Labeled Nornicotine in Smokeless Tobacco

Tobacco Toxicity Clinical Trial

Official title:

Nornicotine in Smokeless Tobacco as a Precursor for Carcinogen Exposure

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT02499198
• Other study ID #: 1502M63481
• Secondary ID: R01CA180880
• Status: Not yet recruiting
• Phase: Phase 1
• Start date: September 30, 2019
• Est. completion date: August 2022

Study information

• Verified date: April 2019
• Source: University of Minnesota - Clinical and Translational Science Institute
• Contact: Hanna Vanderloo, MSN
• Phone: 612-624-4983
• Email: hannav[@]umn.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Smokeless tobacco users who are unable or unwilling to quit tobacco use may be exposed to the potent oral and esophageal carcinogen NNN not only from tobacco itself, but also via its endogenous synthesis from nornicotine. The proposed study will lead to an understanding of the endogenous formation of NNN from nornicotine in humans, and will also investigate the effect of the reduction of nornicotine content in smokeless tobacco on the extent of endogenous NNN formation. The knowledge gained in this study will lead to the development of recommendations for the regulation, or potentially elimination, of nornicotine in smokeless tobacco products in order to minimize exposure to NNN in the users of these products.

Description:

The tobacco alkaloid nornicotine is a precursor to N'-nitrosonornicotine (NNN), a potent tobacco-specific carcinogen. NNN is believed to play an important role in the induction of esophageal and oral cavity cancers in tobacco users. Nornicotine contributes to NNN exposure in tobacco users in two ways. In addition to being a precursor to NNN formation in tobacco, it may also be nitrosated endogenously. Endogenous nitrosation of nornicotine that is present in tobacco products can occur in the oral cavity, in the stomach, or elsewhere in the body of tobacco users. This is particularly relevant to the use smokeless tobacco products - a form of tobacco that is kept in the oral cavity for prolonged periods of time, creating favorable conditions for nornicotine nitrosation. Given the high carcinogenic potency of NNN and the association of smokeless tobacco use with oral and esophageal cancers, regulation of nornicotine content in smokeless tobacco products is urgently needed. The Food and Drug Administration (FDA) has authority to regulate harmful and potentially harmful tobacco constituents under the Family Smoking Prevention and Tobacco Control Act. The information on the extent of endogenous nitrosation of nornicotine as a function of its content in smokeless products is crucial for the adequate regulation of this tobacco constituent by the FDA. Aims of this proposal are: (1) To determine the variation of nornicotine content in smokeless products currently marketed in the U.S. There is no information on nornicotine content in individual smokeless brands, and the extent of variation among the currently marketed U.S. products is unknown. Aim 1 will address this important gap and will also provide critical information for Aim 2 of this proposal. (2) To investigate the endogenous formation of NNN in smokeless tobacco users. Smokeless tobacco users will be randomized to a tobacco-free herbal snuff containing various amounts of stable isotope-labeled nornicotine added to it. Isotope-labeled urinary total NNN - a biomarker of exposure to NNN - will be measured in these subjects by using liquid chromatography-tandem mass-spectrometry. This methodology will allow for specific identification of urinary total NNN from endogenous nitrosation of nornicotine, versus that resulting from exposure to NNN in tobacco products. The effect of nornicotine reduction on the extent of endogenous NNN formation will be studied by gradually decreasing the amount of isotope-labeled nornicotine added to study snuff. The results of this study will provide extremely important new information on the endogenous formation of the carcinogenic nitrosamine NNN upon exposure to nornicotine from tobacco use. An understanding of this process is absolutely necessary for the adequate regulation of nornicotine in tobacco products with the purpose of minimizing public harm.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 150
• Est. completion date: August 2022
• Est. primary completion date: June 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

1. Adults who are regular smokeless tobacco users

2. Subjects are in good physical health and good general oral health;

3. Subjects are in stable, good mental health

Related Conditions & MeSH terms

• Tobacco Toxicity

Intervention

Drug:
• [D4]Nornicotine - Highest
Level equal to highest level of [D4]Nornicotine found in commercial tobacco based snuff

Other:
• [D4]Nornicotine - Mean
Level equal to mean level of [D4]Nornicotine found in commercial tobacco based snuff
• [D4]Nornicotine - Lowest
Level equal to lowest level of [D4]Nornicotine found in commercial tobacco based snuff
• [D4]Nornicotine - 50% Lowest
Level equal to 50% of the lowest level of [D4]Nornicotine found in commercial tobacco based snuff
• [D4]Nornicotine - 10% Lowest
Level equal to 10% of the lowest level of [D4]Nornicotine found in commercial tobacco based snuff
• [D4]Nornicotine - 5% Lowest
Level equal to 5% of the lowest level of [D4]Nornicotine found in commercial tobacco based snuff
• 13C6-NNN
0.5µg/g - below traditional levels found in moist snuff
• Herbal Snuff
A tobacco-free herbal snuff, such as Smokey Mountain or similar

Locations

Country	Name	City	State
United States	University of Minnesota	Minneapolis	Minnesota

Sponsors (2)

Lead Sponsor	Collaborator
University of Minnesota - Clinical and Translational Science Institute	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Endogenous formation of NNN in smokeless tobacco users after exposed to known amount of nornicotine using urine analysis	Urinary excretion daily for 1 day prior and 3 days after 30 minutes exposure, on 3 separate occasions, 20 days apart	baseline, 3 days, up to 20 days