Study design
This will be a multicenter intervention study with centralized enrollment (prospective random allocation).
Sample size
Subjects will be allocated to one of the following two groups: an exercise intervention group actively given exercise instruction in addition to the standard instruction and a control group given the standard instruction. Subjects will be followed for 9 months after enrollment, and the target enrollment is 300 subjects (150 in the intervention group and 150 in the control group).
A previous study involving a limited number of patients examined the effects of adding exercise instruction after drug therapy with a nicotine patch. The addition of exercise instruction increased the odds ratio of successful smoking cessation 3-fold after 6 months14). If the addition of exercise instruction after the anticipated conclusion of drug therapy is estimated to increase the odds ratio 2-fold after 9 months and the standard therapy group is estimated to successfully quit smoking at a rate of 50%, then with a power of 1-β = 0.8 and a type I error of α = 0.05 the minimum sample size would be 134 subjects per group, for a total of 268 subjects in both groups. Assuming the dropout rate during the study is 10%, a randomized intervention study with 150 subjects per group, for a total of 300 subjects in both groups, will be necessary.
Subjects
Patients who have abstained from smoking during the last month while undergoing the standard smoking cessation therapy (3 months after the initial visit).
Inclusion criteria
Individuals who have abstained from smoking during the last month while undergoing the standard smoking cessation therapy (3 months after the initial visit) and fulfilling the following will be included:
- Individuals who do not exercise*
- Age: 20–75 years
- Individuals who agree to the purposes of this study and who provide consent in writing
*Individuals who did not answer “I have continued to exercise 30 minutes a day at least twice a week for over a year” on a questionnaire.
Exclusion criteria
Patients fulfilling any of the following items apply will be excluded:
- Individuals prohibited from exercising by their physician (individuals for whom exercise is contraindicated)
- Individuals who would have difficulty exercising due to a condition such as an orthopedic disorder, neuromuscular disease, or peripheral vascular disease
- Pregnant women
- Inpatients or residents of a facility
- Patients whose participation in this study has otherwise been deemed inappropriate by their primary physician
Discontinuation criteria
This study will be discontinued in the event of any of the following:
- Continuing this study is not feasible due to adverse events
- This study cannot be continued due to patient withdrawal or withdrawal of consent
- Subjects are deemed to meet exclusion criteria or subjects are deemed ineligible after enrollment
- Female patients who are deemed to be pregnant
- Marked noncompliance
- The study itself is discontinued
- If an investigator otherwise deems that continuing this study would not be feasible
Ethical considerations
All procedures will be in accordance with the ethical standards of the facilities involved and those of domestic research councils and in accordance with the 1964 Helsinki Declaration and its subsequent amendments or comparable ethical standards.
Study protocol
An overview of the proposed study protocol is shown in Fig. 1.
Allocation
Subjects will be centrally allocated using the Electronic Data Capture (EDC) system of the University Hospital Medical Information Network.
After consent is obtained in writing from patients who meet the selection criteria, the lead investigator will verify that patients meet all of the eligibility criteria and none of the exclusion criteria, and subject information will be registered in the EDC system. After registration, the EDC system will assign patient numbers that do not include a patient’s personal information. Immediately after entry, the EDC system will randomly assign subjects to one of the two groups (the exercise instruction group or the standard instruction group) via dynamic allocation.
Allocation and allocation adjustment factors
Confounding factors (age, sex, the number of cigarettes smoked per day, the score on the Fagerstrom Test for Nicotine Dependence, and the score on a Self-rating Depression Scale) will be adjusted between the two groups via registration in the EDC system. Subjects will be randomized by minimization (i.e., a method of dynamic allocation).
Intervention
Acquisition of data at the beginning of the study
Patient characteristics (sex, age, past medical history, history of the present illness, alcohol consumption, medications taken and their type, and psychological state), blood chemistry [white blood cell count; red blood cell count; hemoglobin level; hematocrit; platelet count; fasting blood glucose level; and total cholesterol (T-cho), HDL cholesterol (HDL-cho), and triglycerides (TG) levels], and measurements (height, weight, blood pressure, and the concentration of exhaled carbon monoxide) at the beginning of the study will be examined. Smoking status (years of smoking, the number of cigarettes smoked, the score on the Tobacco Dependence Screener, the score on the Fagerstrom Test for Nicotine Dependence, age when the individual started smoking, smokers in the family, and the number of previous attempts to quit smoking) will be as noted in an interview during the initial visit to the smoking cessation clinic.
