The Role of Nicotine Dose and Route of Delivery in Affecting Adoption of E-cigarettes and Reducing Exposure to Toxic Combustion Products

This study proposes to assess the relative role of nicotine dose and route of delivery in
affecting successful switching from combustible cigarettes to e-cigarettes, as well as
concomitant reductions in ad libitum cigarette smoking and exposure to harmful and
potentially harmful constituents of combustion. The strategy will be to assess adoption of
e-cigarette use and concomitant reduction in ad libitum smoking of subjects' usual brands of
cigarettes over an 8-week period, during which they will receive nicotine or non-nicotine
e-cigarettes, and nicotine or non-nicotine skin patches. The nicotine patches will not be
used as a therapeutic treatment in this study, but rather as a way to manipulate the nicotine
dose, while varying the rate and route of nicotine delivery. Behavioral or "habit" aspects of
e-cigarette use will be controlled for by the groups receiving non-nicotine e-cigarettes.

Inclusion Criteria:

- Smoke an average of at least 10 cigarettes per day;

- Have smoked at least one cumulative year;

- Have an expired air CO reading of at least 10ppm;

- Have a body weight of > 110 lbs. (50 kg) and ≤ 300 lbs. (136 kg);

- Are able to read and understand English;

Potential subjects of child bearing potential must agree to use acceptable contraception
during their participation in this study. Potential subjects must agree to avoid the
following during their participation in this study:

- Participation in any other nicotine-related modification strategy outside of this
protocol;

- Use of tobacco products other than cigarettes, including pipe tobacco, cigars, snuff,
and chewing tobacco;

- Use of e-cigarettes other than the ones provided during the study;

- Use of experimental (investigational) drugs or devices;

- Use of illegal drugs;

- Use of exclusionary medications.

Exclusion Criteria:

- Seeking treatment for nicotine dependence.

- Hypertension - systolic BP > 160 mm Hg, diastolic BP > 100 mm Hg. Individuals with a
history of hypertension may be allowed to participate in the study if the study
physician or medical provider determines that the condition is stable and will not
jeopardize the individual's safety.

- Hypotension (with symptoms) - systolic BP < 90 mm Hg, diastolic BP < 60 mm Hg.

- Coronary heart disease with symptoms (e.g., chest pain)

- Heart attack in the past year

- Cardiac rhythm disorder (irregular heart rhythm with symptoms)

- Chest pain in the last month (unless history indicates a non-cardiac source)

- Symptomatic heart disorder such as heart failure

- Advanced liver or kidney disease that requires medication or dialysis, paracentesis

- Major gastrointestinal illness (e.g. Celiac disease, Crohn's dx Ulcerative Colitis)

- Bleeding stomach ulcers in the past 30 days

- Lung disease that requires oxygen

- Major brain disorder (including stroke with residual deficit, brain tumor, and seizure
disorder)

- Migraine headaches that occur more frequently than once per week

- Recent, unexplained fainting spells

- Problems giving blood samples

- Diabetes with insulin use or with HbA1C over 7%

- Current cancer or treatment for cancer in the past six months (except basal or
squa-mous cell skin cancer)

- HIV, Hepatitis B, or Hepatitis C

- History of Tuberculosis or recent positive purified protein derivative (PPD)

- Other major medical condition (as determined by study physician)

- Currently symptomatic psychiatric disease (as determined by study physician)

- Psychosis, bipolar disorder, or psychiatric hospitalization within the past 12 months

- Suicidal ideation (thinking about ways to commit suicide) (within the past 12 months)
or a lifetime occurrence of attempted suicide;

- Current depression - The Patient Health Questionnaire PHQ-9 for Depression will be
used to screen for current (within 2 weeks) depression. Potential subjects who score
>9 (or who score >0 on item #9 ("Thoughts that you would be better off dead, or of
hurting yourself in some way") will be excluded from study participation, and, at the
discretion of the study physician, referred to appropriate psychiatric treatment;

- Pregnant or nursing mothers

- Use (within the past 30 days) of:

- Illegal drugs (or if the urine drug screen is positive for tetrahydrocannabinol
(THC), Cocaine, Amphetamine, Opiates, Methamphetamines, phencyclidine (PCP),
Benzodiazepines, or Barbiturates), unless recent use of prescription Opiates or
Benzodiazepines were taken for management of acute symptoms (e.g., tooth
extraction, recent surgery);

- Experimental (investigational) drugs;

- Psychiatric medications including antidepressants (selective serotonin reuptake
inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs),
tricyclic antidepressant (TCAs), monoamine oxidase inhibitors (MAOIs), St. John's
Wort), lithium, anti-psychotics or any other medications that are known to affect
smoking cessation (e.g. clonidine);

- Phentermine, triptans, tryptophan, linezolid, dextromethorphan, opiates (unless
taken for management of acute symptoms), tramadol, or dopamine agonists;

- Any agents that have documented correlation with increased incidence of
valvulopathy and/or pulmonary hypertension (e.g., cyproheptadine, trazodone,
nefazodone, amoxapine, tricyclic antidepressants, mirtazapine, pergolide,
ergotamine, methysergide) (or anticipated use during the study);

- Wellbutrin, bupropion, Zyban, Chantix, varenicline, nicotine patch, nicotine
replacement therapy or any other smoking cessation aid;

- Use of cigars, cigarillos, pipes, Hookah, dissolvable nicotine, snuff, chewing
tobacco, or e-cigarettes

- Concurrent use of a serotonergic agent/combination associated with severe serotonin
syndrome (within the past 30 days)

- Use of cigars, cigarillos, pipes, Hookah, dissolvable nicotine, snuff, chewing
tobacco, or e-cigarettes within the past 30 days

- Self-report of consuming more than 6 alcoholic drinks on 1 or more days per week

- Significant adverse reaction to nicotine patch in the past

- Current participation or recent participation (in the past 30 days) in another smoking
study at our Center or another research facility

- Current participation in another research study