Smoking Cessation, Tobacco Use Disorder
Conditions
Keywords
smoking cessation, varenicline, deep rTMS, insula, addiction, tobacco use disorder
Brief summary
The purpose of this study is to investigate the effect of deep repetitive transcranial magnetic stimulation (rTMS) using the insula H-coil on smoking outcomes in smokers receiving varenicline. It is hypothesized that active deep rTMS will improve abstinence rates, attenuate craving and reduce cigarette consumption and dependence severity.
Detailed description
This study will be a randomized, double-blind, sham-controlled clinical trial. Nicotine dependent participants will be recruited and randomized tor receive either active or sham rTMS intervention for 4 weeks (5 sessions/week). All participants will receive an open-label treatment of varenicline for 12 weeks and weekly counselling sessions. The aims of the study are: 1. To examine the efficacy of bilateral deep rTMS to the insula on point prevalence smoking abstinence in smokers receiving varenicline treatment. 2. To examine the efficacy of bilateral deep rTMS to the insula on other smoking outcomes such as craving, cigarette smoking and dependence severity. 3. To examine the effect of bilateral deep rTMS to the insula on abstinence at the end of rTMS treatment and at 6-month follow up. Abstinence will be measured by point prevalence at week 4 and 12 and prolonged continuous abstinence at week 26. This will be confirmed using plasma cotinine levels. All other measures will be done using various questionnaires such as Fagerstrom Test of Nicotine Dependence (FTND), Timeline Follow-Back (TLFB), Minnesota Nicotine Withdrawal Scale (MNWS), and Tiffany Questionnaire of Smoking Urges (T-QSU).
Interventions
DEVICEDeep Repetitive Transcranial Magnetic Stimulation (Active)
Active deep rTMS (10 Hz) using the H-coil to target the bilateral insula
DEVICEDeep Repetitive Transcranial Magnetic Stimulation (Sham)
Sham deep rTMS using the H-coil. The sham coil is built into the same helmet as the active coil. It mimics the active coil with regards to acoustics and scalp sensations.
DRUGVarenicline
12 week course treatment of varenicline (0.5 mg/1 mg) using the standard dosage schedule for smoking cessation (Day 1-3: 0.5 mg daily; day 4-7: 0.5 mg twice a day; day 8-end of treatment: 1 mg twice a day).
Sponsors
Pfizer
Brainsway
Centre for Addiction and Mental Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Age 18-65; * Nicotine dependent as assessed by Diagnostic and Statistical Manual of Mental Disorders (DSM-V); * Reported daily cigarette consumption ≥ 10 and expired carbon monoxide (CO) measurement of ≥ 10 ppm; * Fagerstrom Test of Nicotine Dependence (FTND) ≥ 4; * Reported motivation to quit within 30 days as assessed using the Contemplation Ladder score of ≥ 7.
Exclusion criteria
* Reported smoking abstinence in the 3 months preceding screening visit; * Current use of other smoking cessation aids; * Allergy and/or contraindication to varenicline or rTMS; * Pregnancy, trying to become pregnant or breastfeeding; * Current or recent history of cardiovascular or cerebrovascular disease and/or current hypertension; * Current or historical evidence of suicidal behavior; * Serious current or personal history of medical condition/disease (neurological disorders, brain lesions, multiple sclerosis, head trauma, loss of consciousness, hearing loss, etc.); * Current, personal history or family history of seizures; * Cognitive impairment as defined as a Mini Mental State Examination (MMSE) score \<24; * Concomitant use of medication that lowers seizure threshold
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Point Prevalence Abstinence at the End of 12 Weeks | 12 weeks | Measured by self-report of smoking abstinence in the past 7 days and confirmed using plasma cotinine measurement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Expired CO Measurements | 26 weeks | This will be used as a biological confirmation of recent smoking. |
| Cigarettes Per Day (TLFB) | 26 weeks | Self-reported measure of cigarette consumption. |
| Minnesota Nicotine Withdrawal Scale (MNWS) Score | 26 weeks | This will be used to assess withdrawal symptoms. It is an 8 item scale and total scores range from 0 to 24. A higher score indicates more severe nicotine withdrawal. |
| Tiffany Questionnaire for Smoking Urges (T-QSU) Score | 26 weeks | This will be used to assess symptoms of craving/urges for tobacco. It is a 32 item scale and total scores range from 0 to 224. A higher score indicates more severe smoking craving/urges. |
| Fagerstrom Test For Nicotine Dependence (FTND) Score | 26 weeks | This will be used to assess physical dependence severity in participants. It is a 6 item scale and total scores can range from 0-10. A higher score indicates more severe nicotine dependence. |
| Prolonged Abstinence From End of Treatment (Week 12) to End of Follow up (Week 26) | 26 weeks | Measured by self-report of smoking abstinence since the last visit and confirmed using plasma cotinine measurement. |
| Prolonged Abstinence With 2-week Grace Period at End of Follow up (Week 26) | 26 weeks | Measured by self-report of smoking abstinence since the last visit and confirmed using plasma cotinine measurement. |
| Continuous Abstinence at 6 Months | 26 weeks | Measured by self-report of smoking abstinence since the last visit and confirmed using plasma cotinine measurement. |
| Point Prevalence Abstinence at the End of 4 Weeks | 4 weeks | Measured by self-report of smoking abstinence in the past 7 days and confirmed using plasma cotinine measurement. |
Countries
Canada
Participant flow
Pre-assignment details
50 participants were enrolled, however, 8 of them were lost to follow up before randomization and therefore were not assigned to any group.
