Abuse Liability of Reduced Nicotine Content Cigarettes in the Context of Concurrent E-Cigarette Use (DUAL)

Three hundred-twenty (320) adult smokers of menthol or non-menthol combustible cigarettes will be recruited and randomly assigned to one of five groups (n=64/group), who will be asked to switch for 12 weeks to ad libitum use of combustible cigarettes (matched to subjects' menthol preference) containing either 0.4, 1.4, 2.5, 5.6 or 16.9 mg nicotine (standardized nicotine yields ranging from 0.02-0.80 mg/cigarette), respectively. Each group will include 32 heavy (≥ 20 cigarettes/day), and 32 light smokers (≤10 cigarettes/day), who are hypothesized to be more sensitive to nicotine's reinforcing effects. Participants will also have free access to nicotine-containing e-cigarettes (JUUL) throughout the 12-week period. Abuse liability of combustible cigarettes will be assessed by behavioral (cigarettes/day, time to first cigarettes), self-report (rewarding effects, withdrawal symptoms) and biochemical indices (expired air carbon monoxide, cotinine blood sampling).

In laboratory sessions, we will measure nicotine thresholds for detecting and recognizing the addictive, rewarding effects of smoking. This study is designed to help the FDA identify a target nicotine threshold that will not attract young people to smoking or induce relapse in former smokers. Additionally, we will determine the level of cigarette nicotine reduction that will be tolerated without inducing dissatisfaction in smokers, information that is relevant to the FDA for designing a stepwise nicotine reduction policy that can be implemented without widespread objections. The knowledge gained from this project will greatly increase our knowledge of nicotine addiction and will help frame an FDA policy relating to the regulation of the nicotine content of tobacco. Ultimately, a well-designed nicotine reduction policy has the potential to greatly reduce the enormous toll of death and disease caused by cigarette smoking.

Study Overview

• Status: Completed
• Conditions: Cigarette Smoking; Nicotine Addiction
• Intervention / Treatment: Drug: Smoking research cigarettes with e-cigarette; Drug: Nicotine discrimination thresholds

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Charlotte, North Carolina, United States, 28262
      • Rose Research Center
    • Raleigh, North Carolina, United States, 27617
      • Rose Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Subject is healthy as judged by the Investigator based on all available assessments from the Screening Period (e.g., safety laboratory, vital signs, physical examination, ECG, concomitant medications and medical history).
2. Subject smokes on average four days a week for the last 12 months.
3. Subject has no intention of quitting smoking within the next 90 days.
4. Owns a smart phone with text message and data capabilities.
5. Willingness to use and ability to operate e-cigarettes.
6. Willingness to smoke Research Cigarettes.

Exclusion Criteria:

1. Any medical or psychiatric condition (or associated symptoms or medications) determined by a medical professional to be severe enough to be disruptive to the study.
2. Severe or uncontrolled psychiatric disease with the exception of anxiety disorders, obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD);
3. Pregnant or nursing (by self-report) or positive pregnancy test;

