To Assess the Bioequivalence of the 4mg Prototype Mini Nicotine Lozenge to the Reference Product (Nicorette) in Healthy Smokers

Study Overview
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Brief Summary
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This study will assess the bioequivalence of the test product (Nicotine Prototype Mini lozenge 4 milligrams [mg]) to a commercial reference product (nicotine polacrilex mini lozenge 4mg) in healthy smokers under fasting conditions.

Detailed Description
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This study will be a single center, randomized, open label, single dose, two-way crossover in healthy smokers that smoke their first cigarette within 30 minutes of waking. This study will consist of following Visits: Visit 1 (Screening), Visit 2 (Study Period 1), followed by a Washout period and Visit 3 (Study Period 2). This will ensure approximately 29 evaluable participants per treatment arm. Each participant will be treated with a single dose of the two study treatments (test and reference) in a randomized sequence, under fasting conditions. Participants will be confined in the study facility for approximately 60 hours during each study session (for 36 hours pre-dosing and for 24 hours post dosing) during which pharmacokinetic (PK) blood samples will be obtained. Participants are to abstain from smoking during the confinement periods and be subject to random measurements of expired carbon monoxide (CO) to confirm abstinence. The CO levels must be ≤10 parts per million (ppm) throughout the study session. There will be at least 5-day and not more than 7-day clinical furlough period between treatment periods. For each treatment period, the clinical confinement period with restriction of smoking is at least 36 hours prior to dosing.

Official Title
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A Single Dose Bioequivalence Study of a 4 mg Prototype Mini Nicotine Lozenge vs 4 mg Nicotine Mini Lozenge (Nicorette Minis) in Healthy Smokers Under Fasting Conditions

Conditions
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Tobacco Use Disorder

Intervention / Treatment
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* Drug: Nicotine Prototype Mini lozenge
* Drug: Nicorette Mini Lozenge


