For peer review only - BMJ Open...5 In this T&CM tobacco control programme, ear acupuncture, manual...

For peer review only

Study protocol of a pragmatic randomized controlled trial: Clinical effectiveness on smoking cessation of T&CM

interventions, including acupuncture and aromatherapy, in combination with nicotine replacement therapy

Journal: BMJ Open

Manuscript ID bmjopen-2016-014574

Article Type: Protocol

Date Submitted by the Author: 07-Oct-2016

Complete List of Authors: Park, Sunju; Daejeon university JANG, SOOBIN Jang, Bo-Hyoung Park, Yu Lee Lee, Ju Ah; Korea Institute of Oriental Medicine, Go, Hoyeon; Semyung University, Korea, Korean Internal Medicine Cho, Chung Sik; Daejeon University College of Korean Medicine, Shin, Yong-Cheol Ko, Seong-Gyu; Kyung Hee University,

Primary Subject

Heading: Smoking and tobacco

Secondary Subject Heading: Complementary medicine

Keywords: smoking, tobacco control, study protocol, acupuncture, Korean medicine, T&CM

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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Study protocol of a pragmatic randomized controlled trial: Clinical effectiveness

on smoking cessation of T&CM interventions, including acupuncture and

aromatherapy, in combination with nicotine replacement therapy

Sunju Park1,*, Soobin Jang

2,*, Bo-Hyoung Jang

2, Yu Lee Park

2, Ju Ah Lee

3, Chung-Sik Cho

4,

Ho-Yeon Go5, Yong Cheol Shin

2, Seong-Gyu Ko

2,§

*These authors contributed equally to this work

§Corresponding author:

Seong-Gyu Ko M.D., MPH, Ph.D.,

Tel: + 82-2-961-0329, Fax: +82-2-2270-0344

Email: [email protected]

1Department of Preventive Medicine, College of Korean Medicine, Daejeon University, 62

Daehak-ro, Daejeon 34520, Republic of Korea

2Department of Preventive Medicine, College of Korean Medicine, Kyung Hee University, 26

Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea

3KM Fundamental Research Division, Korea Institute of Oriental Medicine, 1672

Yuseongdae-ro, Yuseong-gu, Daejeon 34054, Republic of Korea

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4Department of Korean Internal Medicine, Daejeon University Korean Medicine Hospital, 75,

176 Daedeokdae-ro, Seo-gu, Daejeon 35234, Republic of Korea

5Internal Medicine College of Korean Medicine, Semyung University, 65 Semyung-ro,

Jecheon, Cungchungbuk-do 27136, Republic of Korea

Email address

Sunju Park: [email protected]

Soobin Jang: [email protected]

Bo-Hyoung Jang: [email protected]

Yu Lee Park: [email protected]

Ju Ah Lee: [email protected]

Chung-Sik Cho: [email protected]

Ho-Yeon Go: [email protected]

Yong Cheol Shin: [email protected]

Seong-Gyu Ko: [email protected]

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Abstract

Introduction: Nicotine dependence is a disease by itself, and tobacco use is related to 6

million deaths annually worldwide. Recently, there has been a growing interest in many

countries in using traditional & complementary medicine (T&CM), especially acupuncture,

as a therapeutic intervention for smoking cessation. The aim of this study is to investigate the

effectiveness of T&CM interventions on smoking cessation.

Methods and analysis: The STOP (Stop Tobacco Programme using traditional Korean

medicine) study is designed to be a pragmatic open-label, randomized trial. This trial will

compare conventional cessation methods alone (i.e., nicotine replacement therapy (NRT),

counselling) and in combination with T&CM methods (i.e., ear and manual acupuncture,

aromatherapy). Participants will be more than 19 years old and capable of communicating

normally in Korean. They will also be current smokers who meet one of the following criteria:

1) smoke more than 10 cigarettes a day; 2) smoke less than 10 cigarettes a day and previously

failed to cease smoking; or 3) smoke fewer than 10 cigarettes a day and have a nicotine

dependence score (Fagerstrom Test for Nicotine Dependence) of 4 points or more. The trial

will consist of 4 weeks of treatment and a 20-week follow-up period. A statistician will

perform the statistical analyses for both the intention-to-treat (ITT; all randomly assigned

participants) and per-protocol (PP; participants who completed the trial without any protocol

deviations) data using SAS. Missing data will be handled using qualitative methods.

Ethics and dissemination: This study has been approved by the Institutional Review Board

of the Dunsan Korean Medicine Hospital of Daejeon University (IRB reference no.:

DJDSKH-15-BM-11-1, Protocol No. version. 4.1.).

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Trial registration: ClinicalTrials.gov (NCT02768025).

Keywords: Smoking, tobacco control, study protocol, acupuncture, Korean medicine, T&CM

The strengths and limitations of this study

This study is the first protocol of implementing the Traditional & Complementary Medicine

(T&CM) programme as a smoking cessation treatment. However, the study was designed as a

pragmatic randomized controlled trial because controlling all other conditions is hard to

reflect real world.

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Introduction

Smoking is the main cause of preventable deaths worldwide, and 6 million deaths a year are

related to tobacco use. 1 Smoking is associated with not only nearly every cancer but also

many types of chronic diseases, such as coronary artery disease, stroke, and asthma. 2

Tobacco-related deaths are expected to increase by 8 million by 2030 if proper smoking

cessation policies are not implemented. 1

Recently, traditional & complementary medicine (T&CM) methods, especially acupuncture,

have gained attention in many countries as therapeutic interventions for smoking cessation. In

an American trial, 3 40% of smokers who had been treated with acupuncture successfully

ceased smoking. In a Norwegian trial, 4 the experimental group received acupuncture

treatment at the ‘Shenmen’, ‘Mouth’, and ‘Liver’ acupoints of the ear, and treating points

LI6(Kongzui) and LI7(Leique) led to significant changes in the taste of cigarettes and desire

to smoke compared with the control group, which had been treated at different acupoints.

This clinical trial is going to verify the effectiveness of ear acupuncture, manual acupuncture

and aromatherapy in combination with nicotine replacement therapy (NRT) and counselling,

which are standard regimens applied for smoking cessation. The intervention of this trial is

referred to as the ‘T&CM tobacco control programme’, which is a combination of ear and

manual acupuncture, aromatherapy, NRT and counselling. NRT and counselling have been

widely used in conventional Western medicine in addition to such drugs as varenicline and

bupropion. 5 In this T&CM tobacco control programme, ear acupuncture, manual

acupuncture, and aromatherapy will be applied for smoking cessation instead of Western

interventions. The primary objective of this trial is to estimate whether the smoking cessation

success rate increases with the application of the T&CM tobacco control programme. The

secondary aim is to evaluate the satisfaction of participants in the T&CM tobacco control

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programme. This study is the second research result of our STOP (Stop Tobacco Programme

using traditional Korean medicine) study series.

Methods

Trial design

The STOP study design is a pragmatic open-label, randomized study. This trial will compare

conventional cessation treatment methods (i.e., NRT, counselling) alone and in combination

with T&CM methods (i.e., acupuncture, aromatherapy). The hypothesis of this trial is to

investigate whether the smoking cessation rate increases by adding T&CM methods. The trial

will consist of 4 weeks of treatment and a 20-week follow-up period. An overview of the trial

process is shown in Figure 1.

Participants and recruitment

Smokers who want to stop smoking will be recruited over 6 months at the Dunsan Korean

Medicine Hospital of Daejeon University in Daejeon, Republic of Korea. Posters for

recruiting participants will be posted publicly inside and outside of the hospital. Potential

participants will contact our information centre via email or telephone. Those who agree to

participate in the study and provide written informed consent will be eligible to participate in

the study.

Inclusion criteria

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Participants will be more than 19 years old and able to communicate normally in Korean.

They will also be current smokers who meet one of the following criteria: 1) smokes more

than 10 cigarettes a day; 2) smokes less than 10 cigarettes a day and previously failed to

cease smoking; or 3) smokes fewer than 10 cigarettes a day and has a nicotine dependence

score (Fagerstrom Test for Nicotine Dependence, FTND) of 4 points or more. The FTND is a

representative questionnaire that evaluates nicotine dependence. It consists of 6 questions,

and the score ranges from 0 to 10. Scores of 1 to 3, 4 to 6, and 7 to 10 indicate low, moderate,

and high levels of nicotine dependence, respectively. Questions 1 and 2 assess the heaviness

of smoking index, and high nicotine dependence is indicated if the sum of these two scores is

4 or more. 6

Exclusion criteria

Participants who correspond to one or more of following will be excluded from this trial: 1)

during the previous 2 weeks, suffered from cardiovascular disease, severe arrhythmia, or

unstable angina pectoris; 2) currently suffering from severe arrhythmia; 3) currently suffering

from otitis externa or any other condition that precludes ear acupuncture; 4) cannot be treated

with a nicotine patch because of long-term dermatitis (e.g., psoriasis); 5) diagnosed with and

currently being treated for a mental illness (e.g., dementia, delirium, depression); or 6)

currently pregnant or breastfeeding.

Participant withdrawal criteria

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Participants who meet the criteria of following will be discontinued from the trial: 1)

voluntarily withdrawing of consent, 2) protocol violation such as not complying study

schedule, 3) occurrence of a serious adverse event, 4) investigator’s decision to terminate the

study for the sake of the participant’s health.

Ethical and dissemination

This study was approved by the Institutional Review Board of the Dunsan Korean Medicine

Hospital of Daejeon University (IRB reference no.: DJDSKH-15-BM-11-1, Protocol No.

version. 4.1.) and registered at ClinicalTrials.gov (NCT02768025). The protocol will be re-

approved by IRB if it needs to be amended. The trial will be conducted according to the

Declaration of Helsinki, 7th version (2013).

