Introduction
Globally, China is the largest consumer of tobacco [
1] with more than 300 million smokers [
2], which represents one-third of all smokers worldwide [
3]. Smoking in China is influenced by cultural and environmental factors; the country has a long history of tobacco consumption, and offering cigarettes during conversation remains normal today [
4]. Consequently, the overall prevalence of smoking is fairly high, 28.1%, but there are marked differences between the sexes; smoking is much more common among men (52.9%) than women (2.4%) [
1].
Only 23% of Chinese smokers are aware of the harmfulness of smoking, only one-third are advised to quit by their healthcare providers, and current figures estimate that 92% of quit attempts are unassisted [
2]. There is also a lack of environmental pressure to quit smoking; even in supposedly smoke-free environments, such as hospitals, smoking still occurs. One feature of the smoking pattern is high prevalence among Chinese healthcare professionals, including physicians. Overall, 23% of physicians smoke (41% of male physicians, and 3% of female physicians) [
5]. Even among healthcare professionals, awareness of smoking harm and how to quit are low [
4], which makes smoking cessation a challenge.
To date, the few smoking cessation studies performed in Asian populations have been conducted in Hong Kong and Taiwan [
6,
7], and there is little data from the mainland of China in terms of racial differences in tobacco dependence, smoking cessation and behavioral aspects of quitting smoking. For example, although nicotine replacement therapy (NRT) is well recognized globally as a first-line treatment for smoking cessation [
8], there is a paucity of data on the efficacy, safety, and acceptability of such interventions in Chinese populations.
Given the high prevalence of smoking among Chinese healthcare professionals, we therefore designed a study to investigate the use of NRT in this population. The primary study objectives were to evaluate the safety of nicotine gum and patch in Chinese smokers, and to measure abstinence rates and smoking reduction following treatment with NRT. Secondary objectives included assessment of treatment compliance and acceptability.
Materials and methods
Study design
This was an open label, multi-center clinical study of NRT in 300 Chinese physicians and other healthcare professionals recruited at six general hospitals in Beijing, Shanghai and Guangzhou. Three of the hospitals were smoke-free before the study, and three became smoke-free afterwards. Eligible subjects could choose between treatment with either nicotine gum (Nicorette® Mint Gum, McNeil AB, Helsingborg, Sweden) or nicotine 15 mg/16 h daytime patch (Nicorette® Patch, McNeil AB, Helsingborg, Sweden); the aim was to enroll equal numbers of subjects in both treatment groups. All subjects received active treatment. The total study duration was 24 weeks, a 12-week treatment and a 12-week follow-up. The study was conducted from February to November 2009. Written informed consent was obtained from each subject prior to enrollment. The study protocol was approved by the Ethics Committee of Beijing Chao-Yang Hospital, which is affiliated to Capital Medical University, China, and the study was conducted in compliance with International Conference on Harmonization Good Clinical Practice Guidelines and all applicable local regulatory requirements.
Study subjects
The study enrolled healthy male and female adults, 18 years or older, who were smoking at least ten cigarettes per day, who had smoked for at least three years, and who were motivated to stop smoking. To use gum, subjects had to have normal dental status and chewing ability, and in order to use patch subjects had to have normal skin with no excessive hair growth at the site of patch application. Individuals who were using tobacco-containing products other than cigarettes (e.g., snuff, chewing tobacco, cigars, pipes, etc.) were excluded from the study, as were individuals who had used any smoking cessation medication (nicotine or non-nicotine) or other treatment (e.g., hypnosis, acupuncture, etc.) during the previous 6-month period. Women who were pregnant or breastfeeding, and patients with unstable angina pectoris or myocardial infarction during the previous three months, were also excluded.
Study treatment
Eligible subjects could choose treatment with either nicotine gum or nicotine patch. Subjects who chose nicotine gum were stratified into two groups according to their baseline smoking; those who smoked 20 or fewer cigarettes per day were allocated to 2 mg gum, whereas those who smoked more than 20 cigarettes per day were allocated to 4 mg gum. Subjects were instructed how to use the gum to curb withdrawal symptoms and urges to smoke. The recommended dosage was 8–12 pieces of gum per day during Weeks 1–8, then 4–6 pieces per day during Weeks 9 and 10, and 1–3 pieces per day during Weeks 11 and 12. The maximum dose was 24 gums per day for both dosage groups.