Participants by arm
| Arm | Count |
|---|---|
| Deep rTMS Active + Varenicline Participants undergoing deep rTMS (active) for 4 weeks (5 sessions/week) along with 12 weeks of varenicline.
Deep Repetitive Transcranial Magnetic Stimulation (Active): Active deep rTMS (10 Hz) using the H-coil to target the bilateral insula
Varenicline: 12 week course treatment of varenicline (0.5 mg/1 mg) using the standard dosage schedule for smoking cessation (Day 1-3: 0.5 mg daily; day 4-7: 0.5 mg twice a day; day 8-end of treatment: 1 mg twice a day). | 24 |
| Deep rTMS Sham + Varenicline Participants undergoing deep rTMS (sham) for 4 weeks (5 sessions/week) along with 12 weeks of varenicline.
Deep Repetitive Transcranial Magnetic Stimulation (Sham): Sham deep rTMS using the H-coil. The sham coil is built into the same helmet as the active coil. It mimics the active coil with regards to acoustics and scalp sensations.
Varenicline: 12 week course treatment of varenicline (0.5 mg/1 mg) using the standard dosage schedule for smoking cessation (Day 1-3: 0.5 mg daily; day 4-7: 0.5 mg twice a day; day 8-end of treatment: 1 mg twice a day). | 18 |
| Total | 42 |
Baseline characteristics
| Characteristic | Deep rTMS Active + Varenicline | Total | Deep rTMS Sham + Varenicline |
|---|---|---|---|
| Age, Continuous | 43.8 years STANDARD_DEVIATION 12.5 | 44.8 years STANDARD_DEVIATION 13.16 | 46.2 years STANDARD_DEVIATION 12.9 |
| Alcoholic Drinks/day | 1.1 Drinks/day STANDARD_DEVIATION 1.7 | 1.2 Drinks/day STANDARD_DEVIATION 1.6 | 1.3 Drinks/day STANDARD_DEVIATION 1.6 |
| Cigarettes/day | 16.9 Cigarettes/day STANDARD_DEVIATION 5.3 | 18.0 Cigarettes/day STANDARD_DEVIATION 4.8 | 19.4 Cigarettes/day STANDARD_DEVIATION 1.3 |
| CO Measurement | 24.7 ppm STANDARD_DEVIATION 13.9 | 24.5 ppm STANDARD_DEVIATION 11.9 | 24.3 ppm STANDARD_DEVIATION 11.3 |
| Education Level College/University/Grad School | 15 Participants | 31 Participants | 16 Participants |
| Education Level Highschool | 8 Participants | 9 Participants | 1 Participants |
| Education Level Less than grade 8 | 1 Participants | 2 Participants | 1 Participants |
| Education Years | 14.8 years STANDARD_DEVIATION 3.6 | 14.7 years STANDARD_DEVIATION 3.05 | 14.5 years STANDARD_DEVIATION 2.8 |
| Employment Status Employed | 15 Participants | 26 Participants | 11 Participants |
| Employment Status Retired | 3 Participants | 5 Participants | 2 Participants |
| Employment Status Unemployed | 6 Participants | 11 Participants | 5 Participants |
| Fagerström Test for Nicotine Dependence | 5.6 Score out of 10 STANDARD_DEVIATION 1.5 | 5.9 Score out of 10 STANDARD_DEVIATION 1.47 | 6.3 Score out of 10 STANDARD_DEVIATION 1.4 |
| Housing Apartment | 15 Participants | 26 Participants | 11 Participants |
| Housing Condo | 2 Participants | 2 Participants | 0 Participants |
| Housing House | 7 Participants | 14 Participants | 7 Participants |
| Income <19,999 | 7 Participants | 9 Participants | 2 Participants |
| Income 20,000-49,999 | 9 Participants | 19 Participants | 10 Participants |
| Income 50,000-74,999 | 4 Participants | 8 Participants | 4 Participants |
| Income >75,000 | 4 Participants | 6 Participants | 2 Participants |
| Marital Status Married/Common Law | 6 Participants | 11 Participants | 5 Participants |
| Marital Status Never Married | 12 Participants | 21 Participants | 9 Participants |
| Marital Status Separated/Divorced/Annulled | 6 Participants | 10 Participants | 4 Participants |