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Evidence of a personally signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study before any assessment is performed. Participants who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Healthy participants which is defined as in general good physical health, as judged by the investigator and no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure, respiratory rate, oral body temperature and pulse rate measurement, 12-lead ECG or clinical laboratory tests. Body Mass Index (BMI) of 19 to 27 Kilogram per meter square (kg/m2), inclusive; and a total body weight >50 kg (110 pounds [lbs]). Female participants of childbearing potential and at risk for pregnancy must agree to use a highly effective method of contraception throughout the study and for at least 5 days after the last dose of assigned treatment. Female participants who are not of childbearing potential must meet at least one of the following criteria: a) Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and have a serum follicle-stimulating hormone (FSH) level confirming the post-menopausal state. b) Have undergone a documented hysterectomy and/or bilateral oophorectomy. Participant admits to having smoked commercially available cigarettes daily for the preceding 12 months and to routinely smoking his or her first cigarette within 30 minutes upon awakening. Brief periods of non-smoking (e.g. due to illness, trying to quit, participation in a study where smoking was prohibited) during that time will be permitted at the discretion of the PI (Principal Investigator). Exclusion Criteria: Participants who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or Participants who are GSK employees directly involved in the conduct of the study. Participation in other studies involving investigational drug(s) within 30 days prior to first dose and during study participation. Acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the Participant inappropriate for entry into this study. Pregnant female Participants. Breastfeeding female Participants. Known or suspected intolerance or hypersensitivity to the study materials (or closely related compounds) or any of their stated ingredients. Unwilling or unable to comply with the Lifestyle guidelines described in this protocol. Participant has used any nicotine replacement therapy within 21 days prior to the first study session. Participant has used chewing tobacco, tobacco products or electronic cigarettes other than cigarettes within 21 days of Visit 1. Use of prescription or non-prescription drugs and dietary supplements within two weeks or 5 half-lives, whichever is longer, prior to the first dose of investigational product until the end of the study. Allowed treatments are: Systemic contraceptives and hormone replacement therapy, as long as female Participant is on stable treatment for at least 3 months and continues treatment throughout the study. Evidence or history of clinically significant laboratory abnormality, hematological, renal, endocrine, pulmonary, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease within the last 5 years that may increase the risk associated with study participation. History of regular alcohol consumption exceeding 14 drinks/week (1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor) within 6 months of Screening. A positive urine drug screen for THC, amphetamine, cocaine, 3,4-methylenedioxy-N-methylamphetamine (MDMA)/ecstasy, methamphetamine, or opiates; and urine alcohol testing during screening or baseline testing. Participant is unwilling to abstain from tobacco or nicotine-containing product use during each study session (from start of baseline to the completion of the last PK blood sampling). CO measurement immediately prior to randomization (first treatment session) and dosing (second treatment session) should be ≤ 10 parts per million (ppm) for the Participant to be dosed. Participant ingests more than 5 cups of coffee or tea a day (or equivalent xanthine consumption using other products). Treatment with an investigational drug within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of investigational product (whichever is longer). A medical history that, in the opinion of the investigator, might jeopardize the safety of the Participant, e.g., recent myocardial infarction or cerebrovascular accident (i.e., within 12 weeks prior to the first study session), severe cardiac arrhythmia, history of seizures, orthostatic hypotension, cardiovascular disease, stroke, or TIA. A medical history, which, in the opinion of the investigator, might impact the validity of the study results, may require treatment, or make the Participant unlikely to finish the study. Oral surgery within 4 weeks of dosing, dental work or extractions within 2 weeks of dosing, or presence of any clinically significant (as determined by the principal investigator or designee) oral pathology including lesions, sores or inflammation. Diagnosis of long QT syndrome or QTc > 460 msec for males and > 470 msec for females at screening. Any surgical or medical condition which may significantly alter the absorption, distribution, metabolism or excretion of any drug substance including, but not limited to, any of the following: i)Presence of active oesophagitis, oral or pharyngeal ulceration, inflammation, gastritis, gastric ulcer or peptic ulcer or other diseases; ii) Presence of gum disease, xerostomia, dentures or any dental work that could affect the conduct of the study as determined by the investigator or designee; iii) Renal disease or impaired renal function at screening as indicated by abnormal levels of serum creatinine or urea or the presence of clinically significant abnormal urinary constituents (e.g. albuminuria). Minor deviations of laboratory values from the normal range are permitted, if judged by the investigator to have no clinical relevance; iv) Ongoing hepatic disease or impaired hepatic function at screening. A candidate will be excluded if more than one of the following lab value deviations are found and are clinical ly relevant: aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT), Alanine Aminotransferase/ serum glutamic-pyruvic transaminase (ALT/SGPT), γ-glutamyl transpeptidase (γGGT), alkaline phosphatase, bilirubin or CK. Minor deviations of laboratory values from the normal range are permitted, if judged by the investigator to have no clinical relevance; v) History or clinical evidence at screening of pancreatic injury or pancreatitis; vi)Evidence of urinary obstruction or difficulty in voiding at screening; vii) History of malignancy or neoplastic disease of any organ system (except for localized basal cell skin carcinoma), treated or untreated, within the past 5 years prior to screening, regardless of whether there is evidence of local recurrence or metastases. viii) Clinically relevant chronic or acute infectious illnesses or febrile infections within 2 weeks prior to start of the study (enrollment). ix) Other clinically significant laboratory findings in the opinion of the Investigator at screening. A positive serum Hepatitis B surface antigen, Hepatitis C antibodies, or human immunodeficiency virus (HIV) test result. Blood: a) Has donated or experienced significant blood loss (470 mL) within 56 days of Visit b) Hemoglobin value < 12.0 grams per deciliter (g/dL). Participants who have previously been enrolled in this study.