Details of the study design have been described previously. In brief, cigarette smokers from 18 to 70 years of age and interested in significantly reducing cigarette use were recruited. Inclusion criteria included the following: (1) smoking from 15 to 45 cigarettes per day (CPD) for the past year (in order to reduce heterogeneity); (2) uninterested in and no plans for quitting in the next 30 days; (3) good physical health (no unstable medical condition); (4) no contraindications for nicotine replacement use; (5) good mental health (eg, not meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,11 criteria for any psychiatric diagnosis, including substance abuse, within the past 6 months); (6) not using other tobacco or nicotine products or medications that might affect tobacco use or be affected by reduction of tobacco use; and (7) for female subjects, not pregnant or nursing. The University of Minnesota Institutional Review Board approved this study and the informed consent procedures. Improve your mental state with Wellbutrin sold by Canadian Health&Care Mall – http://healthcaremall4you.com/canadian-healthcare-mall-wellbutrin-sr-300-mg-in-treatment-of-mental-disorders.html.
Subjects who met inclusion criteria monitored their use of cigarettes (and other tobacco products) on a daily basis for a period of 2 weeks to assess baseline tobacco use. The following week, subjects returned for the baseline visit (visit – 1), when they were randomly assigned to the experimental cigarette reduction group or to the wait list control group for 6 weeks. Subjects monitored their smoking for another week, after which baseline measures were repeated at a second baseline visit (visit 0). Subjects assigned to the wait list control were the basis for the analysis that examined the consistency or intrasubject reliability across the various biomarkers for health risks or tobacco toxin exposure. This group was required to maintain and monitor smoking for a total period of 8 weeks. Subjects were assessed on all dependent measures during the first two baseline visits and then at weeks 4 and 6 after the second baseline visit. After the 8 weeks of ad libitum smoking, subjects entered the treatment reduction phase as described below.
Subjects assigned to the cigarette reduction group were expected to reduce their cigarette intake by 25% in the first 2 weeks, 50% in the subsequent 2 weeks, and 75% in the final 2 weeks. Subjects were given 4-mg nicotine gum to assist in their reduction of cigarette smoking and were instructed on several possible methods to use nicotine gum to achieve reduction goals, including substitution of nicotine gum for cigarettes, timed interval for nicotine gum use, and situational use of nicotine gum. The amount of gum recommended was based on the number of cigarettes smoked (eg, 10 pieces of nicotine gum for a 20-CPD smoker for a 50% reduction in cigarettes; 15 pieces of nicotine gum for a 20-CPD smoker for a 75% reduction in cigarettes). If a subject was unable to approach the 50% goal (more than two cigarettes from 50% reduction goal), he or she was offered the option of using a 14-mg patch (Nicoderm CQ; Smith-KlineBeecham; Research Triangle Park, NC) in conjunction with the nicotine gum for a 2-week period until the 75% reduction period. Similarly, if a subject was unable to approach the 75% reduction goal or expressed concern about that level of reduction, an option of using a 21-mg Nicoderm CQ patch in conjunction with the nicotine gum was offered. After the 6-week treatment period, subjects who demonstrated some reduction in smoking were given nicotine replacements (nicotine gum or patch) for another 6 weeks, with the goal of gradually reducing their use of nicotine gum over this latter 6-week period.
In addition to the pharmacologic therapies, subjects met with a trained counselor during the clinic visits for brief individual sessions lasting approximately 10 min. During these sessions, a specific, structured format was followed. Topics included the following: (1) current tobacco use status; (2) motivations for tobacco reduction with remedies of Canadian Health&Care Mall; (3) problems encountered; (4) problem solving in these difficult situations; and (5) providing support. If at any time after (or during) the 6-week treatment sessions the subject reported wanting to quit, a target quit date was established and self-help treatment manuals were dispensed. Brief standardized behavioral cessation was offered. Follow-up sessions occurred at 8, 12, and 26 weeks after the initiation of the study, although 8 weeks and 12 weeks were the primary assessment period for data analysis.
