Nicotine Dependence, Cigarettes, Uncomplicated
Conditions
Brief summary
Adolescents are an important vulnerable population to consider as the FDA moves toward a nicotine reduction policy. Such a policy, which would mandate a reduction of nicotine in all commercially available cigarettes, has the potential to transform public health and greatly reduce the toll of tobacco-related death and disease. Yet, data on the effects of such a policy on cigarette use among adolescents are lacking. Further, the advent of e-cigarettes and the popularity of alternative tobacco products have fundamentally altered the current landscape of nicotine delivery, and these products are widely used by adolescents. Although adolescent cigarette use is at an all-time low in the U.S., this reduction has been mirrored by an increase in e-cigarette use, and multiple tobacco product (MTP) use is the most common pattern of use in youth. Adolescent MTP users are more likely to be dependent on nicotine and to have begun using tobacco earlier than their single-product using peers. Thus, MTP-using youth differ from youth who solely smoke cigarettes in meaningful ways that have implications for responses to a nicotine reduction regulatory policy. In adults, longer-term studies have demonstrated that very low nicotine content (VLNC) cigarette exposure results in fewer cigarettes smoked and reduced toxicant exposure; however, increased use of alternative tobacco products has also been reported. No studies to date have examined the effects of VLNC cigarettes on MTP use or toxicant exposure in youth. This study will use real-time, smartphone-based ecological momentary assessment (EMA) and laboratory-based assessments to: (1) investigate the effects of cigarette nicotine reduction on cigarette and MTP use, (2) assess the influence of cigarette nicotine reduction on the harms associated with tobacco use, including nicotine and toxicant exposure, respiratory symptoms, perceived health risk and nicotine dependence, and (3) use a combination of laboratory and real-time assessment to investigate the effects of nicotine reduction on changes in withdrawal, craving, and the reinforcing efficacy of cigarettes to characterize the mechanisms by which VLNC use may affect behavior. Overall, this project will help determine the effects of VLNC cigarettes on real-world tobacco use behavior and indices of tobacco-related harm in adolescents, and examining the mechanisms through which nicotine reduction in cigarettes may effect such changes.
Interventions
Very Low Nicotine Content Cigarettes
Normal Nicotine Content Cigarettes
Sponsors
National Institute on Drug Abuse (NIDA)
Brown University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
15 Years to 20 Years
Healthy volunteers
Yes
Inclusion criteria
* 1\) Ages 15-20 inclusive 2) Male and female current daily smokers 1. Defined as self-reported daily cigarette smoking at phone screening AND 2. a breath carbon monoxide (CO) criterion of 5 ppm or higher; if this is not met, urine cotinine levels, detected by a NicAlert cotinine screening device, must indicate recent smoking (level 3 or higher) 3) Current users of alternative tobacco product(s) a. Defined as any self-reported use of at least one non-cigarette tobacco product (e.g., e-cigarettes, little cigars, cigarillos, hookah, etc.) in the past 30 days 4) Participants must speak and comprehend English well enough to complete study procedures. a. Participant will be asked to read aloud first few lines of informed consent and then summarize the contents aloud to check for competency 5) Participants under 18 must provide assent and parental consent from a parent/guardian. a. Participants age 18 or 19 may provide their own written consent contingent on photo ID verification of age.