Exercise intervention group
Upon smoking cessation therapy completion: Subjects will be informed of the significance of active exercise while attempting to quit smoking. Subjects will receive an activity tracker for the duration of the study and instructed on exercises to increase and maintain the amount of their physical activity as part of their daily lives.
Setting of exercise goals
During follow-up, subjects will individually record their daily step count, level of activity, and weight. A regular follow-up will be conducted approximately 2–4 times. During the regular follow-up, subjects will be given feedback based on their individual logs, exercise goals will be adjusted, and subjects will be encouraged to maintain the amount of their physical activity and to control their weight. Exercise instruction will be provided in accordance with an exercise instruction manual compiled under the supervision of a certified fitness instructor and a certified cardiac rehabilitation specialist.
Standard therapy group
This group will be followed during the course of the standard smoking cessation program.
Upon conclusion of smoking cessation therapy, subjects will not be actively advised to exercise; therefore, further exercise instruction will not be provided.
Subjects will receive an activity tracker after smoking cessation therapy completion and 8 months after the beginning of the study. They will return the tracker 1 month later in both instances.
Regular follow-up will be conducted approximately 2–4 times. During the regular follow-up, only indices will be ascertained, and subjects will not be given active instructions to exercise.
Items studied during the study and during follow-up
The study will begin on the day the subjects are given the activity tracker. The follow-up period will be 9 months for both groups. In addition to face-to-face, follow-up can be conducted by mail, telephone, or online. Subject status will be ascertained at the beginning of the study and 1 month, 8 months, and 9 months later.
Continuous abstinence from smoking, psychological state, medications taken and their type, blood chemistry (white blood cell count; red blood cell count; hemoglobin level; hematocrit; platelet count; fasting blood glucose level; and T-cho, HDL-cho, and TG levels), and measurements (height, weight, blood pressure, and the concentration of exhaled carbon monoxide) will be assessed for both groups after 9 months.
Items observed and studied
Primary endpoint: Continuous abstinence rate*
*An individual is deemed to have continuously abstained from smoking when he or she reports that he or she has not smoked in the past week during an interview and the concentration of exhaled carbon monoxide is ≤7 ppm12).
Secondary endpoints: Changes in metabolic indices (height; weight; blood pressure; exhaled carbon monoxide concentration; red blood cell count; white blood cell count; hemoglobin level; hematocrit; platelet count; fasting blood glucose level; and T-cho, HDL-cho, and TG levels) and changes in an individual’s psychological state (score on the Self-rating Depression Scale, depressive tendencies, and score on the Patient Activation Measure).
Analysis
Analysis set
The two groups, i.e., the exercise intervention and standard instruction groups, will be compared based on the intention-to-treat principle. All data on the metabolic indices and psychological states of the subjects in each group obtained upon enrollment and 9 months after enrollment will be analyzed. Only patients who have abstained from smoking (excluding patients who have resumed smoking) will be similarly analyzed. The continuous abstinence rate is defined as the proportion of patients who abstain from smoking with respect to all of the subjects in each group. Continuous abstinence from smoking is defined as being available for follow-up 9 months after enrollment, indicating abstinence from smoking during the past month in an interview, and having a concentration of exhaled carbon monoxide of ≤7 ppm.
Items analyzed and analytical methods
The characteristics of subjects in both groups will be described statistically. Mean values for changes in the metabolic indices and psychological states of the subjects from enrollment until 9 months after enrollment will be compared between the two groups. The distribution of individual indices at the baseline and 9 months after enrollment will be determined for the two groups, and a t-test or a Wilcoxon rank-sum test will be performed. In addition, Fisher’s exact test will be used to compare the continuous abstinence rate in the two groups. The level of significance will be ≤0.05. A two-tailed alpha of 5% and a two-sided 95% confidence level will be used.
Early termination of this study
The decision to continue this study will be determined in any of the following situations:
- When vital information regarding the safety or efficacy of this study is obtained
- When achieving planned enrollment is deemed difficult
- When continuing this study does not otherwise appear feasible