This study will be designed to minimize the risk to participants, and the investigators will

explain the information of the study in detail. As an ethical clinical trial, the control group

will also be given conventional cessation treatments, including NRT and counselling. Also,

participants will be given screening and registration number in order to protect personal

information. Informed consent will be obtained from the participants prior to enrolling them

in the trial. Participants will be available to withdraw at any time, without any penalty.

Sample size

There are no previous studies on which to base the sample size calculation. This trial is

designed as a pilot study. According to the previous research on sample size determination

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for pilot trial, approximately 30 patients or greater was recommended to estimate the primary

outcomes that is cessation success rate. 7 Therefore, the number of total sample size was set at

40, considering a 20% drop-out rate. 8 Participants will be assigned to either the intervention

or control group at a ratio of 1:1.

Randomization

All participants will be assigned to either the intervention or control group while maintaining

an equivalent number of heavy (10 cigarettes per day or more) and light smokers in the two

groups. Block randomization with a block size of 4 will be used for the allocation. The

randomization will be conducted on a web-based randomization system by independent

investigator with no contact with the participants or researchers. In the case of an unavoidable

inability to access the website, the investigator will inform the researchers to which group a

participant has been assigned. All the randomization processes will be recorded by the web-

based randomization system.

Blinding

As an open-label trial, the T&CM programme will be applied only to the intervention group.

Neither the participants nor the clinical practitioners will be blinded during the clinical trial.

However, outcome assessors will be blinded for measuring the outcomes.

Interventions

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The intervention group will receive NRT, counselling, manual and ear acupuncture, and

aromatherapy, whereas the control group will be provided with NRT and counselling only.

The treatment period will 4 weeks, and treatments will be applied twice a week for the first 3

weeks and once in 4th week.

Nicotine Replacement Therapy (NRT)

At each visit, participants will be provided with nicotine patches (Nico-free patch, Daewoong

Co., South Korea) and nicotine gum (Nicorette gum, Johnson & Johnson Co., United States).

They will apply one nicotine patch every morning, and the attachment site will be changed

every day. One of Nico-free patch 30 (57mg), Nico-free patch 20 (38mg), and Nico-free

patch 10 (19mg) will be selected, depending on the dose, which is determined as follows: (1)

those who smoke 10 cigarettes per day or more will use 21 mg of nicotine (2) those who

smoke fewer than 10 cigarettes per day or weigh less than 45 kg will use 14 mg. 9 The

nicotine gum contains 2 mg (Nicorette gum, 2 mg), and patients can use up to 15 gum pieces

per day. 10

Counselling

Counselling will be performed by a Korean medical doctor who is qualified for smoking

cessation counselling. The counselling will require 5-10 minutes once a week. The counsellor

will teach each patient about the necessity of cessation, cessation methods, and withdrawal

symptoms with 5A-type (i.e., ‘ask’, ‘advise’, ‘assess’, ‘assist’, and ‘arrange’) counselling.

The 5A counselling will be applied in the following order: ‘asking the smoking status’;

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‘advising to stop smoking’; ‘assessing the will of not smoking’; ‘assisting the smoker in

cessation’; and ‘arranging a follow-up visit’. 11

Manual acupuncture

The intervention group will be treated 7 times during the treatment period on both sides of the

HT7(Shenmen), LI4(Hegu), ST36(Zusanli), LU7(Lieque), and LU6(Kongzui) acupoints.

Acupoints may be added depending on each participant at the doctor’s discretion. Acupoints

will be needled after disinfection, and stimulation will last for 20 minutes. Sterile needles

(Dongbang Co., South Korea) 0.20*30 mm in size will be used for the treatment.

Ear acupuncture

The intervention group will receive ear acupuncture treatment a total of 7 times at the

‘Shenmen’ ‘Lung’, ‘Pharynx’, ‘Trachea’, and ‘Endocrine’ acupoints. Needle stimulation will

alternately be from the right and left. The ear acupuncture sites will be patched until the next

visit. In the case a visit is delayed for more than 3 days, participants will be informed to tear

off intradermal ear acupuncture by themselves. Participants should self-stimulate these

acupoints 3-6 times a day to reduce the desire to smoke. Intradermal needles (Dongbang Co.,

South Korea) 0.2*1.5 mm in size will be used for the treatment.

Aromatherapy

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Participants in the intervention group will be provided with a bottle containing 20 mL of

mixed oil to aid control their tobacco use. The composition of the blended oil will be 4 drops

each of lavender, peppermint, and rosemary (Tisserand Co., United Kingdom) in 15 mL of

jojoba oil (Tisserand Co., United Kingdom). Participants will frequently self-massage 1-2

drops of the blended aroma oil behind their ears.

Outcome measures

Primary outcome

The primary outcome of this trial is the continuous abstinence rate at the end of treatment (4

weeks). Participants will be considered to have successfully ceased smoking upon smoking

fewer than 5 cigarettes during the 4-week treatment period, which will be evaluated by

expired carbon monoxide (CO) with a threshold of 6 ppm.

Secondary outcomes

The secondary outcomes are the 7-day cessation success rate, continuous abstinence rate,

participation rate, smoking reduction rate, amount of smoking, craving of smoking, expired

CO, pulmonary function (FEV1, FVC, FEV1/FVC), urine cotinine level, quality of life (EQ-

5D, EQ-VAS), FTND nicotine dependence score, and withdrawal symptoms (Minnesota

nicotine withdrawal scale, MNWS). The time points of the evaluations are shown in Table 1.

Assessment of adverse events

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All adverse events from the NRT, acupuncture and aromatherapy will be reported in detail

and patients will be treated by doctors. The most common adverse events are expected to be

skin erythema and pruritus at the sites of patch attachment. According to a previous study,

mild local skin reactions were observed in approximately 54% of patients. 12 Adverse events

should be discriminated from withdrawal symptoms, such as hunger, anxiety, depression,

constipation, cough and insomnia.

Data management and monitoring

All the collected data will be entered with double entry method and it will be encrypted. Data

will be monitored by Institute of Safety and Effectiveness Evaluation for Korean Medicine

(ISEE) of Kyung Hee University. This will strengthen the data accuracy and maintain quality

of data.

Statistical analyses

A statistician who is not related to this study will perform the statistical analyses for both the

intention-to-treat (ITT; all randomly assigned participants) and per-protocol (PP; participants

completed the trial without any protocol deviations) data using SAS. Missing data will be

handled using a qualitative method, i.e., filling the data points by asking the subjects for their

reason for withdrawal. Continuous abstinence rate, 7-day point prevalent rate, smoking

reduction rate, daily quantity of smoking, craving of smoking, expired carbon monoxide,

urine cotinine amount, quality of life (EQ-5D, EQ-VAS), FTND nicotine dependence score,

MNWS withdrawal symptoms, satisfaction, age, amount of drinking and amount of exercise

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are continuous variables that will be displayed as the mean, standard deviation, and minimum

and maximum value. Smoking status, cigarette taste, methods of attempted cessation, reason

of cessation failure, sex, education level, occupation and marital status are categorical

variables that will be shown as frequency. Independent t-tests for continuous variables and

chi-square tests for categorical variables will be used to examine significant differences

between the two groups. Two-sided p values less than 0.05 will be considered significant.

Fisher’s exact test will be used instead of the chi-square test when the expected value is less

than 5. All analyses will be conducted after study completion, and interim tests are not

planned.

Discussion

Nicotine dependence is recognized as a disease by itself, and smoking behaviour falls under

the category of ‘mental and behavioural disorders due to psychoactive substance use’

according to the International Classification of Diseases 10th revision. 13 It is necessary to

access to smoking cessation in terms of medical treatment. The U.S. Preventive Services Task

Force strongly recommends that doctors should intervene to help patients to cease smoking

by prescribing treatments approved by the Food and Drug Administration, such as NRT and

bupropion, if needed. 14

This study will investigate the effectiveness of T&CM for smoking cessation. The study is

designed to be a pragmatic randomized controlled trial because excessively controlling other

conditions does not reflect the real clinical field. 15 Participants in the intervention group will

also have the option of being provided with herbal medicines to relieve withdrawal symptoms.

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Additionally, the control group will be provided conventional treatments, including NRT and

counselling because not treating the control group would cause ethical issues and raise the

drop-out rate. As it is difficult to successfully cease smoking with a single intervention,

multiple interventions will be applied to the participants. 16 This will help to increase the

effects of the interventions as well as participant compliance. Meanwhile, successful smoking

cessation typically does not last long; as such, we will manage success rates with 5 follow-up

assessments.

The main intervention of this trial is acupuncture. Because nicotine patches are not

recommended for teenagers, acupuncture may be an appropriate treatment for facilitating

smoking cessation 17. Furthermore, acupuncture and aromatherapy have less-severe adverse

events than conventional drugs used for smoking cessation. Based on various studies,

frequently used manual acupoints for cessation treatment include HT7(Shenmen), 18-20

,

LI4(Hegu), 3 21 ST36(Zusanli),

21-23 LU7(Lieque),

4 21 and LU6(Kongzui).

24 According to the

guidelines on acupuncture treatment and counselling for smoking cessation, the ‘Shenmun’,

‘Lung’, ‘Endocrine’, ‘Pharynx’, ‘Trachea’, ‘Mouth’, and ‘Inner-nose’ ear acupoints are

recommended for cessation treatment. 25. In addition, some clinical trials have demonstrated

the effects of auricular acupuncture treatment for smoking cessation. 26-28

Aromatherapy can

also play a role in relieving withdrawal symptoms. Lavender oil 29 30

and rosemary oil 30 31

help to reduce anxiety after cessation, and peppermint oil 31 can relieve symptoms of

respiratory discomfort, such as phlegm and cough. NRT and counselling will be applied to

both the intervention and control groups as conventional treatments. This trial is designed

such that the T&CM tobacco control programme, including acupuncture, aromatherapy, NRT

and counselling, will be provided to the intervention group to raise the cessation rate.