Exclusion criteria
* 1\) Unwilling to use research cigarettes as part of the study 2) Self-reported daily drinking of alcohol or use of illicit or non-prescribed drugs (excluding marijuana) \> 10 days in the past 30 days a. We will ask about daily alcohol and drug use in the phone screen, and we will use the Timeline Follow-Back to assess current and recent marijuana and alcohol use. 3\) Currently seeking treatment to quit smoking, and/or intending to quit smoking for good in the next 30 days 1. This information corresponds to questions 2 & 3 of the Stages of Change measure which will be administered at the in-person screening. 2. These participants will be excluded, and provided with referral information for cessation services in the community. 4\) Suicidal ideation in the past month or any past-year suicide attempts a. Suicidal ideation determined by the MINI ( Mini International Neuropsychiatric Interview) suicide subscale at the in-person screening (Questions 4 and 5) b. Suicide attempt in the past year determined by MINI question 6.a. (If participant has a lifetime history of suicide attempt between 1 and 10 years ago, licensed medical monitor approval required) c. If a participant indicates that he/she currently has suicidal ideation during this or any future session, the Emergency Protocol will be followed in which a Licensed Clinician will be contacted immediately, and participants will speak with the clinician over the phone and the clinician will determine the appropriate action to take to keep the child safe. 5\) Pregnant or breastfeeding a. Determined by urine test at in-person screening; tested again at each in-person visit; participant will be excluded or withdrawn if test indicates pregnancy b. Self-reports current breastfeeding at in-person screening 6) Any medical or psychiatric conditions in which participation is likely to pose a significant threat to health or for which the condition could interfere with the ability of the participant to fully participate (as determined by LMP). 7\) Having participated in another research study during the past year in which they were switched to research cigarettes for longer than one week.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Average Cigarettes Smoked Per Day | Week 4 | Average number of cigarettes (study and non-study) smoked in the past week prior to the final session. |
| Average Number of Days of Combustible and Noncombustible Use | Week 4 | Average number of days of combustible and noncombustible use. This measure is a sum of the days of combustible use (out of 7 days) and noncombustible use (out of 7 days) recorded in the week prior to week 4, averaged over 14 days. As this measure is a sum of the two variables, its possible range is 0-14. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Amount of Noncombustible Alternative Product Use | Week 4 | Number of days of noncombustible tobacco product use in the past 7 days prior to week 4 |
| Average Study Cigarettes Per Day | Week 4 | Average number of study cigarettes smoked per day across 7 days prior to week 4 |
| Toxicant Exposure | Week 4 | Total Nicotine Equivalents (TNEs) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Subjective Response to Cigarettes | Baseline-Week 4 | Cigarette Evaluation Scale post-smoking in the laboratory; 5 subscales are derived from this scale: Psychological Reward, Smoking Satisfaction, Enjoyment of Respiratory Sensations, Craving Reduction; Aversion. Event level on satisfaction derived from post-use responses on daily Ecological Momentary Assessments. |
| American Thoracic Society Questionnaire | Baseline-Week 4 | Respiratory Health Symptoms; an 8-item questionnaire measuring frequency of experience respiratory symptoms; scores can range from 8 to 40 and greater scores indicate greater frequency. |
| Hypothetical Purchasing of Tobacco Products | Baseline-Week 4 | Purchasing of cigarettes and other tobacco products across changing prices in Experimental Tobacco Marketplace task |
| Hypothetical Purchasing of Cigarettes | Baseline-Week 4 | Cigarette Purchase Task; Five indices of demand for cigarettes are derived from this measure (Intensity, Omax, Breakpoint, Pmax, Alpha) |
| Perceived Health Risk Questionnaire | Week 4 | Perceived risk for developing diseases associated with use study cigarettes and usual brand cigarettes; Scores range from 1 (much less risk) to 5 (much greater risk) for each disease |
| Nicotine Dependence | Baseline-Week 4 | Modified Fagerstrom Tolerance Questionnaire (mFTQ) score; Scale 2-8, higher scores indicate greater nicotine dependence |
| Craving | Baseline-Week 4 | Questionnaire on Smoking Urges (QSU) post- smoking in the laboratory, a 10 item scale that is comprised of 2 factors; Factor 1 included items 1, 3, 6, 7, and 10 Factor 2 included items 2, 4, 5, 8, and 9 The score for each factor is calculated by summing the item scores; the total score is calculated by summing all 10 items. A single-item craving question (ranging from 1-10, not all to greatly) from daily random and post-event Ecological Momentary Assessments. |
| Withdrawal | Baseline-Week 4 | Minnesota Nicotine Withdrawal Scale 7-item version; greater score indicates greater withdrawal |
Countries
United States
Participant flow
Pre-assignment details
Participants were consented at Screening/Baseline 1 (N=57). Those who remained eligible and interested were randomized at Baseline 2 (N=49). Participant flow was documented for randomized participants.
