Abuse Liability of Four Modern Oral Nicotine Products

Smokers who only use filtered menthol or non‐menthol cigarettes and who also use loose orpouched moist snuff smokeless tobacco [Moist Snuff Tobacco (MST)] will be recruited intothis AL study to evaluate elements of AL of four modern oral (MO) nicotine products(hereinafter, Study IPs) compared to combustible cigarettes (CC) and MST.For this study, participant's usual brand smokeless tobacco product needs to be moistsnuff (loose or pouched) and not a Snus smokeless oral tobacco product.Potential participants will complete a pre‐screening telephone interview. They willcomplete a Screening Visit to assess their eligibility within 45 days prior to check‐inand enrollment.Starting on Day 1, participants will check‐in at the clinical site to confirmeligibility. Eligible participants will be enrolled, randomized and confined in theclinic for 7 days (6 nights).Participants will be randomized to a product use sequence (using a Williams Design) inwhich they will evaluate one IP in each of six separate daily Test Sessions, such thateach participant will evaluate a total of six IPs; Wintergreen 12 mg nicotine (fleece A),Wintergreen 9 mg nicotine (fleece A),Wintergreen 9 mg (fleece B), Watermelon Mint 9 mgnicotine (fleece A), participant's usual brand moist snuff tobacco [UB MST], and ahigh‐AL comparator (participant's usual brand cigarette [UB CC]).On Day 2 and continuing through Day 7, participants will participate in daily TestSessions that will last approximately 8 hours, consisting of a 1‐hour controlled firstuse period immediately followed by a 7‐hour ad libitum period. Each Test Session willinclude collection of both types of PD measures (subjective and physiological) and PKmeasures prior to, during, and following IP use. During each test session, used IP willbe collected, and either disposed of (UB CC and loose UB MST) or stored (modern oral IPand pouched UB MST) at ‐20°C, and shipped to a laboratory of the Sponsor's choosing. Forparticipants whose UB MST is loose MST, a fresh unopened tin/can will be weighedimmediately prior to the 'first use' portion of the session before the participantself‐selects the amount of loose MST for their initial IP use. The lid will be replacedon the can/tin and weighed to the nearest 0.01g.Immediately following the 1‐hour 'first use' portion of the test session, a 7‐hour adlibitum use period will commence. Both types of PD (subjective and physiological) and PKmeasures will be measured during the 7‐hour ad libitum use period. The number, time, andduration of use of IPs that participants request will be recorded; every used IPs (MO andpouched UB MST IPs only) will be collected, stored at ‐20°C, and shipped to a laboratoryof the sponsor's choosing. For participants whose test session IP is loose UB MST, afresh unopened tin/can or the tin/can used for the initial 1‐hour 'first use' sessionwill be weighed immediately prior to the participant self‐selects the amount of loose UBMST for their ad libitum test session, then the lid will be replaced to the can/tin andweighed to the nearest 0.01g. After the participant's completion of the 7‐hour ad libitumtest session, the tin/can of UB MST will be weighed to the nearest 0.01g to determine thetotal amount of UB MST used during the 7‐hour and the entire 8‐hour test sessions.During the remaining 4 hours of the day following each 8‐hour Test Session, a ProductAcclimation Period will allow participants ad libitum use of the subsequent day's TestSession assigned MO IP (at least two trial uses; minimum acclimation use requirement),followed by use of their UB CC and UB MST ad libitum, until the 12‐hour tobacco andnicotine abstinence period begins. If the participant's UB CC or UB MST are assigned perrandomized sequence for use in the next day's Test Session, no (MO) product acclimationis required and participants can use their UB CC and UB MST ad libitum, until the 12‐hourtobacco and nicotine abstinence period begins. Used IP (only MO IPs and pouched UB MST)from each of the MO Product Acclimation and/or end of day ad libitum use periods will becollected immediately after use, stored at ‐20°C, and shipped to a laboratory of thesponsor's choosing.Safety will be monitored throughout the study by the Principal Investigator (PI) (ordesignee) by assessing adverse experiences/events (AEs), vital sign measurements,physical examinations (including an oral examination), and clinical laboratory tests.The Medical Monitor will be available for consultation during the study and for anyfollow‐up needs after study discharge.