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Test Product<br>Participants will receive a single Nicotine Prototype Mini lozenge (4mg) by oral/buccal route of administration. | Drug: Nicotine Prototype Mini lozenge<br>* A single dose of a prototype nicotine 4mg lozenge will be placed in participants mouth, occasionally moving it side to side. Allowing it to slowly dissolve and try to minimize swallowing. Participants will be instructed not to chew lozenge. The lozenge should be completely dissolved.<br>|
| Active Comparator: Reference Product<br>Participants will receive a single Nicorette Mini lozenge (4 mg) by oral/buccal route of administration. | Drug: Nicorette Mini Lozenge<br>* A single dose of a 4 mg nicotine polacrilex mini lozenge (Nicorette Minis) will be placed in participants mouth, occasionally moving it side to side. Allowing it to slowly dissolve and try to minimize swallowing. Participants will be instructed not to chew lozenge. The lozenge should be completely dissolved.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of Bioequivalence of Prototype Mini Lozenges With Nicorette Mini Lozenge by Measuring Area Under the Plasma Concentration Versus Time Curve From Time Zero to Time t (AUC [0-t]) | Bioequivalence of prototype mini lozenges with nicorette mini lozenge was assessed by measuring AUC(0-t), where t= time of the last measurable plasma concentration. AUC(0-t) was calculated using the linear trapezoidal with linear interpolation method. A linear mixed-effects model was fit to the natural log (ln)-transformed PK variable (AUC0-t), as the dependent variable, and treatment, period, and sequence as fixed effects. Participant nested within sequence was a random effect. The treatment difference and its 90% CI were exponentiated to obtain the geometric mean ratios (GMR) between the test and reference products and its 90% CI. Geometric Coefficient of variation was provided as percentage. | 0.75, 0.5, 0.25 hours predose and 0.08, 0.17, 0.33, 0.5, 0.67, 0.83, 1, 1.25, 1.5, 2, 3, 4, 6, 8 10, 14, 16, 20 and 24 hours postdose in each treatment period | 
| Assessment of Bioequivalence of Prototype Mini Lozenges With Nicorette Mini Lozenge by Measuring Area Under the Plasma Concentration Versus Time Curve Calculated From Time Zero to Infinity (AUC [(0-inf]) | Bioequivalence of prototype mini lozenges with nicorette mini lozenge was assessed by measuring AUC(0-inf). AUC(0-inf) = AUC0-t + (Clast/kel), where, AUC0-t= area under the plasma concentration versus time curve from time zero to time t; Clast= last observed/measured plasma concentration and kel= elimination rate constant. A linear mixed-effects model was fit to the natural log (ln)-transformed PK variable (AUC[0-inf]), as the dependent variable, and treatment, period, and sequence as fixed effects. Participant nested within sequence was a random effect. The treatment difference and its 90% CI were exponentiated to obtain the GMR between the test and reference products and its 90% CI. Geometric Coefficient of variation was provided as percentage. | 0.75, 0.5, 0.25 hours predose and 0.08, 0.17, 0.33, 0.5, 0.67, 0.83, 1, 1.25, 1.5, 2, 3, 4, 6, 8 10, 14, 16, 20 and 24 hours postdose in each treatment period | 
| Assessment of Bioequivalence of Prototype Mini Lozenges With Nicorette Mini Lozenge by Measuring Maximum Observed Plasma Nicotine Concentration (Cmax) | Blood samples were collected at designated timepoints. Bioequivalence of prototype mini lozenges with nicorette mini lozenge was assessed by measuring Cmax that was taken directly from bioanalytical data. Geometric Coefficient of variation was provided as percentage. A linear mixed-effects model was fit to the natural log (ln)-transformed PK variable (Cmax) as the dependent variable, and treatment, period, and sequence as fixed effects. Participant nested within sequence was a random effect. The treatment difference and its 90% CI were exponentiated to obtain the GMR between the test and reference products and its 90% CI. Geometric Coefficient of variation was provided as percentage. | 0.75, 0.5, 0.25 hours predose and 0.08, 0.17, 0.33, 0.5, 0.67, 0.83, 1, 1.25, 1.5, 2, 3, 4, 6, 8 10, 14, 16, 20 and 24 hours postdose in each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of Prototype Mini Lozenges With Nicorette Mini Lozenge by Measuring Time of Maximum Plasma Nicotine Concentration (Tmax) | Tmax was defined as the time to maximum plasma nicotine concentration. If the maximum value occurred at more than one time point, Tmax was defined as the first time point with this value. | 0.75, 0.5, 0.25 hours predose and 0.08, 0.17, 0.33, 0.5, 0.67, 0.83, 1, 1.25, 1.5, 2, 3, 4, 6, 8 10, 14, 16, 20 and 24 hours postdose in each treatment period | 
| Comparison of Prototype Mini Lozenges With Nicorette Mini Lozenge by Measuring Apparent Elimination Half-Life (t1/2) | t1/2 was defined as apparent elimination half-life that was calculated as t1/2 = ln(2) / Kel, where Kel= elimination rate constant. | 0.75, 0.5, 0.25 hours predose and 0.08, 0.17, 0.33, 0.5, 0.67, 0.83, 1, 1.25, 1.5, 2, 3, 4, 6, 8 10, 14, 16, 20 and 24 hours postdose in each treatment period | 
| Comparison of Prototype Mini Lozenges With Nicorette Mini Lozenge by Measuring Apparent Elimination Rate Constant for Plasma Nicotine (Kel) | kel was defined as apparent elimination rate constant for plasma nicotine that was calculated as negative of the slope of a linear regression of the log(concentration)- time for all concentrations > lower limit of quantification. | 0.75, 0.5, 0.25 hours predose and 0.08, 0.17, 0.33, 0.5, 0.67, 0.83, 1, 1.25, 1.5, 2, 3, 4, 6, 8 10, 14, 16, 20 and 24 hours postdose in each treatment period | 
| Number of Participants With Clinically Significant Change in Laboratory Test Values | Haematological, biochemistry and urinalysis parameters were analyzed. Clinical significance was judged by the investigator based upon the out of range values of standard range set for each parameter. | From signing of the informed consent form until 5 days after last administration of study drug (up to Day 13) |