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Smoking is a habitual behaviour, and smoking cessation requires a strong will. Thus,

participant satisfaction is equally important as intervention effectiveness. T&CM is expected

to be an effective method for helping individuals to quit smoking with emotional comfort,

which will be assessed by evaluating participant satisfaction and quality of life (SF-36). This

study is the first protocol of implementing the T&CM programme as a smoking cessation

treatment. Therefore, this study will examine the effectiveness and safety of several T&CM

interventions and will provide useful evidence for further studies.

Trial status

As of Oct 2016, 10 participants have been enrolled in this study, and 3 of them have

completed the 4-week treatment. The trial is ongoing and scheduled for completion in

January 2017.

List of abbreviations

T&CM: traditional & complementary medicine; NRT: nicotine replacement therapy; STOP:

Stop Tobacco Programme using traditional Korean medicine; FTND: Fagerstrom Test for

Nicotine Dependence; MNWS: Minnesota nicotine withdrawal scale; ISEE: Institute of

Safety and Effectiveness Evaluation for Korean Medicine

Declarations

Ethical approval and consent to participate

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This survey was approved by Institutional Review Board of Dunsan Korean Medicine

Hospital of Daejeon University (IRB No. DJDSKH-15-BM-11-1).

Authors’ contributions

SP and SJ drafted the manuscript. YLP and CSC designed the entire study. BHJ conducted

data analysis and interpretation. JAL and HYG edited the first manuscript. YCS and SKG

supervised this protocol. All authors read and approved the final manuscript.

Funding

None

Competing interests

The authors declare that there are no conflicts of interest regarding the publication of this

paper.

Data sharing statement

No additional data available

Acknowledgements

This research was supported by the Daejeon University Research Grants (2016).

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18. Chae Y, Yeom M, Han J, et al. Effect of acupuncture on anxiety-like behavior during

nicotine withdrawal and relevant mechanisms. Neurosci Lett 2008;430(2):98-102.

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19. Chae Y, Kang OS, Lee HJ, et al. Effect of acupuncture on selective attention for smoking-

related visual cues in smokers. Neurol Res 2010;32(Supple 1):27-30.

20. Chae Y, Park HJ, Kang OS, et al. Acupuncture attenuates autonomic responses to

smoking-related visual cues. Complement Ther Med 2011;19(Supple 1):S1-7.

21. Ma E, Chan T, Zhang O, et al. Effectiveness of acupuncture for smoking cessation in a

Chinese population. Asia Pac J Public Health 2015;27(2):NP2610-22.

22. Lamontagne Y, Annable L, Gagnon MA. Acupuncture for smokers: lack of long-term

therapeutic effect in a controlled study. Can Med Assoc J 1980;122(7):787-90.

23. McFadden DD, Chon TY, Croghan IT, et al. Trial of intensive acupuncture for smoking

cessation: a pilot study. Acupunct Med 2015;33(5):375-80.

24. He D, Medbo JI, Hostmark AT. Effect of acupuncture on smoking cessation or reduction:

an 8-month and 5-year follow-up study. Prev Medicine 2001;33(5):364-72.

25. The Association of Korean Medicine. Guideline on acupuncture treatment and

counselling for smoking cessation. 2010

26. Wu TP, Chen FP, Liu JY, et al. A randomized controlled clinical trial of auricular

acupuncture in smoking cessation. J Chin Med Assoc 2007;70(8):331-38.

27. White AR, Resch KL, Ernst E. Randomized trial of acupuncture for nicotine withdrawal

symptoms. Arch Intern Med 1998;158-(20):2251-55.

28. Waite NR, Clough JB. A single-blind, placebo-controlled trial of a simple acupuncture

treatment in the cessation of smoking. Br J Gen Pract 1998;48(433):1487-90.

29. Louis M, Kowalski SD. Use of aromatherapy with hospice patients to decrease pain,

anxiety, and depression and to promote an increased sense of well-being. Am J Hosp

Palliat Care 2002;19(6):381-86.

30. McCaffrey R, Thomas DJ, Kinzelman AO. The effects of lavender and rosemary essential

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oils on test‐taking anxiety among graduate nursing students. Holist Nurs Pract

2009;23(2):88-93.

31. Ben-Arye E, Dudai N, Eini A, et al. Treatment of upper respiratory tract infections in

primary care: a randomized study using aromatic herbs. Evid Based Complement

Alternat Med 2010;2011:690346.

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Table 1. Study schedule of the T&CM tobacco control programme.

Enrolment Treatment period Follow-up period

Day -10 0 7 10 14 17 21 28 42 56 84 112 168

Time point visit visit visit visit visit visit visit visit tele* tele visit tele visit

Informed consent ✘

Eligibility screening ✘

Allocation ✘

CAM + NRT

NRT

Demographic characteristics ✘

Physical examination ✘ ✘ ✘ ✘ ✘ ✘ ✘

Smoking-related variables ×

Amount of smoking ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘

Craving of smoking ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘

FTND ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘

Expired CO ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘

Urine test ✘ ✘ ✘ ✘

MNWS ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘

EQ-5D, EQ-VAS ✘ ✘ ✘ ✘ ✘ ✘

Pulmonary function test ✘ ✘ ✘

Compliance ✘ ✘ ✘ ✘ ✘ ✘

Adverse events ✘ ✘ ✘ ✘ ✘ ✘

Concomitant medication ✘ ✘ ✘ ✘ ✘ ✘

Satisfaction ✘

Non-smoking efforts ✘ ✘ ✘ ✘ ✘

Treatment history ✘ ✘ ✘ ✘ ✘

*tele: telephone

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Figure 1

110x153mm (150 x 150 DPI)

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SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*

Section/item Item No

Description Addressed on page number

Administrative information

Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym ______1______

Trial registration 2a Trial identifier and registry name. If not yet registered, name of intended registry ______7______

2b All items from the World Health Organization Trial Registration Data Set _Not applicable_

Protocol version 3 Date and version identifier ______7______

Funding 4 Sources and types of financial, material, and other support ______7______

Roles and

responsibilities

5a Names, affiliations, and roles of protocol contributors ______7______

5b Name and contact information for the trial sponsor ______7______

5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and

interpretation of data; writing of the report; and the decision to submit the report for publication, including

whether they will have ultimate authority over any of these activities

_____17______

5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint

adjudication committee, data management team, and other individuals or groups overseeing the trial, if

applicable (see Item 21a for data monitoring committee)

_Not applicable_

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2

Introduction

Background and

rationale

6a Description of research question and justification for undertaking the trial, including summary of relevant

studies (published and unpublished) examining benefits and harms for each intervention

______4______

6b Explanation for choice of comparators ______4______

Objectives 7 Specific objectives or hypotheses ______5______

Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group),

allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)

______5______

Methods: Participants, interventions, and outcomes

Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will

be collected. Reference to where list of study sites can be obtained

______5______

Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and

individuals who will perform the interventions (eg, surgeons, psychotherapists)

______6______

Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be

administered

____9,10,11___

11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose

change in response to harms, participant request, or improving/worsening disease)

______7______

11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence

(eg, drug tablet return, laboratory tests)

_____11______

11d Relevant concomitant care and interventions that are permitted or prohibited during the trial ______7______

Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood

pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg,

median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen

efficacy and harm outcomes is strongly recommended

_____11______

Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for

participants. A schematic diagram is highly recommended (see Figure)

___Figure 1___

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Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including

clinical and statistical assumptions supporting any sample size calculations

______8______

Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size ______5______

Methods: Assignment of interventions (for controlled trials)

Allocation:

Sequence

generation

16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any

factors for stratification. To reduce predictability of a random sequence, details of any planned restriction

(eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants

or assign interventions

______8______

Allocation

concealment

mechanism

16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered,

opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned

______8______

Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to

interventions

______8______

Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome

assessors, data analysts), and how

______8______

17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s

allocated intervention during the trial

_Not applicable_

Methods: Data collection, management, and analysis

Data collection

methods

18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related

processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of

study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known.

Reference to where data collection forms can be found, if not in the protocol

__21 (Table 1)__

18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be

collected for participants who discontinue or deviate from intervention protocols

__ 5,_Table 1__

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Data management 19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality

(eg, double data entry; range checks for data values). Reference to where details of data management

procedures can be found, if not in the protocol

_____12______

Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the

statistical analysis plan can be found, if not in the protocol

____12,13_____

20b Methods for any additional analyses (eg, subgroup and adjusted analyses) _Not applicable_

20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any

statistical methods to handle missing data (eg, multiple imputation)

_____12______

Methods: Monitoring

Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of

whether it is independent from the sponsor and competing interests; and reference to where further details

about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not

needed

_____12______

21b Description of any interim analyses and stopping guidelines, including who will have access to these interim

results and make the final decision to terminate the trial

_____13______

Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse

events and other unintended effects of trial interventions or trial conduct

_____12______

Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent

from investigators and the sponsor

_Not applicable_

Ethics and dissemination

Research ethics

approval

24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval ______7______

Protocol

amendments

25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes,

analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals,

regulators)

______7______

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Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and

how (see Item 32)

______7______

26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary

studies, if applicable

_Not applicable_

Confidentiality 27 How personal information about potential and enrolled participants will be collected, shared, and maintained

in order to protect confidentiality before, during, and after the trial

______7______

Declaration of

interests

28 Financial and other competing interests for principal investigators for the overall trial and each study site _____16______

Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that

limit such access for investigators

_____12______

Ancillary and post-

trial care

30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial

participation

_____12______

Dissemination policy 31a Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals,

the public, and other relevant groups (eg, via publication, reporting in results databases, or other data

sharing arrangements), including any publication restrictions

_Not applicable_

31b Authorship eligibility guidelines and any intended use of professional writers _Not applicable_

31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code _Not applicable_

Appendices

Informed consent

materials

32 Model consent form and other related documentation given to participants and authorised surrogates __Appendix 2__

Biological

specimens

33 Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular

analysis in the current trial and for future use in ancillary studies, if applicable

_Not applicable_

*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items.

Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons

“Attribution-NonCommercial-NoDerivs 3.0 Unported” license.

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Study protocol of a pragmatic randomized controlled pilot trial: Clinical effectiveness on smoking cessation of T&CM

interventions, including acupuncture and aromatherapy, in combination with nicotine replacement therapy

Journal: BMJ Open

Manuscript ID bmjopen-2016-014574.R1


Date Submitted by the Author: 20-Feb-2017

Complete List of Authors: JANG, SOOBIN Park, Sunju; Daejeon university Jang, Bo-Hyoung Park, Yu Lee Lee, Ju Ah; Korea Institute of Oriental Medicine, Go, Hoyeon; Semyung University, Korea, Korean Internal Medicine Cho, Chung Sik; Daejeon University College of Korean Medicine, Shin, Yong-Cheol Ko, Seong-Gyu; Kyung Hee University,

Primary Subject

Heading: Smoking and tobacco


Keywords: Smoking, tobacco control, study protocol, acupuncture, COMPLEMENTARY MEDICINE, Korean medicine


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Study protocol of a pragmatic randomized controlled pilot trial: Clinical

effectiveness on smoking cessation of T&CM interventions, including

acupuncture and aromatherapy, in combination with nicotine replacement

therapy

Soobin Jang1,*, Sunju Park

2,*, Bo-Hyoung Jang

1, Yu Lee Park

1, Ju Ah Lee

3, Chung-Sik Cho

4,


1, Seong-Gyu Ko

1,§



Seong-Gyu Ko M.D., MPH, Ph.D.,

Tel: + 82-2-961-0329, Fax: +82-2-2270-0344








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Email address










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Abstract

Introduction: Nicotine dependence is a disease by itself, and tobacco use is related to 6

million deaths annually worldwide. Recently, there has been a growing interest in many

countries in using traditional & complementary medicine (T&CM), especially acupuncture,

as a therapeutic intervention for smoking cessation. The aim of this pilot study is to

investigate the effectiveness of T&CM interventions on smoking cessation.


medicine) study is designed to be a pragmatic open-label, randomized, pilot trial. This trial

will estimate whether adding T&CM methods (i.e., ear and body acupuncture, aromatherapy)

to conventional cessation methods (i.e., nicotine replacement therapy (NRT), counselling)

increase smoking cessation success rate. Forty participants more than 19 years old and

capable of communicating normally in Korean will be recruited. They will also be current

smokers who meet one of the following criteria: 1) smoke more than 10 cigarettes a day; 2)

smoke less than 10 cigarettes a day and previously failed to cease smoking; or 3) smoke

fewer than 10 cigarettes a day and have a nicotine dependence score (Fagerstrom Test for

Nicotine Dependence) of 4 points or more. The trial will consist of 4 weeks of treatment and

a 20-week follow-up period. A statistician will perform the statistical analyses for both the


who completed the trial without any protocol deviations) data using SAS.


of the Dunsan Korean Medicine Hospital of Daejeon University (IRB reference no.:

DJDSKH-15-BM-11-1, Protocol No. version. 4.1.).

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Trial registration: ClinicalTrials.gov (NCT02768025).


Article summary


• This is the protocol of implementing the Traditional & Complementary Medicine (T&CM)

combining with conventional therapy as a smoking cessation treatment.

• Randomization process was designed to maintain an equivalent number of heavy (10

cigarettes per day or more) and light smokers in the two groups.

• Our study protocol is designed as the pragmatic randomised controlled trial design to reflex

the real world involving multidisciplinary collaborators.

• This is a pilot study, so the sample size is rather small.

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Introduction


related to tobacco use. 1 Smoking is associated with not only nearly every cancer but also

many types of chronic diseases, such as coronary artery disease, stroke, and asthma. 2

Tobacco-related deaths are expected to increase by 8 million by 2030 if proper smoking

cessation policies are not implemented. 1



an American trial, 3 40% of smokers who had been treated with acupuncture successfully

ceased smoking. In a Norwegian trial, 4 the experimental group received acupuncture


LU6 (Kongzui) and LU7 (Leique) led to significant changes in the taste of cigarettes and

desire to smoke compared with the control group, which had been treated at different

acupoints.

This clinical trial is going to verify the effectiveness of acupuncture and aromatherapy in

combination with nicotine replacement therapy (NRT) and counselling, which are standard

regimens applied for smoking cessation. The intervention of this trial is referred to as the

‘T&CM tobacco control programme’, which is a combination of ear and body acupuncture,

aromatherapy, NRT and counselling. NRT and counselling have been widely used in

conventional Western medicine in addition to such drugs as varenicline and bupropion. 5 In

this T&CM tobacco control programme, ear acupuncture, body acupuncture, and

aromatherapy will be applied for smoking cessation instead of Western interventions. The

primary objective of this trial is to estimate whether the smoking cessation success rate

increases with the application of the T&CM tobacco control programme. The secondary aim

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is to evaluate the satisfaction of participants in the T&CM tobacco control programme. This

study is the second research result of our STOP (Stop Tobacco Programme using traditional

Korean medicine) study series.

Methods

Trial design

The STOP study design is a pragmatic open-label, randomized pilot study. This trial will

compare conventional cessation treatment methods (i.e., NRT, counselling) alone and in

combination with T&CM methods (i.e., acupuncture, aromatherapy). The hypothesis of this

trial is to investigate whether the smoking cessation rate increases by adding T&CM methods

to conventional treatment. The trial will consist of 4 weeks of treatment with 7 visits and a

20-week follow-up period. An overview of the trial process is shown in Figure 1.


Smokers who want to quit smoking will be recruited over 6 months at the Dunsan Korean


recruiting participants will be posted publicly inside and outside of the hospital. It will also be

recruited actively by posting leaflets of the bulletin boards of the offices near the hospital.

Potential participants will contact our information centre via email or telephone. Those who

agree to participate in the study and provide written informed consent will be eligible to

participate in the study.

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Inclusion criteria

Participants will be more than 19 years old and able to communicate normally in Korean, and

those who do not disinclined to use NRT will be enrolled. They will also be current smokers

who meet one of the following criteria: 1) smokes more than 10 cigarettes a day; 2) smokes

less than 10 cigarettes a day and previously failed to cease smoking; or 3) smokes fewer than

10 cigarettes a day and has a nicotine dependence score (Fagerstrom Test for Nicotine

Dependence, FTND) of 4 points or more. The FTND is a representative questionnaire that

evaluates nicotine dependence. It consists of 6 questions, and the score ranges from 0 to 10.

Scores of 1 to 3, 4 to 6, and 7 to 10 indicate low, moderate, and high levels of nicotine

dependence, respectively. Questions 1 and 2 assess the heaviness of smoking index, and high

nicotine dependence is indicated if the sum of these two scores is 4 or more. 6

Exclusion criteria








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study for the sake of the participant’s health. Only the reason for withdrawal will be collected

and no more follow-up will be progressed.

Ethical and dissemination

This study was approved by the Institutional Review Board of the Dunsan Korean Medicine

Hospital of Daejeon University (IRB reference no.: DJDSKH-15-BM-11-1, Protocol No.

version. 4.1.) and registered at ClinicalTrials.gov (NCT02768025). The protocol will be re-

approved by IRB if it needs to be amended. The trial will be conducted according to the

Declaration of Helsinki, 7th version (2013).

This study will be designed to minimize the risk to participants, and the investigators will

explain the information of the study in detail. As an ethical clinical trial, the control group

will also be given conventional cessation treatments, including NRT and counselling. Also,

participants will be given screening and registration number in order to protect personal

information. Informed consent will be obtained from the participants prior to enrolling them

in the trial. Participants will be available to withdraw at any time, without any penalty.

Sample size

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designed as a pilot study. According to the previous research on sample size determination

for pilot trial, approximately 30 patients or greater was recommended to estimate the primary

outcomes that is cessation success rate. 7 Therefore, the number of total sample size was set at

40, considering a 20% drop-out rate. 8 Participants will be assigned to either the intervention

or control group at a ratio of 1:1.

Randomization

All participants will be assigned to either the intervention or control group while maintaining

an equivalent number of heavy (10 cigarettes per day or more) and light smokers in the two


randomization will be conducted on a web-based randomization system by independent

investigator with no contact with the participants or researchers. In the case of an unavoidable

inability to access the website, the investigator will inform the researchers to which group a

participant has been assigned. All the randomization processes will be recorded by the web-

based randomization system.

Blinding




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Interventions

The intervention group will receive NRT, counselling, body and ear acupuncture, and


The treatment period will 4 weeks, and treatments will be applied twice a week for the first 3

weeks and once in 4th week.




They will apply one nicotine patch every morning, and the attachment site will be changed

every day. Either Nico-free patch 20 (38mg) or Nico-free patch 10 (19mg) will be selected,

depending on the dose, which is determined as follows: (1) those who smoke 10 cigarettes

per day or more will use Nico-free patch 20 (38mg) (2) those who smoke fewer than 10

cigarettes per day or weigh less than 45 kg will use Nico-free patch 10 (19mg) 9 The nicotine

gum contains 2 mg (Nicorette gum, 2 mg), and patients can use up to 15 gum pieces per day.

