Nicotine Pharmacokinetics From Research Electronic Nicotine Delivery System S-TA-U001 in Smokers and E-Cigarette Users
Nicotine Pharmacokinetics From Research Electronic Nicotine Delivery System S-TA-U001 in Smokers and E-Cigarette Users
To better understand the PK and associated pharmacodynamic (PD) responses produced by the
 Research ENDS S-TA-U001 product, this study will compare the Research ENDS S-TA-U001 to

 -  The subject's own brand combustion (non-menthol) cigarette and a U.S. FDA approved
 smoking cessation product, the NICORETTE Inhalator, in current non-menthol cigarette
 smokers who have some limited e-cigarette experience (Group 1).

 -  Commercially available products in current primarily e-cigarette users (experienced ENDS
 users) (Group 2) The PK/PD session for each product will be conducted in a controlled
 clinical setting with frequent PK sampling after 14 hours of supervised abstinence from
 all forms of nicotine. Subjects will familiarize themselves with the Research ENDS
 S-TA-U001 and NICORETTE Inhalator by using each product in the real world for one day
 before the PK/PD session for that product.

 Primary Objectives:

 Group 1 objectives are to characterize the nicotine PK profile (eg, maximum plasma
 concentration [Cmax], time to maximum plasma concentration [Tmax], area under the
 concentration-time curve [AUC], and terminal half-life [t1/2]) for 10 inhalation and ad lib
 sessions of Research ENDS S-TA-U001 and explore how the Cmax compares to a 15 ng/mL level
 during the 4.5-minute 10 inhalation and the 6 hour ad lib use sessions, to compare the PK
 profiles between Research ENDS S-TA-U001 to the profiles of combustion cigarettes measured at
 the baseline session, and to demonstrate superiority of PK profile of Research ENDS S-TA-U001
 to that of the marketed NICORETTE Inhalator.

 Group 2 objectives are to characterize the nicotine PK profile of Research ENDS S-TA-U001 and
 explore how the Cmax compares to a 15 ng/mL level during the 4.5-minute 10 inhalation and 6
 hour ad lib use sessions, and to compare the PK profile between Research ENDS S-TA-U001 to
 the profile of a commercial ENDS product measured at the baseline session.

 Secondary objectives:

 Secondary objectives include comparison of the nicotine PK of the Research ENDS S-TA-U001 to
 the subjects' normal nicotine source (combustion cigarettes for Group 1 or commercial ENDS
 for Group 2), to evaluate the safety and tolerability of Research ENDS S-TA-U001, to evaluate
 the effects on craving and user satisfaction of the Research ENDS S-TA-U001 vs a combustion
 cigarette or the NICORETTE Inhalator (Group 1) or a commercial ENDS product (Group 2), and to
 evaluate various biomarkers following use of each test product.
Subjects in Group 1 will participate in a Phase 1 2×2 cross-over study of the Research ENDS
 S-TA-U001 (Test Product A) and NICORETTE Inhalator (Test Product B). Subjects in Group 2 will
 participate in a study to examine the effect of the Research ENDS S-TA-U001 (Test Product A).

 Approximately 20 healthy volunteers, ages 21 to 65 inclusive, who are current combustion
 cigarette smokers will be enrolled into Group 1 for the 2×2 cross-over study. Approximately
 14 healthy volunteers, ages 21 to 65 inclusive, who are current primarily e cigarette users
 will be enrolled into Group 2. Initial screening for the study will occur from 7 to 21 days
 before the first PK assessment/in-clinic device Training Visit on Day 1. Subjects in Group 1
 will be randomized to Sequence AB (10 subjects) or Sequence BA (10 subjects).

 On Day 1, subjects will arrive at the research site to begin at least 14 hours of overnight
 supervision to insure abstinence from all forms of nicotine prior to the first administration
 of the Baseline Product. Each subject will complete a 10 inhalation session of his or her
 normal nicotine source (either the subject's own brand of a combustion cigarette [Group 1] or
 the subject's own brand of commercial ENDS product [Group 2]) in 4.5 minutes, abstain for 1
 hour 55 minutes, complete a second session of 10 inhalations in 4.5 minutes, complete a 6
 hour ad lib use session, and complete a series of behavioral assessments over the PK
 sampling/observation period lasting 8 hours and 5 minutes. The first series of 4.5-minute 10
 inhalation sessions will be videotaped to assess inhalation duration and technique. Subjects
 will abstain from food for one hour before each 10 puff session and caffeine within one hour
 of the first 10 puffs through the duration of the entire ad lib session.

