Moxibustion intervention for patients with irritable bowel syndrome: A study protocol for a randomised controlled trial

Accepted Manuscript Title: Moxibustion intervention for patients with irritable bowel syndrome: A study protocol for a randomised controlled trial Author: Taein Kim Jaejun Lee Jiwon Chung Seungwon Choi Jiyu Kim Ju Ah Lee Youn Sang Jun Ho-Yeon Go Seonmi Shin PII: DOI: Reference:

S1876-3820(16)30448-6 http://dx.doi.org/doi:10.1016/j.eujim.2016.12.003 EUJIM 630

To appear in: Received date: Revised date: Accepted date:

28-9-2016 23-11-2016 10-12-2016

Please cite this article as: Kim Taein, Lee Jaejun, Chung Jiwon, Choi Seungwon, Kim Jiyu, Lee Ju Ah, Jun Youn Sang, Go Ho-Yeon, Shin Seonmi.Moxibustion intervention for patients with irritable bowel syndrome: A study protocol for a randomised controlled trial.European Journal of Integrative Medicine http://dx.doi.org/10.1016/j.eujim.2016.12.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Moxibustion intervention for patients with irritable bowel syndrome: a study protocol for a randomised controlled trial Taein Kim1, Jaejun Lee1, Jiwon Chung1, Seungwon Choi1, Jiyu Kim1, Ju Ah Lee2, Youn Sang Jun3,Ho-Yeon Go4, Seonmi Shin4*

1 Department of College of Korean Medicine, Semyung University, Jecheon 2 KM Fundamental Research Division, Korea Institute of Oriental Medicine, Daejeon 3 CJ HealthCare Clinical Development Division, Seoul 4 Department Korean Internal medicine, College of Korean Medicine, Semyung University, Jecheon

*Corresponding author Seonmi Shin, Ph. D. KMD Department Korean Internal medicine, College of Korean Medicine, Semyung University 65 Semyun-ro, Jecheon, Chungbuk, 27136, Republic of Korea Tel. 82-43-649-1873 Fax. 82-43-649-1844 E-mail: [email protected]

Abstract Introduction: This study is designed to evaluate the efficacy and safety of treating irritable bowel syndrome patients with a proper dose of moxibustion. Methods and analysis: This study will be a 4-week-long, randomised controlled pilot clinical trial. Twenty-four patients will be recruited and randomly allocated to 1 of 2 groups: a 3 moxibustion treatment intervention group and a 1 moxibustion treatment control group. Both groups will receive two moxibustion sessions a week for 4 weeks (8 sessions in total). The primary outcome will be measured using the Bowel Symptom Severity Scale. The inclusion criteria are as follows. The patients will be between 18 and 30 years old and of either gender. The patients will have experienced repeated abdominal pain or discomfort (i.e., an uncomfortable sensation not described as pain) at least 3 times per month in association with two or more of the following over the previous 3 months: (a) improvement with defecation; (b) onset associated with a change in the frequency of defecation; (c) onset associated with a change in the form (appearance) of stool. All included patients will have provided written consent to the clinical ethics committee and have agreed with both the clinical trial plan and follow-up observations. Ethics and dissemination: This research protocol has been reviewed and approved by the institutional review board of the trial centre (Semyung Korean Medicine Hospital, IRB No. 2016-06-01). The results will be published in a journal and will be disseminated both electronically and in print. Key words: Irritable bowel syndrome, moxibustion, traditional Korean medicine Registration Number: KCT0002064