10

Counselling

Counselling will be performed by a Korean medical doctor who is qualified for smoking

cessation counselling. The counselling will require 5-10 minutes once a week. The counsellor

will teach each patient about the necessity of cessation, cessation methods, and withdrawal

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symptoms with 5A-type (i.e., ‘ask’, ‘advise’, ‘assess’, ‘assist’, and ‘arrange’) counselling.

The 5A counselling will be applied in the following order: ‘asking the smoking status’;

‘advising to stop smoking’; ‘assessing the will of not smoking’; ‘assisting the smoker in

cessation’; and ‘arranging a follow-up visit’. 11 Even though recruited participants already

will have resolved to quit smoking, entire 5A counselling will be done to reinforce their

willingness.

Acupuncture

The intervention group will receive acupuncture treatment on body acupoints and ear

acupoints. The intervention group will be treated 7 times during the treatment period on both

sides of the HT7 (Shenmen), LI4 (Hegu), ST36 (Zusanli), LU7 (Lieque), and LU6 (Kongzui)

acupoints. Acupoints may be added depending on each participant at the doctor’s discretion.

Acupoints will be needled after disinfection, and stimulation will last for 20 minutes by

qualified Korean medical doctor who trained in Korean medicine for 6 years with more than

5 years of clinical experience. Sterile needles (Dongbang Co., South Korea) 0.20×30 mm in

size will be used for the treatment.

The intervention group will receive ear acupuncture treatment a total of 7 times at the

‘Shenmen’ ‘Lung’, ‘Pharynx’, ‘Trachea’, and ‘Endocrine’ acupoints. Needle stimulation will

alternately be from the right and left. The ear acupuncture sites will be patched until the next

visit. In the case a visit is delayed for more than 3 days, participants will be informed to tear

off intradermal ear acupuncture by themselves. Participants should self-stimulate these

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acupoints 3-6 times a day to reduce the desire to smoke. Intradermal needles (Dongbang Co.,

South Korea) 0.2×1.5 mm in size will be used for the treatment.

Aromatherapy

Participants in the intervention group will be provided with a bottle containing 20 mL of

mixed oil to aid control their tobacco use. The composition of the blended oil will be 4 drops

each of lavender, peppermint, and rosemary (Tisserand Co., United Kingdom) in 15 mL of

jojoba oil (Tisserand Co., United Kingdom). Participants will frequently self-massage 1-2

drops of the blended aroma oil behind their ears.

Outcome measures

Primary outcome




exhaled carbon monoxide (CO) with a threshold of 6 ppm.

Secondary outcomes

The secondary outcomes are the 7-day point prevalence abstinence, prolonged abstinence rate,

participation rate, amount of smoking, tobacco craving, exhaled CO, pulmonary function

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(FEV1, FVC, FEV1/FVC), quality of life (EQ-5D, EQ-VAS), FTND nicotine dependence

score, and withdrawal symptoms (Minnesota nicotine withdrawal scale, MNWS). The time

points of the evaluations are shown in Table 1.


All adverse events from the NRT, acupuncture and aromatherapy will be reported in detail

and patients will be treated by doctors. The most common adverse events are expected to be

skin erythema and pruritus at the sites of patch attachment. According to a previous study,

mild local skin reactions were observed in approximately 54% of patients. 12 Adverse events

should be discriminated from withdrawal symptoms, such as hunger, anxiety, depression,

constipation, cough and insomnia.


All the collected data will be entered with double entry method and it will be encrypted. Data

will be monitored by Institute of Safety and Effectiveness Evaluation for Korean Medicine

(ISEE) of Kyung Hee University. This will strengthen the data accuracy and maintain quality

of data.


A statistician who is not related to this study will perform the statistical analyses for both the


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completed the trial without any protocol deviations) data using SAS. In case of drop-outs and

withdrawals, reasons of each missing value will be captured and documented. Missing values

will be substituted by using the multiple imputation method. Continuous abstinence rate, 7-

day point prevalence abstinence, daily quantity of smoking, tobacco craving, exhaled carbon

monoxide, quality of life (EQ-5D, EQ-VAS), FTND nicotine dependence score, MNWS

withdrawal symptoms, satisfaction, age, amount of drinking and amount of exercise are

continuous variables that will be displayed as the mean, standard deviation, and minimum

and maximum value. Smoking status, cigarette taste, methods of attempted cessation, reason

of cessation failure, sex, education level, occupation and marital status are categorical

variables that will be shown as frequency. Independent t-tests for continuous variables and

chi-square tests for categorical variables will be used to examine significant differences

between the two groups. Two-sided p values less than 0.05 will be considered significant.

Fisher’s exact test will be used instead of the chi-square test when the expected value is less

than 5. All analyses will be conducted after study completion, and interim tests are not

planned.

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Discussion

Nicotine dependence is recognized as a disease by itself, and smoking behaviour falls under

the category of ‘mental and behavioural disorders due to psychoactive substance use’

according to the International Classification of Diseases 10th revision. 13 It is necessary to

access to smoking cessation in terms of medical treatment. The U.S. Preventive Services Task

Force strongly recommends that doctors should intervene to help patients to cease smoking

by prescribing treatments approved by the Food and Drug Administration, such as NRT and

bupropion, if needed. 14


designed to be a pragmatic randomized controlled trial because excessively controlling other

conditions does not reflect the real clinical field. 15 The control group will be provided

conventional treatments, including NRT and counselling because not treating the control

group would cause ethical issues and raise the drop-out rate. As it is difficult to successfully

cease smoking with a single intervention, multiple interventions will be applied to the

participants. 16 This will help to increase the effects of the interventions as well as participant

compliance. Meanwhile, successful smoking cessation typically does not last long; as such,

we will manage success rates with 5 follow-up assessments.

The main intervention of this trial is acupuncture. 17 Based on various studies, frequently used

body acupoints for cessation treatment include HT7 (Shenmen), 18-20

, LI4 (Hegu), 3 21 ST36

(Zusanli), 21-23

LU7 (Lieque), 4 21 and LU6 (Kongzui).

24 According to the guidelines on

acupuncture treatment and counselling for smoking cessation, the ‘Shenmun’, ‘Lung’,

‘Endocrine’, ‘Pharynx’, ‘Trachea’, ‘Mouth’, and ‘Inner-nose’ ear acupoints are recommended

for cessation treatment. 25. In addition, some clinical trials have demonstrated the effects of

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auricular acupuncture treatment for smoking cessation. 26-28

Aromatherapy can also play a

role in relieving withdrawal symptoms. Lavender oil 29 30

and rosemary oil 30 31

help to reduce

anxiety after cessation, and peppermint oil 31 can relieve symptoms of respiratory discomfort,

such as phlegm and cough. NRT and counselling will be applied to both the intervention and

control groups as conventional treatments. This trial is designed such that the T&CM tobacco

control programme, including acupuncture, aromatherapy, NRT and counselling, will be

provided to the intervention group to raise the cessation rate.

However, there are several limitations in this study. First, even though NRT which will be

applied to both groups is proved method of cessation treatment, there is possibility of bias

induced by unblindness. In order to minimize the potential bias, researcher will explain about

that enough at the initial stage. Second, this is pilot study with small sample size, therefore it

is needed to conduct large-scale clinical trial later.


participant satisfaction is equally important as intervention effectiveness. T&CM is expected

to be an effective method for helping individuals to quit smoking with emotional comfort,

which will be assessed by evaluating participant satisfaction and quality of life (SF-36). This

study is the first protocol of implementing the T&CM combining with conventional therapy

as a smoking cessation treatment in Korea. Therefore, this study will examine the

effectiveness and safety of several T&CM interventions and will provide useful evidence for

further studies.

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Trial status


completed the 4-week treatment. The trial is ongoing.






Declarations




Authors’ contributions

SP and SJ drafted the manuscript. YLP, BHJ and CSC designed the study. JAL and HYG

edited the first manuscript. YCS and SKG supervised this protocol. All authors read and

approved the final manuscript.

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Funding

None

Competing interests


paper.



Acknowledgements

This research was supported by a grant of the Korea Health Technology R&D Project through

the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health

& Welfare, Republic of Korea (grant number : HI12C1889). JAL was supported by grants

from Korea Institute of Oriental Medicine (K17111).

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References

1. World Health Organization. Third WHO Report on the Global Tobacco Epidemic. Geneva:

World Health Organization 2012.

2. Siahpush M MA, Hammond D, Fong GT. Socioeconomic and country variations in


from the 2002 International Tobacco Control (ITC) Four Country Survey. Tobacco

Control 2006;15(Supple.3):iii65-iii70.

3. Bier ID WJ, Studt P, Shakleton M. Auricular Acupuncture, Education, and Smoking

Cessation: A Randomized, Sham-Controlled Trial. American Journal of Public Health

2002;92(10):1642-47.

4. He D BJ, Høstmark AT. Effects of acupuncture on smoking cessation or reduction for

motivated smokers. Preventive Medicine 1997;26(2):208-14.

5. Cahill K SS, Perera R, Lancaster T. Pharmacological interventions for smoking cessation:

an overview and networkmeta-analysis (Review). Cochrane Database of Systematic

Reviews 2013(5):Art.No.: CD009329.

6. Heatherton TF KL, Frecker RC, Fagerström KO. The Fagerstrom test for nicotine

dependence: a revision of the Fagerström tolerance questionnaire. British Journal of

Addiction 1991;86(9):1119-27.

7. RH B. On the use of a pilot sample for sample size determination. Stat Med

1995;14(17):1933-40.

8. MA H. Considerations in determining sample size for pilot studies. Research in Nursing &

Health 2008;31(2):180-91.

9. Buller DB HA, Severson HH, Borland R, Slater MD, Bettinghaus EP, Tinkelman D, Cutter

GR, Woodall WG. Effect of nicotine replacement therapy on quitting by young adults

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in a trial comparing cessation services. Journal of Public Health Management and

Practice 2014;20(2):E7-E15.

