Biomarkers of Exposure and Effect in Standardized Research E-cigarette (SREC) Users

Study Overview
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Brief Summary
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This study is focused on characterizing the toxic and carcinogenic potential of the Standardized Research E-cigarette (SREC) developed by the National Institute on Drug Abuse. In the environment of continuously changing e-cigarette market, SREC was developed as a model e-cigarette that will remain available for an extended period of time and can be used as a bridging element in various studies aimed at evaluating the value and limitations of e-cigarettes as tobacco risk reduction tools. Our overall goal is to generate initial reference data on chemical exposures and associated effects in smokers switching to SREC.

Official Title
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Biomarkers of Exposure and Effect in Standardized Research E-cigarette (SREC) Users

Conditions
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Smoking, Cigarette

Intervention / Treatment
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* Drug: Standardized Research E-cigarette (SREC)
* Drug: Nicotine Mini-Lozenge


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female smokers who are 18-65 years of age and are willing to stop smoking and completely switch to e-cigarettes or medicinal nicotine; Report smoking ≥ 5 cigarettes daily and not using any other nicotine or tobacco product; Biochemically confirmed regular smoking status by a NicAlert test level of 6; Smoking daily for at least 1 year and no serious quit attempts (e.g., quit for 24 hours or longer) in the last 3 months (to ensure stability of daily smoking, particularly for those randomized to the continued smoking group); No unstable and significant medical or psychiatric conditions as determined by medical history and Prime-MD (to ensure safety of the subject, to minimize the effects of poor health on biomarker measures and to maximize compliance to study procedures); Subjects are in good physical health (no unstable medical condition); Subjects are in stable, good mental health (e.g. not currently, within the past 6 months, experiencing unstable or untreated psychiatric diagnosis, including substance abuse); Subjects who are not taking anti-inflammatory medications or any medications that affect relevant metabolic enzymes; Women who are not pregnant or nursing or planning to become pregnant; Subject has provided written informed consent to participate in the study (adolescents under the age of 18 will be excluded because this project involves continued use of tobacco products and new tobacco products). Exclusion Criteria: Regular tobacco or nicotine product use (e.g., 9 days in last 30 days) other than cigarettes; Currently using nicotine replacement or other tobacco cessation products; Significant immune system disorders, respiratory diseases, kidney or liver diseases or any other medical disorders that may affect biomarker data; Unstable health conditions (any significant serious, unstable medical condition including, but not limited to, cardiovascular disease, unstable COPD, seizure disorder and cancer, as determined by the licensed medical professional); Unstable mental health (to be determined by medical history, CESD, Prime-MD after review by the licensed medical professional); Excessive drinking (e.g., 5 or more drinks daily) or problems with drinking or drugs (e.g., self-report of binge drinking alcohol or treatment for drug or alcohol abuse within last 3 months); to be assessed by PI or licensed medical professional; Blood alcohol test > 0.01 (g/dL) as measured by a breath sample at screening (participants failing the breath alcohol screen will be allowed to re-screen once; Positive toxicology screen for any of the following drugs: cocaine, opiates, methadone, benzodiazepines, barbiturates, amphetamines, methamphetamines, and PCP. Failing temperature strip for the sample. Marijuana will be tested for, but will not be an exclusionary criterion. Participants with valid prescriptions for opiates, benzodiazepines, barbiturates, amphetamines or methadone will not be excluded. Participants failing the toxicology screen will be allowed to re-screen once; Pregnant or breastfeeding; Failure to agree to take adequate protection to avoid becoming pregnant during the study; Vital signs outside of the following range (participants failing for vital signs will be allowed to re-screen once): Systolic BP greater than or equal to 160 mm/hg Diastolic BP greater than or equal to 100 mm/hg Systolic BP below 90 mm/hg and symptomatic (dizziness, extreme fatigue, difficulty thinking, inability to stand or walk, feeling faint) Diastolic BP below 50 mm/hg and symptomatic (dizziness, extreme fatigue, difficulty thinking, inability to stand or walk, feeling faint) Heart rate greater than or equal to 105 bpm Heart rate lower than 45 bpm and symptomatic (dizziness, extreme fatigue, difficulty thinking, inability to stand or walk, feeling faint) Expired air carbon monoxide (CO) level greater than 80 ppm; Self-reported allergies to propylene glycol or vegetable glycerin; Adverse reactions when previously using electronic cigarettes; Household member enrolled in the study concurrently; Unable to read for comprehension or completion of study documents; Unstable living environment that would compromise the ability to attend visits, sequester study products or complete study procedures outside of visits.