Tobacco Dependence
Conditions
Brief summary
This study aims to determine the health effects of very low nicotine content in cigarettes, in conjunction with the availability of nicotine-containing electronic cigarettes (e-cigs) among smokers with mental health conditions (SMHC).
Detailed description
The specific objective of this study is to recruit a cohort of 240 current exclusive daily SMHC (diagnosed using the MINI International Neuropsychiatric Interview) and to measure a comprehensive battery of behavioral and health indicators at 4, 8, 12 and 16 weeks after being randomized to use either normal nicotine content (NNC) Spectrum cigarettes (11.6 mg nicotine/cigarette) or very low nicotine content (VLNC) Spectrum cigarettes (0.2 mg nicotine/cigarette) while also having access to an electronic cigarette (containing either 0 nicotine or high nicotine e-liquid) in a randomized double-blind, placebo-controlled, 2 by 2 design. All participants will be followed up with a study visit 4 weeks after the final randomized visit to identify whether they have continued to use e-cigs/cigarettes and to assess their motivation in smoking abstinence. Our central hypothesis is that key markers of harms to health (e.g. urinary NNAL, exhaled carbon monoxide, measures of addiction, and mental distress) will be significantly improved among SMHC who are provided VLNC cigarettes and high nicotine e-cigs.
Interventions
OTHERNormal Nicotine Content research cigarettes
Research cigarettes with 11.6 mg nicotine/cigarette.
OTHERHigh Nicotine e-cigarette
E-cigarette containing high nicotine e-liquid
OTHERVery Low Nicotine Content research cigarettes
Research cigarettes with 0.2 mg nicotine/cigarette.
OTHERZero Nicotine e-cigarette
E-cigarette containing zero nicotine e-liquid
Sponsors
National Institute on Drug Abuse (NIDA)
Milton S. Hershey Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Intervention model description
2 X 2 factorial design
Eligibility
Sex/Gender
ALL
Age
21 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Smoke \>5 cigarettes per day for at least the prior 12 months * Smoke regular, filtered cigarettes or machine-rolled cigarettes with a filter * Exhaled CO measurement of ≥ 6 parts per million at baseline * No serious cigarette smoking quit attempt or use of any FDA-approved smoking cessation medication in the prior 30 days (includes any nicotine replacement, varenicline, bupropion \[used specifically as a quitting aid\]) * No plans to quit smoking within the next 3 weeks * Must be willing to both switch to a different type of cigarette that may contain a different amount of nicotine and to try an e-cig to substitute for some of their cigarettes * Must be willing and able to respond to contacts from study staff or attend visits over the study period (not planning to move, not planning extended vacation, no planned surgeries) * 9\. Must meet lifetime diagnostic criteria for a current or lifetime unipolar or bipolar mood disorder (e.g. major depressive disorder, major depressive episode, manic episode, hypomanic episode, bipolar disorder), an anxiety disorder (e.g. panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, , agoraphobia, social anxiety disorder, generalized anxiety disorder), a psychotic disorder (e.g. mood disorder or other psychotic disorder), or an eating disorder (e.g. anorexia or bulimia) based on the MINI-International Neuropsychiatric Interview Standard (MINI) (version 7.0.2) * Able to read and write in English * Able to understand and give informed consent * Access to a computer/smartphone with e-mail and a reliable internet connection
Exclusion criteria
* Women who are pregnant and/or nursing or trying to become pregnant * Unstable or significant medical condition in the past 3 months (e.g., recent heart attack or other serious heart condition, stroke, severe angina, high blood pressure \[systolic \>159 mmHg or diastolic \>99 mmHg during screening) * Respiratory diseases (e.g., exacerbations of asthma or COPD, require oxygen, require oral prednisone), kidney (e.g., dialysis) or liver disease (e.g., cirrhosis), severe immune system disorders (e.g., uncontrolled HIV/AIDS, multiple sclerosis symptoms) or any medical disorder/medication that may affect participant safety or biomarker data * Uncontrolled mental illness or substance abuse, or inpatient treatment for these in the past 6 months * Current suicide risk on clinical assessment (above low risk score (or ≥ 9) on MINI diagnostic interview suicide module during screening (34)) * Use of any non-cigarette nicotine delivery product (e.g., pipe, cigar, dip, chew, snus, hookah, e-cig, strips or sticks, IQOS) in the past 7 days at screening * Use of an e-cig for 5 or more days in the past 28 days or any use in the past 7 days at screening * Use of marijuana or other illegal drugs/prescription drugs for non-medical use daily/almost daily or weekly in the past 3 months per NIDA Quick Screen * Any known allergy to propylene glycol or vegetable glycerin * Surgery requiring general anesthesia in the past 6 weeks * Unwilling to remain on one flavor of cigarette (regular or menthol) for the duration of the trial * Previous use of SPECTRUM research cigarettes in the past 6 months * Other member of household currently participating in the study * History of a seizure disorder or had a seizure in the past 12 months * Currently taking or have taken medications prescribed to prevent seizures (such as Carbamazepine or Phenobarbital). Using seizure medications for off-label use (indications other than treatment for seizures) will not be included as an exclusion, these will be assessed on a case-by-case basis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Urinary NNAL (4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol) | Week 16 | Measure of tobacco-specific nitrosamine |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Exhaled Carbon Monoxide | Week 16 | Measure of cigarette smoke exposure |
| Kessler-6 Score | Week 16 | Measure of serious psychological distress. This scale is a brief, self-report tool used to assess psychological distress. Scores range from 0-24, with higher scores indicating greater distress |
| Penn State Cigarette Dependence Index | Week 16 | Measure of cigarette dependence. This 10-item scale (with scores ranging from 0 to 20) was developed to measure cigarette dependence, where a score of 0 indicates no cigarette dependence and 20 indicates maximum cigarette dependence. |
| Penn State Electronic Cigarette Dependence Index | Week 16 | Measure of e-cigarette dependence. This 10-item scale (with scores ranging from 0 to 20) was developed to measure e-cigarette dependence, where a score of 0 indicates no cigarette dependence and 20 indicates maximum e-cigarette dependence. |
| Cigarette Abstinence | Week 20 | No cigarette use in the past 7 days and exhaled carbon monoxide \< 6ppm |
Countries
United States
Participant flow
Pre-assignment details
88 participants consented and enrolled in the pre-randomization phase of the study. Eight participants were lost to follow-up or withdrawn from the study before being randomized to a study intervention. Therefore, 80 participants were randomized to a study intervention.
Participants by arm
| Arm | Count |
|---|---|
| NNC Cigarettes + High Nicotine Containing E-cigarette Participants are provided with normal nicotine content (NNC) cigarettes (11.6 mg nicotine/cigarette) plus e-cigarette with high nicotine e-liquid.
Normal Nicotine Content research cigarettes: Research cigarettes with 11.6 mg nicotine/cigarette.
High Nicotine e-cigarette: E-cigarette containing high nicotine e-liquid | 20 |
| NNC Cigarettes + Zero Nicotine Containing E-cigarette Participants are provided with normal nicotine content (NNC) cigarettes (11.6 mg nicotine/cigarette) plus e-cigarette with zero nicotine e-liquid.
Normal Nicotine Content research cigarettes: Research cigarettes with 11.6 mg nicotine/cigarette.
Zero Nicotine e-cigarette: E-cigarette containing zero nicotine e-liquid | 20 |
| VLNC Cigarettes + High Nicotine Containing E-cigarette Participants are provided with very low nicotine content (VLNC) cigarettes (0.2 mg nicotine/cigarette) plus e-cigarette with high nicotine e-liquid.
High Nicotine e-cigarette: E-cigarette containing high nicotine e-liquid
Very Low Nicotine Content research cigarettes: Research cigarettes with 0.2 mg nicotine/cigarette. | 20 |
| VLNC Cigarettes + Zero Nicotine Containing E-cigarette Participants are provided with very low nicotine content (VLNC) cigarettes (0.2 mg nicotine/cigarette) plus e-cigarette with zero nicotine e-liquid
Very Low Nicotine Content research cigarettes: Research cigarettes with 0.2 mg nicotine/cigarette.
