Nicotine Dependence, Cigarettes
Conditions
Brief summary
This study will examine the effects of combining Varenicline (VRN) and N-acetylcysteine (NAC) on neural circuitry function and treating nicotine addiction. Healthy adult nicotine dependent cigarette smokers interested in quitting (n=110) will be randomized to one of four PBO-controlled conditions for 4 weeks: 1) VRN+NAC, 2) VRN+PBO, 3) NAC+PBO or 4) PBO+PBO. Following 1 week of medication, participants will be contingently reinforced for 3 days of smoking abstinence and be scanned using functional magnetic resonance imaging (fMRI) techniques, while nicotine deprived during a resting state and a cue-reactivity (CR) task. Participants will be followed over the next 3 weeks of treatment and clinical variables will be assessed.
Detailed description
Cigarette (henceforth nicotine) addiction is a chronic, relapsing brain disorder and remains the leading preventable cause of death and disability in the US, costing nearly $200 billion each year. Although \ 20% of adults in the USA currently smoke, the majority want to quit. In spite of the breadth of research focused on improving health outcomes and reducing the societal burden caused by nicotine addiction, the majority of smokers who attempt to quit will relapse. Nicotine withdrawal-related disturbances in executive function, negative affect and reward processes compel a smoker to self-administer nicotine-each in turn representing the loss of control to remain abstinent and risk factors for relapse. Thus, identifying the effects of nicotine addiction on mechanisms of self-regulation, and the value of novel medications for remediating dysregulated behavior are both needed in order to enhance interventions for treating nicotine addiction. The preliminary data, along with the extant literature, suggest that the maintenance of nicotine addiction is subserved by dysregulated neural function in limbic-striatal and corticostriatal neural circuitry. While VRN may be effective in treating limbic-striatal circuitry that is associated with promoting abstinence and reducing acute withdrawal; NAC may be effective in treating corticostriatal circuitry function that is associated with relapse vulnerability. Thus, the current proposal seeks to investigate two medications (VRN & NAC), with potentially complementary effects on the two different brain circuits- limbic-striatal (VRN) and corticostriatal (NAC) circuitry-and that may therapeutically target two different phases in the recovery of nicotine addiction-the promotion of abstinence (VRN) and relapse prevention (NAC). The placebo (PBO)-controlled design in this proposal will allow the team to identify and translate between the neurobiological substrates and the neurocognitive underpinnings of the effects of VRN+NAC on smoking behavior in humans-thus, advancing the understanding of the pathophysiology of nicotine addiction.
Interventions
DRUGVarenicline (VRN)
VRN will be provided at the standard recommended dose (0.5 mg daily for 3 days, then 0.5 mg twice daily for 4 days, then 1 mg twice daily thereafter for the remaining 21 days of active treatment.
DRUGN-Acetylcysteine (NAC)
NAC will be dosed at 1200 mg twice daily throughout the 28-day active treatment
DRUGPlacebo
Matched placebo
Sponsors
Medical University of South Carolina
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
HEALTH_SERVICES_RESEARCH
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Age 18 - 55 2. Right Handed 3. English fluency 4. 20/20 vision with corrective lenses. 5. Smoke ≥ 10 cigarettes/day for a minimum of two years and have an expired carbon monoxide (CO) concentration of ≥ 10 ppm (to confirm inhalation). 6. Interest in quitting smoking or contemplating a quit attempt in the next 6 months 7. If female, agreement to use birth control
Exclusion criteria
1. Past head injury or primary neurological disorder associated with MRI abnormalities, including dementia, MCI, brain tumors, epilepsy, Parkinson's disease, or demyelinating diseases 2. Any physical or intellectual disability affecting completion of assessments 3. Any contraindication to MRI 4. Positive urine drug screen for illicit substances (such as marijuana or cocaine). 5. Current or past psychosis 6. Electroconvulsive therapy in last 6 months 7. Use of antidepressant medications or other psychotropic medications in the last month. 8. Positive urine pregnancy test or current breast feeding status
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Blood Oxygen Level Dependent (BOLD) Signal Response | 10 Days | Measure the Effects of Varenicline and N-Acetylcysteine (NAC) on brain activation to smoking images while participants undergo Functional Magnetic Resonance (fMRI) Imaging. Mean percent signal change of fMRI BOLD in the insula and nucleus accumbens will be recorded during smoking images. The lower the BOLD signal response, the better the outcome, meaning reduced reactivity to smoking images. |
| rZ Change Score in Resting State Functional Connectivity From Baseline | Baseline to day 10 | Measure the effects of Varenicline and N-Acetylcysteine on resting-state functional connectivity while participants undergo fMRI. Fisher transformed correlation (rZ) scores will be recorded between medial prefrontal cortex and ventral striatum during a resting state scan. The higher the rZ score, the better the outcome, meaning stronger functional connectivity. rZ scores range from -1 to 1. The rZ-score central value is analogous to a central value to of a Z-score of 0, representing the population mean. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Cigarettes Smoked Per Day | 28 Days | Measure the effects of Varenicline and N-Acetylcysteine on smoking behavior over the course of the study |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| VRN+ NAC Titrated VRN up to 1mg BID with NAC at 1200mg BID for 28 days
Varenicline (VRN): VRN will be provided at the standard recommended dose (0.5 mg daily for 3 days, then 0.5 mg twice daily for 4 days, then 1 mg twice daily thereafter for the remaining 21 days of active treatment.
N-Acetylcysteine (NAC): NAC will be dosed at 1200 mg twice daily throughout the 28-day active treatment | 18 |
| NAC+ PBO 1200mg BID for 28 days plus VRN placebo for 28 days
N-Acetylcysteine (NAC): NAC will be dosed at 1200 mg twice daily throughout the 28-day active treatment
Placebo: Matched placebo | 15 |
| VRN+ PBO Titrated VRN up to 1mg BID with NAC placebo for 28 days
Varenicline (VRN): VRN will be provided at the standard recommended dose (0.5 mg daily for 3 days, then 0.5 mg twice daily for 4 days, then 1 mg twice daily thereafter for the remaining 21 days of active treatment.
Placebo: Matched placebo | 17 |
| PBO+PBO Double placebo taken for 28 days
Placebo: Matched placebo | 17 |
| Total | 67 |
Baseline characteristics
| Characteristic | VRN+ NAC | NAC+ PBO | VRN+ PBO | PBO+PBO | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 15 Participants | 17 Participants | 17 Participants | 67 Participants |
| Age, Continuous | 43.6 years STANDARD_DEVIATION 8.9 | 35.1 years STANDARD_DEVIATION 12.8 | 42.4 years STANDARD_DEVIATION 9.8 | 37.1 years STANDARD_DEVIATION 9.6 | 39.7 years STANDARD_DEVIATION 10.7 |
| Cigarettes Smoked Per Day | 16.8 Cigarettes Per Day STANDARD_DEVIATION 12.6 | 13.7 Cigarettes Per Day STANDARD_DEVIATION 10.4 | 17.3 Cigarettes Per Day STANDARD_DEVIATION 11.4 | 20.0 Cigarettes Per Day STANDARD_DEVIATION 19.2 | 17.3 Cigarettes Per Day STANDARD_DEVIATION 11.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 13 Participants | 16 Participants | 16 Participants | 63 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 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 | 6 Participants | 8 Participants | 3 Participants | 3 Participants | 20 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 3 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 | 12 Participants | 7 Participants | 12 Participants | 13 Participants | 44 Participants |
| Region of Enrollment United States | 18 participants | 15 participants | 17 participants | 17 participants | 67 participants |
| Sex: Female, Male Female | 8 Participants | 7 Participants | 8 Participants | 8 Participants | 31 Participants |
| Sex: Female, Male Male | 10 Participants | 8 Participants | 9 Participants | 9 Participants | 36 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 / 18 | 0 / 15 | 0 / 17 | 0 / 17 |
| other Total, other adverse events | 4 / 18 | 5 / 15 | 3 / 17 | 8 / 17 |
| serious Total, serious adverse events | 0 / 18 | 0 / 15 | 0 / 17 | 2 / 17 |
Outcome results
Primary
Percent Change in Blood Oxygen Level Dependent (BOLD) Signal Response
Measure the Effects of Varenicline and N-Acetylcysteine (NAC) on brain activation to smoking images while participants undergo Functional Magnetic Resonance (fMRI) Imaging. Mean percent signal change of fMRI BOLD in the insula and nucleus accumbens will be recorded during smoking images. The lower the BOLD signal response, the better the outcome, meaning reduced reactivity to smoking images.