Introduction Irritable bowel syndrome (IBS) is a common functional gastrointestinal (GI) disorder [1, 2]. IBS is a continuing condition entailing recurrent attacks of a group of symptoms, involving abdominal pain, bowel habit changes, distention, and abnormal stool [3]. The most usual IBS symptoms are abdominal pain related to altered bowel habits (e.g., diarrhea or constipation). Although the exact mechanisms of IBS GI symptoms have not yet been elucidated, visceral hypersensitivity and GI motility disorders are the main pathological causes. There is also evidence that IBS involves altered gut motility. Several brain-gut peptides, for example, substance P (SP) and vasoactive intestinal peptide (VIP), are related to the regulation of GI motor and sensory functions. SP and VIP are significant brain-gut peptides that are extensively distributed in the central nervous system, GI tract, and immune organs. These brain-gut peptides can affect GI movements via the nervous, endocrine, and immune systems, among others, and may be involved in abdominal pain or discomfort, abnormal defecation, and other visceral hypersensitivity reactions. Abnormal SP and/or VIP levels have been observed in both diarrhoea- and constipation-predominant IBS patients (diarrhea predominant Irritable Bowel Syndrome and constipation predominant Irritable Bowel Syndrome ), respectively) [1]. Moxibustion down-regulated the abnormally increased SP and VIP expression in the colonic mucosa using immunohistochemistry assay [1]. IBS is the most common disorder presented to gastroenterologists, with a predominance of up to 10%-20% in the USA and UK and a predominance of 5%-10% in most Asian countries. The occurrence of Irritable bowel syndrome rises with global economic growth [1]. It is a common GI disorder, influencing 10-15% of the population in developed countries. The prevalence rate of IBS is 11.2% globally, 4.7%-25% in Western countries, and 6.5%-10.1% in Eastern countries. In China, the prevalence of IBS is approximately 4.6%-5.67%. 74.1% of

IBS patients in China have diarrhea predominant -IBS, which is the most common type [3]. Epidemiological surveys have showed that the worldwide occurrence of IBS is approximately 10%-15%, that the incidence of IBS among East Asian populations is approximately 5%10%, and that the occurrence of IBS is higher among females than males. With respect to age distribution, IBS is chiefly found among young adults. IBS is typically diagnosed in adulthood, symptoms often present in childhood and adolescence . The recurrent abdominal pain patients that life stress was significantly associated with IBS symptoms. There are several possible explanations for the relation between stress and IBS symptoms in patients with a history of recurrent abdominal pain,

these patients may have a particular sensitivity

to life stress, resulting in physiologic changes from childhood [2].

In addition, this disease

is more common among knowledge workers than among manual workers. Irritable bowel syndrome leads to enormous mental stresses and huge financial burdens for patients. Therefore, it is needed to search for effective and rational therapeutic regimens for IBS [4]. There are many advance researches about irritable bowel syndrome [5-12]. Traditional medicine has long been used to treat IBS, and comparable effectiveness has been demonstrated in traditional medicine trials, as patients reported having control over IBS symptoms. In fact, treating diarrhea predominant -IBS with moxibustion has been shown to have a good clinical effect [3, 5]. This method can effectively relieve abdominal pain and bloating, emergent defecation, defecation frequency, and abnormal stool features [6]. Moxibustion can effectively alleviate the symptoms of diarrhea predominant -IBS, such as diarrhea, abdominal pain, and abdominal discomfort. However, further studies are needed to explain the central mechanisms underlying the therapeutic effects of moxibustion [3]. The aim of this study was to assess the feasibility of treating IBS patients with moxibustion and to obtain preliminary study design safety and efficacy data to inform a future, larger randomised controlled trial (RCT) in the same IBS patients.

Methods and design Objective The primary objective of this study is to assess the therapeutic efficacy of treating IBS patients with moxibustion and to obtain preliminary study design safety and efficacy data to inform a future, larger RCT in the same IBS patients.

Design This will be an assessor- and analyst-blinded, randomised, controlled clinical trial with two parallel groups. The trial will be conducted at single clinical centre in Korea, Semyung Korean Medical Hospital, between 30 June 2016 and 31 May 2017. This protocol has been approved by the ethics review boards of Semyung Korean Medical Hospital, permission number 2016-06-01. Written informed consent will be obtained from all study participants prior to enrolment. Eligible patients will be randomly allocated at a ratio of 1:1 to either the intervention group (3 moxibustion treatments) or the control group (1 moxibustion treatment) and will receive treatment 8 times for 4 weeks (figure 1 and table 1). Outcome measures will be assessed at baseline and at the end of the fourth week after randomisation. The results will be analysed by professionals blinded to the group allocation. This protocol has been registered with the Clinical Research Information Service of the National Research Institution of Health in Korea, a registry in the WHO Registry Network.