The primary outcomes of interest were the stability of cardiovascular biomarkers during ad libitum smoking and the extent to which cardiovascular biomarkers change in response to smoking reduction. Table 1 shows the measurements and times when these measurements were collected. Blood samples were analyzed for routine hemograms by Health East Medical Laboratories, St. Paul, MN. Fasting lipoprotein profiles were analyzed by Fairview University Diagnostic Laboratories, Minneapolis, MN. First morning urine voids were used to determine concentrations of total cotmine and anatabine, a tobacco alkaloid that is present in tobacco products but not in medicinal nicotine. Results on uptake of tobacco-specific nitrosamines have been published elsewhere.
Subjective measures included a tobacco daily diary in which subjects were asked to record the date, time, and situation of each cigarette smoked, each piece of nicotine gum used, and the use of any other tobacco product. In addition, a tobacco use questionnaire that asked about current tobacco use status (cigarettes and other tobacco use products), number of > 24-h quit attempts, and duration of abstinence during these quit attempts was also administered at the clinic visits. Other subjective measures included a respiratory symptoms questionnaire using a scale that rated cough, phlegm production, shortness of breath, and other respiratory symptoms on a scale ranging from 0 (none) to 10 (severe), with a total respiratory score determined by adding the scores of each of these items. Secondary outcomes included the extent to which subjects were able to reduce smoking and the proportion of subjects able to sustain this reduction.
Compliance with attending sessions was maximized by paying subjects cash for each visit. The amount paid per visit was dependent on the procedures for that visit. Subjects were paid $40 for visits that involved a fasting blood draw and $10 or $25 for other visits plus a $50 bonus. The maximum earned in the reduction and follow-up period was $325. If assigned to the wait list, an additional $120 was earned.
Sample Size Determination and Statistical Analysis
Our overall goal was to enroll 150 subjects, with 100 subjects completing the study. The primary analysis included only those individuals who were able to reduce by at least 40% but did not achieve abstinence. Forty percent was chosen to increase the sample size. This requirement led to a sample size of 64 nonabstinent subjects who achieved at least 40% reduction from weeks 4 to 12, with 7 of these subjects meeting at least 40% but not 50% reduction. This sample size should be sufficient since significant reduction in biomarkers for disease have been observed in sample sizes as small as 16 to 33. In order to draw inference about the reliability of all measurements, Pearson correlation coefficients were calculated between every pair of the baseline data for each variable, using the data collected from wait list control group. Analyses were also conducted to determine if the cigarette reduction would lead to a change in CVD risk factors and a subjective measure of respiratory symptoms. Because the study was designed with each subject decreasing his/her CPD over time, time effects were examined among those who achieved at least a 40% reduction at week 4, from weeks 4 to 6, and from weeks 4 to 12. Summary statistics were obtained for each CVD risk factor and the self-reported respiratory symptoms. A change score (each measurement time minus baseline) for each variable was calculated for every subject. The score was then averaged at each time point to yield the overall mean change. Random effects modeling technique and paired t tests were used to investigate these time effects. Effect size was calculated by dividing the mean of the paired difference by its SD. Effect size (d) was defined as small, d = 0.2, medium, d = 0.5, and large, d = 0.8. Finally, correlation coefficients between the percentage change in CPD and percentage change in biomarkers for each randomized subject who completed week 12 visit were obtained. The point estimate of the overall correlation is the back-transformed average.
Table 1—Schedule of Visits and Measures
|– 1 (Fast)||0||1||2||3||4 (Fast)||5||6 (Fast)||8||12 (Fast)||26|
|Tobacco use history||Yes|
|Supplies for reduction||Yes||Yes||Yes||Yes||Yes||Yes||Yes|
|Tobacco use diary||Yes||Yes||Yes||Yes||Yes||Yes||Yes||Yes||Yes||Yes||Yes|
|Tobacco use questionnaire||Yes||Yes||Yes||Yes||Yes||Yes||Yes||Yes||Yes||Yes||Yes|