All subjects who chose nicotine patch followed the same dosage regimen, starting with nicotine patch 15 mg/16 h for eight weeks, followed by a step-down program of 10 mg/16 h patch for two weeks (Weeks 9–10), then 5 mg/16 h patch for two weeks (Weeks 11–12). One patch was applied every morning, and removed at bedtime.
Subjects were provided with instructions for the patch and gum at the baseline visit. They were advised to stop smoking completely and start using study medication (i.e., treatment commenced on Quit Day). Use of any other smoking cessation medication or treatment during the 24-week study period was prohibited.
Behavioral support
All subjects received brief (up to 10 min) individual smoking cessation advice at Baseline and at Weeks 2, 6, 8, 10, and 12, and during telephone calls made to subjects at Weeks 1, 3, 4, 16, and 20. In addition, a Short Message Service (SMS, or text message) was also used as a method of cessation support. Text messages were sent three times daily during the first four days after Quit Day, then twice daily for the next ten days, once daily during Weeks 3 and 4, and twice weekly during Weeks 5 to 11.
Assessments
Subjects attended the clinic at Baseline (Week 0) and at Weeks 2, 6, 8, 10, 12, and 24, and were contacted by telephone at Weeks 1, 3, 4, 16, and 20. At Week 24, attempts were made to contact all subjects who had dropped out during the study.
At baseline, demographic data were collected, and smoking histories were elicited by asking subjects at what age they had started smoking, number of previous quit attempts, and which smoking cessation medications or interventions they had previously tried. Nicotine dependence and smoking pattern were assessed using the Fagerström Test of Nicotine Dependence (FTND) [
9].
Smoking status was assessed at each study visit and during each telephone call. Smoking cessation was assessed by self-reported abstinence, and objectively verified by testing the carbon monoxide (CO) level in exhaled air, using a Micro CO Smokerlyzer monitor, at all visits. To be continuously abstinent at a given visit, the expired CO level had to be less than 10 parts per million (ppm) at all visits up to this visit. If a subject could not be reached by phone at Week 1, 3, 4, 16, or 20, this was not regarded as a treatment failure if continuous abstinence was verified at the next visit to the clinic. However, any subject who dropped out or who was lost to follow-up was classed as a treatment failure (smoker).
Point prevalence abstinence, defined as self-report of no smoking since the previous visit or telephone call, was evaluated and CO-verified at Weeks 2, 6, 8, 10, 12, and 24. For subjects who continued to smoke after Quit Day, the degree of smoking reduction were evaluated at each visit and during each telephone call by asking each subject how many cigarettes per day he/she was smoking, and comparing the response against the subject’s smoking level at baseline. Self-reported reduction in daily cigarette smoking was verified either by an expired CO level lower than that at baseline, if the baseline value exceeded 10 ppm, or by a level lower than 10 ppm.
Compliance with study medication was assessed at each visit. At the end of treatment, subjects were asked: “Considering everything you now know about this product, on a scale of 1 (very poor) to 10 (excellent), how you rate it overall?” Safety was recorded throughout the study using open-ended questions to elicit information about adverse events, which were recorded and coded using Medical Dictionary for Regulatory Activities (MeDRA) coding.
Statistical methods
The primary study variables were number and severity of reported adverse events, continuous abstinence rates and reduction in daily cigarette smoking. Secondary variables were compliance with study medication, and ratings of overall liking. Statistical analyses of study data were performed by the Biometrics and Clinical Data Systems Department at McNeil AB, Helsingborg, Sweden. All subjects enrolled in the study were included in the full analysis set. Descriptive statistics of variables are presented by treatment. No formal statistical tests were performed. All subjects who received at least one dose of study medication were analyzed for safety.