Inclusion criteria Participants will be included if they fulfil the following criteria from Rome Ⅲ (1) The patients are between 18 and 30 years old and of either gender. (2) The patients have experienced repeated abdominal pain or discomfort (an uncomfortable sensation not described as pain) at least 3 times per month over the previous 3 months (3) in association with two or more of the following: (a) improvement with defecation; (b) onset associated with a change in defecation frequency; or (c) onset associated with a change in form (appearance) of stool. (4) The patients have either a) stool with fluffy pieces and ragged edges or that is mushy, watery, or entirely liquid (Bristol Stool Chart Scale 6-7) ≥25% or b) stool with separate hard lumps similar to nuts that are hard to pass or sausage-shaped but lumpy (Bristol Stool Chart Scale 1-2) ≥25%. (5) Female patients must have negative urine pregnancy test results and agree to not become pregnant during the clinical trial. (6) The patients have not been diagnosed with a cardiovascular disease, such as hypertension, diabetes mellitus, or hyperlipidaemia. (7) The patients have not recently had a body temperature greater than 38.5°C for more than 4 hours. (8) The patients have signed the IRBapproved consent form and agreed with both the clinical trial plan and follow-up observations.

Exclusion criteria Patients with any of the following conditions will be excluded because of safety concerns: (1) a diagnosed cardiovascular disease; (2) a high fever in the past 1 week; (3) experience within the past 30 days in clinical trial screening or participation in which they were administered a medication or placebo; or (4) an inappropriate subject status, as determined by a clinical trial

researcher. Randomisation and allocation concealment In this trial, randomisation will be performed according to Good Clinical Practices (GCPs) at the Semyung Korean Medical Hospital. A total of 24 participants who meet the eligibility criteria will be allocated at a ratio of 1:1 to either the intervention or control group. Participants will be randomised using a computerized number generator using the stratified block randomisation method in R software (R version 3. 3. 1, 2016.06.21) by a statistician with no clinical involvement in this trial. The allocation will be concealed in sequentially numbered, opaque, sealed envelopes containing the randomisation assignments. Allocation concealment will be broken only after the participant has met all selection criteria and completed the baseline assessments. The participants will not know the group to which they were allocated, and the outcome assessors and data analysts will be blinded to the intervention allocation.

Blinding In moxibustion research, it is not easy to conceal allocation from the participants. Thus, we will perform an infrared red (IR) radiation in the

lower legs using the same moxibustion

scent and size and covering the investigator’s eyes to prevent the difference in temperature due to the number of moxibustion points from breaking the blind. The IR radiation degree will be 1 (degree range from 1 to 7), and the IR radiation area will focused on lower legs, So, IR radiation will not affected the moxibustion intervention. The treatment and assessment will be performed independently. The outcome assessors and the data analysts will be blinded to the treatment allocation throughout the study.

