Tobacco Smoking
Conditions
Brief summary
Varenicline is the most effective smoking cessation therapy available. Nevertheless, most smokers using varenicline relapse within the first few months after quitting. Varenicline is hypothesized to help smokers to quit in part by reducing the reinforcing effects of smoking during the standard 1-week pre-quitting treatment phase. Learning theory and previous human and animal research support the hypothesis that a longer period of varenicline treatment prior to the target quit date (TQD) will lead to greater reductions in smoking before quitting, and higher long-term cessation rates, compared to standard varenicline treatment. Building on promising preliminary clinical data, the study tests these hypotheses with a full-scale randomized clinical trial (RCT). 320 treatment-seeking smokers will be randomized to a standard run-in group (3 weeks of placebo, followed by the standard 1 week of pre-TQD varenicline) or an extended run-in group (4 weeks of pre-TQD varenicline). Both groups will receive brief individual cessation counseling and 11 weeks of post-TQD varenicline. The primary outcome measure will be bio-verified continuous abstinence at end-of-treatment (weeks 8-11 post-quit; cessation at 26-weeks post TQD will also be examined. Hypothesized mediating mechanisms (e.g., smoking reinforcement) will be evaluated by behavioral, physiological, and subjective measures assessed both in the lab and using real-world, real-time electronic momentary assessments (EMA). The investigators predict that long-term, bio-verified smoking cessation will be improved among the extended run-in group compared to the standard run-in group. The investigators further predict the improved clinical outcomes with extended run-in varenicline will be explained (or mediated) by greater pre-quit reductions in smoking reinforcement among the extended run-in group compared to the standard run-in group. The significance of this work is clear: The project aims to make best available treatment for smoking cessation even better, using a method that is ripe for dissemination and an approach that will elucidate critical mechanisms to target in the next generation of treatment enhancement.
Interventions
DRUGVarenicline
oral varenicline tablets
BEHAVIORALBrief smoking cessation counseling
\ 10-minute individual counseling at each of 6 clinic visits
Sponsors
National Cancer Institute (NCI)
Pfizer
State University of New York at Buffalo
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 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Smoking at least 10 cigarettes per day (CPD) for the past 6 months and expired-air carbon monoxide (CO) \>7 at intake. NOTE: To reduce exclusion of Black participants, the CPD criterion was reduced to 5 and the carbon monoxide criterion was eliminated in November, 2019. * At least moderately motivated to quit smoking and intention to make a quit attempt with varenicline 1 month after treatment begins. * Planning to remain in western New York (NY) during the study period * Willing to use varenicline and to refrain from other cessation treatments and tobacco products during the study period. * English speaker * To be intent-to-treat (ITT), the participant must complete Lab Visit 1 and meet minimal completion rate for real-world (EMA) assessments.
Exclusion criteria
* Use of other tobacco products, including e-cigarettes, in past 7 days * Use of smoking cessation medication, including nicotine replacement therapy, in the past 14 days * Prior allergy/hypersensitivity to varenicline * Pregnant or breast-feeding * Substance use: * Alcohol: AUDIT score \> 15 at intake, suggestive of alcohol dependence and warranting treatment; for those with scores between 8 and 15, the investigators will advise reducing drinking). * Medical treatment for substance use (SU) in past 3 months, including Suboxone (buprenorphine) and methadone (at phone screen) * Using a combination of the National Institute on Drug Abuse (NIDA) modified ASSIST (4-26 = moderate risk; 27+ = high risk) and urine toxicology screen (both at intake): * Cannabis: ASSIST=27+ (tox screen not used) * Cocaine: ASSIST=7+ OR positive tox screen * Methamphetamine: ASSIST=7+ OR positive tox screen * Inhalants, hallucinogens, sedatives, or sleeping pills: ASSIST score = 7+ * Prescription stimulants: With prescription, ASSIST 27+; Without prescription, ASSIST 7+ * Opioids: With prescription, ASSIST 27+ (note ineligible if prescription is for buprenorphine or methadone); Without prescription, ASSIST 7+ OR positive tox screen (Note: ASSIST 4+ modified to 7+ in 2018 to avoid excluding people with past SU problems. clinicaltrials.gov edited 12/18/18) * Psychiatric: * Antipsychotic medications * Lifetime history of schizophrenia or bipolar disorder * Evidence of current major depression (per Patient Health Questionnaire (PHQ-9) at intake * Past 10 years suicidal ideation (SI) / behavior. At intake, all of the following are exclusionary on the baseline Columbia-Suicide Severity Rating Scale (Posner et al., 2008): SI without intent (C-SSRS #1, #2, or #3), if any intensity rating (Frequency, Duration, Controllability, Deterrents, or Reasons for Ideation) is \> 2; SI with intent (C-SSRS #4, or #5), regardless of intensity ratings; Suicidal Behavior (any suicide attempt, interrupted attempt, aborted attempt, or suicide preparatory acts or behavior on the C-SSRS). * Any medical condition, illness, disorder or concomitant medication that compromises participant safety or treatment, as determined by the Principal Investigator and/or Study Physician. * Inability to provide informed consent or complete any of the study tasks as determined by the Principal Investigator and/or Study Physician.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Continuous Abstinence at End-of-Treatment (EOT) as Assessed by Self-Report and Bio-verification | Self-report Treatment Weeks 12-15; bio-verification ~Week 16 | Number of participants with bio-verified (cotinine level of 15 ng/mL or less) self-reported continuous abstinence from smoking (not even a puff) during the final four weeks of treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pre-quit Change in Cigarettes Smoked Per Day | Treatment Week 1 vs. Treatment Week 4 (final week before TQD) | Percent change in smoking behavior (self-reported cigarettes per day; CPD) from timeline follow-back (TLFB) interviews during the pre-quit phase of the study. |
| Number of Participants With Continuous Abstinence at 6-Month Follow-Up as Assessed by Self-Report and Bio-verification | Self-report Treatment Weeks 12-28; bio-verification ~Week 16 and ~Week 29 | Number of participants with continuous abstinence at the 6-month follow-up (no self-reported smoking during weeks 12-28 AND cotinine level 15 ng/mL or less at EOT and 6 month follow-up) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Extended Run-In \*\* 4 weeks of varenicline prior to the target quit date (TQD) \*\*
\+ 11 weeks of post-TQD varenicline
Standard varenicline dosing titration in initial week of therapy (one 0.5 mg tablet orally daily x 3 days, then one 0.5 mg tablet twice daily x 4 days); then 1 mg twice daily thereafter.