Results
Study population
A total of 300 subjects were enrolled in the study, 150 in the nicotine gum group and 150 in the nicotine patch group. Within the gum group, 86 subjects were allocated to 2 mg gum, and 64 subjects to 4 mg gum. Thirteen subjects (four in the 2 mg gum group and nine in the 4 mg gum group) were allocated to the incorrect dosage, but data from these subjects were included in the safety and efficacy analyses. Six subjects withdrew, and 294 completed the study. All 300 subjects enrolled were included in the efficacy and safety analyses.
The baseline characteristics and smoking histories of all subjects are shown in Table 1. All subjects were Asian, their mean age was 41.1 years, and almost all (99%) were male. Overall, subjects were smoking a mean of 21.1 cigarettes per day at baseline, the mean expired CO level was 21.3 ppm, and the mean FTND score was 4.6. The mean age at which subjects had started smoking was 21.8 years. Almost half of the study population (48.0%) had never tried to quit smoking; one-quarter (27.7%) had tried to quit once, and 18.7% had made two to five previous quit attempts. In terms of previous use of smoking cessation pharmacotherapy, the study population was essentially treatment-naïve; only 2% had previously tried either NRT or another stop-smoking medication.
Treatment use and acceptability
Most subjects used at least the recommended dosage of gum (8–9 gums per day) during Weeks 1 and 2, but then use gradually decreased to approximately five gums (median) per day by Week 8. The mean number of gums per day was similar in the 2 mg and 4 mg treatment groups. In the patch group more than 90% of subjects reported daily use of one patch, as instructed, at each visit throughout the 12-week treatment period.
In general, both gum and patch were highly rated; the mean (±SD) overall product rating for all study subjects was 7.0±2.0. Ratings were similar across treatments: 7.2 for 2 mg gum, 6.5 for 4 mg gum, and 7.1 for patch. The overall product rating was higher among abstinent subjects than all study subjects (8.3 vs. 7.0).
Smoking cessation
The rate of continuous CO-verified abstinence from smoking from Week 2 onwards for all subjects is shown in Fig. 1. Overall, 17% of subjects were continuously abstinent from Week 2 to Week 24. The highest abstinence rate at Week 24 was observed among subjects treated with 2 mg gum (20.9%); corresponding rates with 4 mg gum and patch were 15.6% and 15.3%, respectively.
Fig.2 shows CO-verified point prevalence abstinence, defined as no smoking since the previous visit. At Week 24, the overall point prevalence abstinence rate was 35%. In the three treatment groups, the point prevalence abstinence rates at Week 24 were 37.2% with 2 mg gum, 25.0% with 4 mg gum, and 38.0% with patch.
Reduction in smoking
Rates of CO-verified continuous reduction in daily cigarette smoking by at least 50% (versus baseline smoking) over time are shown in Fig. 3. At Week 24, 38% of subjects had continuously reduced their cigarette consumption by at least 50% compared to baseline (this figure excludes subjects continuously abstinent from quit day). The results for reductions in cigarette smoking were similar in all three treatment groups (2 mg and 4 mg gum and patch).
Adverse events
Both nicotine gum and patch were well tolerated. No serious adverse events were reported during the study, and most of the events reported were mild to moderate in severity. Overall, 26.3% of subjects reported at least one treatment-related adverse event; the most common were gastro-intestinal disorders (including nausea, dyspepsia/abdominal discomfort) with both nicotine gum and patch, oropharyngeal pain with nicotine gum, and dermatitis with nicotine patch. Treatment-related adverse events were more frequent in the 4 mg gum group than in either the 2 mg gum or patch groups (39.1% versus 25.6% and 21.3%, respectively). Five subjects withdrew from the study due to adverse events; four in the 4 mg gum group (nausea n = 1, oropharyngeal pain n = 3) and one in the patch group (vesicular rash, n = 1).