Zero Nicotine e-cigarette: E-cigarette containing zero nicotine e-liquid | 20 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Randomization Period | Lost to Follow-up | 2 | 3 | 4 | 4 |
| Randomization Period | PI decision | 0 | 1 | 0 | 0 |
| Randomization Period | Withdrawal by Subject | 1 | 3 | 3 | 3 |
Baseline characteristics
| Characteristic | Total | NNC Cigarettes + High Nicotine Containing E-cigarette | NNC Cigarettes + Zero Nicotine Containing E-cigarette | VLNC Cigarettes + High Nicotine Containing E-cigarette | VLNC Cigarettes + Zero Nicotine Containing E-cigarette |
|---|---|---|---|---|---|
| Age, Continuous | 46.9 years STANDARD_DEVIATION 10.5 | 43.9 years STANDARD_DEVIATION 9.2 | 51.2 years STANDARD_DEVIATION 10.4 | 44.6 years STANDARD_DEVIATION 9 | 47.8 years STANDARD_DEVIATION 12.1 |
| Cigarettes per day | 20.2 cigarettes per day STANDARD_DEVIATION 10.1 | 22 cigarettes per day STANDARD_DEVIATION 11.7 | 18.8 cigarettes per day STANDARD_DEVIATION 9.9 | 22.4 cigarettes per day STANDARD_DEVIATION 8.6 | 17.6 cigarettes per day STANDARD_DEVIATION 9.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 1 Participants | 2 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 71 Participants | 18 Participants | 17 Participants | 18 Participants | 18 Participants |
| Region of Enrollment United States | 80 participants | 20 participants | 20 participants | 20 participants | 20 participants |
| Sex: Female, Male Female | 60 Participants | 18 Participants | 12 Participants | 18 Participants | 12 Participants |
| Sex: Female, Male Male | 20 Participants | 2 Participants | 8 Participants | 2 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 7 / 20 | 11 / 20 | 6 / 20 | 8 / 20 |
| serious Total, serious adverse events | 4 / 20 | 4 / 20 | 2 / 20 | 1 / 20 |
Outcome results
Primary
Urinary NNAL (4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol)
Measure of tobacco-specific nitrosamine
Time frame: Week 16
Population: The Overall Number of Participants Analyzed includes participants with non-missing values at Week 16. Therefore, in one of the groups, 20 people were randomized and 13 people completed the randomization phase, but only 12 of the samples could be analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NNC Cigarettes + High Nicotine Containing E-cigarette | Urinary NNAL (4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol) | 505.6 pg/mg creatinine | Standard Deviation 432.7 |
| NNC Cigarettes + Zero Nicotine Containing E-cigarette | Urinary NNAL (4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol) | 459.1 pg/mg creatinine | Standard Deviation 312.8 |
| VLNC Cigarettes + High Nicotine Containing E-cigarette | Urinary NNAL (4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol) | 373.3 pg/mg creatinine | Standard Deviation 553.1 |
| VLNC Cigarettes + Zero Nicotine Containing E-cigarette | Urinary NNAL (4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol) | 180.5 pg/mg creatinine | Standard Deviation 218.2 |
p-value: 0.017Kruskal-Wallis
Secondary
Cigarette Abstinence
No cigarette use in the past 7 days and exhaled carbon monoxide \< 6ppm
Time frame: Week 20
Population: This is an intent-to-treat analysis so everyone who was randomized was included in the sample analyzed, regardless of whether they completed the Week 20 assessment. Those who did not complete the Week 20 assessment were assumed to be non-abstainers. This is normal practice in smoking cessation research.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NNC Cigarettes + High Nicotine Containing E-cigarette | Cigarette Abstinence | 1 Participants |
| NNC Cigarettes + Zero Nicotine Containing E-cigarette | Cigarette Abstinence | 1 Participants |
| VLNC Cigarettes + High Nicotine Containing E-cigarette | Cigarette Abstinence | 4 Participants |
| VLNC Cigarettes + Zero Nicotine Containing E-cigarette | Cigarette Abstinence | 4 Participants |
p-value: 0.289Fisher Exact
Secondary
Exhaled Carbon Monoxide
Measure of cigarette smoke exposure
Time frame: Week 16
Population: The Overall Number of Participants Analyzed includes participants with non-missing values at Week 16. In two of the groups, 1 person had missing CO values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NNC Cigarettes + High Nicotine Containing E-cigarette | Exhaled Carbon Monoxide | 23.6 parts per million | Standard Deviation 9.4 |
| NNC Cigarettes + Zero Nicotine Containing E-cigarette | Exhaled Carbon Monoxide | 25.2 parts per million | Standard Deviation 14.6 |
| VLNC Cigarettes + High Nicotine Containing E-cigarette | Exhaled Carbon Monoxide | 21.9 parts per million | Standard Deviation 24.5 |
| VLNC Cigarettes + Zero Nicotine Containing E-cigarette | Exhaled Carbon Monoxide | 12.6 parts per million | Standard Deviation 10.3 |
p-value: 0.056Kruskal-Wallis
Secondary
Kessler-6 Score
Measure of serious psychological distress. This scale is a brief, self-report tool used to assess psychological distress. Scores range from 0-24, with higher scores indicating greater distress
Time frame: Week 16
Population: The Overall Number of Participants Analyzed includes all participants with non-missing values at Week 16. In the VLNC cigarettes + High Nicotine Containing E-cigarette group, two participants did not complete the entire Week 16 visit, but they did complete the Kessler-6 survey for Week 16. Therefore, their Kessler-6 survey data are included in this analysis even though they were not included in the final sample size for Week 16, resulting in a sample size of n=15 for this group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NNC Cigarettes + High Nicotine Containing E-cigarette | Kessler-6 Score | 6.9 score on a scale | Standard Deviation 5.9 |
| NNC Cigarettes + Zero Nicotine Containing E-cigarette | Kessler-6 Score | 5.7 score on a scale | Standard Deviation 5.1 |
| VLNC Cigarettes + High Nicotine Containing E-cigarette | Kessler-6 Score | 5.4 score on a scale | Standard Deviation 5.9 |
| VLNC Cigarettes + Zero Nicotine Containing E-cigarette | Kessler-6 Score | 5.9 score on a scale | Standard Deviation 4.3 |
p-value: 0.74Kruskal-Wallis
Secondary
Penn State Cigarette Dependence Index
Measure of cigarette dependence. This 10-item scale (with scores ranging from 0 to 20) was developed to measure cigarette dependence, where a score of 0 indicates no cigarette dependence and 20 indicates maximum cigarette dependence.
Time frame: Week 16
Population: The Overall Number of Participants Analyzed includes everyone with non-missing values at Week 16. In the VLNC cig+High Nic E-cig group, 1 person did not complete the entire Week 16 visit, but they did complete the Cig Dep survey for Week 16. Therefore, their Cig Dep survey data are included in this analysis, even though they were not included in the final sample size for Week 16, resulting in a sample size of n=14 for this group. 1 person had missing data in the VLNC cig+Zero Nic E-cig.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NNC Cigarettes + High Nicotine Containing E-cigarette | Penn State Cigarette Dependence Index | 11.9 score on a scale | Standard Deviation 3 |
| NNC Cigarettes + Zero Nicotine Containing E-cigarette | Penn State Cigarette Dependence Index | 11.5 score on a scale | Standard Deviation 2.9 |
| VLNC Cigarettes + High Nicotine Containing E-cigarette | Penn State Cigarette Dependence Index | 11.8 score on a scale | Standard Deviation 4.3 |
| VLNC Cigarettes + Zero Nicotine Containing E-cigarette | Penn State Cigarette Dependence Index | 9.4 score on a scale | Standard Deviation 3.2 |
p-value: 0.248Kruskal-Wallis
Secondary
Penn State Electronic Cigarette Dependence Index
Measure of e-cigarette dependence. This 10-item scale (with scores ranging from 0 to 20) was developed to measure e-cigarette dependence, where a score of 0 indicates no cigarette dependence and 20 indicates maximum e-cigarette dependence.
Time frame: Week 16
Population: The Overall Number of Participants Analyzed includes everyone with non-missing values at Week 16. In the VLNC cig+High Nic E-cig group, 1 person did not complete the entire Week 16 visit, but they did complete the E-cig Dep survey for Week 16. Therefore, their E-cig Dep survey data are included in this analysis, even though they were not included in the final sample size for Week 16, resulting in a sample size of n=14 for this group. 2 people had missing data in the VLNC cig+0 Nic E-cig group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NNC Cigarettes + High Nicotine Containing E-cigarette | Penn State Electronic Cigarette Dependence Index | 3.1 score on a scale | Standard Deviation 3 |
| NNC Cigarettes + Zero Nicotine Containing E-cigarette | Penn State Electronic Cigarette Dependence Index | 5.8 score on a scale | Standard Deviation 3.8 |
| VLNC Cigarettes + High Nicotine Containing E-cigarette | Penn State Electronic Cigarette Dependence Index | 8.1 score on a scale | Standard Deviation 5.2 |
| VLNC Cigarettes + Zero Nicotine Containing E-cigarette | Penn State Electronic Cigarette Dependence Index | 5.8 score on a scale | Standard Deviation 4.1 |
p-value: 0.025Kruskal-Wallis