| Mini-mental state examination | 28.5 Score out of 30 STANDARD_DEVIATION 1.5 | 28.5 Score out of 30 STANDARD_DEVIATION 1.4 | 28.4 Score out of 30 STANDARD_DEVIATION 1.5 |
| Nicotine Metabolite Ratio | 0.50 Ratio 0-1 STANDARD_DEVIATION 0.3 | 0.52 Ratio 0-1 STANDARD_DEVIATION 0.25 | 0.55 Ratio 0-1 STANDARD_DEVIATION 0.22 |
| Race/Ethnicity, Customized Asian | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized More than one race | 3 Participants | 5 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 19 Participants | 32 Participants | 13 Participants |
| Sex: Female, Male Female | 4 Participants | 12 Participants | 8 Participants |
| Sex: Female, Male Male | 20 Participants | 30 Participants | 10 Participants |
| Smoking Contemplation Ladder | 9 Score out of 10 STANDARD_DEVIATION 1 | 9 Score out of 10 STANDARD_DEVIATION 1 | 9 Score out of 10 STANDARD_DEVIATION 1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 18 |
| other Total, other adverse events | 15 / 24 | 11 / 18 |
| serious Total, serious adverse events | 0 / 24 | 0 / 18 |
Outcome results
Primary
Point Prevalence Abstinence at the End of 12 Weeks
Measured by self-report of smoking abstinence in the past 7 days and confirmed using plasma cotinine measurement.
Time frame: 12 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Deep rTMS Active + Varenicline | Point Prevalence Abstinence at the End of 12 Weeks | Abstinent | 12 Participants |
| Deep rTMS Active + Varenicline | Point Prevalence Abstinence at the End of 12 Weeks | Non-abstinent | 5 Participants |
| Deep rTMS Sham + Varenicline | Point Prevalence Abstinence at the End of 12 Weeks | Abstinent | 6 Participants |
| Deep rTMS Sham + Varenicline | Point Prevalence Abstinence at the End of 12 Weeks | Non-abstinent | 9 Participants |
Secondary
Cigarettes Per Day (TLFB)
Self-reported measure of cigarette consumption.
Time frame: 26 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Deep rTMS Active + Varenicline | Cigarettes Per Day (TLFB) | 3.877 cigarettes/day | Standard Error 1.179 |
| Deep rTMS Sham + Varenicline | Cigarettes Per Day (TLFB) | 4.29 cigarettes/day | Standard Error 1.265 |
p-value: 0.98Mixed Models Analysis
Secondary
Continuous Abstinence at 6 Months
Measured by self-report of smoking abstinence since the last visit and confirmed using plasma cotinine measurement.
Time frame: 26 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Deep rTMS Active + Varenicline | Continuous Abstinence at 6 Months | Abstinent | 5 Participants |
| Deep rTMS Active + Varenicline | Continuous Abstinence at 6 Months | Non-abstinent | 11 Participants |
| Deep rTMS Sham + Varenicline | Continuous Abstinence at 6 Months | Abstinent | 4 Participants |
| Deep rTMS Sham + Varenicline | Continuous Abstinence at 6 Months | Non-abstinent | 11 Participants |
Secondary
Expired CO Measurements
This will be used as a biological confirmation of recent smoking.
Time frame: 26 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Deep rTMS Active + Varenicline | Expired CO Measurements | 8.457 ppm | Standard Error 2.5 |
| Deep rTMS Sham + Varenicline | Expired CO Measurements | 8.124 ppm | Standard Error 2.624 |
p-value: 0.76Mixed Models Analysis
Secondary
Fagerstrom Test For Nicotine Dependence (FTND) Score
This will be used to assess physical dependence severity in participants. It is a 6 item scale and total scores can range from 0-10. A higher score indicates more severe nicotine dependence.
