Switching From Usual Brand Cigarettes to a Tobacco-heating Cigarette or Snus

A randomized, multi-center, 4-group study of health status measures and biomarkers in
subjects who smoke and are switched to either a tobacco-heating cigarette, snus, or a
tobacco-burning cigarette, with a non-treatment group of never-smokers.

Primary Objectives:

- Evaluate select biomarkers of tobacco exposure and biomarkers of harm from subjects who
smoke and who are switched to a tobacco-heating cigarette, snus, or a tobacco-burning
cigarette.

- Evaluate ability of a tobacco-heating cigarette and snus to modify patient-reported
Chronic Obstructive Pulmonary Disease (COPD)-related health status in subjects who
smoke and are switched to either a tobacco-heating cigarette or snus relative to a
control group (a tobacco-burning ultra-low machine yield [ULMY]) cigarette.

- Assess subject compliance.

Secondary Objectives:

- Measure amount and repeatability of smoke components yielded from the cigarettes (yield
in use) and determine relative uptake of selected smoke components.

- Evaluate the ability of a tobacco-heating cigarette and snus to modify general health
status as measured by self-administered health questionnaires in subjects who smoke and
are switched to either a tobacco-heating cigarette or snus relative to a control group
(a tobacco-burning ULMY cigarette).

- Compare health status measures in smokers who are switched to a tobacco-heating
cigarette to smokers who are switched to snus.

- Compare baseline data from all tobacco-using groups to baseline data from the
never-smoking (non-treatment) group.

Inclusion Criteria:

- Males or females, between 28 and 55 years of age, inclusive.

- Cigarette-only smokers who currently smoked at least 15 cigarettes daily and who
smoked for at least 10 years prior to Week 0 (i.e., chronic cigarette smokers).

- Smokers not intending to quit smoking, but willing to switch their tobacco product
(intent to quit was defined as intending to make or making a quit attempt within 1
month prior to Week 0).

- Non-smoking subjects who self-reported "Never-Smoker" per the American Thoracic
Society Questionnaire definition, and did not have urinary cotinine levels exceeding
50 ng/mL.

- Subjects, in the opinion of the Investigators, free of clinically significant health
problems and not on medication on a daily basis for chronic medical disorders deemed
clinically significant by the Investigator(s).

- Subjects not regularly taking creatine supplements.

- Subjects testing negative for selected drugs of abuse at Screening (included alcohol
test).

- Subjects with a negative hepatitis panel (including hepatitis B surface antigen
[HBsAg] and hepatitis C virus antibody [anti-HCV]) and negative Human
Immunodeficiency Virus (HIV) antibody screens (for subjects immunized against
hepatitis B with documentation of this immunization, a positive test result was not
exclusionary).

- Female subjects who were non-pregnant (urine pregnancy test results were negative at
Screening and Weeks 0, 12, and 24), non-lactating, and either postmenopausal (as
verified by Follicle Stimulating Hormone levels) for at least 1 year, surgically
sterile (e.g., tubal ligation, hysterectomy) for at least 90 days, or agreed to use
from the time of signing the informed consent until 30 days after Week 24 (or Study
Completion) a form of contraception considered acceptable to the Investigators (such
as oral, injectable or implantable contraceptives, intrauterine devices and barrier
methods ).

- Subjects able to read and comprehend questionnaires in English and willing to sign an
Informed Consent Form.

Exclusion Criteria:

- Smokers using any other tobacco or nicotine-containing product or device other than
tobacco-burning cigarettes from 6 months prior to the study through Week 24,
including cigars, pipes, chewing tobacco, snuff, snus, nicotine patch, nicotine gum,
etc.

- A history or clinical manifestations of significant metabolic, hepatic, renal,
hematological, pulmonary, cardiovascular, gastrointestinal, urological, neurological,
or psychiatric disorders.

- A history of hypersensitivity or allergies to any drug compound unless approved by
the Investigator(s).

- A history or presence of an abnormal ECG deemed clinically significant by the
Investigator.

- A history of alcoholism or drug addiction within 1 year prior to Study Entry.

- Evidence of visible oral cancer, as found in an oral health examination or based on
oral health questions at each visit.

- Any acute or chronic condition that, in the Investigator(s)' opinion, limited the
subject's ability to complete and/or participate in the study.

- Donation of blood from 30 days prior to Screening through Week 24 (or Study
Completion), inclusive, or plasma from 2 weeks prior to Screening through Week 24 (or
Study Completion), inclusive.

- Receipt of blood products within 2 months prior to Study Entry.

- Subject or a relative of the subject was currently or had ever been employed by the
tobacco industry.

- Subject participated in any other investigational study drug or product trial in
which receipt of an investigational study drug or product occurred within 30 days
prior to Check-in (inclusive).