ng/24 hour) by study group on Days -1, 5 and 7, and absolute change from Baseline on Days 5 and 7 are presented. Subjects with valid sample results are included. Original Values reported as below the limit of quantitation (BLQ) were set to one-half of the lower limit of quantitation (LLOQ) (2.00 pg/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). Absolute change from baseline was calculated as: Post Randomization Value - Baseline Value

Summary of urine total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) amount excreted percent change from Baseline (%) is presented. Subjects with valid sample results are included. Original Values reported as below the limit of quantitation (BLQ) were set to one-half of the LLOQ (2.00 pg/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). % change from Baseline = (Post Randomization Value - Baseline Value) / Baseline Value x 100 %

Summary of N-nitrosonornicotine (NNN) amount excreted (ng/24 hour) by study group on Days -1, 5 and 7, and absolute change from Baseline on Days 5 and 7 are presented. Subjects with valid sample results are included. Original Values reported as below the limit of quantitation (BLQ) were set to one-half of the LLOQ (0.500 pg/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). Absolute change from baseline was calculated as: Post Randomization Value - Baseline Value

Summary of N-nitrosonornicotine (NNN) amount excreted percent change from Baseline (%) is presented. Subjects with valid sample results are included. Original Values reported as below the limit of quantitation (BLQ) were set to one-half of the LLOQ (0.500 pg/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). % change from Baseline = (Post Randomization Value - Baseline Value) / Baseline Value x 100 %

Summary of nicotine equivalents amount excreted (mg/24 hour) by study group on Days -1, 5 and 7, and absolute change from Baseline on Days 5 and 7 are presented. Subjects with valid sample results are included. Original values reported as below the limit of quantitation (BLQ) for each metabolite were set to one-half of the LLOQ for the calculation of nicotine equivalents. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). Nicotine equivalents (mg/g creatinine) = nicotine equivalents (μg/mL) x 100 / creatinine (mg/dL) Absolute change from baseline was calculated as: Post Randomization Value - Baseline Value

Summary of nicotine equivalents amount excreted percent change from Baseline (%) is presented. Subjects with valid sample results are included. Original Values reported as below the limit of quantitation (BLQ) for each metabolite were set to one-half of the LLOQ for the calculation of nicotine equivalents. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). Nicotine equivalents (mg/g creatinine) = nicotine equivalents (μg/mL) x 100 / creatinine (mg/dL) % change from Baseline = (Post Randomization Value - Baseline Value) / Baseline Value x 100 %

Summary of 2-aminonaphthalene (2-AN) amount excreted (ng/24 hour) by study group on Days -1, 5 and 7, and absolute change from Baseline on Days 5 and 7 are presented. Subjects with valid sample results are included. Original Values reported as below the limit of quantitation (BLQ) were set to one-half of the LLOQ (1.7 pg/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). Absolute change from baseline was calculated as: Post Randomization Value - Baseline Value

Summary of 2-aminonaphthalene (2-AN) amount excreted percent change from Baseline (%) is presented. Subjects with valid sample results are included. Original Values reported as below the limit of quantitation (BLQ) were set to one-half of the LLOQ (1.7 pg/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). % change from Baseline = (Post Randomization Value - Baseline Value) / Baseline Value x 100 %

Summary of 4-aminobiphenyl (4-ABP) amount excreted (ng/24 hour) by study group on Days -1, 5 and 7, and absolute change from Baseline on Days 5 and 7 are presented. Subjects with valid sample results are included. Original Values reported as below the limit of quantitation (BLQ) were set to one-half of the LLOQ (1.5 pg/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). Absolute change from baseline was calculated as: Post Randomization Value - Baseline Value

Summary of 4-aminobiphenyl (4-ABP) amount excreted percent change from Baseline (%) is presented. Subjects with valid sample results are included. Original Values reported as below the limit of quantitation (BLQ) were set to one-half of the LLOQ (1.5 pg/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). % change from Baseline = (Post Randomization Value - Baseline Value) / Baseline Value x 100 %

Summary of 2-hydroxyethyl mercapturic acid (HEMA) amount excreted (ug/24 hour) by study group on Days -1, 5 and 7, and absolute change from Baseline on Days 5 and 7 are presented. Subjects with valid sample results are included. Original Values reported as below the limit of quantitation (BLQ) were set to one-half of the LLOQ (0.2 ng/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). Absolute change from baseline was calculated as: Post Randomization Value - Baseline Value

Summary of 2-hydroxyethyl mercapturic acid (HEMA) amount excreted percent change from Baseline (%) is presented. Subjects with valid sample results are included. Original Values reported as below the limit of quantitation (BLQ) were set to one-half of the LLOQ (0.2 ng/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). % change from Baseline = (Post Randomization Value - Baseline Value) / Baseline Value x 100 %

Summary of 2-cyanoethylmercapturic acid (CEMA) amount excreted (ug/24 hour) by study group on Days -1, 5 and 7, and absolute change from Baseline on Days 5 and 7 are presented. Subjects with valid sample results are included. Original Values reported as below the limit of quantitation (BLQ) were set to one-half of the LLOQ (0.25 ng/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). Absolute change from baseline was calculated as: Post Randomization Value - Baseline Value