10. Tosanguan J CN. Cost-effectiveness analysis of clinical smoking cessation interventions

in Thailand. Addiction 2016;111(2):340-50.

11. Chase EC MS, Halpin HA. Medicaid provider delivery of the 5A's for smoking cessation

counseling. Nicotine & tobacco research 2007;9(11):1095-101.

12. Fiore MC JD, Baker TB, Kenford SL. Tobacco dependence and the nicotine patch.

Clinical guidelines for effective use. JAMA 1992;268(19):2687-94.

13. World Health Organization. International Classification of Diseases, 10th revision, online

versions 2016 Available from:

http://apps.who.int/classifications/icd10/browse/2016/en.

14. U.S. Preventive Services Task Force. The Guide to Clinical Preventive Services. Darby,

PA: DIANE Publishing 2008.

15. Agency for Healthcare Research and Quality. Using pragmatic clinical trials to test the

effectiveness of patient-centered medical home models in real-world settings PCMH

Research Methods Series 2013;No. 13-0030-EF

16. Fiore MC, Jaén CR, Baker TB, et al. Treating tobacco use and dependence: 2008 Update.

Rockville, MD: US Department of Health and Human Services 2008.

17. Stead LF, Perera R, Bullen C, et al. Nicotine replacement therapy for smoking cessation

(Review). Cochrane Database Syst Rev 2012(11):CD000146.

18. Chae Y, Yeom M, Han J, et al. Effect of acupuncture on anxiety-like behavior during

nicotine withdrawal and relevant mechanisms. Neurosci Lett 2008;430(2):98-102.

19. Chae Y, Kang OS, Lee HJ, et al. Effect of acupuncture on selective attention for smoking-

related visual cues in smokers. Neurol Res 2010;32(Supple 1):27-30.

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smoking-related visual cues. Complement Ther Med 2011;19(Supple 1):S1-7.

21. Ma E, Chan T, Zhang O, et al. Effectiveness of acupuncture for smoking cessation in a

Chinese population. Asia Pac J Public Health 2015;27(2):NP2610-22.


therapeutic effect in a controlled study. Can Med Assoc J 1980;122(7):787-90.

23. McFadden DD, Chon TY, Croghan IT, et al. Trial of intensive acupuncture for smoking

cessation: a pilot study. Acupunct Med 2015;33(5):375-80.

24. He D, Medbo JI, Hostmark AT. Effect of acupuncture on smoking cessation or reduction:

an 8-month and 5-year follow-up study. Prev Medicine 2001;33(5):364-72.


counselling for smoking cessation. 2010


acupuncture in smoking cessation. J Chin Med Assoc 2007;70(8):331-38.

27. White AR, Resch KL, Ernst E. Randomized trial of acupuncture for nicotine withdrawal

symptoms. Arch Intern Med 1998;158-(20):2251-55.


treatment in the cessation of smoking. Br J Gen Pract 1998;48(433):1487-90.



Palliat Care 2002;19(6):381-86.

30. McCaffrey R, Thomas DJ, Kinzelman AO. The effects of lavender and rosemary essential

oils on test‐taking anxiety among graduate nursing students. Holist Nurs Pract

2009;23(2):88-93.

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Alternat Med 2010;2011:690346.

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Day -10 0 7 10 14 17 21 28 42 56 84 112 168




Allocation ✘

T&CM + NRT

NRT





Tobacco craving ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘

FTND ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘

Exhaled CO ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘

MNWS ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘

EQ-5D, EQ-VAS ✘ ✘ ✘ ✘ ✘ ✘





Satisfaction ✘



*tele: telephone

*T&CM: traditional & complementary medicine

* NRT: nicotine replacement therapy

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* FTND: Fagerstrom test for nicotine dependence

* MNWS: Minnesota nicotine withdrawal scale

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Figure 1

110x153mm (150 x 150 DPI)

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1










Roles and

responsibilities






_____17______




_Not applicable_

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2

Introduction

Background and

rationale



______4______





______5______




______5______



______6______


administered

____9,10,11___



______7______



_____11______






_____11______



___Figure 1___

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3



______8______



Allocation:

Sequence

generation





______8______

Allocation

concealment

mechanism



______8______


interventions

______8______



______8______



_Not applicable_


Data collection

methods





__21 (Table 1)__



__ 5,_Table 1__

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4




_____12______



____12,13_____




_____12______

Methods: Monitoring




needed

_____12______



_____13______



_____12______



_Not applicable_


Research ethics

approval


Protocol

amendments



regulators)

______7______

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5


how (see Item 32)

______7______



_Not applicable_



______7______

Declaration of

interests




_____12______

Ancillary and post-

trial care


participation

_____12______




_Not applicable_



Appendices

Informed consent

materials


Biological

specimens



_Not applicable_




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Study protocol of a pragmatic randomized controlled pilot trial: Clinical effectiveness on smoking cessation of

traditional and complementary medicine interventions, including acupuncture and aromatherapy, in combination

with nicotine replacement therapy

Journal: BMJ Open

Manuscript ID bmjopen-2016-014574.R2


Date Submitted by the Author: 03-Apr-2017

Complete List of Authors: JANG, SOOBIN Park, Sunju; Daejeon university Jang, Bo-Hyoung Park, Yu Lee Lee, Ju Ah; Korea Institute of Oriental Medicine,

Cho, Chung Sik; Daejeon University College of Korean Medicine, Go, Hoyeon; Semyung University, Korea, Korean Internal Medicine Shin, Yong-Cheol Ko, Seong-Gyu; Kyung Hee University,

Primary Subject Heading:

Smoking and tobacco


Keywords: Smoking, tobacco control, study protocol, acupuncture, COMPLEMENTARY MEDICINE, Korean medicine


BMJ Open on A


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Study protocol of a pragmatic randomized controlled pilot trial: Clinical

effectiveness on smoking cessation of traditional and complementary

medicine interventions, including acupuncture and aromatherapy, in

combination with nicotine replacement therapy

Soobin Jang1,3,*

, Sunju Park2,*, Bo-Hyoung Jang

1, Yu Lee Park

1, Ju Ah Lee

3, Chung-Sik Cho

4,


1, Seong-Gyu Ko

1,§



Seong-Gyu Ko M.D., MPH, Ph.D.

Tel: + 82-2-961-0329, Fax: +82-2-2270-0344








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Email addresses










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Abstract

Introduction: Nicotine dependence is a disease, and tobacco use is related to 6 million

deaths annually worldwide. Recently, in many countries, there has been growing interest in

the use of traditional and complementary medicine (T&CM) methods, especially acupuncture,

as therapeutic interventions for smoking cessation. The aim of this pilot study is to

investigate the effectiveness of T&CM interventions on smoking cessation.


medicine) study is designed to be a pragmatic open-label, randomized, pilot trial. This trial

will evaluate whether adding T&CM methods (i.e., ear and body acupuncture, aromatherapy)

to conventional cessation methods (i.e., nicotine replacement therapy (NRT), counselling)

increases smoking cessation rates. Forty participants over 19 years old who are capable of

communicating in Korean will be recruited. They will be current smokers who meet one of

the following criteria: 1) smoke more than 10 cigarettes a day, 2) smoke less than 10

cigarettes a day and previously failed to cease smoking, or 3) smoke fewer than 10 cigarettes

a day and have a nicotine dependence score (Fagerstrom Test for Nicotine Dependence) of 4

points or more. The trial will consist of 4 weeks of treatment and a 20-week follow-up period.

A statistician will perform the statistical analyses for both the intention-to-treat (ITT; all

randomly assigned participants) and per-protocol (PP; participants who completed the trial

without any protocol deviations) data using SAS.


of the Dunsan Korean Medicine Hospital of Daejeon University (IRB reference no:

DJDSKH-15-BM-11-1, Protocol No. version 4.1.).

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Trial registration: ClinicalTrials.gov (NCT02768025)


Article summary


• This article presents a protocol for implementing traditional and complementary medicine

(T&CM) along with conventional therapy as a smoking cessation treatment.

• A randomization process is used to maintain an equivalent number of heavy (10 cigarettes

per day or more) and light smokers in the two groups.

• Our study protocol is designed as a pragmatic, randomized controlled trial designed to reflect

the real world involving multidisciplinary collaborators.

• This is a pilot study; therefore, the sample size is small.

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Introduction


related to tobacco use.[1] Smoking is associated with not only nearly every cancer but also

many types of chronic diseases, such as coronary artery disease, stroke, and asthma.[2]

Tobacco-related deaths are expected to increase by 8 million by 2030 if effective smoking

cessation policies are not implemented.[1]



an American trial,[3] 40% of smokers who had been treated with acupuncture successfully

ceased smoking. In a Norwegian trial,[4] the experimental group received acupuncture


LU6 (Kongzui) and LU7 (Leique) led to significant changes in the taste of cigarettes and

desire to smoke compared with the control group, who had been treated at different acupoints.

This clinical trial aims to verify the effectiveness of acupuncture and aromatherapy in

combination with nicotine replacement therapy (NRT) and counselling, which are standard

regimens applied for smoking cessation. The intervention of this trial is referred to as the

‘T&CM tobacco control programme’, which involves a combination of ear and body

acupuncture, aromatherapy, NRT and counselling. NRT and counselling have been widely

used in conventional Western medicine in addition to such drugs as varenicline and

bupropion.[5] In this T&CM tobacco control programme, ear acupuncture, body acupuncture,

and aromatherapy will be applied instead of Western interventions for smoking cessation.