4. Daily use of:

   1. Experimental (investigational) drugs that are unknown to subject;
   2. Smokeless tobacco (chewing tobacco, snuff), cigars, pipes and hookah;
   3. e-cigarettes;
5. Use in the past 30 days of nicotine replacement therapy or other smoking cessation product
6. Positive drug screen for cocaine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: 0.40mg Nicotine Cigarette w/ e-Cigarette; Participants will be assigned to smoke 0.40mg nicotine Spectrum cigarettes for 12 weeks with unlimited access to JUUL e-cigarettes. Smoking research cigarettes with e-cigarette	Drug: Smoking research cigarettes with e-cigarette; Smoking research cigarettes with varying levels of nicotine with unlimited access to 15 mg/ml nicotine-containing e-cigarettes.; Other Names: Spectrum Cigarettes; JUUL e-Cigarette
ACTIVE_COMPARATOR: 1.40mg Nicotine Cigarette w/ e-Cigarette; Participants will be assigned to smoke 1.40mg nicotine Spectrum cigarettes for 12 weeks with unlimited access to JUUL e-cigarettes. Smoking research cigarettes with e-cigarette	Drug: Smoking research cigarettes with e-cigarette; Smoking research cigarettes with varying levels of nicotine with unlimited access to 15 mg/ml nicotine-containing e-cigarettes.; Other Names: Spectrum Cigarettes; JUUL e-Cigarette
ACTIVE_COMPARATOR: 2.50mg Nicotine Cigarette w/ e-Cigarette; Participants will be assigned to smoke 2.50mg nicotine Spectrum cigarettes for 12 weeks with unlimited access to JUUL e-cigarettes. Smoking research cigarettes with e-cigarette	Drug: Smoking research cigarettes with e-cigarette; Smoking research cigarettes with varying levels of nicotine with unlimited access to 15 mg/ml nicotine-containing e-cigarettes.; Other Names: Spectrum Cigarettes; JUUL e-Cigarette
ACTIVE_COMPARATOR: 5.60mg Nicotine Cigarette w/ e-Cigarette; Participants will be assigned to smoke 5.60mg nicotine Spectrum cigarettes for 12 weeks with unlimited access to JUUL e-cigarettes. Smoking research cigarettes with e-cigarette	Drug: Smoking research cigarettes with e-cigarette; Smoking research cigarettes with varying levels of nicotine with unlimited access to 15 mg/ml nicotine-containing e-cigarettes.; Other Names: Spectrum Cigarettes; JUUL e-Cigarette
ACTIVE_COMPARATOR: 16.9mg Nicotine Cigarette w/ e-Cigarette; Participants will be assigned to smoke 16.9mg nicotine Spectrum cigarettes for 12 weeks with unlimited access to JUUL e-cigarettes. Smoking research cigarettes with e-cigarette	Drug: Smoking research cigarettes with e-cigarette; Smoking research cigarettes with varying levels of nicotine with unlimited access to 15 mg/ml nicotine-containing e-cigarettes.; Other Names: Spectrum Cigarettes; JUUL e-Cigarette
EXPERIMENTAL: Halo G6 & Tribeca e-liquid; Difference detection assessments. Nicotine discrimination thresholds	Drug: Nicotine discrimination thresholds; Measure of nicotine thresholds for detecting and recognizing the addictive, rewarding effects of smoking.; Other Names: Halo G6 with Tribeca e-liquid
EXPERIMENTAL: Spectrum Research Cigarette; Difference detection assessments. Nicotine discrimination thresholds	Drug: Nicotine discrimination thresholds; Measure of nicotine thresholds for detecting and recognizing the addictive, rewarding effects of smoking.; Other Names: Halo G6 with Tribeca e-liquid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Expired air CO Measurement	To determine the effects of cigarette nicotine content manipulations on abuse liability as measured by exhaled breath CO.	12 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nicotine discrimination tests to determine nicotine detection thresholds	Results of the laboratory discrimination tests will be analyzed descriptively to determine nicotine detection thresholds. Thresholds will be calculated based on both group-averaged data as well as by using the best estimates of individual thresholds calculated from each smoker's data. Group averaged data will be determined by graphically plotting the overall percent correct against nicotine concentration.	Weeks 1, 2,8,10,12 and 14
Nicotine discrimination tests to determine nicotine recognition thresholds	Results of the laboratory discrimination tests will be analyzed descriptively to determine nicotine recognition thresholds. Thresholds will be calculated based on both group-averaged data as well as by using the best estimates of individual thresholds calculated from each smoker's data. Group averaged data will be determined by graphically plotting the overall percent correct against nicotine concentration.	Weeks 1, 2,8,10,12 and 14
Extent of e-cigarette use based on self-report	To determine whether the abuse liability of combustible cigarettes is related to the nicotine intake from e-cigarettes or to total nicotine intake, regression analyses will be conducted to correlate indices of abuse liability to levels of cotinine as well as to the estimated intake of nicotine from cigarettes and e-cigarettes based on self-reported values.	12 Weeks
Extent of e-cigarette use based on self-report cotinine levels	To determine whether the abuse liability of combustible cigarettes is related to the nicotine intake from e-cigarettes or to total nicotine intake, regression analyses will be conducted to correlate indices of abuse liability to levels of cotinine as well as to the estimated intake of nicotine from cigarettes and e-cigarettes.	12 Weeks
Mean number of research cigarettes smoked per day as primary index of abuse liability	To assess the effects of cigarette nicotine content on abuse liability among smokers who also use e-cigarettes. The primary index of abuse liability will be mean number of research cigarettes smoked per day. Secondary outcome measures comprise expired air carbon monoxide (CO), Fagerström Test for Nicotine Dependence (FTND) score, withdrawal symptoms and cognitive performance.	12 Weeks

Collaborators and Investigators

• Sponsor: Rose Research Center, LLC
• Collaborators: National Institute on Drug Abuse (NIDA); National Institutes of Health (NIH); Food and Drug Administration (FDA)
• Investigators: Principal Investigator: Jed E Rose, Ph.D., Rose Research Center, LLC

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 1, 2019
• Primary Completion (ACTUAL): July 28, 2021
• Study Completion (ACTUAL): July 28, 2021

Study Registration Dates

• First Submitted: August 10, 2016
• First Submitted That Met QC Criteria: August 12, 2016
• First Posted (ESTIMATE): August 17, 2016

Study Record Updates

• Last Update Posted (ACTUAL): January 14, 2022
• Last Update Submitted That Met QC Criteria: January 12, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Tobacco Use Disorder; 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: 201602820; GRANT12052089 (OTHER: Grants.gov); 5R01DA042541-03 (NIH)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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