 Following the sampling/observation period on Day 1, subjects in Group 1 Sequence AB and
 subjects in Group 2 will be trained on how to properly use the Research ENDS S-TA-U001, and
 Group 1 Sequence BA subjects will be trained on how to properly use the NICORETTE Inhalator.
 Prior to discharge, subjects will be provided with two cartridges of the Research ENDS
 S-TA-U001 or a set of NICORETTE Inhalator for at-home use for 1 day (starting immediately
 after clinic discharge) depending on the group and sequence to which they are assigned.
 Subjects will be encouraged (though not required) to use the Research ENDS S-TA-U001 or
 NICORETTE Inhalator as their exclusive nicotine source. Subjects will record the number of
 combustible cigarettes smoked (if any) and the number of cartridges of the Research ENDS
 S-TA-U001 or NICORETTE Inhalator used, depending on sequence (Group 1), or the number of
 cartridges of the Research ENDS S-TA-U001 used and the amount of e liquid used (if any) from
 their commercial ENDS products (Group 2). All subjects will be required to return all of the
 study devices used as well as used and unused cartridges at the next visit.

 On Day 3, subjects will arrive at the research site to begin at least 14 hours of overnight
 supervision to insure abstinence from all forms of nicotine prior to the first administration
 of the Test Product. Subjects in Group 1 Sequence AB and Group 2 will complete a 10
 inhalation session of Research ENDS S-TA-U001 in 4.5 minutes, abstain for 1 hour 55 minutes,
 complete a second session of 10 inhalations in 4.5 minutes, followed by a 6 hour ad lib use
 session. Subjects in Group 1 Sequence BA will complete a 10 inhalation session of NICORETTE
 Inhalator, abstain for 1 hour 55 minutes, complete a second session of 10 inhalations in 4.5
 minutes, followed by a 6 hour ad lib use session. A series of behavioral assessments will be
 performed during the PK sampling/observation period lasting 8 hours and 5 minutes. The first
 series of 4.5 minute 10 inhalation sessions for both products will be videotaped to assess
 inhalation duration and technique. Subjects will abstain from food for one hour before each
 10 puff session and caffeine within one hour of the first 10 puffs through the duration of
 the entire ad lib session. Subjects in Group 2 will be discharged from the clinic following
 the final PK blood draw and completion of all final clinical assessments on Study Day 3.
 Following the sampling/observation period, subjects in Group 1 Sequence AB will be trained on
 how to properly use the NICORETTE Inhalator and subjects in Group 1 Sequence BA will be
 trained on how to properly use the Research ENDS S-TA-U001. Prior to discharge, subjects,
 depending on the group and sequence to which they are assigned, will be provided with two
 cartridges of the Research ENDS S TA U001 or a set of NICORETTE Inhalator for at-home use for
 1 day (starting immediately after clinic discharge). Subjects will be encouraged (though not
 required) to use the Research ENDS S-TA-U001 or NICORETTE Inhalator as their exclusive
 nicotine source. All subjects will be required to return all of the study devices used as
 well as used and unused cartridges at the next visit.

 On Day 5, subjects in Group 1 will arrive at the research site to begin at least 14 hours of
 overnight supervision to insure abstinence from all forms of nicotine prior to the first
 administration of the Test Product. Subjects in Group 1 Sequence AB will complete a 10
 inhalation session of NICORETTE Inhalator in 4.5 minutes, abstain for 1 hour 55 minutes,
 complete a second session of 10 inhalations in 4.5 minutes, followed by a 6 hour ad lib use
 session. Subjects in Group 1 Sequence BA will complete a 10 inhalation session of Research
 ENDS S-TA-U001 in 4.5 minutes, abstain for 1 hour 55 minutes, complete a second session of 10
 inhalations in 4.5 minutes, followed by a 6-hour ad lib use session. A series of behavioral
 assessments will be performed during the PK sampling/observation period lasting 8 hours and 5
 minutes. The first series of 4.5 minute 10 inhalation sessions for both products will be
 videotaped to assess inhalation duration and technique. Subjects will abstain from food for
 one hour before each 10 puff session and caffeine within one hour of the first 10 puffs
 through the duration of the entire ad lib session. Subjects in Group 1 will be discharged
 from the clinic following the final PK blood draw and completion of all final clinical
 assessments on Study Day 5.
Inclusion Criteria:

 For Group 1: in order to participate in the study, potential subjects must:

 1. Be males and females of any race between 21 and 65 years of age inclusive

 2. Be current combustion cigarette smokers, defined as smoking a minimum of 10 combustion
 cigarettes per day for a period of at least 3 months, who smoke commercial (non
 menthol) cigarettes

 3. Not be currently planning to quit smoking combustion cigarettes in the next 3 months

 4. Have blood cotinine ≥100 ng/mL and carbon monoxide ≥10 ppm at Screening to confirm
 smoking status

 5. Weigh at least 45 kg and have a Body Mass Index (BMI) between 18 and 40 kg/m2,
 inclusive, at Screening

 6. Be healthy, in the Investigator's opinion, according to medical history; physical
 examination; electrocardiogram (ECG); and clinical chemistry, urine, and hematological
 laboratory tests

 7. Be willing to refrain from using any source of nicotine other than study supplies for
 the duration of the study confinement period

 8. Have vital signs as follows:

 -  Resting heart rate between 50 and 90 beats per minute

 -  Systolic blood pressure below 150 mm Hg

 -  Diastolic blood pressure below 90 mm Hg

 9. Have electrolytes (ie, Na, K, Cl, HCO3) and hematocrit that are clinically normal (±
 10% of laboratory limits); subjects marginally outside of this range may be eligible
 at the discretion of the study physician

 10. Have liver function tests (ie, total bilirubin, ALT, AST, GGT, and alkaline
 phosphatase) less than three times the upper normal limit

 11. Have kidney function tests (ie, creatinine and BUN) within clinically normal limits (±
 10% of laboratory limits) and calculated creatinine clearance > 80 mL/min for females
 and > 90 mL/min for males

 12. Have an ECG performed that demonstrates normal sinus rhythm, normal conductivity, and
 no clinically significant abnormalities

 13. Be able to demonstrate the ability to comply with the inhalation instructions for Test
 Product administration (Research ENDS S TA U001 and NICORETTE Inhalator), visually
 confirmed by clinic staff at Screening visit

 14. Be able to verbalize understanding of the consent forms, provide written informed
 consent, and verbalize willingness to comply with the study procedure

 15. Have 5-50 days of use of any ENDS product in their life and no use within 7 days
 before Screening

 16. Have no more than 20 days of use of the NICOTROL Inhaler in their life and no use
 within the 7 days before Screening

 For Group 2: in order to participate in the study, potential subjects must:

 1. Be males and females between 21 and 65 years of age inclusive

 2. Be current daily users of a commercially available ENDS product, with e-liquids of
 nicotine concentration 10 to 20 mg/mL

 3. Consume at least 1 mL per day of e-liquid in their ENDS product

 4. Not smoke more than 2 combustion (non menthol) cigarettes per day

 5. Have carbon monoxide ≤15 ppm at Screening to confirm limited smoking status

 6. Have blood cotinine ≥100 ng/mL at Screening to confirm nicotine dependence

 7. Weigh at least 45 kg and have a Body Mass Index (BMI) between 18 and 40 kg/m2,
 inclusive, at screening

 8. Be healthy, in the Investigator's opinion, according to medical history; physical
 examination; ECG; and clinical chemistry, urine and hematological laboratory tests

 9. Be willing to refrain from using any source of nicotine for the duration of the study
 confinement period

 10. Have vital signs as follows:

 -  Resting heart rate between 50 and 90 beats per minute

 -  Systolic blood pressure below 150 mm Hg

 -  Diastolic blood pressure below 90 mm Hg

 11. Have electrolytes (ie, Na, K, Cl, HCO3) and hematocrit that are clinically normal (±
 10% of laboratory limits); subjects marginally outside of this range may be eligible
 at the discretion of the study physician