The primary objective of this trial is to evaluate whether the smoking cessation success rate

increases with the application of the T&CM tobacco control programme. The secondary

objective is to evaluate the satisfaction of the participants in the T&CM tobacco control

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programme. This study represents the second research result of our STOP (Stop Tobacco

Programme using traditional Korean medicine) study series.

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Methods

Trial design

The STOP study design is a pragmatic open-label, randomized pilot study. This trial will

compare conventional cessation treatment methods (i.e., NRT, counselling) alone and in

combination with T&CM methods (i.e., acupuncture, aromatherapy). The hypothesis of this

trial is to investigate whether the smoking cessation rate increases by adding T&CM methods

to conventional treatment. The trial will consist of 4 weeks of treatment with 7 visits and a

20-week follow-up period. An overview of the trial process is shown in Figure 1.


Smokers who want to quit smoking will be recruited over 6 months at the Dunsan Korean


recruiting participants will be posted publicly inside and outside of the hospital. It will also be

recruited actively by posting leaflets of the bulletin boards of the offices near the hospital.

Potential participants will contact our information centre via email or telephone. Those who

agree to participate in the study and provide written informed consent will be eligible to

participate in the study.

Inclusion criteria

Participants will be more than 19 years old and able to communicate normally in Korean, and

those who do not disinclined to use NRT will be enrolled. They will also be current smokers

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who meet one of the following criteria: 1) smokes more than 10 cigarettes a day; 2) smokes

less than 10 cigarettes a day and previously failed to cease smoking; or 3) smokes fewer than

10 cigarettes a day and has a nicotine dependence score (Fagerstrom Test for Nicotine

Dependence, FTND) of 4 points or more. The FTND is a representative questionnaire that

evaluates nicotine dependence. It consists of 6 questions, and the score ranges from 0 to 10.

Scores of 1 to 3, 4 to 6, and 7 to 10 indicate low, moderate, and high levels of nicotine

dependence, respectively. Questions 1 and 2 assess the heaviness of smoking index, and high

nicotine dependence is indicated if the sum of these two scores is 4 or more. [6]

Exclusion criteria












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study for the sake of the participant’s health. Only the reason for withdrawal will be collected

and no more follow-up will be progressed.

Ethical approval and dissemination

This study has been approved by the Institutional Review Board of the Dunsan Korean

Medicine Hospital of Daejeon University (IRB reference no: DJDSKH-15-BM-11-1,

Protocol No. version. 4.1.) and registered at ClinicalTrials.gov (NCT02768025). The protocol

will be re-approved by IRB if it requires amendment. The trial will be conducted according to

the Declaration of Helsinki, 7th version (2013).

This study is designed to minimize the risk to participants, and the investigators will explain

the study to the participants in detail. As an ethical clinical trial, the control group will also be

given conventional cessation treatments, including NRT and counselling. Participants will be

screened and provided with a registration number to protect their personal information.

Informed consent will be obtained from the participants prior to enrolling them in the trial.

Participants will be allowed to withdraw at any time without penalty.

Sample size


designed as a pilot study. According to previous research on sample size determination for

pilot trials, approximately 30 patients or greater was recommended to estimate a primary

outcome of cessation success rate.[7] Therefore, the total sample size was set at 40,

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considering a 20% drop-out rate.[8] Participants will be assigned to either the intervention or

control group at a ratio of 1:1.

Randomization

All of the participants will be assigned to either the intervention or control group, with

equivalent numbers of heavy (10 cigarettes per day or more) and light smokers in the two


randomization will be conducted via a web-based randomization system by an independent

investigator with no contact with the participants or researchers. In the event of website

inaccessibility, the investigator will inform the researchers to which group a participant has

been assigned. The randomization process will be recorded by the web-based randomization

system.

Blinding




Interventions

The intervention group will receive NRT, counselling, body and ear acupuncture, and


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The treatment period will be 4 weeks. The treatments will be applied twice a week for the

first 3 weeks and then once in the 4th week.




Each participant will apply one nicotine patch every morning, and the attachment site will be

changed every day. Either the Nico-free patch 20 (38 mg) or Nico-free patch 10 (19 mg) will

be selected depending on the dose as follows: (1) those who smoke 10 cigarettes per day or

more will use the Nico-free patch 20 (38 mg), and (2) those who smoke fewer than 10

cigarettes per day or weigh less than 45 kg will use the Nico-free patch 10 (19 mg)[9] The

nicotine gum contains 2 mg of nicotine (Nicorette gum, 2 mg), and participants can use up to

15 gum pieces per day.[10]

Counselling

Counselling will be performed by a Korean medical doctor who is qualified to administer

smoking cessation counselling. Each counselling session will require 5-10 minutes once a

week. The counsellor will teach the patient about the necessity of cessation, cessation

methods, and withdrawal symptoms with 5A-type (i.e., ‘ask’, ‘advise’, ‘assess’, ‘assist’, and

‘arrange’) counselling. The 5A counselling steps will be applied in the following order:

‘asking about smoking status’; ‘advising to stop smoking’; ‘assessing the will to not smoke’;

‘assisting the smoker in cessation’; and ‘arranging a follow-up visit’.[11] Although all of the

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enrolled participants will have already resolved to quit smoking, 5A counselling will be

performed to reinforce their willingness.

Acupuncture

The intervention group will receive acupuncture treatment on body acupoints and ear

acupoints. The intervention group will be treated 7 times during the treatment period on both

sides of the HT7 (Shenmen), LI4 (Hegu), ST36 (Zusanli), LU7 (Lieque), and LU6 (Kongzui)

acupoints. Acupoints may be added depending on each participant at the doctor’s discretion.

Acupoints will be needled after disinfection. Stimulation will be performed for 20 minutes by

a qualified Korean medical doctor with 6 years of training in Korean medicine and more than

5 years of clinical experience. Sterile needles (Dongbang Co., South Korea), 0.20×30 mm in

size, will be used for treatment. The intervention group will receive ear acupuncture

treatment a total of 7 times at the ‘Shenmen’ ‘Lung’, ‘Pharynx’, ‘Trachea’, and ‘Endocrine’

acupoints. Needle stimulation will alternate between the right and left sides. The ear

acupuncture sites will be patched until the next visit. In the event that a visit is delayed for

more than 3 days, the participant will be instructed to remove the intradermal ear acupuncture

himself/herself. Participants will be instructed to self-stimulate the acupoints 3-6 times a day

to reduce the desire to smoke. Intradermal needles (Dongbang Co., South Korea), 0.2×1.5

mm in size, will be used for the treatment.

Aromatherapy

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Participants in the intervention group will be provided with bottles containing 20 mL of

mixed oil to aid control of their tobacco use. The composition of the blended oil will be 4

drops each of lavender, peppermint, and rosemary (Tisserand Co., United Kingdom) in 15

mL of jojoba oil (Tisserand Co., United Kingdom). Participants will be instructed to

frequently self-massage 1-2 drops of the blended aroma oil behind their ears.

Outcome measures

Primary outcome




exhaled carbon monoxide (CO) with a threshold of 6 ppm.

Secondary outcomes

The secondary outcomes are the 7-day point prevalence abstinence, prolonged abstinence rate,

participation rate, amount of smoking, tobacco craving, exhaled CO, pulmonary function

(FEV1, FVC, FEV1/FVC), quality of life (EQ-5D, EQ-VAS), FTND nicotine dependence

score, and withdrawal symptoms (Minnesota nicotine withdrawal scale, MNWS). The time

points of the evaluations are shown in Table 1.


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All adverse events from the NRT, acupuncture and aromatherapy will be reported in detail,

and the affected participants will be treated by doctors. The most common adverse events are

expected to be skin erythema and pruritus at the sites of patch attachment. According to a

previous study, mild local skin reactions were observed in approximately 54% of patients.[12]

Adverse events will be distinguished from withdrawal symptoms, such as hunger, anxiety,

depression, constipation, cough and insomnia.


All collected data will be entered using a double entry method and encrypted. The data will

be monitored by Institute of Safety and Effectiveness Evaluation for Korean Medicine (ISEE)

of Kyung Hee University. This will strengthen the data accuracy and maintain data quality.


A statistician who is not affiliated with this study will perform the statistical analyses for both

the intention-to-treat (ITT; all randomly assigned participants) and per-protocol (PP;

participants who completed the trial without any protocol deviations) data using SAS. In the

event of drop-outs or withdrawals, the reasons for each missing value will be recorded.

Missing values will be substituted using the multiple imputation method. Continuous

abstinence rate, 7-day point prevalence abstinence, daily quantity of smoking, tobacco

craving, exhaled carbon monoxide, quality of life (EQ-5D, EQ-VAS), FTND nicotine

dependence score, MNWS withdrawal symptoms, satisfaction, age, and drinking and exercise

frequency are continuous variables that will be displayed as the mean, standard deviation, and

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minimum and maximum value. Smoking status, cigarette taste, methods of attempted

cessation, reason of cessation failure, sex, education level, occupation and marital status are

categorical variables that will be displayed as frequencies. Independent t-tests for continuous

variables and chi-square tests for categorical variables will be used to examine significant

differences between the two groups. Two-sided p values less than 0.05 will be considered

significant. Fisher’s exact test will be used instead of the chi-square test when the expected

value is less than 5. All analyses will be conducted after study completion, and interim tests

are not planned.

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Discussion

Nicotine dependence is recognized as a disease, and smoking behaviour falls under the

category of ‘mental and behavioural disorders due to psychoactive substance use’ according

to the International Classification of Diseases 10th revision.[13] It is necessary to access to

smoking cessation in terms of medical treatment. The U.S. Preventive Services Task Force

strongly recommends that doctors should intervene to help patients cease smoking by

prescribing treatments approved by the Food and Drug Administration, such as NRT and

bupropion, if needed.[14]


designed to be a pragmatic, randomized controlled trial because excessively controlling other

conditions does not reflect real clinical conditions.[15] The control group will be provided

conventional treatments, including NRT and counselling, because not treating the control

group would cause ethical issues and increase the drop-out rate. As it is difficult to cease

smoking successfully with a single intervention, multiple interventions will be administered

to the participants.[16] This will help increase the effects of the interventions as well as

promote participant compliance. As successful smoking cessation typically does not last long,

we will evaluate success rates by performing 5 follow-up assessments.