Discussion
This study evaluated the safety of nicotine gum and patch in a population of Chinese health care professionals, and measured smoking cessation and reduction in daily smoking after treatment with NRT for 12 weeks and during off-treatment follow-up for 12 weeks. Treating tobacco dependence with pharmacotherapy is a new concept in China, for both healthcare professionals and the public. Currently, many Chinese physicians (mostly male) smoke, but those who quit can act as role models to encourage their patients to give up. To our knowledge, this was the first smoking cessation study conducted in Chinese healthcare professionals.
The smoking cessation findings in our study were in the same range as results in previous studies of nicotine patch or gum. A meta-analysis of the efficacy of NRT reported 6-month abstinence rates of 23.4% following treatment with nicotine patch for 6 to 14 weeks, and 19% following treatment with gum for 6 to 14 weeks [
10]. One investigation of 1186 Chinese smokers reported a 7-day point prevalence abstinence rate of 27% at 12 months following treatment with nicotine gum and patch for at least 4 weeks [
7].
The smoking reduction results in our study are promising, given that reduction in daily cigarette smoking can be an initial step toward cessation for smokers who are not able to stop smoking abruptly [
11,
12]. Previous studies of smoking reduction have reported 6-month reductions in smoking of 4.6%–12.5%, with reduction defined as at least 50% sustained reduction compared to baseline [
13]. However, the smoking reduction studies specifically enrolled smokers who were unable or unwilling to quit abruptly, whereas our study enrolled smokers motivated to quit.
Almost half of our subjects (48.0%) had never tried to quit smoking, which is unsurprising given the low awareness of tobacco-related harm or the importance of quitting, and very few had previously used a smoking cessation medication during previous quit attempts. Compliance with study treatments was good, particularly with nicotine patch, and most subjects rated the products helpful and highly acceptable.
We wanted to investigate the safety of NRT in Chinese subjects because cytochrome P450 2A6, the enzyme that converts nicotine to cotinine, is genetically polymorphic [
14], and individuals carrying variant CYP 2A6 alleles have altered nicotine metabolism kinetics, which has potential implications for NRT use in terms of treatment outcome and adverse events. It is estimated that 16% of the Chinese population are “poor metabolisers” [
15]. Both nicotine gum and patch were well tolerated by Chinese smokers in this study. The local and systemic adverse events reflected those previously reported with gum or patch [
16,
17], and no safety issues were noted among subjects who used nicotine gum or patch to reduce smoking.
However, there are some limitations of this investigation. This study was an open clinical trial, and subjects in this study could choose the NRT products by themselves, so the results might be affected by the study design. We conducted this study for a demonstration project on use of nicotine gum or patch for smoking cessation and smoking reducing in Chinese healthcare professionals. In the future, we plan to design a more rigorously planned clinical randomized control trail for fully exploring the effects of gum or patch on smoking cessation in China. All smokers in this study had motivation to quit, their hospitals were all smoke-free, and we provided behavioral support and text messages to them during treatment, which might increase the smoking cessation or reducing rates. We only analyzed the short-term smoking cessation and reducing rates. In the future, we will design to analyze the long-term smoking cessation and reducing rates. There were only 3 females were involved in the study, so the results might represent the male subjects. In the future, it will need a clinical trial for female.
Since our study ended, many new tobacco control measures have been taken in China. Shanghai and Guangzhou announced smoke-free policies for public areas in March and July 2010, respectively, and Beijing has revised its policy in 2011. In 2009 the Ministry of Health of the People’s Republic of China announced that all military health administration departments, and at least half of all healthcare organizations, should be smoke-free by 2010, and that all healthcare organizations should be smoke-free by 2011. In 2012, the Ministry of Health of the People’s Republic of China released China Report on the Health Hazards of Smoking officially in Beijing, which was an important milestone in the history of public health in China. In addition, many smoking cessation initiatives, including information campaigns, were undertaken to educate the public about the health hazards of tobacco, smoking cessation service and medications were now available. With the rapid growth of the economy and the improvement of the living standards, Chinese public are paying more attention to the health and becoming more interested in smoking cessation. The findings of our study may contribute to promote the progress of tobacco control in China.
Higher Education Press and Springer-Verlag Berlin Heidelberg
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