Pharmacokinetics of Nicotine Film in Smokers

Study Overview
=================
Brief Summary
-----------------
The objective of this study is to test the effect of a range of doses of a novel nicotine film on plasma nicotine levels, expired carbon monoxide and, via a questionnaire, subjective ratings of the film and side effects. The nicotine film is not part of standard of care and is not available in a non-investigational setting. The investigators hypothesize that plasma nicotine levels will be in keeping with those induced by other oral nicotine replacement therapies (NRTs) and by the smoking of a cigarette. Thus, the investigators predict that random delivery of nicotine via the oral film will be safe and well-tolerated by the human subjects.

Detailed Description
-----------------
Briefly, this will be a two-part pharmacokinetic study, each part involving 12 participants. In Part 1, 4 volunteer smokers (both male, and female) each will each abstain from all tobacco/nicotine products for 16 hours before attending the Penn State Clinical Research Center for the measurement of the blood nicotine pharmacokinetic response to a randomly allocated dose of either (a) 0mg, (b) 2mg or (c) 4mg oral nicotine film. A trained nurse will implant an intravenous indwelling catheter in each participant, through which they will provide a baseline blood sample after 16 hours of abstinence, confirmed by an exhaled carbon-monoxide < 6 ppm, and then will place a nicotine film in their mouth and have blood drawn every 10 minutes for the next 60 minutes, and then every 30 minutes for the next 2 hours plus one blood draw one minute after the film dissolves (11 blood draws in all over 3 hours after using the nicotine film). Subjective measures of (a) nicotine withdrawal and craving and (b) potential nicotine effects, including symptoms of nicotine intoxication, will be recorded at scheduled intervals through the study visit, and blood pressure and heart rate will be measured every 30 minutes. The investigators expect to find peak blood nicotine concentrations of around 3-4 ng/ml and 5-6 ng/ml from each of the two active doses of nicotine film, with the peak occurring approximately 30 minutes after film administration, and the level having dropped by at least half by 2 hours later. These peak blood nicotine levels are all within the range that a smoker might obtain after smoking a single cigarette. Upon completion of all blood draws, a trained nurse will remove the catheter and treat the puncture wound. The participant will receive $120 for this visit. In Part 2, 12 participants will again attend the Penn State Clinical Research Center after 16 hours of abstinence, confirmed by an exhaled carbon monoxide < 12 ppm. On this visit participants will consume repeated doses of nicotine films intended to mimic the patterns of delivery that will be used in smoking cessation study 2 and fMRI study 3. The primary issue here is to determine peak blood nicotine concentrations and safety resulting from (a) the highest dose schedule that could be used in study 2 and 3, (b) the steady state levels produced by repeated administration of the 2mg nicotine film, and (c) to compare the subjective effects to placebo. In order to mimic the most aggressive dosing schedule possible in the random nicotine arm of study 2 and 3, the investigators will assess blood nicotine, subjective and basic cardiovascular responses to consuming nicotine film every 3 hours beginning at 8:00 a.m. on the following schedule: 4mg, 4mg, 0mg, 4mg. All 12 participants will attend after 16 hours nicotine abstinence. 4 subjects each will be randomly allocated to consume 4 films over 12 hours in each of the following orders (a) 0,0,0,0 mg (b) 2,2,2,2 or (c) 4,4,0,4. A blood sample will be drawn at baseline prior to each film administration, and then at 30, 60 and 120 minutes after each film administration as well as one minute after film dissolution (20 blood draws in total), with heart rate and BP being assessed every 30 minutes. Nicotine has a half-life of approximately 2 hours, so the investigators expect that with 3-hourly administration there will not be much build-up of nicotine levels and these levels will be on the low end of the typical levels experienced by smokers every day. The participants will each receive $240 for this visit. At clinic visits, in addition to providing blood samples for measurement of plasma nicotine concentration, participants will be asked to complete a battery of survey instruments assessing subjective effects (e.g. withdrawal and craving) and physical symptoms (e.g. dizziness and nausea) that could be caused by either nicotine withdrawal or nicotine exposure.

Official Title
-----------------
Pharmacokinetics of Nicotine Film in Smokers

Conditions
-----------------
Smoking Cessation

Intervention / Treatment
-----------------
* Drug: Nicotine Film
* Drug: Placebo Nicotine Film