Summary of 2-cyanoethylmercapturic acid (CEMA) amount excreted percent change from Baseline (%) is presented. Subjects with valid sample results are included. Original Values reported as below the limit of quantitation (BLQ) were set to one-half of the LLOQ (0.25 ng/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). % change from Baseline = (Post Randomization Value - Baseline Value) / Baseline Value x 100 %

Summary of S-phenyl mercapturic acid (S-PMA) amount excreted (ug/24 hour) by study group on Days -1, 5 and 7, and absolute change from Baseline on Days 5 and 7 are presented. Subjects with valid sample results are included. Original values reported as below the limit of quantitation (BLQ) were set to one-half of the LLOQ (0.02 ng/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). Absolute change from baseline was calculated as: Post Randomization Value - Baseline Value

Summary of S-phenyl mercapturic acid (S-PMA) amount excreted percent change from Baseline (%) is presented. Subjects with valid sample results are included. Original Values reported as below the limit of quantitation (BLQ) were set to one-half of the LLOQ (0.02 ng/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). % change from Baseline = (Post Randomization Value - Baseline Value) / Baseline Value x 100 %

Summary of 3-hydroxy-1-methylpropylmercapturic acid (3-HMPMA) amount excreted (ug/24 hour) by study group on Days -1, 5 and 7, and absolute change from Baseline on Days 5 and 7 are presented. Subjects with valid sample results are included. Original Values reported as below the limit of quantitation (BLQ) were set to one-half of the LLOQ (5 ng/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). Absolute change from baseline was calculated as: Post Randomization Value - Baseline Value

Summary of 3-hydroxy-1-methylpropylmercapturic acid (3-HMPMA) amount excreted percent change from Baseline (%) is presented. Subjects with valid sample results are included. Original Values reported as below the limit of quantitation (BLQ) were set to one-half of the LLOQ (5 ng/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). % change from Baseline = (Post Randomization Value - Baseline Value) / Baseline Value x 100 %

Summary of 3-hydroxypropylmercapturic acid (3-HPMA) amount excreted (ug/24 hour) by study group on Days -1, 5 and 7, and absolute change from Baseline on Days 5 and 7 are presented. Subjects with valid sample results are included. Original values reported as below the limit of quantitation (BLQ) were set to one-half of the LLOQ (25 ng/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). Absolute change from baseline was calculated as: Post Randomization Value - Baseline Value

Summary of 3-hydroxypropylmercapturic acid (3-HPMA) amount excreted percent change from Baseline (%) is presented. Subjects with valid sample results are included. Original Values reported as below the limit of quantitation (BLQ) were set to one-half of the LLOQ (25 ng/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). % change from Baseline = (Post Randomization Value - Baseline Value) / Baseline Value x 100 %

Summary of 2-hydroxypropyl-mercapturic acid (2-HPMA) amount excreted (ug/24 hour) by study group on Days -1, 5 and 7, and absolute change from Baseline on Days 5 and 7 are presented. Subjects with valid sample results are included. Original values reported as below the limit of quantitation (BLQ) were set to one-half of the LLOQ (2.5 ng/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). Absolute change from baseline was calculated as: Post Randomization Value - Baseline Value

Summary of 2-hydroxypropyl-mercapturic acid (2-HPMA) amount excreted percent change from Baseline (%) is presented. Subjects with valid sample results are included. Original Values reported as below the limit of quantitation (BLQ) were set to one-half of the LLOQ (2.5 ng/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). % change from Baseline = (Post Randomization Value - Baseline Value) / Baseline Value x 100 %

Summary of N-acetyl-S-(2-carbamoylethyl)-l-cysteine (AAMA) amount excreted (ug/24 hour) by study group on Days -1, 5 and 7, and absolute change from Baseline on Days 5 and 7 are presented. Subjects with valid sample results are included. Original values reported as below the limit of quantitation (BLQ) were set to one-half of the LLOQ (10 ng/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). Absolute change from baseline was calculated as: Post Randomization Value - Baseline Value

Summary of N-acetyl-S-(2-carbamoylethyl)-l-cysteine (AAMA) amount excreted percent change from Baseline (%) is presented. Subjects with valid sample results are included. Original Values reported as below the limit of quantitation (BLQ) were set to one-half of the LLOQ (10 ng/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). % change from Baseline = (Post Randomization Value - Baseline Value) / Baseline Value x 100 %

Summary of N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-l-cysteine (GAMA) amount excreted (ug/24 hour) by study group on Days -1, 5 and 7, and absolute change from Baseline on Days 5 and 7 are presented. Subjects with valid sample results are included. Original values reported as below the limit of quantitation (BLQ) were set to one-half of the LLOQ (1 ng/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). Absolute change from baseline was calculated as: Post Randomization Value - Baseline Value

Summary of N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-l-cysteine (GAMA) amount excreted percent change from Baseline (%) is presented. Subjects with valid sample results are included. Original values reported as below the limit of quantitation (BLQ) were set to one-half of the LLOQ (1 ng/mL) for summarization and statistical analysis. Baseline = Day -1. 24-hour urine collections occurred on Days -1, 5, and 7 beginning after the first morning void and any void prior to 07:00, and finished the following morning with the last void collected at approximately 07:00 (including first morning void). % change from Baseline = (Post Randomization Value - Baseline Value) / Baseline Value x 100 %