Characterization of Biomarkers of Tobacco Exposure, Urge-to-Smoke Following Exclusive and Dual Ad Lib Use of Electronic Cigarettes

Overview

This is a randomized, open-label, forced-switch, parallel, proof-of-concept study to assess exposure to biomarkers of tobacco exposure following short-term ad lib use of three blu e-cigarette products. The primary objectives of this study are to: 1. Compare changes in selected urine and blood biomarkers of tobacco exposure within cohorts following a 5-day forced-switch from usual brand conventional combustible cigarettes to exclusive use of blu e-cigarettes, dual use of blu e cigarettes and the subject's usual brand combustible cigarette, or smoking cessation. 2. Compare changes in selected urine and blood biomarkers of tobacco exposure among cohorts following a 5-day forced-switch from usual brand conventional combustible cigarettes to exclusive use of a blu e cigarette, dual use of a blu e-cigarette and the subject's usual brand combustible cigarette, or smoking cessation. The secondary objectives of this study are to: 1. Compare changes in selected physiological endpoints affected by tobacco exposure within cohorts during a 5-day forced-switch from usual brand conventional combustible cigarettes to exclusive use of blu e cigarettes, dual use of blu e cigarettes and the subject's usual brand combustible cigarette, or smoking cessation. 2. Compare changes in selected physiological endpoints affected by tobacco exposure among cohorts following a forced-switch to exclusive use of a blu e cigarette, dual use of a blu e-cigarette and the subject's usual brand combustible cigarette, or smoking cessation. 3. Determine daily nicotine consumption from blu e-cigarettes following exclusive use of blu e cigarettes or dual use of blu e-cigarettes and the subject's usual brand combustible cigarette over a 5-day period. 4. Assess the effectiveness of exclusive use of blu e-cigarettes or dual use of blu e-cigarettes and the subject's usual brand combustible cigarette to reduce the urge to smoke. 5. Assess subject opinions of various characteristics of blu e-cigarettes. 6. Assess the safety and tolerability of short-term use of blu e-cigarettes.

Subjects checked in to the clinic on Day -2 and continued to smoke their usual brand cigarette ad lib through the evening of Day -1 upon request to the clinic staff. Baseline assessments were made from the morning of Day -1 through the morning of Day 1 prior to the start of randomized product use. On the morning of Day 1, subjects were randomized into one of the study arms noted above and post-baseline assessments were made through the morning of Day 6. With limited exceptions, all product use was ad lib from 07:30 to 23:00 on Days -2 to 5. Smoking of cigarettes and use of the e-cigarette products were limited to separate sections of the clinic to minimize the chance for illicit product use and cross-contamination. Subjects randomized to the cessation arm were housed in a separate section of the clinic after randomization. From Day 1 to the end of the study all subjects randomized to an e-cigarette cohort were allowed to carry the assigned product with them throughout the day and use their product ad lib within identified sections of the clinic. Subjects randomized to the dual-use cohorts were allowed to smoke no more than 50% of the number of cigarettes per day reported at Screening. Cigarettes were were provided to the subjects upon request to the study staff. Daily product use of blu e-cigarettes and usual brand cigarettes was assessed on Days -1 through Day 5. Each blu e-cigarette was weighed prior to dispensing and following the return of the product and the estimated amount of nicotine delivered from each blu e-cigarette will be calculated by multiplying the weight difference (mg) by 2.4%. Urine biomarkers of exposure and effect were assessed from 24-hour urine collections from the morning of Day -1 to the morning of Day 1 and from the morning of Day 5 to the morning of Day 6. Urine biomarkers of exposure included NNAL, nicotine equivalents (nic + 5), 3-HPMA, CEMA, 1-OHP, NNN, MHBMA, and S-PMA. The urine biomarker of effect included F2-isoprostane (8-iso-PGF2 Type III). Biomarker concentrations were adjusted for urine creatinine concentrations. Blood biomarkers of exposure included COHb, nicotine, cotinine, and trans-3'hydroxycotinine. Samples were collected on Days -1, 1, 3, and 5 in the morning prior to the start of product administration and in the evening. Other physiologic endpoints included spirometry (FVC and FEV1, assessed in the afternoon on Day -1 and Day 5, exhaled CO and NO measurements (assessed in the afternoon on Days -1, 1, 3, and 5), and blood pressure and pulse rate (assessed on Days -1 through 5 in the morning prior to the start of product administration and evening). Questionnaires administered included the Fagerström Test for Nicotine Dependence and the Brief Wisconsin Inventory of Smoking Dependence Motives (Day -1), smoking urge (Days -1 through 5 in the morning prior to the start of product administration and evening), and the Modified Cigarette Evaluation Scale (evening of Day 5, not administered to subjects in the cessation arm). Safety evaluations included physical examinations, vital signs, ECGs, clinical laboratory assessments (clinical chemistry, hematology, urinalysis, and serology), urine drug and alcohol screens, urine cotinine and exhaled CO screens, and pregnancy tests (females only). Adverse events spontaneously reported by the subjects or observed by the Investigator or other study personnel were monitored from the time of Check-in until the End-of-Study (or Early Termination). Any concomitant medications taken from 30 days prior to Check-in through the End-of-Study (or Early Termination) were recorded.