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Switching from Smoking Cigarettes to SREC<br> | Drug: Standardized Research E-cigarette (SREC)<br>* The device operates at a single output voltage (3.30 ± 0.05 V) and uses sealed disposable 3-mL cartridges with tobacco-flavored e-liquid ( 350 puffs/cartridge). The concentration of nicotine in e-liquid is 15 mg/mL, and the vehicle composition is 50:50 propylene glycol and glycerin. The device uses a battery that can be recharged via a micro USB port. A single charge is designed to sustain more than 400 puffs, which is more than the capacity of an e-liquid cartridge. The e-liquid and the aerosol are well-characterized in terms of chemical impurities and by-products (such as aldehydes), which are minimal. Additional information, including the results of pharmacokinetics study is available via NIDA website: https://www.drugabuse.gov/funding/supplemental-information-nida-e-cig<br>|
| Experimental: Switching from Smoking Cigarettes to Nicotine Mini-Lozenge<br> | Drug: Nicotine Mini-Lozenge<br>* We will use commercially available nicotine mini-lozenges containing 2 or 4 mg nicotine/lozenge (Nicorette, manufactured by GlaxoSmithKline). Dose will be determined per instructions on the package (e.g, if smoking within 30 minutes upon awakening, then 4 mg dose will be prescribed).<br>|
| No Intervention: Usual Brand Cigarettes<br> | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exposure Biomarkers | Difference in TNE (biomarker of nicotine) between patients using medicinal nicotine products and usual brand cigarettes. | 1 Year | 
| Exposure Biomarkers | Difference in total NNAL between patients using medicinal nicotine products and usual brand cigarettes. | 1 Year | 
| Exposure Biomarkers | Difference in total NNN (TSNA biomarkers) between patients using medicinal nicotine products and usual brand cigarettes. | 1 Year | 
| Exposure Biomarkers | Difference in PheT (PAH biomarker) between patients using medicinal nicotine products and usual brand cigarettes. | 1 Year | 
| Exposure Biomarkers | Difference in mercapturic acids HMPMA between patients using medicinal nicotine products and usual brand cigarettes. | 1 Year | 
| Exposure Biomarkers | Difference in 2-HPMA between patients using medicinal nicotine products and usual brand cigarettes. | 1 Year | 
| Exposure Biomarkers | Difference in 3-HPMA (biomarkers of VOC) between patients using medicinal nicotine products and usual brand cigarettes. | 1 Year | 
| Formaldehyde-DNA adducts | Changes in inflammatory biomarkers at 4 and 8 weeks after randomization. | 8 Weeks | 
| Oxidative DNA adduct 8-oxo-dG in DNA | Changes in DNA adducts at 4 and 8 weeks after randomization. | 8 Weeks | 
| Salivary NNN | Levels of NNN and nornicotine in saliva in oral cells of complete switchers to SREC and medicinal nicotine. | 1 Year | 
| NNN-derived HPB-releasing DNA adducts | Levels of HPB-releasing DNA adducts in oral cells of complete switchers to SREC and medicinal nicotine. | 1 Year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Product Use | For cigarettes, cigarettes per day will be assessed based on Interactive Voice Response (IVR) system. | 1 Year | 
| Product Use | For SREC, number of bouts will be assessed based on IVR system | 1 Year | 
| Product Use | For SREC, estimated number of puffs will be assessed based on IVR system. | 1 Year | 
| Product Use | For SREC, amount of e-liquid consumed will be assessed by difference in cartridge weights before and after use. | 1 Year | 
| Product Use | For medicinal nicotine, daily number of mini-lozenges will be assessed based on based on IVR system and counting returned unused product. | 1 Year | 
| Cigarette Avoidance | SREC or Medicinal Nicotine: the number of cigarette avoidance days, defined as no tobacco cigarettes smoked in the past 24 hours based on IVR, and the rate of cigarette avoidance, calculated as the proportion of cigarette avoidance days out of the total number of days in the product use period (56 days for those who complete the study). | 1 Year | 
| Cigarette Avoidance | SREC or Medicinal Nicotine: rate of cigarette avoidance, calculated as the proportion of cigarette avoidance days out of the total number of days in the product use period (56 days for those who complete the study). | 1 Year |