The main intervention of this trial is acupuncture.[17] Frequently used body acupoints for

cessation treatment in the literature include HT7 (Shenmen),[18-20], LI4 (Hegu),[3, 21] ST36

(Zusanli),[21-23] LU7 (Lieque),[4, 21] and LU6 (Kongzui).[24] According to the guidelines

on acupuncture treatment and counselling for smoking cessation, the ‘Shenmun’, ‘Lung’,

‘Endocrine’, ‘Pharynx’, ‘Trachea’, ‘Mouth’, and ‘Inner-nose’ ear acupoints are recommended

for cessation treatment.[25] In addition, some clinical trials have demonstrated the effects of

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auricular acupuncture treatment for smoking cessation.[26-28] Aromatherapy can also play a

role in relieving withdrawal symptoms. Lavender oil[29, 30] and rosemary oil[30, 31] help

reduce anxiety after cessation, and peppermint oil[31] can relieve symptoms of respiratory

discomfort, such as phlegm and cough. NRT and counselling will be applied to both the

intervention and control groups as conventional treatments. This trial is designed such that

the T&CM tobacco control programme, including acupuncture, aromatherapy, NRT and

counselling, will be provided to the intervention group to raise the cessation rate.

There are several limitations to this proposed study. First, although NRT, which will be

applied to both groups, is a proven method of cessation treatment, there is the possibility of

bias due to the unblinded design of the study. To minimize the potential bias, the researchers

will explain about that enough at the initial stage. Second, the proposed study is a pilot study

with a small sample size, and a large-scale clinical trial will be necessary later.


participant satisfaction is as important as intervention effectiveness. T&CM is expected to be

an effective method for helping individuals quit smoking with emotional comfort, which will

be assessed by evaluating participant satisfaction and quality of life (SF-36). This article

presents the first protocol of implementing T&CM in combination with conventional therapy

as a smoking cessation treatment in Korea. This study will evaluate the effectiveness and

safety of several T&CM interventions and will provide useful evidence for future studies.

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Trial status


completed the 4-week treatment. This trial is ongoing.






Declarations




Author contributions

SP and SJ drafted the manuscript. YLP, BHJ and CSC designed the study. JAL and HYG

edited the first manuscript. YCS and SKG supervised this protocol. All authors read and

approved the final manuscript.

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Funding

None

Competing interests


paper.



Acknowledgements

This research was supported by a grant of the Korea Health Technology R&D Project through

the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health

& Welfare, Republic of Korea (grant number: HI12C1889). JAL was supported by grants

from Korea Institute of Oriental Medicine (K17111).

Figure 1. Flow chart of T&CM tobacco control program

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References

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Geneva: World Health Organization 2012.

2. Siahpush M, McNeill A, Hammond D, et al. Socioeconomic and country variations in


from the 2002 International Tobacco Control (ITC) Four Country Survey. Tob Control

2006;15:iii65-70. doi:10.1136/tc.2005.013276.

3. Bier ID, Wilson J, Studt P, et al. Auricular acupuncture, education, and smoking

cessation: a randomized, sham-controlled trial. Am J Public Health 2002;92:1642-7.

doi:10.2105/AJPH.92.10.1642.

4. He D, Berg JE, Høstmark AT. Effects of acupuncture on smoking cessation or

reduction for motivated smokers. Prev Med 1997;26:208-14.

doi:10.1006/pmed.1996.0125.

5. Cahill K, Stevens S, Perera R, et al. Pharmacological interventions for smoking

cessation: an overview and networkmeta-analysis (review). Cochrane Database Syst

Rev 2013;5:CD009329. doi:10.1002/14651858.CD009329.pub2.

6. Heatherton TF, Kozlowski LT, Frecker RC, et al. The Fagerstrom test for nicotine

dependence: a revision of the Fagerström tolerance questionnaire. Br J Addict

1991;86:1119-27. doi:10.1111/j.1360-0443.1991.tb01879.x.

7. Browne RH. On the use of a pilot sample for sample size determination. Stat Med

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8. Hertzog MA. Considerations in determining sample size for pilot studies. Res Nurs

Health 2008;31:180-91. doi:10.1002/nur.20247.

9. Buller DB, Halperin A, Severson HH, et al. Effect of nicotine replacement therapy on

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quitting by young adults in a trial comparing cessation services. J Public Health

Manag Pract 2014;20:E7-15. doi:10.1097/PHH.0b013e3182a0b8c7.

10. Tosanguan J, Chaiyakunapruk N. Cost-effectiveness analysis of clinical smoking

cessation interventions in Thailand. Addiction 2016;111:340-50.

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11. Chase EC, McMenamin SB, Halpin HA. Medicaid provider delivery of the 5A's for

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12. Fiore MC, Jorenby DE, Baker TB, et al. Tobacco dependence and the nicotine patch:

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doi:10.1001/jama.1992.03490190087036.

13. World Health Organization. International Classification of Diseases, 10th revision,

online versions. 2016. http://apps.who.int/classifications/icd10/browse/2016/en.

14. U.S. Preventive Services Task Force. The Guide to Clinical Preventive Services.

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15. Agency for Healthcare Research and Quality. Using pragmatic clinical trials to test

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Patient Centered Medical Home Research Methods Series. Rockville, MD: AHRQ

2013:No. 13-0030-EF.

16. Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008

Update. Rockville, MD: US Department of Health and Human Services 2008.

17. Stead LF, Perera R, Bullen C, et al. Nicotine replacement therapy for smoking

cessation (review). Cochrane Database Syst Rev 2012;11:CD000146.

doi:10.1002/14651858.CD000146.pub2.

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18. Chae Y, Yeom M, Han JH, et al. Effect of acupuncture on anxiety-like behavior during

nicotine withdrawal and relevant mechanisms. Neurosci Lett 2008;430:98-102.

doi:10.1016/j.neulet.2007.10.026.

19. Chae Y, Kang OS, Lee HJ, et al. Effect of acupuncture on selective attention for

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doi:10.1179/016164109X12537002793805.


smoking-related visual cues. Complement Ther Med 2011;19:S1-7.

doi:10.1016/j.ctim.2010.09.003.

21. Ma E, Chan T, Zhang O, et al. Effectiveness of acupuncture for smoking cessation in

a Chinese population. Asia Pac J Public Health 2015;27:NP2610-22.


therapeutic effect in a controlled study. Can Med Assoc J 1980;122:787-90.

23. McFadden DD, Chon TY, Croghan IT, et al. Trial of intensive acupuncture for

smoking cessation: a pilot study. Acupunct Med 2015;33:375-80.

24. He D, Medbo JI, Hostmark AT. Effect of acupuncture on smoking cessation or

reduction: an 8-month and 5-year follow-up study. Prev Med 2001;33:364-72.

doi:10.1006/pmed.2001.0901.


counselling for smoking cessation. 2010.


acupuncture in smoking cessation. J Chin Med Assoc 2007;70:331-8.

doi:10.1016/S1726-4901(08)70014-5.

27. White AR, Resch KL, Ernst E. Randomized trial of acupuncture for nicotine

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withdrawal symptoms. Arch Intern Med 1998;158:2251-5.

doi:10.1001/archinte.158.20.2251.


treatment in the cessation of smoking. Br J Gen Pract 1998;48:1487-90.



Palliat Care 2002;19:381-6.

30. McCaffrey R, Thomas DJ, Kinzelman AO. The effects of lavender and rosemary

essential oils on test‐taking anxiety among graduate nursing students. Holist Nurs

Pract 2009;23:88-93. doi:10.1097/HNP.0b013e3181a110aa.



Alternat Med 2010;2011:690346. doi:10.1155/2011/690346.

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Day -10 0 7 10 14 17 21 28 42 56 84 112 168




Allocation ✘

T&CM + NRT

NRT





Tobacco craving ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘

FTND ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘

Exhaled CO ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘

MNWS ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘

EQ-5D, EQ-VAS ✘ ✘ ✘ ✘ ✘ ✘





Satisfaction ✘



*tele: telephone

*T&CM: traditional & complementary medicine

* NRT: nicotine replacement therapy

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* FTND: Fagerstrom test for nicotine dependence

* MNWS: Minnesota nicotine withdrawal scale

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Figure 1 (JPEG)

110x153mm (150 x 150 DPI)

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1










Roles and

responsibilities






_____17______




_Not applicable_

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2

Introduction

Background and

rationale



______4______





______5______




______5______



______6______


administered

____9,10,11___



______7______



_____11______






_____11______



___Figure 1___

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3



______8______



Allocation:

Sequence

generation





______8______

Allocation

concealment

mechanism



______8______


interventions

______8______



______8______



_Not applicable_


Data collection

methods





__21 (Table 1)__



__ 5,_Table 1__

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4




_____12______



____12,13_____




_____12______

Methods: Monitoring




needed

_____12______



_____13______



_____12______



_Not applicable_


Research ethics

approval


Protocol

amendments



regulators)

______7______

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5


how (see Item 32)

______7______



_Not applicable_



______7______

Declaration of

interests




_____12______

Ancillary and post-

trial care


participation

_____12______




_Not applicable_



Appendices

Informed consent

materials


Biological

specimens



_Not applicable_




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For peer review only - BMJ Open...5 In this T&CM tobacco control programme, ear acupuncture, manual...

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