Brief individual counseling at clinic visits
Varenicline: oral varenicline tablets
Brief smoking cessation counseling: \
10-minute individual counseling at each of 6 clinic visits | 163 |
| Standard Run-In \*\* 3 weeks of placebo followed by 1 week of varenicline prior to the target quit date (TQD) \*\*
\+ 11 weeks of post-TQD varenicline
Standard varenicline dosing titration in initial week of therapy (one 0.5 mg tablet orally daily x 3 days, then one 0.5 mg tablet twice daily x 4 days); then 1 mg twice daily thereafter.
Brief individual counseling at clinic visits
Varenicline: oral varenicline tablets
Brief smoking cessation counseling: \
10-minute individual counseling at each of 6 clinic visits | 157 |
| Total | 320 |
Baseline characteristics
| Characteristic | Extended Run-In | Standard Run-In | Total |
|---|---|---|---|
| Age, Continuous | 53.8 years STANDARD_DEVIATION 10.3 | 53.5 years STANDARD_DEVIATION 10 | 53.7 years STANDARD_DEVIATION 10.1 |
| Cigarettes per day | 17.9 Cigarettes per day STANDARD_DEVIATION 7.2 | 18.4 Cigarettes per day STANDARD_DEVIATION 7.3 | 18.1 Cigarettes per day STANDARD_DEVIATION 7.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 4 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 159 Participants | 153 Participants | 312 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race American Indian / Alaska Native | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Black/African American | 33 Participants | 34 Participants | 67 Participants |
| Race/Ethnicity, Customized Race More than 1 race | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Other | 4 Participants | 3 Participants | 7 Participants |
| Race/Ethnicity, Customized Race Refused / prefer not to answer | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White/Caucasian | 122 Participants | 118 Participants | 240 Participants |
| Region of Enrollment United States | 163 participants | 157 participants | 320 participants |
| Salivary cotinine | 312 ng/mL STANDARD_DEVIATION 158 | 312 ng/mL STANDARD_DEVIATION 164 | 312 ng/mL STANDARD_DEVIATION 161 |
| Sex: Female, Male Female | 90 Participants | 89 Participants | 179 Participants |
| Sex: Female, Male Male | 73 Participants | 68 Participants | 141 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 163 | 0 / 157 | 0 / 157 | 0 / 147 | 0 / 150 | 0 / 146 |
| other Total, other adverse events | 125 / 163 | 121 / 157 | 131 / 157 | 104 / 147 | 116 / 150 | 104 / 146 |
| serious Total, serious adverse events | 0 / 163 | 0 / 157 | 1 / 157 | 0 / 147 | 2 / 150 | 2 / 146 |
Outcome results
Primary
Number of Participants With Continuous Abstinence at End-of-Treatment (EOT) as Assessed by Self-Report and Bio-verification
Number of participants with bio-verified (cotinine level of 15 ng/mL or less) self-reported continuous abstinence from smoking (not even a puff) during the final four weeks of treatment
Time frame: Self-report Treatment Weeks 12-15; bio-verification ~Week 16
Population: Intent-to-treat analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Extended Run-In | Number of Participants With Continuous Abstinence at End-of-Treatment (EOT) as Assessed by Self-Report and Bio-verification | 64 Participants |
| Standard Run-In | Number of Participants With Continuous Abstinence at End-of-Treatment (EOT) as Assessed by Self-Report and Bio-verification | 57 Participants |
Secondary
Number of Participants With Continuous Abstinence at 6-Month Follow-Up as Assessed by Self-Report and Bio-verification
Number of participants with continuous abstinence at the 6-month follow-up (no self-reported smoking during weeks 12-28 AND cotinine level 15 ng/mL or less at EOT and 6 month follow-up)
Time frame: Self-report Treatment Weeks 12-28; bio-verification ~Week 16 and ~Week 29
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Extended Run-In | Number of Participants With Continuous Abstinence at 6-Month Follow-Up as Assessed by Self-Report and Bio-verification | 37 Participants |
| Standard Run-In | Number of Participants With Continuous Abstinence at 6-Month Follow-Up as Assessed by Self-Report and Bio-verification | 29 Participants |
Secondary
Pre-quit Change in Cigarettes Smoked Per Day
Percent change in smoking behavior (self-reported cigarettes per day; CPD) from timeline follow-back (TLFB) interviews during the pre-quit phase of the study.
Time frame: Treatment Week 1 vs. Treatment Week 4 (final week before TQD)
Population: This analysis is not based on ITT, as only participants with complete TLFB data for Weeks 1 and 4 were included in the analysis; early in the trial, pre-quit TLFB was not consistently obtained due to staff error.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Extended Run-In | Pre-quit Change in Cigarettes Smoked Per Day | -38.8 percent change in CPD | Standard Error 2.7 |
| Standard Run-In | Pre-quit Change in Cigarettes Smoked Per Day | -17.5 percent change in CPD | Standard Error 2.8 |