 12. Have liver function tests (ie, total bilirubin, ALT, AST, GGT, and alkaline
 phosphatase) less than three times the upper normal limit

 13. Have kidney function tests (ie, creatinine and BUN) within clinically normal limits (±
 10% of laboratory limits) and calculated creatinine clearance > 80 mL/min for females
 and > 90 mL/min for males

 14. Have an ECG performed that demonstrates normal sinus rhythm, normal conductivity, and
 no clinically significant abnormalities

 15. Be able to demonstrate the ability to comply with the inhalation instructions for Test
 Product administration (Research ENDS S TA U001), visually confirmed by clinic staff
 at Screening visit

 16. Be willing to use tobacco-flavored product

 17. Be able to verbalize understanding of the consent forms, provide written informed
 consent, and verbalize willingness to comply with the study procedure

 Exclusion Criteria:

 For Group 1 and Group 2: in order to participate in the study, potential subjects must not:

 1. Have expected inability to comply with study protocol

 2. Have used any of the following in the past 30 days: ultra-light, hand or
 roll-your-own, menthol, or unfiltered combustion cigarettes; any other form of tobacco
 (eg, chews, dips, pipes, cigars, hookah); or any form of nicotine replacement therapy
 (eg, patch, gum, lozenge, inhaler, nasal spray).

 3. Be pregnant (based on serum test) or nursing (by self-report)

 4. Have history or diagnosis of airway disease, including adult onset asthma or chronic
 obstructive pulmonary disease (including emphysema or chronic bronchitis), use of an
 inhaler (apart from a nicotine inhaler) in the previous 5 years, or any episodes of
 wheezing or bronchospasm in the previous 5 years (history of resolved childhood asthma
 is acceptable)

 5. Have baseline spirometry values (FEV1, FVC, and FEV1/FVC) outside of the lower limit
 of normal as defined by Hankinson et al, Am J Respir Crit Care Med 1999; 159:179-187.

 6. Have had treatment with prescription medications within 21 days or over-the-counter
 medication within 24 hours of the planned first product use occasion, except for oral
 or hormonal contraceptive therapies.

 7. Have used any drugs or substances (except tobacco) known to be strong inducers or
 inhibitors of any CYP enzymes (formerly known as cytochrome P450 enzymes) within a 28
 days period prior to first product administration. For a list of such drugs and
 substances, please refer to http://medicine.iupui.edu/clinpharm/ddis/main-table/.

 8. Have an active cough, recent or chronic, excluding "smoker's cough"

 9. Have any active respiratory infection

 10. Have a history of clinically significant cardiac, pulmonary, renal, hepatic,
 endocrine, neurological, gastrointestinal, metabolic, psychiatric, or hematologic
 disorders

 11. Have poor venous access as defined by being unable to draw samples through a catheter
 at the screening visit

 12. Have been hospitalized within 4 weeks before Screening

 13. Have received any other investigational treatment or Test Product within 30 days from
 randomization (or within 5 half-lives of the Test Product, if known, whichever is
 greater)

 14. Have a history of allergic, anaphylactic, or other hypersensitivity reaction to any e
 cigarette , or any of the components associated with these products such as propylene
 glycol

 15. Have any medical history or condition (including physical) considered by the Principal
 Investigator and/or admitting physician to place the subjects at increased risk or
 preclude safe and/or successful completion of the study

 16. Have any history of substance abuse, including alcohol abuse within the last 3 months

 17. Have a positive result for any drug of abuse (opiates, benzodiazepines, barbiturates
 or related CNS depressants, amphetamines or related stimulants, or marijuana) at
 screening or Day -1

 18. Be cognitively impaired to a degree that would affect participation. An adequate level
 of reading and comprehension is needed in order to complete various forms (e.g.,
 behavioural assessments) that are used as dependent variables

 19. Have active syphilis (based on the standard confirmatory test (e.g., FTB-abs))

 20. Be undergoing HIV treatment with antiviral and non-antiviral therapy or treatment for
 HIV-related opportunistic infection

 21. Do not actively meet the inclusion criteria at the time of screening