Participants by arm
| Arm | Count |
|---|---|
| Normal Nicotine Content Cigarettes Normal Nicotine Content Cigarettes:15.8 mg/g nicotine per cigarette | 25 |
| Very Low Nicotine Content Cigarettes Very Low Nicotine Content Cigarettes: 0.4 mg/g nicotine per cigarette | 24 |
| Total | 49 |
Baseline characteristics
| Characteristic | Normal Nicotine Content Cigarettes | Very Low Nicotine Content Cigarettes | Total |
|---|---|---|---|
| Age, Continuous | 18.72 years STANDARD_DEVIATION 0.73 | 19.08 years STANDARD_DEVIATION 0.88 | 18.90 years STANDARD_DEVIATION 0.82 |
| Baseline Number of Other Tobacco Use Days in Past 30 | 4.32 Days in past 30 days STANDARD_DEVIATION 5.7 | 5.7 Days in past 30 days STANDARD_DEVIATION 3.5 | 5.0 Days in past 30 days STANDARD_DEVIATION 3.61 |
| Carbon Monoxide | 10.4 parts per million STANDARD_DEVIATION 9.6 | 11.5 parts per million STANDARD_DEVIATION 11.7 | 11.02 parts per million STANDARD_DEVIATION 10.6 |
| Cigarettes per day | 6.3 Cigarettes smoked per day STANDARD_DEVIATION 4.4 | 7.6 Cigarettes smoked per day STANDARD_DEVIATION 7.4 | 6.9 Cigarettes smoked per day STANDARD_DEVIATION 6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 5 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 15 Participants | 17 Participants | 32 Participants |
| Region of Enrollment United States | 25 participants | 24 participants | 49 participants |
| Sex/Gender, Customized Female | 8 Participants | 13 Participants | 21 Participants |
| Sex/Gender, Customized Male | 13 Participants | 9 Participants | 22 Participants |
| Sex/Gender, Customized Transgender, genderqueer, or other identity not listed | 4 Participants | 2 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 25 |
| other Total, other adverse events | 0 / 24 | 0 / 25 |
| serious Total, serious adverse events | 0 / 24 | 0 / 25 |
Outcome results
Primary
Average Cigarettes Smoked Per Day
Average number of cigarettes (study and non-study) smoked in the past week prior to the final session.
Time frame: Week 4
Population: Participants who completed week 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Nicotine Content Cigarettes | Average Cigarettes Smoked Per Day | 4.3 average cigarettes per day | Standard Deviation 2.6 |
| Very Low Nicotine Content Cigarettes | Average Cigarettes Smoked Per Day | 8.0 average cigarettes per day | Standard Deviation 10.33 |
Comparison: These are results of a 2-group (VLNC \& NNC) x 2 repeated measures (Baseline \& Week 4) mixed effects model to test the effect of the randomization group (VLNC vs. NNC) on change in cigarette use and alternative tobacco product (ATP) use from Baseline to Week 4. Group (VLNC vs. NNC) is a fixed, between-subjects focal predictor. Timepoint (Baseline vs. Week 4) is a fixed, within-subjects repeated measure. Subject is a random effect, accounting for variability in Baseline cigarette and ATP use.p-value: 0.11195% CI: [0.92, 2.19]Mixed Models Analysis
Primary
Average Number of Days of Combustible and Noncombustible Use
Average number of days of combustible and noncombustible use. This measure is a sum of the days of combustible use (out of 7 days) and noncombustible use (out of 7 days) recorded in the week prior to week 4, averaged over 14 days. As this measure is a sum of the two variables, its possible range is 0-14.
