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This is a two-site, open-label, randomized, 4-way (2 arm) cross-over study designed to evaluate elements of abuse liability (AL) including subjective effects and physiological measures (pharmacodynamics [PD]) and plasma nicotine uptake (pharmacokinetics [PK]) during and following ad libitum use of the study investigational products (IPs) by generally healthy smokers
Cigarette smokers of (only) filtered menthol and/or non-menthol cigarettes naĆÆve to smokeless tobacco products (ST) and/or modern oral tobacco (MO) products and smokers also using ST and/or MO will be recruited into this AL study to evaluate elements of AL of five modern oral nicotine products (hereinafter, Study IPs) compared to combustible cigarettes (CC) only (Arm 1) and combustible and and nicotine polacrilex gum (Arm 2). An attempt will be made for at least one-third of the study population to include smokers using ST and/or MO for each arm.
Potential participants will complete a pre-screening telephone interview. They will complete a Screening Visit to assess their eligibility within 45 days prior to check-in and enrollment.
Starting on check in day (Day -1), participants will check-in at the clinical site to complete procedures to confirm eligibility. Eligible participants will be enrolled, randomized and confined for 6 days (5 nights).
Participants will be randomized to a product use sequences (using a Williams Design) in which they will evaluate one IP in each of four separate Test Sessions, such that each participant will evaluate four IPs; Arm 1: Product C (8 and 12 mg), Product D 4 mg, and a high-AL comparator (participant's usual brand [UB] cigarette) or (Arm 2): Product B 8 mg, Product C 8 mg, a high-AL comparator (participant's usual brand [UB] cigarette), and a low-AL comparator (a commercially available nicotine replacement therapy [NRT] nicotine gum).
On Day 1 and continuing through Day 4 for both study arms, participants will participate in Test Sessions that will last approximately 4 hours. Each Test Session will include collection of both types of PD measures (subjective and physiological) and PK measures prior to, during, and following IP use. Following each test session, used IP will be collected, stored at -20°C, and shipped to a laboratory of the sponsor's choosing.
For both study arms, on the half day prior to each respective Test Session, a Product Acclimation Period will allow participants ad libitum use of the subsequent IP (at least two trial uses) as per randomized sequence for product acclimation prior to use in the next day's Test Session. Participants can also use their UB cigarettes ad libitum, until the 12-hour tobacco and nicotine abstinence period begins prior to each Test Session, as long as the minimum use requirement for randomized IP is met. Used IP from each of the Product Acclimation periods will be collected, stored at -20°C, and shipped to a laboratory of the sponsor's choosing.
Safety will be monitored throughout the study by the Principal Investigator (PI) (or designee) by assessing adverse 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 duration of the study and for any follow-ups after study discharge.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm 1 | Experimental | Enrolled subjects will be randomized to one of four product use sequences, such that one of the four IPs (A, B, C, D) will be used in each of the four test sessions. |
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| Arm 2 | Experimental | Enrolled subjects will be randomized to one of four product use sequences, such that one of the four IPs (A, E, F, N) will be used in each of the four test sessions. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Product A | Other | Usual Brand (UB) filtered, non-menthol or menthol combustible cigarette |
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| Measure | Description | Time Frame |
|---|---|---|
| AUECPL 5-240 | area under the effect curve (AUEC) for PL (VAS score-versus-time) from 5 minutes to 240 minutes after the start of IP use area under the effect curve (AUEC) for PL (VAS score-versus-time) from 5 minutes to 240 minutes after the start of IP use area under the effect curve (AUEC) for PL (VAS score-versus-time) from 5 minutes to 240 minutes after the start of IP use area under the effect curve (AUEC) for PL (VAS score-versus-time) from 5 minutes to 240 minutes after the start of IP use. | 5 minutes to 240 minutes |
| Emax PL | maximum effect (maximum PL VAS score after the start of IP use) | 240 minutes |
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Inclusion Criteria:
Able to read, understand, and willing to sign an informed consent form (ICF) and complete questionnaires written in English.
Generally healthy males or females, 21 to 60 years of age, inclusive, at the time of consent.
Smokes combustible, filtered, non-menthol or menthol cigarettes, 83 mm to 100 mm in length as primary source of tobacco.
Smokes an average of at least 10 cigarettes per day (CPD) and inhales the smoke, for at least 6 months prior to Screening. Brief periods of abstinence due to illness, quit attempt (prior to 30 days of Screening), or clinical study participation (prior to 30 days of Screening) will be allowed at the discretion of an investigator.
Smokers who also use ST products (e.g., moist snuff, snus, modern oral), and have used ST within 30 days prior to screening, will be enrolled.
Agrees to smoke the same UB cigarette throughout the study period. The UB cigarette is defined as the reported cigarette brand and style currently smoked most frequently by the participant.
Expired breath carbon monoxide (ECO) level is ℠10 ppm and ⤠100 ppm at Screening.
Positive urine cotinine test (e.g., >200 ng/mL) via dipstick at Screening.
Response at Screening to the Fagerstrƶm Test for Nicotine Dependence (FTND) Question 1 ("How soon after you wake up do you smoke your first cigarette?") is either "Within 5 minutes" or "6-30 minutes" .
Willing to use the UB cigarette, Study IPs, and NicoretteĀ® nicotine gum (Arm 2 only) during the study period.
Willing to abstain from tobacco and nicotine use for at least 12 hours prior to the start of each of four Test Sessions.
Females must be willing to use a form of contraception acceptable to an investigator from the time of signing the ICF until End-of-Study.
Examples of acceptable means of birth control are, but not limited to:
Agrees to an in-clinic confinement of five days (four nights).
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| John Darnell | Contact | 3367410386 | darnelj2@rjrt.com | |
| Kristen Prevette | Contact | 3367411873 | prevetk1@rjrt.com |
| Name | Affiliation | Role |
|---|---|---|
| Brian Keyser | Reynolds American | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Dr. Vince Clinical Research | Recruiting | Overland Park | Kansas | 66212 | United States |
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| ID | Term |
|---|---|
| D012907 | Smoking |
| D064424 | Tobacco Use |
| D000073869 | Tobacco Smoking |
| ID | Term |
|---|---|
| D001519 | Behavior |
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| ID | Term |
|---|---|
| C476054 | HTR3D protein, human |
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| Product B | Other | 8 mg nicotine oral product |
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| Product C | Other | 12 mg nicotine oral product |
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| Product D | Other | 6 mg nicotine oral product |
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| Product E | Other | 8 mg nicotine oral product |
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| Product F | Other | 8 mg nicotine oral product |
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| Product N | Other | NicoretteĀ® White Ice Mint 4 mg nicotine polacrilex gum |
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