A study to investigate the safety, tolerability and concentration in the blood of nicotine compared between different types of nicotine replacement therapies (NRTs)

INTERVENTION: This is a single centre, Phase I, randomised, open‐label 3‐way crossover study of nicotine delivery conducted in healthy male smokers. The duration of study participation is approximately 5 weeks for each individual (from the Screening visit to the post‐study follow‐up visit. Screening (Days ‐28 to Day ‐2): Screening assessments will be performed from Days ‐28 to Day ‐2, to ensure the eligibility of participants. Participants will be selected for participation based on medical history and concurrent conditions, smoking status/history, physical examination, vital signs, 12‐lead ECG, routine clinical laboratory tests, urine drugs of abuse (DOA) (including alcohol and cotinine) screen and body mass inde X(BMI). An estimate of screening end‐tidal alveolar fraction of carbon monoxide (CO) and blood concentration of carboxyhaemoglobin will be recorded by Smokerlyser analysis. The ratio of 3'‐hydroxycotinine/cotinine plasma concentrations will be assessed at Screening as a predictor of an individual’s cigarette consumption and as a non‐invasive probe for their rate of hepatic nicotine metabolism by CYP2A6. A Fagerstrom Test for Nicotine Dependence (FND) will be performed. Treatment Period (Day ‐1 to Day 3): Participants will be admitted to the Clinical Pharmacology Unit on the morning of Day ‐1 where testing for a negative COVID‐19 and DOA result will be performed. Subjects will be trained on the use of the ENHALE Electronic Inhaler, Nicorette® Inhalator and Nicorette® QuickMist and the Smokerlyser assessment will be performed. Before dosing on Days 1 to 3, eligibility will be re‐confirmed, and assessments will be carried out as per the protocol schedule of assessments. Participants will remain in CONDITION: Smoking cessation and nicotine replacement therapies (NRT) ; Not Applicable PRIMARY OUTCOME: ; The primary endpoints for this study are pharmacokinetic parameters derived from the analysis of plasma samples for the concentration of nicotine.; ; 1. The following non‐compartmental pharmacokinetic parameters will be calculated for the 1st administration of nicotine:; 1.1. Cmax, 0‐tau ‐ The maximum plasma concentration of nicotine observed over the dosing interval (i.e., 60 minutes); 1.2. pAUC0‐tau ‐ The partial area under the concentration‐time curve calculated using the trapezoidal rule observed over the dosing interval (i.e., 60 minutes).; ; 2. The following non‐compartmental pharmacokinetic parameters will be calculated for the fifth hourly administration of nicotine:; 2.1. Cmax, lastdose‐t ‐ The maximum plasma concentration of nicotine observed from the last administration to the last measurable concentration; 2.2. pAUClast dose‐t ‐ The partial area under the concentration‐time curve calculated using the trapezoidal rule from the last administration to last measurable concentration.; ; 3. Blood samples for PK analysis of nicotine will be taken at the following timepoints:; 3.1. Days 1‐3; 3.2. First administration: pre‐dose and at 2, 4, 6, 8, 10, 12, 15, 20, 30, and 60 min post‐dose; 3.3. Second, third and fourth hourly administrations: pre‐dose and at 10 minutes post‐dose; 3.4. Fifth administration pre‐dose and at 2, 4, 6, 8, 10, 12, 15, 20, 30, and 60 min post‐dose and 2, 4, 8 and 19 hours post‐dose; SECONDARY OUTCOME: ; The secondary endpoints for this study are pharmacokinetic parameters derived from the analysis of plasma samples for the concentration of nicotine and safety endpoints.; ; 1. Secondary (pharmacokinetic) variables for assessment endpoints are defined as follows. The following non‐compartmental pharmacokinetic parameters will be calculated for the fifth hourly administration of nicotine:; 1.1. AUC0‐8 ‐ The area under the concentration‐time curve extrapolated to infinity from dosing time, based on the last measurable concentration; 1.2. AUC0‐8 ‐ The area under the concentration‐time curve calculated using the trapezoidal rule from the time of dosing to 8 hours post‐dose; 1.3. AUC% extrapolated ‐ Percentage of AUC0‐inf due to extrapolation from last observed concentration to infinity; 1.4. Tma X‐ The time to maximum observed plasma nicotine concentration (also calculated for the 1st administration of nicotine; 1.5. t½ ‐ The terminal half‐life calculated from the terminal slope of the log concentration‐time curve as log(2)/slope; 1.6. ?z ‐ Elimination rate constant; ; 2. The following pharmacokinetic parameters will be calculated for each hourly nicotine administration 1 to 5:; 2.2. Ctrough ‐ The plasma concentration of nicotine immediately prior to each administration; 2.3. Cn ‐ The plasma concentration of nicotine at each planned nominal timepoint post each nicotine administration; ; 3. Secondary (safety) variables for assessment are adverse events, vital signs (as measured by systolic blood pressure, diastolic blood pressure and heart rate, respiration rate and oral temperature), ECG test results and laboratory test results. The safety endpoints:; 3.1. Adverse events (AEs); 3.2. Laboratory safety (biochemistry, haematology and urinalysis); 3.3. Vital signs (systolic/diastolic blood pressure, heart rate, respiration rate, oral body temperature); 3.4. 12 lead ECG (heart rate, PR interval, QRS duration, QT interval and QTcF interval); ; 4. Exploratory (pharmacodynamic) variables for assessment:; 4.1. Visual Analogue Scale of Nicotine Craving; ; 5. Blood samples for PK analysis of nicotine will be taken at the following timepoints:; 5.1. Days 1‐3; 5.2. First administration: pre‐dose and at 2, 4, 6, 8, 10, 12, 15, 20, 30, and 60 min post‐dose; 5.3. Second, third and fourth hourly administrations: pre‐dose and at 10 minutes post‐dose.; 5.4. Fifth administration pre‐dose and at 2, 4, 6, 8, 10, 12, 15, 20, 30, and 60 min post‐dose and 2, 4, 8 and 19 hours post‐dose.; ; AEs ‐ recorded from consent through to post‐study (Day 4); ; Laboratory Safety ‐ Screening only; ; Vital Signs ‐ Screening, Day ‐1, Days 1‐3 (pre‐first dose) & Day 4; ; ECG ‐ Screening & Day 4; ; VAS for Nicotine Craving; Days 1‐3: pre‐dose & 10 mins post‐dose for each administration on each day; Administration 5: pre‐dose, 10 mins & 30 mins post‐dose on each day; INCLUSION CRITERIA: 1. Healthy male participants, aged between 21 and 65 years old, inclusive 2. Participant with a body mass inde X(BMI) of 18‐32 kg/m2. BMI = body weight (kg) / [height (m)]2 3. Participants must be current conventional, factory‐made cigarette smokers (approximately 10 to 20 cigarettes per day for at least two consecutive years, defined by a positive urine cotinine result of = 200 ng/ml and = 7 ppm exhaled CO breath test (Smokerlyser) at Screening) or participants who have been consistent dual users of conventional cigarettes and e‐cigarettes/vape for 12 months, who are not intending to make a quit attempt during the study 4. Participants will be willing to use the study products ENHALE Electronic Inhaler with ENHALE 0.5 mg Nicotine Inhalation Cartridge, Nicorette® Inhalator and Nicorette® QuickMist and use only the products provided to them and abstain from regular cigarette use during clinical confinement (participants are allowed to smo