Interventions Intervention group Subjects will be blind-folded, and then the moxibustion intervention will be applied to Guan Yuan (CV4) using 3 moxibustion treatments lasting 20 minutes. The moxibustions are located apart about 2cm from each other. At the same time, the abdomen will be subjected to IR irradiation(degree 1). The intervention will be conducted over 4 weeks, for a total of 8 sessions (2 times per week x 4 weeks). Guan Yuan (CV4) was used for IBS treatment [1315]. We will use Dan Jeon Gu Hab moxibustion plates (DongBang Acupuncture Inc., 463-400 Korea) and moxa cautery charcoal moxa cones (DongBang Acupuncture Inc., 463-400 Korea). The intervention group will be treated with 3 moxa cautery cones in a moxibustion plate. Each intervention will be conducted only by a licensed practitioner. Control group After the control subjects are blind-folded, the moxibustion treatment will be applied to Guan Yuan (CV4) using 1 moxibustion plate for 20 minutes. At the same time, the abdomen will be subjected to IR irradiation (degree 1). The treatment will be conducted over 4 weeks, for a total of 8 sessions (2 times per week x 4 weeks). We will use Dan Jeon Gu Hab moxibustion plates (DongBang Acupuncture Inc., 463-400 Korea) and moxa cautery charcoal moxa cones (DongBang Acupuncture Inc., 463-400 Korea). The control group will be treated with 1 moxa cautery in 1 moxibustion plate.

Outcomes Primary outcome The primary end point will be differences in the Bowel Symptom Severity Scale (BSSS) scores between the intervention and control groups. The BSSS is a 5-item, self-administered questionnaire measuring the following: abdominal pain severity, abdominal pain duration, abdominal distension/tightness, bowel habits, and quality of life. The scale has a maximum score of 500 with varying levels of severity, as follows: < 75, normal bowel function; 75-174, mild IBS; 175-299, moderate IBS; 300-500, severe IBS [16, 17]. The BSSS has been used to evaluate Traditional Chinese Medicine syndrome efficacy [18], the primary clinical outcome of clinical behavioural therapy in female nursing students with IBS [19], IBS severity reduction in women undergoing mindfulness training [20], and decreases in IBS symptoms in terms of the distress, frequency, and impairment [21].

Secondary outcomes The secondary endpoints will include differences in the following: Irritable Bowel Syndrome Severity Scale - Korean Version (IBSSS-K) scores, Heart Rate Variability test scores, ColdHeat Pattern questionnaire results, Qi Stagnation questionnaire scores, temperature differences between Dan Zhong (CV17) and Chung-wan (CV12), and visceral sensitivity questionnaire results. Measuring the temperature difference between the CV17 and CV12 is planned to check the trunk temperature change during the moxibution treatment. Statistical methods Sample size

Although several studies have investigated the effects of moxibustion on IBS, no RCTs have assessed differences in the effects of moxibustion in diarrhea predominant -IBS and constipation predominant-IBS patients. There have been no clinical trials investigating the moxibustion dosage, and there are no previous studies from which to base the sample size calculations. As the base average difference of four weeks after IBSS-K score of the Intervention group and the base against the control group after four weeks of assuming that the average difference between the IBSSK score, Intervention group and the effect of the average difference between the control groups will be present hypothesis for the primary endpoint of the trial are as follows:

H 0 : D  0 vs H a : D  0 This study is not an existing clinical trial results for the dosage Moxibustion no information required for calculating trial subjects. Miller et al [22] noted that a reduction in clinically significant for the IBS symptom severity scale is 50. In this study, by utilizing the result of Miller et al [22] was the difference between the average effective Intervention group and the control group by 50, the standard deviation is assumed to be 45 so that a CV of 90%. On the basis of these values it is calculated using the following trial calculation formula embroidery [23].

N

2( z1  z1  ) 2  2

2

If the significance level is 0.05, statistical power is 0.8, drop out probability is 10%, the number of subjects required for the study of 24 people per group is required to 12 people.

Statistical analysis Data will be analysed by a statistician blinded to the group allocations using the Statistical

Package for the Social Sciences (SPSS) V.20.0 statistical software package. Significant levels will be reported at p < 0.05. Baseline characteristics and primary and secondary outcomes will be analysed based on the intention-to-treat principle. If an adjustment for possible baseline incomparability is needed, an analysis of covariance will be conducted. If non-normal distributions are found for the BSSS, IBSSS-K, Heart Rate Variability, ColdHeat Pattern, Qi Stagnation, Dan Zhong (CV17) and Chung-wan (CV12) temperature difference, and visceral sensitivity data, the Wilcoxon rank-sum test will be used. If the measurement data have normal distributions, the t test will be used.