Time frame: 10 Days
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| VRN+ NAC | Percent Change in Blood Oxygen Level Dependent (BOLD) Signal Response | Insula | -0.09 Percentage change |
| VRN+ NAC | Percent Change in Blood Oxygen Level Dependent (BOLD) Signal Response | Nucleus Accumbens | 0.11 Percentage change |
| NAC+ PBO | Percent Change in Blood Oxygen Level Dependent (BOLD) Signal Response | Nucleus Accumbens | 0.91 Percentage change |
| NAC+ PBO | Percent Change in Blood Oxygen Level Dependent (BOLD) Signal Response | Insula | 1.07 Percentage change |
| VRN+ PBO | Percent Change in Blood Oxygen Level Dependent (BOLD) Signal Response | Insula | 0.08 Percentage change |
| VRN+ PBO | Percent Change in Blood Oxygen Level Dependent (BOLD) Signal Response | Nucleus Accumbens | 0.12 Percentage change |
| PBO+PBO | Percent Change in Blood Oxygen Level Dependent (BOLD) Signal Response | Insula | 1.19 Percentage change |
| PBO+PBO | Percent Change in Blood Oxygen Level Dependent (BOLD) Signal Response | Nucleus Accumbens | 1.43 Percentage change |
Primary
rZ Change Score in Resting State Functional Connectivity From Baseline
Measure the effects of Varenicline and N-Acetylcysteine on resting-state functional connectivity while participants undergo fMRI. Fisher transformed correlation (rZ) scores will be recorded between medial prefrontal cortex and ventral striatum during a resting state scan. The higher the rZ score, the better the outcome, meaning stronger functional connectivity. rZ scores range from -1 to 1. The rZ-score central value is analogous to a central value to of a Z-score of 0, representing the population mean.
Time frame: Baseline to day 10
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| VRN+ NAC | rZ Change Score in Resting State Functional Connectivity From Baseline | .297 Fisher Z | Standard Error 0.053 |
| NAC+ PBO | rZ Change Score in Resting State Functional Connectivity From Baseline | .060 Fisher Z | Standard Error 0.042 |
| VRN+ PBO | rZ Change Score in Resting State Functional Connectivity From Baseline | .181 Fisher Z | Standard Error 0.053 |
| PBO+PBO | rZ Change Score in Resting State Functional Connectivity From Baseline | .191 Fisher Z | Standard Error 0.058 |
Secondary
Number of Cigarettes Smoked Per Day
Measure the effects of Varenicline and N-Acetylcysteine on smoking behavior over the course of the study
Time frame: 28 Days
Population: Analysis population consists of randomized participants that had data available at study day 7 or beyond.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VRN+ NAC | Number of Cigarettes Smoked Per Day | 5.3 Cigarettes per day | Standard Deviation 5.5 |
| NAC+ PBO | Number of Cigarettes Smoked Per Day | 4.0 Cigarettes per day | Standard Deviation 4.8 |
| VRN+ PBO | Number of Cigarettes Smoked Per Day | 5.3 Cigarettes per day | Standard Deviation 3.9 |
| PBO+PBO | Number of Cigarettes Smoked Per Day | 5.0 Cigarettes per day | Standard Deviation 4.5 |