Determining the effects of exercise after smoking cessation therapy completion on continuous abstinence from smoking: A study protocol

Background: Over the past few years, the rate of success for smoking cessation has improved markedly owing to the widespread availability of drug therapy; however, the quit rate 1 year after the beginning of therapy remains low at approximately 50%. Previous studies have demonstrated that exercise can relieve mental stress during continuous abstinence from smoking and curb the resumption of smoking. Nonetheless, very few studies have examined the effects of exercise therapy combined with continuous abstinence from smoking; those studies involved only a handful of patients. Thus, this study will examine continuous abstinence from smoking coupled with instructions on specific forms of exercise in individuals who are attempting to quit smoking but do not exercise. We aimed to determine the effects of implementing an intervention in the form of exercise instruction after smoking cessation therapy completion on continuous abstinence from smoking. If this study finds that exercise instruction increases the continuous abstinence rate, widespread implementation of the intervention is expected to reduce public smoking rate, promote health, reduce medical expenses, and greatly benefit the public. Methods: We will enroll patients visiting a smoking cessation clinic (over a 3-month period) who have abstained from smoking in the second month after their initial visit as potential subjects and patients aged 20–75 years who do not exercise and who consent to participation in this study as subjects. We aim to enroll 300 patients. Subjects will be randomly assigned to one of the following two groups: an intervention group actively given exercise instruction in addition to the standard instruction and a control group given the standard instruction. The status of the two groups will be assessed after 9 months. The intervention group will receive instruction on exercises that can be incorporated into their daily lives. Additionally, members of this group will be lent a pedometer and encouraged to record their daily step count, level of activity, and weight during follow-up. The control group will be followed during the standard smoking cessation support program. The primary endpoint will be the continuous abstinence rate, and secondary endpoints will be weight, blood pressure, exhaled carbon monoxide concentration, psychological state, and blood test results. These indices will be compared between the intervention and control groups; the study will be conducted over a 9-month period. Discussion: By examining the effects of exercise instruction after 12-weeks smoking cessation therapy completion (covered by the National Health Insurance), this study will yield quality information for the development of protocols to improve the continuous abstinence rate and inhibit weight gain after smoking cessation therapy. Trial registration: The study is registered at UMIN Clinical Trials Registry (UMIN000014615). Registered on 1st October, 2014.

of recurrence or death, and former smokers have a rate of diminished pulmonary function equivalent to that of nonsmokers after 5 years. Moreover, individuals aged 40-59 years who attempt quitting smoking have a significantly lower risk of incurring massive medical expenses in the future than continuing smokers, and individuals attempting to quit smoking have a reduced risk of massive medical expenses similar to that of lifetime nonsmokers 5) . Thus, actively promoting smoking cessation should markedly inhibit the development of cardiovascular disease and vastly reduce medical expenses.

Smoking cessation aids lack sufficient long-term effectiveness
Over the past few years, the rate of success for individuals quitting smoking has markedly improved owing to the widespread availability of drug therapy at smoking cessation clinics. Since its introduction in the Japanese market in 2008, the oral smoking cessation aid varenicline tartrate in particular has greatly improved the rate of success immediately following smoking cessation therapy completion. However, the continuous abstinence rate drops to approximately 50% 1 year after therapy initiation 6) . This means that providing support to individuals attempting to quit smoking to help them avoid resuming the habit is an urgent task for medical personnel.

Exercise can improve the quit rate
Exercise can relieve mental stress during continuous abstinence from smoking and curb the resumption of smoking 7) . A systematic review of the efficacy of exercise on curbing the resumption of smoking showed that exercise helped to curb smoking resumption in 12 of 14 studies 8) . A metaanalysis similarly indicated that exercise as part of a cardiac rehabilitation program significantly reduced the smoking rate 9) . Active incorporation of exercise may lead to improvements in the quit rate.

Exercise can inhibit weight gain after quitting smoking
Weight gain typically occurs after smoking cessation. A recent meta-analysis noted an average weight gain of 4.7 kg 1 year after subjects quit smoking 10) . Weight gain after smoking cessation can lead to the resumption of smoking, and the prevention of weight gain is a vital aspect of smoking cessation support. In fact, Japanese smoking cessation programs using drug therapy provide instruction primarily in the form of diet and cognitive behavioral therapy; however, numerous studies have reported that such programs do not necessarily result in adequate weight control 11,12) . Explaining specific forms of exercise to individuals who are attempting to quit smoking and do not exercise should help to improve the rate of success for quitting smoking and also help facilitate subsequent weight control.
Given this context, numerous intervention studies overseas have examined the effects of combining exercise instruction with drug therapy. However, few studies had a large enough sample size, and the effects of adding exercise instruction are still unclear 13) .

Study objective
The aim of this study is to determine the effects of exercise instruction provided after 12-weeks smoking cessation therapy completion (covered by the National Health Insurance) on continuous abstinence from smoking.

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 months 14) . If the addition of exercise instruction after the anticipated conclusion of drug therapy is estimated to increase the odds ratio 2fold after 9 months and the standard therapy group is estimated to successfully quit smoking at a

Discontinuation criteria
This study will be discontinued in the event of any of the following:

1.
Continuing this study is not feasible due to adverse events 2. This study cannot be continued due to patient withdrawal or withdrawal of consent 3.
Subjects are deemed to meet exclusion criteria or subjects are deemed ineligible after enrollment

4.
Female patients who are deemed to be pregnant 5.
The study itself is discontinued 7.
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.  Figure 1 Overview of the study protocol.

Figure 2
The schedule of enrolment, interventions, and assessments.

Supplementary Files
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