Patient safety Adverse events will be investigated as follows. If an adverse event occurs, an investigator will evaluate the subject at each visit and complete an ‘Adverse event report’ regarding the potential causality between the trial intervention and the adverse event. Subjects who experience adverse events will be treated at Semyung Korean Medical Hospital. All vital signs and adverse events will be measured and recorded at each visit.

Quality control All staff will be required to undergo special training before participating in the trial. For example, staff will be trained to select participants and to conduct the moxibustion intervention. Monitors will evaluate study protocol compliance and informed consent documents and assess the progress of the study, including participant recruitment, moxibustion intervention and data quality, once a month. Dropouts and withdrawals from the study will be recorded throughout the study period.

Discussion The primary objective of this study is to assess the therapeutic efficacy of moxibustion in treating IBS patients. We designed this study to determine the efficacy and safety of moxibustion in the intervention group (3 moxibustion treatments) versus the control group (1 moxibustion treatment). The results of this study will determine whether moxibustion is an effective therapy for IBS patients. The outcomes include BSSS scores, IBSSS-K scores, Heart Rate Variability test results, Cold-Heat Pattern questionnaire scores, Qi Stagnation questionnaire scores, temperature differences between Dan Zhong (CV17) and Chung-wan (CV12), and visceral sensitivity questionnaire scores. These outcomes will also need to be assessed in a future long-term clinical trial. In addition to appropriate outcome measures, the use of an appropriate control group is a critical issue in designing a high-quality clinical trial. The purpose of this study is to evaluate the efficacy and safety of treating IBS patients with an appropriate dose of moxibustion. This study will be the basic research of moxibustion clinical trials. In conclusion, assessor-blinded and analystblinded, single-centre RCT will investigate the efficacy and safety of moxibustion for treating IBS, assess the therapeutic effect and relevance of the moxibustion therapy study design, and provide a clinical foundation for future, large-scale, multicentre clinical trials.

Ethics This study will be conducted according to Korean GCPs and the Declaration of Helsinki. Before subjects will be allowed to participate in this study, the study will be explained to them, and they must voluntarily provide written informed consent.

Application of the protocol This study will evaluate the feasibility of conducting further moxibustion research to determine the efficacy and safety of treating IBS patients with moxibustion.

Conflicts of interest The authors declare that they have no competing interests.

Acknowledgements This study is supported by the Korea Institute of Oriental Medicine (C 16011).

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Fig 1. – A flowchart of the study

Participant Recruitment Eligibility Assessment Random Allocation

Treatment Group (n=12)

Control Group (n=12)

Evaluation

Evaluation

Analysis

Analysis

Table 1. Clinical trial schedule Before

1wk

2wk

3wk

4wk

6wk

2wk Screening 0 Obtain subject’s consent

√

Demographic investigation

√

Vital sign

√

Physical

√

1st

2nd

3rd

4th

5th

6th

7th

8th

9th

visit

visit

visit

visit

visit

visit

visit

visit

visit

√

√

√

√

√

√

√

√ √

examination(height/weight) √

Family history

√

√

√

√

√

√

√

√

√

pregnancy urine test

√

√

√

√

√

√

√

√

√

Enrollement

√

Randomization

√ √

√

√

√

√

√

√

√

medical

history

and

drug

administration history

Moxibustion (treatment), Temperature

measurement

at

(CV17) and (CV12) BSSS questionnaire, IBSSS-K

√

Adverse event

√

√ √

√

√

√

√

√

√

PI Questionnaire

√

√

HRV

√

√

QSCC2

√

wk: week, BSSS: Bowel Symptom Severity Scale, IBSSS-K: Irritable Bowel Syndrome Severity Scale–Korean, PI: Pattern Identification, HRV: Heart Rate Variability, QSCC2: Constitutional Sasang Constitutional examination