Design, baseline characteristics, and retention of African American light smokers into a randomized trial involving biological data

Tobacco use remains the leading preventable cause of disease and death in the United States [1]. Differences in patterns of tobacco use, access to treatment, and treatment outcomes between African American and white smokers have been well documented [2‐7]. Compared to white smokers, African American smokers consume fewer cigarettes per day and are more likely to be classified as "light" smokers, smoking 10 or fewer cigarettes per day [8‐11]. However, African American smokers are more likely to smoke high-tar and mentholated cigarettes [12, 13], to inhale more deeply [14], and to have a slower rate of nicotine metabolism [15] and show higher levels of cotinine per cigarette smoked [4, 16, 17]. Unfortunately, African American smokers are less likely to receive treatment, have poorer treatment outcomes, and suffer a disproportionately greater share of tobacco-related morbidity and mortality [1], making treatment of these smokers a continued public health priority. African American smokers historically have been under-represented in smoking cessation research and few studies have focused on treating light smokers [18, 19].

The current paper describes the study design and baseline characteristics from Kick It at Swope III (KIS-III), a clinical trial of bupropion and health education counseling for African American light smokers. KIS-III is the third in a series of studies aimed at enhancing tobacco use treatment for African American smokers. The first KIS-I trial [20] was a double-blind, placebo-controlled trial that demonstrated the efficacy of sustained release bupropion in African American moderate to heavy smokers, those who smoked 10 or more cigarettes per day (cpd). Because over 50% of African American smokers are light smokers, the second KIS trial (KIS-II) focused on treating light smokers (1-10 cpd) and evaluated nicotine gum compared to placebo in combination with either motivational interviewing (MI) or health education (HE) counseling using a 2x2 factorial design [21, 22]. Findings from KIS-II showed no benefit of nicotine gum, but demonstrated a doubling in rates of abstinence for smokers who received HE compared to MI counseling [22]. The lack of response to nicotine replacement therapy may have been due to under-dosing related to low dose of drug used (2mg rather than 4mg), insufficient frequency of dosing, or poor adherence. For these reasons, a non-nicotine medication was considered for the present trial of African American light smokers. Of note, we explored more completely the issues of biomarkers and found neither carbon monoxide nor cotinine were strongly associated with self-reported smoking level in this light smoking population [4]. We also found that abstinence was influenced by genetically variable rates of nicotine metabolism [15].

The present KIS-III study was designed to build upon KIS-I and KIS-II findings. Because bupropion was found to be effective in African American moderate to heavy smokers, KIS-III was designed to extend this evaluation within African American light smokers, in combination with effective HE counseling. Based on prior research, bupropion treatment is expected to reduce the rewarding effects of smoking and aid withdrawal reduction for smokers independent of smoking level. In addition, we continued investigation of genetic and pharmacokinetic influences on cessation in KIS-III.

Because genetic, sociocultural, and pharmacological determinants of smoking vary across racial and ethnic groups and may impact tobacco use treatment, empirical evaluation of these factors in the context of smoking cessation intervention has been recommended [15, 16, 23]. The consistent disparity of finding higher cotinine levels per cigarette in African American smokers is likely due to greater intake of nicotine per cigarette smoked combined with slower nicotine metabolism [4, 17]. The enzyme CYP2A6 [24, 25] and genetic variation in CYP2A6 is associated with multiple smoking behaviors including cessation, as well as tobacco-related disease risk [25‐28]. Genetic variation in the CYP2B6 gene, coding the enzyme responsible for bupropion metabolism, is also associated with smoking cessation in the context of both bupropion and placebo treatment [29‐31]. KIS-III was designed to extend previous studies of African American smokers by incorporating biological evaluation of both nicotine and bupropion metabolism, and the genetic variation in the main metabolic enzymes CYP2A6 and CYP2B6, in addition to other smoking and psychosocial factors, within this clinical trial of light smokers. This paper describes the study design, baseline characteristics and retention of African-American light smokers into a smoking cessation treatment trial that involves biological data collection.

An overview of screening and enrollment for KIS-III is provided in Figure 1. Of 2,628 individuals who expressed interest in study participation and were screened for eligibility, 999 (38%) were phone-eligible and were scheduled for in-person screening. Radio was the most common source of information about the study (29%), followed by recruitment through the Swope clinic (20%), television (17%), word of mouth (13%), and Truman Medical Center (9%). Most of those screened (70%) were ineligible for study participation with the primary reasons for ineligibility being smoking >10 CPD, not medically eligible, use of other forms of tobacco, and binge drinking within the past 6 months. Of smokers who passed phone eligibility, one third (370) did not keep the final eligibility study appointment. Of those who attended final eligibility screening (629), 89 (14%) were not eligible for randomization. Five hundred and forty (86% of those attending final eligibility screening) were eligible, consented, and randomized to the bupropion or placebo treatment group.

Participant randomization by month (from December 2007 to October 2009) is presented in Figure 2. The bar graph represents monthly numbers of individuals screened, those ineligible, those who did not keep appointment and participants randomized, while the line graph reflects cumulative enrolment over the study period. Participant enrollment was completed 7 weeks ahead of the projected schedule.