Time frame: 26 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Deep rTMS Active + Varenicline | Fagerstrom Test For Nicotine Dependence (FTND) Score | 0.636 score on a scale | Standard Error 0.447 |
| Deep rTMS Sham + Varenicline | Fagerstrom Test For Nicotine Dependence (FTND) Score | 1.468 score on a scale | Standard Error 0.47 |
p-value: 0.98Mixed Models Analysis
Secondary
Minnesota Nicotine Withdrawal Scale (MNWS) Score
This will be used to assess withdrawal symptoms. It is an 8 item scale and total scores range from 0 to 24. A higher score indicates more severe nicotine withdrawal.
Time frame: 26 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Deep rTMS Active + Varenicline | Minnesota Nicotine Withdrawal Scale (MNWS) Score | 8.291 score on a scale | Standard Error 1.922 |
| Deep rTMS Sham + Varenicline | Minnesota Nicotine Withdrawal Scale (MNWS) Score | 9.372 score on a scale | Standard Error 2.107 |
p-value: 0.24Mixed Models Analysis
Secondary
Point Prevalence Abstinence at the End of 4 Weeks
Measured by self-report of smoking abstinence in the past 7 days and confirmed using plasma cotinine measurement.
Time frame: 4 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Deep rTMS Active + Varenicline | Point Prevalence Abstinence at the End of 4 Weeks | Abstinent | 11 Participants |
| Deep rTMS Active + Varenicline | Point Prevalence Abstinence at the End of 4 Weeks | Non-abstinent | 7 Participants |
| Deep rTMS Sham + Varenicline | Point Prevalence Abstinence at the End of 4 Weeks | Abstinent | 9 Participants |
| Deep rTMS Sham + Varenicline | Point Prevalence Abstinence at the End of 4 Weeks | Non-abstinent | 7 Participants |
Secondary
Prolonged Abstinence From End of Treatment (Week 12) to End of Follow up (Week 26)
Measured by self-report of smoking abstinence since the last visit and confirmed using plasma cotinine measurement.
Time frame: 26 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Deep rTMS Active + Varenicline | Prolonged Abstinence From End of Treatment (Week 12) to End of Follow up (Week 26) | Abstinent | 5 Participants |
| Deep rTMS Active + Varenicline | Prolonged Abstinence From End of Treatment (Week 12) to End of Follow up (Week 26) | Non-abstinent | 11 Participants |
| Deep rTMS Sham + Varenicline | Prolonged Abstinence From End of Treatment (Week 12) to End of Follow up (Week 26) | Abstinent | 4 Participants |
| Deep rTMS Sham + Varenicline | Prolonged Abstinence From End of Treatment (Week 12) to End of Follow up (Week 26) | Non-abstinent | 11 Participants |
Secondary
Prolonged Abstinence With 2-week Grace Period at End of Follow up (Week 26)
Measured by self-report of smoking abstinence since the last visit and confirmed using plasma cotinine measurement.
Time frame: 26 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Deep rTMS Active + Varenicline | Prolonged Abstinence With 2-week Grace Period at End of Follow up (Week 26) | Abstinent | 5 Participants |
| Deep rTMS Active + Varenicline | Prolonged Abstinence With 2-week Grace Period at End of Follow up (Week 26) | Non-abstinent | 11 Participants |
| Deep rTMS Sham + Varenicline | Prolonged Abstinence With 2-week Grace Period at End of Follow up (Week 26) | Abstinent | 4 Participants |
| Deep rTMS Sham + Varenicline | Prolonged Abstinence With 2-week Grace Period at End of Follow up (Week 26) | Non-abstinent | 11 Participants |
Secondary
Tiffany Questionnaire for Smoking Urges (T-QSU) Score
This will be used to assess symptoms of craving/urges for tobacco. It is a 32 item scale and total scores range from 0 to 224. A higher score indicates more severe smoking craving/urges.
Time frame: 26 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Deep rTMS Active + Varenicline | Tiffany Questionnaire for Smoking Urges (T-QSU) Score | 61.683 score on a scale | Standard Error 9.624 |
| Deep rTMS Sham + Varenicline | Tiffany Questionnaire for Smoking Urges (T-QSU) Score | 73.236 score on a scale | Standard Error 10.311 |
p-value: 0.26Mixed Models Analysis