Cardiovascular Assessment of the Effects of Tobacco and Nicotine Delivery Products

The overarching goal of this project is to develop a panel of cardiovascular risk biomarkers that can detect differences in the cardiovascular safety of various tobacco products, whether conventional, new or emerging, in order to help the FDA with the task of regulating them. This will be achieved through 4 aims:

Aim 1: Determine the relative contributions of nicotine and combustion products to the cardiovascular risk of active cigarette smoking.

Aim 2: Determine which cardiovascular risk biomarkers are affected by exposure to secondhand smoke.

Aim 3: Determine the cardiovascular risk of smokeless tobacco use.

Aim 4: Determine the cardiovascular risk of electronic cigarettes and the respective contributions of nicotine and electronic cigarette vapor.

Study Overview

• Status: Completed
• Conditions: Adverse Effect of Other Agents Primarily Affecting the Cardiovascular System, Initial Encounter
• Intervention / Treatment: Other: Cigarette, NIDA test type with 16.6 mg nicotine; Other: Cigarette, NIDA test type with <0.45 mg nicotine; Other: Sham Smoking; Other: Secondhand cigarette smoke (SHS); Other: Conditioned, filtered air; Other: Moist snuff; Other: Sham Moist Snuff; Other: Electronic cigarette with 18 mg/ml nicotine; Other: Electronic Cigarette with no nicotine

Detailed Description

Cigarette smoking is a major cause of cardiovascular disease (CVD).1 In contrast, the cardiovascular risks of other popular tobacco products (smokeless tobacco), new tobacco products ( e-cigarettes) and proposed products (reduced nicotine cigarettes) are not adequately understood. The FDA will need information about the cardiovascular safety of these products to inform their regulatory decisions. While long-term clinical outcome studies of the cardiovascular risks of these tobacco products would be optimal, they take too long to provide the data that the FDA needs now. Disturbances in the function of vascular endothelium (the lining of arteries, which plays an important role in regulating vascular function) and the activation of the autonomic nervous system, as well as increased inflammation, oxidative stress and propensity to thrombosis (clotting), are key mechanisms in the progression of CVD and validated biomarkers of CVD risk. These biomarkers form the basis for our model to assess the CVD risks of tobacco product use and secondhand smoke exposure. We will conduct controlled, short-term exposures of human subjects to test products that provide a wide range of nicotine, particle, and other cardiovascular toxin concentrations to determine how these components associated with tobacco use adversely affect cardiovascular risk.

• Study Type: Interventional
• Enrollment (Actual): 81
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California, San Francisco

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• All Groups: Age 18-50
• Can tolerate withholding their medications for two weeks at a time
• Group 1: Active smokers
• Group 2: Nonsmokers
• Group 3: Active users of smokeless tobacco
• Group 4: Active users of electronic cigarettes
• Additional Inclusion Criteria for E-Cigarette Users:
• Currently use ofe-cigarettes > 5 times a day
• Has used e-cigarettes for >3 months
• Additional Inclusion Criteria for Active Smokers: Currently smoke >5 cigarettes per day ≥ 1 pack year

Exclusion Criteria:

• Exclusion Criteria for all subjects
• Physician diagnosis of:
• asthma
• heart disease
• hypertension
• dyslipidemia
• thyroid disease
• diabetes
• renal or liver impairment
• glaucoma.
• Unstable psychiatric condition (such as current major depression, history of schizophrenia or bipolar disorder)
• current use of more than two psychiatric medications
• Pregnancy or breastfeeding (by history)
• Alcohol, opiate, cocaine, amphetamine or methamphetamine dependence within the past 5 years
• BMI > 35 and < 18
• Current opiate, cocaine, amphetamine or methamphetamine use (by history or urine test)
• Occupational exposure to smoke, dusts and fumes
• Concurrent participation in another clinical trial
• Unable to communicate in English
• Additional Exclusion Criteria for Active Smokers:
• Unable to hold marijuana for 1 week prior to each study visit.
• Exhaled carbon monoxide (CO) <10 ppm at each visit
• Negative salivary cotinine test using a rapid-read, over the counter test with 30 ng/ml cutoff
• Additional Exclusion Criteria for Nonsmokers:
• More than 1 pack year smoking history
• Quit smoking < 5 years ago
• Ever a daily marijuana smoker
• Smoked anything within the last 3 months
• Additional Inclusion Criteria for Smokeless Tobacco Users:
• Use of moist oral snuff > 5 times a day
• Has used moist oral snuff for at least 0.5 years
• Additional Exclusion Criteria for Smokeless Tobacco Users:
• Current smoker
• Quit smoking < 0.5 years ago
• Additional Exclusion Criteria for E-Cigarette Users:
• Current use of other tobacco products
• Unable to hold marijuana for 1 week prior to each study visit