Table 3 presents baseline characteristics of KIS-III study participants. Participants had a mean age of 46.5 years, the majority, (66.1%) were women, one in three were married or living with a partner, and over 84% had obtained a high school degree. Almost two in three earned less than $1,800 monthly. Participants smoked an average of 8.0 cigarettes per day, had a mean exhaled carbon monoxide of 16.4ppm with a range of (1-55), a mean cotinine of 275.8ng/ml. Mean Body Mass Index (BMI) was 31.1. Over 72% smoked within 30 minutes of waking with a mean FTND dependence score of 3.2 with a range of (0-7). Most (83.7%) reported smoking menthol cigarettes. Only 24.4% reported living in a smoke-free household. The average number of quit attempts in the past year was 3.7 and 24.2% reported using pharmacotherapy during their most recent quit attempts. Motivation and confidence to quit were high. These demographic and smoking history characteristics are similar to African American light smokers from our previous KIS-II trial [22].

Retention of participants for Weeks 1, 3, 5, 7, 16, and 26 was 90.6%, 78.7%, 75.7%, 72.8%, 67.6%, and 70.2%, respectively. Of six total counseling sessions, participants completed a mean (SD) of 4.85 (1.49) sessions.

The Kick It at Swope III (KIS-III) trial was designed as the first treatment study of bupropion for African American light smokers. To date, KIS-III is the fourth study to evaluate pharmacotherapy for light smokers [22, 77, 78] and the second to evaluate treatment for African American light smokers [22]. KIS-III is also the first study to examine both nicotine and bupropion metabolism, evaluating CYP2A6 and CYP2B6 phenotype and genotype as possible predictors of outcome, within the context of treatment of African American smokers. Collecting data on metabolism and genotype allows us to evaluate biological mechanisms in conjunction with psychosocial and smoking data to further advance our understanding of African American smoking behavior and ultimately enhance treatment outcomes.

We have demonstrated the feasibility of recruiting and enrolling African American light smokers into a clinical treatment trial involving biological data collection and genetic analysis. These feasibility findings are consistent with studies that have successfully enrolled African American smokers for treatment and provide further evidence of willingness to share genetic information within a research study of smoking behavior [19, 79]. KIS-II enrolled smokers into a cessation trial but conducted the genetic portion of the study using a second consent process. In KIS-II, there was 83% participation in the genetic portion of the study [79]. Based in part on this excellent consent rate, indicating consent for genetic analysis posed little barrier to enrollment, KIS-III included genetic analysis as part of overall study participation and enrolled accordingly. Participants were informed during screening about the goals of the study, the requirement of multiple collections of biological samples, and the rationale for collecting such data. This information was reviewed in further detail within the consent process. Of 1629 individuals who completed any screening for study participation, only 18 (1.1%) were ineligible to participate in the study because they refused blood draws, suggesting that the inclusion of phenotype and genotype assessments did not impede recruitment in this African American population. Factors that contributed to recruitment success may include conducting this research within a trusted community medical setting, having an established history of smoking cessation treatment and research within the community, and using a multi-method approach to recruitment. The current data add to the literature demonstrating support for inclusion of African American smokers in smoking cessation treatment studies, in genetic investigation of tobacco use and treatment, and more broadly in cancer control research.

Consistent with our previous KIS trials, study participants were largely low income and predominantly menthol cigarette smokers. Despite excluding individuals currently using pharmacotherapy for the treatment of depression, we found approximately one third of participants reported symptoms of depression. As other research has shown bupropion to reduce negative mood during smoking cessation treatment [80, 81] and to be effective in supporting abstinence in moderate to heavy smokers with or without a history of depression [82], we are planning analyses examining changes in mood and depression in relation to smoking behavior within the current sample of African American light smokers. Importantly, while low income, use of menthol, and depression previously have been associated with poorer smoking cessation treatment outcomes [21, 83‐87], this sample was highly motivated to stop smoking. Our previous KIS-II trial found health education counseling contributed to higher rates of abstinence in highly motivated African American light smokers, when compared to motivational counseling [22]. The finding that smokers in the current trial show similarly high levels of motivation provided support for the use of health education counseling within the current study.

Examination of KIS-III screening data points to some limitations related to generalizability and recommendations for needed research. Over half of individuals who expressed interest in enrolling in this smoking cessation study were ineligible to use bupropion according to study protocol. Future research should examine other pharmacotherapy for light smokers, such as varenicline, which has been found to be effective in moderate to heavy smokers (>10cpd) [18]. Findings also showed over one third of interested smokers screened in KIS-III reported use of other forms of tobacco and were excluded from treatment. While smoking cessation clinical trials typically exclude smokers who report use of other forms of tobacco, future studies may provide greater generalizability by examining tobacco use treatment more broadly defined. Inclusion of smokers who use other forms of tobacco would require consideration of appropriate measures of tobacco use and abstinence verification.

In summary, the KIS-III study provides a unique opportunity to evaluate psychosocial and biological mechanisms related to drug use and treatment outcomes in African-American light smokers. Baseline findings support the feasibility of enrolling African American light smokers in a treatment study involving genetic analysis. Identifying individuals for whom treatments are most effective and, in contrast, identify characteristics related to relapse risk will contribute to advancing tailored tobacco use treatment, with the ultimate goal of enhancing treatment and reducing tobacco-related health disparities for African-American smokers.