Time frame: Week 4
Population: Those who completed Week 4 are included in the outcome means.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Nicotine Content Cigarettes | Average Number of Days of Combustible and Noncombustible Use | 4.80 days | Standard Deviation 3.12 |
| Very Low Nicotine Content Cigarettes | Average Number of Days of Combustible and Noncombustible Use | 5.17 days | Standard Deviation 3.87 |
Comparison: This outcome was recoded as a dichotomous outcome with a binary distribution and log link. The focal test is the difference in change from Baseline to Week 4 (i.e., Time) in the VLNC vs. NNC condition (i.e., Group), which is a cross-level interactive effect of Time and Group.p-value: 0.72195% CI: [0.11, 4.75]Mixed Models Analysis
Secondary
Amount of Noncombustible Alternative Product Use
Number of days of noncombustible tobacco product use in the past 7 days prior to week 4
Time frame: Week 4
Population: Those who completed week 4.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Nicotine Content Cigarettes | Amount of Noncombustible Alternative Product Use | 4.76 average days | Standard Deviation 3.11 |
| Very Low Nicotine Content Cigarettes | Amount of Noncombustible Alternative Product Use | 4.29 average days | Standard Deviation 3.4 |
p-value: 0.56495% CI: [0.08, 3.99]Mixed Models Analysis
Secondary
Average Study Cigarettes Per Day
Average number of study cigarettes smoked per day across 7 days prior to week 4
Time frame: Week 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Nicotine Content Cigarettes | Average Study Cigarettes Per Day | 3.32 average cigarettes per day | Standard Deviation 2.86 |
| Very Low Nicotine Content Cigarettes | Average Study Cigarettes Per Day | 4.98 average cigarettes per day | Standard Deviation 5.92 |
Comparison: The study cigarette outcome is modeled with a normal, Gaussian distribution. The focal test is the difference in change from Baseline to Week 4 (i.e., Time) in the VLNC vs. NNC condition (i.e., Group), which is a cross-level interactive effect of Time and Group. Baseline in this analysis is average number of usual brand cigarettes at baseline, prior to randomization.p-value: 0.87695% CI: [-2.92, 3.42]Mixed Models Analysis
Secondary
Toxicant Exposure
Total Nicotine Equivalents (TNEs)
Time frame: Week 4
Population: All participants who provided urine data at Week 4, and for whom there were analyzable levels of TNEs.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Nicotine Content Cigarettes | Toxicant Exposure | 3875.395 ng/ml | Standard Deviation 4700.761 |
| Very Low Nicotine Content Cigarettes | Toxicant Exposure | 6284.507 ng/ml | Standard Deviation 6641.2956 |
p-value: 0.22695% CI: [-5743.04, 1409.47]Mixed Models Analysis
Other Pre-specified
American Thoracic Society Questionnaire
Respiratory Health Symptoms; an 8-item questionnaire measuring frequency of experience respiratory symptoms; scores can range from 8 to 40 and greater scores indicate greater frequency.
Time frame: Baseline-Week 4
Other Pre-specified
Craving
Questionnaire on Smoking Urges (QSU) post- smoking in the laboratory, a 10 item scale that is comprised of 2 factors; Factor 1 included items 1, 3, 6, 7, and 10 Factor 2 included items 2, 4, 5, 8, and 9 The score for each factor is calculated by summing the item scores; the total score is calculated by summing all 10 items. A single-item craving question (ranging from 1-10, not all to greatly) from daily random and post-event Ecological Momentary Assessments.
Time frame: Baseline-Week 4
Other Pre-specified
Hypothetical Purchasing of Cigarettes
Cigarette Purchase Task; Five indices of demand for cigarettes are derived from this measure (Intensity, Omax, Breakpoint, Pmax, Alpha)
Time frame: Baseline-Week 4
Other Pre-specified
Hypothetical Purchasing of Tobacco Products
Purchasing of cigarettes and other tobacco products across changing prices in Experimental Tobacco Marketplace task
Time frame: Baseline-Week 4
Other Pre-specified
Nicotine Dependence
Modified Fagerstrom Tolerance Questionnaire (mFTQ) score; Scale 2-8, higher scores indicate greater nicotine dependence
Time frame: Baseline-Week 4
Other Pre-specified
Perceived Health Risk Questionnaire
Perceived risk for developing diseases associated with use study cigarettes and usual brand cigarettes; Scores range from 1 (much less risk) to 5 (much greater risk) for each disease
Time frame: Week 4
Other Pre-specified
Subjective Response to Cigarettes
Cigarette Evaluation Scale post-smoking in the laboratory; 5 subscales are derived from this scale: Psychological Reward, Smoking Satisfaction, Enjoyment of Respiratory Sensations, Craving Reduction; Aversion. Event level on satisfaction derived from post-use responses on daily Ecological Momentary Assessments.
Time frame: Baseline-Week 4
Other Pre-specified
Withdrawal
Minnesota Nicotine Withdrawal Scale 7-item version; greater score indicates greater withdrawal
Time frame: Baseline-Week 4