Study design
This will be a multicenter intervention study with a centralized enrollment (open-label, prospective, parallel-group randomized controlled trial). Three institutions participated in this study (Kyoto Medical Center, Kumamoto Red Cross Hospital, Komoro Kosei Hospital). The two facilities are located on the west side of Japan and one on the east side.
Sample size
The previous study showed, the addition of exercise instruction increased the odds ratio of successful smoking cessation 3-fold after six months. Of the 306 people screened by phone in this study, eligibility for study participation was determined and eventually consented from 40 people. After the two-week run-in period, 26 individuals were randomized to the intervention and control groups, including 13 women and 12 men (excluding one participant who developed lung cancer) 14). Assuming that the addition of exercise instruction after the anticipated conclusion of drug therapy is estimated to increase the odds ratio 2-fold after nine months, and the standard therapy group is estimated to successfully quit smoking at a rate of 50%, then a power of 1-β = 0.8 and a type I error of α = 0.05 would indicate that the minimum sample size required would be 134 participants per group, making a total of 268 participants. Assuming a dropout rate of 10% during the study, a randomized intervention study with 150 participants per group will require a total of 300 participants25). Study participants will be allocated to one of two groups: an exercise intervention group, who will receive additional exercise instruction in addition to the standard instruction, and a control group, who will receive the standard instruction. Participants will be followed for nine months after enrollment. The target number of participants to be enrolled is 300 (150 in each group).
Participants
Study participants will include individuals who have abstained from smoking during the last month while undergoing a standard smoking cessation therapy (three months after the initial visit).
Inclusion criteria
Individuals who have abstained from smoking during the last month while undergoing a standard smoking cessation therapy (three months after the initial visit) and fulfilling the following will be included: (1) individuals who do not exercise (those who do not answer “I have continued to exercise 30 min a day at least twice a week for over a year” in a questionnaire); (2) age 20–75 years; (3) individuals who agree to the purpose of this study and who provide written consent.
Exclusion criteria
Individuals fulfilling any of the following items will be excluded: (1) those prohibited from exercising by their physician (individuals for whom exercise is contraindicated); (2) those who would have difficulty exercising due to conditions, such as an orthopedic disorder, neuromuscular disease, or peripheral vascular disease; (3) pregnant women; (4) in-patients or residents of a facility; (5) individuals whose participation in this study has been deemed inappropriate by their primary physician.
Discontinuation criteria
This study will be discontinued in the event of any of the following: (1) continuation of the study is not feasible due to adverse events; (2) the study cannot be continued due to participant withdrawal or withdrawal of consent; (3) participants meet the exclusion criteria or are deemed ineligible after enrollment; (4) females who are pregnant; (5) marked noncompliance; (6) the study itself is discontinued; (7) if an investigator otherwise deems that continuing this study is not feasible.
Ethical considerations
All procedures will be carried out 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
Participants will be centrally allocated using the electronic data capture (EDC) system of the University Hospital Medical Information Network.
After written consent is obtained from participants who meet the selection criteria, the lead investigator will verify that the participants meet all of the eligibility criteria and none of the exclusion criteria, and their 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 participants to one of two groups (exercise intervention or control groups) via dynamic allocation.
Allocation and allocation adjustment factors
Confounding factors [age, sex, number of cigarettes smoked per day, Fagerstrom test for nicotine dependence (FTND) score, and self-rating depression scale (SDS) score will be adjusted between the two groups via registration in the EDC system. Participants will be randomized by minimization, which is a method of dynamic allocation.
Intervention
Acquisition of data at the beginning of the study
Patient characteristics (sex, age, medical history, history of present illness, alcohol consumption, type of medications taken, 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], high-density lipoprotein cholesterol [HDL-cho], and triglyceride [TG] levels), and measurements (height, weight, blood pressure, and concentration of exhaled carbon monoxide) at the beginning of the study will be examined. Smoking status (number of years of smoking, number of cigarettes smoked, tobacco dependence screener score, FTND score, age the individual started smoking, smokers in the family, and number of previous attempts to quit smoking) will be recorded during an interview at the initial visit to the smoking cessation clinic.
Exercise intervention group
After completion of the smoking cessation therapy, participants will be informed of the significance of active exercise while attempting to quit smoking. Participants will receive an activity tracker for the duration of the study and will be instructed on exercises to increase and maintain their physical activity as part of their daily lives.
Setting of exercise goals
During the follow-up, participants will individually record their daily step count, level of activity, and weight. A regular follow-up will be conducted approximately 2–4 times over nine months. During regular follow-up, participants will receive feedback based on their individual logs, exercise goals will be adjusted, and will be encouraged to maintain their amount of physical activity and 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 (control) group
The control group will be followed during the course of the standard smoking cessation program.
After completing the smoking cessation therapy, participants will not be actively advised to exercise; therefore, further exercise instruction will not be provided.
Participants will receive an activity tracker immediately after completing the smoking cessation therapy and eight months after beginning the study. They will return the tracker one month later in both instances.
Regular follow-up will be performed 2–4 times over nine months. During regular follow-up, it will be confirmed whether smoking cessation continues, and participants will not receive active instructions for exercise.
Items studied during the study and follow-up periods
The study will begin on the day the participant is given an activity tracker. The follow-up period will be nine months for both groups. In addition to face-to-face meetings, follow-up may be conducted by mail, telephone, or online. Participant status will be ascertained at the beginning of the study and one, eight, and nine months after beginning the study.
Continuous abstinence from smoking, psychological state, type of medications taken, 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 concentration of exhaled carbon monoxide) will be assessed in both groups after nine months.
Items observed and studied
Primary endpoint: Continuous abstinence rate
An individual is deemed to have continuously abstained from smoking when they report that they have not smoked in the past week when interviewed and if 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 (SDS score, depressive tendencies, and patient activation measure score).
Analysis
Analysis set
The two groups (exercise intervention and control groups) will be compared based on the intention-to-treat principle. All data for the metabolic indices and psychological states of the participants in each group obtained upon enrollment and nine months after enrollment will be analyzed. Individuals who quit smoking for a prolonged period will be similarly analyzed, and those who resume smoking will be excluded. Quitting smoking for a prolonged period is defined as not smoking for nine months since enrolling in the study (determined via an interview) and having exhaled carbon monoxide levels of ≤7 ppm. The continuous abstinence rate is defined as the proportion of participants who abstain from smoking with respect to the total number of participants in each group.
Items analyzed and analytical methods
The characteristics of the participants in both groups will be described statistically. Changes in the metabolic index and psychological state from the enrollment until nine months after enrollment will be compared between the two groups. The distribution of individual indices at the baseline and nine months after enrollment will be determined for the two groups, and a t-test or a Wilcoxon rank-sum test will be performed. For factor adjustment, analysis of covariance, multiple regression, or logistic regression will be used. 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. The statistical analysis will be performed by a statistician.
Early termination of this study
The trial will be discontinued in the event of any of the following situations: (1) if the trial cannot be safely conducted due to serious adverse events; (2) if it is not possible to enroll the planned sample size; or (3) if it is not feasible to continue the study.