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Aged 18 - 55 Smoke >9 cigarettes/day for at least the past 12 months Able to understand and consent to study procedures Able to read and write in English Exhaled Carbon Monoxide <12 ppm at in-person screening Exclusion Criteria: Unstable or significant medical conditions and conditions such as elevated blood pressure (Systolic >140 mm Hg or diastolic >90mm Hg at baseline), COPD and those that are likely to affect biomarker data such as kidney or liver disease. Individuals with sodium-restricted diet, heart disease, recent heart attack, irregular heartbeat, stomach ulcers, or diabetes as well as those taking prescription medications for depression or asthma as indicated under Warnings section on FDA approved NRT Drug Facts Label. More than weekly use in the past 3 months of illegal drugs or prescription drugs that are not being used for medically prescribed purposes or inpatient treatment for these in the past 6 months. Use of non-cigarette nicotine delivery product in the prior week (including cigars, pipes, chew, snus, hookah, electronic cigarette and marijuana mixed with tobacco). Use of an FDA approved cessation medication in past week (any NRT, Chantix, Wellbutrin) Women who are pregnant (verified by urine pregnancy test at visit), trying to become pregnant (not using a medically acceptable form of birth control for at least one month prior to visit i.e., oral contraceptives, intrauterine device, double barrier), or nursing. Uncontrolled serious psychiatric illness or inpatient treatment in the past 6 months. Unwillingness to provide blood samples or history of repeatedly fainting during blood draws Any previous adverse reaction to NRT. Any other condition, serious illness, or situation that would, in the investigator's opinion, make it unlikely that the participant could comply with the study protocol.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: 0 mg Nicotine Film<br>In Part 1, 4 participants will be allocated to this arm and receive one placebo nicotine film. | Drug: Placebo Nicotine Film<br>* Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.<br>|
| Experimental: 2 mg Nicotine Film<br>In Part 1, 4 participants will be allocated to this arm and receive one 2 mg nicotine film. | Drug: Nicotine Film<br>* Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.<br>|
| Experimental: 4 mg Nicotine Film<br>In Part 1, 4 participants will be allocated to this arm and receive one 4 mg nicotine film. | Drug: Nicotine Film<br>* Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.<br>|
| Placebo Comparator: 0, 0, 0, 0mg Nicotine Film Regimen<br>In Part 2, 4 participants will be allocated to this arm and receive one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 0, 0, 0, 0 mg. | Drug: Placebo Nicotine Film<br>* Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.<br>|
| Experimental: 2, 2, 2, 2mg Nicotine Film Regimen<br>In Part 2, 4 participants will be allocated to this arm and receive one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 2, 2, 2, 2 mg. | Drug: Nicotine Film<br>* Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.<br>|
| Experimental: 4, 4, 0, 4mg Nicotine Film Regimen<br>In Part 2, 4 participants will be allocated to this arm and receive one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 4, 4, 0, 4 mg. | Drug: Nicotine Film<br>* Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Plasma Nicotine Concentrations Following Ingestion of a Single (Phase 1) or Repeated (Phase 2) Doses of Nicotine Film | In Phase 1, a trained nurse will implant an intravenous (IV) indwelling catheter in each participant. Participants will place a film containing zero, 2, or 4 mg of nicotine in their mouths and blood will be drawn every 10 minutes thereafter for the next 60 minutes, and then every 30 minutes for the next 2 hours (11 blood draws in all over 3 hours after using the nicotine film). In Phase 2, all 12 participants will receive an IV catheter and randomly allocated to consume 4 films over 12 hours in each of the following orders (a) 0,0,0,0 mg (b) 2,2,2,2 or (c) 4,4,0,4. A blood sample will be drawn at baseline prior to each film administration, and then at 30, 45, 60 and 120 minutes after each film administration and when the film is reported dissolved (20 blood draws in total). | 10 min - 12 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Questionnaire of Smoking Urges-Brief Mean Total Score by Dose Group | The Questionnaire of Smoking Urges-Brief (QSU-Brief) with a possible total score range of 10 to 70 was used to measure cigarette craving at baseline and at several points throughout the study visit for each participant. A score of 10 on this scale indicates very low cigarette craving, while a score of 70 indicates very high cigarette craving. Part 1: The QSU-Brief was measured at baseline and at 15, 35, 55, 80, 140, and 200 minutes post film administration. Part 2: The QSU-Brief was measured at baseline and at 50, 110, 230, 290, 410, 470, 590, and 690 minutes post FIRST film administration. | Part 1: The QSU-Brief was measured at baseline and at 15, 35, 55, 80, 140, and 200 minutes post film administration. Part 2: The QSU-Brief was measured at baseline and at 50, 110, 230, 290, 410, 470, 590, and 690 minutes post FIRST film administration. | 
| Mean Systolic Blood Pressure | Systolic blood pressure was measured using an electronic sphygmomanometer just prior to film administration and at every 30 minutes after film administration for the duration of each study visit. | Part 1: Systolic blood pressure was measured at baseline and at every 30 minutes, up to 180 minutes post film administration. Part 2: Systolic blood pressure was measured at baseline and at every 30 minutes, up to 660 minutes post film administration. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Nicotine, Random Delivery, Smoking Cessation, Plasma Nicotine, Oral Film