Nicotine Pharmacokinetics From Research Electronic Nicotine Delivery System S-TA-U001 in Smokers and E-Cigarette Users

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