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cigarette smokers; Will smoke 1 cigarette, National Institute of Drug Abuse (NIDA) test type with 16.6 mg nicotine; 1 cigarette, NIDA test type with <0.45 mg nicotine; perform sham smoking by puffing on a drinking straw. Each intervention will last 10 minutes, and each will take place one time, on one of 3 study visits, in random order.	Other: Cigarette, NIDA test type with 16.6 mg nicotine; Smoke a single cigarette for up to 10 minutes; Other Names: Cigarette; Other: Cigarette, NIDA test type with <0.45 mg nicotine; Smoke a single low-nicotine cigarette for up to 10 minutes; Other Names: Cigarette; Other: Sham Smoking; Sham smoking or e-cigarette use consists of puffing on a drinking straw for 10 minutes
Experimental: Nonsmokers; Will undergo secondhand cigarette smoke (SHS) exposure and conditioned, filtered air exposure. Each intervention will last 180 minutes, and each will take place one time, on one of 2 study visits, in random order.	Other: Secondhand cigarette smoke (SHS); 180-minute exposure to SHS generated by controlled dilution of smoke from machine-smoked cigarettes; Other Names: SHS; ETS; Environmental Tobacco Smoke (ETS); Other: Conditioned, filtered air; Exposure to conditioned, filtered air for 180 minutes; Other Names: Clean, filtered, temperature and humidity controlled air; Negative control for SHS exposure
Experimental: Smokeless tobacco users; Will use 1 pouch of commercially available moist oral snuff and will chew gum (sham moist snuff). Each intervention will last 30 minutes, and each will take place one time, on one of 2 study visits, in random order.	Other: Moist snuff; Use moist snuff for 30 minutes; Other Names: commercially available moist oral snuff; Other: Sham Moist Snuff; Chew gum for 30 minutes; Other Names: Chewing gum; Negative control for moist oral snuff use
Experimental: e-cigarette users; Will use one electronic cigarette with 18 mg/ml nicotine, one electronic cigarette with no nicotine, and will perform sham smoking by puffing on a drinking straw. Each intervention will last 10 minutes, and each will take place one time, on one of 3 study visits, in random order.	Other: Sham Smoking; Sham smoking or e-cigarette use consists of puffing on a drinking straw for 10 minutes; Other: Electronic cigarette with 18 mg/ml nicotine; Use electronic cigarette with 18 mg/ml nicotine for 30 minutes; Other: Electronic Cigarette with no nicotine; Use electronic cigarette with no nicotine for 30 minutes

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Flow-mediated Dilation of the Brachial Artery	Vascular function as measured by Flow-mediated Dilation of the Brachial Artery	up to 3 hours after use of tobacco product

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart Rate Variability (HRV)	HRV refers to variation in the intervals between consecutive heart beats. Low HRV predicts poor prognosis and increased mortality in patients with cardiovascular disease and in apparently healthy subjects	up to 3 hours after use of product.

Other Outcome Measures

Outcome Measure	Time Frame
Clot strength and plasma levels of interleukin-6 (IL-6) and 8-isoprostane	up to 3 hours after use of product.

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: National Cancer Institute (NCI); Food and Drug Administration (FDA)
• Investigators: Principal Investigator: Peter Ganz, M.D., University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (Actual): November 3, 2013
• Primary Completion (Actual): May 31, 2021
• Study Completion (Actual): May 31, 2021

Study Registration Dates

• First Submitted: October 4, 2013
• First Submitted That Met QC Criteria: October 14, 2013
• First Posted (Estimate): October 17, 2013

Study Record Updates

• Last Update Posted (Actual): December 27, 2021
• Last Update Submitted That Met QC Criteria: December 17, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: tobacco; Cardiovascular; oxidative stress; smokeless tobacco; cigarettes; particles; FMD; electronic cigarettes; chewing tobacco; snus; SHS; secondhand cigarette smoke; vapor; flow-mediated dilation (FMD)
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Agents; Ganglionic Stimulants; Nicotinic Agonists; Cholinergic Agonists; Nicotine
• Other Study ID Numbers: P0052956; P50CA180890 (U.S. NIH Grant/Contract); 136316 (Other Identifier: University of California, San Francisco)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Information might be disclosed as part of study activities to the FDA

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes